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Figure S2. Representative IPA mechanistic network for signaling regulators predicted to contribute to the RABL6A knockdown phenotype.

Figure S4. Quantitative RT-PCR showing effective silencing of Rb1 mRNA by Rb1 shRNAs in RABL6A knockdown cells.

Table S1. List of differentially regulated genes caused by RABL6A knockdown (KD), relative to control (CON), in BON-1 PNET cells.

Figure S3. Quantitative RT-PCR showing RABL6A depletion does not affect p21 mRNA expression

Figure S1. Quantitative PCR measurement of human RABL6A DNA copy number in human PNET patient samples.

Figure S5. Effect of RABL6A overexpression on Rb1 and p21 mRNA and protein expression

Figure S6. Down-regulation of p27 in arrested RABL6A knockdown cells promotes S phase entry.

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.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of desmoplastic small round cell tumor, breast, and gastrointestinal stromal tumor specifically related to peritoneal surface malignancy. These guidelines are developed with input from leading experts including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides multidisciplinary recommendations for palliative care specifically related to peritoneal surface malignancies. These guidelines are developed with input from leading experts including surgical oncologists, medical oncologists, gynecologic oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of neuroendocrine tumors specifically related to the management of peritoneal surface malignancy. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

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.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.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; p0.001). 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 (p0.001). 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.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.

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.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.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).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.

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. 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.

BACKGROUND: Management of duodenal neuroendocrine tumors (DNETs) is not standardized, with smaller lesions (

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.

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

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.

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.

Jejunoileal or small bowel neuroendocrine tumors (SBNETs), as with neuroendocrine tumors arising from other anatomic locations, are increasing in incidence. Given the small intestine’s relative inaccessibility to endoscopy and the fact that SBNETs are frequently small, they often elude preoperative identification. Nodal and liver metastases are common at the time of diagnosis. The majority of SBNETs are low grade with slow growth, and with optimal treatment patients can survive for many years, even with metastatic disease. Definitive management includes surgery to remove the primary tumor, associated nodal tissue, and distant metastases, when feasible. For unresectable or recurrent disease, an ever-increasing range of medical therapies including somatostatin analogues, peptide receptor radionuclide therapy, and targeted molecular inhibitors can delay progression and potentially extend survival.

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.

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.

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.

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: 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.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of peritoneal surface malignancies of various causes. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness of the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence. This article explains the process and methodology of building these guidelines and pathways.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of peritoneal mesothelioma. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness of the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides the following multidisciplinary recommendations for the care of patients with peritoneal surface malignancies. This article focuses on the standards of a peritoneal surface malignancy center, standards of billing and coding, standards of operative reports for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, standards of cytoreductive surgery training, and standards of intraoperative chemotherapy preparation. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of ovarian neoplasms specifically related to the management of peritoneal surface malignancy. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, gynecologic oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

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

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.

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.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 χOf 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).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.

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.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, calcium7.0 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.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).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.

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_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.