A step towards personalizing next line therapy for resected pancreatic and related cancer patients: A single institution\u27s experience

Background: There is a lack of precision medicine in pancreatic ductal adenocarcinoma (PDA) and related cancers, and outcomes for patients with this diagnosis remain poor despite decades of research investigating this disease. Therefore, it is necessary to explore novel therapeutic options for these patients who may benefit from personalized therapies. Objective: Molecular profiling of hepatopancreaticobiliary malignancies at our institution, including but not limited to PDA, was initiated to assess the feasibility of incorporating molecular profiling results into patient oncological therapy planning. Methods: All eligible patients from Thomas Jefferson University (TJU) with hepatopancreaticobiliary tumors including PDA, who agreed to molecular testing profiling, were prospectively enrolled in a registry study from December 2014 to September 2017 and their tumor samples were tested to identify molecular markers that can be used to guide therapy options in the future. Next generation sequencing (NGS) and protein expression in tumor samples were tested at CLIA-certified laboratories. Prospective clinicopathologic data were extracted from medical records and compiled in a de-identified fashion. Results: Seventy eight (78) patients were enrolled in the study, which included 65/78 patients with PDA (local and metastatic) and out of that subset, 52/65 patients had surgically resected PDA. Therapy recommendations were generated based on molecular and clinicopathologic data for all enrolled patients. NGS uncovered actionable alterations in 25/52 surgically resected PDAs (48%) which could be used to guide therapy options in the future. High expression of three proteins, TS (p = 0.005), ERCC1 (p = 0.001), and PD-1 (p = 0.04), was associated with reduced recurrence-free survival (RFS), while TP53 mutations were correlated with longer RFS (p = 0.01). Conclusions: The goal of this study was to implement a stepwise strategy to identify and profile resected PDAs at our institution. Consistent with previous studies, approximately half of patients with resected PDA harbor actionable mutations with possible targeted therapeutic implications. Ongoing studies will determine the clinical value of identifying these mutations in patients with resected PDA

Validation of American Joint Committee on Cancer 8th edition of TNM staging in resected distal pancreatic cancer

BACKGROUND In order to improve risk stratification and clinical management of the pancreatic ductal adenocarcinoma (PDAC), the American Joint Committee on Cancer (AJCC) has published its eighth edition staging manual. Some major changes have been introduced in the new staging system for both T and N categories. Given the rarity of resectable disease, distal pancreatic cancer is likely underrepresented in the published clinical studies, and how the impact of the staging system actually reflects on to clinical outcomes remain unclear. AIM To validate the AJCC 8th edition of TNM staging in distal PDAC. METHODS A retrospective cohort study was performed in seven academic medical centers in the United States. Clinicopathological prognostic factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated through univariate and multivariate analyses. RESULTS Overall, 454 patients were enrolled in the study, and were divided into 2 subgroups: Invasive intraductal papillary mucinous neoplasms (IPMN) (115 cases) and non-IPMN associated adenocarcinoma (339 cases). Compared to invasive IPMN, non-IPMN associated adenocarcinomas are more common in relatively younger patients, have larger tumor size, are more likely to have positive lymph nodes, and are associated with a higher tumor (T) stage and nodal (N) stage, lymphovascular invasion, perineural invasion, tumor recurrence, and a worse PFS and OS. The cohort was predominantly categorized as stage 3 per AJCC 7th edition staging manual, and it’s more evenly distributed based on 8th edition staging manual. T and N staging of both 7th and 8th edition sufficiently stratify PFS and OS in the entire cohort, although dividing into N1 and N2 according to the 8th edition does not show additional stratification. For PDAC arising in IPMN, T staging of the 7th edition and N1/N2 staging of the 8th edition appear to further stratify PFS and OS. For PDAC without an IPMN component, T staging from both versions fails to stratify PFS and OS. CONCLUSION The AJCC 8th edition TNM staging system provides even distribution for the T staging, however, it does not provide better risk stratification than previous staging system for distal pancreatic cancer

Old man gallbladder syndrome: Gangrenous cholecystitis in the unsuspected patient population

Introduction: Acute cholecystitis is a common surgical condition, but not many are aware of the serious complication of gangrenous cholecystitis (GC). Presence of GC increases patients’ postoperative complications, morbidity and mortality. Predictive factors for GC include age >45, male gender, white blood cell count >13,000/mm3 and ultrasound findings of a negative Murphy’s sign. Case presentation: (1) GW, 83 male with dull right upper quadrant pain and a negative Murphy’s sign with further imaging showing a thickened septated gallbladder suggestive of GC. Patient’s surgery was difficult and he received a cholecystostomy tube for drainage. (2) PH, 75 male with minimal right upper quadrant pain, equivocal ultrasound with a negative Murphy’s sign and computer tomography (CT) showing acute cholecystitis. Patient was taken to the operating room for cholecystectomy, with pathology consistent with gangrenous cholecystitis. Discussion: Multiple laboratory findings and imaging patterns have been found to be highly predictive of GC. Along with age and WBC, thickened gallbladder wall and lack of mucosal enhancement have been predictive of GC. On physical examination, lack of Murphy’s sign secondary to denervation from gangrenous changes also increases the index of suspicion for GC. Conclusion: GC is a serious complication of acute cholecystitis with increased morbidity and mortality. There should be a high index of suspicion for GC if the above unique physical and laboratory findings are present

Bacteriological study of the cervix of females suffering from unexplained infertility

Abstract The aim of the present study was microbiological investigation of cervical samples of females suffering from unexplained infertility. 16 women were evaluated by standard bacterial culture method. Among total cases, all showed at least one type of bacteria. In total 27 isolates were obtained and most of these bacteria were isolated several times from different specimens. Staphylococcus was the main microorganism isolated, other common microorganisms generally isolated were Escherichia coli, Pseudomonas, Streptococcus, Micrococcus and Bacillus. When the effect of 24 and 48h old cell culture and cell free supernatant of cervical isolates on human motility was studied in vitro, the results showed that 63% isolates significantly decreased the sperm motility. Heat treated cell culture and cell free supernatant failed to inhibit sperm motility, suggesting the presence of heat labile proteins that may be responsible for decrease in spermatozoal motility. 5 out of 27 isolates were capable of agglutinating spermatozoa. Only washed cells/cell culture could agglutinate spermatozoa while cell free supernatant failed to do so. It seems that there may be certain ligands on bacterial cell surface responsible for sperm agglutination. These results in general suggest that, in vitro co-incubation of spermatozoa with cervical isolates does cause a significant decline in numbers of motile spermatozoa, however, what role do the microorganisms play in vivo has yet to be elucidated

Genetic Drivers of Pancreatic Cancer Are Identical Between the Primary Tumor and a Secondary Lesion in a Long-Term (>5 Years) Survivor After a Whipple Procedure

Background: A new mass in the remnant pancreas of a patient with previously resected pancreatic ductal adenocarcinoma (PDA) typically represents either a recurrence of the initial primary tumor or a second primary tumor. Recent advances in next-generation sequencing (NGS) strategies allow us to compare the genetic makeup of primary and secondary lesions. Case presentation: A 50-year-old Caucasian female presented for a surgical evaluation of a new biopsy-proven PDA at the junction of the body and tail of the pancreas. Six years prior, in 2011, the patient was found to have a T3N0M0 PDA of the pancreatic head, which was surgically resected with a classic Whipple procedure and concurrent hemicolectomy. Pathology showed pancreatic intraepithelial neoplasia grade 2 and PDA with negative surgical margins, positive perineural spread, and negative lymphovascular spread, and the patient received adjuvant chemotherapy and local radiation. In 2017, she was diagnosed with a new PDA lesion in the remaining pancreatic body far from the previous anastomosis site and was taken to surgery for a completion pancreatectomy and revision of the gastrojejunostomy. NGS was performed on both specimens. Both lesions shared identical mutations in KRAS, TP53, and CDKN2A genes. Amplifications of MYC and mutant KRAS were identified in the 2017 tumor and an ACVR1B mutation was identified in the 2011 tumor, but was not found in the 2017 tumor. Conclusions: This case demonstrates the ability to evaluate similarities between key genetic drivers from a resected primary tumor and a PDA lesion that presented in the same patient 6 years later. Histological analysis and NGS can be used to understand potential differences and similarities between lesions and may be useful in future studies as predictive markers or to provide insight into resistance mechanisms (e.g., MYC amplification)