A Novel Machine Learning Algorithm Combined With Multivariate Analysis for the Prognosis of Renal Collecting Duct Carcinoma

ObjectivesTo investigate the clinical and non-clinical characteristics that may affect the prognosis of patients with renal collecting duct carcinoma (CDC) and to develop an accurate prognostic model for this disease.MethodsThe characteristics of 215 CDC patients were obtained from the U.S. National Cancer Institute’s surveillance, epidemiology and end results database from 2004 to 2016. Univariate Cox proportional hazard model and Kaplan-Meier analysis were used to compare the impact of different factors on overall survival (OS). 10 variables were included to establish a machine learning (ML) model. Model performance was evaluated by the receiver operating characteristic curves (ROC) and calibration plots for predictive accuracy and decision curve analysis (DCA) were obtained to estimate its clinical benefits.ResultsThe median follow-up and survival time was 16 months during which 164 (76.3%) patients died. 4.2, 32.1, 50.7 and 13.0% of patients were histological grade I, II, III, and IV, respectively. At diagnosis up to 61.9% of patients presented with a pT3 stage or higher tumor, and 36.7% of CDC patients had metastatic disease. 10 most clinical and non-clinical factors including M stage, tumor size, T stage, histological grade, N stage, radiotherapy, chemotherapy, age at diagnosis, surgery and the geographical region where the care delivered was either purchased or referred and these were allocated 95, 82, 78, 72, 49, 38, 36, 35, 28 and 21 points, respectively. The points were calculated by the XGBoost according to their importance. The XGBoost models showed the best predictive performance compared with other algorithms. DCA showed our models could be used to support clinical decisions in 1-3-year OS models.ConclusionsOur ML models had the highest predictive accuracy and net benefits, which may potentially help clinicians to make clinical decisions and follow-up strategies for patients with CDC. Larger studies are needed to better understand this aggressive tumor.

A genomic mutation spectrum of collecting duct carcinoma in the Chinese population

Background Renal collecting duct carcinoma (CDC) is a rare and lethal subtype of renal cell carcinoma (RCC). The genomic profile of the Chinese population with CDC remains unclear. In addition, clinical treatments are contradictory. In this study, we aimed to identify the genomic mutation spectrum of CDC in the Chinese population. Methods Whole-exome sequencing was performed using the Illumina Novaseq™ 6000 platform. MuTect2 detects single-nucleotide variants (SNVs) and small scale insertions/deletions (INDELs). The identified mutations were annotated with ANNOVAR and validated by Sanger sequencing. Control-FREEC was used to detect copy number variation (CNV), and GISTIC was applied to detect frequently mutated altered regions. These data were compared with associated The Cancer Genome Atlas cohorts. Results Ten normal-matched CDC patients were included. The mean tumour mutation burden was 1.37 Mut/Mb. Six new recurrent somatic mutated genes were identified, including RBM14, MTUS1, GAK, DST, RNF213 and XIRP2 (20% and 2 of 10, respectively), and validated by Sanger sequencing. In terms of common mutated genes, SETD2 was altered in both CDC and other RCC subtypes but not in bladder urothelial carcinoma (BLCA); CDKN2A was a driver gene in both CDC (SNV: 10%, 1 of 10) and BLCA but not in other RCC subtypes. Next, 29 amplifications and 6 deletions of recurrent focal somatic CNVs were identified by GISTIC2.0, which displayed differences from kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP) and BLCA cohorts. Of note, CDKN2A (CNV alteration: 30%, 3 of 10) and CDKN2A-AS1 were the only overlapping genes of these four cohorts. Importantly, the CDKN2A mutation in our cohort differed from previous studies in urinary carcinomas. Moreover, CDKN2A-altered cases had significantly worse overall survival than wild-type cases in both KIRC and KIRP cohorts. In addition, the most frequently altered genomic pathway of our CDC cohort was the CDKN2A-mediated p53/RB1 pathway. Conclusions Our study offers the first genomic spectrum of the Chinese population with CDC, which differs from that of the Western population. The altered CDKN2A-mediated p53/RB1 pathway might provide new insight into potential therapeutic targets for CDC patients.

Heterogeneity of tumor microenvironment is associated with clinical prognosis of non-clear cell renal cell carcinoma: a single-cell genomics study

Non-clear renal cell carcinomas (nccRCCs) are less frequent in kidney cancer with histopathological heterogeneity. A better understanding of the tumor biology of nccRCC can provide more effective treatment paradigms for different subtypes. To reveal the heterogeneity of tumor microenvironment (TME) in nccRCC, we performed 10x sing-cell genomics on tumor and normal tissues from patients with papillary renal cell carcinoma (pRCC), chromophobe RCC (chrRCC), collecting duct carcinoma (CDRCC) and sarcomatoid RCC (sarRCC). 15 tissue samples were finally included. 34561 cells were identified as 16 major cell clusters with 34 cell subtypes. Our study presented the sing-cell landscape for four types of nccRCC, and demonstrated that CD8+ T cells exhaustion, tumor-associated macrophages (TAMs) and sarcomatoid process were the pivotal factors in immunosuppression of nccRCC tissues and were closely correlated with poor prognosis. Abnormal metabolic patterns were present in both cancer cells and tumor-infiltrating stromal cells, such as fibroblasts and endothelial cells. Combined with CIBERSORTx tool, the expression data of bulk RNA-seq from TCGA were labeled with cell types of our sing-cell data. Calculation of the relative abundance of cell types revealed that greater proportion of exhausted CD8+ T cells, TAMs and sarRCC derived cells were correlated with poor prognosis in the cohort of 274 nccRCC patients. To the best of our knowledge, this is the first study that provides a more comprehensive sight about the heterogeneity and tumor biology of nccRCC, which may potentially facilitate the development of more effective therapies for nccRCC.

Novel Multicentric Hepatic Lymphoma with Extrahepatic Biliary Obstruction Associated with Duodenal Perforation in a Cat

An 11-year-old male castrated domestic shorthair cat was presented for evaluation due to clinical deterioration and potential extrahepatic biliary obstruction (EHBO). Further investigations confirmed EHBO and revealed severe and previously unreported comorbidities. On initial examination, the cat was markedly icteric with a poor body condition score and severe muscle wasting. Serum chemistry and complete blood count showed evidence of cholestasis and anemia. Primary diagnostics and therapeutics targeted these abnormalities. Abdominal ultrasound revealed peritoneal effusion, multifocal mixed echogenic hepatic and splenic foci, small intestinal thickening, cholelithiasis, choledocholithiasis, and common bile duct and pancreatic duct dilation with evidence of obstruction. Peritoneal effusion cytology confirmed septic peritonitis. Hepatic and splenic cytology was consistent with lymphoma. Based on these results, euthanasia was elected by the owners of the animal. Necropsy confirmed the ultrasound diagnoses, septic peritoneal effusion associated with a duodenal perforation, multiorgan lymphoma, and common bile duct carcinoma. Flow cytometry classified the lymphoma as a double-negative phenotype of T-cell lymphoma (CD3+ and CD5+, but CD4- and CD8-) present in the duodenum and liver and suspected in the spleen which has previously not been reported in cats. This case report documents a cat with EHBO caused by multiple disease processes including a novel T-cell lymphoma phenotype, biliary carcinoma, duodenal perforation and septic abdomen, and choleliths, as well as inflammatory hepatobiliary disease.

NS-11021 Modulates Cancer-Associated Processes Independently of BK Channels in Melanoma and Pancreatic Duct Adenocarcinoma Cell Lines

Potassium channels have emerged as regulators of carcinogenesis, thus introducing possible new therapeutic strategies in the fight against cancer. In particular, the large-conductance Ca2+-activated K+ channel, often referred to as BK channel, is involved in several cancer-associated processes. Here, we investigated the effects of different BK activators, NS-11021, NS-19504, and BMS-191011, in IGR39 (primary melanoma cell line) and Panc-1 (primary pancreatic duct carcinoma cell line), highly expressing the channel, and in IGR37 (metastatic melanoma cell line) that barely express BK. Our data showed that NS-11021 and NS-19504 potently activated BK channels in IGR39 and Panc-1 cells, while no effect on channel activation was detected in IGR37 cells. On the contrary, BK channel activator BMS-191011 was less effective. However, only NS-11021 showed significant effects in cancer-associated processes, such as cell survival, migration, and proliferation in these cancer cell lines. Moreover, NS-11021 led to an increase of intracellular Ca2+ concentration, independent of BK channel activation, thus complicating any interpretation of its role in the regulation of cancer-associated mechanisms. Overall, we conclude that the activation of the BK channel by itself is not sufficient to produce beneficial anti-cancer effects in the melanoma and PDAC cell lines examined. Importantly, our results raise an alarm flag regarding the use of presumably specific BK channel openers as anti-cancer agents.

Chemo preventive potential of Methanolic extract of bark of Albizia lebbeck (L.) benth on n-methyl-n-nitrosourea induced mammary carcinoma in female sprague dawley rats

Introduction: Use of plants as a source of medicine has been inherited and is an important component of the health care system. Plants are a good source of biologically active compounds known as phytochemicals. The search for anticancer agents from plant sources started in 1950s with the discovery and development of vinca alkaloids, vincristine and vinblastine and the isolation of cytotoxic podophyllotoxin. Many chemotherapeutic agents are avilable their usage is limited due to development of side effects. Recent research demonstrates that plant based phytonutrients are effective in combating the incidence of carcinogenesis. So the purpose of this study is to reveal the relationship between breast cancer and chemopreventive effect of bark of Albizia lebbeck benth to protect against NMU induced mammary cancer in female spraque- dawley rats, and would foster further studies that could ultimately lead to prevention and therapy for breast cancer. Materials and methods: Virgin Female Sprague-Dawley rats were grouped into 5 groups (n=6). Thirty days before the induction of tumor the animals were treated with extracts. At the end of the 30th day tumor was induced by administrating NMU (50 mg/ kg i.p) was induced by single i.p injection, and then the treatment is continued up to a period of 120 days. At the end of the 120th day the animals were sacrificed through cervical decapitation, the mammary tumors were excised out and various parameters were studied such as tumor incidence, tumor burden, tumor volume, tumor weight and tumor latency. Also immunohistochemistry and histopathology were performed. Result: The i.p administration of NMU to the rats showed significant decrease in the body weight compared to normal control rats. After the administration of methanolic extract of Albizia lebbeck benth at different doses showed considerable prevention of weight loss when compared to NMU control rats. Also,in treated groups tumor incidence and tumor burden was decreased and tumor latency got increased. In addition histopathological studies supported significant decrease in formation of infiltrating duct carcinoma in mammory tissue sections. Conclusion: In the present study, methanolic extract of Albizia lebbeck benth showed protective effect against N-methyl-N-nitrosourea induced breast cancer.

Major Salivary Gland Cancer With Distant Metastasis Upon Presentation: Patterns, Outcomes, and Imaging Implications

Objectives Given limited data availability on distant metastasis (DM) in major salivary gland (MSG) malignancy presentation, we aimed to evaluate the rate, histologic patterns, location, and predictors of DM at first MSG cancer presentation and suggest potential implications on diagnostic workup. Study Design Retrospective cohort. Setting Commission on Cancer–accredited hospitals. Methods We included patients in the National Cancer Database (2010-2016) with MSG malignancy. Site and rate of DM were stratified by histologic subtype. Factors predictive of DM at presentation were determined by multivariate regression analysis. Survival analyses were conducted via the Kaplan-Meier method, log-rank test, and Cox regression analysis. Results Of 5776 patients with MSG carcinoma, 333 (5.8%) presented with DM. The most common DM site was the lung (57.1%), followed by bone (46.8%) and liver (19.5%). DM was most common in adenocarcinoma–not otherwise specified (15.1%, 132/874) and salivary duct carcinoma (10.4%, 30/288). High-grade mucoepidermoid carcinoma had the highest rate of lung metastases (81.6%, 31/38). Conversely, myoepithelial carcinoma had the highest rate of bone metastases (85.7%, 6/7). DM at presentation was independently associated with an increased mortality risk (hazard ratio, 1.62; 95% CI, 1.40-1.90). Conclusion We identified a DM rate of 5.8% in MSG malignancy at presentation. Overall 43% of patients presented without DM to the lung but with DM to the bones, liver, and/or brain. The most common metastatic sites differed by tumor histology. Staging with computed tomography neck and chest alone may fail to detect sites of DM; this work can be used for patient counseling in the clinical setting.