Multifocal Insulinoma as the Unique Presenting Feature of Multiple Endocrine Neoplasia Type 1 in an Adolescent.

INTRODUCTION: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited disorder defined by the presence of two of the following endocrinopathies: primary hyperparathyroidism, anterior pituitary tumors, and duodenopancreatic neuroendocrine tumors (NETs). NETs, which can secrete hormones including insulin, gastrin, and glucagon, among others, are common in patients with MEN1 and are a major cause of morbidity and premature death. NETs are more common later in life, with very few cases described in children. Here, we describe a unique case of an adolescent with multifocal pancreatic NETs as the single presenting feature of MEN1. CASE PRESENTATION: A 13-year-old healthy male presented with severe weakness, altered mental status, and syncope in the setting of a venous blood glucose (BG) of 36 mg/dL. Workup showed an elevated insulin level (14 µIU/mL) when BG was 39 mg/dL with positive response to glucagon, concerning for hyperinsulinism. Diazoxide and chlorothiazide were started but not well tolerated secondary to emesis. Three suspected NETs were identified by magnetic resonance imaging and 68-Ga DOTATATE PET-CT imaging, including the largest, a 2.1 cm mass in the pancreatic head. A fourth mass in the pancreatic tail was identified via intraoperative ultrasound. All lesions were successfully enucleated and excised, and glucose levels normalized off diazoxide by post-op day 2. While the primary lesion stained for insulin and somatostatin by immunofluorescence (IF), consistent with his clinical presentation, the additional tumors expressed glucagon, somatostatin, pancreatic polypeptide, and chromogranin A but were negative for insulin. Genetic testing confirmed a pathogenic heterozygous mutation in MEN1 (c.969C>A, p.Tyr323). He had no other signs of MEN-associated comorbidities on screening. DISCUSSION/CONCLUSION: This case demonstrates that young patients with MEN1 can present with multifocal NETs. These NETs may have polyhormonal expression patterns despite a clinical presentation consistent with one primary hormone. Our patient had clinical symptoms and laboratory evaluation consistent with an insulinoma but was found to have four NETs, each with different IF staining patterns. Advanced preoperative and intraoperative imaging is important to identify and treat all present NETs. Moreover, serum hormone levels pre- and posttreatment could help evaluate whether NETs are actively secreting hormones into the bloodstream or simply expressing them within the pancreas. Finally, this case highlights the importance of genetic testing for MEN1 in all young patients with insulinomas.

A Multi-Institutional Study Comparing Stoma Location in Neonates With Intestinal Perforation.

INTRODUCTION: Neonates with intestinal perforation often require laparotomy and intestinal stoma creation, with the stoma placed in either the laparotomy incision or a separate site. We aimed to investigate if stoma location is associated with risk of postoperative wound complications. METHODS: A multi-institutional retrospective review was performed for neonates ≤3 mo who underwent emergent laparotomy and intestinal stoma creation for intestinal perforation between January 1, 2009 and April 1, 2021. Patients were stratified by stoma location (laparotomy incision versus separate site). Outcomes included wound infection/dehiscence, stoma irritation, retraction, stricture, and prolapse. Multivariable regression identified factors associated with postoperative wound complications, controlling for gestational age, age and weight at surgery, and diagnosis. RESULTS: Overall, 79 neonates of median gestational age 28.8 wk (interquartile range [IQR]: 26.0-34.2 wk), median age 5 d (IQR: 2-11 d) and median weight 1.4 kg (IQR: 0.9-2.42 kg) had perforated bowel from necrotizing enterocolitis (40.5%), focal intestinal perforation (31.6%), or other etiologies (27.8%). Stomas were placed in the laparotomy incision for 41 (51.9%) patients and separate sites in 38 (48.1%) patients. Wound infection/dehiscence occurred in 7 (17.1%) neonates with laparotomy stomas and 5 (13.2%) neonates with separate site stomas (P = 0.63). There were no significant differences in peristomal irritation, stoma retraction, or stoma stricture between the two groups. On multivariable regression, separate site stomas were associated with increased likelihood of prolapse (odds ratio 6.54; 95% confidence interval: 1.14-37.5). CONCLUSIONS: Stoma incorporation within the laparotomy incision is not associated with wound complications. Separate site stomas may be associated with prolapse. Patient factors should be considered when planning stoma location in neonates undergoing surgery for intestinal perforation.

Practice Patterns and Guideline Non-Adherence in Surgical Management of Appendiceal Carcinoid Tumors.

BACKGROUND: Surgical management of appendiceal carcinoid tumors is heavily debated, despite National Comprehensive Cancer Network guidelines recommending aggressive resection of tumors >2 cm. We investigated national practice patterns and the predictors and impact of guideline non-adherence. STUDY DESIGN: The National Cancer Database was queried for cases of appendiceal carcinoids diagnosed from 2004 to 2015 treated with either appendectomy or hemicolectomy. Multivariable logistic regression, adjusted for demographic and clinical factors, identified associations with the procedure type among patients stratified by tumor size ≤2 cm and >2 cm. Cox Proportional Hazards then identified associations with overall survival among stratified patient groups. RESULTS: Of 3,198 cases of appendiceal carcinoids, 1,893 appendectomies and 1,305 hemicolectomies were identified. Contrary to National Comprehensive Cancer Network guidelines, 32.4% of tumors ≤2 cm were treated with hemicolectomy and 31.3% of tumors >2 cm were treated with definitive appendectomy. Hemicolectomy for small tumors was associated with age 65 years and older (odds ratio [OR] 2.4; 95% CI 1.7 to 3.3; reference group age 18 to 39 years), history of malignancy (OR 2.0; 95% CI 1.6 to 2.6), tumor size 1.1 to 2 cm (OR 2.8; 95% CI 2.3 to 3.4; reference group size ≤1 cm), and lymphovascular invasion (OR 2.2; 95% CI 1.6 to 3.2); appendectomy for large tumors was associated with age 65 years and older only (OR 2.2; 95% CI 1.1 to 4.2). Procedure type was not associated with survival for small or large tumors (hazard ratio 1.0; 95% CI 0.7 to 1.4 and hazard ratio 1.1; 95% CI 0.6 to 2.0, respectively). CONCLUSIONS: Despite well-known size-based treatment guidelines for appendiceal carcinoids, one-third of patients in the US undergo hemicolectomy for small tumors and appendectomy for large tumors. Guideline non-adherence, however, is not associated with overall survival. Reasons for these practice patterns should be explored, and guidelines revisited.

Defining Early-Onset Colon and Rectal Cancers.

Background: Colorectal cancer (CRC) incidence is rising in the young, yet the age of those affected is not clearly defined. In this study, we identify such cohorts and define clinicopathological features of early-onset colon and rectal cancers. Methods: The Surveillance, Epidemiology and End Results Program (SEER) database was queried to compare clinicopathological characteristics of colon and rectal cancers diagnosed during 1973-1995 with those diagnosed during 1995-2014. Results: We identified 430,886 patients with colon and rectal cancers. From 1973-1995 to 1995-2014, colon cancer incidence increased in patients aged 20-44 years, while rectal cancer incidence increased in patients aged ≤54 years. The percent change of cancer incidence was greatest for rectal cancer with a 41.5% (95% confidence interval (CI): 37.4-45.8%) increase compared to a 9.8% (CI: 6.2-13.6%) increase in colon cancer. Colon cancer has increased in tumors located in ascending, sigmoid, and rectosigmoid locations. Adenocarcinoma histology has increased in both colon and rectal cancers (P < 0.01), but mucinous and signet ring cell subtypes have not increased (P = 0.13 and 0.08, respectively). Incidence increases were race-specific, with rectal cancer seeing similar rises in white (38.4%, CI: 33.8-43.1%) and black populations (38.0%, CI: 26.2-51.2%), while colon cancer as a whole saw a rise in white (11.5%, CI: 7.2-15.9%) but not black populations (-6.8%, CI: -14.6-1.9%). Conclusions: Our study underscores the existence of key differences between early-onset colon (20-44 years) and rectal cancers (≤54 years) and provides evidence-based inclusion criteria for future investigations. We recommend that future research of CRC in the young should avoid investigating these cases as a single entity.

Clinical impact of underutilization of adjuvant therapy in node positive gastric adenocarcinoma.

BACKGROUND: Adjuvant therapy for gastric adenocarcinoma has shown a survival advantage, though it may be underutilized. The purpose of this study is to examine how infrequently adjuvant therapy is administered with curative intent gastrectomy for node positive gastric cancer and the long-term effects to patients. METHODS: The National Cancer Database was queried from 2006-2013 for patients with node positive gastric adenocarcinoma undergoing a potentially curative gastrectomy. Overall survival was compared between patients who received adjuvant chemotherapy or chemoradiation and those who did not. RESULTS: Of 2,565 patients, 793 (30.9%) patients did not receive any adjuvant chemotherapy or radiation therapy, while 147 (5.7%) received peri-operative chemotherapy and 723 (28.2%) received post-operative chemoradiation. From 2006-2013, the percentage of patients receiving peri-operative chemotherapy rose from 1.1% to 9.9%, while those receiving post-operative chemoradiation decreased from 39.7% to 21.6%. The adjusted restricted mean survival time over 5 years for no adjuvant therapy was 27.7 months, peri-operative chemotherapy was 39.6 months, and post-operative chemoradiation was 37.7 months (P<0.0001). CONCLUSIONS: Approximately one third of patients treated for node positive gastric cancer undergo surgical resection without adjuvant therapy. This is associated with poorer survival, highlighting the need for improvement in multimodality care and cancer outcomes.

Distinctive features of gastrointestinal stromal tumors arising from the colon and rectum.

BACKGROUND: Colon and rectal gastrointestinal stromal tumors (GISTs) are rare and poorly characterized. Because the majority of treatment guidelines for GISTs are extrapolated from tumors of gastric and small bowel origin, our aim was to better characterize the unique clinicopathologic features and prognostic factors of colon and rectal GISTs to guide clinical care. METHODS: The National Cancer Data Base (NCDB) was queried from 2006 to 2013 for cases of GISTs in the stomach, colon, and rectum. Patient demographics, clinical characteristics, and survival were compared. RESULTS: A total of 11,302 gastric GISTs were compared to 398 colon and 393 rectal GISTs. After propensity matching, compared to gastric GISTs, rectal GISTs had improved overall survival (HR =0.695, P=0.0264), while colon GISTs had worse overall survival (HR =1.6, P=0.0005). Surgical treatment for rectal GISTs was more likely to be local excision compared to colonic GISTs (51.1% vs. 8.4%, P<0.0001). Colon and gastric GISTs were less likely to receive systemic therapy compared to rectal GISTs (34.2% vs. 34.0% vs. 55.2%, P<0.0001). Adjuvant systemic therapy conveyed a survival advantage to rectal GISTs (HR =0.47, P=0.042) but not colon GISTs. There was a negative impact of adjuvant therapy on survival for colon GISTs <5 cm (HR =3.41, P=0.032). CONCLUSIONS: Patients with rectal GISTs live longer than those with colon and gastric GISTs, and adjuvant therapy prolongs their survival. Many patients with colon GISTs are treated with adjuvant therapy despite a detrimental effect on survival. Tumor biology of colon and rectal GISTs needs to be better studied to tailor treatment.

Complications in pediatric hepatobiliary surgery.

This review highlights the complications and their risk factors encountered in pediatric hepatobiliary surgery, specifically in the context of pediatric hepatic resection, excision of choledochal cyst, and the Kasai hepatoportoenterostomy procedure for biliary atresia as well as other procedures potentially affecting the biliary tree. With the understanding that these are relatively rare procedures, case reports and small case series are included in addition to larger series when available. The review focuses on publications in English over the past 15 years. Complications included both surgery-specific pathology, such as biliary stricture after excision of choledochal cyst, and disease-specific entities, such as malnutrition in biliary atresia. This review may be useful when considering a particular procedure or in the discussion thereof with a patient and family. Additionally, it illuminates the need for additional work with larger patient databases to refine and expand our knowledge of these complications and precipitating risk factors.

Pancreaticoduodenectomy for locally advanced colon cancer in hereditary nonpolyposis colorectal cancer.

BACKGROUND: Hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome, accounts for 3% of newly diagnosed cases of colorectal cancer. While a partial or subtotal colectomy is indicated for early stage disease, there is a paucity of data addressing locally advanced disease involving the foregut. CASE PRESENTATION: We report two patients with hereditary nonpolyposis colorectal cancer presenting with locally advanced colon cancer surgically managed by pancreaticoduodenectomy with en bloc partial colectomy and a review of the literature. CONCLUSIONS: Locally advanced colorectal cancer in HNPCC is a rare clinical entity that requires special surgical consideration. Multidisciplinary treatment, including multi-visceral resection, offers the best long-term outcome.

The effect of mutant SOD1 dismutase activity on non-cell autonomous degeneration in familial amyotrophic lateral sclerosis.

Mutant superoxide dismutase type 1 (MTSOD1), the most common known cause of familial amyotrophic lateral sclerosis (FALS), is believed to cause FALS as a result of a toxicity of the protein. MTSOD1s with full dismutase enzymatic activity (e.g., G37R) and without any enzymatic activity (e.g., G85R) cause FALS, demonstrating that the ability of MTSOD1 to cause FALS is not dependent on the dismutase activity; however, it remains unclear whether MTSOD1 dismutase activity can influence disease phenotype. In the present study, we selectively knocked down G85R expression in particular cell types of G85R mice. Results following knockdown of G85R in motor neurons (MNs)/interneurons of G85R mice were similar to results from a published study involving knockdown of G37R in G37R mice; however, G85R knockdown in microglia/macrophages induced a prolonged early and late disease phase while G37R knockdown in the same cells only affected late phase. These results show that: (i) MN as well as non-MN expression of G85R, like G37R, has a significant effect on disease in transgenic mice - indicating the role of non-cell autonomous degeneration in both dismutase-active and inactive MTSOD1s. (ii) The effect of MTSOD1 expression in microglia/macrophages varies with different mutants, and may be influenced by the MTSOD1's dismutase activity.