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Background: Peptide receptor radionuclide therapy (PRRT) is an effective treatment for advanced gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). We investigated a 2-decade experience with PRRT to determine whether PRRT confers a survival advantage to patients who progress after surgery versus other therapies., Methods: We identified patients from our clinic who had resection/cytoreduction of GEP-NETs, then disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The Kaplan-Meier method assessed progression-free survival (PFS) and overall survival (OS), calculated from progression after surgery (no-PRRT group) or the start of PRRT. Cox regression with time-dependent covariates controlled for immortal time bias and other confounders., Results: Overall, 237 patients progressed after surgery; 95 received PRRT and 142 did not. No differences existed in sex, T or N stage, tumor grade/differentiation, primary site, or time to progression; 94% of PRRT patients had metastases at diagnosis versus 77% in the no-PRRT group. Median PFS was longer in the PRRT group versus the no-PRRT group (32.4 vs. 11.0 months, p < 0.001), as was median OS (49.8 vs. 38.4 months; p = 0.009). In subgroup analysis, the PRRT group had improved PFS in small bowel NETs and pancreatic NETs. Time-dependent covariate analysis revealed a lower risk of death associated with PRRT (hazard ratio 0.61, p = 0.028) after adjusting for sex, age, M stage, tumor grade, and primary site., Conclusion: Surgical resection and cytoreduction is an effective treatment for patients with GEP-NETs, but most patients with metastatic disease develop recurrent disease. Surgery followed by PRRT after progression conferred superior PFS and OS over no PRRT/other therapies, and is an effective strategy for managing patients with GEP-NETs., (© 2024. Society of Surgical Oncology.)

Introduction: Studies conflict on whether sex influences survival in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). GEP-NETs express receptors and genes responsive to female hormones. We hypothesized that women would have improved survival and this difference would be greater in premenopausal age women compared to older women., Materials and Methods: The National Cancer Database from 2004 to 2016 was queried for patients with GEP-NETs based on histologic code. Demographic, tumor, treatment, and socioeconomic characteristics were compared between men and women and age ≤45 or >65 y using Fisher's exact and Wilcoxon tests as appropriate. The primary endpoint was overall survival (OS), assessed by Kaplan-Meier survival analysis., Results: Included in the study were 73,521 patients with small bowel neuroendocrine tumors (SBNETs), gastric neuroendocrine tumors (GNETs), or pancreas neuroendocrine tumors (36,197 female, 37,324 male). Women lived longer regardless of primary site, with the largest difference in GNETs (median OS 139 versus 85 mo) and smallest in SBNETs (121 versus 116, P < 0.001 for both). While male patients more often had high grade and metastatic disease, female sex remained independently associated with improved OS after adjusting for confounders (hazard ratio 0.84, P < 0.001). In GNETs and SBNETs, female sex had a larger beneficial effect on OS in premenopausal than postmenopausal patients., Conclusions: Women with GEP-NETs have improved survival over men, especially in the premenopausal age group. This may be due to a protective effect of female hormones; however, further studies are necessary to uncover the biologic basis of this difference., (Published by Elsevier Inc.)

Introduction: Chat Generative Pretrained Transformer (ChatGPT) is a large language model capable of generating human-like text. This study sought to evaluate ChatGPT's performance on Surgical Council on Resident Education (SCORE) self-assessment questions., Methods: General surgery multiple choice questions were randomly selected from the SCORE question bank. ChatGPT (GPT-3.5, April-May 2023) evaluated questions and responses were recorded., Results: ChatGPT correctly answered 123 of 200 questions (62%). ChatGPT scored lowest on biliary (2/8 questions correct, 25%), surgical critical care (3/10, 30%), general abdomen (1/3, 33%), and pancreas (1/3, 33%) topics. ChatGPT scored higher on biostatistics (4/4 correct, 100%), fluid/electrolytes/acid-base (4/4, 100%), and small intestine (8/9, 89%) questions. ChatGPT answered questions with thorough and structured support for its answers. It scored 56% on ethics questions and provided coherent explanations regarding end-of-life discussions, communication with coworkers and patients, and informed consent. For many questions answered incorrectly, ChatGPT provided cogent, yet factually incorrect descriptions, including anatomy and steps of operations. In two instances, it gave a correct explanation but chose the wrong answer. It did not answer two questions, stating it needed additional information to determine the next best step in treatment., Conclusions: ChatGPT answered 62% of SCORE questions correctly. It performed better at questions requiring standard recall but struggled with higher-level questions that required complex clinical decision making, despite providing detailed responses behind its rationale. Due to its mediocre performance on this question set and sometimes confidently-worded, yet factually inaccurate responses, caution should be used when interpreting ChatGPT's answers to general surgery questions., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Although correlation between center volume and survival has been reported for several complex cancers, it remains unknown if this is true for colorectal neuroendocrine carcinomas (CRNECs). We hypothesized that higher center annual volume of colorectal neuroendocrine neoplasm resections would be associated with overall survival (OS) for patients with CRNECs., Methods: Patients in the National Cancer Database diagnosed with stages I-III CRNEC between 2006 and 2018 and who underwent surgical resection were identified. The mean annual colorectal neuroendocrine neoplasm resection volume threshold associated with significantly worse mortality hazard was determined using restricted cubic splines. Kaplan-Meier (KM) method was used to compare OS, while Cox proportional hazards model was used for multivariable analysis., Results: There were 694 patients with CRNEC who met inclusion criteria across 1229 centers. Based on the cubic spline, centers treating fewer than one colorectal neuroendocrine neoplasm patient every 3 years on average had worse outcomes. Centers below this threshold were classified as low-volume (LV) centers corresponding with 42% of centers and about 15% of the patient cohort. In unadjusted survival analysis, LV patients had a median OS of 14 months (95% confidence interval [CI]: 10-19) while those treated at HV centers had a median OS of 33 months (95% CI: 25-49). In multivariable analysis, resection at a LV center was associated with increased risk of mortality (1.42 [95% CI: 1.01-2.00], p = 0.04)., Conclusion: CRNEC patients have a dire prognosis; however, treatment at an HV center may be associated with decreased risk of mortality., (© 2024 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Introduction: Despite improvements in preoperative image resolution, approximately 10% of curative-intent resection attempts for pancreatic ductal adenocarcinoma are aborted at the time of operation. To avoid nontherapeutic laparotomy, many surgeons perform intraoperative diagnostic laparoscopy (DL) to identify radiographically occult metastatic disease. There are no consensus guidelines regarding DL in pancreatic cancer. The goal of this study is to investigate the efficacy of same-procedure DL at avoiding nontherapeutic laparotomy., Methods: A single-institution retrospective review was performed from 2016 to 2022, identifying 196 patients with pancreatic ductal adenocarcinoma who were taken to the operating room for open curative-intent resection. Patient demographic, tumor characteristic, treatment, and outcome data were abstracted. Univariate and multivariate Cox hazard ratio analysis was performed to investigate risk factors for overall survival and recurrence-free survival. Number needed to treat (NNT) was calculated to identify number of DLs necessary to avoid one nontherapeutic laparotomy., Results: Curative-intent resection was achieved in 161 (82.1%) patients. One hundred twenty six (64.0%) patients received DL prior to resection and DL identified metastatic disease in three (2.4%) patients with an NNT of 42. NNT of DL in a subgroup analysis performed on clinically high-risk patients (defined by preoperative or preneoadjuvant therapy carbohydrate antigen 19-9 > 500 U/mL) is 11. Receipt of DL did not prolong operative times in patients receiving pancreaticoduodenectomy when accounting for completed versus aborted resection., Conclusions: Although intraoperative DL is a short procedure with minimal morbidity, these data demonstrate that same-procedure DL has potential efficacy in avoiding nontherapeutic laparotomy only in a subgroup of clinically high-risk patients. Focus should remain on optimizing preoperative patient selection and further investigating novel diagnostic markers predictive of occult metastatic disease., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Imaging of peritoneal malignancies using conventional cross-sectional imaging is challenging, but accurate assessment of peritoneal disease burden could guide better selection for definitive surgery. Here we demonstrate feasibility of high-resolution, high-contrast magnetic resonance imaging (MRI) of peritoneal mesothelioma and explore optimal timing for delayed post-contrast imaging., Methods: Prospective data from inpatients with malignant peritoneal mesothelioma (MPM), imaged with a novel MRI protocol, were analyzed. The new sequences augmenting the clinical protocol were (I) pre-contrast coronal high-resolution T2-weighted single-shot fast spin echo (COR hr T2w SSH FSE) of abdomen and pelvis; and (II) post-contrast coronal high-resolution three-dimensional (3D) T1-weighted modified Dixon (COR hr T1w mDIXON) of abdomen, acquired at five delay times, up to 20 min after administration of a double dose of contrast agent. Quantitative analysis of contrast enhancement was performed using linear regression applied to normalized signal in lesion regions of interest (ROIs). Qualitative analysis was performed by three blinded radiologists., Results: MRI exams from 14 participants (age: mean ± standard deviation, 60±12 years; 71% male) were analyzed. The rate of lesion contrast enhancement was strongly correlated with tumor grade (cumulative nuclear score) (r=-0.65, P<0.02), with 'early' delayed phase (12 min post-contrast) and 'late' delayed phase (19 min post-contrast) performing better for higher grade and lower grade tumors, respectively, in agreement with qualitative scoring of image contrast., Conclusions: High-resolution, high-contrast MRI with extended post-contrast imaging is a viable modality for imaging peritoneal mesothelioma. Multiple, extended (up to 20 min post-contrast) delayed phases are necessary for optimal imaging of peritoneal mesothelioma, depending on the grade of disease., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-13/coif). H.L.K. has received consulting fees from AstraZeneca and is on the advisory board of Tempus, Bluestar Genomics, and Sanofi. R.M.E. receives royalties and licensing fees for computer-aided diagnosis technologies through the University of Chicago. A.O. has received funding from NIH and the Sanford J. Grossman Charitable Trust, has received payment for expert testimony, and is a co-owner of Quantitative MR Imaging Solutions (QMIS). S.G.A. is a past president of the International Mesothelioma Interest Group. K.K.T. has received consulting fees from Merck for unrelated work. The other authors have no conflicts of interest to declare., (2024 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Background: Mixed neuroendocrine-non-neuroendocrine neoplasms are a rare subtype of neuroendocrine neoplasm consisting of ≥30% each of neuroendocrine and non-neuroendocrine differentiation. Neuroendocrine carcinomas are poorly differentiated neuroendocrine tumors. The epidemiology and prognosis of colorectal mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas are not clearly defined in the literature. We sought to examine the presentation, patterns of care, and outcomes of patients with mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas., Methods: We identified patients diagnosed with stage I-III colorectal (excluding appendix) mixed neuroendocrine-non-neuroendocrine neoplasms or neuroendocrine carcinomas with only one-lifetime cancer diagnosis who underwent surgical resection between 2010 and 2018 from the National Cancer Database. We performed bidirectional selection to identify variables to include in a multivariable Cox proportional hazards model., Results: We identified 189 patients with a diagnosis of stage I to III colorectal mixed neuroendocrine-non-neuroendocrine neoplasms, 66% of whom had poorly differentiated tumors and 482 with neuroendocrine carcinomas. Among patients with stage III disease, 68% of patients with mixed neuroendocrine-non-neuroendocrine neoplasms and 54% of patients with neuroendocrine carcinomas received adjuvant chemotherapy. The median survival for the overall patients with mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas cohorts were 38 and 42 months, respectively (P = .22), and the median survival for patients with mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas with stage III disease were 30 and 25 months, respectively (P = .27). In multivariable analysis, fewer number of positive nodes and receipt of adjuvant chemotherapy were independently associated with decreased risk of mortality for patients with mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas., Conclusion: Adjuvant chemotherapy is associated with improved survival in stage III mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas. Future studies are warranted to identify subsets of patients benefiting most from adjuvant therapy., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The incidence of colorectal cancer in patients <50 years has rapidly risen recently. Understanding the presenting symptoms may facilitate earlier diagnosis. We aimed to delineate patient characteristics, symptomatology, and tumor characteristics of colorectal cancer in a young population., Methods: A retrospective cohort study was conducted evaluating patients <50 years diagnosed between 2005 and 2019 with primary colorectal cancer at a university teaching hospital. The number and character of colorectal cancer-related symptoms at presentation was the primary outcome measured. Patient and tumor characteristics were also collected., Results: Included were 286 patients with a median age of 44 years, with 56% <45 years. Nearly all patients (95%) were symptomatic at presentation, with 85% having 2 or more symptoms. The most common symptoms were pain (63%), followed by change in stool habits (54%), rectal bleeding (53%), and weight loss (32%). Diarrhea was more common than constipation. More than 50% had symptoms for at least 3 months before diagnosis. The number and duration of symptoms were similar in patients older than 45 compared to those younger. Most cancers were left-sided (77%) and advanced stage at presentation (36% stage III, 39% stage IV)., Conclusion: In this cohort of young patients with colorectal cancer, the majority presented with multiple symptoms having a median duration of 3 months. It is essential that providers be mindful of the ever-increasing incidence of colorectal malignancy in young patients, and that those with multiple, durable symptoms should be offered screening for colorectal neoplasms based on symptoms alone., (Published by Elsevier Inc.)

Introduction: Peritoneal metastases (PMs) following resection of pancreatic intraductal papillary mucinous neoplasms (IPMNs) are rare. Consequently, prevalence, risk factors, and prognosis are not well known. We reviewed our institution's experience and published literature to further characterize the scope of this phenomenon., Methods: All pancreatectomy cases (556 patients) performed at a tertiary care center between 2010 and 2020 were reviewed to identify IPMN diagnoses. Patients with adenocarcinoma not arising from IPMN, or a history of other malignancies were excluded., Results: Seventy-eight patients underwent pancreatectomy with IPMN on final pathology at our institution; 51 met inclusion criteria. Of these, there were five cases of PMs (4:1 females:males). Four had invasive carcinoma arising from IPMN and one had high-grade dysplasia at the index operation. Female sex and invasive histology were significantly associated with PM (P < 0.05). PM rates by sex were 3% (95% confidence interval [CI]: 0.5-15) in males and 22% (95% CI: 9-45) in females. Rates by histology were 2.9% (95% CI: 0.5-15) for noninvasive IPMN, and 23.5% (95% CI: 9.5-47) for invasive carcinoma arising from IPMN. Median interval from surgery to PMs was 7 mo (range: 3-13)., Conclusions: PMs following IPMN resection are rare but may be more common in patients with invasive histology. Although rare, PMs can arise in patients with noninvasive IPMNs. Further studies on pathophysiology and risk factors of PM following IPMN resection are needed and may reinforce adherence to guidelines recommending long-term surveillance., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Grade 3 (G3) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are rare, aggressive tumors with poor prognosis. The World Health Organization 2017 and 2019 classifications further subdivided G3 NENs into G3 neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). Current guidelines favor medical management in most of these patients, and the role of surgical management is not well defined. We performed a systematic literature review and meta-analysis of surgical management versus nonsurgical management for G3 GEP NENs., Materials and Methods: A PRISMA-compliant systematic review of the MEDLINE, Embase, Scopus, and Cochrane Library databases (end-of-search date: 16 July 2021) was conducted. Individual patient survival data were reconstructed, and random-effects meta-analyses were performed., Results: Fourteen studies comprising 1810 surgical and 910 nonsurgical patients were systematically reviewed. Publication bias adjusted meta-analysis of 12 studies (1788 surgical and 857 nonsurgical patients) showed increased overall survival (OS) after surgical compared with nonsurgical management for G3 GEP NENs [hazard ratio (HR) 0.40, 95% confidence interval (CI) 0.31-0.53]. Subgroup meta-analyses showed increased OS after surgical management for both pancreatic and gastrointestinal primary sites separately. In another subgroup meta-analysis of G3 GEP NETs (not NECs), surgical management was associated with increased OS compared with nonsurgical management (HR 0.26, 95% CI 0.11-0.61)., Conclusions: Surgical management of G3 GEP NENs may provide a potential survival benefit in well-selected cases. Further research is needed to define which patients will benefit most from surgical versus nonsurgical management. The current literature is limited by inconsistent reporting of survival outcomes in surgical versus nonsurgical groups, tumor grade, differentiation, primary tumor site, and selection criteria for surgical and nonsurgical management., (© 2022. Society of Surgical Oncology.)

Background: Grade 3 (G3) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are aggressive tumors with poor survival outcomes for which medical management is generally recommended. This study sought to evaluate outcomes of surgically treated G3 GEP-NEN patients., Methods: A single-institutional prospective NEN database was reviewed. Patients with G3 GEP-NENs based on World Health Organization (WHO) 2019 definitions included well-differentiated neuroendocrine tumors (G3NET) and poorly differentiated neuroendocrine carcinomas (G3NEC). Clinicopathologic factors were compared between groups. Overall survival from G3 diagnosis was assessed by the Kaplan-Meier method., Results: Surgical resection was performed for 463 patients (211 G1, 208 G2, 44 G3). Most had metastatic disease at presentation (54% G1, 69% G2, 91% G3; p < 0.001). The G3 cohort included 39 G3NETs and 5 G3NECs, 22 of pancreatic and 22 of midgut origin. Median overall survival (mOS; in months) was 268.1 for G1NETs, 129.9 for G2NETs, 50.5 for G3NETs, and 28.5 for G3NECs (p < 0.001). Over the same period, 31 G3 patients (12 G3NETs, 19 G3NECs) were treated non-surgically, with mOS of 19.0 for G3NETs and 12.4 for G3NECs., Conclusions: Surgical resection of G3 GEP-NENs remains controversial due to poor prognosis, and surgical series are rare. This large, single-institutional study found significantly lower mOS in patients with resected G3NENs than those with G1/G2 tumors, reflecting more aggressive tumor biology and a higher proportion with metastatic disease. The mOS for resected G3NETs and G3NECs exceeded historical non-surgical G3NEN series (mOS 11-19 months), suggesting surgery should be considered in carefully selected patients with G3NENs, especially those with well-differentiated tumors., (© 2022. Society of Surgical Oncology.)

Background: Relapse of early-stage colon cancer (CC) after curative-intent resection occurs. We hypothesized that known risk factors for peritoneal metastases (PM) can define a high-risk state (HRS) that predicts recurrence and mortality., Methods: CALGB9581 trial patients receiving no adjuvant treatment after stage-II CC resection were included. Positive radial margins, T4 invasion, obstruction/perforation or lymphovascular invasion defined the HRS. Cox proportional hazard models determined association with overall (OS) and disease-free survival (DFS)., Results: Median follow-up in 873 included patients was 8.1 years. Five-year OS was 85.8%. HRS+ patients had lower 5-year DFS (68.7 vs. 82.4%, P = 0.003) and OS (75.5 vs. 87.8%, P = 0.001). HRS+ was independently predictive of worse DFS and OS (HR 1.52 and 1.64, P < 0.01). Among recurrences, HRS+ patients showed shorter median OS (3.3 vs. 5.3 years, P = 0.01)., Conclusions: HRS criteria identify a cohort of CC patients at high-risk of recurrence and death. Studies of novel surveillance techniques in such patients are warranted., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Biopsy to achieve tissue diagnosis (TD) of hepatocellular carcinoma (HCC) risks needle tract seeding. With chest wall and peritoneal recurrences reported, TD could worsen cancer outcomes. We investigated HCC outcomes after TD compared to clinical diagnosis (CD), hypothesizing that TD adversely affects overall survival (OS)., Methods: The National Cancer Database (NCDB) Participant User File for liver cancer was reviewed, including patients with nonmetastatic HCC treated with major hepatectomy or transplantation. Clinical diagnosis patients were matched 1:1 to TD patients per propensity score. Survival was examined in the unmatched and matched cohorts., Results: Of 172 283 cases, 16 366 met inclusion criteria. Mean age was 60.8 years, 12 100 (73.9%) were male, and 48.4% of patients received hepatectomies. Clinical diagnosis occurred in 70.4% of cases, and 29.6% underwent TD. Cox regression confirmed the diagnostic method as an independent predictor of OS in addition to age, Charlson-Deyo score, grade, delay of surgery, lymphovascular invasion, nodal stage, and procedure type, favoring transplantation over hepatectomy. After propensity matching on these factors, 4251 patients were matched from each group. In the matched cohort, patients with TD had a significantly lower OS than patients with CD (median: 65.5 vs. 85.6 ± 2.7 months, P < .001). The corresponding 5-year survival was lower in the TD group (47.6% vs. 60.9% P < .001)., Conclusion: Hepatocellular carcinoma patients with preoperative TD had decreased OS compared to CD, which persisted after propensity matching. This study supports avoiding biopsy for HCC whenever possible.

Pancreatic neuroendocrine tumors (PNETs) are a heterogeneous and orphan group of neoplasms that vary in their histology, clinical features, prognosis, and management. The treatment of PNETs is highly dependent on the stage at presentation, tumor grade and differentiation, presence of symptoms from hormonal overproduction or from local growth, tumor burden, and rate of progression. The US Food and Drug Administration has recently approved many novel treatments, which have altered decision making and positively impacted the care and prognosis of these patients. In this review, we focus on the significant progress made in the management of PNETs over the past decade, as well as the active areas of research.

Background: Management of duodenal neuroendocrine tumors (DNETs) is not standardized, with smaller lesions (< 1-2 cm) generally treated by endoscopic mucosal resection (EMR) and larger DNETs by surgical resection (SR). This study reviewed how patients were selected for treatment and compared outcomes., Patients and Methods: Patients with DNETs undergoing resection were identified through institutional databases, and clinicopathologic data recorded. χ 2 and Wilcoxon tests compared variables. Survival was determined by Kaplan-Meier, and Cox regression tested association with survival., Results: Among 104 patients, 64 underwent EMR and 40 had SR. Patients selected for SR had larger tumor size, younger age, and higher T, N, and M stage. There was no difference in progression-free (PFS) or overall survival (OS) between SR and EMR. In 1-2 cm DNETs, there was no difference in PFS between SR and EMR [median not reached (NR), P = 0.1]; however, longer OS was seen in SR (median NR versus 112 months, P = 0.03). In 1-2 cm DNETs, SR patients were more likely to be node-positive and younger. After adjustment for age, resection method did not correlate with survival. Comparison of surgically resected DNETs versus jejunoileal NETs revealed longer PFS (median NR versus 73 months, P < 0.001) and OS (median NR versus 119 months, P = 0.004) DISCUSSION: In 1-2 cm DNETs, there was no difference in survival between EMR and SR after adjustment for age. Recurrences could be salvaged, suggesting that EMR is a reasonable strategy. Compared with jejunoileal NETs, DNETs treated by SR had improved PFS and OS., (© 2021. Society of Surgical Oncology.)

Optimal management of duodenal neuroendocrine tumors (DNETs) has not been well-defined, especially for DNETs 1-2 cm in size. Recent studies comparing endoscopic mucosal resection (EMR) and surgical resection demonstrate EMR is safe and effective for these intermediate-sized DNETs. Expert and consensus guidelines could consider updating recommendations to reflect the outcomes of EMR in DNETs and the importance of endoscopic surveillance in these patients to evaluate for local recurrence., (© 2021. Society of Surgical Oncology.)

Background: Young adults with metastatic colorectal cancer (mCRC) may have higher rates of deficient mismatch repair (dMMR) than older patients. This study sought to assess patterns of MMR-testing and survival among young adult mCRC patients in the National Cancer Database (NCDB), hypothesizing that dMMR correlates with worse survival than in MMR-proficient (pMMR) patients., Methods: Stage-IV colorectal cancers were identified in NCDB (2010-2016). Demographic and clinical features were compared between younger (age ≤ 30) and older mCRC patients and tested for association with overall survival. Stage-IV disease without other recorded metastatic sites defined peritoneal metastasis (PM). Fisher-exact tests compared proportions and Cox models tested association with overall survival., Results: Of 124,587 stage-IV colorectal cancers, 1,123 (0.9%) were in young patients. Young patients were more likely to have mucinous histology, high-grade, rectal primaries, and isolated peritoneal metastases (P < 0.001). Younger patients more often had MMR-testing (29.1 versus 16.6%), with dMMR found at similar rates in young and older patients (21.7 versus 17.1% of those tested, P= 0.4). Despite higher rates of adverse prognostic features, younger patients had better survival (median 20.7 versus 14.8 months, P < 0.001). In MMR-tested patients, dMMR correlated with higher mortality risk compared to pMMR (median 16.6 months versus 25.5 months, P = 0.01). On multivariable analysis, grade and MMR-status remained independently associated with survival., Conclusions: Median survival was worse with dMMR by 8.9 months compared to pMMR in young adults with mCRC. Despite higher rates of familial syndromes in young patients and recommendations for universal MMR-testing, over 70% of young mCRC patients had no MMR-status recorded., Competing Interests: Declaration of competing interests None, (Copyright © 2021. Published by Elsevier Inc.)

Surgical treatment is central to management of small bowel neuroendocrine tumors (SBNETs). Current controversies include whether to resect asymptomatic primary tumors in the setting of unresectable metastases, the role of minimally invasive surgery, and how best to incorporate/sequence medical treatments. Low SBNET incidence, long event-times, and variability in disease burden, surgical technique, and institutional treatment preferences remain obstacles to conducting randomized surgical trials for SBNETs. With increasing referral of these patients to high-volume centers, cooperation between experienced SBNET clinicians should allow design of high-quality randomized trials to test new treatments and answer key questions.

Surgical resection is the foundation for treatment of small bowel neuroendocrine tumors (SBNETs). Guidelines for surgical management of SBNETs rely on retrospective data, which suggest that primary tumor resection and cytoreduction improve symptoms, prevent future complications, and lengthen survival. In advanced NETs, improvement in progression-free survival has been reported in large, randomized, controlled trials of various medical treatments, including somatostatin analogues, targeted therapy, and peptide receptor radionuclide therapy. This review discusses important studies influencing the management of SBNETs and the limitations of current evidence regarding surgical interventions for SBNETs.

Background: Cerebral palsy (CP) is the leading cause of disability in children. While motor deficits define CP, many patients experience behavioral and cognitive deficits which limit participation. The purpose of this study was to contribute to our understanding of developmental delay and how to measure these deficits among children with CP., Methods: Children 5 to 15 years with hemiplegic CP were recruited. Cognition and motor ability were assessed. The brain injury associated with observed motor deficits was identified. Accelerometers measured real-world bilateral upper extremity movement and caregivers completed behavioral assessments., Results: Eleven children participated, 6 with presumed perinatal stroke. Four children scored below average intelligence quotient while other measures of cognition were within normal limits (except processing speed). Motor scores confirmed asymmetrical deficits. Approximately one third of scores indicated deficits in attention, behavior, or depression., Conclusions: Our findings corroborate that children with CP experience challenges that are broader than motor impairment alone. Despite the variation in brain injury, all participants completed study procedures., Implications: Our findings suggest that measuring behavior in children with CP may require a more comprehensive approach and that caregivers are amenable to using online collection tools which may assist in addressing the therapeutic needs of children with CP., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Background: Tumor biomarkers (TBMs) reflect disease burden and correlate with survival for small bowel neuroendocrine tumors (SBNETs). This study sought to determine the performance of chromogranin A (CgA), pancreastatin (PST), neurokinin A (NKA), and serotonin (5HT) during follow-up assessment of resected SBNETs., Methods: An institutional database identified patients undergoing surgery for SBNETs. Tumor biomarker levels were assessed as categorical (normal vs elevated) and continuous variables for association with progression-free survival (PFS) and overall survival (OS) via the Kaplan-Meier method with Cox multivariable models adjusted for confounders. Sensitivity, specificity, and predictive values of TBM levels in identifying imaging-confirmed progression were calculated., Results: In 218 patients (44% female, 92% node + , 73% metastatic, 97% G1 or G2), higher levels of CgA, PST, NKA, and 5HT correlated with higher-grade and metastatic disease at presentation (p < 0.05). Elevated pre- and postoperative CgA, PST, and NKA correlated with lower PFS and OS (p < 0.05; median follow-up period, 49.6 months). Normal CgA, PST, and NKA were present in respectively 20.3%, 16.9%, and 72.6% of the patients with progression, whereas elevated levels were present in respectively 69.5%, 24.8%, and 1.3% of the patients without progression. Using TBMs to determine progression showed superiority of PST (78.9% accuracy) over CgA (63.3% accuracy) or CgA and PST together (60.3% accuracy)., Conclusion: Although specific for progression, NKA was rarely elevated, limiting its usefulness. Pre- and postoperative PST and CgA correlated with disease burden and survival, with PST providing better discrimination of outcomes. During the follow-up period, use of PST most accurately detected progression. These results suggest that PST should replace CgA for SBNET surveillance.

Patients with neuroendocrine tumor liver metastases (NETLMs) may develop carcinoid syndrome, carcinoid heart disease, or other symptoms from overproduction of hormones. Hepatic resection and cytoreduction is the most direct treatment of NETLMs in eligible patients, and cytoreduction improves symptoms, may reduce the sequelae of carcinoid syndrome, and extends survival. Parenchymal-sparing procedures, such as ablation and enucleation, should be considered during cytoreduction to maximize treatment of multifocal tumors while preserving healthy liver tissue. For patients with large hepatic tumor burdens, high-grade disease, or comorbidities precluding surgery, liver-directed and systemic therapies can be used to palliate symptoms and improve progression-free survival., Competing Interests: Disclosure Dr C. Chandrasekharan serves on the advisory board of Lexicon Pharmaceuticals. The other authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Patients with pancreatic neuroendocrine tumors often present with metastases, which reduce survival. Molecular features associated with pancreatic neuroendocrine tumor tumorigenesis have been reported, but mechanisms of metastasis remain incompletely understood., Methods: RNA sequencing was performed on primary and metastatic pancreatic neuroendocrine tumors from 43 patients. Differentially expressed genes were identified, and quantitative polymerase chain reaction used to confirm expression differences. BON cells were transfected with short interfering RNAs and short hairpin RNAs to create knockdowns. Expression changes were confirmed by quantitative polymerase chain reaction, cell viability assessed, and protein levels evaluated by Western blot and immunofluorescence., Results: Nodal and hepatic metastases had decreased expression of somatostatin compared with primary tumors (P = .003). Quantitative polymerase chain reaction in a validation cohort confirmed 5.3-fold lower somatostatin expression in hepatic metastases (P = .043) with no difference in somatostatin receptor, synaptophysin, or chromogranin A expression. Somatostatin knockdown in BON cells increased cell metabolic activity, viability, and growth. Somatostatin-knockdown cells had significantly higher levels of phosphorylated Akt protein and higher mTOR compared with controls., Conclusion: Pancreatic neuroendocrine tumor metastases have lower expression of somatostatin than primary tumors, and somatostatin knockdown increased growth in pancreatic neuroendocrine tumor cell lines. This was associated with increased activation of Akt, identifying this pathway as a potential mechanism by which loss of somatostatin expression promotes the metastatic phenotype., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Mismatch-repair deficiency (dMMR) predicts worse chemoresponsiveness but better survival in early-stage colorectal adenocarcinoma. This study examined metastatic colorectal and appendix cancers with and without peritoneal metastasis (PM) in the National Cancer Database (NCDB), hypothesizing that dMMR tumors show better survival., Methods: Stage 4 colon, rectum, and appendix cancers (2010-2016) were identified in the NCDB (including goblet cell carcinoids, excluding neuroendocrine tumors). Stage 4 disease without liver, bone, brain, lung, or distant nodal metastases defined PM. Fisher's exact tests were used to compare proportions, and Kaplan-Meier analysis was used to evaluate survival., Results: Of 130,125 stage 4 colon, rectum, and appendix cancers, 27,848 (21.4%) had PM. Appendix primary tumors had PM more commonly than colon or rectum cancer (83.6% vs. 20.6% and 12.1% of stage 4 cases; p < 0.0001). More PM patients had MMR testing than patients with other metastasis (OM) (21.4% vs. 16.1%), and testing increased from 9.6% in 2010 to 26.3% in 2016 (both p < 0.0001). Among the PM patients, MMR testing was least common for appendix cancers (9.0%). When tested, PM patients more often had dMMR (22.9% [1122/4900] vs. 15.4% [2532/16,495] of OM patients; p < 0.0001). Colon primary tumor had dMMR most frequently (25.0% vs. 14.6% and 14.5% for rectal and appendix tumor; p < 0.0001). Most PM patients received chemotherapy (66.2%). Immunotherapy use increased over time (1.1% of PM diagnoses in 2010 vs. 20.8% in 2016). For MMR-tested stage 4 patients, dMMR correlated with worse survival (median OM, 19.7 vs. 23.9 months, p < 0.0001; median PM, 19.9 vs. 24.6 months, p = 0.035)., Conclusions: The NCDB showed dMMR predicting worse survival for stage 4 colorectal cancers with and without PM and dMMR existing in 14.5-25% of tested patients, suggesting that increased attention to MMR testing in stage 4 colorectal and appendix cancers can identify many patients who could potentially benefit from immunotherapy.

Background: When detected, children with asymmetrical motor impairment are referred for therapeutic interventions to maximize the child's ability to reach their health and developmental potential. Referal is dependent on standardized evaluation, which rarely examines upper extremity (UE) function within the context of real-world activity. Accelerometry provides an efficient method to objectively measure movement in children. The purpose of this study was to compare accelerometry to clinical assessment, specifically the Melbourne Assessment of Unilateral Upper Limb Function-2 (MA-2)., Methods: A total of 52 children between 1-17 years of age with asymmetrical motor deficits and age matched controls participated in this study. Participants wore bilateral accelerometers for 4 x 25 h. The use ratio (UR) and mono-arm use index (MAUI) were calculated to quantify asymmetrical impairment. The Melbourne Assessment of Unilateral Upper Limb Function-2 (MA-2) was administered and compared to accelerometry variables., Results: The UR and MAUI were significantly different in children with and without deficits. The MAUI was significantly correlated with all domains of the MA-2: accuracy (r = 0.44, p = 0.026); fluency (r = 0.52, p = 0.006); dexterity (r = 0.53, p = 0.005); and range of motion (r = 0.49, p = 0.011)., Conclusions: Our findings suggest a relationship between real-world movement and clinical evaluation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

In the original article Fadi Dahdaleh's last name was spelled incorrectly. It is correct as reflected here.

Background: The small bowel and pancreas are the most common primary sites of neuroendocrine tumors (NETs) giving rise to metastatic disease. Some patients with small bowel NETs (SBNETs) present with synchronous or metachronous pancreatic NETs (PNETs), and it is unclear whether these are separate primaries or metastases from one site to the other., Methods: A surgical NET database including patients undergoing operations for SBNETs or PNETs was reviewed. Patients with synchronous or metachronous tumors in both the small bowel and pancreas were identified, and available tissues from primary tumors and metastases were examined using a 4-gene quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC) panel developed for evaluating NETs of unknown primary., Results: Of 338 patients undergoing exploration, 11 had NETs in both the small bowel and pancreas. Tissues from 11 small bowel tumors, 9 pancreatic tumors, and 10 metastases were analyzed. qPCR and IHC data revealed that three patients had separate SBNET and PNET primaries, and five patients had SBNETs that metastasized to the pancreas. Pancreatic tissue was unavailable in two patients, and qPCR and IHC gave discrepant results in one patient., Conclusions: NETs in both the small bowel and pancreas were found in 3% of our patients. In nearly two-thirds of evaluable patients, the pancreatic tumor was a metastasis from the SBNET primary, while in the remaining one-third of patients it represented a separate primary. Determining the origin of these tumors can help guide the choice of systemic therapy and surgical management.

Importance: Unregulated drug prices increase cancer therapy costs. After induction chemotherapy, patients with metastatic colon cancer can receive maintenance capecitabine and bevacizumab therapy based on improved progression-free survival, but whether this treatment's cost justifies its benefits has not been evaluated in the United States., Objective: This study sought to determine the influence of capecitabine and bevacizumab drug prices on cost-effectiveness from a Medicare payer's perspective., Design, Setting, and Participants: The incremental cost-effectiveness of capecitabine and bevacizumab maintenance therapy was determined with a Markov model using a quality-of-life penalty based on outcomes data from the CAIRO phase 3 randomized clinical trial (RCT), which included 558 adults in the Netherlands with unresectable metastatic colorectal cancer who had stable disease or better following induction chemotherapy. The outcomes were modeled using Markov chains to account for patients who had treatment complications or cancer progression. Transition probabilities between patient states were determined, and each state's costs were determined using US Medicare data on payments for capecitabine and bevacizumab treatment. Deterministic and probabilistic sensitivity analyses identified factors affecting cost-effectiveness., Main Outcomes and Measures: Life-years gained were adjusted using CAIRO3 RCT quality-of-life data to determine quality-adjusted life-years (QALYs). The primary end point was the incremental cost-effectiveness ratio, representing incremental costs per QALY gained using a capecitabine and bevacizumab maintenance regimen compared with observation alone., Results: Markov model estimated survival and complication outcomes closely matched those reported in the CAIRO3 RCT, which included 558 adults (n = 197 women, n = 361 men; median age, 64 and 63 years for patients in the observation and maintenance therapy groups, respectively) in the Netherlands with unresectable metastatic colorectal cancer who had stable disease or better following induction chemotherapy. Incremental costs for a 3-week maintenance chemotherapy cycle were $6601 per patient. After 29 model iterations corresponding to 60 months of follow-up, mean per-patient costs were $105 239 for maintenance therapy and $21.10 for observation. Mean QALYs accrued were 1.34 for maintenance therapy and 1.20 for observation. The incremental cost-effectiveness ratio favored maintenance treatment, at an incremental cost of $725 601 per QALY. The unadjusted ratio was $438 394 per life-year. Sensitivity analyses revealed that cost-effectiveness varied with changes in drug costs. To achieve an incremental cost-effectiveness ratio of less than $59 039 (median US household income) per unadjusted life-year would require capecitabine and bevacizumab drug costs to be reduced from $6173 (current cost) to $452 per 3-week chemotherapy cycle., Conclusions and Relevance: Antineoplastic therapy is expensive for payers and society. The price of capecitabine and bevacizumab maintenance therapy would need to be reduced by 93% to make it cost-effective, a finding useful for policy decision making and payment negotiations.

Background: Patients undergoing subtotal parathyroidectomy for renal-origin hyperparathyroidism often develop postoperative hypocalcemia, requiring calcitriol and intravenous calcium (Postop-IVCa). We hypothesized that in subtotal parathyroidectomy for renal-origin hyperparathyroidism, preoperative calcitriol treatment reduces the use of postoperative administration of intravenous calcium., Methods: A retrospective chart review compared subtotal parathyroidectomy for renal-origin hyperparathyroidism patients who received preoperative calcitriol treatment with those patietns who did not receive preoperative calcitriol treatment at one institution. Preoperative calcitriol treatment loading doses were 0.5 mcg twice daily for 5 days. All patients received postoperative calcitriol and oral calcium carbonate. Postoperative administration of intravenous calcium was given for symptoms, calcium <7.0 mg/dL, or surgeon preference. The Fisher exact test was used to compare proportions. The Wilcoxon test was used to compare continuous data. Multivariable logistic regression adjusted for confounders., Results: Included were 81 patients who received subtotal parathyroidectomy for renal-origin hyperparathyroidism (41 patients who received preoperative calcitriol treatment, 40 patients who did not receive preoperative calcitriol treatment). Preoperative calcitriol treatment use increased over time (0% 2004-2010, 69% 2011-2016). Groups who received preoperative calcitriol treatment and groups who did not receive preoperative calcitriol treatment were similar in preoperative serum calcium, vitamin D, parathyroid hormone, and median age (P > .05 for all). Patients who received preoperative calcitriol treatment less often required postoperative administration of intravenous calcium (34% vs 90% of patients who did not receive preoperative calcitriol treatment, P < .001). Median length of stay was 2.0 days shorter for patients who received preoperative calcitriol treatment versus patients who did not receive preoperative calcitriol treatment patients (P < .001). Factors associated with postoperative administration of intravenous calcium included not receiving preoperative calcitriol treatment, low preoperative calcium, and high preoperative parathyroid hormone. After multivariable adjustment, preoperative calcitriol treatment remained independently associated with reduced postoperative administration of intravenous calcium (OR 0.02, P < .001)., Conclusion: Preoperative calcitriol therapy lowered use of postoperative administration of intravenous calcium by 56% and length of stay by 50% in subtotal parathyroidectomy for renal-origin hyperparathyroidism patients. We believe preoperative calcitriol treatment should become standard of care for subtotal parathyroidectomy for renal-origin hyperparathyroidism., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Patients with colon cancer often present with obstruction. Large series have reported obstruction among the high-risk features, yet prospective data on its specific prognostic influence are lacking. We hypothesized that obstruction is an independent risk factor for poor prognosis in patients with stage III colon cancer., Methods: N0147 was a trial conducted between 2004 and 2009 that randomly assigned patients with stage III colon cancer to adjuvant regimens of folinic acid (leucovorin calcium), fluorouracil, and oxaliplatin or fluorouracil, leucovorin, and irinotecan, with or without cetuximab. Patient-level data from the control chemotherapy-only arms were obtained. Patient, tumor, and treatment characteristics were abstracted. Disease-free survival and overall survival were estimated by the Kaplan-Meier method. Proportions were compared by χ 2 and Fisher exact tests. Univariable and multivariable survival analyses were performed using Cox proportional hazards models., Results: Of 1,543 patients with stage III colon cancer, 250 (16.2%) presented with obstruction. Patients with obstruction were equally likely to complete 12 cycles of adjuvant chemotherapy (75.9% vs 77.1%, P = .6). With median follow-up time of 30.9 months among survivors, five-year overall survival and disease-free survival were worse among patients with obstruction (overall survival 67.7% vs 78.0%, P < .001; disease-free survival 53.9% vs 67.0%, P < .0001). On multivariable analysis, obstruction remained significantly associated with worse survival after adjusting for T stage, N stage, performance status, age, sex, histologic grade, and body mass index (overall survival hazard ratio 1.57, 95% confidence interval 1.12-2.20, P = .001; disease-free survival 1.52, 95% confidence interval 1.18-1.95, P < .001)., Conclusion: In this prospectively followed cohort of patients with stage III colon cancer treated with adjuvant chemotherapy, obstruction was associated with recurrence and worse survival. Moreover, this effect was independent of T and N stage and histologic grade. These results suggest that obstruction should be incorporated into novel risk-stratification models., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The Iowa Rectal Surgery Risk Calculator estimates risk for proctectomy procedures. The Iowa Calculator performed well on NSQIP 2010-2011 training and 2005-2009 validation datasets, but was not prospectively validated and did not include low anterior resections. This study sought to demonstrate validity on new independent data, to update the calculator to include low anterior resection, and to compare performance to other risk assessment tools., Methods: Non-emergent ACS-NSQIP proctectomy and low anterior resection data from 2010 to 2015 (n = 65,683) were included. The Iowa Calculator generated risk estimates for 30-day morbidity using 2012-2015 data. An Updated Calculator used 2010-2011 training data to include low anterior resection, with validation on 2012-2015 data. NSQIP data provided NSQIP Morbidity Model predictions and a custom web-script collected ACS-NSQIP Online Surgical Risk Calculator predictions for all patients., Results: Proctectomy morbidity (not including low anterior resection) decreased from 40.4% in 2010-2011 to 37.0% in 2012-2015. Low anterior resection had lower morbidity (22.4% in 2012-15). The Iowa Calculator demonstrated good discrimination and calibration using 2012-2015 data (C-statistic 0.676, deviance + 9.2%). After including low anterior resection, the Updated Iowa Calculator performed well during training (c-statistic 0.696, deviance 0%) and validation (C-statistic 0.706, deviance + 7.9%). The Updated Iowa Calculator had significantly better discrimination and calibration than morbidity predictions from the ACS Online Calculator (C-statistic 0.693, P < 0.001, deviance - 28.1%) and NSQIP General/Vascular Surgery Model (C-statistic 0.703, P < 0.05, deviance - 40.8%)., Conclusion: When applied to new independent data, the Iowa Calculator supplies accurate risk estimates. The Updated Iowa Calculator includes low anterior resection, and both are prospectively validated. Risk estimation by the Iowa Calculators was superior to ACS-provided risk tools.

Introduction: Neuroendocrine tumors (NETs) frequently metastasize to the liver. Operative debulking offers symptomatic relief and improved survival; however, the frequent presence of multifocal, bilobar disease and high recurrence rates introduces doubt regarding their optimal management. Parenchyma-sparing debulking (PSD) procedures (ablation, enucleation, wedge resections) may offer similar survival improvements as resection while minimizing morbidity and preserving functional liver tissue., Methods: Clinicopathologic variables from 228 patients with small bowel or pancreatic NETs managed operatively at one institution were collected. Liver-directed surgery was carried out when substantial debulking was deemed feasible. Survival was assessed by use of the Kaplan-Meier method., Results: A total of 108 patients with pancreatic NET or small bowel NET underwent liver-directed surgery with primarily PSD procedures. Nearly two-thirds of patients achieved 70% cytoreduction and 84% had concurrent resection of their primary. The median number of lesions treated was 6 (range, 1-36). There were no 30-day operative mortalities. The 30-day major complication rate was 13.0%. Patients who achieved 70% cytoreduction enjoyed improved progression free (median 3.2 years) and overall survival (median not reached)., Conclusion: PSD procedures are safe and can achieve significant cytoreduction, which is associated with improved survival. Lowering the debulking target threshold to 70% may benefit NET patients by increasing eligibility for cytoreduction., (Copyright © 2016 Elsevier Inc. All rights reserved.)

CDKN1B, a cyclin-dependent kinase inhibitor associated with G1 arrest, was recently proposed as an important tumor suppressor gene in small bowel neuroendocrine tumors (SBNETs). The rate of frameshift mutations in SBNET primaries are reportedly 7.4%, and hemizygous deletions are 6.7%. We set out to confirm the role of CDKN1B mutations and copy number variants (CNVs) in primary SBNETs, and whether these are also found in pancreatic neuroendocrine tumors (PNETs). Genomic DNA was isolated from 90 primary SBNETs and 67 PNETs. Coding exons of CDKN1B were amplified by PCR and sequenced. CNV analysis was performed by quantitative PCR, p27 expression was evaluated using immunohistochemistry. In SBNETS, three frameshifts, one missense mutation, and three CNVs were observed. The total rate of CDKN1B alterations was 7.0% (6 of 86; 95% confidence interval (CI) 3.2-4.4%). The frameshift rate was 3.5% (95% CI 1.1-9.8%). One SBNET patient had a hemizygous deletion of CDKN1B, and two patients had duplications (3.4%; 95% CI -0.41-7.2%). One PNET patient had a duplication, and two patients had hemizygous deletions (4.8%; 95% CI -0.44-10%). Alterations of cell-cycle control due to alterations in CDKN1B may be one mechanism by which SBNETs develop, which could have implications for new treatment modalities., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Germline mutations in the PTEN tumor-suppressor gene cause autosomal-dominant conditions such as Cowden and Bannayan-Riley-Ruvalcaba syndromes with variable presentations, including hamartomatous gastrointestinal tumors, dermatologic abnormalities, neurologic symptoms, and elevated cancer risk. We describe a father and son with extensive hamartomatous gastrointestinal polyposis who both developed early-onset esophageal cancer. Exome sequencing identified a novel germline PTEN frameshift mutation (c.568&#95;569insC, p.V191Sfs*11). In addition, a missense mutation of SMAD7 (c.115G>A, p.G39R) with an allele frequency of 0.3% in the Exome Variant Server was detected in both affected individuals. Fluorescence in situ hybridization for PTEN in the resected esophageal cancer specimen demonstrated no PTEN copy loss in malignant cells; however, results of an immunohistochemical analysis demonstrated a loss of PTEN protein expression. While the risks of many cancers are elevated in the PTEN hamartoma tumor syndromes, association between esophageal adenocarcinoma and these syndromes has not been previously reported. Esophageal adenocarcinoma and extensive polyposis/ganglioneuromatosis could represent less common features of these syndromes, potentially correlating with this novel PTEN frameshift and early protein termination genotype. Alternatively, because simultaneous disruption of both the PTEN and TGF-β/SMAD4 pathways is associated with development of esophageal cancer in a mouse model and because SMAD4 mutations cause gastrointestinal hamartomas in juvenile polyposis syndrome, the SMAD7 mutation may represent an additional modifier of these individuals' PTEN-mutant phenotype., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Small bowel (SBNETs) and pancreatic neuroendocrine tumors (PNETs) often present with liver metastases. Although liver biopsy establishes a neuroendocrine diagnosis, the primary tumor site is frequently unknown without exploratory surgery. Gene expression differences in metastases may distinguish primary SBNETs and PNETs. This study sought to determine expression differences of four genes in neuroendocrine metastases and to create a gene expression algorithm to distinguish the primary site. Nodal and liver metastases from SBNETs and PNETs (n = 136) were collected at surgery under an Institutional Review Board-approved protocol. Quantitative PCR measured expression of bombesin-like receptor-3, opioid receptor kappa-1, oxytocin receptor, and secretin receptor in metastases. Logistic regression models defined an algorithm predicting the primary tumor site. Models were developed on a training set of 21 nodal metastases and performance was validated on an independent set of nodal and liver metastases. Expression of all four genes was significantly different in SBNET compared to PNET metastases. The optimal model employed expression of bombesin-like receptor-3 and opioid receptor kappa-1. When these genes did not amplify, the algorithm used oxytocin receptor and secretin receptor expression, which allowed classification of all 136 metastases with 94.1 % accuracy. In the independent liver metastasis validation set, 52/56 (92.9 %) were correctly classified. Positive predictive values were 92.5 % for SBNETs and 93.8 % for PNETs. This validated algorithm accurately distinguishes SBNET and PNET metastases based on their expression of four genes. High accuracy in liver metastases demonstrates applicability to the clinical setting. Studies assessing this algorithm's utility in prospective clinical decision-making are warranted.

Introduction: The site of a primary neuroendocrine tumor (NET) tumor is unknown before treatment in approximately 20% of small bowel (SBNET) and pancreatic (PNET) cases despite extensive workup. It can be difficult to discern a PNET from an SBNET on hematoxylin and eosin stains, and thus, more focused diagnostic tests are required. Immunohistochemistry (IHC) and gene expression profiling are two methods used to identify the tissue of origin from biopsied metastases., Methods: Tissue microarrays were created from operative specimens and stained with up to seven antibodies used in the NET-specific IHC algorithm. Expression of four genes for differentiating between PNETs and SBNETs was determined by quantitative polymerase chain reaction and then used in a previously validated gene expression classifier (GEC) algorithm designed to determine the primary site from gastrointestinal NET metastases., Results: The accuracy of the IHC algorithm in identifying the primary tumor site from a set of 37 metastases was 89%, with only one incorrect call. Three other samples were indeterminate as the result of pan-negative staining. The GEC's accuracy in a set of 136 metastases was 94%. The algorithm identified the primary tumor site in all cases in which IHC failed., Conclusion: Performing IHC, followed by GEC for indeterminate cases, identifies accurately the primary site in SBNET and PNET metastases in virtually all patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Mechanisms of neuroendocrine tumor (NET) proliferation are poorly understood, and therapies that effectively control NET progression and metastatic disease are limited. We found amplification of a putative oncogene, RABL6A, in primary human pancreatic NETs (PNET) that correlated with high-level RABL6A protein expression. Consistent with those results, stable silencing of RABL6A in cultured BON-1 PNET cells revealed that it is essential for their proliferation and survival. Cells lacking RABL6A predominantly arrested in G1 phase with a moderate mitotic block. Pathway analysis of microarray data suggested activation of the p53 and retinoblastoma (Rb1) tumor-suppressor pathways in the arrested cells. Loss of p53 had no effect on the RABL6A knockdown phenotype, indicating that RABL6A functions independent of p53 in this setting. By comparison, Rb1 inactivation partially restored G1 to S phase progression in RABL6A-knockdown cells, although it was insufficient to override the mitotic arrest and cell death caused by RABL6A loss. Thus, RABL6A promotes G1 progression in PNET cells by inactivating Rb1, an established suppressor of PNET proliferation and development. This work identifies RABL6A as a novel negative regulator of Rb1 that is essential for PNET proliferation and survival. We suggest RABL6A is a new potential biomarker and target for anticancer therapy in PNET patients., (©2014 American Association for Cancer Research.)

Medullary thyroid cancer (MTC) is an aggressive form of thyroid cancer that occurs in both heritable and sporadic forms. Discovery that mutations in the rearranged during transfection (RET) proto-oncogene predispose to familial cases of this disease has allowed for presymptomatic identification of gene carriers and prophylactic surgery to improve the prognosis of these patients. A significant number of patients with the sporadic type of MTC and even those with familial disease still present with lymph node or distant metastases, making surgical cure difficult. Over the past several decades, many different types of therapy for metastatic disease have been attempted with limited success. Improved understanding of the molecular defects and pathways involved in both familial and sporadic MTC has resulted in new hope for these patients with the development of drugs targeting the specific alterations responsible. This new era of targeted therapy with kinase inhibitors represents a significant step forward from previous trials of chemotherapy, radiotherapy, and hormone therapy. Although much progress has been made, additional agents and strategies are needed to achieve durable, long-term responses in patients with metastatic MTC. This article reviews the history and results of medical management for metastatic MTC from the early 1970s up until the present day., (© 2014 American Cancer Society.)

Background: Single-institution studies demonstrate a correlation between preoperative pelvic radiation and poor long-term pouch function after IPAA. The rarity of the radiated pelvis before these procedures limits the ability to draw conclusions on the effects of preoperative radiation on short-term outcomes, which may contribute to long-term pouch dysfunction., Objective: The purpose of this work was to better understand the impact of pelvic radiation on short-term outcomes in patients undergoing IPAA., Design: We conducted a retrospective review of the American College of Surgeons National Surgical Quality Improvement Program database (2005-2011)., Settings: The study was conducted at all participating NSQIP institutions., Patients: The cohort was composed of patients undergoing nonemergent IPAA procedures., Main Outcome Measures: Proportions of patients experiencing postoperative complications within 30 days were compared by Fisher exact and Wilcoxon rank-sum tests based on whether they received preoperative radiation. Multivariate logistic regression models controlled for the effects of multiple risk factors., Results: Included were 3172 patients receiving IPAA; 162 received pelvic radiation. The postoperative complication rate was not significantly different in patients receiving pelvic radiation versus not receiving pelvic radiation (p = 0.06). In a subset of patients with cancer diagnoses (n = 598), 157 received pelvic radiation; complication rates were not significantly different (p = 0.16). Patients receiving pelvic radiation had significantly lower rates of sepsis in both the overall and cancer diagnosis groups (p = 0.005 and p = 0.047), a finding which persisted after controlling for the effects of multiple risk factors (multivariate p values = 0.030 and 0.047)., Limitations: This was a retrospective database design with short-term follow-up., Conclusions: Patients who received radiation before IPAA had no difference in overall 30-day complication rates but had significantly lower rates of sepsis when compared with patients not receiving pelvic radiation. The perceived inferior long-term pouch function in patients undergoing preoperative pelvic radiation does not appear to be attributable to increases in 30-day complications.

Background: Serum neurokinin A, chromogranin A, serotonin, and pancreastatin reflect tumor burden in neuroendocrine tumors. We sought to determine whether their levels correlate with survival in surgically managed small bowel (SBNETs) and pancreatic neuroendocrine tumors (PNETs)., Methods: Clinical data were collected with Institutional Review Board approval for patients undergoing surgery at one center. Progression-free (PFS) and overall (OS) survival were from the time of surgery. Event times were estimated by the Kaplan-Meier method. Preoperative and postoperative laboratory values were tested for correlation with outcomes. A multivariate Cox model adjusted for confounders., Results: Included were 98 SBNETs and 78 PNETs. Median follow-up was 3.8 years; 62 % had metastatic disease. SBNETs had lower median PFS than PNETs (2.0 vs. 5.6 years; p < 0.01). Median OS was 10.5 years for PNETs and was not reached for SBNETs. Preoperative neurokinin A did not correlate with PFS or OS. Preoperative serotonin correlated with PFS but not OS. Higher levels of preoperative chromogranin A and pancreastatin showed significant correlation with worse PFS and OS (p < 0.05). After multivariate adjustment for confounders, preoperative and postoperative pancreastatin remained independently predictive of worse PFS and OS (p < 0.05). Whether pancreastatin normalized postoperatively further discriminated outcomes. Median PFS was 1.7 years in patients with elevated preoperative pancreastatin versus 6.5 years in patients with normal levels (p < 0.001)., Conclusions: Higher pancreastatin levels are significantly associated with worse PFS and OS in SBNETs and PNETs. This effect is independent of age, primary tumor site, and presence of nodal or metastatic disease. Pancreastatin provides valuable prognostic information and identifies surgical patients at high risk of recurrence who could benefit most from novel therapies.