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.

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.

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.

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.

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.

Demographics and anthropometrics impact benefits of health intervention: data from the Reduce Obesity and Diabetes Project.

OBJECTIVE: To determine the efficacy of a 4-month school-based health, nutrition and exercise intervention on body fatness and examine possible effects of demographic and anthropometric covariates. METHODS: Height, weight, waist circumference and body composition were measured in a diverse population of 644 NYC middle school students (mean ± SD age 12.7 ± 0.9 years; 46% male; 38% Hispanic, 17% East Asian, 15% South Asian, 13.5% African American, 8.5% Caucasian, 8% other) during the fall and spring semesters. Year 1 participants (n = 322) were controls. Experimental participants (year 2, n = 469) received a 12-session classroom-based health and nutrition educational programme with an optional exercise intervention. RESULTS: Groups were demographically and anthropometrically similar. The intervention resulted in significant reductions in indices of adiposity (ΔBMI z-scores [-0.035 ± 0.014; p = 0.01], Δ% body fat [-0.5 ± 0.2; p < 0.0001] and Δwaist circumference [-0.73 ± 0.30 cm; p < 0.0001]). Intervention effects were greater (p = 0.01) in men (ΔBMI z-score = -0.052 ± 0.015) versus women (0.022 ± 0.018), participants who were obese (ΔBMI z-score -0.083 ± 0.022 kg m-2) versus lean (-0.0097 ± 0.020 kg m-2) and South Asians (Δ% body fat -1.03 ± 0.35) versus total (-0.49 ± 0.20%) participants (p = 0.005). CONCLUSION: A 4-month school-based health intervention was effective in decreasing measures of adiposity in middle school students, particularly in men, participants who were obese and South Asians.

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.

Long-Term Safety Experience with Telotristat Ethyl Across Five Clinical Studies in Patients with Carcinoid Syndrome.

BACKGROUND: Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience considerable morbidity and mortality; carcinoid syndrome may be associated with shorter survival. Carcinoid syndrome is linked to tumoral secretion of serotonin and other bioactive substances. The subsequent debilitating diarrhea and urgency to defecate pose significant health risks. In previous studies, telotristat ethyl, a tryptophan hydroxylase inhibitor, was effective and well tolerated in treating carcinoid syndrome diarrhea. We present pooled safety data from five clinical trials with telotristat ethyl in patients with carcinoid syndrome. SUBJECTS, MATERIALS, AND METHODS: Adverse events reported during telotristat ethyl treatment were pooled from two phase II and three phase III clinical trials in 239 patients with carcinoid syndrome. Long-term safety of telotristat ethyl and causes of hospitalization and death were reviewed; overall survival was estimated. RESULTS: Mean (median; range) duration of exposure and follow-up was 1.3 years (1.1 years; 1 week to 5.7 years), with 309 total patient-years of exposure. Leading causes of hospitalization were gastrointestinal disorders or were related to the underlying tumor and related treatment. Survival estimates at 1, 2, and 3 years were 93%, 88%, and 77%. Nearly all deaths were due to progression or complication of the underlying disease; none were attributable to telotristat ethyl. There was one death in year 4. CONCLUSION: Based on long-term safety data, telotristat ethyl is well tolerated and has a favorable long-term safety profile in patients with carcinoid syndrome. IMPLICATIONS FOR PRACTICE: Carcinoid syndrome can cause persistent diarrhea, even in patients treated with somatostatin analogs. Across five clinical trials in patients with carcinoid syndrome, telotristat ethyl has been well tolerated and efficacious, providing clinicians with a new approach to help control carcinoid syndrome diarrhea, in addition to somatostatin analog therapy. By reducing the stool frequency in patients with carcinoid syndrome whose diarrhea is refractory to anticholinergics, such as loperamide and atropine/diphenoxylate, and somatostatin analog dose escalation, improvement in quality of life becomes an achievable goal.

Management of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia: Review and a Single Center Experience.

BACKGROUND: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare pulmonary condition, characterized by diffuse proliferation of neuroendocrine cells in the respiratory epithelium. DIPNECH lesions are less than 5 mm in size and are limited to the basement membrane with no invasion. There is limited information regarding epidemiology, natural history of disease progression, or the management of this rare entity. We present the experience of a center with extensive expertise in neuroendocrine disease. METHODS: A cohort of patients (N = 13) with DIPNECH treated and followed at our institution was identified. We describe the our approach to their care, our disease management and also provide a review of DIPNECH pathophysiology. RESULTS: Our patient cohort consisted of twelve females and one male with a mean age of 63 years at the time of diagnosis. Dyspnea on exertion and dry cough were the most common presenting symptoms. Two patients were under surveillance without treatment; three patients were treated with a short-acting somatostatin analog; three patients were treated with azithromycin alone; four were treated with a combination of long-acting monthly somatostatin analogs and azithromycin; one patient received a combination of long-acting somatostatin analog and everolimus. Five patients had concomitant bronchial carcinoids. CONCLUSIONS: DIPNECH is a rare pathology that can profoundly affect a patient's quality of life. Paroxysmal coughing episodes can be difficult to treat. Our limited single center experience shows encouraging response to use of somatostatin analogs, azithromycin, and everolimus in the management of debilitating DIPNECH associated symptoms.

Changes in Weight Associated With Telotristat Ethyl in the Treatment of Carcinoid Syndrome.

PURPOSE: In the placebo-controlled Phase III TELESTAR (Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled Carcinoid Syndrome) trial, the oral tryptophan hydroxylase inhibitor telotristat ethyl significantly reduced bowel movement (BM) frequency during a 12-week, double-blind treatment period in 135 patients with metastatic neuroendocrine tumors with carcinoid syndrome and ≥4 BMs per day. Patients (mean [SD] age, 63.5 [8.9] years; mean [SD] body mass index, 24.9 [4.9] kg/m2) received placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg 3 times per day (TID) in addition to somatostatin analogue therapy. Weight loss is associated with uncontrolled carcinoid syndrome and may be associated with reduced survival. METHODS: Assessment of the occurrence of weight change ≥3% at week 12 was prespecified in the statistical analysis plan. FINDINGS: In 120 patients with weight data available, weight gain ≥3% was observed in 2 of 39 patients (5.1%) taking placebo TID, 7 of 41 (17.1%) taking telotristat ethyl 250 mg TID, and 13 of 40 (32.5%) taking telotristat ethyl 500 mg TID (P = 0.0017) at week 12. Weight loss ≥3% was observed in 5 of 39 patients (12.8%) taking placebo TID, 4 of 41 (9.8%) taking telotristat ethyl 250 mg TID, and 6 of 40 (15.0%) taking telotristat ethyl 500 mg TID (P = 0.77). Biochemical and metabolic parameters of serum albumin and cholesterol significantly increased (P = 0.02 and P = 0.001, respectively) in patients gaining weight and decreased in patients who lost weight, suggesting an improvement in overall nutritional status. IMPLICATIONS: Up to 32.5% of patients treated with telotristat ethyl experienced significant, dose-dependent weight gain, associated with reduced diarrhea severity and improved biochemical and metabolic parameters. Improved nutritional status could be an additional aspect of telotristat ethyl efficacy among patients with functioning metastatic neuroendocrine tumors. ClinicalTrials.gov identifier: NCT01677910.

Global burden of neuroendocrine tumors and changing incidence in Kentucky.

BACKGROUND: Neuroendocrine tumors (NETs) have a low incidence but relatively high prevalence. Over the last three decades, the incidence of NETs has risen 6-fold in the United States. We conducted an observational study to compare the incidence of NETs reported to the Kentucky Cancer Registry (KCR) versus that reported to Surveillance, Epidemiology, and End Results Program (SEER). We also provide a systematic review of the state of neuroendocrine tumors worldwide, and compare the available global and local published data. METHODS: KCR and SEER databases were queried for NET cases between 1995 and 2015. A detailed literature review of epidemiological data for various nations worldwide summarize epidemiological data from various countries. RESULTS: KCR recorded 6179 individuals with newly diagnosed NETs between 1995 and 2015. Between 1995-2012, the incidence of NETs in KCR increased from 3.1 to 7.1 per 100,000 cases, while it increased from 3.96 to 6.61 in the SEER database. The incidence rates in both KCR and SEER databases were linear. 90.57% were Caucasians with 54.74% females. 27.67% of the Kentucky population was from the Appalachian region. Patients aged 50-64 years had the highest prevalence (38%). Lung NET (30.60%) formed the bulk of cases, followed by small intestine (16.82%), rectum/anus (11.35%) and colon (9.71%). CONCLUSIONS: NETs incidence between 1995 and 2015 show a linear increase in both KCR and SEER databases. Because of this increased incidence it is imperative for community oncologists to familiarize themselves with this entity, which until recently was under-studied and with few viable treatment options.

Telotristat ethyl in carcinoid syndrome: safety and efficacy in the TELECAST phase 3 trial.

Telotristat ethyl, a tryptophan hydroxylase inhibitor, was efficacious and well tolerated in the phase 3 TELESTAR study in patients with carcinoid syndrome (CS) experiencing ≥4 bowel movements per day (BMs/day) while on somatostatin analogs (SSAs). TELECAST, a phase 3 companion study, assessed the safety and efficacy of telotristat ethyl in patients with CS (diarrhea, flushing, abdominal pain, nausea or elevated urinary 5-hydroxyindoleacetic acid (u5-HIAA)) with <4 BMs/day on SSAs (or ≥1 symptom or ≥4 BMs/day if not on SSAs) during a 12-week double-blind treatment period followed by a 36-week open-label extension (OLE). The primary safety and efficacy endpoints were incidence of treatment-emergent adverse events (TEAEs) and percent change from baseline in 24-h u5-HIAA at week 12. Patients (N = 76) were randomly assigned (1:1:1) to receive placebo or telotristat ethyl 250 mg or 500 mg 3 times per day (tid); 67 continued receiving telotristat ethyl 500 mg tid during the OLE. Through week 12, TEAEs were generally mild to moderate in severity; 5 (placebo), 1 (telotristat ethyl 250 mg) and 3 (telotristat ethyl 500 mg) patients experienced serious events, and the rate of TEAEs in the OLE was comparable. At week 12, significant reductions in u5-HIAA from baseline were observed, with Hodges-Lehmann estimators of median treatment differences from placebo of -54.0% (95% confidence limits, -85.0%, -25.1%, P < 0.001) and -89.7% (95% confidence limits, -113.1%, -63.9%, P < 0.001) for telotristat ethyl 250 mg and 500 mg. These results support the safety and efficacy of telotristat ethyl when added to SSAs in patients with CS diarrhea (ClinicalTrials.gov identifier: Nbib2063659).

Prognostic Factors in Typical and Atypical Pulmonary Carcinoids.

BACKGROUND: Typical and atypical carcinoids represent approximately 2% of all lung tumors. Survival of patients with typical bronchial carcinoids, unlike the survival of patients with most lung tumors, is generally long but dependent on stage. We report the findings of the Ochsner Medical Center/Louisiana State University (LSU) Health Sciences Center neuroendocrine tumor (NET) program. METHODS: A database with all patients seen at the Ochsner Medical Center/LSU NET program was queried for patients with bronchopulmonary NET. We included patients who had confirmed pathologic bronchopulmonary carcinoid and who had at least 1 clinic visit. Patients with large or small cell NETs or diffuse idiopathic pulmonary neuroendocrine cell hyperplasia were excluded. RESULTS: A total of 169 patients seen from January 1996 to March 2015 met the inclusion criteria. The mean age at diagnosis was 53 years. Of the tumors, 51% percent (86/169) were well-differentiated, 12% (21/169) were moderately differentiated, and 85% and 53% were positive on positron emission tomography and octreotide scanning, respectively. The 5- and 10-year survival rates were 88% and 81% for well-differentiated tumors and 80% and 42% for moderately differentiated tumors, respectively. The 10-year survival rates stratified by Ki-67 index ranges 0-2%, >2%-10%, and >10% were 90%, 72%, and 44%, respectively (P<0.05). CONCLUSION: Overall, patients with bronchial carcinoids have long 5- and 10-year survival rates. We found significant survival differences between nodal status, differentiation status, and carcinoid phenotype. Interestingly, the difference in survival stratified by Ki-67 indices was statistically significant despite its absence in the World Health Organization grading system. As with gastroenteropancreatic NETs, Ki-67 index could become a valuable prognostic indicator for bronchial carcinoids.

mTOR Kinase Inhibition Effectively Decreases Progression of a Subset of Neuroendocrine Tumors that Progress on Rapalog Therapy and Delays Cardiac Impairment.

Inhibition of mTOR signaling using the rapalog everolimus is an FDA-approved targeted therapy for patients with lung and gastroenteropancreatic neuroendocrine tumors (NET). However, patients eventually progress on treatment, highlighting the need for additional therapies. We focused on pancreatic NETs (pNET) and reasoned that treatment of these tumors upon progression on rapalog therapy, with an mTOR kinase inhibitor (mTORKi), such as CC-223, could overcome a number of resistance mechanisms in tumors and delay cardiac carcinoid disease. We performed preclinical studies using human pNET cells in vitro and injected them subcutaneously or orthotopically to determine tumor progression and cardiac function in mice treated with either rapamycin alone or switched to CC-223 upon progression. Detailed signaling and RNA sequencing analyses were performed on tumors that were sensitive or progressed on mTOR treatment. Approximately 57% of mice bearing pNET tumors that progressed on rapalog therapy showed a significant decrease in tumor volume upon a switch to CC-223. Moreover, mice treated with an mTORKi exhibited decreased cardiac dilation and thickening of heart valves than those treated with placebo or rapamycin alone. In conclusion, in the majority of pNETs that progress on rapalogs, it is possible to reduce disease progression using an mTORKi, such as CC-223. Moreover, CC-223 had an additional transient cardiac benefit on valvular fibrosis compared with placebo- or rapalog-treated mice. These results provide the preclinical rationale to further develop mTORKi clinically upon progression on rapalog therapy and to further test their long-term cardioprotective benefit in those NET patients prone to carcinoid syndrome. Mol Cancer Ther; 16(11); 2432-41. ©2017 AACR.

Comprehensive genomic profiling in routine clinical practice leads to a low rate of benefit from genotype-directed therapy.

BACKGROUND: Describe a single-center real-world experience with comprehensive genomic profiling (CGP) to identify genotype directed therapy (GDT) options for patients with malignancies refractory to standard treatment options. METHODS: Patients who had CGP by a CLIA-certified laboratory between November 2012 and December 2015 were included. The medical records were analyzed retrospectively after Institutional Review Board (IRB) approval. The treating oncologist made the decision to obtain the assay to provide potential therapeutic options. The objectives of this study were to determine the proportion of patients who benefited from GDT, and to identify barriers to receiving GDT. RESULTS: A total of 125 pediatric and adult patients with a histologically confirmed diagnosis of malignancy were included. Among these, 106 samples were from adult patients, and 19 samples were from pediatric patients. The median age was 54 years for adults. The majority had stage IV malignancy (53%) and were pretreated with 2-3 lines of therapy (45%). The median age was 8 years for pediatric patients. The majority had brain tumors (47%) and had received none or 1 line of therapy (58%) when the profiling was requested. A total of 111 (92%) patients had genomic alterations and were candidates for GDT either via on/off-label use or a clinical trial (phase 1 through 3). Fifteen patients (12%) received GDT based on these results including two patients who were referred for genomically matched phase 1 clinical trials. Three patients (2%) derived benefit from their GDT that ranged from 2 to 6 months of stable disease. CONCLUSIONS: CGP revealed potential treatment options in the majority of patients profiled. However, multiple barriers to therapy were identified, and only a small minority of the patients derived benefit from GDT.

Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome.

Purpose Preliminary studies suggested that telotristat ethyl, a tryptophan hydroxylase inhibitor, reduces bowel movement (BM) frequency in patients with carcinoid syndrome. This placebo-controlled phase III study evaluated telotristat ethyl in this setting. Patients and Methods Patients (N = 135) experiencing four or more BMs per day despite stable-dose somatostatin analog therapy received (1:1:1) placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg three times per day orally during a 12-week double-blind treatment period. The primary end point was change from baseline in BM frequency. In an open-label extension, 115 patients subsequently received telotristat ethyl 500 mg. Results Estimated differences in BM frequency per day versus placebo averaged over 12 weeks were -0.81 for telotristat ethyl 250 mg ( P < .001) and ‒0.69 for telotristat ethyl 500 mg ( P < .001). At week 12, mean BM frequency reductions per day for placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg were -0.9, -1.7, and -2.1, respectively. Responses, predefined as a BM frequency reduction ≥ 30% from baseline for ≥ 50% of the double-blind treatment period, were observed in 20%, 44%, and 42% of patients given placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg, respectively. Both telotristat ethyl dosages significantly reduced mean urinary 5-hydroxyindole acetic acid versus placebo at week 12 ( P < .001). Mild nausea and asymptomatic increases in gamma-glutamyl transferase were observed in some patients receiving telotristat ethyl. Follow-up of patients during the open-label extension revealed no new safety signals and suggested sustained BM responses to treatment. Conclusion Among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in BM frequency and urinary 5-hydroxyindole acetic acid.

Defining the optimal timing of adjuvant therapy for resected pancreatic adenocarcinoma: A statewide cancer registry analysis.

BACKGROUND: Long-term results of the ESPAC-3 trial suggest that while completing adjuvant therapy (AT) is necessary after resection of pancreatic ductal adenocarcinoma (PDAC), early initiation (within 8 weeks) may not be associated with improved overall survival (OS). The primary aim of this study was to evaluate the OS impact of early versus late AT in a statewide analysis. METHODS: Patients with stages I-III PDAC in the Kentucky Cancer Registry (KCR) from 2004 to 2013, were evaluated. Those undergoing pancreatectomy were stratified into two groups ("early," <8 weeks, vs. "late," 8-16 weeks). RESULTS: Of 2,221 diagnosed patients with stages I-III, 831 (37.4%) underwent pancreatectomy upfront. Of these, only 420 (50.5%) received AT. Initiation date of AT was not associated with OS (median OS: early, 20.2 vs. late, 19.0 months, P = 0.97). On multivariate analysis, factors that affected OS included stage (II, HR-1.82, P = 0.017; III, HR-3.77, P < 0.001), node positivity (HR-1.51, P = 0.004), poorly/undifferentiated grade (HR-1.34; P = 0.011), but not AT initiation date. CONCLUSIONS: In this statewide analysis, there was no difference in OS between early and late AT initiation for resected PDAC. The ideal window for AT initiation remains unknown as tumor biology continues to trump regimens from the past decade. J. Surg. Oncol. 2016;114:451-455. © 2016 Wiley Periodicals, Inc.

Dynorphin inhibits basal forebrain cholinergic neurons by pre- and postsynaptic mechanisms.

KEY POINTS: The basal forebrain is an important component of the ascending arousal system and may be a key site through which the orexin neurons promote arousal. It has long been known that orexin-A and -B excite basal forebrain cholinergic neurons, but orexin-producing neurons also make the inhibitory peptide dynorphin. Using whole-cell recordings in brain slices, we found that dynorphin-A directly inhibits basal forebrain cholinergic neurons via κ-opioid receptors, and decreases afferent excitatory synaptic input to these neurons. While the effects of dynorphin-A and orexin-A desensitize over multiple applications, co-application of dynorphin-A and orexin-A produces a sustained response that reverses depending on the membrane potential of basal forebrain cholinergic neurons. At -40 mV the net effect of the co-application is inhibition by dynorphin-A, whereas at -70 mV the excitatory response to orexin-A prevails. ABSTRACT: The basal forebrain (BF) is an essential component of the ascending arousal systems and may be a key site through which the orexin (also known as hypocretin) neurons drive arousal and promote the maintenance of normal wakefulness. All orexin neurons also make dynorphin, and nearly all brain regions innervated by the orexin neurons express kappa opiate receptors, the main receptor for dynorphin. This is remarkable because orexin excites target neurons including BF neurons, but dynorphin has inhibitory effects. We identified the sources of dynorphin input to the magnocellular preoptic nucleus and substantia innominata (MCPO/SI) in mice and determined the effects of dynorphin-A on MCPO/SI cholinergic neurons using patch-clamp recordings in brain slices. We found that the orexin neurons are the main source of dynorphin input to the MCPO/SI region, and dynorphin-A inhibits MCPO/SI cholinergic neurons through κ-opioid receptors by (1) activation of a G protein-coupled inwardly rectifying potassium current, (2) inhibition of a voltage-gated Ca(2+) current and (3) presynaptic depression of the glutamatergic input to these neurons. The responses both to dynorphin-A and to orexin-A desensitize, but co-application of dynorphin-A and orexin-A produces a sustained response. In addition, the polarity of the response to the co-application depends on the membrane potential of BF neurons; at -40 mV the net effect of the co-application is inhibition by dynorphin-A, whereas at -70 mV the excitatory response to orexin-A prevails. This suggests that depending on their state of activation, BF cholinergic neurons can be excited or inhibited by signals from the orexin neurons.