BACKGROUND: American Indians (AI) in North Dakota present with higher rates of advanced-stage disease for screening detectable colorectal cancers and have lower overall baseline colorectal cancer screening rates than non-AIs. We sought to identify the perceived barriers and facilitators for the engagement with colorectal cancer prevention within North Dakota tribal communities. METHODS: Twelve semi-structured interviews were carried out across four tribal reservation communities in the state of North Dakota with American Indian adults between the ages of 30 and 75 years. We utilized purposive sampling to ensure maximum variation in age, sex, and tribal community until data saturation was achieved. The interviews were transcribed, and thematic analysis was carried out to identify consistent themes rooted within the data. Ethical approval was gained for this project from all relevant institutional review boards. RESULTS: Four main themes were identified as barriers for the engagement with colorectal cancer prevention, including: colorectal cancer screening barriers, focused on other health problems, lack of colorectal cancer tailored health promotion, and socio-cultural factors affecting colorectal cancer prevention. Three main themes were identified as facilitators for the engagement with colorectal cancer prevention, including: reasons for getting colorectal cancer screening, role of culture, and getting out into the community. CONCLUSION: There is need for more community-rooted, strengths-based approaches to colorectal cancer prevention activities in AI communities in North Dakota. Socio-cultural factors, such as the use of storytelling, and the use of traditional knowledge have been demonstrated to be an important element of consideration for colorectal cancer tribal community engagement and prevention planning in the state.

BACKGROUND: Comprehensible, relevant information empowers patients, allowing them to take an active part in their care. We aim to investigate how Swedish melanoma patients perceive information provided in routine clinical practice and explore the correlation between satisfaction with information, symptoms and functioning scales, and quality of life. METHODS: A cross-sectional study where EORTC QLQ-C30, EORTC QLQ-INFO25 and EQ-5D-3L questionnaires were sent to 1213 patients by post and 792 responded (65%). RESULTS: Only 0.5% reported that they wished to have received less information. The amount of information received and the satisfaction with that information was age-dependent, where older patients reported receiving less information than younger patients. Middle-aged patients were more satisfied with the information compared to both younger and older patients. The perception of having received sufficient information correlated negatively with anxiety. Higher satisfaction with the information also correlated positively with scores for functioning scales and negatively with degree of symptoms. No difference was perceived in information levels between disease stage apart from the scale "information about other services", where patients with more severe disease reported receiving more information. Men and women reported equal satisfaction concerning the information received. CONCLUSIONS: Patients lack sufficient information and age affects the perception of it. It is of utmost importance to tailor the information to suit the individual needs of a given patient, as satisfaction with the information received correlates with the patient's well-being.

BACKGROUND: In childhood (CCS) and testicular cancer (TCS) survivors, low-grade inflammation may represent a link between testosterone deficiency (hypogonadism) and risk of metabolic syndrome. We aimed to study levels of inflammatory markers in CCS and TCS and the association with hypogonadism and future cardio-metabolic risk factors. METHODS: Serum levels of inflammatory markers and testosterone were analyzed in CCS (n = 90), and TCS (n = 64, median time from diagnosis: 20 and 2.0 years, respectively), and in controls (n = 44). Differences in levels between patients and controls were calculated using univariate analysis of variance. T-test and logistic regression were applied to compare levels of cardio-metabolic risk factors and odds ratio (OR) of hypogonadism and metabolic syndrome in low and high inflammatory marker groups after 4-12 years of follow up. Adjustment for age, smoking, and active cancer was made. RESULTS: TCS and CCS, as compared to controls, had 1.44 (95%CI 1.06-1.96) and 1.25 (95 CI 1.02-1.53) times higher levels of IL-8, respectively. High IL-6 levels were associated with hypogonadism at baseline (OR 2.83, 95%CI 1.25-6.43) and the association was stronger for high IL-6 combined with low IL-10 levels (OR 3.10, 95%CI 1.37-7.01). High IL-6 levels were also associated with higher BMI, waist circumference, insulin, and HbA1c at follow up. High TNF-α was associated with higher diastolic blood pressure. No individual inflammatory marker was significantly associated with risk of metabolic syndrome at follow up. High IL-6 combined with low IL-10 levels were associated with risk of metabolic syndrome (OR 3.83, 95%CI 1.07-13.75), however not statistically significantly after adjustment. CONCLUSION: TCS and CCS present with low-grade inflammation. High IL-6 levels were associated with hypogonadism and cardio-metabolic risk factors. Low IL-10 levels might reinforce the IL-6 mediated risk of developing metabolic syndrome.

BACKGROUND: In aging populations, the number of people with high cholesterol levels is increasing. Appropriate management of high cholesterol levels with drugs such as statins may prevent secondary diseases. Despite many studies on the effects of statins on various types of cancer, the effectiveness of lipid-lowering therapy in preventing cancer remains controversial. This study aimed to evaluate its long-term effect on developing gastrointestinal (GI) cancer in patients with dyslipidemia. METHODS: This study used the National Health Insurance Sampling (NHIS) cohort data (2002-2015), which included patients with dyslipidemia without diabetes, and measured patients' adherence to lipid-lowering therapy using the medication possession ratio. We used the Cox proportional hazard ratio (HR) to identify the association between the continuity of lipid-lowering therapy and the risk of GI cancer. We also evaluated the association between a combination of lipid-lowering drugs and a reduced risk of GI cancer. RESULTS: A total of 49,351 patients were diagnosed with dyslipidemia, of which 579 were diagnosed with GI cancer. Patients with higher adherence to lipid-lowering therapy had a significantly reduced risk of GI cancer compared to patients without drugs, and high adherence was associated with a reduced incidence of all types of GI cancer. Specifically, the combination of statins and ezetimibe or fibrates appears to reduce GI cancer risk effectively. Overall, the continuity of lipid-lowering therapy had a protective effect on GI cancer in middle-aged and elderly patients with dyslipidemia compared to non-users. CONCLUSIONS: Our findings suggest that the continuity of lipid-lowering therapy is vital in patients with dyslipidemia. In addition, for individuals vulnerable to GI cancer, combination therapy may be associated with more effective protection against GI cancer. Healthcare providers need patient education and monitoring to improve drug adherence in patients with dyslipidemia.

BACKGROUND: Immune checkpoint inhibitors prolong the survival of non-small cell lung cancer (NSCLC) patients. Although it has been acknowledged that there is some correlation between the efficacy of anti-programmed cell death-1 (PD-1) antibody therapy and immunohistochemical analysis, this technique is not yet considered foolproof for predicting a favorable outcome of PD-1 antibody therapy. We aimed to predict the efficacy of nivolumab based on a comprehensive analysis of RNA expression at the gene level in advanced NSCLC. METHODS: This was a retrospective study on patients with NSCLC who were administered nivolumab at the Kansai Medical University Hospital. To identify genes associated with response to anti-PD-1 antibodies, we grouped patients into responders (complete and partial response) and non-responders (stable and progressive disease) to nivolumab therapy. Significant genes were then identified for these groups using Welch's t-test. RESULTS: Among 42 analyzed cases (20 adenocarcinomas and 22 squamous cell carcinomas), enhanced expression of MAGE-A4, BBC3, and OTOA genes was observed in responders with adenocarcinoma, and enhanced expression of DAB2, HLA-DPB,1 and CDH2 genes was observed in responders with squamous cell carcinoma. CONCLUSIONS: This study predicted the efficacy of nivolumab based on a comprehensive analysis of mRNA expression at the gene level in advanced NSCLC. We also revealed different gene expression patterns as predictors of the effectiveness of anti PD-1 antibody therapy in adenocarcinoma and squamous cell carcinoma.

BACKGROUND: Previous researches have associated Helicobacter pylori (H. pylori) with a prognosis of gastric cancer (GC), however, without a concert conclusion. This study aimed to study this issue further by a prospective cohort study and a meta-analysis. METHODS: Histologically diagnosed gastric cancer (GC) patients were recruited into the primary prospective cohort study between January 2009 to December 2013. All the patients were followed-up periodically to record information on post-surgery therapy and overall survival status. The pre-surgery status of H. pylori was measured by enzyme-linked immunosorbent assay. A meta-analysis was conducted after retrieving related researches in the databases of PubMed and Embase up to April 2020. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were summarized to validate the relationship between H. pylori infection and the survival time of GC patients. I2 statistics and Q test were used to assess the heterogeneity. Sensitivity analyses were performed using Galbraith's plot, leave-one-out analysis, subgroup analyses and meta-regression to explore the sources of heterogeneity and the stability of the summary results. RESULTS: A total of 743 GC patients with radical tumorectomy were included prospectively and 516 (69.4%) were positive on H. pylori. H. pylori-positive patients tended to survive longer than -negative ones (HR 0.92, 95%CI: 0.74-1.15), though the tendency was not statistically significant. Cohort studies on the prognosis of GC were retrieved comprehensively by assessing the full-text and 59 published studies, together with the result of our study, were included in the further meta-analysis. The summarized results related the positive status of H. pylori to better overall survival (HR 0.81, 95%CI: 0.72-0.90) and disease-free survival (HR 0.83, 95%CI: 0.67-0.99). Results from subgroup analyses indicated that the pooled magnitude of this association was relatively lower in studies not referring to H. pylori in title and abstract. CONCLUSIONS: In conclusion, gastric cancer patients with H. pylori have a better prognosis than patients of H. pylori negative. More stringent surveillance strategies may be necessary for patients with H. pylori negative at cancer diagnosis.

PURPOSE: The purpose of the current study is to analyze the difference of short-term and oncologic outcomes between younger and older colorectal cancer (CRC) patients who underwent primary CRC surgery using a propensity score matching (PSM) analysis. METHODS: We retrospectively collected CRC patients who underwent primary surgery in a single clinical database from Jan 2011 to Jan 2020. The short-term and oncologic outcomes were compared between younger aged group and older aged group. RESULTS: A total of 4599 patients were included in this study, and there were 4196 patients in older aged group and 403 patients in younger aged group. After 1:1 ratio PSM, there were 401 patients in each group. No significant difference was found in terms of baseline information after PSM (p>0.05). Younger aged group had larger retrieved lymph nodes before (p<0.001) and after PSM (p=0.001) than older aged group. In multivariate analysis, younger age was an independent predictor of better overall survival (OS) (p<0.001, HR=2.303, 95% CI=1.658-3.199) and disease-free survival (DFS) (p=0.008, HR=1.425, 95% CI=1.098-1.850). In terms of different tumor stage after PSM, younger aged group had better OS than older group in stage II (p<0.001) and stage IV (p=0.028) CRC, and younger aged group had better DFS than older group in stage II (p=0.016) CRC. CONCLUSION: Younger CRC patients had larger retrieved lymph nodes and better prognosis than older CRC patients after primary CRC surgery.

BACKGROUND: Pregnancy-associated breast cancer (PABC) is a rare disease with increasing incidence. The prognosis, pregnancy outcomes and subsequent ovarian function of PABC patients are attracting attention. METHODS: Sixty-three PABC patients and 126 age-matched non-PABC patients were obtained in Tongji Hospital from January 2011 to September 2019. The clinical characteristics and ovarian function of PABC patients were compared with those of non-PABC patients. The pregnancy outcomes and neonatal outcomes of patients with breast cancer diagnosed during pregnancy (BCP) were described. Nonparametric tests, the χ2-test Kaplan-Meier, Cox regression and binomial logistic regression were used for analysis. RESULTS: PABC patients were diagnosed with a more advanced tumour stage (II: 47.6% vs. 45.2%, III: 33.3% vs. 19.8%, IV 3.2% vs. 0%, p = 0.003), which caused worse progression-free survival (PFS) (log-rank p = 0.0138) and breast cancer-specific survival (CSS) (log-rank p = 0.0076) than non-PABC patients. Tumour stage (III/IV vs. 0/I/II) (HR 16.017, 95% CI 5.830 ~ 44.006, p < 0.001) and endocrine therapy (HR 0.254, 95% CI 0.099 ~ 0.653, p = 0.004) were predictors of PFS. Tumour stage (III/IV vs. 0/I/II) (HR 30.875, 95% CI 7.232 ~ 131.820, p < 0.001), endocrine therapy (HR 0.200, 95% CI 0.049 ~ 0.818, p = 0.025) and targeted therapy (HR 0.143, 95% CI 0.028 ~ 0.743, p = 0.021) were predictors for breast CSS. Among the 15 BCP patients, 11 patients voluntarily continued their pregnancy, and the newborns had no obvious birth defects, either in 5 patients who received chemotherapy or in 6 patients who did not receive chemotherapy during pregnancy. Among the patients who received chemotherapy and did not receive endocrine therapy, 24 PABC patients and 48 non-PABC patients experienced chemotherapy-induced amenorrhea. There was no significant difference in resumption of menstruation between the two groups at 6 months and 12 months after the end of chemotherapy. No potential factors affecting resumption of menstruation were found. CONCLUSION: Pregnancy at diagnosis or within 1 year after delivery was not a risk factor for a worse prognosis in PABC patients. Compared with non-PABC patients, patients with PABC presented more aggressive tumour characteristics, which could mostly explain the worse prognosis observed in PABC patients. Receiving the appropriate regimen of chemotherapy in the second and third trimesters did not affect the maternal outcomes or neonatal outcomes of BCP patients. The special physiological state during pregnancy and lactation did not interfere with the damage of chemotherapy to ovarian function.

BACKGROUND: The surgical management of Mayo III/IV tumor thrombi is difficult and risky, and robotic surgery is even more difficult. The purpose of this study was to introduce the step-by-step and orderly lowering of the height of inferior vena cava tumor thrombus, which was the core technique of robot operation for Mayo III/IV tumor thrombus. METHOD: A total of 18 patients were included in this study. The average tumor thrombus height was 2.4 cm above the level of the second porta hepatis (SPH), and 9 patients were prepared for cardiopulmonary bypass (CPB) before surgery. During the operation, the height of the tumor thrombus was lowered orderly for 2-3 times, and the blood flow blocking method was changed sequentially. The CPB was required when tumor thrombus in the atrium; After the height of the thrombus was lowered to the atrium entrance, CPB was stopped and the blood flow was blocked in the upper- and retro-hepatic inferior vena cava (IVC); After the tumor thrombus continued to descend to the lower part of the SPH, liver blood flow could be restored, and then, the blood flow was simply blocked in the retro-hepatic IVC to complete the removal of the thrombus and the repair or resection of the IVC. Finally, the diseased kidney and renal vein were removed. RESULTS: All operations were successfully completed, and 2 cases were transferred to laparotomy. Seven cases received CPB, while the other 11 did not. 15 patients underwent two times of the lowering of the tumor thrombus, 2 patients underwent one time and 1 patient underwent three times. The mean liver/IVC dissociation and vascular suspension time was 22.0 min. All patients had less than Clavien-Dindo grade III complications, no serious complications occurred during operation, and no patient died within 90 days. CONCLUSIONS: The step-by-step and orderly decline of tumor thrombus height is the key to the success of robot Mayo III / IV tumor thrombus surgery. This method can shorten FPH and CPB time and improve the success rate of surgery.

BACKGROUND: Pancreatic cancer (PC) is one of the most aggressive and challenging cancer types to effectively treat, ranking as the fourth-leading cause of cancer death in the United States. We investigated if exposures to angiotensin II receptor blockers (ARBs) or angiotensin I converting enzyme (ACE) inhibitors after PC diagnosis are associated with survival. METHODS: PC patients were identified by ICD-9 diagnosis and procedure codes among the 3.7 million adults living in the Emilia-Romagna Region from their administrative health care database containing patient data on demographics, hospital discharges, all-cause mortality, and outpatient pharmacy prescriptions. Cox modeling estimated covariate-adjusted mortality hazard ratios for time-dependent ARB and ACE inhibitor exposures after PC diagnosis. RESULTS: 8,158 incident PC patients were identified between 2003 and 2011, among whom 20% had pancreas resection surgery, 36% were diagnosed with metastatic disease, and 7,027 (86%) died by December 2012. Compared to otherwise similar patients, those exposed to ARBs after PC diagnosis experienced 20% lower mortality risk (HR=0.80; 95% CI: 0.72, 0.89). Those exposed to ACE inhibitors during the first three years of survival after PC diagnosis experienced 13% lower mortality risk (HR=0.87; 95% CI: 0.80, 0.94) which attenuated after surviving three years (HR=1.14; 95% CI: 0.90, 1.45). CONCLUSIONS: The results of this large population study suggest that exposures to ARBs and ACE inhibitors after PC diagnosis are significantly associated with improved survival. ARBs and ACE inhibitors could be important considerations for treating PC patients, particularly those with the worst prognosis and most limited treatment options. Considering that these common FDA approved drugs are inexpensive to payers and present minimal increased risk of adverse events to patients, there is an urgent need for randomized clinical trials, large simple randomized trials, or pragmatic clinical trials to formally and broadly evaluate the effects of ARBs and ACE inhibitors on survival in PC patients.

BACKGROUND: Cervical cancer is the fourth most common cancer that occurs to women worldwide. This study aims to assess trends in incidence and mortality of cervical cancer in India and its states over past three decades for tracking the progress of strategies for the prevention and control of cervical cancer. METHODS: Data on cervical cancer incidence and mortality from 1990 to 2019 for India and its states were extracted from Global Burden of Disease study and were utilized for the analysis. Spatial and rank map has been used to see the changes in incidence and mortality of cervical cancer in different Indian states. Further, joinpoint regression analysis is applied to determine the magnitude of the time trends in the age standardized incidence and mortality rates of cervical cancer. We obtained the average annual percent change (AAPC) and corresponding 95% confidence intervals (CI) for each state. RESULTS: Overall, from 1990 to 2019 Jharkhand (Incidence: -50.22%; Mortality: -56.16%) recorded the highest percentage decrement in cervical cancer incidence and mortality followed by the Himachal Pradesh (Incidence: -48.34%; Mortality: -53.37%). Tamilnadu (1st rank), Jammu & Kashmir and Ladakh (32nd rank) maintained the same rank over the period of three decade for age standardized cervical cancer incidence and mortality. The regression model showed a significant declining trend in India between 1990 and 2019 for age standardized incidence rate (AAPC: -0.82; 95%CI: -1.39 to -0.25; p < 0.05) with highest decline in the period 1998-2005 (AAPC: -3.22; 95%CI: -3.83 to -2.59; p < 0.05). Similarly, a significant declining trend was observed in the age standardized mortality rate of India between 1990 and 2019(AAPC: -1.35; 95%CI: -1.96 to -0.75; p < 0.05) with highest decline in the period 1998-2005 (AAPC: -3.52; 95%CI: -4.17 to -2.86; p < 0.05). CONCLUSION: Though the incidence and mortality of cervical cancer declined over past three decades but it is still a major public health problem in India. Information, education and communication activities for girls, boys, parents and community for the prevention and control of cervical cancer should be provided throughout the country.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in North America. Previous studies have shown improved progression free survival (PFS) and response rates in unfit patients treated with obinutuzumab compared to other regimens. The aim of this study was to evaluate the obinutuzumab-chlorambucil regimen in the context of historical treatments and first-dose infusion reactions at CancerCare Manitoba (CCMB). METHODS: A retrospective chart review was conducted for patients treated with obinutuzumab from January 1, 2014 to December 31, 2017 at CCMB. A minimum data set was extracted for patients treated with other front-line therapies. Descriptive statistics were used to evaluate patient demographics, toxicity, duration and dosing of obinutuzumab treatment. Kaplan-Meier curves were used to evaluate time-to-next-treatment (TTNT), overall survival (OS) and PFS for patients treated with obinutuzumab. A multivariable logistic regression model was used to investigate associations between infusion related reactions (IRRs) and age at treatment, pre-treatment lymphocyte count, cumulative illness rating scale (CIRS) and receipt of prior chemotherapy. RESULTS: Forty seven percent of patients receiving frontline therapy received chlorambucil and obinutuzumab. Sixty-seven patients were treated with obinutuzumab and consisted of 36 males (53.7%) and 31 females (46.3%) with 29 patients (43.3%) over age 75 years. Rates of grade 3 and 4 obinutuzumab IRRs were lower (6%) compared to the CLL11 clinical trial (20%) due to local practices including slower infusion rates and using chlorambucil before starting obinutuzumab treatment. Many patients had difficulty tolerating the full dosage of chlorambucil. Only 26 patients (38.8%) had their dose of chlorambucil escalated to the full dose of 0.5 mg/kg. In addition, only 18 patients (26.9%) received all doses of obinutuzumab and all 12 doses of chlorambucil. CONCLUSIONS: In summary, first dose infusion reactions with obinutuzumab can be markedly reduced by using chlorambucil to decrease the lymphocyte count before obinutuzumab and by using a very slow initial obinutuzumab infusion rate. Modifications in chlorambucil dosing and obinutuzumab administration can improve tolerance without significant loss in efficacy.

BACKGROUND: We have previously reported that a new intronless gene for casein kinase 2α (CK2α), CSNK2A3, is expressed in human cells. The promoter of the well-known CK2α, CSNK2A1, displays characteristics of a housekeeping gene, whereas CSNK2A3 has a characteristic of a regulated promoter with two TATA boxes and a CAAT box. GPR68, a family of the G protein-coupled receptors, is also known as ovarian cancer G protein-coupled receptor 1 (OGR1). In the current study, we analyzed the roles of CK2α genes and neutral endopeptidase (NEP), a key enzyme that influences a variety of malignancies, in the OGR1-induced inhibition of A549 cell migration. METHODS: We analyzed the transcript expressions of both the CK2α genes (CSNK2A1 and CSNK2A3) and NEP upon OGR1 overexpression. Protein expression of CK2α and NEP were also analyzed. We further elucidated the functional roles of both CK2α and NEP in the OGR1-induced inhibition of A549 cell migration in vitro using a wound-healing assay. We also analyzed the molecular mechanisms involved in the OGR1-induced inhibition of lung cancer cell migration. RESULTS: The findings of this study showed that OGR1 upregulated the expression of CSNK2A3 but not CSNK2A1 in the A549 cells. The findings further suggested OGR1 also upregulates the expression of NEP. The OGR1-induced inhibition of A549 cell migration was abrogated completely by inhibition of CK2α activity, whereas partial abrogation (~ 30%) was observed in the presence of NEP inhibition. The results also revealed that OGR1 regulates CSNK2A3 via activation of Rac1/cdc42 and MAPKs pathways. CK2 is ubiquitously expressed, and in contrast, is believed to be a constitutively active enzyme, and its regulation appears to be independent of known second messengers. CONCLUSION: In the current study, we report for the first time the OGR1-induced regulation of CSNK2A3, CK2αP, and NEP in A549 cancer cells. Our study also decoded the downstream cellular proteins of OGR1 as well as the molecular mechanism involved in OGR1-induced inhibition of A549 cell migration. The findings of this research suggest the potential therapeutic targets to inhibit lung cancer progression.

BACKGROUND: Anastomotic leakage is the most important surgical complication following esophagectomy. A major cause of leakage is ischemia of the gastric tube that is used for reconstruction of the gastrointestinal tract. Generalized cardiovascular disease, expressed by calcifications of the aorta and celiac axis stenosis on a pre-operative CT scan, is associated with an increased risk of anastomotic leakage. Laparoscopic ischemic conditioning (ISCON) aims to redistribute blood flow and increase perfusion at the anastomotic site by occluding the left gastric, left gastroepiploic and short gastric arteries prior to esophagectomy. This study aims to assess the safety and feasibility of laparoscopic ISCON in selected patients with esophageal cancer and concomitant arterial calcifications. METHODS: In this prospective single-arm safety and feasibility trial based upon the IDEAL recommendations for surgical innovation, a total of 20 patients will be included recruited in 2 European high-volume centers for esophageal cancer surgery. Patients with resectable esophageal carcinoma (cT1-4a, N0-3, M0) with "major calcifications" of the thoracic aorta accordingly to the Uniform Calcification Score (UCS) or a stenosis of the celiac axis accordingly to the modified North American Symptomatic Carotid Endarterectomy Trial (NASCET) score on preoperative CT scan, who are planned to undergo esophagectomy are eligible for inclusion. The primary outcome variables are complications grade 2 and higher (Clavien-Dindo classification) occurring during or after laparoscopic ISCON and before esophagectomy. Secondary outcomes include intra- and postoperative complications of esophagectomy and the induction of angiogenesis by biomarkers of microcirculation and redistribution of blood flow by measurement of indocyanine green (ICG) fluorescence angiography. DISCUSSION: We hypothesize that in selected patients with impaired vascularization of the gastric tube, laparoscopic ISCON is feasible and can be safely performed 12-18 days prior to esophagectomy. Depending on the results, a randomized controlled trial will be needed to investigate whether ISCON leads to a lower percentage and less severe course of anastomotic leakage in selected patients. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03896399 . Registered 4 January 2019.

BACKGROUND: Multiple myeloma remains an incurable disease with multiple relapses due to residual myeloma cells in the bone marrow of patients after therapy. Presence of small number of cancer cells in the body after cancer treatment, called minimal residual disease, has been shown to be prognostic for progression-free and overall survival. However, for multiple myeloma, it is unclear whether patients attaining minimal residual disease negativity may be candidates for treatment discontinuation. We investigated, if longitudinal flow cytometry-based monitoring of minimal residual disease (flow-MRD) may predict disease progression earlier and with higher sensitivity compared to biochemical assessments. METHODS: Patients from the Nordic countries with newly diagnosed multiple myeloma enrolled in the European-Myeloma-Network-02/Hovon-95 (EMN02/HO95) trial and undergoing bone marrow aspiration confirmation of complete response, were eligible for this Nordic Myeloma Study Group (NMSG) substudy. Longitdudinal flow-MRD assessment of bone marrow samples was performed to identify and enumerate residual malignant plasma cells until observed clinical progression. RESULTS: Minimal residual disease dynamics were compared to biochemically assessed changes in serum free light chain and M-component. Among 20 patients, reaching complete response or stringent complete response during the observation period, and with ≥3 sequential flow-MRD assessments analysed over time, increasing levels of minimal residual disease in the bone marrow were observed in six cases, preceding biochemically assessed disease and clinical progression by 5.5 months and 12.6 months (mean values), respectively. Mean malignant plasma cells doubling time for the six patients was 1.8 months (95% CI, 1.4-2.3 months). Minimal malignant plasma cells detection limit was 4 × 10-5. CONCLUSIONS: Flow-MRD is a sensitive method for longitudinal monitoring of minimal residual disease dynamics in multiple myeloma patients in complete response. Increasing minimal residual disease levels precedes biochemically assessed changes and is an early indicator of subsequent clinical progression. TRIAL REGISTRATION: NCT01208766.

BACKGROUND: Glioblastoma is the most aggressive and common malignant primary brain tumor in adults. Many genetic, epigenetic and genomic mutations have been identified in this tumor, but no driving cause has been identified yet for glioblastoma pathogenesis. Autophagy has proved to be deregulated in different diseases such as cancer where it has a dual role, acting as a tumor suppression mechanism during the first steps of tumor development and promoting cancer cells survival in stablished tumors. METHODS: Here, we aimed to assess the potential association between several candidate polymorphisms in autophagy genes (ATG2B rs3759601, ATG16L1 rs2241880, ATG10 rs1864183, ATG5 rs2245214, NOD2 rs2066844 and rs2066845) and glioblastoma susceptibility. RESULTS: Our results showed a significant correlation between ATG2B rs3759601, ATG10 rs1864183 and NOD2 rs2066844 variants and higher risk to suffer glioblastoma. In addition, the relationship between the different clinical features listed in glioblastoma patients and candidate gene polymorphisms was also investigated, finding that ATG10 rs1864183 might be a promising prognosis factor for this tumor. CONCLUSIONS: This is the first report evaluating the role of different variants in autophagy genes in modulating glioblastoma risk and our results emphasize the importance of autophagy in glioblastoma development.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver cancer in the world. Although great advances in HCC diagnosis and treatment have been achieved, due to the complicated mechanisms in tumor development and progression, the prognosis of HCC is still dismal. Recent studies have revealed that the Warburg effect is related to the development, progression and treatment of various cancers; however, there have been a few explorations of the relationship between glycolysis and HCC prognosis. METHODS: mRNA expression profiling was downloaded from public databases. Gene set enrichment analysis (GSEA) was used to explore glycolysis-related genes (GRGs), and the LASSO method and Cox regression analysis were used to identify GRGs related to HCC prognosis and to construct predictive models associated with overall survival (OS) and disease-free survival (DFS). The relationship between the predictive model and the tumor mutation burden (TMB) and tumor immune microenvironment (TIME) was explored. Finally, real-time PCR was used to validate the expression levels of the GRGs in clinical samples and different cell lines. RESULTS: Five GRGs (ABCB6, ANKZF1, B3GAT3, KIF20A and STC2) were identified and used to construct gene signatures to predict HCC OS and DFS. Using the median value, HCC patients were divided into low- and high-risk groups. Patients in the high-risk group had worse OS/DFS than those in the low-risk group, were related to higher TMB and were associated with a higher rate of CD4+ memory T cells resting and CD4+ memory T cells activated. Finally, real-time PCR suggested that the five GRGs were all dysregulated in HCC samples compared to adjacent normal samples. CONCLUSIONS: We identified five GRGs associated with HCC prognosis and constructed two GRGs-related gene signatures to predict HCC OS and DFS. The findings in this study may contribute to the prediction of prognosis and promote HCC treatment.

BACKGROUND: High-risk human papillomavirus (HR-HPV) is the main aetiological factor for the development of cervical cancer. While nearly 70% of HR-HPV infections are cleared within 12 months, in the remainder of women they persist and can progress into cervical cancer. Oestradiol and progesterone have been shown to be involved in the development and progression of cervical cancer. The objective of this study was to investigate, for the first time, whether diurnal oestradiol and progesterone are also involved in HR-HPV persistence - before cervical cancer develops. METHODS: A total of N = 39 women between 18 and 31 years of age were investigated. All were nulliparous and regular users of combined oral contraceptives. Presence of HR-HPV was determined by cervical swabs. Salivary oestradiol and progesterone were measured upon awakening and at 11 am, 2 pm, and 5 pm. All HR-HPV positive women were re-tested in terms of HR-HPV status 12 months later. RESULTS: HR-HPV positive women had significantly higher morning (p = .007, partial eta2 = .221) and daily oestradiol levels (p < .001, partial eta2 = .442) when compared to HR-HPV negative women. In addition, those with persistent HR-HPV 12 months later had significantly elevated morning (p = .005, partial eta2 = .534) and daily (p = .027, partial eta2 = .346) oestradiol. Progesterone was found to be unrelated to HR-HPV. CONCLUSIONS: Oestradiol was positively linked to HR-HPV presence and persistence. Provided that these findings are replicated, regular monitoring of oestradiol levels may prove useful in identifying women who are at risk of developing cervical cancer.

BACKGROUND: Tumor-associated macrophages (TAMs) are closely related to unfavorable prognosis of patients with clear cell renal cell carcinoma (ccRCC). However, the important molecules in the interaction between ccRCC and TAMs are unclear. METHODS: TCGA-KIRC gene expression data of tumor tissues and normal tissues adjacent to tumor were compared to identify differentially expressed genes in ccRCC. TAMs related genes were discovered by analyzing the correlation between these differentially expressed genes and common macrophage biomarkers. Gene set enrichment analysis was performed to predict functions of TAMs related gene. The findings were further validated using RNA sequencing data obtained from the CheckMate 025 study and immunohistochemical analysis of samples from 350 patients with ccRCC. Kaplan-Meier survival curve, Cox regression analysis and Harrell's concordance index analysis were used to determine the prognostic significance. RESULTS: In this study, we applied bioinformatic analysis to explore TAMs related differentially expressed genes in ccRCC and identified 5 genes strongly correlated with all selected macrophage biomarkers: STAC3, LGALS9, TREM2, FCER1G, and PILRA. Among them, FCER1G was abundantly expressed in tumor tissues and showed prognostic importance in patients with ccRCC who received treatment with Nivolumab; however, it did not exhibit prognostic value in those treated with Everolimus. We also discovered that high expression levels of FCER1G are related to T cell suppression. Moreover, combination of FCER1G and macrophage biomarker CD68 can improve the prognostic stratification of patients with ccRCC from TCGA-KIRC. Based on the immunohistochemical analysis of samples from patients with ccRCC, we further validated that FCER1G and CD68 are both highly expressed in tumor tissue and correlate with each other. Higher expression of CD68 or FCER1G in ccRCC tissue indicates shorter overall survival and progression-free survival; patients with high expression of both CD68 and FCER1G have the worst outcome. Combining CD68 and FCER1G facilitates the screening of patients with a worse prognosis from the same TNM stage group. CONCLUSIONS: High expression of FCER1G in ccRCC is closely related to TAMs infiltration and suppression of T cell activation and proliferation. Combining the expression levels of FCER1G and macrophage biomarker CD68 may be a promising postoperative prognostic index for patients with ccRCC.

BACKGROUND: As the combination of systemic and targeted chemotherapies is associated with severe adverse side effects and long-term health complications, there is interest in reducing treatment intensity for patients with early-stage breast cancer (EBC). Clinical trials are needed to determine the feasibility of reducing treatment intensity while maintaining 3-year recurrence-free survival of greater than 92%. To recruit participants for these trials, it is important to understand patient perspectives on reducing chemotherapy. METHODS: We collected qualitative interview data from twenty-four patients with Stage II-III breast cancer and sixteen patient advocates. Interviews explored potential barriers and facilitators to participation in trials testing reduced amounts of chemotherapy. As the COVID-19 pandemic struck during data collection, seventeen participants were asked about the potential impact of COVID-19 on their interest in these trials. Interviews were audio-recorded and transcribed, and researchers used qualitative content analysis to code for dominant themes. RESULTS: Seventeen participants (42.5%) expressed interest in participating in a trial of reduced chemotherapy. Barriers to reducing chemotherapy included (1) fear of recurrence and inefficacy, (2) preference for aggressive treatment, (3) disinterest in clinical trials, (4) lack of information about expected outcomes, (5) fear of regret, and (6) having young children. Facilitators included (1) avoiding physical toxicity, (2) understanding the scientific rationale of reducing chemotherapy, (3) confidence in providers, (4) consistent monitoring and the option to increase dosage, (5) fewer financial and logistical challenges, and (6) contributing to scientific knowledge. Of those asked, nearly all participants said they would be more motivated to reduce treatment intensity in the context of COVID-19, primarily to avoid exposure to the virus while receiving treatment. CONCLUSIONS: Among individuals with EBC, there is significant interest in alleviating treatment-related toxicity by reducing chemotherapeutic intensity. Patients will be more apt to participate in trials testing reduced amounts of chemotherapy if these are framed in terms of customizing treatment to the individual patient and added benefit-reduced toxicities, higher quality of life during treatment and lower risk of long-term complications-rather than in terms of taking treatments away or doing less than the standard of care. Doctor-patient rapport and provider support will be crucial in this process.

BACKGROUND: Gastric cancer is a heterogeneous disease with poorly understood genetic and microenvironmental factors. Mutations in collagen genes are associated with genetic diseases that compromise tissue integrity, but their role in tumor progression has not been extensively reported. Aberrant collagen expression has been long associated with malignant tumor growth, invasion, chemoresistance, and patient outcomes. We hypothesized that somatic mutations in collagens could functionally alter the tumor extracellular matrix. METHODS: We used publicly available datasets including The Tumor Cancer Genome Atlas (TCGA) to interrogate somatic mutations in collagens in stomach adenocarcinomas. To demonstrate that collagens were significantly mutated above background mutation rates, we used a moderated Kolmogorov-Smirnov test along with combination analysis with a bootstrap approach to define the background accounting for mutation rates. Association between mutations and clinicopathological features was evaluated by Fisher or chi-squared tests. Association with overall survival was assessed by Kaplan-Meier and the Cox-Proportional Hazards Model. Gene Set Enrichment Analysis was used to interrogate pathways. Immunohistochemistry and in situ hybridization tested expression of COL7A1 in stomach tumors. RESULTS: In stomach adenocarcinomas, we identified individual collagen genes and sets of collagen genes harboring somatic mutations at a high frequency compared to background in both microsatellite stable, and microsatellite instable tumors in TCGA. Many of the missense mutations resemble the same types of loss of function mutations in collagenopathies that disrupt tissue formation and destabilize cells providing guidance to interpret the somatic mutations. We identified combinations of somatic mutations in collagens associated with overall survival, with a distinctive tumor microenvironment marked by lower matrisome expression and immune cell signatures. Truncation mutations were strongly associated with improved outcomes suggesting that loss of expression of secreted collagens impact tumor progression and treatment response. Germline collagenopathy variants guided interpretation of impactful somatic mutations on tumors. CONCLUSIONS: These observations highlight that many collagens, expressed in non-physiologically relevant conditions in tumors, harbor impactful somatic mutations in tumors, suggesting new approaches for classification and therapy development in stomach cancer. In sum, these findings demonstrate how classification of tumors by collagen mutations identified strong links between specific genotypes and the tumor environment.

BACKGROUND: Colorectal cancer (CRC) is major cancer-related death. The aim of this study was to identify differentially expressed and differentially methylated genes, contributing to explore the molecular mechanism of CRC. METHODS: Firstly, the data of gene transcriptome and genome-wide DNA methylation expression were downloaded from the Gene Expression Omnibus database. Secondly, functional analysis of differentially expressed and differentially methylated genes was performed, followed by protein-protein interaction (PPI) analysis. Thirdly, the Cancer Genome Atlas (TCGA) dataset and in vitro experiment was used to validate the expression of selected differentially expressed and differentially methylated genes. Finally, diagnosis and prognosis analysis of selected differentially expressed and differentially methylated genes was performed. RESULTS: Up to 1958 differentially expressed (1025 up-regulated and 993 down-regulated) genes and 858 differentially methylated (800 hypermethylated and 58 hypomethylated) genes were identified. Interestingly, some genes, such as GFRA2 and MDFI, were differentially expressed-methylated genes. Purine metabolism (involved IMPDH1), cell adhesion molecules and PI3K-Akt signaling pathway were significantly enriched signaling pathways. GFRA2, FOXQ1, CDH3, CLDN1, SCGN, BEST4, CXCL12, CA7, SHMT2, TRIP13, MDFI and IMPDH1 had a diagnostic value for CRC. In addition, BEST4, SHMT2 and TRIP13 were significantly associated with patients' survival. CONCLUSIONS: The identified altered genes may be involved in tumorigenesis of CRC. In addition, BEST4, SHMT2 and TRIP13 may be considered as diagnosis and prognostic biomarkers for CRC patients.

BACKGROUND: There is still controversy regarding the clinical value and significance of lateral pelvic lymph node (LPN) dissection (LPND). The present study aimed to investigate whether the addition of LPND to total mesorectal excision (TME) confers survival benefits in rectal cancer patients with clinical lateral pelvic node metastasis (LPNM). METHODS: From January 2015 to January 2021, a total of 141 rectal cancer patients with clinical evidence of LPNM who underwent TME + LPND were retrospectively analysed and divided into the LPNM group (n = 29) and the non-LPNM group (n = 112). The LPNM group was further subdivided into a high-risk LPNM group (n = 14) and a low-risk LPNM group (n = 15). Propensity score matching (PSM) was performed to minimize selection bias. The primary outcomes of this study were 3-year overall survival (OS) and disease-free survival (DFS). RESULTS: Of the 141 patients undergoing LPND, the local recurrence rate of patients with LPNM was significantly higher than that of patients without LPNM both before (27.6% vs. 4.5%, P = 0.001) and after (27.6% vs. 3.4%, P = 0.025) PSM. Multivariate analysis revealed that LPNM was an independent risk factor for not only OS (HR: 3.06; 95% CI, 1.15-8.17; P = 0.025) but also DFS (HR: 2.39; 95% CI, 1.18-4.87; P = 0.016) in patients with LPNM after TME + LPND. When the LPNM group was further subdivided, multivariate logistic regression analysis showed that OS and DFS were significantly better in the low-risk group (obturator/internal iliac artery region and < 2 positive LPNs). CONCLUSION: Even after LPND, LPNM patients have a poor prognosis. Moreover, LPNM is an independent poor prognostic factor affecting OS and DFS after TME + LPND. However, LPND appears to confer survival benefits to specific patients with single LPN involvement in the obturator region or internal iliac vessel region. Furthermore, LPND may have no indication in stage IV patients and should be selected carefully.

BACKGROUND: Telomeres are protective structures at chromosome ends which shorten gradually with increasing age. In chronic lymphocytic leukemia (CLL), short telomeres have been associated with unfavorable disease outcome, but the link between clonal evolution and telomere shortening remains unresolved. METHODS: We investigated relative telomere length (RTL) in a well-characterized cohort of 198 CLL patients by qPCR and focused in detail on a subgroup 26 patients who underwent clonal evolution of TP53 mutations (evolTP53). In the evolTP53 subgroup we explored factors influencing clonal evolution and corresponding changes in telomere length through measurements of telomerase expression, lymphocyte doubling time, and BCR signaling activity. RESULTS: At baseline, RTL of the evolTP53 patients was scattered across the entire RTL spectrum observed in our CLL cohort. RTL changed in the follow-up samples of 16/26 (62%) evolTP53 cases, inclining to reach intermediate RTL values, i.e., longer telomeres shortened compared to baseline while shorter ones prolonged. For the first time we show that TP53 clonal shifts are linked to RTL change, including unexpected RTL prolongation. We further investigated parameters associated with RTL changes. Unstable telomeres were significantly more frequent among younger patients (P = 0.032). Shorter telomeres were associated with decreased activity of the B-cell receptor signaling components p-ERK1/2, p-ZAP-70/SYK, and p-NFκB (P = 0.04, P = 0.01, and P = 0.02, respectively). CONCLUSIONS: Our study revealed that changes of telomere length reflect evolution in leukemic subclone proportion, and are associated with specific clinico-biological features of the explored cohort.

BACKGROUND: Breast cancer survivors (BCSs) often have potential unmet needs. Identification of the specific needs of BCSs is very significant for medical service provision. This study aimed to (1) investigate the unmet needs and quality of life (QoL) of BCSs in China, (2) explore the diverse factors associated with their unmet needs, and (3) assess the association between their unmet needs and QoL. METHODS: A multicentre, cross-sectional survey was administered to 1210 Chinese BCSs. The Cancer Survivor Profile-Breast Cancer and the Functional Assessment of Cancer Therapy-Breast scale were administered to survivors who gave informed consent to participate. Data were analysed using t-test, ANOVA, multiple regression analysis, and Pearson correlations. RESULTS: The 1192 participants completed questionnaires (response rate 98.51%). Our study reveals that the most prevalent unmet needs were in the 'symptom burden domain'. The unmet needs of BCSs depend on eleven factors; age, time since diagnosis, education level, occupation, payment, family income status, stage of cancer, treatment, family history of cancer, pain, and physical activities. To ensure the provision of high-quality survivorship care and a high satisfaction level, more attention should be paid to actively identifying and addressing the unmet needs of BCSs. The problem areas identified in the Cancer Survivor Profile for breast cancer were negatively associated with all subscales of QoL except the health behaviour domain, with the correlation coefficient ranging from - 0.815 to - 0.011. CONCLUSION: Chinese BCSs exhibit a high demand for unmet needs in this study, and the most prevalent unmet needs were in the 'symptom burden domain'. There was a significant association between patients' unmet needs (as defined in the Cancer Survivor Profile for breast cancer) and QoL. Future research should focus on enhancements to survivorship or follow-up care to address unmet needs and further improve QoL.

OBJECTIVE: Neuroblastoma is a common extracranial solid tumor of childhood. Recently, multiple treatments have been practiced including Iodine-131-metaiodobenzylguanidine radiation (131I-MIBG) therapy. However, the outcomes of efficacy and safety vary greatly among different studies. The aim of this meta-analysis is to evaluate the efficacy and safety of 131I-MIBG in the treatment of neuroblastoma and to provide evidence and hints for clinical decision-making. METHODS: Medline, EMBASE database and the Cochrane Library were searched for relevant studies. Eligible studies utilizing 131I-MIBG in the treatment of neuroblastoma were included. The pooled outcomes (response rates, adverse events rates, survival rates) were calculated using either a random-effects model or a fixed-effects model considering of the heterogeneity. RESULTS: A total of 26 clinical trials including 883 patients were analyzed. The pooled rates of objective response, stable disease, progressive disease, and minor response of 131I-MIBG monotherapy were 39%, 31%, 22% and 15%, respectively. The pooled objective response rate of 131I-MIBG in combination with other therapies was 28%. The pooled 1-year survival and 5-year survival rates were 64% and 32%. The pooled occurrence rates of thrombocytopenia and neutropenia in MIBG monotherapy studies were 53% and 58%. In the studies of 131I-MIBG combined with other therapies, the pooled occurrence rates of thrombocytopenia and neutropenia were 79% and 78%. CONCLUSION: 131I-MIBG treatment alone or in combination of other therapies is effective on clinical outcomes in the treatment of neuroblastoma, individualized 131I-MIBG is recommended on a clinical basis.

BACKGROUND: Annexin A10 expression influences the prognosis of several gastrointestinal cancers. We explored the association of annexin A10 expression with the overall survival (OS) of patients who underwent curative surgery for cholangiocarcinoma. METHODS: Patients who underwent curative surgery for cholangiocarcinoma (except gallbladder cancer) and had pathological stage T1-3N0M0 disease were enrolled. Annexin A10 expression was examined by performing immunohistochemical staining. Patient demographics and survival outcome data were retrieved from medical records. RESULTS: In total, 185 patients were enrolled. The primary tumor location was intrahepatic and extrahepatic (including the perihilar region) for 89% and 11% of patients, respectively. Positive annexin A10 staining was detected for 61 (33%) patients and associated with extrahepatic or perihilar cholangiocarcinoma (p = 0.001) and lower histological grade (p < 0.001). Patients with positive annexin A10 staining exhibited significantly poorer survival relative to patients with negative staining results (median OS, 2.5 vs. 4.9 years, p = 0.025). In the multivariate analysis adjusting for age, sex, tumor location, tumor grade, hepatitis infection, and disease stage, positive annexin A10 remained an independent predictor of poor OS (hazard ratio 1.572, p = 0.034). In the subgroup analysis, the association between annexin A10 and prognosis was restricted to intrahepatic cholangiocarcinoma. Among patients with intrahepatic cholangiocarcinoma, patients with positive annexin A10 staining exhibited significantly poorer survival compared with patients with negative annexin A10 staining (median OS, 2.3 vs. 4.9 years, p = 0.008). CONCLUSION: Positive annexin A10 expression was associated with poor prognosis of intrahepatic cholangiocarcinoma.

BACKGROUND: Fear of cancer recurrence (FCR) has been addressed as a cause of emotional distress among breast cancer survivors (BCSs). This study aimed to systematically review the evidence on randomized controlled trials (RCTs) of cognitive behavioral therapy (CBT) designed to reduce FCR among BCSs. METHODS: A systematic review of published original research articles meeting the inclusion criteria was conducted. Five electronic databases, including the Cochrane Library, CINAHL, PubMed, PsycINFO, and Web of Science, were independently searched to identify relevant articles. The Consolidated Standards of Reporting Trials (CONSORT) 2010 checklist was used to evaluate the quality of the eligible studies. RESULTS: Through a database search and a manual review process, seventeen quantitative studies with an RCT study design were included in the current systematic review. The interventions varied greatly in length and intensity, but the study designs and methodologies were similar. RCTs with face-to-face interventions of at least 1 month seemed to be more effective in reducing FCR outcomes and complying with than the CONSORT 2010 criteria than those with a brief online or telephone format of interventions; nevertheless, most RCT interventions appeared to be effective. CONCLUSIONS: These findings highlight the importance of conducting well-designed CBT interventions to reduce FCR in BCSs with diverse populations at multiple sites, thereby improving the quality of research in this area.

BACKGROUND: Low-grade glioma (LGG) is susceptible to ferroptosis, which is involved in TMZ resistance. Ferroptosis induction can enhance the sensitivity to TMZ and synergistically kill glioma cells. T cell-promoted tumor ferroptosis is a vital anti-tumor mechanism of immune checkpoint inhibitors. The SAT1 activation is closely related to ferroptosis upon ROS induction due to the upregulation of arachidonate 15-lipoxygenase (ALOX15) expression. METHODS: The expression of SAT1 in pan-cancer and corresponding normal tissue from the TCGA data portal was primarily explored. The landscape of SAT1 and immune cell infiltration and their corresponding gene marker sets in different tissues were further explored. Additionally, we evaluated the relationships between SAT1 and the clinicopathologic parameters of LGG, and the disease-specific survival (DSS), progression-free interval (PFI), and overall survival (OS) were also assessed using KM survival curves and multivariate analysis in LGG. Meanwhile, the Gene Set Enrichment Analysis (GSEA) was also implemented to determine the potential effect of the SAT1 gene in LGG. Furthermore, the predictive power of SAT1 was validated using an independent LGG cohort from the Chinese Glioma Genome Atlas (CGGA) data. RESULTS: In general, the expression of SAT1 is different between most tumors and their adjacent normal tissues. The results demonstrated that SAT1 expression is positively associated with TMB in LGG, BRCA, and THYM. The results displayed that the expression level of SAT1 is obviously correlated with the level of infiltrating macrophages and CD8 + T cells, and the levels of most immune gene sets were associated with the SAT1 expression in LGG. Interestingly, univariate and multivariate models significantly indicated that the OS and PFI of patients with LGG with high SAT1 levels were poorer than those with low SAT1 expression in the TCGA LGG cohort. GSEA showed that SAT1 was involved in immune regulation and multiple signaling pathways. Finally, our analysis demonstrated that SAT1 was closely associated with IDH mutation, 1p19q codeletion, chemoradiotherapy resistance and disease recurrence. CONCLUSIONS: Abundant expression of SAT1 was related to poor disease prognosis and abundant immune cell infiltration in LGG.

BACKGROUND: Hepatocellular carcinoma (HCC) has high incidence and mortality worldwide. Local ablation using radiofrequency ablation (RFA) or microwave ablation (MWA) is potentially curative for early-stage HCC with outcomes comparable to surgical resection. We explored the influence of demographic, clinical, and laboratory factors on outcomes of HCC patients receiving ablation. METHODS: This retrospective cohort study included 221 HCC patients receiving local ablation at Mayo Clinic between January 2000 and October 2018, comprising 140 RFA and 81 MWA. Prognostic factors determining overall survival (OS) and disease-free survival (DFS) were identified using multivariate analysis. RESULTS: There was no clinically significant difference in OS or DFS between RFA and MWA. In multivariate analysis of OS, pre-ablation lymphocyte-monocyte ratio [Hazard ratio (HR) 0.7, 95% confidence interval (CI) 0.58-0.84, P = 0.0001], MELD score [HR 1.12, 95%CI 1.068-1.17, P <  0.0001], tumor number [HR 1.23, 95%CI 1.041-1.46, P = 0.015] and tumor size [HR 1.18, 95%CI 1.015-1.37, P = 0.031] were clinically-significant prognostic factors. Among HCC patients with chronic hepatitis C (HCV) infection, positive HCV PCR at HCC diagnosis was associated with 1.4-fold higher hazard of death, with 5-year survival of 32.8% vs 53.6% in HCV PCR-negative patients. Regarding DFS, pre-ablation lymphocyte-monocyte ratio [HR 0.77, 95%CI 0.66-0.9, P = 0.001], MELD score [HR 1.06, 95%CI 1.022-1.11, P = 0.002], Log2 AFP [HR 1.11, 95%CI 1.033-1.2, P = 0.005], tumor number [HR 1.29, 95%CI 1.078-1.53, P = 0.005] and tumor size [HR 1.25, 95%CI 1.043-1.51 P = 0.016] were independently prognostic. CONCLUSIONS: Pre-ablation systemic inflammation represented by lymphocyte-monocyte ratio is significantly associated with OS and DFS in HCC patients treated with local ablation. HCV viremia is associated with poor OS. Tumor biology represented by tumor number and size are strongly prognostic for OS and DFS while AFP is significantly associated with DFS only.

BACKGROUND: Cancer patient pathways (CPPs) were implemented in Norway to reduce unnecessary waiting times, regional variations, and to increase the predictability of cancer care for the patients. This study aimed to determine if 70% of cancer patients started treatment within the recommended time frames, and to identify potential delays. METHODS: Patients registered with a colorectal, lung, breast, or prostate cancer diagnosis at the Cancer Registry of Norway in 2015-2016 were linked with the Norwegian Patient Registry and Statistics Norway. Adjusting for sociodemographic variables, multivariable quantile (median) regressions were used to examine the association between place of residence and median time to start of examination, treatment decision, and start of treatment. RESULTS: The study included 20 668 patients. The proportions of patients who went through the CPP within the recommended time frames were highest among colon (84%) and breast (76%) cancer patients who underwent surgery and lung cancer patients who started systemic anticancer treatment (76%), and lowest for prostate cancer patients who underwent surgery (43%). The time from treatment decision to start of treatment was the main source of delay for all cancers. Travelling outside the resident health trust prolonged waiting time and was associated with a reduced odds of receiving surgery and radiotherapy for lung and rectal cancer patients, respectively. CONCLUSIONS: Achievement of national recommendations of the CCP times differed by cancer type and treatment. Identified bottlenecks in the pathway should be targeted to decrease waiting times. Further, CPP guidelines should be re-examined to determine their ongoing relevance.

Bladder cancer (BC) is one of the most frequent cancer in the world, and its incidence is rising worldwide, especially in developed countries. Urine metabolomics is a powerful approach to discover potential biomarkers for cancer diagnosis. In this study, we applied an ultra-performance liquid chromatography coupled to mass spectrometry (UPLC-MS) method to profile the metabolites in urine from 29 bladder cancer patients and 15 healthy controls. The differential metabolites were extracted and analyzed by univariate and multivariate analysis methods. Together, 19 metabolites were discovered as differently expressed biomarkers in the two groups, which mainly related to the pathways of phenylacetate metabolism, propanoate metabolism, fatty acid metabolism, pyruvate metabolism, arginine and proline metabolism, glycine and serine metabolism, and bile acid biosynthesis. In addition, a subset of 11 metabolites of those 19 ones were further filtered as potential biomarkers for BC diagnosis by using logistic regression model. The results revealed that the area under the curve (AUC) value, sensitivity and specificity of receiving operator characteristic (ROC) curve were 0.983, 95.3% and 100%, respectively, indicating an excellent discrimination power for BC patients from healthy controls. It was the first time to reveal the potential diagnostic markers of BC by metabolomics, and this will provide a new sight for exploring the biomarkers of the other disease in the future work.

BACKGROUND: Malignant ascites often causes discomfort in advanced cancer patients. Paracentesis is the most common treatment modality, but it requires frequently repeated treatment. Cell-free and concentrated ascites reinfusion therapy (CART) may prolong the paracentesis interval, but controlled trials are lacking. We assessed the feasibility of a randomized controlled trial of CART vs. paracentesis alone for patients with refractory malignant ascites. METHODS: This study was an open-label, fast-track, randomized controlled, feasibility trial. Patients admitted to four designated cancer hospitals who received no further anticancer treatments were eligible. Patients were randomly assigned 1:1 to a CART arm or control (simple paracentesis) arm. The feasibility endpoint was the percentage of patients who completed the study intervention. Secondary endpoints included paracentesis-free survival, patient's request on the questionnaire for paracentesis (PRO-paracentesis)-free survival (the period until the patients first reported that they would want paracentesis if indicated), and adverse events. RESULTS: We screened 953 patients for eligibility. Of 61 patients with refractory malignant ascites, 21 patients were determined as eligible. Finally, 20 patients consented and were allocated; 18 patients (90%, 95% CI: 68.3-98.8) completed the study intervention. All patients had an ECOG performance status of 3 or 4. The median drained ascites volume was 3,200 mL in the CART arm and 2,500 mL in the control arm. In the CART arm, the median reinfused albumin volume was 12.6 g. Median paracentesis-free survivals were 5 days (95% CI: 2-6) in the CART arm, and 6 days (3-9) in the control arm. Median PRO-paracentesis-free survivals were 4 days (2-5) and 5 days (1-9), respectively. A total of 73% of patients received paracentesis within 2 days from their first request for the next paracentesis. One patient in the CART arm developed Grade 1 fever. CONCLUSIONS: A fast-track randomized controlled trial of CART for patients with malignant ascites is feasible. The efficacy and safety of CART should be assessed in future trials. PRO-paracentesis-free survival may be a complementary outcome measure with paracentesis-free survival in future trials. TRIAL REGISTRATION: Registered at University Hospital Medical Information Network Clinical Trial Registry as UMIN000031029 . Registered on 28/01/2018.

BACKGROUND: Glioma cells are characterized by high migration ability, resulting in aggressive growth of the tumors and poor prognosis of patients. It has been reported that the stress-induced hormone norepinephrine (NE) contributes to tumor progression through mediating a number of important biological processes in various cancers. However, the role of NE in the regulation of glioma migration is still unclear. Epithelial-to-mesenchymal transition (EMT) is one of the most important steps for tumor migration and metastasis. Twist1, as a key regulator of EMT, has been found to be elevated during glioma migration. But it is still unknown whether Twist1 is involved in the effect of NE on the migration of glioma cells. METHODS: Wound healing assay and transwell assay were conducted to evaluate the migration of glioma cells upon different treatments. The mesenchymal-like phenotype and the expression of Twist1 after NE treatment were assessed by cell diameters, real-time PCR, western blot and immunofluorescence staining. The gain-and loss-of-function experiments were carried out to investigate the biological function of Twist1 in the migration induced by NE. Finally, the clinical significance of Twist1 was explored among three public glioma datasets. RESULTS: In this study, our finding revealed a facilitative effect of NE on glioma cell migration in a β-adrenergic receptor (ADRB)-dependent way. Mechanistically, NE induced mesenchymal-like phenotype and the expression of Twist1. Twist1 overexpression promoted glioma cells migration, while knockdown of Twist1 abolished the discrepancy in the migration ability between NE treated glioma cells and control cells. In addition, the clinical analysis demonstrated that Twist1 was up-regulated in malignant gliomas and recurrent gliomas, and predicted a poor prognosis of glioma patients. CONCLUSIONS: NE enhanced the migration ability of glioma cells through elevating the expression of Twist1. Our finding may provide potential therapeutic target for protecting patients with glioma from the detrimental effects of stress biology on the tumor progression.

BACKGROUND: Immunotherapy is a novel hotspot for the treatment of pancreatic adenocarcinoma (PAAD). However, potential biomarkers which could identify the inflamed tumor microenvironment (TME) are urgently required. METHODS: In the present study, we measured the levels of B7-H3, B7-H4, and major tumor-infiltrating immune cells (TIICs) using bioinformatics analyses and immunohistochemistry (IHC) staining on PAAD samples represented in the tissue microarray (TMA) format. Statistical analysis and figures exhibition were performed using R 4.1.0, SPSS 26.0, and GraphPad Prism 6.0. RESULTS: B7-H3 and B7-H4 were up-regulated in PAAD compared with para-tumor tissues, and their expression exhibited no tight correlation in PAAD tissues. B7-H3 and B7-H4 were lowly expressed in well-differentiated PAAD tissues and correlated with poorly differentiated grades. Besides, single B7-H3 or B7-H4 expression exhibited limited prognostic value, but co-deficiency of B7-H3 and B7-H4 predicted a better prognosis in PAAD. Moreover, co-deficiency of B7-H3 and B7-H4 indicated immuno-hot tumors with high CD8 + T cell infiltration. CONCLUSIONS: Overall, combined B7-H3 and B7-H4 expression is a promising stratification strategy to assess prognosis and immunogenicity in PAAD, which could be used as a novel classifier in clinical practice.

BACKGROUND: Peri-operative chemo-radiotherapyplayed important rolein locally advanced gastric cancer. Whether preoperative strategy can improve the long-term prognosis compared with postoperative treatment is unclear. The study purpose to compare oncologic outcomes in locally advanced gastric cancer patients treated with preoperative chemo-radiotherapy (pre-CRT) and postoperative chemo-radiotherapy (post-CRT). METHODS: From January 2009 to April 2019, 222 patients from 2 centers with stage T3/4 and/or N positive gastric cancer who received pre-CRT and post-CRT were included. After propensity score matching (PSM), comparisons of local regional control (LC), distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) were performed using Kaplan-Meier analysis and log-rank test between pre- and post-CRT groups. RESULTS: The median follow-up period was 30 months. 120 matched cases were generated for analysis. Three-year LC, DMFS, DFS and OS for pre- vs. post-CRT groups were 93.8% vs. 97.2% (p = 0.244), 78.7% vs. 65.7% (p = 0.017), 74.9% vs. 65.3% (p = 0.042) and 74.4% vs. 61.2% (p = 0.055), respectively. Pre-CRT were significantly associated with DFS in uni- and multi-variate analysis. CONCLUSION: Preoperative CRT showed advantages of oncologic outcome compared with postoperative CRT. TRIAL REGISTRATION: ClinicalTrial.gov NCT01291407 , NCT03427684 and NCT04062058 , date of registration: Feb 8, 2011.

BACKGROUND: Elucidation of specific and recurrent/founder pathogenic variants (PVs) in BRCA (BRCA1 and BRCA2) genes can make the genetic testing, for breast cancer (BC) and/or ovarian cancer (OC), affordable for developing nations. METHODS: To establish the knowledge about BRCA PVs and to determine the prevalence of the specific and recurrent/founder variants in BRCA genes in BC and/or OC women in North Africa, a systematic review was conducted in Morocco, Algeria, and Tunisia. RESULTS: Search of the databases yielded 25 relevant references, including eleven studies in Morocco, five in Algeria, and nine in Tunisia. Overall, 15 studies investigated both BRCA1 and BRCA2 genes, four studies examined the entire coding region of the BRCA1 gene, and six studies in which the analysis was limited to a few BRCA1 and/or BRCA2 exons. Overall, 76 PVs (44 in BRCA1 and32 in BRCA2) were identified in 196 BC and/or OC patients (129 BRCA1 and 67 BRCA2 carriers). Eighteen of the 76 (23.7%) PVs [10/44 (22.7%) in BRCA1 and 8/32 (25%) in BRCA2] were reported for the first time and considered to be novel PVs. Among those identified as unlikely to be of North African origin, the BRCA1 c.68_69del and BRCA1 c.5266dupC Jewish founder alleles and PVs that have been reported as recurrent/founder variants in European populations (ex: BRCA1 c.181T>G, BRCA1 c1016dupA). The most well characterized PVs are four in BRCA1 gene [c.211dupA (14.7%), c.798_799detTT (14%), c.5266dup (8.5%), c.5309G>T (7.8%), c.3279delC (4.7%)] and one in BRCA2 [c.1310_1313detAAGA (38.9%)]. The c.211dupA and c.5309G>T PVs were identified as specific founder variants in Tunisia and Morocco, accounting for 35.2% (19/54) and 20.4% (10/49) of total established BRCA1 PVs, respectively. c.798_799delTT variant was identified in 14% (18/129) of all BRCA1 North African carriers, suggesting a founder allele. A broad spectrum of recurrent variants including BRCA1 3279delC, BRCA1 c.5266dup and BRCA2 c.1310_1313detAAGA was detected in 42 patients. BRCA1 founder variants explain around 36.4% (47/129) of BC and outnumber BRCA2 founder variants by a ratio of ≈3:1. CONCLUSIONS: Testing BC and/or OC patients for the panel of specific and recurrent/founder PVs might be the most cost-effective molecular diagnosis strategy.

BACKGROUND: We collected information on patients with rectal adenocarcinoma in the United States from the Surveillance, Epidemiology, and EndResults (SEER) database. We used this information to establish a model that combined deep learning with a multilayer neural network (the DeepSurv model) for predicting the survival rate of patients with rectal adenocarcinoma. METHODS: We collected patients with rectal adenocarcinoma in the United States and older than 20 yearswho had been added to the SEER database from 2004 to 2015. We divided these patients into training and test cohortsat a ratio of 7:3. The training cohort was used to develop a seven-layer neural network based on the analysis method established by Katzman and colleagues to construct a DeepSurv prediction model. We then used the C-index and calibration plots to evaluate the prediction performance of the DeepSurv model. RESULTS: The 49,275 patients with rectal adenocarcinoma included in the study were randomly divided into the training cohort (70%, n = 34,492) and the test cohort (30%, n = 14,783). There were no statistically significant differences in clinical characteristics between the two cohorts (p > 0.05). We applied Cox proportional-hazards regression to the data in the training cohort, which showed that age, sex, marital status, tumor grade, surgery status, and chemotherapy status were significant factors influencing survival (p < 0.05). Using the training cohort to construct the DeepSurv model resulted in a C-index of the model of 0.824, while using the test cohort to verify the DeepSurv model yielded a C-index of 0.821. Thesevalues show that the prediction effect of the DeepSurv model for the test-cohort patients was highly consistent with the prediction resultsfor the training-cohort patients. CONCLUSION: The DeepSurv prediction model of the seven-layer neural network that we have established can accurately predict the survival rateand time of rectal adenocarcinoma patients.

BACKGROUND: The Kaiser Permanente Research Bank (KPRB) is collecting biospecimens and surveys linked to electronic health records (EHR) from approximately 400,000 adult KP members. Within the KPRB, we developed a Cancer Cohort to address issues related to cancer survival, and to understand how genetic, lifestyle and environmental factors impact cancer treatment, treatment sequelae, and prognosis. We describe the Cancer Cohort design and implementation, describe cohort characteristics after 5 years of enrollment, and discuss future directions. METHODS: Cancer cases are identified using rapid case ascertainment algorithms, linkage to regional or central tumor registries, and direct outreach to KP members with a history of cancer. Enrollment is primarily through email invitation. Participants complete a consent form, survey, and donate a blood or saliva sample. All cancer types are included. RESULTS: As of December 31, 2020, the cohort included 65,225 cases (56% female, 44% male) verified in tumor registries. The largest group was diagnosed between 60 and 69 years of age (31%) and are non-Hispanic White (83%); however, 10,076 (16%) were diagnosed at ages 18-49 years, 4208 (7%) are Hispanic, 3393 (5%) are Asian, and 2389 (4%) are Black. The median survival time is 14 years. Biospecimens are available on 98% of the cohort. CONCLUSIONS: The KPRB Cancer Cohort is designed to improve our understanding of treatment efficacy and factors that contribute to long-term cancer survival. The cohort's diversity - with respect to age, race/ethnicity and geographic location - will facilitate research on factors that contribute to cancer survival disparities.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are an important component of the tumour microenvironment. Recent studies revealed CAFs are heterogeneous and CAF subset(s) that suppress cancer progression (cancer-restraining CAFs [rCAFs]) must exist in addition to well-characterised cancer-promoting CAFs (pCAFs). However, the identity and specific markers of rCAFs are not yet reported. We recently identified Meflin as a specific marker of rCAFs in pancreatic and colon cancers. Our studies revealed that rCAFs may represent proliferating resident fibroblasts. Interestingly, a lineage tracing experiment showed Meflin-positive rCAFs differentiate into α-smooth muscle actin-positive and Meflin-negative CAFs, which are generally hypothesised as pCAFs, during cancer progression. Using a pharmacological approach, we identified AM80, a synthetic unnatural retinoid, as a reagent that effectively converts Meflin-negative pCAFs to Meflin-positive rCAFs. We aimed to investigate the efficacy of a combination of AM80 and gemcitabine (GEM) and nab-paclitaxel (nab-PTX) in patients with advanced pancreatic cancer. METHODS: The phase I part is a 3 + 3 design, open-label, and dose-finding study. The dose-limiting toxicity (DLT) of these combination therapies would be evaluated for 4 weeks. After the DLT evaluation period, if no disease progression is noted based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or if the patient has no intolerable toxicity, administration of AM80 with GEM and nab-PTX would be continued for up to 24 weeks. The phase II part is an open-label, single-arm study. The maximum tolerated dose (MTD) of AM80 with GEM and nab-PTX, determined in phase I, would be administered until intolerable toxicity or disease progression occurs, up to a maximum of 24 weeks, to confirm efficacy and safety. The primary endpoints are frequency of DLT and MTD of AM80 with GEM and nab-PTX in the phase I part and response rate based on the RECIST in the phase II part. Given the historical control data, we hope that the response rate will be over 23% in phase II. DISCUSSION: Strategies to convert pCAFs into rCAFs have been developed in recent years. We hypothesised that AM80 would be a promising enhancer of chemosensitivity and drug distribution through CAF conversion in the stroma. TRIAL REGISTRATION: Clinicaltrial.gov: NCT05064618 , registered on 1 October 2021. jRCT: jRCT2041210056 , registered on 27 August 2021.

PURPOSE: The purpose of the present study was to investigate risk factors for esophageal fistula (EF) in patients with recurrent esophageal cancer receiving re-radiotherapy with or without chemotherapy. METHODS: We reviewed retrospectively the clinical characters and dosimetric parameters of 96 patients with recurrent esophageal cancer treated with re-radiotherapy in Cancer Hospital Affiliated to Shandong First Medical University between August 2014 and January 2021.Univariate and multivariate logistic regression analyses were provided to determine the risk factors of EF induced by re-radiotherapy. RESULTS: The median time interval between two radiotherapy was 23.35 months (range, 4.30 to 238.10 months). EF occurred in 19 patients (19.79%). In univariate analysis, age, T stage, the biologically equivalent dose in the re-radiotherapy, total biologically equivalent dose, hyperfractionated radiotherapy, ulcerative esophageal cancer, the length of tumor and the maximum thickness of tumor had a correlation with the prevalence of EF. In addition, age (HR = 0.170, 95%CI 0.030-0.951, p = 0.044), T stage (HR = 8.369, 95%CI 1.729-40.522, p = 0.008), ulcerative esophageal cancer (HR = 5.810, 95%CI 1.316-25.650, p = 0.020) and the maximum thickness of tumor (HR = 1.314, 95%CI 1.098-1.572, p = 0.003) were risk factors of EF in multivariate logistic regression analysis. CONCLUSIONS: The incidence of EF was significantly increased in patients with recurrent esophageal cancer who underwent re-radiotherapy. This study revealed that age, T stage, ulcerative esophageal cancer and the maximum thickness of the tumor were risk factors associated with EF. In clinical work, patients with risk factors for EF ought to be highly concerned and individualized treatment plans should be taken to reduce the occurrence of EF.

OBJECTIVE: The aims of this study were to investigate the long-term outcomes of primary versus postoperative Gamma Knife radiosurgery (GKRS) for benign meningiomas. METHODS: Three hundred and forty meningioma patients underwent GKRS were retrospectively reviewed. Patients in the postoperative GKRS group were matched to those in the primary GKRS group, in a 1:1 ratio. RESULTS: The study consisted of 122 patients, including primary (n = 61) and postoperative (n = 61) GKRS group. Thirty-four patients (27.9%) occurred radiological progression after a median follow-up of 72.5 (range, 24.2-254.5) months. The median time to radiological progression was 85.1 (range, 20.7-205.1) months. The radiological progression-free survival (PFS) was 100%, 93%, 87%, and 49%, at 1, 3, 5, and 10 years respectively. Thirty-one patients (25.4%) occurred clinical progression. The clinical PFS was 92%, 89%, 84%, and 60%, at 1, 3, 5, and 10 years. In combined group, only max diameter ≥ 50 mm was associated with radiological (p = 0.020) and clinical PFS (hazard ratio [HR] = 2.896, 95% confidence interval [CI] = 1.280-6.553, p = 0.011). Twenty-five patients (20.5%) developed GKRS related adverse effects, including radiation-induced edema (n = 21). Non-skull base tumors (HR = 3.611, 95% CI = 1.489-8.760, p = 0.005) and preexisting peritumoral edema (HR = 3.571, 95% CI = 1.167-10.929, p = 0.026) were significantly related to radiation-induced edema in combined group. There was no significant difference in radiological PFS (p = 0.403), clinical PFS (p = 0.336), and GKRS related adverse effects (p = 0.138) between primary and postoperative GKRS groups. CONCLUSIONS: Primary GKRS could provide similar radiological and clinical outcomes, as well as similar complication rate compared with postoperative GKRS. For selective benign meningioma patients (asymptomatic or mildly symptomatic tumors; unfavorable locations for surgical resection; comorbidities or an advanced age), GKRS could be an alternative primary treatment.

PURPOSE: To evaluate the impact of different adjuvant therapy on IB1 and IIA1 stage cervical squamous cell cancer patients with lymphovascular space invasion. It also aimed to analyze the relationship between lymphovascular space invasion and other clinical pathological characteristics on IB1 and IIA1 stage cervical squamous cell cancer patients. METHODS: This retrospective observational study collected data of FIGO stages IB1 and IIA1 squamous cervical cancer patients at the First Affiliated Hospital of Chongqing Medical University between 2014 and 2018. A correlation analysis between lymphovascular space invasion and other clinical or pathological factors was conducted. Prognosis analysis of patients with lymphovascular space invasion were performed to assess associations between clinical-pathological characteristics and survival. RESULTS: A total of 357 women were identified including 110 (30.8%) with lymphovascular space invasion, 247 (69.2%) without lymphovascular space invasion. Both middle 1/3 cervical stromal invasion (p = 0.000) and deep 1/3 cervical stromal invasion (p = 0.000) were independently associated with lymphovascular space invasion. Among lymphovascular space involved women, tumor differentiation (P = 0.001) and postoperative therapy (P = 0.036) had a significant influence on disease recurrence. Multivariate analysis showed that lymph node metastasis (P = 0.017), poorer tumor differentiation (P = 0.036) and postoperative chemotherapy alone (P = 0.021) can increase the risk of tumor relapse. CONCLUSION: Our study suggested that the presence of deep stromal invasion independently increases the risk of lymphovascular space invasion. Compared with chemotherapy, chemoradiotherapy seems to improve progression-free survival in squamous cervical cancer patients with lymphovascular space invasion.

BACKGROUND: Lung cancer is a leading cause of cancer-related deaths in Uganda. In this study, we aimed to describe the baseline characteristics and survival of patients with lung cancer at the Uganda Cancer Institute (UCI). METHODS: We retrospectively reviewed medical records of all patients with a histological diagnosis of lung cancer registered at UCI between January 2008 and August 2018. Data on demographic, clinical, and treatment characteristics, and vital status were abstracted and analyzed. Patients with undocumented vital status on the medical records were contacted through phone calls. We determined survival as time from histological diagnosis to death. The Kaplan-Meier survival analysis was performed to estimate the median survival time and the 5-year overall survival rate. RESULTS: Of the 207 patients enrolled, 56.5% (n = 117) were female, median age was 60 years (range: 20-94), 78.7% (n = 163) were never-smokers and 18 (8.7%) were living with HIV. Presumptive anti-tuberculosis treatment was given to 23.2% (n = 48). Majority had non-small cell lung cancer (96.6%, n = 200) with 74.5% (n = 149) adenocarcinoma and 19% (n = 38) squamous cell carcinoma. All had advanced (stage III or IV) disease with 96.1% (n = 199) in stage IV. Chemotherapy (44.9%, n = 93) and biological therapy (34.8%, n = 72) were the commonest treatments used. Overall survival at 6 months, 1-, 2- and 5-years was 41.7, 29.7, 11.8, and 1.7%, respectively. The median survival time of 4.4 months was not statistically significantly different between participants with NSCLC or SCLC (4.5 versus 3.9 months, p = .335). CONCLUSION: In Uganda, adenocarcinoma is the predominant histologic subtype of lung cancer and patients are predominantly females, and non-smokers. Patients present late with advanced disease and poor overall survival. Public awareness should be heightened to facilitate early detection and improve outcomes.

Erratum in BMC Cancer. 2022 Mar 22;22(1):306.

BACKGROUND: Acute promyelocytic leukemia (APL) is considered a hematologic emergency due to high risk of bleeding and fatal hemorrhages being a major cause of death. Despite lower death rates reported from clinical trials, patient registry data suggest an early death rate of 20%, especially for elderly and frail patients. Therefore, reliable diagnosis is required as treatment with differentiation-inducing agents leads to cure in the majority of patients. However, diagnosis commonly relies on cytomorphology and genetic confirmation of the pathognomonic t(15;17). Yet, the latter is more time consuming and in some regions unavailable. METHODS: In recent years, deep learning (DL) has been evaluated for medical image recognition showing outstanding capabilities in analyzing large amounts of image data and provides reliable classification results. We developed a multi-stage DL platform that automatically reads images of bone marrow smears, accurately segments cells, and subsequently predicts APL using image data only. We retrospectively identified 51 APL patients from previous multicenter trials and compared them to 1048 non-APL acute myeloid leukemia (AML) patients and 236 healthy bone marrow donor samples, respectively. RESULTS: Our DL platform segments bone marrow cells with a mean average precision and a mean average recall of both 0.97. Further, it achieves high accuracy in detecting APL by distinguishing between APL and non-APL AML as well as APL and healthy donors with an area under the receiver operating characteristic of 0.8575 and 0.9585, respectively, using visual image data only. CONCLUSIONS: Our study underlines not only the feasibility of DL to detect distinct morphologies that accompany a cytogenetic aberration like t(15;17) in APL, but also shows the capability of DL to abstract information from a small medical data set, i. e. 51 APL patients, and infer correct predictions. This demonstrates the suitability of DL to assist in the diagnosis of rare cancer entities. As our DL platform predicts APL from bone marrow smear images alone, this may be used to diagnose APL in regions were molecular or cytogenetic subtyping is not routinely available and raise attention to suspected cases of APL for expert evaluation.

BACKGROUND: Breast cancer is a global health issue and a leading cause of death among women. Early detection through increased awareness and knowledge on breast cancer and breast cancer screening is thus crucial. The aim of the present study was to assess the effect of an educational intervention program on breast cancer knowledge and the practice of breast self-examination among young female students of a university in Bangladesh. METHODS: A quasi-experimental (pre-post) study design was conducted at Jahangirnagar University in Bangladesh. Educational information on breast cancer and breast self-examination (BSE), demonstration of BSE procedure and leaflets were distributed among 400 female students after obtaining written informed consent. The stepwise procedures of BSE performance were demonstrated with images. Pre-intervention and 15 days post-intervention assessments were conducted to assess the changes in knowledge on breast cancer and practices of BSE. Mc-Nemar's tests and paired sampled t-tests were performed to investigate the differences between pre- and post-test stages. RESULTS: A total of 400 female university students aged 18-26 years were included in the sample. Significant changes were found in knowledge and awareness about breast cancer and BSE practices after the educational intervention. The significant differences were measured in the mean scores of pre-test vs. post-test: breast cancer symptoms (2.99 ± 1.05 vs. 6.35 ± 1.15; p < 0.001), risk factors (3.35 ± 1.19 vs. 7.56 ± 1.04; p < 0.001), treatment (1.79 ± 0.90 vs. 4.63 ± 0.84; p < 0.001), prevention (3.82 ± 1.32 vs. 7.14 ± 1.03; p < 0.001), screening of breast cancer (1.82 ± 0.55 vs. 3.98 ± 0.71; p < 0.001) and process of BSE (1.57 ± 1.86 vs. 3.94 ± 0.93; p < 0.001). Likewise, a significant percentage of change in BSE practices was obtained between pre-test and post-test (21.3% vs. 33.8%; p < 0.001). CONCLUSIONS: Study findings confirm that the study population had inadequate awareness and knowledge at baseline which was improved significantly after educational intervention. A nationwide roll-out with community-based interventions is recommended for the female population in both rural and urban areas.

BACKGROUND: Several investigations have reported diverse roles of long non-coding RNA (lncRNA) in biological processes, tumor development, and progression of colorectal cancer (CRC). In this study, we investigated the lncRNA AC087388.1 tumorigenic role in CRC cells. METHODS: The CRC tissues were collected at the Reza Radiotherapy and Oncology Center, Mashhad, Iran. The human SW-48 and HT-29 CRC cell lines were obtained from the national cell bank of Iran. The cells were cultured according to ATCC (the American Type Culture Collection) recommendations. Quantitative real-time PCR was applied to assess the RNA expression. ShRNA transfection was done to downregulate the target gene. MTT and apoptosis assays were conducted to evaluate cell proliferation and viability, respectively. Colony formation assay, wound healing assay, and invasion assay were applied to determine growth, motility, and invasion of the cells, respectively. ENCORI online tool was used as downstream enrichment analysis. RESULTS: Forty CRC patients were encompassed in this study. The results demonstrated that the lncRNA SLC16A1-AS1, AC087388.1, and ELFN1-AS1 were significantly overexpressed in the CRC tissues in comparison to their normal counterpart margins. All the lncRNAs have shown significant Area Under Curve (AUC) values in the patients. Downregulation of lncRNA AC087388.1 remarkably decreased the cell proliferation and viability of the CRC cells. In addition, the data demonstrated that the downregulation of lncRNA AC087388.1 significantly suppressed cell growth and colony formation capability in the cells. Also, downregulation of lncRNA AC087388.1 attenuated motility and invasion of CRC cells, and significantly decreased the expression of invasion genes. In-silico functional enrichment analysis indicated that the lncRNA AC087388.1 has contributed to crucial signaling pathways in tumorigenesis such as the p53 and Wnt signaling pathways, apoptosis, and cell cycle. CONCLUSIONS: Altogether, we showed that lncRNA AC087388.1 has an oncogenic role in tumorigenesis of CRC, and it can be considered as a novel diagnostic and prognostic biomarker in CRC.

BACKGROUND: DNA polymerase delta 1 catalytic subunit (POLD1) plays a key role in DNA replication and damage repair. A defective DNA proofreading function caused by POLD1 mutation contributes to carcinogenesis, while POLD1 overexpression predicts poor prognosis in cancers. However, the effect of POLD1 in hepatocellular carcinoma (HCC) is not well-understood. METHODS: Expression patterns of POLD1 were evaluated in TCGA and the HPA databases. Kaplan-Meier curves and Cox regression were used to examine the prognostic value of POLD1. The prognostic and predictive value of POLD1 was further validated by another independent cohort from ICGC database. The influences of DNA copy number variation, methylation and miRNA on POLD1 mRNA expression were examined. The correlation between infiltrating immune cells and POLD1 expression was analyzed. GO and KEGG enrichment analyses were performed to detect biological pathways associated with POLD1 expression in HCC. RESULTS: POLD1 was overexpressed in HCC (n = 369) compared with adjacent normal liver (n = 50). POLD1 upregulation was significantly correlated with positive serum AFP and advanced TNM stage. Kaplan-Meier and multivariate analyses suggested that POLD1 overexpression predicts poor prognosis in HCC. DNA copy gain, low POLD1 methylation, and miR‑139-3p downregulation were associated with POLD1 overexpression. Besides, POLD1 expression was associated with the infiltration levels of dendritic cell, macrophage, B cell, and CD4 + T cell in HCC. Functional enrichment analysis suggested "DNA replication", "mismatch repair" and "cell cycle" pathways might be involved in the effect of POLD1 on HCC pathogenesis. Additionally, POLD1 mRNA expression was significantly associated with tumor mutation burden, microsatellite instability, and prognosis in various tumors. CONCLUSIONS: POLD1 may be a potential prognostic marker and promising therapeutic target in HCC.

BACKGROUND: Cervical cancer is frequently detected gynecological cancer all over the world. This study was designed to develop a prognostic signature for an effective prediction of cervical cancer prognosis. METHODS: Differentially expressed genes (DEGs) were identified based on copy number variation (CNV) data and expression profiles from different databases. A prognostic model was constructed and further optimized by stepwise Akaike information criterion (stepAIC). The model was then evaluated in three groups (training group, test group and validation group). Functional analysis and immune analysis were used to assess the difference between high-risk and low-risk groups. RESULTS: The study developed a 5-gene prognostic model that could accurately classify cervical cancer samples into high-risk and low-risk groups with distinctly different prognosis. Low-risk group exhibited more favorable prognosis and higher immune infiltration than high-risk group. Both univariate and multivariate Cox regression analysis showed that the risk score was an independent risk factor for cervical cancer. CONCLUSIONS: The 5-gene prognostic signature could serve as a predictor for identifying high-risk cervical cancer patients, and provided potential direction for studying the mechanism or drug targets of cervical cancer. The integrated analysis of CNV and mRNA expanded a new perspective for exploring prognostic signatures in cervical cancer.

BACKGROUND: Lung cancer is among the major diseases threatening human health. Although the immune response plays an important role in tumor development, its exact mechanisms are unclear. MATERIALS AND METHODS: Here, we used CIBERSORT and ESTIMATE algorithms to determine the proportion of tumor-infiltrating immune cells (TICs) as well as the number of immune and mesenchymal components from the data of 474 lung cancer patients from the Gene Expression Omnibus database. And we used data from The Cancer Genome Atlas database (TCGA) for validation. RESULTS: We observed that immune, stromal, and assessment scores were only somewhat related to survival with no statistically significant differences. Further investigations revealed these scores to be associated with different pathology types. GO and KEGG analyses of differentially expressed genes revealed that they were strongly associated with immunity in lung cancer. In order to determine whether the signaling pathways identified by GO and KEGG signaling pathway enrichment analyses were up- or down-regulated, we performed a gene set enrichment analysis using the entire matrix of differentially expressed genes. We found that signaling pathways involved in hallmark allograft rejection, hallmark apical junction, hallmark interferon gamma response, the hallmark P53 pathway, and the hallmark TNF-α signaling via NF-ĸB were up-regulated in the high-ESTIMATE-score group. CIBERSORT analysis for the proportion of TICs revealed that different immune cells were positively correlated with the ESTIMATE score. Cox regression analysis of the differentially expressed genes revealed that CPA3, C15orf48, FCGR1B, and GNG4 were associated with patient prognosis. A prognostic model was constructed wherein patients with high-risk scores had a worse prognosis (p < 0.001 using the log-rank test). The Area Under Curve (AUC)value for the risk model in predicting the survival was 0.666. The validation set C index was 0.631 (95% CI: 0.580-0.652). The AUC for the risk formula in the validation set was 0.560 that confirmed predictivity of the signature. CONCLUSION: We found that immune-related gene expression models could predict patient prognosis. Moreover, high- and low-ESTIMATE-score groups had different types of immune cell infiltration.

BACKGROUND: In selected patients with bladder cancer, partial cystectomy is an alternative treatment for bladder preservation with fair oncologic result. During partial cystectomy, tumor margin demarcation is difficult. Various methods were adopted, however, there is no standard for tumor margin demarcation. We aimed to introduce and provide our experience with holmium laser-assisted method with ten patients. METHODS: From March 2016 and February 2019, patients who want partial cystectomy for bladder cancer were enrolled in this study. Inclusion criteria were stage T2 or T3 disease and tumor location restricted within the dome, and lateral, posterior side of the bladder were included. Transurethral holmium laser-assisted mucosal incision was made and deepened until perivesical fat. Minimal Safety margin for 5-10 mm were spared, and tumor removal was done laparoscopically. RESULTS: Ten patients underwent holmium laser-assisted laparoscopic partial cystectomy. All procedures were done without complication. The tumor locations were laterally in seven patients, dome in two patients, and posterior wall in one patient. Pathologic examination of surgical margin showed no cancer cell involvement in all cases. There were no recurrences or metastases for 12 months follow up. CONCLUSIONS: Holmium laser-assisted laparoscopic partial cystectomy is effective and safe technique in carefully selected patients. To achieve precise and appropriate surgical margin during the laparoscopic partial cystectomy, holmium laser resection provides feasible and safe method that assists in bladder incision with minimal ureteral orifice involvement. TRIAL REGISTRATION: Retrospectively registered.

BACKGROUND: The clinical features, survival outcomes and patterns of treatment failure of advanced non-small cell lung cancer (NSCLC) patients harboring distinct subtypes of EGFR mutations and receiving first-line EGFR tyrosine kinases inhibitor (TKIs) are not fully understood. METHODS: Consecutive metastatic EGFR-mutant NSCLC patients receiving first-line EGFR-TKIs from October 2010 to March 2020 were enrolled and classified into two main groups based on the EGFR mutation subtypes: common mutation (L858R or exon 19 deletion), uncommon mutation (other EGFR mutations). RESULTS: Of the 1081 patients included, 74 (6.8%) harbored uncommon mutations. The baseline characteristics were generally balanced between the two groups, except that bone metastasis developed less frequently in patients with uncommon mutations (p = 0.02). No significant difference of survival outcomes was found between the two groups, except that among patients with baseline brain metastasis, the intracranial time to progression was significantly shorter in patients with uncommon mutations. Nine of the 17 patients with de novo T790M mutation received Osimertinib, whose overall survival tended to be longer than the remaining 8 patients without Osimertinib treatment (p = 0.08). The patterns of treatment failure were generally consistent between the two groups, except which patients with uncommon mutations had a higher risk developing progressive disease in the brain. CONCLUSION: First-line EGFR-TKIs seemed to be less effective in controlling and preventing brain metastasis in patients with uncommon EGFR mutations and Osimertinib was associated with promising efficacy in patients with de novo T790M mutation, which warranted further validation.

BACKGROUND: The malignant pleural mesothelioma (MPM) response rate to chemotherapy is low. The identification of imaging biomarkers that could help guide the most effective therapy approach for individual patients is highly desirable. Our aim was to investigate the dynamic contrast-enhanced (DCE) MR parameters as predictors for progression-free (PFS) and overall survival (OS) in patients with MPM treated with cisplatin-based chemotherapy. METHODS: Thirty-two consecutive patients with MPM were enrolled in this prospective study. Pretreatment and intratreatment DCE-MRI were scheduled in each patient. The DCE parameters were analyzed using the extended Tofts (ET) and the adiabatic approximation tissue homogeneity (AATH) model. Comparison analysis, logistic regression and ROC analysis were used to identify the predictors for the patient's outcome. RESULTS: Patients with higher pretreatment ET and AATH-calculated Ktrans and ve values had longer OS (P≤.006). Patients with a more prominent reduction in ET-calculated Ktrans and kep values during the early phase of chemotherapy had longer PFS (P =.008). No parameter was identified to predict PFS. Pre-treatment ET-calculated Ktrans was found to be an independent predictive marker for longer OS (P=.02) demonstrating the most favourable discrimination performance compared to other DCE parameters with an estimated sensitivity of 89% and specificity of 78% (AUC 0.9, 95% CI 0.74-0.98, cut off > 0.08 min-1). CONCLUSIONS: In the present study, higher pre-treatment ET-calculated Ktrans values were associated with longer OS. The results suggest that DCE-MRI might provide additional information for identifying MPM patients that may respond to chemotherapy.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a specific subtype of non-Hodgkin lymphoma that is highly invasive and confined to the central nervous system (CNS). The vast majority of PCNSLs are diffuse large B-cell lymphomas (DLBCLs). PCNSL is a highly heterogeneous disease, and its pathogenesis has not yet been fully elucidated. Further studies are needed to guide individualized therapy and improve the prognosis. METHODS: In this study, we detected 1) the expression of p-AKT, p-mTOR, p-S6 and p-4E-BP1 by immunohistochemistry (IHC) and Western blotting, 2) the mRNA expression by real-time qPCR and 3) the deletion of PTEN gene by immunofluorescence in situ hybridization (FISH) in order to investigate the activation status of the PI3K/AKT/mTOR signaling pathway in PCNSL. Samples of reactive hyperplasia lymphnods were used as the control group. The correlations between the clinical characteristics and prognosis of PCNSL patients and the expression of p-AKT, p-mTOR, p-S6 and p-4E-BP1 and the deletion of PTEN were assessed. RESULTS: The IHC results showed that the positive expression rates of p-AKT, p-mTOR, p-S6 and p-4E-BP1 in PCNSL were significantly higher in the PCNSL group than in the control group (P < 0.05). The relative mRNA expression level of MTOR in PCNSL samples was significantly increased (P = 0.013). Correlation analysis revealed that the expression of p-mTOR was correlated with that of p-AKT, p-S6, p-4E-BP1. PTEN deletion was found in 18.9% of PCNSL samples and was correlated with the expression of p-AKT (P = 0.031). Correlation analysis revealed that the PCNSL relapse rate in the p-mTOR-positive group was 64.5%, significantly higher than that in the negative group (P = 0.001). Kaplan-Meier survival analysis showed inferior progression-free survival (PFS) in the p-mTOR- and p-S6-positive groups (P = 0.002 and 0.009, respectively), and PTEN deletion tended to be related to shorter overall survival (OS) (P = 0.072). Cox regression analysis revealed p-mTOR expression as an independent prognostic factor for a shorter PFS (hazard ratio (HR) =7.849, P = 0.046). CONCLUSIONS: Our results suggest that the PI3K/AKT/mTOR signaling pathway is aberrantly activated in PCNSL and associated with a poor prognosis, which might indicate new therapeutic targets and prognostic factors.

BACKGROUND: Following sentinel lymph node biopsy (SLNB), the axillary recurrence rate is very low although SLNB has a false-negative rate of 5-10%. In the ACOSOG Z0011 trial, non-sentinel positive-lymph nodes were found in more than 20% of the axillary dissection group; the SLNB only group did not have a higher axillary recurrence rate. These findings raised questions about the direct therapeutic effect of the SLNB. SLNB has post-surgical complications including lymphedema. Considering advances in imaging modalities and adjuvant therapies, the role of SLNB in early breast cancer needs to be re-evaluated. METHODS: The NAUTILUS trial is a prospective multicenter randomized controlled trial involving clinical stage T1-2 and N0 breast cancer patients receiving breast-conserving surgery. Axillary ultrasound is mandatory before surgery with predefined imaging criteria for inclusion. Ultrasound-guided core needle biopsy or needle aspiration of a suspicious node is allowed. Patients will be randomized (1:1) into the no-SLNB (test) and SLNB (control) groups. A total of 1734 patients are needed, considering a 5% non-inferiority margin, 5% significance level, 80% statistical power, and 10% dropout rate. All patients in the two groups will receive ipsilateral whole-breast radiation according to a predefined protocol. The primary endpoint of this trial is the 5-year invasive disease-free survival. The secondary endpoints are overall survival, distant metastasis-free survival, axillary recurrence rate, and quality of life of the patients. DISCUSSION: This trial will provide important evidence on the oncological safety of the omission of SLNB for early breast cancer patients undergoing breast-conserving surgery and receiving whole-breast radiation, especially when the axillary lymph node is not suspicious during preoperative axillary ultrasound. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04303715 . Registered on March 11, 2020.

BACKGROUND: The World Health Organization recommends thermal ablation as an alternative to cryotherapy to treat women with precancerous lesions in low-resource settings. However, limited data are available on women's experience and adverse events (AEs) of the procedure in the context of Sub-Saharan Africa. The objective of this study was to evaluate the acceptability and safety of thermal ablation in women screened positive for precancerous cervical lesions. METHODS: Asymptomatic women aged 30-49 years old living in the Dschang Health District were invited to participate in a cervical cancer screening campaign termed "3 T-Approach" (for Test-Triage and Treat). Recruited women were asked to perform HPV self-sampling followed by triage with visual assessment and treatment with thermal ablation if required. After treatment and 4-6 weeks later, interviews were conducted to assess women's experience on anxiety, discomfort, and pain during thermal ablation. AEs were recorded on pre-defined electronic forms 4-6 weeks after treatment to assess the procedure's safety. RESULTS: Between September 2018 and December 2020, 399 HPV-positive women (18.7% of women screened) were recruited, 236 (59.1%) had a positive visual assessment, 234 were treated by thermal ablation and 198 (84.6%) received therapy in the same visit. Treatment was not considered as painful (score ≤ 4/10) by 209 (90.9%) patients while 5 (2.5%) reported high pain (score 8-10/10). During post-treatment interviews 4-6 weeks later, most reported AEs were graded mild or moderate (grade I-II). The most frequent symptoms reported as mild AEs (grade 1-2) were vaginal watery discharge (75.5%), vaginal bloody-stained discharge (21.5%) and malodourous discharge (14.5%). None of the participants experienced serious AEs (grade 3-4) or AEs requiring admission to hospital or emergency consultation. The vast majority of women (99.6%) would agree to repeat the procedure if necessary and (99.6%) would recommend it to friends or family. CONCLUSION: Thermal ablation is widely accepted by women and appears as a safe procedure. It may contribute to improving the link between screening and treatment in a single visit and to optimizing cervical cancer control in low-resource settings. TRIAL REGISTRATION: The study was registered on clinicaltrials.gov ( NCT03757299 ) in November 2018 (28/11/2018).

BACKGROUND: This study aimed to clarify predictors of depressive symptoms and anxiety symptoms after cancer diagnosis among Japanese cancer survivors (CSs). METHODS: As part of a Japanese cancer survivorship research project commissioned by the Ministry of Health, Labour and Welfare (MHLW) of Japan, we conducted a web-based nationwide survey of CSs in 2018. We analyzed the risk factors for depressive and anxiety symptoms, as measured by the Hospital Anxiety and Depression Scale Japanese version (HADS). RESULTS: Of 1,234 Japanese CSs, mean score of HADS-depression and HADS-anxiety were 4.08 and 4.78, respectively. At the time of the study, the number of CSs with symptoms of depression and anxiety were 111 (9.0%) and 269 (21.8%), respectively. After multivariable analysis, CSs ≥ 60 years old (reference: ≤ 39 years old, odds ratios (OR): 0.39, 95%CI: 0.17-0.90) and those ≥ 10 years from cancer diagnosis (reference: 0-4 years, OR: 0.55, 95%CI: 0.32-0.96) had lower odds for depressive symptoms. And CSs ≥ 60 years old (reference: ≤ 39 years old, OR: 0.27, 95%CI: 0.15-0.49) and those ≥ 10 years from cancer diagnosis (reference: 0-4 years, OR: 0.62, 95%CI: 0.42-0.90) also had lower odds for anxiety symptoms. CSs who received chemotherapy (OR: 1.56, 95%CI: 1.10-2.20) had higher odds for anxiety symptoms. CONCLUSIONS: Based on manifestation of symptoms, CSs who were younger, closer to the time of cancer diagnosis, had advanced-staged cancer, or received chemotherapy may be at higher risk for depressive or anxiety symptoms. Those CSs who have higher risk for depression and anxiety symptoms, should be followed-up more carefully for better cancer survivorship, by medical professionals, companies, and society.

BACKGROUND: Gonadotropin-releasing hormone (GnRH) receptor, a rhodopsin-like G-protein coupled receptor (GPCR) family member involved in GnRH signaling, is reported to be expressed in several tumors including glioblastoma multiforme (GBM), one of the most malignant and aggressive forms of primary brain tumors. However, the molecular targets associated with GnRH receptor are not well studied in GBM or in other cancers. The present study aims at investigating the effect of GnRH agonist (Gosarelin acetate) on cell proliferation and associated signaling pathways in GBM cell line, LN229. METHODS: LN229 cells were treated with different concentrations of GnRH agonist (10-10 M to 10-5 M) and the effect on cell proliferation was analyzed by cell count method. Further, total protein was extracted from control and GnRH agonist treated cells (with maximum reduction in cell proliferation) followed by trypsin digestion, labeling with iTRAQ reagents and LC-MS/MS analysis to identify differentially expressed proteins. Bioinformatic analysis was performed for annotation of proteins for the associated molecular function, altered pathways and network analysis using STRING database. RESULTS: The treatment with different concentrations of GnRH agonist showed a reduction in cell proliferation with a maximum reduction of 48.2% observed at 10-6 M. Quantitative proteomic analysis after GnRH agonist treatment (10-6 M) led to the identification of a total of 29 differentially expressed proteins with 1.3-fold change (23 upregulated, such as, kininogen-1 (KNG1), alpha-2-HS-glycoprotein (AHSG), alpha-fetoprotein (AFP), and 6 downregulated, such as integrator complex subunit 11 (CPSF3L), protein FRG1 (FRG1). Some of them are known [KNG1, AHSG, AFP] while others such as inter-alpha-trypsin inhibitor heavy chain H2 (ITIH2), ITIH4, and LIM domain-containing protein 1 (LIMD1) are novel to GnRH signaling pathway. Protein-protein interaction analysis showed a direct interaction of KNG1, a hub molecule, with GnRH, GnRH receptor, EGFR and other interactors including ITIH2, ITIH4 and AHSG. Overexpression of KNG1 after GnRH agonist treatment was validated using Western blot analysis, while a significant inhibition of EGFR was observed after GnRH agonist treatment. CONCLUSIONS: The study suggests a possible link of GnRH signaling with EGFR signaling pathways likely via KNG1. KNG1 inhibitors may be investigated independently or in combination with GnRH agonist for therapeutic applications.

BACKGROUND: We aimed to explore the potential of German claims data for describing initial and long-term treatment patterns of breast cancer patients undergoing surgery. METHODS: Using the German Pharmacoepidemiological Research Database (GePaRD, ~ 20% of the German population) we included patients with invasive breast cancer diagnosed in 2008 undergoing breast surgery and followed them until 2017. We described initial and long-term treatment patterns and deaths. Analyses were stratified by stage (as far as available in claims data), age at diagnosis, and mode of detection (screen-detected vs. interval vs. unscreened cases). RESULTS: The cohort comprised 10,802 patients. The proportion with neoadjuvant therapy was highest in patients < 50 years (19% vs. ≤ 8% at older ages). The proportion initiating adjuvant chemotherapy within four months after diagnosis decreased with age (< 50 years: 63%, 50-69: 46%, 70-79: 27%, 80 + : 4%). Among women < 69 years, ~ 30% had two breast surgeries in year one (70-79: 21%, 80 + : 14%). Treatment intensity was lower for screen-detected compared to interval or unscreened cases, both in year one (e.g., proportion with mastectomy ~ 50% lower) and within 2-10 years after surgery (proportions with radiotherapy or chemotherapy about one third lower each). CONCLUSIONS: This study illustrates the potential of routine data to describe breast cancer treatment and provided important insights into differences in initial and long-term treatment by mode of detection and age.

BACKGROUND: The response to neoadjuvant cisplatin-based chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC) is impaired in up to 50% of patients due to chemoresistance, with no predictive biomarkers in clinical use. The proto-oncogene RNA-binding motif protein 3 (RBM3) has emerged as a putative modulator of chemotherapy response in several solid tumours but has a hitherto unrecognized role in MIBC. METHODS: RBM3 protein expression level in tumour cells was assessed via immunohistochemistry in paired transurethral resection of the bladder (TURB) specimens, cystectomy specimens and lymph node metastases from a consecutive cohort of 145 patients, 65 of whom were treated with NAC. Kaplan-Meier and Cox regression analyses were applied to estimate the impact of RBM3 expression on time to recurrence (TTR), cancer-specific survival (CSS), and overall survival (OS) in strata according to NAC treatment. The effect of siRNA-mediated silencing of RBM3 on chemosensitivity was examined in RT4 and T24 human bladder carcinoma cells in vitro. Cellular functions of RBM3 were assessed using RNA-sequencing and gene ontology analysis, followed by investigation of cell cycle distribution using flow cytometry. RESULTS: RBM3 protein expression was significantly higher in TURB compared to cystectomy specimens but showed consistency between primary tumours and lymph node metastases. Patients with high-tumour specific RBM3 expression treated with NAC had a significantly reduced risk of recurrence and a prolonged CSS and OS compared to NAC-untreated patients. In high-grade T24 carcinoma cells, which expressed higher RBM3 mRNA levels compared to RT4 cells, RBM3 silencing conferred a decreased sensitivity to cisplatin and gemcitabine. Transcriptomic analysis revealed potential involvement of RBM3 in facilitating cell cycle progression, in particular G1/S-phase transition, and initiation of DNA replication. Furthermore, siRBM3-transfected T24 cells displayed an accumulation of cells residing in the G1-phase as well as altered levels of recognised regulators of G1-phase progression, including Cyclin D1/CDK4 and CDK2. CONCLUSIONS: The presented data highlight the potential value of RBM3 as a predictive biomarker of chemotherapy response in MIBC, which could, if prospectively validated, improve treatment stratification of patients with this aggressive disease.

BACKGROUND: Accumulating evidence indicates that long non-coding RNAs (lncRNAs) are involving in the tumorigenesis and metastasis of lung cancer. The aim of the study is to systematically characterize the lncRNA-associated competing endogenous RNA (ceRNA) network and identify key lncRNAs in the development of stage I lung adenocarcinoma (LUAD). METHODS: Totally, 1,955 DEmRNAs, 165 DEmiRNAs and 1,107 DElncRNAs were obtained in 10 paired normal and LUAD tissues. And a total of 8,912 paired lncRNA-miRNA-mRNA network was constructed. Using the Cancer Genome Atlas (TCGA) dataset, the module of ME turquoise was revealed to be most relevant to the progression of LUAD though Weighted Gene Co-expression Network Analysis (WGCNA). RESULTS: Of the lncRNAs identified, LINC00639, RP4-676L2.1 and FENDRR were in ceRNA network established by our RNA-sequencing dataset. Using univariate Cox regression analysis, FENDRR was a risk factor of progression free survival (PFS) of stage I LUAD patients (HRs = 1.69, 95%CI 1.07-2.68, P < .050). Subsequently, diffe rential expression of FENDRR in paired normal and LUAD tissues was detected significant by real-time quantitative (qRT-PCR) (P < 0.001). CONCLUSIONS: This study, for the first time, deciphered the regulatory role of FENDRR/miR-6815-5p axis in the progression of early-stage LUAD, which is needed to be established in vitro and in vivo.

BACKGROUND: Emerging cell- or tissue-based evidence has demonstrated that opsin 3 (OPN3) mediates a variety of pathological processes affecting tumorigenesis, clinical prognosis, and treatment resistance in some cancers. However, a comprehensive analysis of OPN3 across human cancers is unavailable. Therefore, a pancancer analysis of OPN3 expression was performed and its potential oncogenic roles were explored. METHODS: The expression and characterization of OPN3 were evaluated among 33 tumour types using The Cancer Genome Atlas (TCGA) dataset. Additionally, the OPN3 RNA level and overall survival (OS) in relation to its expression level in 33 cancer types were estimated. Based on the analysis above, 347 samples from 5 types of tumours were collected and detected for the protein expression of OPN3 by immunohistochemical assay. Furthermore, the biological role of OPN3 in cancers was evaluated via gene set enrichment analysis (GSEA). RESULTS: The OPN3 expression level was heterogeneous across cancers, yet a remarkable difference existed between OPN3 expression and patient overall survival among the 7 types of these 33 cancers. Consistently, a high immunohistochemical score of OPN3 was significantly associated with a poor prognosis among patients with 5 types of tumours. Additionally, OPN3 expression was involved in cancer-associated fibroblast infiltration in 5 types of tumours, and promoter hypomethylation of OPN3 was observed in 3 tumour types. Additionally, OPN3 protein phosphorylation sites of Tyr140 and Ser380 were identified via posttranscriptional modification analysis, suggesting the potential function of Tyr140 and Ser380 phosphorylation in tumorigenesis. Furthermore, the enrichment analysis was mainly concentrated in C7orf70, C7orf25 and the "ribosome" pathway by GSEA in 5 types of cancers, indicating that OPN3 might affect tumorigenesis and progression by regulating gene expression and ribosome biogenesis. CONCLUSIONS: High expression of OPN3 was significantly associated with a poor clinical prognosis in five types of cancers. Its molecular function was closely associated with the ribosomal pathway.

BACKGROUND: S100A1 expression is deregulated in a variety of human malignancies, but its role in normal and malignant endometrial cells is unclear. METHODS: We used endometrial carcinoma (Em Ca) cell lines to evaluate the physical and functional interaction of S100A1 with p53 and its negative regulator, mouse double minute 2 (MDM2). We also evaluated the expression of S100A1, p53, and MDM2 in clinical samples consisting of 89 normal endometrial and 189 Em Ca tissues. RESULTS: S100A1 interacted with MDM2 but not p53 in Em Ca cell lines. Treatment of cells stably overexpressing S100A1 with Nutlin-3A, an inhibitor of the p53/MDM2 interaction, increased expression of p53-target genes including p21waf1 and BAX. S100A1 overexpression enhanced cellular migration, but also sensitized cells to the antiproliferative and proapoptotic effects of Adriamycin, a genotoxic agent; these phenotypes were abrogated when S100A1 was knocked down using shRNA. In clinical samples from normal endometrium, S100A1 expression was significantly higher in endometrial glandular cells of the middle/late secretory and menstrual stages when compared to cells in the proliferative phases; high S100A1 was also positively correlated with expression of MDM2 and p21waf1 and apoptotic status, and inversely correlated with Ki-67 scores. However, such correlations were absent in Em Ca tissues. CONCLUSION: The interaction between S100A1 and MDM2 may modulate proliferation, susceptibility to apoptosis, and migration through alterations in p53 signaling in normal- but not malignant-endometrial cells.

BACKGROUND: Many breast, colorectal, and cervical cancer screening programs were disrupted due to the COVID-19 pandemic. This study aimed to estimate the short-term impact of the temporary shutdown (from March until May- June) of the cancer screening programs invitations in Flanders (Belgium) by looking at invitation coverage, percentage of people screened after invitation and the screening interval. METHODS: Yearly invitation coverage was calculated as the number of people who received an invitation, as a proportion of the people who should have received an invitation that year. Weekly response to the invitation was calculated as the number of people who were screened within 40 days of their date of invitation, as a percentage of the people who received an invitation that week (as a proxy for willingness to screen). Weekly screening interval was calculated as the mean number of months between the current screening and the previous screening of all the people who screened that week. The two last indicators were calculated for each week in 2019 and 2020, after which the difference between that week's value in 2020 and 2019 with 95% confidence intervals. Results of these two indicators were also analysed after stratification for gender, age and participation history. RESULTS: Invitation coverage was not impacted in the colorectal and cervical cancer screening program. In the breast cancer screening program invitation coverage went down from 97.5% (2019) to 88.7% (2020), and the backlog of invitations was largely resolved in the first six months of 2021. The willingness to screen was minimally influenced by COVID-19. The breast cancer screening program had a temporary increase in screening interval in the first months following the restart after COVID-19 related shutdown, when it was on average 2.1 months longer than in 2019. CONCLUSIONS: Willingness to screen was minimally influenced by COVID-19, but there may be an influence on screening coverage because of lower invitation coverage, mainly for the for breast Cancer Screening Program. The increases in screening intervals for the three Cancer Screening Program seem reasonable and would probably not significantly increase the risk of delayed screening cancer diagnoses. When restarting a Cancer Screening Program after a COVID-19 related shutdown, monitoring is crucial.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the major subtype of pancreatic cancer and head PDACs show distinct characteristics from body/tail PDACs. With limited studies based on Asian population, the mutational landscape of Asian PDAC remains unclear. METHODS: One hundred fifty-one Chinese patients with head PDAC were selected and underwent targeted 425-gene sequencing. Genomic alterations, tumor mutational burden, and microsatellite instability were analyzed and compared with a TCGA cohort. RESULTS: The genomic landscape of Chinese and Western head PDAC had identical frequently-mutated genes including KRAS, TP53, SMAD4, and CDKN2A. KRAS hotspot in both cohorts was codon 12 but Chinese PDACs containing more G12V but fewer G12R variants. Potentially pathogenic fusions, CHD2-BRAF and KANK1-MET were identified in two KRAS wild-type patients. Serum cancer antigens CA125 and CA19-9 were positively associated with SMAD4 alterations while high CEA was enriched in wild-type CDKN2A subgroup. The probability of vascular invasion was lower in patients with RNF43 alterations. The nomogram developed including histology grade, the mutation status of SMAD4, TGFBR2, and PREX2 could calculate the risk score of prognoses validated by Chinese and TCGA cohort. CONCLUSIONS: Chinese head PDAC contained more KRAS G12V mutation than Western population. The well-performed nomogram may improve post-operation care in real-world practice.

BACKGROUND: The number of young patients with hepatocellular carcinoma (HCC) is increasing, but whether patients of different ages have a survival advantage is unclear. This study was conducted to investigate whether age differences in the Barcelona Clinic Liver Cancer (BCLC) classification system contribute to the long-term survival outcomes of patients with HCC. METHODS: A total of 1602 patients with HCC admitted to the Beijing Ditan Hospital was included in this study. Patients were divided into younger (≤45 years) and older (> 45 years) groups. Factors determining overall survival and progression-free survival were analyzed using univariate and multivariate analyses with the Kaplan-Meier method and Cox proportional hazard regression model. We calculated the cumulative incidence function using the Fine-Gray model. The effect of mortality on age was also estimated using a restricted cubic spline. RESULTS: After matching, overall survival and progression-free survival were significantly better in younger patients than in older patients with BCLC stage 0-B (p = 0.015 and p = 0.017, respectively). In BCLC stage 0-B, all-cause mortality increased with age and increased rapidly around the age of 40 years (non-linear, p < 0.05). In BCLC stages 0-B, HCC-related and non-HCC-related deaths significantly differed between younger and older individuals (p = 0.0019). CONCLUSION: In stage BCLC 0-B, age affects the long-term prognosis of patients.

BACKGROUND: Radiation-induced brainstem necrosis (RIBN) is a late life-threatening complication that can appear after treatment in patients with nasopharyngeal carcinoma (NPC). However, the relationship between RIBN and radiation dose is not still well-defined. METHODS: During January 2013 and December 2017, a total of 1063 patients with NPC were treated at Sichuan cancer hospital with IMRT. A total of 479 patients were eligible for dosimetric analysis. Dosimetric parameters of the RIBN, Dmax(the maximum dose), D0.1c (maximum average dose delivered to a 0.1-cc volume), D1cc, D2cc, D3cc, D5cc, D10cc and Dmean (mean does) were evaluated and recorded. ROC curve was used to analyze the area under curve (AUC) and cutoff points. Logistic regression for screening dose-volume parameter and logistic dose response model were used to predict the incidence of brainstem necrosis. RESULTS: Among the 479 patients with NPC, 6 patients were diagnosed with RIBN, the incidence of RIBN was 1.25% (6/479), and the median time to RIBN after treatment was 28.5 months (range 18-48 months). The dose of the brainstem in patients with RIBN were higher than that in patients without necrosis. ROC curve showed that the area under the curve (AUC) of Dmax was the largest (0.987). Moreover, logistic stepwise regression indicated that Dmax was the most important dose factor. The RIBN incidence at 5% over 5 years (TD5/5) and 50% incidence over 5 years (TD50/5) was 69.59 Gy and76.45 Gy, respectively. CONCLUSIONS: Brainstem necrosis is associated with high dose irritation. Dmax is the most significant predictive dosimetric factor for RIBN. Dmax of brainstem should be considered as the dose limitation parameter. We suggest that the limitation dose for brainstem was Dmax < 69.59 Gy.

BACKGROUND: Kruppel-like factor 4 (KLF4) is a zinc finger-containing transcription factor predominantly expressed in terminally differentiated epithelial tissues. Many studies have shown that KLF4 has various mechanisms in different tumours; however, the prognostic role of KLF4 remains unclear. METHODS AND RESULTS: We searched the relevant literature that evaluated the prognostic value of KLF4 in different cancers, and the original survival data were obtained from the text, tables or Kaplan-Meier curves for both comparative groups. Thirty studies were included in this meta-analysis, and a total of 10 malignant tumours were involved. The expression of KLF4 was not associated with the prognosis for overall survival (hazard ratio(HR)0.86, 95% confidence interval (CI): 0.65-1.13, P = 0.28), disease-free survival/recurrence-free survival/metastasis-free survival (HR 0.87, 95% CI: 0.52-1.44, P = 0.58) or disease-specific survival (HR 1.13, 95% CI: 0.44-2.87, P = 0.8). CONCLUSION: This study showed that the expression of KLF4 was not related to the prognosis of the tumours that were included in the study.

BACKGROUND: Breast cancer is the most common malignancy in women, and is both pathologically and genetically heterogeneous, making early detection and treatment difficult. A subset of breast cancers express normal levels of REST (repressor element 1 silencing transcription factor) mRNA but lack functional REST protein. Loss of REST function is seen in ~ 20% of breast cancers and is associated with a more aggressive phenotype and poor prognosis. Despite the frequent loss of REST, little is known about the role of REST in the molecular pathogenesis of breast cancer. METHODS: TCGA data was analyzed for the expression of REST target genes in breast cancer patient samples. We then utilized gene knockdown in MCF-7 cells in the presence or absence of steroid hormones estrogen and/ progesterone followed by RNA sequencing, as well as chromatin immunoprecipitation and PCR in an attempt to understand the tumor suppressor role of REST in breast cancer. RESULTS: We show that REST directly regulates CEMIP (cell migration-inducing and hyaluronan-binding protein, KIAA1199) and MMP24 (matrix metallopeptidase 24), genes known to have roles in invasion and metastasis. REST knockdown in breast cancer cells leads to significant upregulation of CEMIP and MMP24. In addition, we found REST binds to RE-1 sites (repressor element-1) within the genes and influences their transcription. Furthermore, we found that the estrogen receptor (ESR1) signaling pathway is activated in the absence of REST, regardless of hormone treatment. CONCLUSIONS: We demonstrate a critical role for the loss of REST in aggressive breast cancer pathogenesis and provide evidence for REST as an important diagnostic marker for personalized treatment plans.

BACKGROUND: Sarcopenia predicts poor prognosis of a variety of gastrointestinal malignancies. However, there is a lack of study on the association between skeletal muscle index (SMI) and the prognosis of gastrointestinal stromal tumor (GIST). The aim of this study is to develop a novel nomogram based on sarcopenia for GIST patients to predict overall survival (OS). METHODS: SMI was measured by computed tomography scan of 107 patients who underwent resection for primary localized gastrointestinal stromal tumor (GIST). Sarcopenia was defined by cutoff values for SMI as 40.1 cm2/m2 and 39.8 cm2/m2 using optimum stratification for males and females respectively. Factors were included in the nomogram were specified by univariate and multiple Cox proportional hazard analysis. Concordance index (C-index) and calibration curves were conducted to measure the discrimination and accuracy of the nomogram. The utility of the nomogram was assessed by the decision curve analysis (DCA). RESULTS: Twenty-eight (26.2%) of 107 patients were sarcopenic. Sarcopenia was correlated significantly with body mass index, albumin, female sex, resection style, mitotic index, rupture status, survival. Sarcopenia was significantly related to decreased overall survival (p = 0.003).The nomogram including sarcopenia status, resection style and mitotic index had an excellent discrimination with C-index 0.794. The calibration curves represented a good accordance between the actual observation and nomogram prediction for overall survival. Decision curve analysis illustrated that the nomogram was helpful in clinic. CONCLUSIONS: We developed a nomogram based on sarcopenia to predict overall survival after resection of GISTs which is an effective and favorable prognostication tool.

BACKGROUND: Androgen deprivation therapy (ADT) combined with docetaxel chemotherapy is the standard treatment for metastatic castration-resistant prostate cancer (mCRPC) patients. However, mCRPC patients are mainly frail elderly men, constantly accompanied by comorbidities and showing poor tolerance to standard docetaxel chemotherapy. Some exploratory studies administering modified chemotherapy regimens have reported noninferior oncologic outcomes with fewer adverse events, yet most are retrospective or small studies, and prospective randomized controlled trials have rarely been conducted. Therefore, we designed this modified docetaxel chemotherapy regimen in patients with mCRPC, aiming to evaluate its efficacy and safety compared with the standard docetaxel chemotherapy regimen. METHODS: This is an open-label, multi-institutional, prospective, randomized non-inferiority trial. A total of 128 patients with mCRPC will be randomized to receive ADT combined with modified docetaxel chemotherapy (experimental group, n=64) or ADT combined with standard docetaxel chemotherapy (control group, n=64). Patients in the experimental group will receive a modified regimen with docetaxel 40 mg/m2 on the 1st day and 35 mg/m2 on the 8th day, repeated every 21 days. The primary endpoint is progression-free survival at 2 years. Secondary endpoints include overall survival, prostate-specific antigen response rate, pain response rate, toxicity and quality of life. DISCUSSION: The expected benefit for the patient in the experimental arm is noninferior efficacy with decreased toxicity and improved quality of life compared with that in the control arm. To the best of our knowledge, this will be the first multicentre prospective randomized study to assess the efficacy and safety of modified docetaxel chemotherapy in patients with mCRPC in China. The results of this trial may provide benefit to mCRPC patients, especially those with poor performance. TRIAL REGISTRATION: chictr.org.cn Identifier: ChiCTR2100046636 (May 24, 2021). Ongoing study.

BACKGROUND: Bevacizumab (Bev) plays the central role of the adjuvant therapy for patients with ovarian carcinoma. The aim of our study was to examine whether differences in the administration of Bev influence the prognosis of patients. METHODS: Patients with ovarian carcinoma who received treatment at two hospitals between 1999 and 2020 were identified. Patients treated with weekly low-dose administration of Bev (100 mg Bev on days 1 and 8 and 200 mg Bev on day 15, monthly) at one hospital (group A) and those with monthly high-dose administration of Bev (15 mg/kg of Bev on day 1, monthly) at another hospital (group B) were retrospectively compared. RESULTS: Among the total patients, 44 were assigned to group A and 33 were assigned to group B. More patients in group A had advanced disease (p = 0.03) and a lower dose of Bev at the first time during the first cycle administration (p < 0.01) than in group B. Progression-free survival (PFS) was better in group A than in group B (p < 0.01). Multivariate analysis revealed that group A was a better prognostic factor for PFS (hazard ratio 0.53, p = 0.03). Stable duration was longer in group A than in group B (p < 0.01). The incidences of adverse effects, including hematological toxicities such as neutropenia (p = 0.01) and nonhematological toxicities such as hypertension (p < 0.01), intestinal obstruction (p < 0.01), and thromboembolic events (p < 0.01), were lower in group A than in group B. CONCLUSIONS: Weekly low-dose administration of Bev might improve prognosis and decrease the frequency of adverse effects associated with this drug although the prospective study was needed to get corroboration.

BACKGROUND: Both modified FOLFIRINOX (mFFX) and gemcitabine/nab-paclitaxel chemotherapy regimens have been shown to improve clinical outcomes in patients with pancreatic cancer, and are often used interchangeably as the standard of care. Preclinical studies often do not use these regimens, since administering these multiagent approaches can be difficult. In this study, we assessed the feasibility of administering these two chemotherapy regimens in spontaneous pancreatic tumors using KPC mice with the ultimate goal of advancing preclinical studies. METHODS: KPC mice were created by breeding KrasLSL-G12D/+ to Trp53fl/fl;Ptf1αCre/+, resulting in KrasLSL-G12D/+;p53fl/+;Ptf1αCre/+ mice. At 14 weeks of age, mice were palpated for spontaneous tumor growth that was verified using ultrasounds. Mice with tumors under 15 mm in diameter were used. The mice were assigned to one of seven treatment regimens: 1 cycle of mFFX (FFX X1), 2 cycles of mFFX (FFX X2), 1 cycle of mFFXwith 40 Gy SBRT (FFX SBRT), 1 cycle of gemcitabine/nab-paclitaxel (GEM/AB X1), 2 cycles of gemcitabine/nab-paclitaxel (GEM/AB X2), 2 cycles of gemcitabine/nab-paclitaxel with 40 Gy SBRT (GEM/AB SBRT), or saline only (control). RESULTS: In total, 92 mice were included. The median OS in the FFX X2 group was slightly longer that the median OS in the FFX X1 group (15 days vs 11 days, P = 0.003). Mice in the GEM/AB X2 group had longer OS when compared to mice in the GEM/AB X1 group (33.5 vs 13 days, P = 0.001). Mice treated with chemotherapy survived longer than untreated control animals (median OS: 6.5 days, P < 0.001). Moreover, in mice treated with chemotherapy, mice that received 2 cycles of GEM/AB X2 had the longest survival, while the FFX X1 group had the poorest OS (P < 0.001). The addition of chemotherapy was associated with reduced number of myeloid and lymphoid cell types, except for CD4 + cells whose levels were largely unaltered only in tumors treated with gemcitabine/nab-paclitaxel. Lastly, chemotherapy followed by consolidative SBRT trended towards increased local control and survival. CONCLUSIONS: We demonstrate the utility and feasibility of clinically relevant mFOLFIRINOX and gemcitabine/nab-paclitaxel in preclinical models of pancreatic cancer.

Erratum in BMC Cancer. 2022 Feb 22;22(1):200.

BACKGROUND: To evaluate the clinical outcomes of patients who received stereotactic body radiation therapy (SBRT) for single viable hepatocellular carcinoma (HCC) at the site of incomplete transarterial chemoembolization (TACE). METHODS: Patients treated with SBRT for single viable HCC after incomplete TACE between 2012 and 2017 at Asan Medical Center (Seoul, South Korea) were included. Incomplete TACE was defined as (1) evidence of viable HCC at the site of TACE on follow-up dynamic computed tomography (CT) or magnetic resonance imaging following one or more consecutive TACEs, (2) no definite tumor staining on superselective hepatic angiogram, or (3) no definite iodized oil uptake on post-embolization angiogram or CT. Doses of 10-15 Gy per fraction were given over 3-4 consecutive days. The primary outcome was local control rate at 3 years and secondary outcome included tumor response, overall survival rate, out-of-field intrahepatic recurrence-free survival, distant metastasis-free survival and treatment-related toxicities. Treatment-related adverse events were evaluated according to the common terminology criteria for adverse events, version 4.03. RESULTS: A total of 302 patients were analyzed. The median follow-up duration was 32.9 months (interquartile range [IQR], 23.6-41.7) and the median tumor size was 2.0 cm (range, 0.7-6.9). The local control (LC) and overall survival rates at 3 years were 91.2 and 72.7%, respectively. 95.4% of the tumors reached complete response (CR) during the entire follow-up period (anyCR). The median interval from SBRT to anyCR was 3.4 months (IQR, 1.9-4.7), and 39.9 and 83.3% of the lesions reached CR at 3- and 6-months after SBRT, respectively. Radiation-induced liver disease was observed in 8 (2.6%) patients. No patients experienced gastroduodenal bleeding within the radiation field. CONCLUSION: SBRT could be considered a feasible salvage treatment option for HCC after incomplete TACE.

BACKGROUND: The efficacy of adjuvant chemotherapy for high-risk stage II colon cancer (CC) has not been well established. We compared the effects of surgery with and without oral uracil and tegafur plus leucovorin (UFT/LV) in patients with high-risk stage II CC, adjusting for potential risk factors. METHODS: We enrolled patients with histologically confirmed stage II colon adenocarcinoma with at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes. Patients chose to be non-randomized or randomized to undergo surgery alone (NR-Group S or R-Group S) or surgery followed by 6 months of UFT/LV (NR-Group U or R-Group U). The primary endpoint was disease-free survival (DFS) after adjusting for previously reported risk factors using propensity score matching (1:2) and inverse probability of treatment weighting (IPTW) in the non-randomized arm. RESULTS: Overall, 1,902 (98%) and 36 (2%) patients were enrolled in the non-randomized and randomized arms, respectively. There were too few patients in the randomized arm and these were therefore excluded from the analysis. Of the 1,902 patients, 402 in NR-Group S and 804 in NR-Group U were propensity score-matched. The 3-year DFS rate (95% confidence interval) was significantly higher in NR-Group U (80.9% [77.9%-83.4%]) than in NR-Group S (74.0% [69.3%-78.0%]) (hazard ratio, 0.64 [0.50-0.83]; P = 0.0006). The 3-year overall survival rate was not significantly different between NR-Group S and NR-Group U. Significantly higher 3-year DFS (P = 0.0013) and overall survival (P = 0.0315) rates were observed in NR-Group U compared with NR-Group S using IPTW. CONCLUSIONS: Adjuvant chemotherapy with UFT/LV showed a significant survival benefit over surgery alone in patients with high-risk stage II CC characterized by at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs031180155 (date of registration: 25/02/2019) (UMIN Clinical Trials Registry: UMIN000007783 , date of registration: 18/04/2012).

BACKGROUND: The treatment of recurrent or metastatic head and neck squamous-cell carcinoma (R/M HNSCC) remains challenging. Preclinical studies revealed that B cell depletion could modulate the microenvironment and overcome chemoresistance. We conducted a phase I study to evaluate the feasibility and safety of B cell depletion using the anti-CD20 antibody rituximab to treat HNSCC. METHODS: Ten patients were enrolled in two protocols. The first four patients treated using protocol 1 received rituximab 1000 mg on days -14 and -7, followed by gemcitabine/cisplatin every 3 weeks, and rituximab was administered every 6 months thereafter. Because of disease hyperprogression, protocol 1 was amended to protocol 2, which consisted of the concomitant administration of rituximab 375 mg/m2 and gemcitabine/cisplatin every 3 weeks. Another six patients were enrolled and treated using protocol 2. RESULTS: Three patients treated using protocol 1 exhibited rapid disease progression, and the remaining patient could not undergo evaluation after rituximab treatment. Conversely, no unpredicted harm was observed in the six patients treated using protocol 2. Among these patients, one achieved complete response, and two had partial responses. The disease-free durations in these patients were 7.0, 6.2, and 7.1 months, respectively. Immune cell analysis revealed a higher ratio of cytotoxic T cells to regulatory T cells in responders than in non-responders. CONCLUSIONS: B cell depletion using rituximab alone in patients with HNSCC can cause hyperprogressive disease. Contrarily, the co-administration of rituximab and cisplatin/gemcitabine was feasible and safe. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04361409 , 24 April 2020, retrospectively registered.

BACKGROUND: Consistent participation in colorectal cancer (CRC) screening with repeated fecal immunochemical test (FIT) is important for the success of the screening program. We investigated whether lifestyle risk factors for CRC were related to inconsistent participation in up to four rounds of FIT-screening. METHOD: We included data from 3,051 individuals who participated in up to four FIT-screening rounds and returned a lifestyle questionnaire. Using logistic regression analyses, we estimated associations between smoking habits, body mass index (BMI), physical activity, alcohol consumption, diet and a healthy lifestyle score (from least favorable 0 to most favorable 5), and inconsistent participation (i.e. not participating in all rounds of eligible FIT screening invitations). RESULTS: Altogether 721 (24%) individuals were categorized as inconsistent participants Current smoking and BMI ≥30 kg/m2 were associated with inconsistent participation; odds ratios (ORs) and 95% confidence intervals (CIs) were 1.54 (1.21-2.95) and 1.54 (1.20-1.97), respectively. A significant trend towards inconsistent participation by a lower healthy lifestyle score was observed (p < 0.05). CONCLUSIONS: Lifestyle behaviors were associated with inconsistent participation in FIT-screening. Initiatives aimed at increasing participation rates among those with the unhealthiest lifestyle have a potential to improve the efficiency of screening.

BACKGROUND: Serotonin (or 5-Hydroxytryptamine, 5-HT) signals in mammary gland becomes dysregulated in cancer, also contributing to proliferation, metastasis, and angiogenesis. Thus, the discovery of novel compounds targeting serotonin signaling may contribute to tailor new therapeutic strategies usable in combination with endocrine therapies. We have previously synthesized serotoninergic receptor ligands (SER) with high affinity and selectivity towards 5-HT2A and 5-HT2C receptors, the main mediators of mitogenic effect of serotonin in breast cancer (BC). Here, we investigated the effect of 10 SER on viability of MCF7, SKBR3 and MDA-MB231 BC cells and focused on their potential ability to affect Tamoxifen responsiveness in ER+ cells. METHODS: Cell viability has been assessed by sulforhodamine B assay. Cell cycle has been analyzed by flow cytometry. Gene expression of 5-HT receptors and Connective Tissue Growth Factor (CTGF) has been checked by RT-PCR; mRNA levels of CTGF and ABC transporters have been further measured by qPCR. Protein levels of 5-HT2C receptors have been analyzed by Western blot. All data were statistically analyzed using GraphPad Prism 7. RESULTS: We found that treatment with SER for 72 h reduced viability of BC cells. SER were more effective on MCF7 ER+ cells (IC50 range 10.2 μM - 99.2 μM) compared to SKBR3 (IC50 range 43.3 μM - 260 μM) and MDA-MB231 BC cells (IC50 range 91.3 μM - 306 μM). This was paralleled by accumulation of cells in G0/G1 phase of cell cycle. Next, we provided evidence that two ligands, SER79 and SER68, improved the effectiveness of Tamoxifen treatment in MCF7 cells and modulated the expression of CTGF, without affecting viability of MCF10A non-cancer breast epithelial cells. In a cell model of Tamoxifen resistance, SER68 also restored drug effect independently of CTGF. CONCLUSIONS: These results identified serotoninergic receptor ligands potentially usable in combination with Tamoxifen to improve its effectiveness on ER+ BC patients.

BACKGROUND: Upper urinary tract urothelial carcinoma (UTUC) accounts for only about 5-10% of all urothelial cancers and is characterized by an aggressive and frequently rapidly fatal behavior. However, detailed knowledge of its molecular profile is still lacking. MATERIALS AND METHODS: We identified, by chart analysis, patients who underwent radical nephroureterectomy or diagnostic biopsy for UTUC between January 2015 and August 2020 at the Santa Maria Hospital of Terni, in Italy. Eligible patients were required to have also adequate clinical informations and follow-up details. The primary objective of the study was to evaluate DNA mismatch repair (MMR) proteins and Nectin-4 immunohistochemical expression in UTUC, looking also for an eventual correlation between these molecular features. The secondary objective was to investigate genomic instability in the case of a MMR protein loss. Expression of proteins was assessed by using immunohistochemistry and microsatellite instability (MSI) performed by next generation sequencing. Nectin-4 expression was reported using an intensity scoring system (score, 0-3+), instead the expression of DNA MMR proteins was indicated as present (no loss) or not present (loss). RESULTS: Thirty four cases have been evaluated and 27 considered eligible for the study with their tumor samples analyzed. Nectin-4 was found to be expressed in 44% of cases and 18.5% of patients showed defective-MMR phenotype. We found a significant correlation between Nectin-4 expression and MSH2/MSH6 protein loss. Out of 7 patients with DNA MMR proteins loss or equivocal phenotype, 3 showed MSI. CONCLUSIONS: Our pilot study suggest a possible relationship between Nectin-4 and DNA MMR protein expression in UTUC and a clinically significant correlation between defective MMR phenotype and genomic instability. Because of the possible implications of these data for innovative treatment approaches, the need for further studies in this area is warranted.

BACKGROUND: Therapeutic agents for dyslipidaemia, in particular statins, have been recently reported to suppress growth and metastasis of breast cancer. However, the predictive value of lipid control in breast cancer patients has not been discussed sufficiently. In addition, though immunometabolism is a relatively novel approach for tumour immunotherapy, the relationship between lipid metabolism and immune status has not been well documented. We therefore investigated the effects of lipid metabolism on antitumour immune response and cancer prognosis. METHODS: Except for patients with ductal carcinoma in situ, 938 patients treated with curative surgery were examined. The correlation between treatment for dyslipidaemia or serum lipid levels and clinicopathological features, including the prognosis, was evaluated retrospectively. Also, we stratified these results by intrinsic subtype of breast cancer, menopause, and type of therapeutic agents for dyslipidaemia. Moreover, neutrophil- to-lymphocyte ratio (NLR) and tumour-infiltrating lymphocytes (TILs) were used as indicators of systemic and local immune status, respectively. RESULTS: Of 194 patients treated for dyslipidaemia, recurrence-free survival (RFS) and overall survival (OS) did not differ significantly between users of drugs for dyslipidaemia and non-users (p = 0.775 and p = 0.304, log-rank, respectively). Among postmenopausal, hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients treated for dyslipidaemia, the good serum lipid control group had significantly better RFS (p = 0.014, log-rank), lower postoperative NLR (p = 0.012), and higher TILs in resected tissues (p = 0.024) than the poor control group. Multivariate analysis showed that postoperative serum lipid levels were a risk factor for recurrence (hazard ratio = 4.722, 95% confidence interval 1.006-22.161, p = 0.049). CONCLUSIONS: Good control of serum lipid metabolism may improve the tumour immune microenvironment and prognosis in postmenopausal HR-positive/HER2-negative breast cancer patients.

BACKGROUND: In breast cancer (BC), recurrent fusion genes of estrogen receptor alpha (ESR1) and AKAP12, ARMT1 and CCDC170 have been reported. In these gene fusions the ligand binding domain of ESR1 has been replaced by the transactivation domain of the fusion partner constitutively activating the receptor. As a result, these gene fusions can drive tumor growth hormone independently as been shown in preclinical models, but the clinical value of these fusions have not been reported. Here, we studied the prognostic and predictive value of different frequently reported ESR1 fusion transcripts in primary BC. METHODS: We evaluated 732 patients with primary BC (131 ESR1-negative and 601 ESR1-positive cases), including two ER-positive BC patient cohorts: one cohort of 322 patients with advanced disease who received first-line endocrine therapy (ET) (predictive cohort), and a second cohort of 279 patients with lymph node negative disease (LNN) who received no adjuvant systemic treatment (prognostic cohort). Fusion gene transcript levels were measured by reverse transcriptase quantitative PCR. The presence of the different fusion transcripts was associated, in uni- and multivariable Cox regression analysis taking along current clinico-pathological characteristics, to progression free survival (PFS) during first-line endocrine therapy in the predictive cohort, and disease- free survival (DFS) and overall survival (OS) in the prognostic cohort. RESULTS: The ESR1-CCDC170 fusion transcript was present in 27.6% of the ESR1-positive BC subjects and in 2.3% of the ESR1-negative cases. In the predictive cohort, none of the fusion transcripts were associated with response to first-line ET. In the prognostic cohort, the median DFS and OS were respectively 37 and 93 months for patients with an ESR1-CCDC170 exon 8 gene fusion transcript and respectively 91 and 212 months for patients without this fusion transcript. In a multivariable analysis, this ESR1-CCDC170 fusion transcript was an independent prognostic factor for DFS (HR) (95% confidence interval (CI): 1.8 (1.2-2.8), P = 0.005) and OS (HR (95% CI: 1.7 (1.1-2.7), P = 0.023). CONCLUSIONS: Our study shows that in primary BC only ESR1-CCDC170 exon 8 gene fusion transcript carries prognostic value. None of the ESR1 fusion transcripts, which are considered to have constitutive ER activity, was predictive for outcome in BC with advanced disease treated with endocrine treatment.

BACKGROUND: Synovial sarcoma (SS) is a type of soft tissue sarcoma (STS) of undetermined tissue origin, which is characterized by the recurrent pathognomonic chromosomal translocation t (X;18)(p11.2; q11.2). Studies have shown that SS is a malignant tumor originating from cancer stem cells or pluripotent mesenchymal stem cells and may be related to fusion genes. In addition, some studies have indicated that the induction of epithelial-mesenchymal transition (EMT) via the TGF-β1/Smad signaling pathway leads to SS metastasis. METHODS: We analyzed the effects of SYT-SSX1 on the stemness of SS cells via TGF-β1/Smad signaling in vitro. The SYT-SSX1 fusion gene high expression cell was constructed by lentiviral stable transfer technology. SYT-SSX1 and SW982 cells were cultured and tested for sphere-forming ability. The transwell migration assay and flow cytometry were used to assess the migration ability of the sphere cells as well as the expression of CSC-related markers. We treated SYT-SSX1 cells with rhTGF-β1 (a recombinant agent of the TGF-β1 signaling pathway) and SB431542 and observed morphological changes. A CCK-8 experiment and a western blot (WB) experiment were conducted to detect the expression of TGF-β1 signaling pathway- and EMT-related proteins after treatment. The SYT-SSX1 cells were then cultured and their ability to form spheres was tested. Flow cytometry, WB, and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression of CSC surface markers on SYT-SSX1 sphere cells. RESULTS: It was found that SYT-SSX1 has stronger sphere-forming ability, migration ability, and higher expression of CSC-related molecules than SW982 cells. Through treating SYT-SSX1 and SW982 cells with rhTGF-β1 and SB431542, we found that TGF-β1 enhanced the proliferation of cells, induced EMT, and that TGF-β1 enhanced the characteristics of tumor stem cells. CONCLUSIONS: Our results suggest that SYT-SSX1 enhances invasiveness and maintains stemness in SS cells via TGF-β1/Smad signaling. These findings reveal an effective way to potentially improve the prognosis of patients with SS by eliminating the characteristics of cancer stem cells (CSCs) during treatment.

BACKGROUND: Renal cell carcinoma (RCC) is one of the most common malignancies worldwide. Noninvasive imaging techniques, such as magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET), have been involved in increasing evolution to detect RCC. This meta-analysis aims to compare to compare the performance of MRI, SPECT, and PET in the detection of RCC in humans, and to provide evidence for decision-making in terms of further research and clinical settings. METHODS: Electronic databases including PubMed, Web of Science, Embase, and Cochrane Library were systemically searched. The keywords such as "magnetic resonance imaging", "MRI", "single-photon emission computed tomography", "SPECT", "positron emission tomography", "PET", "renal cell carcinoma" were used for the search. Studies concerning MRI, SPECT, and PET for the detection of RCC were included. Pooled sensitivity, specificity, and the area under the summary receiver operating characteristic (SROC) curve (AUC), etc. were calculated. RESULTS: A total of 44 articles were finally detected for inclusion in this study. The pooled sensitivities of MRI, 18F-FDG PET and 18F-FDG PET/CT were 0.80, 0.83, and 0.89, respectively. Their respective overall specificities were 0.90, 0.86, and 0.88. The pooled sensitivity and specificity of MRI studies at 1.5 T were 0.86 and 0.94, respectively. With respect to prospective PET studies, the pooled sensitivity, specificity and AUC were 0.90, 0.93 and 0.97, respectively. In the detection of primary RCC, PET studies manifested a pooled sensitivity, specificity, and AUC of 0.77, 0.80, and 0.84, respectively. The pooled sensitivity, specificity, and AUC of PET/CT studies in detecting primary RCC were 0.80, 0.85, and 0.89. CONCLUSION: Our study manifests that MRI and PET/CT present better diagnostic value for the detection of RCC in comparison with PET. MRI is superior in the diagnosis of primary RCC.

BACKGROUND: The detection of suspicious microcalcifications on mammography represents one of the earliest signs of a malignant breast tumor. Assessing microcalcifications' characteristics based on their appearance on 2D breast imaging modalities is in many cases challenging for radiologists. The aims of this study were to: (a) analyse the association of shape and texture properties of breast microcalcifications (extracted by scanning breast tissue with a high resolution 3D scanner) with malignancy, (b) evaluate microcalcifications' potential to diagnose benign/malignant patients. METHODS: Biopsy samples of 94 female patients with suspicious microcalcifications detected during a mammography, were scanned using a micro-CT scanner at a resolution of 9 μm. Several preprocessing techniques were applied on 3504 extracted microcalcifications. A high amount of radiomic features were extracted in an attempt to capture differences among microcalcifications occurring in benign and malignant lesions. Machine learning algorithms were used to diagnose: (a) individual microcalcifications, (b) samples. For the samples, several methodologies to combine individual microcalcification results into sample results were evaluated. RESULTS: We could classify individual microcalcifications with 77.32% accuracy, 61.15% sensitivity and 89.76% specificity. At the sample level diagnosis, we achieved an accuracy of 84.04%, sensitivity of 86.27% and specificity of 81.39%. CONCLUSIONS: By studying microcalcifications' characteristics at a level of details beyond what is currently possible by using conventional breast imaging modalities, our classification results demonstrated a strong association between breast microcalcifications and malignancies. Microcalcification's texture features extracted in transform domains, have higher discriminating power to classify benign/malignant individual microcalcifications and samples compared to pure shape-features.

BACKGROUND: Exosomes play a key role in cell-to-cell communication and are integral component of the tumor microenvironment. Recent observations suggest transfer of RNA through tumor-derived exosomes that can potentially translate into regulatory proteins in the recipient cells. Role of cervical cancer-derived exosomes and their transcript cargo is poorly understood. MATERIALS AND METHODS: The total RNA of exosomes from HPV-positive (SiHa and HeLa) and HPV-negative (C33a) cervical cancer cell lines were extracted and the transcripts were estimated using Illumina HiSeq X. Further, validation of HPV transcripts were performed using RT-PCR. RESULTS: 3099 transcripts were found to be differentially-exported in HPV-positive vs. HPV-negative exosomes (p value <0.05). Analysis of top 10 GO terms and KEGG pathways showed enrichment of transcripts belonging to axon guidance and tumor innervation in HPV-positive exosomes. Among top 20 overexpressed transcripts, EVC2, LUZP1 and ANKS1B were the most notable due to their involvement in Hh signaling, cellular migration and invasion, respectively. Further, low levels of HPV-specific reads were detected. RT-PCR validation revealed presence of E6*I splice variant of HPV18 in exosomal RNA of HeLa cells. The E6*I transcripts were consistently retained in exosomes obtained from HeLa cells undergoing 5-FU and cisplatin-induced oxidative stress. CONCLUSION: Our data suggests the enrichment of poly-A RNA transcripts in the exosomal cargo of cervical cancer cells, which includes pro-tumorigenic cellular RNA and viral transcripts such as HPV E6, which may have clinical utility as potential exosomal biomarkers of cervical cancer.

BACKGROUND: Despite evidence of the positive impact of routine assessment of patient-reported outcome measures (PROMs), their systematic collection is not widely implemented in cancer care. AIM: To assess the knowledge, use and attitudes of healthcare professionals (HCPs) towards PROMs and electronically collected PROMs (ePROMs) in clinical practice and research and to explore respondent-related factors associated with the above dimensions. METHOD: An ad hoc developed online survey was administered to all HCPs employed in clinical activity in an Italian comprehensive cancer center. The survey investigated which PROMs were known and used, as well as HCPs' opinions on the advantages and drawbacks of routine PROM assessment, including electronic assessment (ePROM). Linear and logistic regression models were used for association analyses. RESULTS: Five Hundred Eleven of nine hundred ninety-two invited HCPs (52%) provided analyzable responses. 68% were women, 46% were nurses and 42% physicians, and 52.5% had > 20 years seniority. The average number of PROMs known was six among 17 proposed. All proved to be under-used (< 28%) except unidimensional and multidimensional pain scales (77 and 36%). Respondents expressed an overall positive attitude towards PROMs, with strengths outweighing weaknesses (mean overall scores 3.6 and 2.9, respectively, on a 1-5 scale). 67% of respondents preferred electronic collection over paper and pencil. Profession was associated with knowledge and use (physicians reported knowing more PROMs than other professionals) and with a preference for electronic collection (nurses were less likely to prefer the electronic format than physicians). Senior HCPs were slightly more critical about both PROMs and electronic administration. CONCLUSIONS: This survey indicates an acceptable level of knowledge of common PROM tools but low usage in practice. Based on the generally positive attitude of HCPs, routine implementation of ePROMs can be promoted as long as adequate resources and training are provided. TRIAL REGISTRATION: Not registered.

BACKGROUND: Serum indicators AFP, CA50, CA125, CA153, CA19-9, CEA, f-PSA, SCC-Ag have been confirmed as tumor markers (TMs). We conducted a genome-wide association study on 8 tumor markers of our 427 Han population in southern China, in order to identify genetic loci that are significantly associated with the level of 8 tumor markers. METHODS: We use Gene Titan multi-channel instrument and Axiom Analysis Suite 6.0 software for genotyping. We used IMPUTE2 software for imputation, and 1000 Genomes Project (Phase 3) was used as haplotype reference. After necessary quality control and statistical analysis, genetic loci genome-wide associated with TMs (p < 5E-8) will be identified. Finally, we selected Top SNPs (p < 5E-7) from the GWAS results for replication test. We used SPSS software to draw the distribution box plots of serum TMs under different genotypes of significant loci. RESULTS: The results showed that there were only MUC1 (mucin 1)-rs4072037 significantly genome-wide associated with CA153 (p = 1.28E-18). However, we found that a total of 30 genetic loci have a suggestively significant genome-wide association with the level of 8 serum tumor markers (p < 5E-6). Then 3 Top SNPs (p < 5E-7) were selected for replication verification. The results showed that MUC1-rs4072037 was still significantly associated with CA153 in another population (p = 3.73E-08). Comparing with the TT genotype of rs4072037, the CA153 level was higher under CC or CT genotype of rs4072037. CONCLUSION: MUC1-rs4072037 is significantly genome-wide associated with CA153 level. There are 30 genetic loci suggestively genome-wide associated with level of tumor markers among the Han population from Southern China.

BACKGROUND: BCD-021 is a bevacizumab biosimilar which was shown to be equivalent to reference bevacizumab in a wide panel of physicochemical studies as well as preclinical studies in vitro and in vivo. International multicenter phase III clinical trial was conducted to compare efficacy and safety of BCD-021 and reference bevacizumab in combination with paclitaxel and carboplatin in a first-line treatment of inoperable or advanced non-squamous non-small-cell lung cancer (NSCLC). METHODS: Patients with no previous treatment for advanced non-squamous NSCLC were randomly assigned 3:2 to BCD-021 or reference bevacizumab and were treated with bevacizumab + paclitaxel + carboplatin. Therapy continued for 6 cycles (every 3 weeks), until progression of the disease or unbearable toxicity. The primary study endpoint was the overall response rate. The study goal was to prove the equivalent efficacy of BCD-021 and reference bevacizumab. Equivalence margins for 95% CI for the difference in the overall response rates were set at [-18%; 18%], for 90% CI for the ratio of overall response rate were set at [67%; 150%]. RESULTS: In total 357 patients were enrolled in the study, 212 in the BCD-021 group and 145 in the reference bevacizumab group. The ORR was 34.63% in the BCD-022 group and 33.82% in the reference bevacizumab group. Limits of 95% CI for the difference in overall response rates between the groups were [-9.47%; 11.09%]. Limits of 90% CI for the ratio of overall response rate between the groups were [79.6%; 131.73%]. For both approaches CI lied within predetermined equivalence margins. Profile of adverse events (AEs) was similar between the groups (any AEs were reported in 86.89% of patients in BCD-021 group and 89.05% of patients in reference group). No unexpected adverse reactions were reported throughout the study. No statistically significant differences regarding anti-drug antibody occurrence rate was found between BCD-022 (n=4; 1.96%) and comparator (n=5; 3.65%). Both drug products showed low occurrence rate and short life of anti-bevacizumab antibodies. Pharmacokinetics assessment after 1st and 6th study drug injection also demonstrated equivalent PK parameters by all outcome measures. CONCLUSIONS: Thus, the results of this study demonstrated therapeutic equivalence of bevacizumab biosimilar BCD-021 and referent bevacizumab drug. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov (Study Number NCT01763645, date of registration 09/01/2013).

BACKGROUND: Imatinib is the gold standard for the treatment of all phases of Philadelphia positive Chronic Myeloid Leukemia (CML). During treatment, patients may develop cytopenia. We aimed to study the baseline characteristics and factors associated with cytopenia at a Nairobi Hospital. METHODS: This was a retrospective case-control study of patients aged ≥18 years on follow-up at the Glivec International Patient Access Program (GIPAP) clinic from 2007 to 2015. The cases consisted of CML patients on imatinib who developed cytopenia. The controls were CML patients on imatinib who did not develop cytopenia. Baseline socio - demographic, clinical, hematologic, and molecular data were retrieved from patients' files. Chi square or fishers' exact tests were used to analyze for differences between cytopenia and no cytopenia. Binary logistic regressions were employed to identify relationships. Univariate and multivariate analyses were done to identify independent predictors of cytopenia. Odds ratios (OR) were presented including the 95% confidence intervals and respective p values. RESULTS: A total of 201 patients were studied consisting of ninety-four (94) patients with cytopenia and 107 with no cytopenia. Among the entire population, males were 52, and 42% were aged 36-50 years. Sex, age, marital status, occupation and education level were similar between the cytopenia and no cytopenia groups. Among the 201 patients, 70% had symptoms for > 12 months before diagnosis, 78.6% had B symptoms at baseline, 80% had a moderate splenomegaly at baseline. Among patients with cytopenia, 40 and 37.4% developed cytopenia within 3 months and 3-6 months respectively after imatinib initiation. Baseline neutrophilia, neutropenia, anaemia, thrombocytosis, thrombocytopenia was found in 68, 11, 11, 23.5 and 11% respectively. Baseline hemoglobin, neutrophil and platelet level were significantly different between the cytopenia and the no cytopenia group. On univariable analysis, baseline anemia with hb < 7.9 g/dL (p = 0.002), neutropenia (p = 0.001), neutrophilia > 100,000/mm3 (p = 0.002) and thrombocytopenia (p = 0.001) increased the odds of developing cytopenia. On multivariable analysis, baseline anaemia (p value < 0.002), neutropenia (p value < 0.001), thrombocytopenia (p value, < 0.001) and thrombocytosis (p value, 0.033) increased the odds of developing cytopenia. CONCLUSION: Odds of cytopenia were higher in presence of baseline cytopenia and thrombocytosis. Clinicians should have a high index of suspicion for these patients.