Advances in the treatment of gastroenteropancreatic neuroendocrine tumors

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a rare and heterogeneous class of neoplasms. While surgical resection is the mainstay of treatment, non-surgical therapies play a role in the setting of unresectable and metastatic disease. The goals of medical therapy are directed both at alleviating symptoms of peptide release and shrinking tumor mass. Biotherapies such as somatostatin analogs and interferon can decrease the secretion of peptides and inhibit their end-organ effects. A second objective for treatment of unresectable GEP-NETs is limiting tumor growth. Options for limiting tumor growth include somatostatin analogs, systemic chemotherapy, locoregional therapies, ionizing radiation, external beam radiation, and newer targeted agents. In particular, angiogenesis inhibitors, tyrosine kinase inhibitors, and mTOR inhibitors have shown early promising results. The rarity of these tumors, their resistance to standard chemotherapy, and the excellent performance status of most of these patients, make a strong argument for consideration of novel therapeutic trials

Ice-age megafauna in Arctic Alaska: extinction, invasion, survival

Radical restructuring of the terrestrial, large mammal fauna living in arctic Alaska occurred between 14,000 and 10,000 years ago at the end of the last ice age. Steppe bison, horse, and woolly mammoth became extinct, moose and humans invaded, while muskox and caribou persisted. The ice age mega fauna was more diverse in species and possibly contained 6x more individual animals than live in the region today. Mega faunal biomass during the last ice age may have been 30x greater than present. Horse was the dominant species in terms of number of individuals. Lions, short-faced bears, wolves, and possibly grizzly bears comprised the predator/scavenger guild. The youngest mammoth so far discovered lived ca 13,800 years ago, while horses and bison persisted on the North Slope until at least 12,500 years ago during the Younger Dry as cold interval. The first people arrived on the North Slope ca 13,500 years ago. Bone-isotope measurements and foot-loading characteristics suggest mega faunal niches were segregated along a moisture gradient, with the surviving species (muskox and caribou) utilizing the warmer and moister portions of the vegetation mosaic. As the ice age ended, the moisture gradient shifted and eliminated habitats utilized by the dry land, grazing species (bison, horse, mammoth). The proximate cause for this change was regional paludification, the spread of organic soil horizons and peat. End-Pleistocene extinctions in arctic Alaska represent local, not global extinctions since the mega faunal species lost there persisted to later times elsewhere. Hunting seems unlikely as the cause of these extinctions, but it cannot be ruled out as the final blow to mega faunal populations that were already functionally extinct by the time humans arrived in the region

A rare case of an aldosterone secreting metastatic adrenocortical carcinoma and papillary thyroid carcinoma in a 31-year-old male

We report a rare synchronous presentation of adrenocortical carcinoma (ACC) and papillary thyroid carcinoma (PTC). A 31-year-old male first presented with a large left adrenal mass that was identified during the workup for refractory hypertension due to hyperaldosteronism. The mass was removed surgically with pathology showing ACC. The patient was then treated with adjuvant radiation therapy and mitotane chemotherapy. Four months post ACC resection, metastatic ACC to the right upper lung and PTC in the left lobe of the thyroid were found in surveillance imaging. He subsequently developed pulmonary, contralateral adrenal and brain metastases from his ACC. Li Fraumeni syndrome and Multiple Endocrine Neoplasia Type I (MEN I) were considered, but testing of both P53 and menin genes showed no mutation. We also performed a review of the literature and found three similar cases, however gene mutation analysis was not performed.

Water deficit tolerance of bean cultivars

O objetivo deste trabalho foi avaliar a resposta das cultivares de feijão (Phaseolus vulgaris) Triunfo, Garapiá e BRS-FC104 ao déficit hídrico representado pela fração de água transpirável no solo (FATS). O delineamento experimental foi inteiramente casualizado, em arranjo bifatorial 3×2 (cultivares × irrigação e sem irrigação). Avaliaram-se a transpiração, o crescimento e a produtividade na safra e na safrinha. Na safra, com baixa demanda atmosférica do ar (inferior a 15 hPa em 55% dos dias), 'Garapiá' apresentou fechamento precoce dos estômatos com FATS crítica (FATSc) de 0,36, mas teve a mesma produtividade que 'Triunfo', cujos estômatos fecharam tardiamente (FATSc = 0,23). Na safrinha, com alta demanda atmosférica do ar (superior a 15 hPa em 83,3% dos dias), 'Garapiá' apresentou fechamento estomático precoce (FATSc = 0,17) e maior produtividade (392,2 kg ha-1 a mais que 'Triunfo'). Na safra e na safrinha, 'Garapiá' apresentou tolerância ao déficit hídrico no período reprodutivo. O déficit hídrico resultou em menores valores de estatura, massa seca da parte aérea, massa seca da raiz e área foliar. Tanto 'Garapiá' como 'Triunfo' apresentaram alta produtividade na safra, mas apenas Garapiá na safrinha. 'Garapiá' apresenta tolerância ao déficit hídrico, com controle estomático eficiente e com altos crescimento e produtividade.The objective of this work was to evaluate the response of the Garapiá, Triunfo, and BRS-FC104 bean (Phaseolus vulgaris) cultivars to the water deficit represented by the fraction of transpirable soil water (FTSW). The experimental design was completely randomized in a 3×2 bifactorial arrangement (cultivars × irrigation and no irrigation). Transpiration, growth, and yield were evaluated in the crop season and off-season. In the crop season, with a low atmospheric air demand (below 15 hPa in 55% of the days), 'Garapiá' presented early stomatal closure with the critical FTSW (FTSWc) of 0.36, but had the same yield as 'Triunfo', whose stomata closed late (FTSWc = 0.23). In the off-season, with a high atmospheric air demand (greater than 15 hPa in 83.3% of the days), 'Garapiá' presented an early stomatal closure (FTSWc = 0.17) and a higher yield (392.2 kg kg ha-1 more than 'Triunfo'). In the crop season and off-season, 'Garapiá' showed tolerance  to water deficit in the reproductive period. Water deficit resulted in  lower values of height, shoot dry mass, root dry mass, and leaf area. Both 'Garapiá' and 'Triunfo' showed a high yield in the crop season, but only 'Garapiá' in the off-season. 'Garapiá' presents tolerance to water deficit, with efficient stomatal control and high growth and yield

Regionalización provincial y asociativismo intermunicipal en Córdoba (2005-2007): balance y recomendaciones

A partir de un amplio acuerdo entre los gobiernos locales de todos los partidos políticos y el gobierno provincial, el 22 de diciembre de 2004, la Legislatura de Córdoba sancionó la Ley orgánica de regionalización provincial Nº 9206. Con el desarrollo como fin, la Ley Nº 9206 supuso dos innovaciones trascendentes: por una parte, la creación de 26 nuevas regiones a razón de una por cada departamento existente y, por la otra, el reconocimiento de Comunidades Regionales a integrarse por decisión autónoma de los municipios y comunas (gobernadas por los Intendentes municipales y Presidentes comunales de cada región). En el 2005, se integraron 212 municipios y 152 comunas (es decir el 85% del total provincial) en 23 Comunidades Regionales que, además, acordaron sus prioridades de gestión regional y un Indicador de Desarrollo Regional, mediante la asistencia técnica del Programa de Fortalecimiento Institucional de Municipios (PROFIM) de la UCC. Sobre esas bases, en el 2006; las universidades cordobesas (mediante convenios con el Gobierno provincial) asesoraron a 17 Comunidades Regionales en el diseño de políticas de desarrollo. Esta investigación problematiza la regionalización en Córdoba, analizando críticamente sus avances y demoras, desde su puesta en marcha (diciembre de 2004) hasta el recambio de autoridades (diciembre de 2007) con el propósito de recomendar correcciones.Fil: Graglia, José Emilio. Universidad Católica de Córdoba. Facultad de Ciencia Política y Relaciones Internacionales; ArgentinaFil: Kunz, Daniela Ivana. Universidad Católica de Córdoba. Facultad de Ciencia Política y Relaciones Internacionales; ArgentinaFil: Mosquera Sadleir, Carlos Mariano. Universidad Católica de Córdoba. Facultad de Ciencia Política y Relaciones Internacionales; Argentin

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)

Understanding the Patient Experience with Carcinoid Syndrome: Exit Interviews from a Randomized, Placebo-Controlled Study of Telotristat Ethyl

Purpose: Telotristat ethyl, an oral tryptophan hydroxylase inhibitor, is intended to treat carcinoid syndrome by reducing serotonin production. Telotristat ethyl was evaluated in TELESTAR, a Phase III study for patients who had carcinoid syndrome with at least 4 bowel movements (BMs) per day and who were receiving somatostatin analogue therapy. This interview substudy was conducted to provide insight into the patient experience in TELESTAR and to help understand whether reductions in BM frequency (the primary end point) and other symptoms were clinically meaningful. Methods: Participating sites were asked to invite (before randomization) all eligible patients to telephone interviews scheduled at the end of the double-blind treatment period. Patients and interviewers were blinded to treatment. Findings: All 35 interviewed participants reported diarrhea and/or excessive BMs at baseline. Patients reported that these symptoms negatively affected emotional, social, physical, and occupational well-being. Prespecified criteria for treatment response (achieving ≥ 30% reduction in BM frequency for at least 50% of the days) were met by 8 of 26 patients taking telotristat ethyl and 1 of 9 patients taking placebo. All 8 patients taking telotristat ethyl described clinically meaningful reductions in BM frequency and were very satisfied with the ability of the study drug to control their carcinoid syndrome symptoms. Overall, reports of being very satisfied were observed in 12 patients taking telotristat ethyl and 0 taking placebo. Implications: Patient interviews revealed that TELESTAR patients, at baseline, were significantly affected by their high BM frequency. Patient reports of their clinical trial experience supported the significance of the primary end point and clinical responder analysis in TELESTAR, helping identify and understand clinically meaningful change produced by telotristat ethyl

Impact of Poxvirus Vector Priming, Protein Coadministration, and Vaccine Intervals on HIV gp120 Vaccine-Elicited Antibody Magnitude and Function in Infant Macaques

ABSTRACT Despite success in reducing vertical HIV transmission by maternal antiretroviral therapy, several obstacles limit its efficacy during breastfeeding, and breast-milk transmission is now the dominant mode of mother-to-child transmission (MTCT) of HIV in infants. Thus, a pediatric vaccine is needed to eradicate oral HIV infections in newborns and infants. Utilizing the infant rhesus macaque model, we compared 3 different vaccine regimens: (i) HIV envelope (Env) protein only, (ii) poxvirus vector (modified vaccinia virus Ankara [MVA])-HIV Env prime and HIV Env boost, and (iii) coadministration of HIV Env and MVA-HIV Env at all time points. The vaccines were administered with an accelerated, 3-week-interval regimen starting at birth for early induction of highly functional HIV Env-specific antibodies. We also tested whether an extended, 6-week immunization interval using the same vaccine regimen as in the coadministration group would enhance the quality of antibody responses. We found that pediatric HIV vaccines administered at birth are effective in inducing HIV Env-specific plasma IgG. The vaccine regimen consisting of only HIV Env protein induced the highest levels of variable region 1 and 2 (V1V2)-specific antibodies and tier 1 neutralizing antibodies, whereas the extended-interval regimen induced both persistent Env-specific systemic IgG and mucosal IgA responses. Antibody-dependent cell-mediated cytotoxicity (ADCC) antibodies in plasma were elicited by all vaccine regimens. These data suggest that infant immunizations beginning at birth are effective for the induction of functional HIV Env-specific antibodies that could potentially protect against breast milk transmission of HIV and set the stage for immunity prior to sexual debut

Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia

Drug sensitivity and resistance testing on diagnostic leukemia samples should provide important functional information to guide actionable target and biomarker discovery. We provide proof of concept data by profiling 60 drugs on 68 acute lymphoblastic leukemia (ALL) samples mostly from resistant disease in cocultures of bone marrow stromal cells. Patient-derived xenografts retained the original pattern of mutations found in the matched patient material. Stromal coculture did not prevent leukemia cell cycle activity, but a specific sensitivity profile to cell cycle-related drugs identified samples with higher cell proliferation both in vitro and in vivo as leukemia xenografts. In patients with refractory relapses, individual patterns of marked drug resistance and exceptional responses to new agents of immediate clinical relevance were detected. The BCL2inhibitor venetoclax was highly active below 10 nM in B-cell precursor ALL (BCP-ALL) subsets, including MLL-AF4 and TCF3-HLF ALL, and in some T-cell ALLs (T-ALLs), predicting in vivo activity as a single agent and in combination with dexamethasone and vincristine. Unexpected sensitivity to dasatinib with half maximal inhibitory concentration values below 20 nM was detected in 2 independent T-ALL cohorts, which correlated with similar cytotoxic activity of the SRC inhibitor KX2-391 and inhibition of SRC phosphorylation. A patient with refractory T-ALL was treated with dasatinib on the basis of drug profiling information and achieved a 5-month remission. Thus, drug profiling captures disease-relevant features and unexpected sensitivity to relevant drugs, which warrants further exploration of this functional assay in the context of clinical trials to develop drug repurposing strategies for patients with urgent medical needs.Peer reviewe

Pituitary Neoplasm Nomenclature Workshop: Does Adenoma Stand the Test of Time?

The WHO Classification of Endocrine Tumours designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written précis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges