Splenic-vasculature involvement is associated with poor prognosis in resected distal pancreatic cancer.

BACKGROUND: Distal pancreatic carcinoma is one of the most lethal cancers largely due to its high incidence of distant metastasis. This study aims to assess the prognostic value of splenic-vasculature involvement in resected distal pancreatic carcinoma. METHODS: In this retrospective study, we collected the clinicopathologic information of 454 patients with pancreatic cancer and performed univariate and multivariate analyses to identify factors associated with progression-free survival (PFS) and overall survival (OS), with an emphasis on the prognostic value of splenic-artery and -vein involvement. RESULTS: Univariate analysis revealed that larger tumor size, non-intraductal papillary mucinous neoplasm (non-IPMN)-associated adenocarcinoma, poor differentiation, stage pT3, nodal metastasis, lymphovascular invasion, perineural invasion, and pathologic and radiographic evidence of splenic-vein invasion were significantly associated with shorter PFS and OS (all P < 0.05). Multivariate analysis confirmed non-IPMN-associated adenocarcinoma, stage pT3, stage pN1-2, and post-operative adjuvant chemotherapy as independent risk factors for both PFS and OS, and larger tumor size and radiographic evidence of splenic-artery invasion as predictors of PFS only. CONCLUSION: Guidelines should be developed for a uniform approach with regard to the examination and reporting of the status of the splenic vasculature when dealing with distal-pancreatic-cancer specimens.

Selecting the optimal parameters for sonoporation of pancreatic cancer in a pre-clinical model.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the modern world, in part due to poor delivery of chemotherapeutics. Sonoporation can be used to enhance the efficacy of standard of care therapies for PDAC. Using xenograft models of PDAC we investigate sonoporation using four ifferent ultrasound contrast agents (UCAs) and two ultrasound regimens to identify the ideal parameters to increase therapeutic efficacy. MIA-PaCa2 xenografts in over 175 immunodeficient mice were treated with gemcitabine and paclitaxel and subjected to low or high power ultrasound (60 and 200 mW/cm2 respectively) in conjunction with one of four different UCAs. The UCAs investigated were Definity®, SonoVue®, Optison™ or Sonazoid™. Tumor volumes, vascularity, hemoglobin, and oxygenation were measured and compared to controls. High power treatment in conjunction with Sonazoid sonoporation led to significantly smaller tumors when started early (tumors ~50mm3; p = .0105), while no UCAs significantly increased efficacy in the low power cohort. This trend was also found in larger tumors (~250mm3) where all four UCA agents significantly increased therapeutic efficacy in the high power group (p < .01), while only Definity and SonoVue increased efficacy in the low power cohort (p < .03). Overall, the higher power ultrasound treatment modality was more consistently effective at decreasing tumor volume and increasing vascularity characteristics. In conclusion, Sonazoid was the most consistently effective UCA at decreasing tumor volume and increasing vascularity. Thus, we are pursuing a larger phase II clinical trial to validate the increased efficacy of sonoporation in conjunction with chemotherapy in PDAC patients.

Understanding and targeting the disease-related RNA binding protein human antigen R (HuR).

Altered gene expression is a characteristic feature of many disease states such as tumorigenesis, and in most cancers, it facilitates cancer cell survival and adaptation. Alterations in global gene expression are strongly impacted by post-transcriptional gene regulation. The RNA binding protein (RBP) HuR (ELAVL1) is an established regulator of post-transcriptional gene regulation and is overexpressed in most human cancers. In many cancerous settings, HuR is not only overexpressed, but it is "overactive" as denoted by increased subcellular localization within the cytoplasm. This dysregulation of HuR expression and cytoplasmic localization allows HuR to stabilize and increase the translation of various prosurvival messenger RNA (mRNAs) involved in the pathogenesis of numerous cancers and various diseases. Based on almost 20 years of work, HuR is now recognized as a therapeutic target. Herein, we will review the role HuR plays in the pathophysiology of different diseases and ongoing therapeutic strategies to target HuR. We will focus on three ongoing-targeted strategies: (1) inhibiting HuR's translocation from the nucleus to the cytoplasm; (2) inhibiting the ability of HuR to bind target RNA; and (3) silencing HuR expression levels. In an oncologic setting, HuR has been demonstrated to be critical for a cancer cell's ability to survive a variety of cancer relevant stressors (including drugs and elements of the tumor microenvironment) and targeting this protein has been shown to sensitize cancer cells further to insult. We strongly believe that targeting HuR could be a powerful therapeutic target to treat different diseases, particularly cancer, in the near future. This article is categorized under: RNA in Disease and Development > RNA in Disease NRA Turnover and Surveillance > Regulation of RNA Stability Translation > Translation Regulation.

Effect of complement C1-esterase inhibitor on brain edema and inflammation after mild traumatic brain injury in an animal model.

OBJECTIVE: Traumatic brain injury (TBI) is characterized by damage to the blood-brain barrier, inflammation, and edema formation. In this pilot study, we aimed to investigate the effects of a complement inhibitor, C1-esterase inhibitor (C1 INH), on brain edema and inflammation in a rat model of mild TBI. METHODS: Thirty-six male Sprague Dawley rats were randomly assigned to control, TBI, or TBI plus C1 INH groups. TBI and TBI plus C1 INH rats received an injection of saline or 25 IU/kg C1 INH, respectively, with TBI using a weight drop model. Control rats received saline only. Rats were subsequently euthanized and their brain tissue harvested for analysis. The primary outcome was the extent of edema as assessed by the brain's water content. Secondary outcomes included enzyme-linked immunosorbent assays to determine levels of pro-inflammatory mediators. RESULTS: Tumor necrosis factor-α levels were significantly greater in TBI rats than control rats, indicating that inflammation was generated by the weight drop impact. Brain water content following TBI was significantly different between TBI rats treated with C1-INH (78.7%±0.12), untreated TBI rats (79.3%±0.12), and control rats (78.6%±0.15, P=0.001). There was a significant decrease in C3a and interleukin 2 levels among C1 INH-treated rats compared with untreated TBI rats, but no change in levels of tumor necrosis factor-α and S100ß. CONCLUSION: C1-INH inhibited the complement pathway, suggesting that C1-INH may have a therapeutic benefit in TBI. Further studies are needed to investigate the effect of C1-INH on clinical outcomes.

A step towards personalizing next line therapy for resected pancreatic and related cancer patients: A single institution's 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.

Abemaciclib Is Effective Against Pancreatic Cancer Cells and Synergizes with HuR and YAP1 Inhibition.

Mutation or promoter hypermethylation of CDKN2A is found in over 90% of pancreatic ductal adenocarcinomas (PDAC) and leads to loss of function of cell-cycle inhibitors p16 (INK4A) and p14 (ARF) resulting in unchecked proliferation. The CDK4/6 inhibitor, abemaciclib, has nanomolar IC50s in PDAC cell lines and decreases growth through inhibition of phospho-Rb (pRb), G1 cell-cycle arrest, apoptosis, and the senescent phenotype detected with ß-galactosidase staining and relevant mRNA elevations. Daily abemaciclib treatments in mouse PDAC xenograft studies were safe and demonstrated a 3.2-fold decrease in tumor volume compared with no treatment (P < 0.0001) accompanying a decrease in both pRb and Ki67. We determined that inhibitors of HuR (ELAVL1), a prosurvival mRNA stability factor that regulates cyclin D1, and an inhibitor of Yes-Associated Protein 1 (YAP1), a pro-oncogenic, transcriptional coactivator important for CDK6 and cyclin D1, were both synergistic with abemaciclib. Accordingly, siRNA oligonucleotides targeted against HuR, YAP1, and their common target cyclin D1, validated the synergy studies. In addition, we have seen increased sensitivity to abemaciclib in a PDAC cell line that harbors a loss of the ELAVL1 gene via CRISP-Cas9 technology. As an in vitro model for resistance, we investigated the effects of long-term abemaciclib exposure. PDAC cells chronically cultured with abemaciclib displayed a reduction in cellular growth rates (GR) and coresistance to gemcitabine and 5-fluorouracil (5-FU), but not to HuR or YAP1 inhibitors as compared with no treatment controls. We believe that our data provide compelling preclinical evidence for an abemaciclib combination-based clinical trial in patients with PDAC. IMPLICATIONS: Our data suggest that abemaciclib may be therapeutically relevant for the treatment in PDAC, especially as part of a combination regimen inhibiting YAP1 or HuR.

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).

The impact of enoxaparin administration in relationship to hemorrhage in mild traumatic brain injury.

BACKGROUND: Venous thromboembolism prophylaxis in the general trauma population is well established. However, risk of increased intracranial hemorrhage in traumatic brain injury (TBI) population is of concern. The aim for this study is to identify a reproducible model of mild traumatic brain injury (mTBI), evaluated by clinical and histological markers and test the hypothesis that enoxaparin increases the risk of spontaneous brain hemorrhage. METHODS: 40 male Sprague Dawley rats were randomly assigned to 5 groups: group 1 (sham) with no TBI along with 4 groups comparing mTBI with and without pharmacological intervention using enoxaparin at 24 h and 72 h respectively. Mild traumatic brain injury was induced using a weight drop apparatus, with a clinical endpoint of time to right (TTR), along with histological and spectrophotometer analysis for qualitative hemorrhage. RESULTS: There is a statistically significant difference between group 1 (sham) and all other groups with a mean longer time to right of 64 s (p = 0.005) in the mTBI groups. There was a statistically significant difference between group 1 (sham) and all other groups with an increase of 6 g/dL hemoglobin (p < 0.001) in the mTBI groups with no difference in hemorrhage between groups that were treated with enoxaparin. CONCLUSION: The weight drop apparatus is a reproducible model for mTBI that has correlations with clinical and qualitative data. This model was able to produce clinical signs of concussion, as reflected by longer TTR and increased hemoglobin in the mTBI groups. Upon further analysis, there wasno increase in hemorrhage in the pharmacological intervention groups with enoxaparin.

Laparoscopic-assisted Ventral Hernia Repair: Primary Fascial Repair with Polyester Mesh versus Polyester Mesh Alone.

Laparoscopic-assisted ventral hernia repair (LAVHR) with mesh is well established as the preferred technique for hernia repair. We sought to determine whether primary fascial closure and/or overlap of the mesh reduced recurrence and/or complications. We conducted a retrospective review on 57 LAVHR patients using polyester composite mesh between August 2010 and July 2013. They were divided into mesh-only (nonclosure) and primary fascial closure with mesh (closure) groups. Patient demographics, prior surgical history, mesh overlap, complications, and recurrence rates were compared. Thirty-nine (68%) of 57 patients were in the closure group and 18 (32%) in the nonclosure group. Mean defect sizes were 15.5 and 22.5 cm(2), respectively. Participants were followed for a mean of 1.3 years [standard deviation (SD) = 0.7]. Recurrence rates were 2/39 (5.1%) in the closure group and 1/18 (5.6%) in the nonclosure group (P = 0.947). There were no major postoperative complications in the nonclosure group. The closure group experienced four (10.3%) complications. This was not a statistically significant difference (P = 0.159). The median mesh-to-hernia ratio for all repairs was 15.2 (surface area) and 3.9 (diameter). Median length of stay was 14.5 hours (1.7-99.3) for patients with nonclosure and 11.9 hours (6.9-90.3 hours) for patients with closure (P = 0.625). In conclusion, this is one of the largest series of LAVHR exclusively using polyester dual-sided mesh. Our recurrence rate was about 5 per cent. Significant mesh overlap is needed to achieve such low recurrence rates. Primary closure of hernias seems less important than adequate mesh overlap in preventing recurrence after LAVHR.

Surgical Residency Recruitment-Opportunities for Improvement.

INTRODUCTION: The Association of Program Directors in Surgery convened a panel during Surgical Education Week 2016 to discuss the current state of the general surgery residency application process and to review alternative ways to evaluate the suitability of each applicant to a residency program. METHODS/RESULTS: Over 40,000 applicants registered for the National Resident Matching Program's 2016 Main Residency Match. General Surgery had 2345 applicants for 1241 categorical postgraduate year (PGY)-1 positions, and 1239 of those positions were filled when the matching algorithm was processed. Program Directors reported that only 33% of applications received an in-depth review, and 62% were rejected with minimal review. Eventually (after all applications had been reviewed), only 13% of applicants were invited to interview. CONCLUSIONS: There are several opportunities for improvement within the current application process. These included standardized letter of recommendation and personal statements, refinement of the interview process, and recalibration of the Medical Student Performance Evaluation.

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.

Hepatitis C prevalence in HIV-infected individuals: a comparison of inpatient and outpatient care.

Summary Due to the shared risk factors for viral transmission, coinfection of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is common. This study examined the seroprevalence of HCV among HIV-infected patients in inpatient and outpatient settings. A retrospective chart review of 256 HIV-infected patients was conducted in Prince George's Hospital Center (inpatients from 1 September 2011 to 1 March 2012) and Glenridge Medical Center (outpatients from 1 January 2011 to 31 December 2012). The mean age of the population was 46 ± 12 and 44 ± 11 for inpatients and outpatients, respectively. HIV-infected men comprised 61.9% inpatients and 64.8% outpatients. The overall prevalence of HCV infection in HIV/AIDS patients was 12.5% (32/256), with a higher prevalence in the inpatient group than that in the outpatient group (24.6% vs 11.2%, p < 0.01). The percentages of drug abuse (43.8% vs 16.5%, p < 0.01) and alcoholism (25.0% and 14.3%, p < 0.05) in HCV/HIV-coinfected patients were higher than those in HIV-monoinfected patients. In addition, only 64.9% of HIV-infected and 50.0% of HCV/HIV-coinfected inpatients were followed up with outside care after discharge. To our knowledge, this study, for the first time, revealed that HCV/HIV coinfection was significantly higher in inpatients compared to outpatients. Considering the high prevalence and comorbidities associated with HCV/HIV coinfection, it is recommended that evaluation of hepatic damage, especially fibrosis, should be initiated during hospitalization as well as outpatient care.

Misleading Elevation of Troponin T caused by Polymyositis.

BACKGROUND: Elevations of cardiac enzymes are commonly used to indicate myocardial ischemia, but they can be elevated due to other conditions. Different forms of Troponin (cTnT, sTnT, cTnI), can cause cross-reactivity in the Troponin T assay, leading to false positives. This report describes a patient with polymyositis who had elevated Troponin T, but no cardiac abnormalities. The purpose is to show that Troponin T, which is believed to be solely from cardiac muscle breakdown, can be seen in inflammatory muscle disease, so Troponin I should be used instead. DESCRIPTION: This is a case report of a 70-year-old woman with a history of diabetes, hypertension, gout and polymyositis, who presented with one-day history of lightheadedness and abdominal pain. To rule out myocardial ischemia, cardiac enzyme testing was ordered which showed elevated CK, CK-MB, and Troponin T. A full cardiac workup was performed which showed no signs of ischemia. Troponin I was <0.05 ng/mL, (normal). DISCUSSION: In inflammatory myositis, there are elevations in many cardiac markers due to non-cardiac causes, which could be related to muscle regeneration and gene expression. This is not seen certain isoforms of Troponin I, specifically cardiac Troponin I. CONCLUSION: In patients with history of diabetes and other comorbidities, silent myocardial ischemias should be ruled out. Non-cardiac elevations in Troponin T can be seen in patients with inflammatory, so Troponin I should be ordered to get an accurate interpretation. Patients with inflammatory myopathies can have elevations in CK, CK-MB, and Troponin T, but not Troponin I.