An Age-Stratified Analysis of Early Postoperative Mortality Among Medicare-Eligible Patients With Common Gastrointestinal and Hepato-pancreato-biliary Malignancies.

Background: The frequency of major cancer surgery in the elderly (≥80 years) has increased concomitantly with the rise in average age of the population. We assessed early postoperative mortality following hepato-pancreato-biliary (HPB) and gastrointestinal (GI) procedures for common malignancies stratified by age. Methods: The National Cancer Database (2004-2017) was queried for patients who underwent resection for GI (gastroesophageal and colorectal) or HPB (pancreatic adenocarcinoma, biliary tract, and primary liver) cancers. We compared early postoperative mortality (30 d and 90 d) stratified by age (65-79 vs ≥80 years) and procedure, and compared survival outcomes by age and operative vs nonoperative management. Results: A total of 709,358 patients were included. The 30-day mortality ranged from 1.8% to 5.8% among patients 65-79 years and from 3.2% to 12.4% among patients ≥80 years depending on procedure. The 90-day mortality ranged from 3.6% to 10.6% in patients 65-79 years compared to 8.4%-21.0% among patients ≥80 years. The overall 90-day mortality was 5.2% for patients 65-79 years and 12.0% for patients ≥80 years (P < .001). Age ≥80 was associated with worse survival among operatively managed patients with each upper GI, HPB, and lower GI malignancy relative to younger patients on multivariable analysis. However, operative management of patients ≥80 years was associated with improved survival relative to nonoperative management. Discussion: Elderly patients suffer higher postoperative mortality after major GI and HPB cancer surgery, but operative management is associated with improved survival among patients ≥80 years as compared to nonoperative management. These data are important to contextualize when counseling elderly patients on their treatment options for localized GI and HPB cancers.

Cancer in the Anal Transition Zone and Ileoanal Pouch following Surgery for Ulcerative Colitis.

Restorative proctocolectomy with ileal pouch-anal anastomosis remains the gold standard treatment for patients with ulcerative colitis who desire restoration of intestinal continuity. Despite a significant cancer risk reduction after surgical removal of the colon and rectum, dysplasia and cancers of the ileal pouch or anal transition zone still occur and are a risk even if an anal canal mucosectomy is performed. Surgical care and maintenance after ileoanal anastomosis must include consideration of malignant potential along with other commonly monitored variables such as bowel function and quality of life. Cancers and dysplasia of the ileal pouch are rare but sometimes difficult-to-manage sequelae of pouch surgery.

Hyperglycemia in the Perioperative Period.

Perioperative hyperglycemia is a risk factor in surgical patients. Complications, including infection and mortality, are associated with hyperglycemia in both diabetic and nondiabetic patients. Stress hyperglycemia results in a state of insulin resistance. Insulin administration has been shown to reduce the complications associated with hyperglycemia. Glycemic targets provide goals for individualized treatment of hyperglycemia in surgical patients in the preoperative, intraoperative, and postoperative periods.

Standardized Letter of Recommendation: Can Everyone Be Awesome?

OBJECTIVE: Standardized letters of recommendation (SLOR) are hypothesized to decrease bias and provide consistent domains for evaluation. However, their ability to differentiate among applicants is unknown. The utilization and functionality of SLOR and the impact of SLOR domain rating on matching for colon and rectal surgery (CRS) residency applicants have yet to be assessed. DESIGN: Descriptive statistics and bivariate analysis were employed. Applicants were categorized into 3 groups; Top-tier(TT): applicants rated 100% Excellent/Very Good; Mid-Tier(MT) applicants rated 80-99% Excellent/Very Good; and Non-Top Tier(NTT) applicants rated <80% Excellent/Very Good. SETTING: University of Hospitals Cleveland Medical Center. PARTICIPANTS: SLORs submitted to a single colorectal surgery residency in 2019 were analyzed RESULTS: A total of 101 applicants were included, 54 (53.5%) of the applicants were male. 75 (74.2%) applicants who applied to our residency matched into a CRS residency, compared to the national rate of 66%. Of the 101 applicants with SLOR, 54 (53.5%) were categorized as TT, 26 (25.7%) as MT, and 21(20.8%) as NTT. The univariable analysis demonstrated a statistically significant difference in research experience (p=0.029) and match status (p=0.01) between applicant tiers. There were no statistically significant differences between applicant-tier and demographics, foreign medical graduates (FMG), H-indices, ABSITE scores, type of residency, preliminary year, completing an unaccredited CRS, and applicants with an additional degree. On multivariable analysis age (OR=0.65; CI=0.48-0.87) and FMG applicants (OR=0.05; CI=0.01-0.44) were inversely associated with successfully matching. Compared to TT applicants, MT (OR=0.07; CI=0.01-0.57) and NTT (OR=0.04; CI=0.01-0.34) applicants were inversely associated with a successful match. Individuals who completed research prior to residency but after medical school was associated with successfully matching (p=0.009). CONCLUSIONS: The presence of MT and NTT ratings is associated with failure to match and may represent an area of concern for CRS programs rather than a tool to discern differences between candidates.

The Evolution of Pelvic Pouch Surgery: Optimal Pouch Design for an Ileal Pouch Anal Anastomosis.

The history of pouch surgery is rooted in surgical innovation to improve quality of life in patients requiring surgical extirpation of the colon and rectum. From the early straight ileoanal anastomosis to the continent ileostomy to the modern ileal pouch anal anastomosis (IPAA), techniques have evolved in response to pitfalls in design. Optimal IPAA design and construction have changed in response to functional outcomes. Nowadays, restorative proctocolectomy with IPAA is the optimal treatment for patients with ulcerative colitis or familial adenomatous polyposis. The J-pouch with stapled anastomosis has become the preferred procedure. Historical configurations and technical pearls, as described in this article, should be considered by surgeons who regularly care for patients requiring ileal pouch surgery.

Factors Associated with Treatment and Survival of Early Stage Pancreatic Cancer in the Era of Modern Chemotherapy: An Analysis of the National Cancer Database.

Background: Underutilization of operative management of early stage pancreatic cancer is associated with sociodemographic variables, including age, race, facility type, insurance, and education. It is currently unclear how these variables are associated with survival in patients who undergo surgery. Methods: Patients with clinical stage I pancreatic adenocarcinoma were identified within the National Cancer Database (2010-2016). Utilization of surgery and nonoperative management was determined. Nonclinical factors associated with nonoperative management were identified by multivariable analysis. The association between nonclinical factors and survival was assessed in patients who received operative management. Results: A total of 17,833 patients with clinical stage I pancreatic cancer were identified, and 41.2% underwent operative intervention. Approximately 46% of nonoperatively managed patients lacked a contraindication. Operatively managed patients had longer overall survival (OS) than those who were nonoperatively managed or untreated (25.1 months vs. 11.1 months vs. 5.1 months, p < 0.0001). Factors associated with nonoperative management included age, black/Hispanic race, nonacademic facilities, nonprivate health insurance, lower education level, and lower income. In operatively managed patients, nonclinical factors associated with lower OS included Medicaid (hazard ratio [HR] 1.27) and treatment at nonacademic facilities (HR 1.20-1.22). Patients on Medicaid received less adjuvant therapy and had higher 30- and 90-day mortality rates. Patients treated at nonacademic facilities received less neoadjuvant therapy, had worse pathologic outcomes, and had higher 30- and 90-day mortality rates. Conclusions: Surgical management is underutilized in clinical stage I pancreatic cancer. Primary insurance payor and facility type appear to be associated with OS in patients who undergo operative management.

Is Sentinel Lymph Node Biopsy Necessary for Ductal Carcinoma In Situ Patients Undergoing Mastectomy?

BACKGROUND: Current treatment guidelines for ductal carcinoma in situ (DCIS) treated with mastectomy recommend sentinel lymph node biopsy (SLNB). In the modern era, there is a trend toward minimizing invasive staging and treatment of the axilla. In this study, we seek to determine the role of SLNB in patients undergoing mastectomy for the treatment of DCIS. METHODS: Patients undergoing mastectomy were identified from our institution's SLNB database from 2012 to 2016. Patients were included if core needle biopsy demonstrated DCIS. Patient demographics, tumor characteristics, and pathologic variables were abstracted. RESULTS: Of 187 patients undergoing mastectomy with SLNB from 2012 to 2016 for DCIS or invasive ductal carcinoma, 39 (21%) were diagnosed with DCIS on core biopsy. Mean age was 57 years. 70% were Caucasian, 18% were African American, 8% were Asian, and the remaining 5% were unknown. One patient (3%) had positive nodes on SLNB and underwent axillary lymph node dissection. Of those with DCIS on core biopsy, 14 (36%) were upstaged to invasive disease on final surgical pathology, including the patient with positive SLNB. Of the remaining 25 (64%) patients with DCIS on final pathology, 0 (0%) had SLNB positivity. CONCLUSION: Only 3% of patients with DCIS undergoing mastectomy were found to have SLN metastases. However, a significant number of patients (36%) were upstaged due to invasive cancer. Although limited by a small sample size, our results suggest that SLNB should still be recommended to patients undergoing mastectomy for DCIS on core needle biopsy due to the high rate of upstage rate to invasive disease.

Is Excisional Biopsy Needed for Pure FEA Diagnosed on a Core Biopsy?

BACKGROUND: The management of flat epithelial atypia (FEA) on core needle biopsy remains controversial. The upstaging rates after surgical excision are variable. In this study, we seek to determine the upstaging rate of FEA at our institution. METHODS: Patients with a diagnosis of FEA were identified from the institution's pathology database from 2009 to 2018. Patients were included in the study if FEA alone, without atypia or cancer, was identified on core needle biopsy. Patient demographics, imaging, management, and pathology characteristics were obtained. Statistical analysis performed using IBM SPSS 26.0 (Armonk, NY, USA). RESULTS: FEA was diagnosed on core needle biopsy in 235 patients from 2009 to December 2018. Forty-eight patients met the inclusion criteria. The majority of patients presented with calcifications on mammogram (n = 21, 64%) with the remainder as masses (n = 6, 18%) or architectural distortion (n = 6, 18%). Of those, 15 (31%) patients declined surgical excision, of which none developed cancer over a mean follow-up of 4.4 years. Of the 33 (69%) patients undergoing excisional biopsy, 17 (52%) confirmed FEA, 11 (33%) had benign findings, and 3 (9%) demonstrated atypical ductal hyperplasia on final pathology. One (3%) case revealed ductal carcinoma in situ (DCIS) and 1 (3%) was upgraded to invasive cancer for an overall upstaging rate of 4% (2/48). After a mean follow-up of 3.4 years, none of the excisional biopsy patients developed invasive breast cancer. Adjuvant therapy was used in the cases of DCIS and invasive cancer; however, chemoprevention with raloxifene or tamoxifen was not chosen by any of the remaining patients. CONCLUSION: In our cohort, expectant management of FEA alone appears to be a safe option as our upstaging rate to DCIS or invasive cancer for FEA diagnosed on core biopsy was only 4%. Our study suggests that close follow-up is a safe and feasible option for pure FEA without a radiographic discordance found on core biopsy.

DNA released from neutrophil extracellular traps (NETs) activates pancreatic stellate cells and enhances pancreatic tumor growth.

Neutrophil extracellular trap (NET) formation results in the expulsion of granulocyte proteins and DNA into the extracellular space. This process is mediated by the enzyme peptidyl arginine deiminase 4 (PADI4) and translocation of elastase to the nucleus. NET formation, marked by increased levels of extracellular DNA, promotes pancreatic cancer proliferation and metastasis. Mice deficient in Padi4 demonstrate decreased pancreatic tumor growth, associated with a reduction in circulating extracellular DNA levels, diminished pancreatic stromal activation and improved survival in murine orthotopic pancreatic adenocarcinoma. Transplantation of Padi4-/- bone marrow into genetically engineered mice with Kras driven pancreatic adenocarcinoma (Pdx1-Cre:KrasG12D/+, KC mice) limits the frequency of invasive cancers when compared with syngeneic controls. DNA from neutrophils activates pancreatic stellate cells that form dense, fibrous stroma which can promote and enable tumor proliferation. DNase treatment diminishes murine tumor growth and stromal activation to reverse the effect of NETs within the tumor microenvironment. Furthermore, deletion of the receptor for advanced glycation end products (RAGE) in pancreatic stellate cells abrogates the effects of DNA in promoting stellate cell proliferation and decreases tumor growth. Circulating neutrophil-derived DNA correlates with the stage in patients with pancreatic ductal adenocarcinoma, confirming the role of NETs in human pancreatic cancer. These findings support further investigation into targeting of NETs, PADI4 and extracellular DNA as a potential treatment strategy in patients with pancreatic cancer. Trial Registration: This study reports correlative data from a clinical trial registered with clinicaltrials.gov, NCT01978184 (November 7, 2013).

The platelet NLRP3 inflammasome is upregulated in a murine model of pancreatic cancer and promotes platelet aggregation and tumor growth.

Platelets are activated in solid cancers, including pancreatic ductal adenocarcinoma (PDA), a highly aggressive malignancy with a devastating prognosis and limited therapeutic options. The mechanisms by which activated platelets regulate tumor progression are poorly understood. The nucleotide-binding domain leucine-rich repeat containing protein 3 (NLRP3) inflammasome is a key inflammatory mechanism recently identified in platelets, which controls platelet activation and aggregation. In an orthotopic PDA mouse model involving surgical implantation of Panc02 murine cancer cells into the tail of the pancreas, we show that the NLRP3 inflammasome in circulating platelets is upregulated in pancreatic cancer. Pharmacological inhibition or genetic ablation of NLRP3 in platelets resulted in decreased platelet activation, platelet aggregation, and tumor progression. Moreover, interfering with platelet NLRP3 signaling significantly improved survival of tumor-bearing mice. Hence, the platelet NLRP3 inflammasome plays a critical role in PDA and might represent a novel therapeutic target.

Inhibition of endoplasmic-reticulum-stress-mediated autophagy enhances the effectiveness of chemotherapeutics on pancreatic cancer.

BACKGROUND: Endoplasmic reticulum (ER) stress and its consequent unfolded protein response (UPR) are believed to be associated with progression, survival and chemoresistance of a variety of tumor cells through multiple cellular processes, including autophagy. Therefore, the ER stress-autophagy pathway presents a potential molecular target for therapeutic intervention. The objective of this study was to evaluate the therapeutic efficacy of ER stress and autophagy modulators in the context of pancreatic ductal adenocarcinoma (PDAC). METHODS: We first targeted IRE1α, an important regulator of the UPR, through STF-083010 treatment in PDAC cell lines in vitro. Chloroquine was then used to target autophagy and an optimal combination treatment was developed using chloroquine, sunitinib and gemcitabine. Apoptosis was analyzed using TUNEL assay, autophagy was estimated using lysotracker staining and electron microscopy, and UPR was analyzed using anti-GRP78 immunostaining and XBP1 splicing. Transplantation of PDAC derived KPCP1 and Panc02 cells in mouse pancreas were performed to study treatment efficacy in vivo. RESULTS: Suppression of the IRE1α by STF-083010 alone resulted in increased lysosomes and reduced viability of PDAC cells. Chloroquine treatment alone inhibited downstream autophagy but was insufficient in reducing PDAC cell growth. However, combining STF-083010 and chloroquine had additive anti-tumor efficacy when used with gemcitabine. Sunitinib alone caused abnormal maturation of the autolysosomes with increased intracellular multivesicular bodies and increased apoptosis evident in PDAC cells. Sunitinib showed a synergistic effect with chloroquine in reducing in vitro PDAC cell viability and significantly increased the efficacy of gemcitabine in human and murine PDAC cell lines. The anti-proliferative effect of gemcitabine was significantly increased when used in combination with sunitinib and/or chloroquine in both in vitro and in vivo PDAC models. The addition of sunitinib and/or chloroquine to gemcitabine, resulted in a significantly increased survival of the animals without noticeably increased toxicity. Sunitinib, gemcitabine and chloroquine treated mice showed a significant reduction of GRP78 expression, reduced cell proliferation and increased apoptosis in pancreas, compatible with a tumor response. CONCLUSIONS: Sunitinib combined with chloroquine reduces tumor growth through suppression of autophagy and increased apoptosis. Co-administration of modulators of ER stress-mediated autophagy with chemotherapy presents a novel therapeutic approach in PDAC.

A margin distance analysis of the impact of adjuvant chemoradiation on survival after pancreatoduodenectomy for pancreatic adenocarcinoma.

BACKGROUND: The role of adjuvant chemoradiotherapy (CRT) following pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PDA) remains controversial. Recent data suggest that increased margin clearance (MC: distance between tumor and cut surface) is associated with improved survival after PD, but the role of adjuvant CRT in patients with known MC is undefined. We sought to delineate the impact of adjuvant CRT on survival based on MC following PD. METHODS: Patients who underwent PD for PDA between 2002 and 2014 were retrospectively stratified into three groups based on MC: 0 mm, ≤1 mm, and >1 mm. The impact of CRT on survival in each MC group was determined by univariate and multivariate analysis. RESULTS: Three hundred and ten patients with known MC were analyzed (0 mm =67, ≤1 mm =113, and >1 mm =130). Increasing MC was independently associated with improved OS (≤1 mm, HR 0.66, 95% CI 0.46-0.96, P=0.03; >1 mm, HR 0.51, 95% CI 0.35-0.75, P=0.001; compared to 0 mm). Adjuvant CRT was administered to 62 patients (20%). On margin-stratified multivariate analysis, adjuvant CRT was independently associated with increased OS in patients with ≤1 mm margins (HR 0.36; 95% CI 0.18-0.69, P=0.002) but not for 0 mm and >1 mm margins. CONCLUSIONS: This analysis suggests that the benefit of adjuvant CRT may be restricted to patients with ≤1 mm MC after PD for pancreatic cancer.

Failure to Treat: Audit of an Institutional Cancer Registry Database at a Large Comprehensive Cancer Center Reveals Factors Affecting the Treatment of Pancreatic Cancer.

BACKGROUND: National Cancer Database analysis showed 70% of patients with stage I pancreatic adenocarcinoma (PDA) did not have surgery. We sought to analyze adherence to expected treatment (ET) by stage for PDA and identify factors that led to no treatment (NT) or unexpected treatment (UT) in a recent cohort. METHODS: Using our Institutional Cancer Registry (ICR), we identified patients with PDA from 2004 to 2013. ET was defined as surgery ± chemotherapy ± radiation for stages I and II, chemotherapy ± radiation for stage III, and chemotherapy for stage IV, while UT was defined as no surgery for stages I and II, surgery for stage III, or ± surgery ± XRT for stage IV. RESULTS: Overall, 2340 patients were identified (stages I and II = 51%, stage III = 11%, stage IV = 38%; ET = 58%, UT = 18%, NT = 24%). A total of 1183 patients had resectable PDA (stages I and II; ET = 57%, UT = 27%, NT = 16%), with ET demonstrating the best overall survival, but UT showing better survival than NT (p < 0.0001). In addition, 261 patients had unresectable PDA (stage III; ET = 69%, UT = 12%, NT = 18%), and survival was best in UT, but ET had a survival advantage over NT (p < 0.0001). Finally, 896 patients had metastatic PDA (stage IV; ET = 55%; UT = 9%; NT = 36%), with the NT group showing worse survival than the ET and UT groups (p < 0.0001). CONCLUSIONS: Unlike previous reports, most patients with early-stage disease had ET. ET and UT were associated with better survival than NT in all stages, and surgical cohorts have improved survival regardless of stage. Younger age, male sex, white race, and less comorbidity were predictors of receiving treatment.

The NLRP3 inflammasome and bruton's tyrosine kinase in platelets co-regulate platelet activation, aggregation, and in vitro thrombus formation.

Cleavage of interleukin-1ß (IL-1ß) is a key inflammatory event in immune cells and platelets, which is mediated by nucleotide-binding domain leucine rich repeat containing protein (NLRP3)-dependent activation of caspase-1. In immune cells, NLRP3 and caspase-1 form inflammasome complexes with the adaptor proteins apoptosis-associated speck-like protein containing a CARD (ASC) and bruton's tyrosine kinase (BTK). In platelets, however, the regulatory triggers and the functional effects of the NLRP3 inflammasome are unknown. Here, we show in vitro that the platelet NLRP3 inflammasome contributes to platelet activation, aggregation, and thrombus formation. NLRP3 activity, as monitored by caspase-1 activation and cleavage and secretion of IL-1ß, was upregulated in activated platelets, which was dependent on platelet BTK. Pharmacological inhibition or genetic ablation of BTK in platelets led to decreased platelet activation, aggregation, and in vitro thrombus formation. We identify a functionally relevant link between BTK and NLRP3 in platelets, with potential implications in disease states associated with abnormal coagulation and inflammation.

Robotic and open distal pancreatectomy with celiac axis resection for locally advanced pancreatic body tumors: a single institutional assessment of perioperative outcomes and survival.

BACKGROUND: Distal pancreatectomy with celiac axis resection (DP-CAR) is an option for T4 tumors of the pancreatic body. We examined the perioperative and oncologic outcomes of open and robotic DP-CAR at a high-volume pancreatic center. METHODS: Retrospective review of all consecutive DP-CARs. Patient demographics, 90-day perioperative outcomes, and disease specific survival were collected. RESULTS: 30 DP-CARs were performed (11 Robotic, 19 Open). Both groups had similar preoperative/tumor characteristics, and 27 of 28 PDA patients received neoadjuvant chemotherapy. Robotic DP-CAR was associated with decreased OT (316 vs. 476 min), reduced EBL (393 vs. 1736 ml) and lower rates of blood transfusion (0% vs. 54%) (all p < 0.05). No robotic DP-CAR required conversion. Both groups had similar rates of 90-day mortality, major morbidity, LOS, readmission, and receipt of adjuvant therapy. Similarly, both approaches were associated with high R0 resection rates (82% vs. 79%). At a median follow-up of 33 months, median overall survival for the PDA cohort was 35 months, with no difference in the robotic and open approach (33 and 40 months, p = 0.310). CONCLUSIONS: With a median survival approaching 3 years, DP-CAR represents an effective treatment for select patients with locally advanced pancreatic body cancer, regardless of approach.