Schizophrenia outcomes in the 21st century: A systematic review.

OBJECTIVE: We report a review of outcomes in schizophrenia in the twenty-first century, replicating and extending work undertaken by the late Richard Warner in his seminal book, "Recovery from Schizophrenia: Psychiatry and Political Economy" (1985;2004). METHOD: Warner's methods were followed as closely as possible. Only observational/naturalistic studies were included. Six scientific databases were searched from 2000 to 2020. 6,640 records were retrieved. 47 met inclusion criteria. RESULTS: Overall, complete recovery is higher in this study than in Warner's (37.75% cf 20.4%), especially for first episode psychosis (FEP) (57.1% cf 20.7%). Clinical recovery, annualized remission rate (ARR), and employment outcomes were significantly superior for first episode psychosis compared with multiple episode psychosis (MEP). ARR shows a trend toward reduction over time, from 2.2 before the financial crash of 2008 to 1.6 after (t = 1.85 df 40 p = .07). The decline is statistically significant for the MEP group (t = 2.32 df18 p = .03). There were no differences in outcome by region, sample characteristics, outcome measures used, or quality of studies. Heterogeneity of clinical outcome measures across the literature makes evidence synthesis difficult. Weak and inconsistent reporting of functional and employment outcomes mean that findings lack meaning with respect to lived experience. CONCLUSION: Future research strategies should aim to reduce heterogeneity in clinical outcome measures and to increase the emphasis on capture and reporting of more sophisticated measures of social and functional outcome. Outcome domains should be disaggregated rather than conflated into unitary recovery constructs.

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.

Establishment of Structure-Function Relationship of Tissue Inhibitor of Metalloproteinase-1 for Its Interaction with CD63: Implication for Cancer Therapy.

Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a pleiotropic protein, promoting both tumor-suppressive and tumor-promoting activities. While TIMP-1 is primarily known as an endogenous inhibitor of matrix metalloproteinases (MMPs) and thus associated with tumor cell invasion, clinical studies demonstrated increased expression of TIMP-1 and its association with poor prognosis in cancer. Non-MMP-inhibitory and oncogenic functions of TIMP-1 are mediated by induction of intracellular signaling via its cell surface receptor CD63, a tetraspanin. The present study investigates the structure-function relationship of TIMP-1 for its interaction with CD63, which may eventually help design a novel approach for targeting TIMP-1's pro-oncogenic activity without interfering its tumor suppressive MMP-inhibitory function. Importantly, our analysis includes TIMP-1/CD63 interactions at the cell surface of live cells. Here, we demonstrate that the 9 C-terminal amino acid residues of TIMP-1 and the large extracellular loop of CD63 are required for their interaction. Considering that the N-terminal half of TIMP-1 is sufficient for TIMP-1's MMP-inhibitory activity, we propose that those C-terminal amino acid residues are a potentially targetable motif of TIMP-1 oncogenic activity. As a proof of concept, we present the potential for the development of neutralizing antibodies against the C-terminal motif of TIMP-1 for disruption of TIMP-1 interaction with CD63 and the subsequent signal transduction.

EVIDENCE OF LEPTOSPIRA SEROVARS IN WILDLIFE AND LEPTOSPIRAL DNA IN WATER SOURCES IN A NATURAL AREA IN EAST-CENTRAL ILLINOIS, USA.

We identified seven Leptospira serovars in wildlife and the presence of leptospiral DNA in water sources at a natural area within a fragmented habitat in Illinois, US. These serovars have been implicated in domestic animal and human leptospirosis, a reemerging zoonotic disease, whose reservoirs include wildlife and domestic animals. We live trapped medium-sized mammals (n=351) near building (H-sites) or forest sites (F-sites). Using serology, we evaluated exposure to Leptospira (L. interrogans serovars Autumnalis, Bratislava, Canicola, Icterohaemorrhagiae, Pomona; L. kirschneri serovar Grippotyphosa; L. borgpetersenii serovar Hardjo). Using PCR, we tested for the presence of leptospires in eight water samples (ponds, creeks, and rainwater runoff) collected near trapping sites. We identified antibody titers in raccoons (Procyon lotor; 121/221) and Virginia opossums (Didelphis virginiana; 60/112), but not in feral cats (Felis catus; 0/18). We found significant differences in overall Leptospira seroprevalence between years (P=0.043) and animal's age in 2008 (P=0.005) and 2009 (P=0.003). Serovars Autumnalis, Bratislava, and Grippotyphosa showed significant differences among age groups with the highest seroprevalence in adults. Females had a higher seroprevalence for Icterohaemorragiae in 2008 (P=0.003) and Hardjo in 2009 (P=0.041). Risk of exposure to Leptospira was higher at F-sites compared to H-sites (odds ratio 2.3, 95% confidence interval 1.3-3.9, P=0.002). We captured more animals with titers >1:800 at H-sites, but there was no association between titer levels and capture site. Six of eight water sources were Leptospira-positive; however, there was no correlation between trapping locations of seropositive animals and positive water sources. Natural areas create opportunities for interspecies interactions, favoring leptospires transmission across species. Understanding that Leptospira serovars are present in natural areas is an integral part of the safe human and pet recreational use of these areas. Our study should raise awareness and build on public education designed to prevent disease transmission between species.

Environmental conditions for Jamestown Canyon virus correlated with population-level resource selection by white-tailed deer in a suburban landscape.

Suburban landscapes can alter spatial patterns by white-tailed deer (Odocoileus virginianus) and increase animal contact with vectors, pathogens, and humans. Close-contact relationships at a landscape level can have broad implications for disease epidemiology. From 1995-1999, we captured and radio-collared 41 deer in two suburban forest preserves in Chicago, Illinois. We collected blood to determine if animals were seronegative or seropositive for Jamestown Canyon virus and tracked deer movements within suburban habitats. We developed utilization distributions at the population-level and evaluated resource selection for seronegative and seropositive deer. We used maximum likelihood estimation for model selection via Akaike information criterion and then restricted maximum likelihood estimation to attain unbiased estimates of the parameters in the top-ranking models. The top-ranking model describing the resource selection of seronegative deer received almost the full weight of evidence (Akaike information criterion ωi = 0.93), and included the proportion of wetlands, precipitation in year t, and an interaction of the proportion of wetlands and precipitation in year t. The top-ranking model describing resource selection of seropositive deer received the full weight of evidence (Akaike information criterion ωi = 1.00). The model included distance to nearest populated place, distance to nearest river, length of road in each grid cell, precipitation in year t, and an interaction of the length of road in each grid cell and precipitation in year t. These results are valuable for mapping the spatial configuration of hotspots for Jamestown Canyon virus and could be used to educate local residents and recreationalists to reduce human exposure.

EndoVascular Occlusion and Tumor Excision (EVOTE): a Hybrid Approach to Small-Bowel Neuroendocrine Tumors with Mesenteric Metastases.

BACKGROUND: Mesenteric metastases from small-bowel neuroendocrine tumors (SBNETs) present a surgical challenge due to encasement of mesenteric vessels. In this study, we evaluate the feasibility and safety of a new, hybrid surgical approach to these mesenteric masses, EndoVascular Occlusion and Tumor Excision (EVOTE). METHODS: From 2014 to 2018, 13 patients underwent the EVOTE procedure after being referred to our institution for primary SBNETs with "unresectable" mesenteric metastases. During stage 1 of the hybrid EVOTE procedure, angiographic evaluation of the mesenteric mass is performed. If adequate collateralization is demonstrated, the encased mesenteric vessel(s) is embolized. Mass excision is performed the following day during stage 2 of the EVOTE procedure. RESULTS: Preoperative embolization was successful in 86% of cases; 2 cases were aborted for persistent abdominal pain following occlusion testing. Complete surgical excision of the mesenteric mass was achieved in 86% of cases. The 30-day overall morbidity and mortality rate was 29% and 0%, respectively. There was one local recurrence at 31.8 months post-op; this patient underwent a repeat EVOTE procedure with successful complete excision. DISCUSSION: EVOTE represents a new technique that aids in preoperative planning and surgical resection of SBNETs with mesenteric metastases.

Suburban white-tailed deer seropositive for Toxoplasma gondii from Chicago, Illinois.

The presence and abundance of vertebrates influences the circulation of zoonotic diseases. White-tailed deer (Odocoileus virginianus) are widely distributed in North America and deer densities are frequently high in unhunted areas, including most major metropolitan regions. This study investigated the seroprevalence for Toxoplasma gondii from live-captured and culled deer sampled in two suburban forest preserves around Chicago, Illinois, from 1995 to 1999. Seroprevalence for T. gondii was 55.9% (n = 443) and was significantly higher at the northern study site, Des Plaines. Seroprevalence for T. gondii varied by year and month. Multivariate logistic regression (LR) screened main effect variables (age, sex, site, year, and month) by backward stepwise elimination. The final LR model for T. gondii contained all main effect variables. This study provides baseline data for future T. gondii suburban deer studies and information to public health and wildlife officials regarding the prevalence a parasitic pathogen present in two public forest preserves in Chicago, Illinois.

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.

Gastric Neuroendocrine Tumor and Duodenal Gastrinoma With Chronic Autoimmune Atrophic Gastritis.

Our group observed the first case of synchronous gastric neuroendocrine tumor (NET) and duodenal gastrinoma with autoimmune chronic atrophic gastritis (CAG), in the absence of Helicobacter pylori infection. Demographic, clinical, endoscopic, and pathologic data were abstracted from the electronic medical record at Mount Sinai Hospital from 2013 to 2015. The patient's anonymity was carefully protected, and informed consent was obtained for publication of protected health information. A 53-year-old woman with hypertension presented to Mount Sinai Hospital in June 2013 for a second opinion for management of gastric and duodenal NETs. After evaluation by gastroenterology and surgery, repeat upper endoscopy with ultrasound and fine-needle aspiration revealed multiple diminutive type I gastric NETs and 2 duodenal NETs, against a background of autoimmune CAG, with biopsy pathology negative for H. pylori. She subsequently underwent a transduodenal resection of the duodenal NETs, confirming low-grade, gastrin-positive, stage T2 duodenal NET. On routine follow-up over the next 2 years, clinical, radiographic, and endoscopic surveillance revealed no recurrent or metastatic gastric or duodenal disease. This first report of synchronous duodenal gastrinoma and gastric NET in the setting of autoimmune CAG can broaden our understanding of gastric NET pathophysiology.

Long-term Outcomes of Gastroenteropancreatic Neuroendocrine Tumors.

OBJECTIVES: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare but have been increasing in incidence. Limited data on the long-term outcomes of patients with these tumors are available. METHODS: In this study, we used population-based data from the National Cancer Institute to assess long-term disease-specific survival (DSS) of patients who have undergone surgery for nonmetastatic disease. All patients with NETs of the stomach, small intestine, colon, rectum, appendix, and pancreas diagnosed between 1988 and 2009 were identified from the Surveillance, Epidemiology and End Results registry. Staging was derived from Surveillance, Epidemiology and End Results data using the European Neuroendocrine Tumor Society guidelines. Cases with incomplete staging data were excluded, along with those with stage IV disease, or those who did not undergo surgical resection. RESULTS: Kaplan-Meier analyses were constructed to determine DSS. Analyses were further stratified according to tumor site, stage at diagnosis, and tumor grade. Overall, 13,348 patients with GEP-NETs meeting the inclusion criteria were identified. CONCLUSIONS: There were excellent outcomes for most GEP-NET patients, with a 20-year DSS of greater than 75% across all sites and stages. Pancreatic tumors had the worst outcomes, but DSS remains greater than 50% at 20 years.

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).

Assessing the Impact of Removing Select Materials from Coal Mine Overburden, Central Appalachia Region, USA.

The exposure of readily soluble components of overburden materials from surface coal mining to air and water results in mineral oxidation and carbonate mineral dissolution, thus increasing coal mine water conductivity. A conductivity benchmark of 300 µS/cm for mine water discharges in the Appalachian region has been suggested to protect aquatic life and the environment. A USGS screening-level leach test was applied to individual strata from three cores collected from a surface mine site in the Central Appalachian region to generate preliminary conductivity rankings, which were used to classify strata for two disposal scenarios: (i) Unmodified Scenario, which included all extracted strata and (ii) Modified Scenario, which excluded 15% (by mass) of the overburden materials with the highest conductivities. We evaluated overburden leaching conductivity using EPA Method 1627 in 18 dry-wet cycles, generating conductivities of 1,020-1,150 µS/cm for the Unmodified Scenario and 624-979 µS/cm for the Modified Scenario. Hence, overburden segregation was successful in reducing the leachate conductivity, but did not reach the proposed benchmark. The leachate was dominated by sulfate in the first four cycles and by bicarbonates in cycles 5-18 in columns with higher sulfur content, while bicarbonates were dominant throughout experiments with lower sulfur content in overburden. The use of conductivity rankings, isolation of potentially problematic overburden strata, and appropriate materials management could reduce conductivity in Central Appalachian streams and other surface mining areas.

Impact of out-of-hours admission on patient mortality: longitudinal analysis in a tertiary acute hospital.

BACKGROUND: Emergency hospital admission on weekends is associated with an increased risk of mortality. Previous studies have been limited to examining single years and assessing day-not time-of admission. We used an enhanced longitudinal data set to estimate the 'weekend effect' over time and the effect of night-time admission on all-cause mortality rates. METHODS: We examined 246 350 emergency spells from a large teaching hospital in England between April 2004 and March 2014. Outcomes included 7-day, 30-day and in-hospital mortality rates. We conducted probit regressions to estimate the impact on the absolute difference in the risk of mortality of two key predictors: (1) admission on weekends (19:00 Friday to 06:59 Monday); and (2) night-time admission (19:00 to 06:59). Logistic regressions were used to estimate ORs for relative mortality risk differences. RESULTS: Crude 30-day mortality rate decreased from 6.6% in 2004/2005 to 5.2% in 2013/2014. Adjusted mortality risk was elevated for all out-of-hours periods. The highest risk was associated with admission on weekend night-times: 30-day mortality increased by 0.6 percentage points (adjusted OR: 1.17, 95% CI 1.10 to 1.25), 7-day mortality by 0.5 percentage points (adjusted OR: 1.23, 95% CI 1.12 to 1.34) and in-hospital mortality by 0.5 percentage points (adjusted OR: 1.14, 95% CI 1.08 to 1.21) compared with admission on weekday daytimes. Weekend night-time admission was associated with increased mortality risk in 9 out of 10 years, but this was only statistically significant (p<0.05) in 5 out of 10 years. CONCLUSIONS: There is an increased risk of mortality for patients admitted as emergencies both on weekends and during the night-time. These effects are additive, so that the greatest risk of mortality occurs in patients admitted during the night on weekends. This increased risk appears to be consistent over time, but the effects are small and are not statistically significant in individual hospitals in every year.

Lymph Node Metastasis in the Prognosis of Gastroenteropancreatic Neuroendocrine Tumors.

OBJECTIVES: This study aimed to determine the prognostic use of the extent of lymph node (LN) involvement in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) by analyzing population-based data. METHODS: Patients in the Surveillance, Epidemiology, and End Results registry were identified with histologically confirmed, surgically resected GEP-NETs. We divided patients into 3 lymph node ratio (LNR) groups based on the ratio of positive LNs to total LNs examined: 0.2 or less, greater than 0.2 to 0.5, and greater than 0.5. Disease-specific survival was compared according to LNR group. RESULTS: We identified 3133 patients with surgically resected GEP-NETs. Primary sites included the stomach (11% of the total), pancreas (30%), colon (32%), appendix (20%), and rectum (7%). Survival was worse in patients with LNRs of 0.2 or less (hazard ratio [HR], 1.5; 95% confidence interval [CI], 1.2-2.0), greater than 0.2 to 0.5 (HR, 2.0; 95% CI, 1.6-2.5), and greater than 0.5 (HR, 3.1; 95% CI, 2.5-3.9) compared with N0 patients. Ten-year disease-specific survival decreased as LNR increased from N0 (81%) to 0.2 or less (69%), greater than 0.2 to 0.5 (55%), and greater than 0.5 (50%). Results were consistent for patients with both low- and high-grade tumors from most primary sites. CONCLUSIONS: Degree of LN involvement is a prognostic factor at the most common GEP-NET sites. Higher LNR is associated with decreased survival.

Patient-Reported Burden of a Neuroendocrine Tumor (NET) Diagnosis: Results From the First Global Survey of Patients With NETs.

PURPOSE: Despite the considerable impact of neuroendocrine tumors (NETs) on patients' daily lives, the journey of the patient with a NET has rarely been documented, with published data to date being limited to small qualitative studies. NETs are heterogeneous malignancies with nonspecific symptomology, leading to extensive health care use and diagnostic delays that affect survival. A large, international patient survey was conducted to increase understanding of the experience of the patient with a NET and identify unmet needs, with the aim of improving disease awareness and care worldwide. METHODS: An anonymous, self-reported survey was conducted (online or on paper) from February to May 2014, recruiting patients with NETs from > 12 countries as a collaboration between the International Neuroendocrine Cancer Alliance and Novartis Pharmaceuticals. Survey questions captured information on sociodemographics, clinical characteristics, NET diagnostic experience, disease impact/management, interaction with medical teams, NET knowledge/awareness, and sources of information. This article reports the most relevant findings on patient experience with NETs and the impact of NETs on health care system resources. RESULTS: A total of 1,928 patients with NETs participated. A NET diagnosis had a substantially negative impact on patients' personal and work lives. Patients reported delayed diagnosis and extensive NET-related health care resource use. Patients desired improvement in many aspects of NET care, including availability of a wider range of NET-specific treatment options, better access to NET experts or specialist centers, and a more knowledgeable, better-coordinated/-aligned NET medical team. CONCLUSION: This global patient-reported survey demonstrates the considerable burden of NETs with regard to symptoms, work and daily life, and health care resource use, and highlights considerable unmet needs. Further intervention is required to improve the patient experience among those with NETs.

Fluorine-18-fluorodihydroxyphenylalanine Positron-emission Tomography Scans of Neuroendocrine Tumors (Carcinoids and Pheochromocytomas).

OBJECTIVES: Conventional methods of imaging neuroendocrine tumors with computed tomography, magnetic resonance imaging, indium-111-octreotide, or radiolabeled metaiodobenzilguanidine scintigraphy have limitations. This pilot study tried to improve the localization of these tumors with fluorine-18-fluorodihydroxyphenylalanine (F-DOPA) positron-emission tomography (PET) scanning. MATERIALS AND METHODS: We studied 22 patients, the majority of whom were referred with clinical diagnosis or suspicion of carcinoid (n = 11), neuroendocrine tumors (n = 7) or pheochromocytoma/paraganglioma (PGL) (n = 4). The comparison was made with the prior conventional imaging. RESULTS: The F-DOPA findings were compared with the results of subsequent surgery (2), endoscopy (1), or a long-term follow-up (mean duration, 49 months) for 17 patients. Two patients were lost to follow-up. Foci of F-DOPA deposition were detected in eight patients (final diagnosis of carcinoid in six, of neuroendocrine tumors in one, and of PGL in another). Comparison with the final diagnoses revealed concordance in 16 of the 22 patients. F-DOPA results appeared superior to those obtained with conventional imaging. Despite the small number and diagnostic heterogeneity, in a substantial fraction of patients F-DOPA PET added information relevant to clinical management. CONCLUSION: F-DOPA scanning added prognostic value, particularly when multiple abnormal foci versus a negative examination were considered.

Improving survival prognostication of gastroenteropancreatic neuroendocrine neoplasms: Revised staging criteria.

PURPOSE: Current staging criteria for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), while useful, have limitations. In this study, we used a population-based registry to evaluate the prognostic utility of the current staging systems and assess whether evidence-based modifications can improve survival predictions. METHODS: We identified patients with confirmed GEP-NENs from the Surveillance, Epidemiology and End Results registry. We assigned tumour-node-metastasis status according to American Joint Committee on Cancer and European Neuroendocrine Tumor Society criteria. We derived a revised staging classification using Kaplan-Meier methods and Cox regression to assess disease-specific survival and compared the accuracy of potential models based on the Akaike Information Criterion (AIC) and Harrell's C-index. The revised classification was validated in an independent set. RESULTS: We identified 10,268 patients with GEP-NENs. We found that multiple stages, as determined by current criteria, misclassified patients' prognosis. In particular, stage IIIB (T1-4N1) had overlapping survival with stage IIIA (T4N0). A revised system which reclassifies N1 disease into different stages based on T status (T1-2N1, T3N1 and T4N1) had an improved AIC (difference = 38) and C-index (0.86) compared to current staging. These revisions improved predictions in patients with both low and high-grade tumours from all primary sites. Results also were confirmed across all primary sites in the validation set. CONCLUSION: Current staging guidelines misclassify the prognosis of N1 patients. Our results suggest that a revised system could lead to better prognostication for GEP-NEN patients. Further validation followed by implementation of these revisions may improve treatment selection and design of clinical trials.

Patient-Reported Experience of Diagnosis, Management, and Burden of Neuroendocrine Tumors: Results From a Large Patient Survey in the United States.

OBJECTIVES: The aim of this survey was to examine the experience of patients with neuroendocrine tumors (NETs) to raise awareness of the NET-related burden and identify unmet needs. Here, we report data from patients in the United States. METHODS: Patients with NETs participated in a 25-minute anonymous survey, conducted primarily online from February to May 2014. Survey questions captured information on sociodemographics, clinical characteristics, NET diagnostic experience, disease impact/management, interaction with medical teams, and NETs knowledge/awareness. RESULTS: Of 1928 patients who participated globally, the largest percentage was from the United States (39%). Approximately 50% of US patients reported being diagnosed with other conditions before receiving their NET diagnosis, which for 34% took 5 years or more. Patients experienced many symptoms on a daily basis as a result of NETs, which had a substantial negative impact on their work and daily lives. Numerous improvements were suggested by patients, including better access to NET-specific treatments and medical teams/centers and better education for the management of disease-related and treatment-related symptoms. CONCLUSIONS: This survey demonstrated the significant burden of NETs on patients' lives and identified key areas for improvement in diagnosis and long-term management, including better access to NET-specific treatments and specialist medical teams/centers.

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.

Development of an electrical conductivity screening test for mine waste assessments.

An environmental concern at mining operations is the potential leaching of trace elements from overburden and byproduct streams of processing plants. To provide a timely assessment of this concern, electrical conductivity of the leachate emanating from the plant waste streams can be measured as an indicator of the trace element content levels using the USGS Field Leach Test (FLT). However, the research reported in this publication revealed the need to modify the FLT procedure to improve the precision of the test results. The primary issue involved the importance of leachant volume-to-particle surface area ratio in the assessment of the leaching potential for a given source. To determine the key factors impacting leachability of a given material, a statistically-designed parametric study was performed. The experimental program evaluated the effects of particle surface area, the leachant volume-to-surface area ratio, and the amount of oxidant used to expedite the leaching rate during the test. The results revealed that the significant parameters are leachant volume-to-solid surface area ratio and the amount of oxidant. The findings were used to recommend a modification to the conductivity screening test.