Bradley R. Hall

MUC4 mucin- a therapeutic target for pancreatic ductal adenocarcinoma

ABSTRACT Introduction: Pancreatic cancer (PC) is characterized by mucin overexpression. MUC4 is the most differentially overexpressed membrane-bound mucin that plays a functional role in disease progression and therapy resistance. Area covered: We describe the clinicopathological significance of MUC4, summarize mechanisms contributing to its deregulated expression, review preclinical studies aimed at inhibiting MUC4, and discuss how MUC4 overexpression provides opportunities for developing targeted therapies. Finally, we discuss the challenges for developing MUC4-based therapeutics, and identify areas where efforts should be directed to effectively exploit MUC4 as a therapeutic target for PC. Expert opinion: Studies demonstrating that abrogation of MUC4 expression reduces proliferation and metastasis of PC cells and enhances sensitivity to therapeutic agents affirm its utility as a therapeutic target. Emerging evidence also supports the suitability of MUC4 as a potential immunotherapy target. However, these studies have been limited to in vitro, ex vivo or in vivo approaches using xenograft tumors in immunodeficient murine models. For translational relevance, MUC4-targeted therapies should be evaluated in murine models with intact immune system and accurate tumor microenvironment. Additionally, future studies evaluating MUC4 as a target for immunotherapy must entail characterization of immune response in PC patients and investigate its association with immunosuppression and survival.

Emergent cholecystectomy is superior to percutaneous cholecystostomy tube placement in critically ill patients with emergent calculous cholecystitis

BACKGROUND The role of percutaneous cholecystostomy (PC) is undefined in patients with multiple comorbidities presenting with emergent calculous cholecystitis (CC). This study compared outcomes between PC, laparoscopic (LC), and open cholecystectomy (OC). METHODS The Vizient UHC database was queried for high-risk patients with CC who underwent PC, LC, OC, or laparoscopic converted to open cholecystectomy (CONV). Demographics, outcomes, mortality, length of stay (LOS), and direct cost were compared between the groups. RESULTS LC was the most common approach with the lowest risk of death, complications, LOS, and cost. Complication risk was highest in OC. Nearly 20% of patients underwent PC. Complication rate, LOS, infection, aspiration pneumonia, and mortality were higher in PC. Direct cost was lowest in LC, followed by CONV, PC, and OC. CONCLUSIONS Emergent cholecystectomy for CC in high-risk patients is safer and more cost effective than PC and this study supports the use of cholecystectomy as the primary treatment approach in these patients.

Advanced pancreatic cancer: A meta-analysis of clinical trials over thirty years

Background In contrast to other cancers, survival rates for pancreatic ductal adenocarcinoma (PDAC) patients have improved but minimally over the past thirty years. The aim of this study was to perform a meta-analysis of clinical trials published since 1986 to determine trends in median overall survival in primarily metastatic PDAC. Materials and methods All Phase 2–4 clinical trials published during or after 1986 investigating first-line systemic chemotherapy in metastatic PDAC were included in the meta-analysis. Publications obtained through PubMed and www.ClinicalTrials.gov were cross-referenced to identify additional trials. Trials enrolling fewer than 50% of study participants with metastatic disease were excluded. Results Of 19,488 patients enrolled in 151 clinical trials, 84% had metastatic disease and 16% had locally advanced pancreatic cancer. In clinical trials published from 1986 to 2016, the weighted median overall survival (wMOS) increased by 3.0 months. The median wMOS was higher in combination therapy (7.31 months, IQR 5.4 to 8.5) compared to non-gemcitabine, single-agent therapy (4.76 months, IQR 3.5 to 6.0), gemcitabine monotherapy (6.48 months, IQR 5.9 to 7.2), and gemcitabine plus single-agent therapy (7.09 months, IQR 6.3 to 8.2). Of all regimens used in more than one study arm, FOLFIRINOX had the highest wMOS (10.9 months). Conclusions Regardless of treatment regimen, survival rates in PDAC have minimally improved over time. Of drugs used in two or more study arms, only FOLFIRINOX has a wMOS greater than ten months. Emphasis should, therefore, be placed on identification of novel targets that promote early diagnosis and intervention. Funding The authors on this manuscript are in parts, supported by grants from the National Institutes of Health (EDRN U01 CA200466, SPORE P50 CA127297, R01 CA183459, R21 AA026428 and R01 CA 195586).

Acute symptomatic hyponatremia following elective rhinoplasty: A case report

We present the first reported case of symptomatic hyponatremia after elective rhinoplasty. A 42-year old female underwent cosmetic rhinoplasty without complication and was discharged home after an uneventful recovery from general anesthesia. Just prior to midnight on the day of surgery, she reported nausea, which was treated with supportive care. Four hours later, she developed emesis, altered mental status, and seizure-like activity prompting medical transport to the emergency department. Upon arrival, she was hypotensive (BP 78/54), tachycardic (HR 112 bpm), hyponatremic (116 mmol/L), hypoosmotic (239 mOsm/kg), and had decreased consciousness (GCS = 10). She was admitted to the intensive care unit and had a central line placed for hypertonic saline infusion. Urinalysis was suggestive of SIADH (UrNa 111 mmol/L, UrOsm 546 mOsm/kg) and Nephrology was consulted. Her serum sodium was corrected over three days and her mental status improved. Surgeons should maintain a low threshold for further evaluation in patients who deviate from the expected postoperative recovery pathway. This report demonstrates that normal postoperative symptoms may mask underlying physiological abnormalities that can progress to acute life-threatening illness and underscores the importance of direct patient observation in the immediate postoperative period.

No survival advantage exists for patients undergoing loop ileostomy for clostridium difficile colitis

BACKGROUND We aim to compare outcomes between loop ileostomy (LI) and total abdominal colectomy (TAC) for clostridium difficile infection (CDI) and hypothesize that LI is associated with fewer complications. METHODS The 2011-2016 ACS-NSQIP database was queried for patients undergoing LI or TAC for CDI. Patients with high outlying age, LOS, and operative time were excluded. Statistics were performed using IBM-SPSS and NCSS PASS-11. RESULTS Of 457 patients identified, 47 underwent LI. Predicted morbidity was higher in the TAC cohort (62% vs. 37%, p < 0.001). Patients in the LI cohort experienced fewer complications (72% vs. 87%, p = 0.021); however, mortality did not differ between LI (36%) and TAC (31%). Blood transfusions were more than twice as frequent in the TAC cohort (54% vs. 19%, p < 0.001). Four patients in the LI cohort required reoperation; however, none required colectomy. CONCLUSIONS No mortality difference was observed between LI and TAC. Prospective studies are required to determine the utility of LI. SUMMARY An analysis of the ACS-NSQIP database was performed and demonstrates that no survival benefit exists for patients who undergo loop ileostomy for C difficile infection compared to those who undergo total colectomy; however, patients who undergo loop ileostomy are likely to retain their colon with low risk of requiring subsequent colectomy.

Abstract 5792: Development of cell line derived organoids to evaluate stroma targeted therapies in pancreatic cancer

Background: Most solid tumors have extensive stroma that not only facilitates the tumor progression but also impedes the delivery of the chemotherapeutic agents. Due to lack of any in-vitro system, presently it is difficult to evaluate any stroma-targeted therapies. Therefore, we developed an organoid system using labeled pancreatic cancer and stellate cell lines. Methods: Murine (FC 1295 and imPSCc-2) cell lines cultured in different combinations were grown as an organoid system using matrigel. The organoids, starting day four were treated with either gemcitabine or EC359, a novel mifepristone derived steroidal cytotoxic agent that targets tumor stroma, or both in combination. qRT-PCR analysis of activated stroma signature genes was performed on the mRNA isolated from different treatment groups. HE 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5792. doi:10.1158/1538-7445.AM2017-5792