Identification of Comprehensive Biomarkers in Patients With Mismatch Repair-Deficient Colon Adenocarcinoma Based on Parallel Multiomics.

Immunocheckpoint inhibitors have shown impressive efficacy in patients with colon cancer and other types of solid tumor that are mismatch repair-deficient (dMMR). Currently, PCR-capillary electrophoresis is one of the mainstream detection methods for dMMR, but its accuracy is still limited by germline mismatch repair (MMR) mutations, the functional redundancy of the MMR system, and abnormal methylation of MutL Homolog 1 promoter. Therefore, this study aimed to develop new biomarkers for dMMR based on artificial intelligence (AI) and pathologic images, which may help to improve the detection accuracy. To screen for the differential expression genes (DEGs) in dMMR patients and validate their diagnostic and prognostic efficiency, we used the expression profile data from the Cancer Genome Atlas (TCGA). The results showed that the expression of Immunoglobulin Lambda Joining 3 in dMMR patients was significantly downregulated and negatively correlated with the prognosis. Meanwhile, our diagnostic models based on pathologic image features showed good performance with area under the curves (AUCs) of 0.73, 0.86, and 0.81 in the training, test, and external validation sets (Jiangsu Traditional Chinese Medicine Hospital cohort). Based on gene expression and pathologic characteristics, we developed an effective prognosis model for dMMR patients through multiple Cox regression analysis (with AUC values of 0.88, 0.89, and 0.88 at 1-, 3-, and 5-year intervals, respectively). In conclusion, our results showed that Immunoglobulin Lambda Joining 3 and nucleus shape-related parameters (such as nuclear texture, nuclear eccentricity, nuclear size, and nuclear pixel intensity) were independent diagnostic and prognostic factors, suggesting that they could be used as new biomarkers for dMMR patients.

Efficacy and safety of XELOX combined with anlotinib and penpulimab vs XELOX as an adjuvant therapy for ctDNA-positive gastric and gastroesophageal junction adenocarcinoma: a protocol for a randomized, controlled, multicenter phase II clinical trial (EXPLORING study).

Background: The efficacy of current adjuvant chemotherapy for gastric adenocarcinoma/gastroesophageal junction adenocarcinoma (GA/GEJA) leaves much to be desired. ctDNA could serve as a potential marker to identify patients who are at higher risk of recurrence. Reinforcing standard adjuvant chemotherapy with immunotherapy has already been indicated to significantly improve clinical outcome, albeit such evidence is rare in GA/GEJA. Here, we intend to explore the clinical benefit of the reinforcement of adjuvant immunotherapy and antiangiogenics alongside with chemotherapy in patients who are deemed in high risk of recurrence by ctDNA analysis, which might shed light on further improvements in adjuvant therapy for GA/GEJA. Methods/Design: This study is designed as a prospective, multicenter, randomized, controlled phase II study in patients histologically or cytologically diagnosed with GA/GEJA who underwent D2 gastrectomy and achieved R0 or R1 resection. From February 2022, a total of 300 stage III patients will be enrolled and subjected according to ctDNA sequencing results, and those with positive results will subsequently be randomized 1:1 to arm A or B. Patients in arm A will receive anlotinib, penpulimab and XELOX for 6-8 cycles, maintained with anlotinib and penpulimab for up to 1 year, while patients in arm B will receive XELOX alone for 6-8 cycles. ctDNA-negative patients will be assigned to arm C, and patients who are ctDNA positive but failed in randomization will be assigned to arm D. Patients in arms C and D will receive the investigator's choice of therapy. The primary endpoint is the median disease-free survival (DFS) of arm A versus arm B determined via CT/MRI imaging. Secondary endpoints include the DFS of ctDNA positive patients versus ctDNA negative patients, the 2- and 3-year DFS rates, overall survival (OS), the impact of hallmark molecules on the treatment response, adverse events (AEs), and the impact of nutrition status or exercise on recurrence. Discussion: We expect that ctDNA would be a strong prognostic factor and ctDNA-positive patients are at higher risk of relapse than ctDNA-negative patients. The addition of anlotinib and penpulimab to XELOX, may contribute to delaying relapse in ctDNA-positive patients. Trial registration: https://www.clinicaltrials.gov, identifier NCT05494060.

KCNQ potassium channels modulate Wnt activity in gastro-oesophageal adenocarcinomas.

Voltage-sensitive potassium channels play an important role in controlling membrane potential and ionic homeostasis in the gut and have been implicated in gastrointestinal (GI) cancers. Through large-scale analysis of 897 patients with gastro-oesophageal adenocarcinomas (GOAs) coupled with in vitro models, we find KCNQ family genes are mutated in ∼30% of patients, and play therapeutically targetable roles in GOA cancer growth. KCNQ1 and KCNQ3 mediate the WNT pathway and MYC to increase proliferation through resultant effects on cadherin junctions. This also highlights novel roles of KCNQ3 in non-excitable tissues. We also discover that activity of KCNQ3 sensitises cancer cells to existing potassium channel inhibitors and that inhibition of KCNQ activity reduces proliferation of GOA cancer cells. These findings reveal a novel and exploitable role of potassium channels in the advancement of human cancer, and highlight that supplemental treatments for GOAs may exist through KCNQ inhibitors.

Active ingredients Isorhamnetin of Croci Srigma inhibit stomach adenocarcinomas progression by MAPK/mTOR signaling pathway.

Gastric cancer (GC) remains the third leading cause of cancer-related mortality in the world, and ninety-five percent of GC are stomach adenocarcinomas (STAD). The active ingredients of Croci Stigma, such as Isorhamnetin, Crocin, Crocetin and Kaempferol, all have antitumor activity. However, their chemical and pharmacological profiles remain to be elusive. In this study, network pharmacology was used to characterize the action mechanism of Croci Stigma. All compounds were obtained from the traditional Chinese medicine systems pharmacology (TCMSP) database, and active ingredients were selected by their oral bioavailability and drug-likeness index. The targets of Croci Stigma active ingredients were obtained from the traditional Chinese medicine integrated database (TCMID), whereas the related genes of STAD were obtained from DisGeNET platform. Cytoscape was used to undertake visual analyses of the Drug Ingredients-Gene Symbols-Disease (I-G-D) network, and 2 core genes including MAPK14, ERBB3 were obtained, which are the predicted targets of isorhamnetin (IH) and quercetin, respectively. Data analysis from TCGA platform showed that MAPK14 and ERBB3 all upregulated in STAD patients, but only the effect of MAPK14 expression on STAD patients' survival was significant. Molecular docking showed that IH might affect the function of MAPK14 protein, and then the underlying action mechanisms of IH on STAD were experimentally validated using human gastric cancer cell line, HGC-27 cells. The results showed that IH can inhibit cell proliferation, migration, clonal formation, and arrest cell cycle, but promote the apoptosis of HGC-27 cells. qRT-PCR data demonstrated that IH downregulated the MAPK14 mRNA expression and EMT related genes. WB results showed that IH regulates MAPK/mTOR signaling pathway. These findings suggest that IH has the therapeutic potential for the treatment of STAD.

TRIM69: a marker of metastasis and potential sensitizer to 5-Fluorouracil and PD-1 blockers in colon adenocarcinoma.

BACKGROUND: Several proteins in the tripartite-motif (TRIM) family are associated with the development of colorectal cancer (CRC), but research on the role of TRIM69 was lacking. The present study examined the correlation between TRIM69 expression and colon adenocarcinoma (COAD). METHODS: mRNA sequencing data for COAD patients was extracted from The Cancer Genome Atlas to analyze correlations between TRIM69 expression and patients' clinical features as well as survival. Potential associations with immune cells and chemosensitivity also were predicted using various algorithms in the TIMER, Limma, clusterProfiler, GeneMANIA, and Gene Set Cancer Analysis platforms. Subsequently, polymerase chain reaction analysis and immunohistochemical staining were used to detect TRIM69 expression in COAD tissue samples from real-world patients. RESULTS: TRIM69 expression was lower in COAD tissues than in normal tissues and correlated with the pathologic stage and metastasis (M category). Additionally, TRIM69 was found to be involved in several immune-related pathways, notably the NOD-like signaling pathway. These results suggest that high TRIM69 expression has the potential to enhance tumor sensitivity to 5-fluorouracil and programmed cell death protein 1 (PD-1) blockers. CONCLUSIONS: From our findings that TRIM69 expression was significantly reduced in COAD compared with non-cancer tissues and associated with pathologic stage and metastasis, we conclude that increasing TRIM69 expression and/or activity may help to improve therapeutic outcomes. Accordingly, TRIM69 represents a potentially valuable marker of metastasis and target for adjuvant therapy in COAD.

A network pharmacology-based investigation of emodin against pancreatic adenocarcinoma.

Pancreatic adenocarcinoma (PAAD) is one of the most common malignancies worldwide with an increasing incidence and poor outcome due to the lack of effective diagnostic and treatment methods. Emerging evidence implicates that emodin displays extensive spectrum anticancer properties. Differential expression genes in PAAD patients were analyzed by Gene Expression Profiling Interactive Analysis (GEPIA) website, and the targets of emodin were obtained via Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. Subsequently, enrichment analyses were performed using R software. A protein-protein interaction (PPI) network was constructed by STRING database and Cytoscape software was used to identify the hub genes. Prognostic value and immune infiltration landscapes were explored through Kaplan-Meier plotter (KM plotter) website and the Single-Sample Gene Set Enrichment Analysis package of R. Finally, molecular docking was used to computationally verify the interaction of ligand and receptor proteins. A total of 9191 genes were significantly differentially expressed in PAAD patients and 34 potential targets of emodin were obtained. Intersections of the 2 groups were considered as potential targets of emodin against PAAD. Functional enrichment analyses illustrated that these potential targets were linked to numerous pathological processes. Hub genes identified through PPI networks were correlated with poor prognosis and infiltration level of different immune cells in PAAD patients. Perhaps emodin interacted with the key molecules and regulate the activity of them. We revealed the inherent mechanism of emodin against PAAD with the aid of network pharmacology, which provided reliable evidence and a novel guideline for clinical treatment.

Identification and validation of a novel prognostic circadian rhythm-related gene signature for stomach adenocarcinoma.

Circadian rhythm genes were reported to be strongly associated with the development and prognosis of circadian rhythm disorders related to stomach adenocarcinoma (STAD), which is one of the most prevalent cancers. This study aimed to identify a circadian rhythm-related gene signature that could help predict STAD outcome. Using bioinformatics analysis approaches, 105 genes were examined in 350 patients with STAD. Overall, six hub-type circadian rhythm-associated genes (GNA11, PER1, SOX14, EZH2, MAGED1, and NR1D1) were identified using univariate and multivariate Cox regression analyses. These genes were then used to build a genetic predictive model, which was further validated using a publicly available dataset (GSE26899). Overall, genes associated with the circadian rhythm were found to be substantially correlated with the characteristics of the STAD patients (grade, sex, and M stage). In addition, the circadian rhythm-related gene signature was significantly associated with the MAPK and Notch signaling pathways, which are known risk factors for poorer STAD outcome. Taken together, these findings suggest that the herein proposed prognostic model based on six circadian rhythm-associated genes may have predictive value and potential application for clinical decision-making and for personalized treatment of STAD.

Pathology Data-Based Risk Group Stratification Is Equivalent to That Obtained by Oncotype DX Testing in Prostatic Adenocarcinoma.

CONTEXT.­: Low-risk (Gleason score 3 + 3 = 6) and intermediate-risk (Gleason score 3 + 4 = 7) prostate carcinoma cases diagnosed on needle biopsies are frequently referred for gene expression studies such as Oncotype DX to help validate the risk. Risk assessment helps in determining prognosis and therapeutic decision making. OBJECTIVE.­: To determine if addition of molecular testing is necessary, by evaluating its correlation with risk stratification provided by pathology report (Gleason score, Grade Group, proportion of positive cores) and serum prostate-specific antigen (PSA) level. DESIGN.­: Our institutional database was searched for cases that had Oncotype DX testing after prostate biopsy. The final risk category determined by molecular testing was compared to the risk stratification predicted by the pathology report and serum PSA levels. Cases were classified as concordant if they fell under the same National Comprehensive Cancer Network risk and recommended initial therapy group. Follow-up information on discordant cases was obtained and used to determine if risk stratification by molecular testing was superior to that obtained from the clinicopathologic data. RESULTS.­: A total of 4967 prostate biopsies (2015-2020) were screened. Of these, 131 prostate carcinoma cases (2.6%) had Oncotype DX testing and 111 of 131 cases (85%) had follow-up information. There was risk stratification concordance in 93 of 111 cases (84%). All 18 of 111 cases (16%) that were discordant had a follow-up course that matched the risk predicted by pathology data and serum PSA. CONCLUSIONS.­: Risk stratification provided by information in the pathology report on routine biopsy assessment coupled with the serum PSA level is equivalent to that obtained by Oncotype DX testing.

Mutational profiles and prognostic impact in colorectal and high-grade appendiceal adenocarcinoma with peritoneal metastases.

BACKGROUND: Next-generation sequencing (NGS) personalizes cancer treatments. In this study, we analyze outcomes based on NGS testing for colorectal cancer (CRC) and high-grade appendiceal adenocarcinoma (HGA) with peritoneal metastases. METHODS: Retrospective review of genomic analyses and outcomes in patients with CRC or HGA with peritoneal metastases at a high-volume center from 2012 to 2019. RESULTS: Ninety-two patients (57 CRC, 35 HGA) were identified. Overall survival was longer for CRC (52.8 vs. 30.5 months, p = 0.03), though rates of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) were similar. Multiple genes were more frequently mutated in CRC, including KRAS (51% vs. 29%, p = 0.04), TP53 (47% vs. 20%, p < 0.01), and APC (46% vs. 6%, p < 0.01). For CRC, multivariate regression showed an increased hazard ratio (HR) with increasing peritoneal cancer index (1.06 [1.01-1.11], p = 0.02) and a decreased HR following CRS/HIPEC (0.30 [0.11-0.80], p = 0.02). PIK3CA mutation associated with significantly increased HR (3.62 [1.06-12.41], p = 0.04), though only in non-CRS/HIPEC patients. Multivariate analysis in the HGA group showed a benefit following CRS/HIPEC (0.18 [0.06-0.61], p = 0.01) and for mucinous disease (0.38 [0.15-0.96], p = 0.04), while there was an increased HR with TP53 mutation (6.89 [2.12-22.44], p < 0.01). CONCLUSION: CRC and HGA with peritoneal spread have distinct mutational profiles. PIK3CA and TP53 mutations are associated with survival for CRC or HGA with peritoneal metastases, respectively.

Compliance with the Current NCCN Guidelines and Its Critical Role in Pancreatic Adenocarcinoma.

OBJECTIVES: Since 2019, the National Comprehensive Cancer Network (NCCN) has recommended genetic testing for patients diagnosed with pancreatic adenocarcinoma that includes universal germline testing and tumor gene profiling for metastatic, locally advanced, or recurrent disease. However, testing compliance with this guideline has not yet been published in the English literature. METHODS: A quality assurance/quality improvement retrospective review was done to identify patients diagnosed with pancreatic adenocarcinoma from January 2019 to February 2021 to include the patient's clinical status and genetic test results. RESULTS: There were 20 patient cases identified with pancreatic adenocarcinoma. A total of 11 cases had molecular tumor gene profiling and microsatellite instability/mismatch repair (MSI/MMR) testing performed and 1 case had only MSI/MMR testing by immunohistochemistry performed. Only 3 patients of the 20 in total received germline testing. CONCLUSION: There was a significant number of patients for whom tumor gene profiling or germline testing had never been attempted as per recommended NCCN guidelines.

A Constellation of Rare Gynecological Malignancies and Familial Adenomatous Polyposis Gastrointestinal Adenocarcinoma: A Case Report.

Ovarian microcystic stromal tumors (MST) are a rare subtype of sex-cord stromal tumors. We are presenting a case of a MST arising in a patient with familial adenomatous polyposis (FAP) and concurrent colonic adenocarcinoma. During the patient's workup of an ampullary adenoma associated with her FAP, she was found to have an enlarged uterus with a thickened endometrium and an incidental pelvic mass on the fundus of the uterus. Subsequent imaging identified heterogenous bulky ovaries. This patient underwent surgical resection including a total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, bilateral pelvic sentinel lymph node biopsy during her planned total proctocolectomy and transduodenal ampullectomy. Extensive histologic and immunohistochemical investigations were completed and the final pathology report revealed a unique compilation of International Federation of Gynecology and Obstetrics Stage II, grade 1 endometrioid endometrial adenocarcinoma, bilateral ovarian MST, a sperate pedunculated mass favoring a diagnosis of uterine tumor resembling ovarian sex cord tumor (UTROSCT), 2 distinct adenocarcinomas of the colon (T2N0 and T1N0) and a tubular adenoma of the ampulla. The pathology showed the endometroid adenocarcinoma was ß-catenin negative while the MST and UTROSCT both showed nuclear positivity with ß-catenin. To our knowledge this is the first reported case of a UTROSCT with concurrent endometrial adenocarcinoma presenting with bilateral ovarian MST's and adenomatous polyposis coli gene positive FAP colon adenocarcinoma.

HDAC5 Loss Enhances Phospholipid-Derived Arachidonic Acid Generation and Confers Sensitivity to cPLA2 Inhibition in Pancreatic Cancer.

HDAC5 is a class IIa histone deacetylase member that is downregulated in multiple solid tumors, including pancreatic cancer, and loss of HDAC5 is associated with unfavorable prognosis. In this study, assessment of The Cancer Genome Atlas pancreatic adenocarcinoma dataset revealed that expression of HDAC5 correlates negatively with arachidonic acid (AA) metabolism, which has been implicated in inflammatory responses and cancer progression. Nontargeted metabolomics analysis revealed that HDAC5 knockdown resulted in a significant increase in AA and its downstream metabolites, such as eicosanoids and prostaglandins. HDAC5 negatively regulated the expression of the gene encoding calcium-dependent phospholipase A2 (cPLA2), the key enzyme in the production of AA from phospholipids. Mechanistically, HDAC5 repressed cPLA2 expression via deacetylation of GATA1. HDAC5 knockdown in cancer cells enhanced sensitivity to genetic or pharmacologic inhibition of cPLA2 in vitro and in vivo. Fatty acid supplementation in the diet reversed the sensitivity of HDAC5-deficient tumors to cPLA2 inhibition. These data indicate that HDAC5 loss in pancreatic cancer results in the hyperacetylation of GATA1, enabling the upregulation of cPLA2, which contributes to overproduction of AA. Dietary management plus cPLA2-targeted therapy could serve as a viable strategy for treating HDAC5-deficient pancreatic cancer patients. SIGNIFICANCE: The HDAC5-GATA1-cPLA2-AA signaling axis regulates sensitivity to fat restriction plus cPLA2 inhibition in pancreatic ductal adenocarcinoma, proposing dietary management as a feasible strategy for treating a subset of patients with pancreatic cancer.

Underutilization of Guideline-Recommended Mismatch Repair/Microsatellite Instability Biomarker Testing in Advanced Colorectal Cancer.

BACKGROUND: In 2017, DNA mismatch repair/microsatellite instability (MMR/MSI) testing was nationally recommended for advanced colorectal cancers based on favorable immune checkpoint inhibitor responses among patients with MMR-deficient/MSI-high tumors. METHODS: Patients ages ≥20-years-old presenting with stage IV colorectal adenocarcinoma from 2010 to 2017 were identified from the National Cancer Database. 2017 was the latest year with available testing utilization data. Patient, tumor, socioeconomic, and care setting characteristics were evaluated for association with upfront MMR/MSI testing in 2017 using multivariable logistic regression and average adjusted predicted probabilities (%AAP). RESULTS: Among 72,830 stage IV colorectal cancers, upfront MMR/MSI testing levels increased from 16.4% in 2010 to 56.4% in 2017. For patients diagnosed in 2017 (i.e., following national recommendations, n = 10,022), testing levels were lower for older patients (Padj < 0.001), and were independent of patients' race/ethnicity and insurance status. Patients from the poorest quartile of households received less testing [49.6%AAP, 99.9% confidence interval (CI) 45.5-53.7] than patients from the 3rd (56.9%AAP, 99.9% CI, 53.3-60.6; Padj < 0.001) or 4th quartiles (57.6%AAP, 99.9% CI, 54.3-60.9; Padj < 0.001). Although testing levels improved most at community programs, they remained lower in 2017 (46.6%AAP, 99.9% CI, 41.0-52.1) compared with academic/NCI-designated comprehensive cancer centers (62.8%AAP, 99.9% CI, 59.7-65.8; Padj < 0.001). CONCLUSIONS: Upfront MMR/MSI testing utilization for patients with advanced colorectal cancer has increased but there is still substantial need for optimization. Testing utilization disproportionately lagged for patients who were older, from the poorest quartile of households, or managed at community cancer programs. IMPACT: Our findings indicate opportunities for improving rates of MMR/MSI testing and reporting, possibly through incorporation into quality control and accreditation metrics.

Evaluation of methylated DCR1 as a biomarker for response to adjuvant irinotecan-based therapy in stage III colon cancer: cancer and leukaemia Group B 89803 (Alliance).

Aberrantly methylated genes contribute to the landscape of epigenetic alterations in colorectal adenocarcinoma. The global CpG Island methylator phenotype (CIMP) and individually methylated genes are potential prognostic/predictive biomarkers. Research suggests an association between methylated DCR1 (mDCR1) and lack of benefit with irinotecan (IFL) treatment. We assessed the association between DCR1 methylation status and survival in patients receiving adjuvant fluorouracil/ leucovorin (5-FU/LV) or IFL. We analysed data from patients with stage III colon adenocarcinoma randomly assigned to adjuvant 5-FU/LV or IFL in CALGB 89803 (Alliance). The primary endpoint was overall survival (OS), and the secondary endpoint was disease-free survival (DFS). Using tumour sample DNA, we evaluated the association between survival, DCR1 methylation status, and molecular subgroups (BRAF, KRAS, mismatch repair status, CIMP status) using Kaplan-Meier estimator and Cox proportional hazard model. mDCR1 was observed in 221/400 (55%) colon cancers. Histopathologic features were similar between mDCR1 and unmethylated DCR1 (unDCR1) colon cancers. There was no difference in OS (p = 0.83) or DFS (p = 0.85) based on DCR1 methylation status. There was no association between methylation status and response to IFL . In patients with unDCR1 and KRAS-wildtype tumours, those who received IFL had a nearly two-fold worse DFS compared to patients who received 5-FU/LV (HR = 1.85, 95% CI (0.97-3.53, p = 0.06). This relationship was not notable among other subgroups. In stage III colon cancer patients, mDCR1 status did not associate with response to irinotecan. Larger studies may suggest an association between the iridocene response and molecular subgroups.

Mutational profiles of primary pulmonary adenocarcinoma and paired brain metastases disclose the importance of KRAS mutations.

BACKGROUND: Brain metastases present a significant complication in lung cancer with an unmet therapeutic need. METHODS: In this single-centre, retrospective study, we genotyped a clinico-pathologically well-annotated cohort of consecutively resected brain metastases of lung adenocarcinomas and paired primary tumours, diagnosed from 2000 to 2015, using the Ion Torrent Oncomine Comprehensive Cancer Panel v3. RESULTS: Among 444 consecutive brain metastases, 210 (49%) originated from lung cancer. Analysis was successful in 111 samples, including 54 pairs of brain metastasis and primary tumour. Most driver alterations were preserved in brain metastases. Private alterations exclusive to primary tumours, brain metastases or both sites (intersecting cases) were present in 22%, 26% and 26% of cases, respectively. Seven percent had no shared mutations. KRAS mutations were more frequent in primary tumours metastasised to the brain (32/55, 58%) compared to TCGA (33%, p < 0.005) and own data from routine diagnostics, independent from clinical or pathological characteristics. Fourteen cases showed alterations in the EGFR signalling pathway including additional KRAS alterations that were private to brain metastases. KRAS G12C was detected most frequently (26% of patients) and KRAS G12C and G13C variants were significantly enriched in brain metastases. Synchronous and metachronous cases had a similar mutation profile. CONCLUSIONS: Our results suggest an important role of KRAS alterations in the pathobiology of brain metastases from lung adenocarcinomas. This has direct therapeutic implications as inhibitors selectively targeting KRAS G12C are entering the clinics.

[Clinicopathological Features and Expression of P504s,E-cadherin,Erythroblast Transformation-specific Related Gene and Estrogen Receptor in Prostate Adenocarcinoma in Tibet].

Objective To investigate the clinicopathological features and immunohistochemical expression of P504s,E-cadherin,erythroblast transformation-specific related gene(ERG)and estrogen receptor(ER)in prostate adenocarcinoma in Tibet.Methods The clinical data of 15 patients with prostate adenocarcinoma diagnosed by the Department of Pathology of Tibet Autonomous Region People's Hospital from September 2013 to September 2020 were analyzed retrospectively.All patients were assigned to prognostic grade groups based on Gleason score according to the WHO 2016 criteria.Immunostaining of P504s,E-cadherin,ERG,and ER was performed.Results The age of all 15 patients ranged from 61 to 86 years.The serum prostate specific antigen(PSA)concentration was ≥20 ng/ml in 12 patients and<20 ng/ml in 3 patients.Among the 15 patients,11 underwent needle biopsy,1 transurethral resection of the prostate,and 3 radical prostatectomy.Prognostic grouping results revealed 5 cases in grade groups 1-3,4 cases in grade group 4,and 6 cases in grade group 5.Immunohistochemistrically,15 cases(100%)were positive for P504s,E-cadherin and PSA;one case(7%)was positive for ERG;all cases were negative for P63,ER and CK34ßE12.Thirteen cases were followed up for 2-48 months,with 2 cases treated with total prostatectomy and 11 cases with non-surgical treatment.Two cases were lost to follow-up. Conclusions Prostate adenocarcinoma is rare relatively in Tibet.The accuracy of diagnosis can be improved by using multiple immunohistochemical markers.The cases of grades 4 and 5 by pathological confirmed are relatively common in Tibet.P504s and E-cadherin are highly expressed in prostate adenocarcinoma patients in Tibet,while ERG presents low expression,ER is unexpressed.

Identification of potential targets of triptolide in regulating the tumor microenvironment of stomach adenocarcinoma patients using bioinformatics.

This study aimed to identify potential pharmacological targets of triptolide regulating the tumor microenvironment (TME) of stomach adenocarcinoma (STAD) patients. A total of 343 STAD cases from The Cancer Genome Atlas (TCGA) were assigned into high- or low-score groups applying Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE). Hub genes were identified from differentially expressed genes (DEGs) shared by stromal- and immune-related components in the TME of STAD patients using R software. Cox regression analysis was used to identify genes significantly correlated with STAD patient survival. Triptolide target genes were predicted from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Top 30 genes filtered by Cytohubba from 734 DEGs were screened as hub genes. Forty-two genes were found to be at high risk for STAD prognosis. Thirty-four targets of triptolide were predicted using the TCMSP database. Importantly, C-X-C chemokine receptor type 4 (CXCR4) was identified as a potential target of triptolide associated with the TME in STAD. Analysis of survival highlighted the association between CXCR4 upregulation with STAD progression and poor prognosis. Gene Set Enrichment Analysis (GSEA) confirmed that genes in the CXCR4- upregulated group had significant enrichment in immune-linked pathways. Additionally, triptolide targets were found to be significantly enriched in CXCR4-related chemokine and cancer-related p53 signaling pathways. Molecular docking demonstrated a high affinity between triptolide and CXCR4. In conclusion, CXCR4 may be a therapeutic target of triptolide in the treatment of STAD patients by modulating the TME.

Rapid Progression of Metastatic Pancreatic Adenocarcinoma During Platinum-Based Therapy in a Patient Harboring a Pathogenic BRCA2 Germline Variant.

Familial pancreatic adenocarcinoma (PDAC) is most commonly related to inheritance of a pathogenic BRCA variant (J Med Genet 2005;42:711-719). The National Comprehensive Cancer Network recommends germline testing for patients diagnosed with PDAC and recommends platinum-based chemotherapy as the preferred initial systemic therapy for patients harboring a pathogenic BRCA germline variant with PDAC (https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455). PDACs related to pathogenic BRCA germline variants typically demonstrate BRCA loss of heterozygosity (LOH), which results in ineffective DNA damage repair due to a lack of normal BRCA gene product activity. By causing DNA damage, platinum-based therapies have been shown to be highly effective therapies (Cancer Cell 2010;18:499-509, Gen Med 2015;17:569). In contrast, platinum-based therapies would be predicted to be significantly less effective for PDACs in patients with pathogenic BRCA germline variants who have cancers that lack BRCA LOH. Poly (ADP-ribose) polymerase 1 (PARP) is also key to effective DNA repair. The Food and Drug Administration has approved PARP inhibitors for patients carrying germline pathogenic BRCA variants and metastatic breast cancer or ovarian cancer (Ann Oncol 2019;30:558-566, J Clin Oncol 2015;33:244-250). PARP inhibitors would again be expected to be far less effective in patients who carry pathogenic BRCA germline variants with breast and ovarian cancers (those that lack BRCA LOH) than in those with BRCA-related breast and ovarian cancers (which typically demonstrate BRCA LOH), because PARP is involved in DNA repair. Here, we present a patient harboring a pathogenic BRCA germline variant whose PDAC grew rapidly during platinum-based therapy and lacked BRCA LOH and therefore was not likely BRCA related. Given the molecular fingerprint of BRCA-related PDAC in patients with pathogenic BRCA germline variants and the mechanism of action of platinum-based therapies and PARP inhibitors, this case underscores the importance of future studies aimed at determining whether the lack of BRCA LOH in PDACs in pathogenic BRCA germline variant carriers is a biomarker of less responsiveness to platinum-based chemotherapy and PARP inhibitors. KEY POINTS: Platinum-based therapy or Poly (ADP-ribose) polymerase 1 (PARP) inhibitor therapies are highly effective systemic therapy options for most patients with pancreatic adenocarcinoma who carry a germline pathogenic BRCA variant. In the case presented here, a patient carrying a germline pathogenic BRCA variant saw rapid progression of his pancreatic adenocarcinoma while on platinum-based therapy. Next-generation sequencing confirmed that his pancreatic cancer was likely not related to BRCA loss of heterozygosity (LOH). Studies are needed to determine, in patients who harbor germline pathogenic BRCA variants, whether similar cancers (i.e., those that lack BRCA LOH) are less responsive to platinum-based or PARP inhibitor therapies than are those more common BRCA-related cancers (i.e., those that demonstrate LOH).

Melatonin: A regulator of the interplay between FoxO1, miR96, and miR215 signaling to diminish the growth, survival, and metastasis of murine adenocarcinoma.

Melatonin (Mel.), also known as the magic hormone, is a nocturnally secreted hormone orchestrates the clearance of free radicals that have been built up and cumulated during day. This study aims to detect the impact of pineal gland removal on the incidence of tumor development and to assess the signaling pathways via which exogenous melatonin counteract cancer growth. This goal has been achieved by novel approach for pineal destruction using dental micromotor which validated by melatonin downregulation in blood plasma. Mice were injected sub-cutenously with Ehrlich cells to develop solid tumor as a murine model of breast cancer. The increase at tumor markers carcino embryonic antigen, TNFα, and nuclear factor kappa-light-chain-enhancer of activated B cells was over countered by exogenous melatonin supplementation (20 mg/kg) daily for 1 month. The anticancer effects of melatonin were significantly mediated by scavenging H2 O2 and NO and diminishing of lipid peroxidation marker malondialdehyde. The real-time polymerase chain Rx analyses indicated a significant effect of Melatonin in upregulating the expression of miR215, fork head box protein O1 (foxO1), and downregulation of miR96. Flowcytometric analyses indicated a significant effect of melatonin on induction of cell cycle arrest at G1 phase which was further confirmed by Ki67 downregulation. Immunohistochemical analyses indicated the role of melatonin in upregulating P53-dependent apoptosis and downregulating CD44 signaling for survivin, matrix metallo-protein kinase 2, and vascular endothelial growth factor to inhibit cell survival and metastasis. In conclusion, this study sheds the light on M./P53/miR215/CD44 with an emphasis on M./miR96//foxO1 signaling cascades, as a novel pathway of melatonin signaling in adenocarcinoma to diminish cancer cell growth, survival and metastasis.

Is Microsatellite Status Associated With Prognosis in Stage II Colon Cancer With High-Risk Features?

BACKGROUND: The influence of microsatellite instability on prognosis in high-risk stage II colon cancer is unknown. OBJECTIVE: This study aimed to investigate the relationship between microsatellite instability and overall survival in high-risk stage II colon cancer. DESIGN: This is a retrospective review of the National Cancer Database from 2010 to 2016. SETTINGS: This study included national cancer epidemiology data from the American College of Surgeons Commission on Cancer. PATIENTS: Included were 16,788 patients with stage II colon adenocarcinoma and known microsatellite status (1709 microsatellite unstable). MAIN OUTCOME MEASURES: The primary outcome measured was overall survival. RESULTS: Microsatellite unstable cancers with high-risk features had significantly better overall survival than microsatellite stable cancers with high-risk features (5-year survival 80% vs 72%, p = 0.01), and had survival equivalent to microsatellite stable cancers with low-risk features (5-year survival, 80%). When stratified by specific high-risk features, patients with lymphovascular invasion, perineural invasion, or high-grade histology had overall survival similar to patients without these features, only in microsatellite unstable cancers. However, patients with high-risk features of T4 stage, positive margins, and <12 lymph nodes saw no survival benefit based on microsatellite status. This was confirmed on multivariable Cox regression modeling. A subgroup analysis of patients who did not receive chemotherapy similarly demonstrated that microsatellite unstable cancers with lymphovascular invasion, perineural invasion, or high-grade histology had overall survival similar to microsatellite unstable cancers without those features. LIMITATIONS: The study is limited by the lack of specific clinical data and potential treatment bias. CONCLUSIONS: In microsatellite unstable cancers, lymphovascular invasion, perineural invasion, and high-grade histology are not associated with worse overall survival, even when deferring adjuvant chemotherapy. These data support National Comprehensive Cancer Network recommendations to forego chemotherapy in stage II cancers with microsatellite instability and these features. In contrast, some high-risk features were associated with worse survival despite microsatellite unstable biology, and therapies to improve survival need to be explored. See Video Abstract at http://links.lww.com/DCR/B500. ¿EL ESTADO MICROSATÉLITE ESTÁ ASOCIADO CON EL PRONÓSTICO EN EL CÁNCER DE COLON EN ESTADIO II CON CARACTERÍSTICAS DE ALTO RIESGO: Se desconoce la influencia de la inestabilidad microsatélite en el pronóstico del cáncer de colon en estadio II de alto riesgo.Investigar la relación entre la inestabilidad microsatélite y la supervivencia general en el cáncer de colon en estadio II de alto riesgo.Revisión retrospectiva de la base de datos nacional del cáncer de 2010 a 2016.Este estudio incluyó datos nacionales de epidemiología del cáncer de la Comisión de Cáncer del Colegio Americano de Cirujanos.16,788 pacientes con adenocarcinoma de colon en estadio II y estado microsatélite conocido (1,709 microsatélite inestables).Supervivencia global.Los cánceres microsatélite inestables con características de alto riesgo tuvieron una supervivencia general significativamente mejor que los cánceres microsatélite estables con características de alto riesgo (supervivencia a 5 años 80% vs 72%, p = 0.01), y tuvieron una supervivencia equivalente a los cánceres microsatélite estables con características de bajo riesgo (supervivencia a 5 años 80%). Al estratificar por características específicas de alto riesgo, los pacientes con invasión linfovascular, invasión perineural o histología de alto grado tuvieron una supervivencia general similar a la de los pacientes sin estas características, solo en cánceres microsatélite inestables. Sin embargo, los pacientes con características de alto riesgo en estadio T4, márgenes positivos y <12 ganglios linfáticos no tuvieron ningún beneficio de supervivencia basado en el estado de microsatélites. Esto se confirmó en un modelo de regresión de Cox multivariable. Un análisis de subgrupos de pacientes que no recibieron quimioterapia demostró de manera similar que los cánceres microsatélite inestables con invasión linfovascular, invasión perineural o histología de alto grado tenían una supervivencia general similar a los cánceres microsatélite inestables sin esas características.El estudio está limitado por la falta de datos clínicos específicos y el posible sesgo de tratamiento.En los cánceres microsatélite inestables, la invasión linfovascular, la invasión perineural y la histología de alto grado no se asocian con una peor sobrevida general, incluso cuando se aplaza la quimioterapia adyuvante. Estos datos respaldan las recomendaciones de la National Comprehensive Cancer Network de omitir la quimioterapia en los cánceres en estadio II con inestabilidad microsatélite y estas características. Por el contrario, algunas características de alto riesgo se asociaron con una peor supervivencia a pesar de la biología microsatélite inestable, y es necesario considerar las terapias para mejorar la supervivencia.Consulte Video Resumen en http://links.lww.com/DCR/B500. (Traducción-Dr. Jorge Silva Velazco).