Prescribing Characteristics of Octreotide Immediate-Release and Long-Acting Release in Patients with Neuroendocrine Tumors.

BACKGROUND: Treatment recommendations for patients with neuroendocrine tumors (NETs) include the use of octreotide long-acting release (LAR) for long-term therapy and immediate-release (IR) as rescue therapy to control the breakthrough symptoms of carcinoid syndrome (CS). High doses of LAR are commonly used in clinical practice. This study aimed to evaluate the real-world utilization of LAR and preceding IR use at the prescription and patient levels. METHODS: We used an administrative claims database (2009-2018) containing privately insured enrollees. We calculated the normalized LAR dose from pharmacy claims and the initial mean IR daily dose at the prescription level. At the patient level, we conducted a retrospective cohort study that included patients continuously enrolled with ≥1 pharmacy claim of LAR and evaluated the frequency and the clinical reason for dose escalation of LAR. The definition of the above-label maximum dose of LAR was ≥30 mg/4 weeks. RESULTS: Nineteen percent of LAR prescriptions had an above-label maximum dose. Only 7% of LAR prescriptions had preceding IR use. There were 386 patients with NETs or CS vs. 570 with an unknown diagnosis. Comparing patients with NETs or CS to those with an unknown diagnosis, 22.3% vs. 11.0 % experienced dose escalations and 29.0% vs. 26.6% had IR use before dose escalation, respectively. LAR dose escalation occurred in 50.9% vs. 39.2% for symptom control, 12.3% vs. 7.1% for tumor progression control, and 16.6% vs. 6.0% for both reasons in NETs/CS and unknown groups, respectively. CONCLUSION: Octreotide LAR dosing above the label-maximum dose is common and IR rescue dosing appears to be underutilized.

hPG80 (Circulating Progastrin), a Novel Blood-Based Biomarker for Detection of Poorly Differentiated Neuroendocrine Carcinoma and Well Differentiated Neuroendocrine Tumors.

Current blood-based biomarkers for neuroendocrine neoplasms (NENs) lack both sensitivity and specificity. Human circulating progastrin (hPG80) is a novel biomarker that can be easily measured in plasma by ELISA. This study is the first to examine hPG80 in NENs. Plasma hPG80 was quantified from 95 stage IV NEN patients, using DxPG80 technology (ECS Progastrin, Switzerland) and compared with hPG80 concentrations in two cohorts of healthy donor controls aged 50-80 (n = 252) and 18-25 (n = 137). Median hPG80 in NENs patients was 5.54 pM compared to 1.5 pM for the 50-80 controls and 0.29 pM the 18-25 cohort (p < 0.0001). Subgroup analysis revealed median hPG80 levels significantly higher than for either control cohort in neuroendocrine carcinoma (NEC; n = 25) and neuroendocrine tumors (NET; n = 70) including the small-cell lung cancer (SCLC) sub-cohort (n = 13). Diagnostic accuracy, estimated by AUCs, was high for NENs, as well as both sub-groups (NEC/NET) when compared to the younger and older control groups. Plasma hPG80 in NENs may be a diagnostic blood biomarker for both low- and high-grade NENs; further study is warranted. A prospective multi-center trial is ongoing in NET to evaluate hPG80 as a means of monitoring disease (NCT04750954).

68Ga-DOTATATE PET/CT: The Optimum Standardized Uptake Value (SUV) Internal Reference.

RATIONALE AND OBJECTIVES: Standardized Uptake Value (SUV) is an important semiquantitative measurement used in the clinical and research domains to assess radiopharmaceutical concentration in tumors versus normal organs, but is susceptible to many factors beyond the tumor biological environment. So, the aim of this study is to identify the optimum internal reference among organs with physiological uptake in 68Ga-DOTATATE PET/CT (DOTA PET/CT) scans. MATERIALS AND METHODS: This HIPAA-compliant, IRB-approved study with waiver of consent included retrospective imaging review of 180 consecutive patients with neuroendocrine tumors presenting for DOTA PET/CT image acquisition: Ga-68 DOTATATE dose was reported as (0.054 mCi/Kg) scans between September 2018 and May 2019. Mean value of body weight normalized SUV (SUVbw) and lean body mass normalized SUV (SUL) of liver and spleen were measured. Information about the patients and scan characteristics were collected. The paired Grambsch test was used to compare variance among the measured SUVs. Spearman's rank correlation coefficient was used to assess correlation between SUVs and potential patient- and scan-specific confounding factors. RESULTS: Variance of SUL was significantly lower than variance of SUVbw in both liver and spleen (p-value < 0.0001). Variances of liver SUVbw and SUL were significantly lower than the corresponding spleen SUVs. Liver SUL showed the lowest variance (3.69% ± 1.25%) among all measured SUVs. CONCLUSION: SUL is a more reproducible, less variable, and therefore more reliable quantitative measure in DOTA PET/CT scans, compared SUVbw. Among the available organs with physiological uptake, liver SUL is the optimum internal reference given the liver's larger size and uniform SUL values resulting in lower variability and better reproducibility.

Long-Term Treatment with Telotristat Ethyl in Patients with Carcinoid Syndrome Symptoms: Results from the TELEPATH Study.

INTRODUCTION: Telotristat ethyl is indicated for use in combination with somatostatin analogs (SSAs) to treat carcinoid syndrome (CS) diarrhea uncontrolled by SSAs alone in adults, but long-term safety and efficacy data beyond 48 weeks are needed. OBJECTIVES: The aims of the study were to evaluate the long-term safety and tolerability of telotristat ethyl and its effect on quality of life (QOL) in patients with CS. METHODS: In this phase 3, nonrandomized, multicenter, open-label, long-term extension study (TELEPATH), patients who participated in phase 2 or 3 trials of telotristat ethyl continued treatment at their present dose level (250 or 500 mg thrice daily) for 84 weeks. Safety and tolerability, the primary endpoint, were assessed by monitoring adverse events (AEs), serious AEs, AEs of special interest (AESIs; including liver-related AEs, depression, and gastrointestinal AEs), and deaths. The secondary objective was to evaluate changes in patients' QOL using validated cancer questionnaires and a subjective global assessment of CS symptoms. RESULTS: In 124 patients exposed to telotristat ethyl for a mean of 102.6 ± 53.2 weeks, the type and frequency of AEs were consistent with those reported in previous trials. The occurrence of AESIs was not related to dosage or duration of therapy. Most AEs were mild to moderate in severity, and no deaths were related to telotristat ethyl. QOL scores remained stable, and the majority of patients reported adequate symptom relief throughout the study. CONCLUSIONS: Safety results of TELEPATH support the long-term use of telotristat ethyl in patients with CS diarrhea. Telotristat ethyl was well-tolerated and associated with sustained improvement in QOL scores (NCT02026063).

Management of Large Cell Neuroendocrine Carcinoma.

BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive cancer with a dismal prognosis. The majority of cases occur in the lung and the gastrointestinal tract; however, it can occur throughout the body. Recently advances in the understanding of the molecular underpinnings of this disease have paved the way for additional novel promising therapies. This review will discuss the current best evidence for management of LCNEC and new directions in the classification and treatment of this rare disease. METHODS: We performed a PubMed search for "Large cell neuroendocrine carcinoma" and "High grade neuroendocrine carcinoma." All titles were screened for relevance to the management of LCNEC. Papers were included based on relevance to the management of LCNEC. RESULTS: Papers were included reviewing both pulmonary and extra pulmonary LCNEC. We summarized the data driven best practices for the management of both early and advanced stage LCNEC. We describe emerging therapies with promising potential. DISCUSSION: LCNEC are rare and aggressive neoplasms. In advanced disease, the historical regimen of platinum based therapy in combination with etoposide or irinotecan remains among the commonly used first line therapies, however for extra thoracic LCNEC regimens like FOLFOX, FOLFOIRI and CAPTEM can also be used. Further effective and safe treatment options are desperately needed. Recently, new advances including a new understanding of the genetic subcategories of LCNEC and immunotherapy agents may guide further treatments.

A phase I/II study of rovalpituzumab tesirine in delta-like 3-expressing advanced solid tumors.

Delta-like protein 3 (DLL3) is highly expressed in solid tumors, including neuroendocrine carcinomas/neuroendocrine tumors (NEC/NET). Rovalpituzumab tesirine (Rova-T) is a DLL3-targeting antibody-drug conjugate. Patients with NECs and other advanced DLL3-expressing tumors were enrolled in this phase I/II study (NCT02709889). The primary endpoint was safety. Two hundred patients were enrolled: 101 with NEC/NET (large-cell NEC, gastroenteropancreatic NEC, neuroendocrine prostate cancer, and other NEC/NET) and 99 with other solid tumors (melanoma, medullary thyroid cancer [MTC], glioblastoma, and other). The recommended phase II dose (RP2D) was 0.3 mg/kg every 6 weeks (q6w) for two cycles. At the RP2D, grade 3/4 adverse events included anemia (17%), thrombocytopenia (15%), and elevated aspartate aminotransferase (8%). Responses were confirmed in 15/145 patients (10%) treated at 0.3 mg/kg, including 9/69 patients (13%) with NEC/NET. Rova-T at 0.3 mg/kg q6w had manageable toxicity, with antitumor activity observed in patients with NEC/NET, melanoma, MTC, and glioblastoma.

PI3K/mTOR Dual Inhibitor PF-04691502 Is a Schedule-Dependent Radiosensitizer for Gastroenteropancreatic Neuroendocrine Tumors.

Patients with advanced-stage gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have a poor overall prognosis despite chemotherapy and radiotherapy (e.g., peptide receptor radionuclide therapy (PRRT)). Better treatment options are needed to improve disease regression and patient survival. The purpose of this study was to examine a new treatment strategy by combining PI3K/mTOR dual inhibition and radiotherapy. First, we assessed the efficacy of two PI3K/mTOR dual inhibitors, PF-04691502 and PKI-402, to inhibit pAkt and increase apoptosis in NET cell lines (BON and QGP-1) and patient-derived tumor spheroids as single agents or combined with radiotherapy (XRT). Treatment with PF-04691502 decreased pAkt (Ser473) expression for up to 72 h compared with the control; in contrast, decreased pAkt expression was noted for less than 24 h with PKI-402. Simultaneous treatment with PF-04691502 and XRT did not induce apoptosis in NET cells; however, the addition of PF-04691502 48 h after XRT significantly increased apoptosis compared to PF-04691502 or XRT treatment alone. Our results demonstrate that schedule-dependent administration of a PI3K/mTOR inhibitor, combined with XRT, can enhance cytotoxicity by promoting the radiosensitivity of NET cells. Moreover, our findings suggest that radiotherapy, in combination with timed PI3K/mTOR inhibition, may be a promising therapeutic regimen for patients with GEP-NET.

Opportunities to Improve Symptom Control with Somatostatin Congeners in GEP-NETs: A Review of Key Issues.

Octreotide acetate (octreotide) is the most prescribed and most studied somatostatin congener, or analog, for gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and carcinoid syndrome, the latter of which may be characterized by debilitating diarrhea and flushing. Approved in the U.S. more than 30 years ago, octreotide is widely used to control the symptoms of carcinoid syndrome and has been shown to demonstrate antiproliferative activity. The two formulations available in the U.S. include a subcutaneous immediate-release (IR) injection introduced in 1989 and a long-acting repeatable (LAR) intramuscular injection approved in 1999. Lanreotide depot (lanreotide), a more recent somatostatin congener, has been available in the U.S. since 2014. Despite widespread use of octreotide LAR, several key challenges exist with the current depot-based treatment paradigm. Studies indicate that LAR formulations are associated with continued unmet patient needs, owing in part to a loss of bioactivity over time that may necessitate progressive supplemental treatment with IR octreotide to adequately control symptoms. Clinicians should understand the key differences in the pharmacokinetic profiles of the LAR and IR formulations that may contribute to bioactivity loss and somatostatin receptor desensitization. In addition, there is a need to re-evaluate the role of IR octreotide in combination with depot therapy to provide consistent bioavailability and better control of carcinoid syndrome symptoms. The purpose of this review is to explore all these issues and to re-establish a rationale for the IR formulation, particularly with respect to novel use cases and its use during the COVID-19 pandemic. IMPLICATIONS FOR PRACTICE: There is a need to re-evaluate the role of immediate-release octreotide in combination with depot therapy to provide consistent bioavailability and better control of carcinoid syndrome symptoms.

Can an amino acid mixture alleviate gastrointestinal symptoms in neuroendocrine tumor patients?

BACKGROUND: Neuroendocrine tumors, although relatively rare in incidence, are now the second most prevalent gastrointestinal neoplasm owing to indolent disease biology. A small but significant sub-group of neuroendocrine tumor patients suffer from diarrhea. This is usually secondary to carcinoid syndrome but can also be a result of short gut syndrome, bile acid excess or iatrogenic etiologies. Recently, an amino acid based oral rehydration solution (enterade® Advanced Oncology Formula) was found to have anti-diarrheal properties in preclinical models. METHODS: A retrospective chart review of all NET patients treated with enterade® AO was performed after IRB approval. RESULTS: Ninety-eight NET patients who had received enterade® AO at our clinic from May 2017 through June 2019 were included. Patients (N = 49 of 98) with follow up data on bowel movements (BMs) were included for final analysis. Eighty-four percent of patients (41/49) had fewer BMs after taking enterade® AO and 66% (27/41) reported more than 50% reduction in BM frequency. The mean number of daily BMs was 6.6 (range, 3-20) at baseline before initiation of therapy, while the mean number of BMs at 1 week time point post enterade® AO was 2.9 (range, 0-11). CONCLUSIONS: Our retrospective observations are encouraging and support prospective validation with appropriate controls in NET patients. This is first published report of the potential anti-diarrheal activity of enterade® AO in NET patients.

Time to Sustained Improvement in Bowel Movement Frequency with Telotristat Ethyl: Analyses of Phase III Studies in Carcinoid Syndrome.

BACKGROUND: Telotristat ethyl is approved to treat carcinoid syndrome diarrhea in combination with somatostatin analogs. In TELESTAR and TELECAST phase III studies, patients with carcinoid syndrome received telotristat ethyl 250 or 500 mg 3 times per day (tid) or placebo tid in addition to somatostatin analogs. The aim of this prespecified analysis was to examine the time to reductions in bowel movements (BMs) in the TELESTAR and TELECAST studies using survival analysis methods. METHODS: First occurrence of sustained response was defined as the time to the first day of 2 consecutive weeks with a mean BM frequency improvement of ≥ 30% from baseline during the 12-week double-blind treatment periods. Time to first ≥ 30% worsening in BM frequency was also measured. Treatments were compared with the log-rank test; Cox regression models provided point and confidence interval estimates of the hazard ratios for each trial. RESULTS: In TELESTAR and TELECAST, majority of patients (69%) on telotristat ethyl experienced a sustained ≥ 30% improvement in BM frequency. The median time to sustained reduction of at least 30% in BM frequency was significantly faster (fewer days to onset) for telotristat ethyl compared with placebo in both TELESTAR (250 mg, HR = 2.3 [95% CI, 1.3-4.1, P = 0.004]; 500 mg, HR = 2.2 [95% CI, 1.2-3.9, P = 0.009]) and TELECAST (250 mg, HR = 3.9 [95% CI, 1.6-11.1, P = 0.003]; 500 mg, HR = 4.2 [95% CI, 1.7-11.7, P = 0.002]). In TELECAST, 42% of patients on placebo experienced sustained worsening in BM frequency compared with 20% on telotristat ethyl; no significant difference was observed in TELESTAR. CONCLUSION: The time of onset of sustained BM frequency improvement mean and range are important when considering use of telotristat ethyl in patients with carcinoid syndrome diarrhea. Telotristat ethyl may also reduce sustained worsening in BM frequency. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT01677910, NCT02063659.

Benchmarks for Academic Oncology Faculty.

The role of clinical researchers is vital to cancer progress. The teaching, research, and leadership roles that academic oncologists hold need to be accounted for and appropriately compensated. National metrics are currently inexistent, but are necessary to move the oncology research field forward. Clinical research and routine clinical care must be harmoniously integrated without competing. This article reviews the national landscape of clinical cancer research and proposes a call for action.

Gynecologic large cell neuroendocrine carcinoma: A review.

Large cell neuroendocrine carcinomas (LCNEC) are rare, aggressive high-grade neuroendocrine neoplasms within the neuroendocrine cell lineage spectrum. This manuscript provides a detailed review of published literature on LCNEC of gynecological origin. We performed a PubMed search for material available on gynecologic LCNEC. We analyzed 104 unique cases of gynecologic LCNECs, of which 45 were cervical primary, 45 were ovarian, 13 were uterine, and 1 was vaginal. A total of 45 cases of cervical LCNEC were identified with a median age of 36 years. Median overall survival was 16 months. We identified 45 ovarian LCNEC cases in the published literature with a median age of 54 years. Median overall survival was 8 months. 13 LCNEC cases of uterine origin were identified; 12 out of 13 were of endometrial origin and the median age was 71 years. The majority of patients presented with Stage III/IV disease (stages I-IV were 31%, 8%, 38%, and 23%, respectively). Gynecologic LCNEC is an aggressive malignancy. Our current understanding of the disease biology is very limited. Efforts are required to better understand the genomic and molecular characterizations of gynecological LCNEC. These efforts will elucidate the underlying oncogenic pathways and driver mutations as potential targets.

Differential Diagnosis of Diarrhea in Patients With Neuroendocrine Tumors.

Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience diarrhea that can have a debilitating effect on quality of life. Diarrhea also may develop in response to other hormonal syndromes associated with NETs, surgical complications, medical comorbidities, medications, or food sensitivities. Limited guidance on the practical approach to the differential diagnosis of diarrhea in these patients can lead to delays in appropriate treatment. This clinical review and commentary underscore the complexity in identifying the etiology of diarrhea in patients with NETs. Based on our collective experience and expertise, we offer a practical algorithm to guide medical oncologists and other care providers to expedite effective management of diarrhea and related symptoms in patients with NETs.

Post FDA approval analysis of 200 gallium-68 DOTATATE imaging: A retrospective analysis in neuroendocrine tumor patients.

Gallium-68 DOTATATE provides physiologic imaging and assists in disease localization for somatostatin receptor (SSTR) positive neuroendocrine tumor (NET) patients. However, questions regarding usefulness of gallium- 68 DOTATATE imaging in identifying the primary site in neuroendocrine tumors (NETS) of unknown primary, correlation of NET grade with median Standardized Uptake Value (SUV) and effects of long acting somatostatin analog on gallium-68 DOTATATE imaging quality needs to be evaluated. A single institution retrospective review of the first 200 NET patients with gallium-68 DOTATATE imaging from Dec 2016 to Dec 2017 was conducted. Questions related to NETs of unknown primary, correlation of Standardized Uptake Value (SUV) to Ki-67 (which signifies proliferation rate), the effects of long-acting systemic somatostatin analog (SSA) on SUV were part of our data analysis. From these 200 patients, 59.5% (119) were females, 40.5% (81) were males; the median age was 62 years. The following primary tumor sites were identified: small bowel-37.5%; pancreas-18.5%; bronchial-14%; colon-3.5%; rectum-2%; appendix-1.5%; adrenal-0.5%; prostate-0.5%; others-3% and unknown primary-19%. Mean hepatic SUV of the lesion with the greatest radiolabeled uptake in 96 patients was similar irrespective to exposure to long acting SSA. Patients exposed to long acting SSA had mean SUV of 31.3 vs 27.8 for SSA naïve patients. The difference was not statistically significant. Gallium-68 DOTATATE imaging seems to distinguished G3 NET from G1/G2 based on mean SUV, and also identified the primary tumor site in 17 of 38 (45%) patients with unknown primary. Systemic exposure to long acting SSA does not appear to influence mean SUV of gallium-68 DOTATATE scan.

Biliary tract large cell neuroendocrine carcinoma: current evidence.

BACKGROUND: Primary neuroendocrine carcinomas of the gallbladder and biliary tract are rare, with pure large cell neuroendocrine carcinomas (LCNEC) being exceedingly rare and with a particularly poor prognosis. METHODS: We performed a review of published data on biliary tract large cell neuroendocrine carcinomas in PubMed. RESULTS: Preliminary search revealed over 2000 results but we found only 12 cases of pure large cell neuroendocrine carcinomas of biliary tract noted in literature to date. Because it commonly presents with non-specific symptoms of abdominal pain and jaundice, diagnosis is made after resection with histo-pathological and immunohistochemical analysis. These cancers are particularly aggressive with high recurrence rates, most often presenting with metastasis to regional lymph nodes and/or the liver resulting in a poor prognosis. Overall, complete surgical excision with systemic chemotherapy is the treatment mainstay. If the cancer is unresectable due to multiple metastases, medical management with systemic chemotherapy is the primary treatment modality. CONCLUSION: The prognosis of hepatobiliary LCNEC remains poor with median survival of only 11 months from initial diagnosis. Studies focusing on high grade neuroendocrine carcinoma are needed to enhance our understanding of biology and therapeutics in this rare but aggressive cancer.

Current Practices and Novel Techniques in the Diagnosis and Management of Neuroendocrine Tumors of Unknown Primary.

Neuroendocrine tumors (NETs) comprise a heterogeneous group of neoplasms in which tumor staging/prognosis and response to treatments depend heavily on accurate and timely identification of the anatomic primary site or NET subtype. Despite recent technological advancements and use of multiple diagnostic modalities, 10% to 14% of newly diagnosed NETs are not fully characterized based on subtype or anatomic primary site. Inability to fully characterize NETs of unknown primary may cause delays in surgical intervention and limit potential treatment options. To address this unmet need, clinical validity and utility are being demonstrated for novel approaches that improve NET subtype or anatomic primary site identification. Functional imaging using Ga-radiolabeled DOTATATE positron emission tomography/computed tomography has been shown to overcome some false-positive and resolution issues associated with octreotide scanning and computed tomography/magnetic resonance imaging. Using a genomic approach, molecular tumor classification based on differential gene expression has demonstrated high diagnostic accuracy in blinded validation studies of different NET types and subtypes. Given the widespread availability of these technologies, we propose an algorithm for the workup of NETs of unknown primary that integrates these approaches. Including these technologies in the standard workup will lead to better NET subtype identification and improved treatment optimization for patients.

Evaluation of meaningful change in bowel movement frequency for patients with carcinoid syndrome.

BACKGROUND: Carcinoid syndrome is associated with a reduced quality of life that can be attributed to symptoms such as diarrhea and fatigue as well as social and financial issues. This study was conducted to psychometrically assess meaningful change in bowel movement frequency among carcinoid syndrome patients using data from the TELESTAR clinical study. METHODS: An anchor-based approach for deriving meaningful change thresholds consisted of mapping change from baseline bowel movement frequency to other patient-reported assessments of change. These included the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core Questionnaire (QLQ-C30) Diarrhea Symptom responders, the EORTC Gastrointestinal NET questionnaire (GI.NET21) GI Symptom responders, and reported adequate relief at Week 12 (≥ 10-point score decrease from Day 1 to Week 12). Parameters included within-group mean change from baseline to Week 12, t-tests of the change (Wilcoxon rank sum for adequate relief), and effect size. RESULTS: There were 135 carcinoid syndrome patients with a mean baseline frequency of 5.7 bowel movements a day. A distribution-based method yielded meaningful change estimates of 0.62 bowel movements a day for overall frequency and 0.83 bowel movements a day at Week 12. Anchor-based analysis indicated a large effect size among patients who reported adequate relief at Week 12 (- 1.58; n = 18; P = 0.014), the QLQ-C30 Diarrhea domain responders (- 1.24; n = 40; P < 0.001), and the GI.NET21 GI Symptoms Domain responders (- 1.49; n = 25; P = 0.005). Exit interview data for meaningful change yielded effect size estimates of - 1.57 for overall change during the Double-blind Treatment Period and - 1.97 for change between Baseline and Week 12. CONCLUSIONS: Meaningful change derivation is critical to interpret patient outcomes for evaluating treatment efficacy. In this study, carcinoid syndrome patients experienced clinically meaningful reductions in bowel movement frequency of ≥30% over 12 weeks with telotristat ethyl treatment. TRIAL REGISTRATION: NCT01677910 .

Does the addition of adjuvant intraoperative tumor bed chemotherapy during midgut neuroendocrine tumor debulking procedures benefit patients?

BACKGROUND: Midgut neuroendocrine tumor (NET) patients are often diagnosed at advanced stages with extensive mesenteric nodal and hepatic metastasis. The only potentially curative treatment is surgical tumor eradication. Despite an aggressive resection, macro and microscopic residual disease still may remain in the resection bed. We hypothesize that the application of 5-fluorouracil (5-FU) within the tumor bed will help eliminate microscopic residual disease. METHODS: Records of 189 patients who underwent extensive cytoreductive surgeries during 2003-2012 for advanced, midgut NETs with extensive mesenteric lymphadenopathy were reviewed. Eighty-six patients (46%) who had 5-FU saturated gel foam strips secured into their mesenteric resection sites served as the study group and a matching 103 patients (54%) who did not have such an intra-operative chemotherapy served as controls. Survival from the time of diagnosis and post-operative complications between the two groups were compared. RESULTS: Mortality rates at 30, 60 and 90 days post-operatively were 4%, 0%, 0% versus 2%, 0%, 2% for study and control groups, respectively. Major complications (Grades III & IV) at the same intervals were 0, 0, 1 versus 2, 3, 2 for study and control groups, respectively. Median survival was 236 months versus 148 months for the study and control groups, respectively 24 (P=0.15). CONCLUSIONS: Intraoperative tumor resection bed chemotherapy is a safe adjuvant without discernible toxicity. This procedure may provide survival benefits to midgut NET patients with extensive mesenteric lymphadenopathy undergoing extensive cytoreductive surgery. Further study in prospective trials must be conducted to determine definitive benefit to the NET patient.

Multiple sclerosis outcomes after cancer immunotherapy.

INTRODUCTION: Neurological immune-related adverse events are a rare but potentially deadly complication after immune checkpoint inhibitor (ICI) treatment. As multiple sclerosis (MS) is an immune-mediated disease, it is unknown how ICI treatment may affect outcomes. METHODS: We analyzed the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database for pembrolizumab, atezolizumab, nivolumab, ipilimumab, avelumab, and durvalumab 2 years prior their FDA approval until December 31, 2017, to include all cases with confirmed diagnosis/relapse of MS. We also included cases reported in the literature and a patient from our institution. RESULTS: We identified 14 cases of MS with median age of presentation of 52 years. Indications for ICI included melanoma in 7 (36.36%) cases, non-small cell lung carcinoma in 2 (18.18%) cases, 1 case (9.09%) each of pleural mesothelioma, renal cell carcinoma, and colorectal cancer, and unreported in 2 (18.18%) cases. History of MS was confirmed in 8 (57.1%) cases. Median time to beginning of symptoms was 29 days with rapid disease progression; two patients died due to their relapse. Median time for symptom resolution was 8 weeks. Outcomes did not vary by comparing CTLA-4 and PD-1/PD-L1 inhibitors. CONCLUSIONS: Reported MS relapses after ICI are rare, but the adverse events described include rapid neurologic progression and death. Larger and prospective studies are warranted to assess disability and long-term outcomes and outweigh the risks of starting immunotherapy in patients with MS.

Can a High-grade Neuroendocrine Carcinoma be Functional?

We present a rare high-grade, functional, neuroendocrine carcinoma of the pancreas secreting vasoactive intestinal peptide. This case is unique, given the tumor's aggressive features and high Ki-67 index while also secreting functional hormones, which is unusual in high-grade neuroendocrine tumors (NETs). Our patient initially presented with diarrhea and was found to have a 4.7 × 3.1 × 3.3 cm pancreatic mass with diffuse hepatic metastasis staining positive for vasoactive intestinal peptide, chromogranin A and synaptophysin. She was initially underscored as grade 2 NET due to low mitosis, but subsequently restaged based on Ki-67 index as a grade 3 neuroendocrine carcinoma. She unfortunately was not a candidate for chemotherapy at that time. We conclude that high-grade NETs have the potential to secrete active peptide hormones. We therefore recommend that NETs with aggressive features be biopsied and assessed for Ki-67 activity and mitosis regardless if they are functional tumors, with goal for early initiation of chemotherapy.