Association Between Female Sex and Better Survival in Gastroenteropancreatic Neuroendocrine Tumors.

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.

Performance of ChatGPT on American Board of Surgery In-Training Examination Preparation Questions.

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.

Developing a predictive model for metastatic potential in pancreatic neuroendocrine tumor.

CONTEXT: Pancreatic neuroendocrine tumors (PNETs) exhibit a wide range of behavior from localized disease to aggressive metastasis. A comprehensive transcriptomic profile capable of differentiating between these phenotypes remains elusive. OBJECTIVE: Use machine learning to develop predictive models of PNET metastatic potential dependent upon transcriptomic signature. METHODS: RNA-sequencing data were analyzed from 95 surgically-resected primary PNETs in an international cohort. Two cohorts were generated with equally balanced metastatic PNET composition. Machine learning was used to create predictive models distinguishing between localized and metastatic tumors. Models were validated on an independent cohort of 29 formalin-fixed, paraffin-embedded samples using NanoString nCounter®, a clinically-available mRNA quantification platform. RESULTS: Gene expression analysis identified concordant differentially expressed genes between the two cohorts. Gene set enrichment analysis identified additional genes that contributed to enriched biologic pathways in metastatic PNETs. Expression values for these genes were combined with an additional 7 genes known to contribute to PNET oncogenesis and prognosis, including ARX and PDX1. Eight specific genes (AURKA, CDCA8, CPB2, MYT1L, NDC80, PAPPA2, SFMBT1, ZPLD1) were identified as sufficient to classify the metastatic status with high sensitivity (87.5% - 93.8%) and specificity (78.1% - 96.9%). These models remained predictive of the metastatic phenotype using NanoString nCounter® on the independent validation cohort, achieving a median AUROC of 0.886. CONCLUSIONS: We identified and validated an eight-gene panel predictive of the metastatic phenotype in PNETs, which can be detected using the clinically-available NanoString nCounter® system. This panel should be studied prospectively to determine its utility in guiding operative versus non-operative management.

NSQIP 5-factor modified frailty index and complications after ileal anal pouch anastomosis for ulcerative colitis.

Background: Frailty has been associated with worse postoperative outcomes. The 5-factor modified frailty index (mFI-5) is an objective measure although its validity in measuring frailty in patients undergoing ileal pouch-anal anastomosis (IPAA) for chronic ulcerative colitis (CUC) has not been reported. Methods: This study used the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) targeted proctectomy database. The mFI-5 was calculated by five preoperative diagnoses: insulin-dependent or noninsulin-dependent diabetes, congestive heart failure, hypertension, chronic obstructive pulmonary disease, and dependent or partially dependent functional status. The impact of mFI-5 on minor and major postoperative morbidity in CUC patients undergoing IPAA was analyzed. Results: The cohort included 1454 patients (median age 38 years, median body mass index [BMI] 26 kg/m2) of which 87 % had a mFI-5 = 0, 11 % had a mFI-5 = 1, and 2.5 % a mFI-5 ≥ 2. In multivariable logistic regression, mFI-5 ≥ 2 was significantly associated with minor complications (OR = 2.29, 95 % CI [1.00-5.22], p = 0.049), but not with major complications (p = 0.860). Conclusion: IPAA for CUC is associated with high postoperative morbidity, however, the mFI-5 alone has limited utility in determining which patients are at a higher risk of complications due to frailty. These observations suggest there is a need for more relevant instruments to measure frailty in this patient cohort.

Epidemiology and survival outcomes of colorectal mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinoma.

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.

Conditional Overall Survival After Diagnosis of Non-Metastatic Colon Cancer: Impact of Laterality, MSI, and KRAS Status.

BACKGROUND: The prognostic relevance of laterality, microsatellite instability (MSI), and KRAS status in colon cancer has been established. However, their effect on conditional overall survival (COS) remains unknown. METHODS: COS is the probability of surviving additional years after a time from diagnosis. The National Cancer Database (2010-2017) was queried for adults with non-metastatic colon cancer and known mutation status undergoing curative resection. COS was investigated at 2 years. RESULTS: Of 4838 patients, 3716 survived at least 2 years: 15% had stage I, 38% stage II, and 46% stage III disease. Fifty-nine percent had a right-sided tumor, 16% were MSI-high, and 37% were mutated KRAS (mKRAS). The proportion of patients alive at 2 years was higher for stage I compared with stage II and III (65 vs. 61 vs. 54%). The 5-year overall survival for stage I-III was 80, 76, and 67% for the initial cohort, and 90, 88, and 86% for those alive at 2 years. After adjustment, higher pathologic T and N stage, tumor deposits, and no chemotherapy were associated with worse COS (p < 0.01). While laterality and MSI status were not associated with COS, mKRAS was independently associated with decreased COS (HR 1.35, 95% CI 1.12-1.62). CONCLUSION: Patients with mKRAS had worse COS, suggesting that these mutations confer an aggressive biologic behavior, with patients remaining at higher risk of death 2 years after diagnosis. Routine evaluation of KRAS status should be considered in patients with non-metastatic disease for prognostication and to identify those who might benefit from modified surveillance protocols.

ATAGI 2023 Annual Statement on Immunisation.

The Australian Technical Advisory Group on Immunisation (ATAGI) 2023 Annual Statement on Immunisation is the third publication in this series. It highlights the key successes, trends and challenges in the use of vaccines and control of vaccine preventable diseases (VPDs) in Australia in 2022. It also signals ATAGI's priority actions for addressing key issues for 2023 and beyond.

Inhibition of serotonin biosynthesis in neuroendocrine neoplasm suppresses tumor growth in vivo.

Small bowel neuroendocrine tumors (SBNETs) originate from enterochromaffin cells in the intestine which synthesize and secrete serotonin. SBNETs express high levels of tryptophan hydroxylase 1 (Tph1), a key enzyme in serotonin biosynthesis. Patients with high serotonin level may develop carcinoid syndrome, which can be treated with somatostatin analogues and the Tph1 inhibitor telotristat ethyl in severe cases. Although the active drug telotristat can efficiently reduce serotonin levels, its effect on tumor growth is unclear. This study determined the effect of serotonin inhibition on tumor cell growth in vitro and in vivo . The levels of Tph1 in various neuroendocrine neoplasms (NENs) were determined and the biological effects of Tph1 inhibition in vitro and in vivo using genetic and pharmacologic approaches was tested. Gene and protein expression analyses were performed on patient tumors and cancer cell lines. shRNAs targeting TPH1 were used to create stable knockdown in BON cells. Control and knockdown lines were assessed for their growth rates in vitro and in vivo , angiogenesis potential, serotonin levels, endothelial cell tube formation, tumor weight, and tumor vascularity. TPH1 is highly expressed in SBNETs and many cancer types. TPH1 knockdown cells and telotristat treated cells showed similar growth rates as control cells in vitro . However, TPH1 knockdown cells formed smaller tumors in vivo and tumors were less vascularized. Although Tph1 inhibition with telotristat showed no effect on tumor cell growth in vitro , Tph1 inhibition reduced tumor formation in vivo . Serotonin inhibition in combination with other therapies is a promising new avenue for targeting metabolic vulnerabilities in NENs.

Development of Early Abdominal Compartment Syndrome Leading to Emergent Decompressive Laparotomy in Full-Thickness Burn Injury.

Burn injuries carry an increased risk of intra-abdominal hypertension and are an independent risk factor for abdominal compartment syndrome (ACS). ACS is most commonly due to large volume resuscitation. The added concern of ACS can complicate resuscitative efforts. Early monitoring for ACS (intra-abdominal pressure > 20 mm Hg with associated new-onset organ dysfunction) and performing prudent decompressive laparotomies are important factors to keep in mind when treating large surface area burn patients. This case report describes the hospitalization of a 60-year-old male who presented with 45% full-thickness (FT) total body surface area (TBSA) and inhalation injury. On arrival to the emergency department (ED), he had received a total of 6 L of intravenous lactate Ringers, and vasopressors were initiated due to hypotension. During the tertiary examination it was noted that there was increased difficulty ventilating the patient, and his abdomen was becoming increasingly distended and tense. His intra-abdominal pressure was measured in the ED and found to be elevated at 32 mm Hg. The findings were suggestive of ACS and a decompressive laparotomy was performed in the ED. Upon entering the abdominal cavity, the abdominal contents extruded through the incision and diffuse venous congestion and gastric distention were noted. Items commonly found in operating rooms (Top-Draper® warmer drape, Kerlix rolls, Jackson-Pratt suction drains, and 3M® Ioban sterile antimicrobial incise drape) were utilized to maintain an open abdomen where abdominal contents could easily be observed and to prevent delay in performing a decompressive laparotomy. Here we describe a patient with 45% FT TBSA and inhalation injuries requiring an emergent decompressive laparotomy for ACS after only 6 L of lactate Ringers were administered. This highlights the importance of early monitoring for ACS and the ease of performing a decompressive laparotomy with commonly found items in the ED and operating rooms.

Is There a Role for Surgical Resection of Grade 3 Neuroendocrine Neoplasms?

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.

Equivalency of short-term perioperative outcomes after open, laparoscopic, and robotic ileal pouch anal anastomosis. Does procedure complexity override operative approach?

Background: Ileal pouch anal anastomosis is the treatment of choice for patients with chronic ulcerative colitis and familial adenomatous polyposis undergoing a proctocolectomy and desiring bowel continuity. It is a technically complex operation associated with significant morbidity and may be performed by an open, laparoscopic, or robotic approach. However, there is a paucity of data regarding the comparative perioperative outcomes between these 3 techniques outside of institutional studies. Methods: The NSQIP targeted proctectomy data set was used to identify patients who underwent open, laparoscopic, and robotic ileal pouch anal anastomosis between 2016 and 2019. Thirty-day outcomes between different surgical approaches were compared using univariate and multivariable analysis. Results: During the study period, 1,067 open, 971 laparoscopic, and 341 robotic ileal pouch anal anastomosis were performed. The most frequent indications were inflammatory bowel disease (64%), malignancy (18%), and familial adenomatous polyposis (7%). Mean age of the cohort was 43 ±â€¯15 years with 43% female and 76% with body mass index ≤ 30 kg/m2. Overall morbidity was 26.8% for the entire cohort with 4% anastomotic leak, 6% reoperation, 21% ileus, and 21% readmission rate. After adjusting for available confounders, operative approach was not associated with better short-term outcomes, including length of stay, overall morbidity, anastomotic leak, reoperation, incidence of ileus, and 30-day readmissions. Conclusion: Ileal pouch anal anastomosis continues to be associated with significant postoperative morbidity regardless of operative approach. Patient-related advantages in terms of perioperative outcomes for laparoscopic and robotic platforms compared to open surgery are less pronounced in complex operations such as ileal pouch anal anastomosis.

Establishment of Novel Neuroendocrine Carcinoma Patient-Derived Xenograft Models for Receptor Peptide-Targeted Therapy.

Gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) are rare cancers consisting of neuroendocrine carcinomas (NECs) and neuroendocrine tumors (NETs), which have been increasing in incidence in recent years. Few cell lines and pre-clinical models exist for studying GEP NECs and NETs, limiting the ability to discover novel imaging and treatment modalities. To address this gap, we isolated tumor cells from cryopreserved patient GEP NECs and NETs and injected them into the flanks of immunocompromised mice to establish patient-derived xenograft (PDX) models. Two of six mice developed tumors (NEC913 and NEC1452). Over 80% of NEC913 and NEC1452 tumor cells stained positive for Ki67. NEC913 PDX tumors expressed neuroendocrine markers such as chromogranin A (CgA), synaptophysin (SYP), and somatostatin receptor-2 (SSTR2), whereas NEC1452 PDX tumors did not express SSTR2. Exome sequencing revealed loss of TP53 and RB1 in both NEC tumors. To demonstrate an application of these novel NEC PDX models for SSTR2-targeted peptide imaging, the NEC913 and NEC1452 cells were bilaterally injected into mice. Near infrared-labelled octreotide was administered and the fluorescent signal was specifically observed for the NEC913 SSTR2 positive tumors. These 2 GEP NEC PDX models serve as a valuable resource for GEP NEN therapy testing.

The impact of KRAS mutation, microsatellite instability, and tumor laterality on the prognosis of nonmetastatic colon cancer.

BACKGROUND: KRAS mutations, microsatellite instability, and tumor location have been found to be significant prognostic factors in colorectal cancer. The interaction between these variables and its effect on overall survival in nonmetastatic colon cancer has not been well elucidated. METHODS: The National Cancer Database (2010-2016) was queried for patients with stage I-III colon cancer and known microsatellite instability and KRAS status undergoing curative resection. RESULTS: A total of 5,292 patients were identified: 60.4% had right-sided cancers, 36.4% had KRAS mutations, and 15.6% had microsatellite instability. Right-sided tumors were more likely to have microsatellite instability and KRAS mutations compared to left-sided tumors. On univariable analysis, KRAS mutations and microsatellite instability status were not associated with differences in survival, whereas right-sided cancers had worse overall survival compared to left-sided cancers (hazard ratio 1.32, 95% confidence interval: 1.18-1.47). On multivariable analysis, right-sided location, KRAS mutations, and microsatellite instability were not independent prognostic factors. However, a significant interaction between laterality and KRAS status was observed. In patients with mutated KRAS cancers, left-sided tumors were at increased risk of death compared to right-sided tumors (hazard ratio: 1.30, 95% confidence interval: 1.03-1.63), whereas in patients with wild-type KRAS cancers, left-sided tumors were at decreased risk of death (hazard ratio: 0.81, 95% confidence interval: 0.67-0.97). CONCLUSION: In patients with stage I-III colon cancer, laterality, KRAS mutation, and microsatellite instability status were not independently prognostic after curative resection. However, the effect of laterality was opposite based on KRAS status, with left-sided (compared to right-sided) tumors associated with worse overall survival in mutated KRAS patients and better overall survival in wild-type KRAS individuals. Laterality itself may not be an independent prognostic factor but a reflection of differing genetic profiles within the colon.

ASO Author Reflections: Endoscopic Management is Reasonable for <2 cm Duodenal Neuroendocrine Tumors.

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.

Management of Duodenal Neuroendocrine Tumors: Surgical versus Endoscopic Mucosal Resection.

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. χ2 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.