Grading Pancreatic Neuroendocrine Tumors Via Endoscopic Ultrasound-guided Fine Needle Aspiration: A Multi-institutional Study.

OBJECTIVES: To identify factors associated with concordance between World Health Organization (WHO) grade on cytological analysis (c-grade) and histopathological analysis (h-grade) of surgical specimen in patients with PanNETs and examine trends in utilization and accuracy of EUS-FNA in preoperatively predicting grade. BACKGROUND: WHO grading system is prognostic in pancreatic neuroendo-crine tumors (PanNETs). The concordance between c-grade and h-grade is reported to be between 50% and 92%. METHODS: A multicenter retrospective study was performed on patients undergoing resection for PanNETs at four high-volume centers between 2010 and 2019. Patients with functional or syndrome-associated tumors, and those receiving neoadjuvant therapy were excluded. Factors associated with concordance between c-grade and h-grade and trends of utilization of EUS-FNA were assessed. RESULTS: Of 869 patients included, 517 (59.5%) underwent EUS-FNA; 452 (87.4%) were diagnostic of PanNETs and WHO-grade was reported for 270 (59.7%) patients. The concordance between c-grade and h-grade was 80.4% with moderate concordance ( Kc = 0.52, 95% CI: 0.41-0.63). Significantly higher rates of concordance were observed in patients with smaller tumors (<2 vs. ≥2cm, 81.1% vs. 60.4%, P = 0.005). Highest concordance (98.1%) was observed in patients with small tumors undergoing assessment between 2015-2019 with a near-perfect concordance ( Kc = 0.88, 95% CI: 0.61-1.00). An increase in the utilization of EUS-FNA (56.1% to 64.1%) was observed over the last 2 decades ( P = 0.017) and WHO-grade was more frequently reported (44.2% vs. 77.6%, P < 0.001). However, concordance between c-grade and h-grade did not change significantly (P = 0.118). CONCLUSION: Recently, a trend towards increasing utilization and improved diagnostic accuracy of EUS-FNA has been observed in PanNETs. Concordance between c-grade and h-grade is associated with tumor size with near-perfect agreement when assessing PanNETs <2cm in size.

Recurring Pancreatic Neuroendocrine Tumor: Timing and Pattern of Recurrence and Current Treatment.

OBJECTIVE: The objective of this study was to describe the pattern of recurrence, treatments received, as well the oncological outcomes, of pancreatic neuroendocrine tumors (PanNETs) following curative surgery. BACKGROUND: PanNETs recur in 10% to 15% of cases following surgery. Information on the natural history and management of recurring disease is lacking. MATERIALS AND METHODS: Patients with PanNET that underwent curative surgery at 4 institutions between 2000 and 2019 were identified. Patients with poorly differentiated tumors, unknown tumor grade and differentiation, hereditary syndromes, unknown margin or R2 status, metastatic, and those that had neoadjuvant treatment or perioperative mortality were excluded. Clinical variables were assessed including first site of recurrence, treatment received, and survival outcomes. RESULTS: A total of 1402 patients were included: 957 (74%) had grade 1, 322 (25%) had grade 2, and 13 (1%) had grade 3 tumors. Median follow-up was 4.8 years (interquartile range: 2-8.2 years). Cumulative incidence of recurrence at 5 years was 13% (95% CI: 11%-15.2%) for distant disease, 1.4% (95% CI: 0.8%-2.3%) for locoregional recurrence, and 0.8% (95% CI: 0.4%-1.5%) for abdominal nodal recurrence. Patients who recurred had 2.89 increased risk of death (95% CI: 2-4.1) as compared with patients who did not recur. Therapy postrecurrence included: somatostatin analogs in 111 (61.0%), targeted therapies in 48 (26.4%), liver-directed therapies in 61 (33.5%), peptide receptor radionuclide therapy in 30 (16.5%), and surgery in 46 (25.3%) patients. Multiple treatments were used in 103 (57%) cases. After the first recurrence, 5-year overall survival was 74.6% (95% CI: 67.4%-82.5%). CONCLUSIONS: Recurrence following surgery is infrequent but reduces survival. Most recurrences are distant and managed with multiple therapies. Prospective studies are needed to establish strategies for surveillance and the sequence of treatment to control the disease and prolong survival.

Predicting recurrence in pancreatic neuroendocrine tumours: role of ARX and alternative lengthening of telomeres (ALT).

BACKGROUND: While many pancreatic neuroendocrine tumours (PanNET) show indolent behaviour, predicting the biological behaviour of small nonfunctional PanNETs remains a challenge. Nonfunctional PanNETs with an epigenome and transcriptome that resemble islet alpha cells (ARX-positive) are more aggressive than neoplasms that resemble islet beta cells (PDX1-positive). In this study, we explore the ability of immunohistochemistry for ARX and PDX1 and telomere-specific fluorescence in situ hybridisation (FISH) for alternative lengthening of telomeres (ALT) to predict recurrence. METHODS: Two hundred fifty-six patients with PanNETs were identified, and immunohistochemistry for ARX and PDX1 was performed. Positive staining was defined as strong nuclear staining in >5% of tumour cells. FISH for ALT was performed in a subset of cases. RESULTS: ARX reactivity correlated with worse disease-free survival (DFS) (P = 0.011), while there was no correlation between PDX1 reactivity and DFS (P = 0.52). ALT-positive tumours (n = 63, 31.8%) showed a significantly lower DFS (P < 0.0001) than ALT-negative tumours (n = 135, 68.2%). ARX reactivity correlated with ALT positivity (P < 0.0001). Among nonfunctional tumours, recurrence was noted in 18.5% (30/162) of ARX-positive tumours and 7.5% (5/67) of ARX-negative tumours. Among WHO grade 1 and 2 PanNETs with ≤2 cm tumour size, 14% (6/43) of ARX-positive tumours recurred compared to 0 of 33 ARX-negative tumours and 33.3% (3/9) ALT-positive tumours showed recurrence versus 4.4% (2/45) ALT-negative tumours. CONCLUSION: Immunohistochemistry for ARX and ALT FISH status may aid in distinguishing biologically indolent cases from aggressive small low-grade PanNETs, and help to identify patients who may preferentially benefit from surgical intervention.

Conflicts of Interest in Studies Related to Mesh Use in Ventral Hernia Repair and Abdominal Wall Reconstruction.

OBJECTIVE: To examine the accuracy of the reporting of conflicts of interest (COI) among studies related to mesh use in ventral hernia repair and abdominal wall reconstruction. SUMMARY BACKGROUND DATA: Accurate declaration of COI is integral to ensuring transparency of study results. Multiple studies have demonstrated undeclared COI are prevalent in surgical literature. METHODS: Studies with at least 1 American author accepted between 2014 and 2018 in 12 major, peer-reviewed general surgery and plastic surgery journals were included. Declared COI were compared with payments listed in the "Open Payments" database [maintained by the Centers for Medicare & Medicaid Services (CMS)] during the year of acceptance and 1 year prior. Studies and authors were considered to have a COI if they received payments from any of 8 major mesh companies totaling >$100.00 from each company. Risk factors for undeclared COI were determined at the study and author levels. RESULTS: One hundred twenty-six studies (553 authors) were included. One hundred two studies (81.0%) had one or more authors who received payments from industry and inaccurately declared their COI. Two hundred forty-eight authors (44.8%) did not declare their COI accurately. On multivariate analysis, last authors were found to be at highest risk for undeclared payments (OR 3.59, 95%CI 2.02-6.20), whereas middle authors were at significantly higher risk for undeclared payments than first authors (OR 1.64, 95%CI 1.04-2.56). CONCLUSIONS: The majority of studies investigating the use of mesh in ventral hernia repairs and abdominal wall reconstructions did not accurately declare COI. Last authors are at highest risk of undisclosed payments. Current policies on disclosing COI seem to be insufficient to ensure transparency of publications.

Long-term Outcomes of Parenchyma-sparing and Oncologic Resections in Patients With Nonfunctional Pancreatic Neuroendocrine Tumors <3 cm in a Large Multicenter Cohort.

INTRODUCTION: The role of parenchyma-sparing resections (PSR) and lymph node dissection in small (<3 cm) nonfunctional pancreatic neuroendocrine tumors (PNET) is unlikely to be studied in a prospective randomized clinical trial. By combining data from 4 high-volume pancreatic centers we compared postoperative and long-term outcomes of patients who underwent PSR with patients who underwent oncologic resections. METHODS: Retrospective review of prospectively collected clinicopathologic data of patients who underwent pancreatectomy between 2000 and 2021 was collected from 4 high-volume institutions. PSR and lymph node-sparing resections (enucleation and central pancreatectomy) were compared to those who underwent oncologic resections with lymphadenectomy (pancreaticoduodenectomy, distal pancreatectomy). Statistical testing was performed using χ 2 test and t test, survival estimates with Kaplan-Meier method and multivariate analysis using Cox proportional hazard model. RESULTS: Of 810 patients with small sporadic nonfunctional PNETs, 121 (14.9%) had enucleations, 100 (12.3%) had central pancreatectomies, and 589 (72.7%) patients underwent oncologic resections. The median age was 59 years and 48.2% were female with a median tumor size of 2.5 cm. After case-control matching for tumor size, 221 patients were selected in each group. Patients with PSR were more likely to undergo minimally invasive operations (32.6% vs 13.6%, P <0.001), had less intraoperative blood loss (358 vs 511 ml, P <0.001) and had shorter operative times (180 vs 330 minutes, P <0.001) than patients undergoing oncologic resections. While the mean number of lymph nodes harvested was lower for PSR (n=1.4 vs n=9.9, P <0.001), the mean number of positive lymph nodes was equivalent to oncologic resections (n=1.1 vs n=0.9, P =0.808). Although the rate of all postoperative complications was similar for PSR and oncologic resections (38.5% vs 48.2%, P =0.090), it was higher for central pancreatectomies (38.5% vs 56.6%, P =0.003). Long-term median disease-free survival (190.5 vs 195.2 months, P =0.506) and overall survival (197.9 vs 192.6 months, P =0.372) were comparable. Of the 810 patients 136 (16.7%) had no lymph nodes resected. These patients experienced less blood loss, shorter operations ( P <0.001), and lower postoperative complication rates as compared to patients who had lymphadenectomies (39.7% vs 56.9%, P =0.008). Median disease-free survival (197.1 vs 191.9 months, P =0.837) and overall survival (200 vs 195.1 months, P =0.827) were similar for patients with no lymph nodes resected and patients with negative lymph nodes (N0) after lymphadenectomy. CONCLUSION: In small <3 cm nonfunctional PNETs, PSRs and lymph node-sparing resections are associated with lower blood loss, shorter operative times, and lower complication rates when compared to oncologic resections, and have similar long-term oncologic outcomes.

Arterial involvement and resectability scoring system to predict R0 resection in patients with pancreatic ductal adenocarcinoma treated with neoadjuvant chemoradiation therapy.

OBJECTIVES: To derive a CT-based scoring system incorporating arterial involvement and resectability status to predict R0 resection in patients with pancreatic ductal adenocarcinoma (PDAC) undergoing neoadjuvant chemoradiation therapy (CRT). METHODS: This retrospective study included 112 patients with PDAC who underwent dynamic contrast-enhanced CT before and after neoadjuvant CRT. A 5-point score was used to determine arterial involvement (A score; 1 = no involvement, 2 = haziness, 3 = abutment, 4 = encasement, 5 = deformity) and 4-point score evaluating resectability status (R score; 1 = resectable, 2 = borderline resectable [BR] with venous involvement, 3 = BR with arterial involvement, 4 = locally advanced [LA]). A score before and after CRT were summed with R score before and after CRT to compute the AR score (ARtotal). The associations between ARtotal, R0 resection, overall survival (OS), and disease-free survival (DFS) were assessed. RESULTS: The ARtotal was associated with R0 resection (p < .001) and showed area under the ROC curve of 0.79 for differentiating R0 and R1 resections. Median OS was significantly lower for patients with ARtotal  > 9 (median: 35.2 months) compared to patients with ARtotal ≤ 9 (median: not estimable) (p < .001). Similar results were observed for DFS (median, 16.8 months in > 9 vs median, not estimable in ≤ 9; p < .001). CONCLUSIONS: A composite score which incorporates degree of arterial involvement and resectability status before and after neoadjuvant CRT is associated with R0 resection and discriminates between R0 and R1 resections in PDAC. KEY POINTS: • A scoring system incorporating arterial involvement and resectability status was associated with R0 resection. • ARtotal > 9 could predict patients' overall and disease-free survival.

A Cost-Utility Analysis Comparing Immediate Oncoplastic Surgery with Delayed Oncoplastic Surgery in Smoking Breast Cancer Patients.

BACKGROUND: Oncoplastic reduction mammoplasty for smoking breast cancer patients committed to smoking cessation may be performed immediately (increasing smoking-related risk) or in a delayed fashion (increasing radiation-related risk). OBJECTIVE: Our aim was to examine the cost utility of immediate versus delayed oncoplastic reconstruction when operating on a smoking patient with breast cancer and macromastia with a long-term commitment to smoking cessation. METHODS: A literature review determined the probabilities and outcomes for the treatment of unilateral breast cancer with immediate or delayed oncoplastic surgery. Reported utility scores were used to estimate quality-adjusted life-years (QALYs) for varying health states. A decision analysis tree was constructed with rollback analysis to highlight the more cost-effective strategy, and an incremental cost-utility ratio (ICUR) was calculated. Sensitivity analyses were performed to validate the robustness of the results. RESULTS: Immediate oncoplastic surgery is associated with a higher clinical effectiveness (QALY) of 33.3 compared with delayed oncoplastic surgery (33.26), with a higher increment of clinical effectiveness of 0.07 and relative cost reduction of $3458.11. This resulted in a negative ICUR of -50,194, which favored immediate reconstruction, indicating a dominant strategy. In one-way sensitivity analyses, delayed reconstruction was the more cost-effective strategy if the probability of successful immediate reconstruction falls below 29% or its cost exceeds $29,611. Monte-Carlo analysis showed a confidence of 99% that immediate oncoplastic surgery is more cost effective. CONCLUSIONS: Despite the risk of postoperative complications associated with smoking, immediate oncoplastic surgery is more cost effective compared with delayed oncoplastic surgery in which reconstructive surgery would occur after radiation.

Discordance in Oncotype DX Breast Recurrence Score® Results for Bilateral Breast Cancer.

BACKGROUND: The Oncotype DX Breast Recurrence Score® assay is a clinically useful tool to determine the benefit of chemotherapy in the treatment of early-stage, hormone-receptor-positive breast cancer. Bilateral breast cancer (BBC) is found in ~ 5% of patients with breast cancer, and data regarding discordance of Oncotype DX results between BBC defined by current TAILORx subgroups are limited. Our goals are to study the rate of Oncotype DX discordance between BBC and investigate whether such differences can affect chemotherapy treatment discussions. METHODS: Patients with BBC were identified in US samples submitted to Genomic Health for 21-gene testing between January 2019 and July 2020. The risk categories were defined as 0-25 and 26-100 as well as 0-17, 18-30, and 31-100 for all patients. Subgroup analysis was also performed for node-negative women age ≤ 50 years with Recurrence Score results of 0-15, 16-20, 21-25, and 26-100. RESULTS: 944 BBC patients with known nodal status (702 node negative, 242 node positive) were identified and included. Among node-negative patients aged > 50 years, the rate of discordance in Recurrence Score by group (0-25 and 26-100) was 4.2% (n = 598). For node-negative patients aged ≤ 50 years, the risk group was discordant in < 3% when considering the risk grouping of 0-25 and 26-100. However, upon subgroup analysis based on TAILORx analysis, the rate of discordance was 48.1% in these younger patients (n = 104). CONCLUSIONS: This study shows that a clinically relevant rate of discordance in Oncotype DX results in patients with BBC may impact medical decision-making regarding chemotherapy.

Assessment of the Long-Term Impact of Pancreatoduodenectomy on Health-Related Quality of Life Using the EORTC QLQ-PAN26 Module.

BACKGROUND: Long-term pancreatoduodenectomy (PD) survivors have previously reported favorable quality of life (QoL). However, there has been a paucity of studies utilizing pancreas-specific modules for QoL assessment, which may uncover disability that general modules cannot detect. METHODS: The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-PAN26 questionnaires were administered to PD survivors who were at least 5 years out of their operations for neoplasms (1998-2011, study cohort) and compared their scores with published preoperative scores of patients with pancreatic cancer (control cohort). The clinical relevance (CR) of differences was scored as small (5-10), moderate (10-20), or large (> 20) based on validated interpretation of clinically important differences. RESULTS: Of 1266 patients who underwent PD, there were 305 survivors with valid contact information, of whom 248 responded to the questionnaire (response rate 81.3%) and made up the study cohort. The median follow-up was 9.1 years (range 5.1-21.2 years). When compared with the control cohort, patients in the study cohort reported higher pancreatic pain (41.7 ± 17.6 vs. 18.1 ± 20.5, p < 0.001, CR large), sexuality dissatisfaction (63.0 ± 37.5 vs. 35.1 ± 34.3, p < 0.001, CR large), altered bowel habits (37.6 ± 30.6 vs. 20.0 ± 24.5, p < 0.001, CR moderate), and digestive symptoms (26.3 ± 29.5 vs. 18.7 ± 27.8, p = 0.002, CR small) scores. There was a higher prevalence of bloating, indigestion, and flatulence, but lower prevalence of future health worry (71.7% vs. 89.6%, p < 0.001) and limitation in planning activities (30.1% vs. 48.3%, p < 0.001) at 5 years. CONCLUSION: While post-PD patients had better long-term global QoL than healthy controls, a more granular, pancreas-specific questionnaire uncovered digestive abnormalities and sexuality dissatisfaction. These data can better inform clinical decision making and provide potential areas for improvement and patient support.

Intraoperative Radiation Mitigates the Effect of Microscopically Positive Tumor Margins on Survival Among Pancreatic Adenocarcinoma Patients Treated with Neoadjuvant FOLFIRINOX and Chemoradiation.

BACKGROUND: Microscopically positive margins (R1) negatively impact survival in pancreatic ductal adenocarcinoma (PDAC). For patients with close/positive margins, intraoperative radiotherapy (IORT) can improve local control. The prognostic impact of an R1 resection in patients who receive total neoadjuvant therapy (TNT; FOLFIRINOX with chemoradiation) and IORT is unknown. METHODS: Clinicopathologic data were retrospectively collected for borderline/locally advanced (BR/LA) PDAC patients who received TNT and underwent resection between 2011 and 2019. Disease-free (DFS) and overall survival (OS) measured from time of diagnosis were compared between groups. RESULTS: Two hundred one patients received TNT and were resected, with a median DFS and OS of 24 months and 47 months, respectively. Eighty-eight patients (44%) received IORT; of these, 69 (78%) underwent an R0 and 19 (22%) an R1 resection. There was no significant difference in clinicopathologic factors between the IORT and no-IORT groups, except for resectability status (LA: IORT 69%, no-IORT 53%, p = 0.021) and surgeons' concern for a positive/close margin. R1 resection was associated with worse DFS and OS in the no-IORT population. However, among patients who received IORT, there was no difference in DFS (R0: 29 months, IQR 14-47 vs R1: 20 months, IQR 15-28; p = 0.114) or OS (R0: 48 months, IQR 25-not reached vs R1: 37 months, IQR 30-47; p = 0.307) between patients who underwent R0 vs R1 resection. In multivariate analysis, within the IORT group, R1 resection was not associated with DFS or OS. CONCLUSION: IORT may mitigate the adverse effect of an R1 resection on DFS and OS in BR/LA PDAC patients receiving TNT.

Assessment of Conflicts of Interest in Studies of Breast Implants and Breast Implant Mesh.

BACKGROUND: With increased collaboration between surgeons and industry, there has been a push towards improving transparency of conflicts of interest (COI). METHODS: A literature search identified all articles published between 2016 - 2018 involving breast implants/implantable mesh from three major United States plastic surgery journals. Industry payment data from 8 breast implant/implantable mesh companies was collected using the CMS Open Payments database. COI discrepancies were identified by comparing author declaration statements with payments >$100.00 found for the year of publication and year prior. Risk factors for discrepancy were determined at study and author levels. RESULTS: A total of 162 studies (548 authors) were identified. 126 (78%) studies had at least one author receive undisclosed payments. 295 (54%) authors received undisclosed payments. Comparative studies were significantly more likely to have COI discrepancy than non- comparative studies (83% vs 69%, p < 0.05). Multivariate analysis showed no association between COI discrepancy and final product recommendation. Authors who accurately disclosed payments received higher payments compared to authors who did not accurately disclose payments (median $40,349 IQR 7278-190,413 vs median $1300 IQR 429-11,1544, p <0.001). CONCLUSIONS: The majority of breast implant-based studies had undisclosed COIs. Comparative studies were more likely to have COI discrepancy. Authors who accurately disclosed COIs received higher payments than authors with discrepancies. This study highlights the need for increased efforts to improve the transparency of industry sponsorship for breast implant-based studies.

The Adoption of Oncoplastic Surgery Using Breast Reduction or Mastopexy Techniques in an Academic Breast Cancer Center Program Can Increase Breast Conservation Rates.

BACKGROUND: Interest in oncoplastic surgery (OPS), a form of breast conservation surgery (BCS), has grown in the United States over the last decade. Oncoplastic surgery allows for the removal of larger tumors without compromising esthetic outcome or oncologic safety. One of the quality measures on which breast cancer centers in the United States are evaluated is rate of BCS. The purpose of this study was to investigate whether the adoption of OPS increases BCS rates and decreases mastectomy rates at the institutional level. METHODS: Clinicopathologic data were retrospectively collected for breast cancer patients in a single institution database. Rates of BCS vs mastectomy and partial mastectomy versus OPS were measured between 2012 and 2018 to capture 3 years before and 3 years after the hiring of an oncoplastic surgeon in 2015 with subsequent practice adoption of oncoplastic techniques. We compared the 2 periods using χ and Fisher exact test for categorical variables. Rates of breast conservation and mastectomy were further stratified by tumor stage. RESULTS: Four hundred sixty-eight patients underwent breast cancer surgery at Tufts Medical Center between 2012 and 2018.Patients who underwent surgery between 2012-2015 and 2016-2018 were similar in terms of age, histological type, tumor size, receipt of neoadjuvant therapy, receptor status, and Charlson Comorbidity Index. There was a statistically significant (P < 0.0001) increase in BCS rate after 2015 attributable to the practice adoption of OPS. The proportion of patients who were recommended reexcision did not significantly increase with the introduction of OPS suggesting an appropriate and safe patient selection process for patients undergoing these breast conservation techniques. When stratified by T stage (tumor size), rates of mastectomy for T2 tumors (greater than 2 cm but less than 5 cm) decreased precipitously after 2015 and BCS increased proportionately. The rate of BCS for T1 tumors also increased but less drastically. CONCLUSIONS: The adoption of OPS in an academic breast cancer center can result in significantly higher rates of BCS, particularly for those with larger tumors (T2). Academic breast cancer centers should strongly consider incorporating OPS to their treatment paradigm to provide patients with the option to avoid mastectomy.

Morbidity of curative cancer surgery and suicide risk.

IMPORTANCE: Curative cancer operations lead to debility and loss of autonomy in a population vulnerable to suicide death. The extent to which operative intervention impacts suicide risk is not well studied. OBJECTIVE: To examine the effects of morbidity of curative cancer surgeries and prognosis of disease on the risk of suicide in patients with solid tumors. DESIGN: Retrospective cohort study using Surveillance, Epidemiology, and End Results data from 2004 to 2011; multilevel systematic review. SETTING: General US population. PARTICIPANTS: Participants were 482 781 patients diagnosed with malignant neoplasm between 2004 and 2011 who underwent curative cancer surgeries. MAIN OUTCOMES AND MEASURES: Death by suicide or self-inflicted injury. RESULTS: Among 482 781 patients that underwent curative cancer surgery, 231 committed suicide (16.58/100 000 person-years [95% confidence interval, CI, 14.54-18.82]). Factors significantly associated with suicide risk included male sex (incidence rate [IR], 27.62; 95% CI, 23.82-31.86) and age >65 years (IR, 22.54; 95% CI, 18.84-26.76). When stratified by 30-day overall postoperative morbidity, a significantly higher incidence of suicide was found for high-morbidity surgeries (IR, 33.30; 95% CI, 26.50-41.33) vs moderate morbidity (IR, 24.27; 95% CI, 18.92-30.69) and low morbidity (IR, 9.81; 95% CI, 7.90-12.04). Unit increase in morbidity was significantly associated with death by suicide (odds ratio, 1.01; 95% CI, 1.00-1.03; P = .02) and decreased suicide-specific survival (hazards ratio, 1.02; 95% CI, 1.00-1.03, P = .01) in prognosis-adjusted models. CONCLUSIONS: In this sample of cancer patients in the Surveillance, Epidemiology, and End Results database, patients that undergo high-morbidity surgeries appear most vulnerable to death by suicide. The identification of this high-risk cohort should motivate health care providers and particularly surgeons to adopt screening measures during the postoperative follow-up period for these patients.

Conditional Survival as a Patient Centered Metric for Patients with Appendiceal Adenocarcinoma.

BACKGROUND: Prognosis of appendiceal adenocarcinoma patients is based on burden of disease, histology, and nature of therapy, which remains static despite time in follow-up. We hypothesized that conditional survival provides an informative metric that allows patients better understanding of their disease. METHODS: Using the Surveillance, Epidemiology and End Results database, patients with appendiceal adenocarcinoma from 1988 to 2012 were included. Actuarial Life table analyses and Kaplan-Meier curves were used for statistical inference. RESULTS: Of 5,952 patients, the median age was 60 years (IQR 50-72) and 52 % were female. Histologies included were adenocarcinoma (NOS 37 %), mucinous adenocarcinoma (MA 53 %), and signet ring cell (SRC 10 %). Five-year overall survival (OS) at diagnosis for patients with metastatic disease was 11 % (NOS), 45 % (MA), and 8 % (SRC), respectively. Annual conditional probability of survival from years 1-5 after diagnosis for patients with SRC with metastatic disease was 55, 60, 68, 55, and 82 % compared with 84, 86, 86, 88, and 92 % with MA. Probability of surviving the first year after extended surgery was 77 % (NOS), 85 % (MA), and 75 % (SRC). Those that survived 5 years after surgery had a 94 % (NOS), 93 % (MA), and 86 % (SRC) probability of surviving the sixth year. CONCLUSIONS: In the setting of dismal cumulative probability of survival (or overall survival), conditional probability is more informative in providing prognostication. This distinction might be important for patients especially with SRC who may live in constant fear of disease. Such data can be used to reassure patients and perhaps modify surveillance strategies for patients.

IκB kinase ß (IKBKB) mutations in lymphomas that constitutively activate canonical nuclear factor κB (NFκB) signaling.

Somatic mutations altering lysine 171 of the IKBKB gene that encodes (IKKß), the critical activating kinase in canonical (NFκB) signaling, have been described in splenic marginal zone lymphomas and multiple myeloma. Lysine 171 forms part of a cationic pocket that interacts with the activation loop phosphate in the activated wild type kinase. We show here that K171E IKKß and K171T IKKß represent kinases that are constitutively active even in the absence of activation loop phosphorylation. Predictive modeling and biochemical studies establish why mutations in a positively charged residue in the cationic pocket of an activation loop phosphorylation-dependent kinase result in constitutive activation. Transcription activator-like effector nuclease-based knock-in mutagenesis provides evidence from a B lymphoid context that K171E IKKß contributes to lymphomagenesis.

De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease.

BACKGROUND: IgG4-related disease (IgG4-RD) is a poorly understood, multiorgan, chronic inflammatory disease characterized by tumefactive lesions, storiform fibrosis, obliterative phlebitis, and accumulation of IgG4-expressing plasma cells at disease sites. OBJECTIVE: The role of B cells and IgG4 antibodies in IgG4-RD pathogenesis is not well defined. We evaluated patients with IgG4-RD for activated B cells in both disease lesions and peripheral blood and investigated their role in disease pathogenesis. METHODS: B-cell populations from the peripheral blood of 84 patients with active IgG4-RD were analyzed by using flow cytometry. The repertoire of B-cell populations was analyzed in a subset of patients by using next-generation sequencing. Fourteen of these patients were longitudinally followed for 9 to 15 months after rituximab therapy. RESULTS: Numbers of CD19(+)CD27(+)CD20(-)CD38(hi) plasmablasts, which are largely IgG4(+), are increased in patients with active IgG4-RD. These expanded plasmablasts are oligoclonal and exhibit extensive somatic hypermutation, and their numbers decrease after rituximab-mediated B-cell depletion therapy; this loss correlates with disease remission. A subset of patients relapse after rituximab therapy, and circulating plasmablasts that re-emerge in these subjects are clonally distinct and exhibit enhanced somatic hypermutation. Cloning and expression of immunoglobulin heavy and light chain genes from expanded plasmablasts at the peak of disease reveals that disease-associated IgG4 antibodies are self-reactive. CONCLUSIONS: Clonally expanded CD19(+)CD27(+)CD20(-)CD38(hi) plasmablasts are a hallmark of active IgG4-RD. Enhanced somatic mutation in activated B cells and plasmablasts and emergence of distinct plasmablast clones on relapse indicate that the disease pathogenesis is linked to de novo recruitment of naive B cells into T cell-dependent responses by CD4(+) T cells, likely driving a self-reactive disease process.

Interplay between B7-H3 and HLA class I in the clinical course of pancreatic ductal adenocarcinoma.

Human leukocyte antigen (HLA) class I defects are associated with cancer progression. However, their prognostic significance is controversial and may be modulated by immune checkpoints. Here, we investigated whether the checkpoint B7-H3 modulates the relationship between HLA class I and pancreatic ductal adenocarcinoma (PDAC) prognosis. PDAC tumors were analyzed for the expression of B7-H3, HLA class I, HLA class II molecules, and for the presence of tumor-infiltrating immune cells. We observed defective HLA class I and HLA class II expressions in 75% and 59% of PDAC samples, respectively. HLA class I and B7-H3 expression were positively related at mRNA and protein level, potentially because of shared regulation by RELA, a sub-unit of NF-kB. High B7-H3 expression and low CD8+ T cell density were indicators of poor survival, while HLA class I was not. Defective HLA class I expression was associated with unfavorable survival only in patients with low B7-H3 expression. Favorable survival was observed only when HLA class I expression was high and B7-H3 expression low. Our results provide the rationale for targeting B7-H3 in patients with PDAC tumors displaying high HLA class I levels.

Closed Incision Negative Pressure Therapy in Oncoplastic Breast Surgery: A Comparison of Outcomes.

We aim to discern the impact of closed incision negative pressure therapy (ciNPT) on wound healing in the oncoplastic breast surgery population. Methods: A retrospective analysis was conducted on patients who underwent oncoplastic breast surgery with and without ciNPT in a single health system over 6 years. Oncoplastic breast surgery was defined as breast conservation surgery involving partial mastectomy with immediate volume displacement or replacement techniques. Primary outcomes were rates of clinically significant complications requiring either medical or operative intervention, including seroma, hematoma, fat necrosis, wound dehiscence, and infection. Secondary outcomes were rates of minor complications. Results: ciNPT was used in 75 patients; standard postsurgical dressing was used in 142 patients. Mean age (P = 0.73) and Charlson Comorbidity Index (P = 0.11) were similar between the groups. The ciNPT cohort had higher baseline BMIs (28.23 ± 4.94 versus 30.55 ± 6.53; P = 0.004), ASA levels (2.35 ± 0.59 versus 2.62 ± 0.52; P = 0.002), and preoperative macromastia symptoms (18.3% versus 45.9%; P ≤ 0.001). The ciNPT cohort had statistically significant lower rates of clinically relevant complications (16.9% versus 5.3%; P = 0.016), the number of complications (14.1% versus 5.3% with one complication, 2.8% versus 0% with >2; P = 0.044), and wound dehiscence (5.6% versus 0%; P = 0.036). Conclusions: The use of ciNPT reduces the overall rate of clinically relevant postoperative complications, including wound dehiscence. The ciNPT cohort had higher rates of macromastia symptoms, BMI, and ASA, all of which put them at increased risk for complications. Therefore, ciNPT should be considered in the oncoplastic population, especially in those patients with increased risk for postoperative complications.

Learning Curve of Single-site Robotic Cholecystectomy: A Cumulative Sum Analysis.

BACKGROUND: Minimally invasive surgery has significantly improved cosmesis and clinical outcomes after either laparoscopic or robotic cholecystectomy. In an effort to minimize the number of incisions in multiport procedures, single-site approaches have been developed. However, single-site robotic cholecystectomy (SSRC) can be technically challenging for novice surgeons. The goal of this study is to establish the learning curve (LC) of SSRC through an assessment of operative times and clinical outcomes. MATERIALS AND METHODS: A retrospective analysis of patients undergoing SSRC over a period of 5 years was performed. Consecutive cholecystectomy cases were assessed based on the procedure setting (elective vs. emergent). Cumulative sum analysis were used to establish the LC through an evaluation of the skin-to-skin (STS) time and postoperative complications rate. Afterward, a direct comparison was performed between the established phases. RESULTS: This study included a total of 259 SSRCs with an overall mean STS time of 41.1 minutes. Elective cases took on average of 38.8 minutes, whereas emergent cases spanned over 60.5 minutes ( P= 0.005). The cumulative sum-LC was obtained by summing the differences between each procedure's STS time, revealing a quadratic best-fit line maximum and an inflection point between the early and late phases at case 91. A significant difference between STS time was seen between the early and late phases (53.8 vs. 30.0 min, P< 0.0001). There were no significant differences in terms of postoperative complications between the 2 phases. Incisional hernia rates were comparable between the 2 phases (early: 4.4% vs. late: 2.5%, P< 0.461). CONCLUSIONS: This is the largest study to assess the LC of SSRC through operative time and clinical outcomes. A steady decrease in STS time was observed during the completion of the first 91 consecutive cases.

Association between Preoperative Steroids and Outcomes in Patients Undergoing Pancreaticoduodenectomy using the National Surgical Quality Improvement Program.

BACKGROUND: A national study analyzing the association between preoperative steroid use and outcomes after pancreatic resections is lacking. The purpose of this study is to evaluate the association between preoperative steroids and outcomes after pancreaticoduodenectomy using a national database. MATERIALS AND METHODS: A retrospective analysis of patients undergoing pancreaticoduodenectomy was performed using the National Surgical Quality Improvement Program (NSQIP) database (2014-2019). In addition, we utilized propensity score matching to compare patients on preoperative steroids to those who were not. Outcomes measured included 30-day complications and mortality, need for readmission, a prolonged hospital length of stay, delayed gastric emptying, and pancreatic fistula. RESULTS: After propensity score matching, there were 438 patients in the steroid group and 876 patients in the no steroid group. There was no difference in pancreatic fistula (23.8% vs. 21.7%; p-0.3), delayed gastric emptying (21.1% vs.20.1%; p-0.06), major complications (31.8% vs. 30.1%; p-0.1), and mortality (3.5% vs. 3.2%; p-0.6) between the two groups. CONCLUSION: Glucocorticoids did not reduce the incidence of overall complications, postoperative fistula, and delayed gastric emptying following pancreaticoduodenectomy.