Essential cancer protein identification using graph-based random walk with restart.

Protein-protein interaction (PPI) network analysis holds significant promise for cancer diagnosis and drug target identification. This paper introduces a novel random walk-based method called essential cancer protein identification using graph-based random walk with restart (EPI-GBRWR) to address this gap. This proposed method incorporates local and global topological features of proteins, enhancing the accuracy of essential protein identification in PPI networks. Starting with meticulous preprocessing of cancer gene datasets from NCBI, including breast, lung, colorectal, and ovarian cancers, and identifying a core set of common genes. The proposed method constructs PPI networks to capture complex protein interactions from these common cancer genes. Topological analysis, including a centrality measures matrix, is generated to perform the analysis to identify essential nodes. The study revealed that 40 essential proteins among breast, colorectal, lung and ovarian cancer showcase the potency of integrative methodologies in unravelling cancer complexity, signalling a transformative era in cancer research and treatment. The strength of the findings from the study has direct clinical relevance in cancer diseases. It contributes to the field of precision medicine to guide personalized treatment strategies.

Effect of Preoperative Body Mass Index on Postoperative and Long-Term Outcomes in an East Indian Gastric Cancer Cohort.

BACKGROUND: Gastric cancer is a global health concern with varying clinical outcomes. This study aims to investigate the influence of preoperative Body Mass Index (BMI) on survival in patients who underwent curative resection for gastric cancer in Eastern India. METHODS: Data from a prospectively maintained Surgical Oncology database were analysed for patients who underwent curative resection for primary gastric adenocarcinoma between May 2016 and March 2022. Patients with incomplete data were excluded. Preoperative BMI was categorised into three groups: Underweight (< 18.5 kg/m2), Normal (18.5-22.9 kg/m2), and Overweight/Obese (=23 kg/m2). Clinicopathological details, short-term outcomes, and long-term oncological outcomes were assessed. Statistical analysis included survival estimates, Cox proportional hazard models, and subgroup analysis. RESULT: Of 162 patients, 145 met the inclusion criteria. Patients were predominantly male (68%) with middle or lower socioeconomic status. No significant differences amongst BMI groups were observed in performance score, tumour grade, clinical stage, or short-term outcomes. Postoperative complications and 30-day mortality were similar. However, underweight patients had poorer 4-year disease-free survival (DFS) compared to overweight/obese patients (14.3% vs. 39.7%, p = 0.03). Overweight/obese patients showed significantly better 4-year overall survival (OS) than underweight patients (47.8% vs. 20.4%, p = 0.03). CONCLUSIONS: In Eastern Indian gastric cancer patients undergoing curative resection, preoperative higher BMI (overweight/obese) was associated with better long-term survival. Understanding these findings could guide tailored interventions to improve outcomes in this population.

Laparoendoscopic hybrid procedure - Oncologically safe and feasible option for gastrointestinal stromal tumours of the stomach.

Minimally invasive resection of gastrointestinal stromal tumours of the stomach is a feasible alternative to the traditional open approach, without the need for advanced laparoscopic training, as lymph node dissection is not necessary and excision with a negative margin is the only requirement. The loss of tactile feedback is a known drawback of laparoscopic surgery, causing difficulty in assessing the margin of resection. Earlier described laparoendoscopic techniques require advanced endoscopic procedures, which are not readily available in all places. We present a novel method wherein we use an endoscope to guide the resection margins during laparoscopic surgery. In our experience of five patients, we were able to successfully use this technique to get the negative margins pathologically. This hybrid procedure can thus be used to ensure adequate margin, keeping all the benefits of laparoscopic surgery.

Correlation of 18-fluorodeoxyglucose uptake values on PET-CT scan with histological prognostic markers in breast cancer.

BACKGROUND: Positron emission tomography-computed tomography (PET-CT) scan utilizes 18-fluorodeoxyglucose (18-FDG), based on the principle of higher glycolytic activity and reduced glucose-6-phosphatase levels in cancer cells. This imaging modality is usually advised in the metastatic evaluation of stage III breast cancer patients. The correlation of maximum standard uptake values of primary lesion with different pathological and molecular markers has not been studied extensively. METHODS: Retrospective analysis of the data was performed from our prospectively maintained breast cancer database. All the patients who had undergone 18-FDG PET-CT scan at initial evaluation for staging between June 2017 and April 2020 were included in the study. One-way ANOVA test or Student's t-test as appropriate was performed to assess the difference of means in maximum standard uptake values (SUVmax) of the primary lesion and axillary nodes with clinical stage, histological grade, molecular subtype. Bonferroni post hoc test was also applied. RESULTS: Out of 388 patients in the breast cancer database, 45 patients met inclusion criteria. There was a significant correlation of molecular subtype (p = 0.029) with SUVmax of the primary lesion. Higher primary SUVmax was associated with higher T stage (p = 0.01) and higher histological grade (p = 0.06). In each molecular subtype, there was an increase in mean SUVmax of the primary lesion with increasing histological grade and vice versa. CONCLUSIONS: SUVmax of the primary lesion in breast cancer patients reflects tumor biology. Higher SUVmax can predict patients with triple-negative breast cancers and higher grades in primary tumors. However, further large-scale validatory studies are essential.

Inclusion of Perineural Invasion with AJCC-TNM Staging: Outcomes from a South Asian Cohort of Curatively Treated Gastric Cancer Patients.

BACKGROUND: The incidence of perineural invasion (PNI) in patients with gastric cancer (GC) is high, and patients with PNI positive disease have a poor prognosis compared to PNI-negative disease. The present study aims to study the incidence and evaluate the impact of PNI on the survival outcome of a cohort of South Asian GC patients. MATERIAL AND METHODS: All consecutive patients undergoing curative gastrectomy were included in the study. The incidence of PNI and correlation with different clinico-pathological features and overall survival was performed. RESULTS: A total of 59.54% had PNI-positive disease and the median OS of PNI + ve patients was 29.3 months, while it was not reached in PNI-ve patients. The PNI positivity was a significant prognostic factor for overall survival both on univariate and multivariate analysis. On TNM-PNI staging, those with TNM stage I/II patients with PNI + ve disease had similar OS to all stage III patients (p = 0.835) and were worse than that of PNI-ve patients (p < 0.05). CONCLUSION: The incidence of PNI in gastric cancer is high. The inclusion of PNI with AJCC-TNM staging may better stratify prognostic staging in curatively treated gastric cancer patients.

Prophylactic Drain Versus No Drain in Curative Gastric Cancer Surgery-A Randomized Controlled Trial.

BACKGROUND: The adoption of enhanced recovery after surgery protocols has questioned the placement of prophylactic drain after curative gastrectomy. A 2015 Cochrane meta-analysis did not find convincing evidence of routine drain placement in gastrectomy, but the quality of evidence was questioned. The present study compared short-term outcomes of prophylactic drain placement versus no drain in gastrectomy. METHODOLOGY: The study is a prospective, non-inferiority, and randomized controlled trial. Histologically proven adenocarcinoma of the stomach undergoing curative gastrectomy with D2 lymphadenectomy was included in the study. Randomization was done intra-operatively. The primary outcome was a postoperative hospital stay. Secondary outcomes included the return of bowel function, achieving adequate enteral feeding, re-surgery, morbidity, and mortality. RESULTS: One hundred fifty-seven patients were registered, of which 108 patients underwent curative surgery, and were randomized to 54 patients in each group. The median age was 55 years (range: 23-78) and 58.5 years (range: 35-80) in the drain and no drain group. No significant difference was noticed in primary or secondary outcomes in both groups. CONCLUSION: Avoid placing a prophylactic drain is not inferior to drain placement following gastrectomy with D2 lymphadenectomy for stomach adenocarcinoma. So, routine prophylactic drain placement can be avoided.

RRBP1 rewires cisplatin resistance in oral squamous cell carcinoma by regulating Hippo pathway.

BACKGROUND: Chemoresistance is one of the major factors for treatment failure in OSCC. Identifying key resistance triggering molecules will be useful strategy for developing novel treatment methods. METHODS: To identify the causative factors of chemoresistance, we performed RNA sequencing and global proteomic profiling of human OSCC lines presenting with sensitive, early and late cisplatin-resistance patterns. RESULTS: From the common set of dysregulated genes from both the analysis, RRBP1 was identified to be upregulated in both early and late cisplatin-resistant cells with respect to the sensitive counterpart. Analysis of OSCC patient sample indicates that RRBP1 expression is upregulated in chemotherapy-non-responder tumours as compared to chemotherapy-responder tumours. Genetic (knockout) or pharmacological (Radezolid, represses expression of RRBP1) inhibition of RRBP1 restores cisplatin-mediated cell death in chemo-resistant OSCC. Mechanistically, RRBP1 regulates Yes-associated protein1 (YAP1), a key protein in the Hippo pathway to induce chemoresistance. The PDC xenograft data suggests that knockout of RRBP1 induces cisplatin-mediated cell death and facilitates a significant reduction of tumour burden. CONCLUSION: Overall, our data suggests that (I) RRBP1 is a major driver of cisplatin-resistance in OSCC, (II) RRBP1 regulates YAP1 expression to mediate cisplatin-resistance, (III) Radezolid represses RRBP1 expression and (IV) targeting RRBP1 reverses cisplatin-induced chemoresistance in advanced OSCC.

CMTM6 drives cisplatin resistance by regulating Wnt signaling through the ENO-1/AKT/GSK3ß axis.

Rewiring tumor cells to undergo drug-induced apoptosis is a promising way to overcome chemoresistance. Therefore, identifying causative factors for chemoresistance is of high importance. Unbiased global proteome profiling of sensitive, early, and late cisplatin-resistant oral squamous cell carcinoma (OSCC) lines identified CMTM6 as a top-ranked upregulated protein. Analyses of OSCC patient tumor samples demonstrated significantly higher CMTM6 expression in chemotherapy (CT) nonresponders as compared with CT responders. In addition, a significant association between higher CMTM6 expression and poorer relapse-free survival in esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, and lung squamous cell carcinoma was observed from Kaplan-Meier plot analysis. Stable knockdown (KD) of CMTM6 restored cisplatin-mediated cell death in chemoresistant OSCC lines. Upon CMTM6 overexpression in CMTM6-KD lines, the cisplatin-resistant phenotype was rescued. The patient-derived cell xenograft model of chemoresistant OSCC displaying CMTM6 depletion restored the cisplatin-induced cell death and tumor burden substantially. The transcriptome analysis of CMTM6-KD and control chemoresistant cells depicted enrichment of the Wnt signaling pathway. We demonstrated that CMTM6 interaction with membrane-bound Enolase-1 stabilized its expression, leading to activation of Wnt signaling mediated by AKT-glycogen synthase kinase-3ß. CMTM6 has been identified as a stabilizer of programmed cell death ligand 1. Therefore, as CMTM6 facilitates tumor cells for immune evasion and mediates cisplatin resistance, it could be a promising therapeutic target for treating therapy-resistant OSCC.

DDX3 modulates cisplatin resistance in OSCC through ALKBH5-mediated m6A-demethylation of FOXM1 and NANOG.

Platinum based drugs alone or in combination with 5FU and docetaxel are common regimen chemotherapeutics for the treatment of advanced OSCC. Chemoresistance is one of the major factors of treatment failure in OSCC. Human RNA helicase DDX3 plays an important role in cell proliferation, invasion, and metastasis in several neoplasms. The potential role of DDX3 in chemoresistance is yet to be explored. Enhanced cancer stem cells (CSCs) population significantly contributes to chemoresistance and recurrence. A recent study showed that m6A RNA regulates self-renewal and tumorigenesis property in cancer. In this study we found genetic (shRNA) or pharmacological (ketorolac salt) inhibition of DDX3 reduced CSC population by suppressing the expression of FOXM1 and NANOG. We also found that m6A demethylase ALKBH5 is directly regulated by DDX3 which leads to decreased m6A methylation in FOXM1 and NANOG nascent transcript that contribute to chemoresistance. Here, we found DDX3 expression was upregulated in both cisplatin-resistant OSCC lines and chemoresistant tumors when compared with their respective sensitive counterparts. In a patient-derived cell xenograft model of chemoresistant OSCC, ketorolac salt restores cisplatin-mediated cell death and facilitates a significant reduction of tumor burdens. Our work uncovers a critical function of DDX3 and provides a new role in m6 demethylation of RNA. A combination regimen of ketorolac salt with cisplatin deserves further clinical investigation in advanced OSCC.

STAT3- and GSK3ß-mediated Mcl-1 regulation modulates TPF resistance in oral squamous cell carcinoma.

Cisplatin alone or in combination with 5FU (5-fluorouracil) and docetaxel (TPF) are common regimen chemotherapeutics for treatment of advanced oral squamous cell carcinoma (OSCC). Despite the initial positive response, several patients experience relapse due to chemoresistance. The potential role of Bcl-2 antiapoptotic members in acquired chemoresistance is yet to be explored. To address this, we designed two different relevant OSCC chemoresistant models: (i) acquired chemoresistant cells, where OSCC lines were treated with conventional chemotherapy for a prolonged period to develop chemoresistance, and (ii) chemoresistant patient-derived cells, where primary cells were established from tumor of neoadjuvant-treated OSCC patients who do not respond to TPF. Among all Bcl-2 antiapoptotic members, Mcl-1 expression (but not Bcl-2 or Bcl-xL) was found to be upregulated in both chemoresistant OSCC lines and chemoresistant tumors when compared with their respective sensitive counterparts. Irrespective of all three chemotherapy drugs, Mcl-1 expression was elevated in OSCC cells that are resistant to either cisplatin or 5FU or docetaxel. In chemoresistant OSCC, Mcl-1 mRNA was upregulated by signal transducer and activator of transcription 3 (STAT3) activation, and the protein was stabilized by AKT-mediated glycogen synthase kinase 3 beta (GSK3ß) inactivation. Genetic (siRNA) or pharmacological (Triptolide, a transcriptional repressor of Mcl-1) inhibition of Mcl-1 induces drug-mediated cell death in chemoresistant OSCC. In patient-derived xenograft model of advanced stage and chemoresistant OSCC tumor, Triptolide restores cisplatin-mediated cell death and facilitates significant reduction of tumor burdens. Overall, our data suggest Mcl-1 dependency of chemoresistant OSCC. A combination regimen of Mcl-1 inhibitor with conventional chemotherapy deserves further clinical investigation in advanced OSCC.

A Comparative Study of Clinical Profile and Relapse Patterns in TRIPLE-NEGATIVE and Non-Triple-Negative Breast Cancer Patients Treated with Curative Intent.

Molecular subtyping in breast cancer is recently emerging as an important determinant of treatment and outcomes, and triple negative breast cancer (TNBC) has been established as a distinct clinical entity with unique features and adverse outcomes. A retrospective analysis of a prospectively maintained computerized breast cancer database was performed, and all the non-metastatic female breast cancer patients undergoing potentially curative multimodality treatment between 2005 and 2012 were included for analysis. Patients with incomplete information regarding ER, PR, and HER2/neu status were excluded. All the eligible patients were divided into TNBC and non-TNBC group based on molecular subtyping. A comparative analysis between the two groups was performed to analyze the clinical spectrum and patterns of relapse. A total of 861 patients qualified for the final analysis and the proportion of TNBC was 254 (29.5%) and non-TNBC was 607 (70.5%). Patients in the TNBC group were slightly younger than the non-TNBC group (median age 46 vs. 49, p value = 0.006). TNBC group had a higher breast conservation surgery (BCS) rate, and there was no difference in the need for chemo and radiotherapy between two groups. The overall recurrence rates were significantly higher in TNBC group compared to non-TNBC group (26.8 vs. 19.3%, p value = 0.01). Local disease recurrences were significantly higher in TNBC compared to non-TNBC (7.9 vs. 3.1%, p value = 0.002). Both the regional and systemic recurrences were higher in TNBC group compared to non-TNBC, though the difference failed to attain statistical significance (for regional recurrences 2.4 vs. 1.5%, p value = 0.36; for systemic recurrences 23.2 vs. 17.8%, p value = 0.06). The brain metastasis was significantly higher in TNBC group (6.7 vs. 3.3%, p value = 0.02). In addition, time to relapse was also significantly less in TNBC cohort (16.1 vs. 22.1 months). TNBC accounts for almost one-third of the breast cancer patients with a relatively younger age at presentation, higher volume of disease burden and high breast conservation rates. Despite a standard multimodality therapy the local, systemic, and CNS recurrence rates are high in TNBC and majority relapse within first 2 years after completion of therapy.

Accuracy of Focused Assessment with Sonography for Trauma (FAST) in Blunt Trauma Abdomen-A Prospective Study.

Focused assessment with sonography for trauma (FAST) is a limited ultrasound examination, primarily aimed at the identification of the presence of free intraperitoneal or pericardial fluid. In the context of blunt trauma abdomen (BTA), free fluid is usually due to hemorrhage, bowel contents, or both; contributes towards the timely diagnosis of potentially life-threatening hemorrhage; and is a decision-making tool to help determine the need for further evaluation or operative intervention. Fifty patients with blunt trauma abdomen were evaluated prospectively with FAST. The findings of FAST were compared with contrast-enhanced computed tomography (CECT), laparotomy, and autopsy. Any free fluid in the abdomen was presumed to be hemoperitoneum. Sonographic findings of intra-abdominal free fluid were confirmed by CECT, laparotomy, or autopsy wherever indicated. In comparing with CECT scan, FAST had a sensitivity, specificity, and accuracy of 77.27, 100, and 79.16 %, respectively, in the detection of free fluid. When compared with surgical findings, it had a sensitivity, specificity, and accuracy of 94.44, 50, and 90 %, respectively. The sensitivity of FAST was 75 % in determining free fluid in patients who died when compared with autopsy findings. Overall sensitivity, specificity, and accuracy of FAST were 80.43, 75 and 80 %, respectively, for the detection of free fluid in the abdomen. From this study, we can safely conclude that FAST is a rapid, reliable, and feasible investigation in patients with BTA, and it can be performed easily, safely, and quickly in the emergency room with a reasonable sensitivity, specificity, and accuracy. It helps in the initial triage of patients for assessing the need for urgent surgery.

Primary leiomyosarcoma of epididymis.

Primary leiomyosarcomas rarely arise from epididymis. But they are the most common histopathological types of sarcoma arising from the epididymis. Primary epididymal leiomyosarcoma occurs usually in older patients. We report a young patient of 35 years presenting with leiomyosarcoma of left epididymis. He did not have any metastasis and underwent left high inguinal orchiectomy. He is on regular follow-up and disease free for last two years.