tbuckley/cabot-search huggingface dataset:
Phase I/II study of cetuximab plus temozolomide as radiochemotherapy for primary glioblastoma (GERT)—Eudract number 2005–003911–63; NCT00311857
Authors: S. E. Combs, D. Schulz-Ertner, C. Hartmann, T. Welzel, C. Timke, K. Herfarth, A. von Deimling, L. Edler, M. Platten, W. Wick, J. Debus
Journal: Journal of Clinical Oncology (2008)

2077 Background: Glioblastomas (GB) are known to express high levels of EGFR; targeting of EGFR using cetuximab has proven to be a successful treatment. This phase I/II trial of radiochemotherapy (RCHT) with TMZ and cetuximab in patients with primary GB evaluates feasibility and toxicity. Methods: Seventeen patients with pathologically confirmed GB were included into this analysis. Radiotherapy (RT) is delivered with a median dose of 60 Gy, 5*2Gy/week. TMZ is prescribed concomitantly at a dose of 75mg/m2, followed by 6 cycles of adjuvant TMZ. Cetuximab is applied as weekly infusions (loading dose 400 mg/m2 on day 1, and concomitant with RT on days 8, 15, 22, 29, 36, 43 at 250 mg/m2). Fourteen patients were male and 3 patients were female. Median age at diagnosis was 48 years. Neurosurgical resections had been complete in 7, subtotal in 7, and a biopsy in 3 patients. O(6)-methylguanine DNA methyltransferase (MGMT) gene promoter methylation was investigated in the tumor tissue: 33% of the patients were MGMT-positive, and 66% were MGMT-negative. EGFR-analysis is currently being conducted. Treatment was initiated after a median of 15 days after primary diagnosis. Median follow-up time at the time of this analysis was 13 months. Results: RCHT with cetuximab is safe and well tolerated. Cetuximab-related side effects included acneiform rash. In one patient cetuximab infusions were discontinued after occurrence of bilateral pulmonary embolism in treatment week 7. One patient died in treatment week 4 after tumor progression and massive brain edema which could not be controlled by medication including high-dose steroids. In all other patients the scheduled 7 cycles of cetuximab could be applied. Overall survival (OS) was 87% at 12 months. No prognostic factors could be determined until now. Methylated MGMT was not associated with longer OS (p=0.22). Progression-free survival (PFS) was 81% at 6 months and 37% at 12 months. Methylated MGMT was not associated with longer PFS (p=0.59). No prognostic factors of PFS could be identified. Conclusions: Early data from trimodal therapy in GB patients with RT, TMZ and cetuximab indicate feasibility without an increased toxicity profile. PFS as well as OS appear to be very promising. No significant financial relationships to disclose.
Should We Screen for Type 2 Diabetes?
Authors: Gerald W. Smetana, Martin J. Abrahamson, David M. Rind
Journal: Annals of Internal Medicine (2016)

The prevalence of diabetes in the United States is rising. Twelve percent of U.S. adults have diabetes and another 37% have impaired fasting glucose or impaired glucose tolerance. Diabetes is a major risk factor for such outcomes as cardiovascular disease, blindness, chronic kidney disease, and limb amputation. An important consideration is whether screening for abnormal glucose levels or diabetes reduces cardiovascular or all-cause morbidity and mortality. In October 2015, the U.S. Preventive Services Task Force published recommendations on screening for abnormal blood glucose and concluded that intensive lifestyle interventions have a moderate benefit in reducing progression to diabetes in patients who have abnormal blood glucose levels detected by screening. It found inadequate evidence that such screening reduces cardiovascular or all-cause mortality and no evidence of psychological or other harms from screening. The Task Force recommends glucose screening every 3 years for adults aged 40 to 70 years who are overweight or obese and do not have symptoms of diabetes. In this article, we present the case of a man who meets these criteria and explore his preferences and concerns regarding screening. Two experts then debate screening merits and benefits, the significance of abnormal blood glucose levels and diabetes as cardiovascular risk factors, and application of the guidelines to this particular patient.
Dissonant health transition in the states of Mexico, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013
Authors: Héctor Gómez-Dantés, Nancy Fullman, Héctor Lamadrid-Figueroa, Lucero Cahuana-Hurtado, Blair Darney, Leticia Avila-Burgos, Ricardo Correa-Rotter, Juan A Rivera, Simon Barquera, Eduardo González-Pier, Tania Aburto-Soto, Elga Filipa Amorin de Castro, Tonatiuh Barrientos-Gutiérrez, Ana C Basto-Abreu, Carolina Batis, Guilherme Borges, Ismael Campos-Nonato, Julio C Campuzano-Rincón, Alejandra de Jesús Cantoral-Preciado, Alejandra G Contreras-Manzano, Lucia Cuevas-Nasu, Vanessa V de la Cruz-Gongora, Jose L Diaz-Ortega, María de Lourdes García-García, Armando Garcia-Guerra, Teresita González de Cossío, Luz D González-Castell, Ileana Heredia-Pi, Marta C Hijar-Medina, Alejandra Jauregui, Aida Jimenez-Corona, Nancy Lopez-Olmedo, Carlos Magis-Rodríguez, Catalina Medina-Garcia, Maria E Medina-Mora, Fabiola Mejia-Rodriguez, Julio C Montañez, Pablo Montero, Alejandra Montoya, Grea L Moreno-Banda, Andrea Pedroza-Tobías, Rogelio Pérez-Padilla, Amado D Quezada, Vesta L Richardson-López-Collada, Horacio Riojas-Rodríguez, Maria J Ríos Blancas, Christian Razo-Garcia, Martha P Romero Mendoza, Tania G Sánchez-Pimienta, Luz M Sánchez-Romero, Astrid Schilmann, Edson Servan-Mori, Teresa Shamah-Levy, Martha M Téllez-Rojo, José L Texcalac-Sangrador, Haidong Wang, Theo Vos, Mohammad H Forouzanfar, Mohsen Naghavi, Alan D Lopez, Christopher J L Murray, Rafael Lozano
Journal: The Lancet (2016)
Adipocyte-specific deletion of Ip6k1 reduces diet-induced obesity by enhancing AMPK-mediated thermogenesis
Authors: Qingzhang Zhu, Sarbani Ghoshal, Ana Rodrigues, Su Gao, Alice Asterian, Theodore M. Kamenecka, James C. Barrow, Anutosh Chakraborty
Journal: Journal of Clinical Investigation (2016)

Enhancing energy expenditure (EE) is an attractive strategy to combat obesity and diabetes. Global deletion of Ip6k1 protects mice from diet-induced obesity (DIO) and insulin resistance, but the tissue-specific mechanism by which IP6K1 regulates body weight is unknown. Here, we have demonstrated that IP6K1 regulates fat accumulation by modulating AMPK-mediated adipocyte energy metabolism. Cold exposure led to downregulation of Ip6k1 in murine inguinal and retroperitoneal white adipose tissue (IWAT and RWAT) depots. Adipocyte-specific deletion of Ip6k1 (AdKO) enhanced thermogenic EE, which protected mice from high-fat diet-induced weight gain at ambient temperature (23°C), but not at thermoneutral temperature (30°C). AdKO-induced increases in thermogenesis also protected mice from cold-induced decreases in body temperature. UCP1, PGC1α, and other markers of browning and thermogenesis were elevated in IWAT and RWAT of AdKO mice. Cold-induced activation of sympathetic signaling was unaltered, whereas AMPK was enhanced, in AdKO IWAT. Moreover, beige adipocytes from AdKO IWAT displayed enhanced browning, which was diminished by AMPK depletion. Furthermore, we determined that IP6 and IP6K1 differentially regulate upstream kinase-mediated AMPK stimulatory phosphorylation in vitro. Finally, treating mildly obese mice with the IP6K inhibitor TNP enhanced thermogenesis and inhibited progression of DIO. Thus, IP6K1 regulates energy metabolism via a mechanism that could potentially be targeted in obesity.
Is adjuvant chemotherapy necessary for patients with stage B1 testicular cancer?
Authors: J P Richie, P W Kantoff
Journal: Journal of Clinical Oncology (1991)

Controversy exists concerning the role of adjunctive chemotherapy in patients with regional nodal involvement. A randomized study reported a 48% relapse rate for patients with positive nodes (stage B1 or stage B2), all of whom were salvaged by full-dose platinum-based chemotherapy. In a series of patients with positive nodes who received two cycles of adjunctive chemotherapy postoperatively, the relapse rate was only 2%. In order to evaluate the effect of retroperitoneal lymph node dissection on relapse rates in patients with stage B1 testicular cancer, a retrospective review of a series of 39 patients was performed. Criteria for inclusion included pathologic stage B1 (less than six positive nodes, located in the primary landing site, with no node greater than 2 cm in diameter and no extracapsular lymph node extension). Patients who fulfilled the criteria along with normalization of tumor markers were followed-up expectantly after retroperitoneal lymph node dissection. Thirty-nine patients were followed from 1 to 10 years with the median duration of follow-up of 3.5 years. Ten of the 39 patients had modified retroperitoneal lymph node dissections with preservation of antegrade ejaculation. The other 29 had full retroperitoneal lymph node dissections. Three relapses were seen, one patient with retrocrural and pulmonary metastases and two patients with pulmonary metastases only for a relapse rate of 8% (three of 39). Patients with stage B2 disease received adjunctive chemotherapy with two or three cycles of platinum-based chemotherapy. We conclude that retroperitoneal lymph node dissection alone is adequate treatment for the majority of patients with pathologic stage B1 testicular cancer. In that subset of patients, adjunctive chemotherapy should be reserved for relapse.
Evaluation du contrôle de qualité des tests pour la grippe et le VRS en Europe, saison 2000-01
Authors: M Valette, M Aymard
Journal: Eurosurveillance (2002)

L’evaluation du controle de qualite (ECQ) a ete initiee pour estimer la qualite des analyses pour la detection et l’identification des virus grippaux et du virus respiratoire syncytial (VRS) dans les centres de reference nationaux appartenant au Reseau europeen de surveillance de la grippe (EISS). Des prelevements ont ete codes et envoyes a 16 laboratoires en deux panels de 12 prelevements dans un intervalle de deux semaines pendant la saison d’hiver 2000-01. Les titres d’anticorps au test IHA ont ete notifies par 60 % des laboratoires (n=16), et les resultats etaient corrects pour 56 % d’entre eux. Un laboratoire a rapporte une fausse detection d’anticorps a la grippe B et pour les autres, la sensibilite etait tres variable. Pour la souche A(H3N2), la sensibilite des tests pour l’identification du virus grippal variait de 10 a 100 000 TCID50/ml. Le sous-typage de la grippe A a ete realise par 87 % des laboratoires, avec 31 % de resultats corrects. Six laboratoires ont effectue la caracterisation des variants, parfaitement reussie pour la moitie d’entre eux. La technique de RT-PCR a ete utilisee par 56 % des laboratoires pour les diagnostics ; les resultats etaient specifiques et la sensibilite equivalente a celle de la culture cellulaire.
Combined systemic elimination of MET and epidermal growth factor receptor signaling completely abolishes liver regeneration and leads to liver decompensation
Authors: Shirish Paranjpe, William C. Bowen, Wendy M. Mars, Anne Orr, Meagan M. Haynes, Marie C. DeFrances, Silvia Liu, George C. Tseng, Anastasia Tsagianni, George K. Michalopoulos
Journal: Hepatology (2016)

Receptor tyrosine kinases MET and epidermal growth factor receptor (EGFR) are critically involved in initiation of liver regeneration. Other cytokines and signaling molecules also participate in the early part of the process. Regeneration employs effective redundancy schemes to compensate for the missing signals. Elimination of any single extracellular signaling pathway only delays but does not abolish the process. Our present study, however, shows that combined systemic elimination of MET and EGFR signaling (MET knockout + EGFR-inhibited mice) abolishes liver regeneration, prevents restoration of liver mass, and leads to liver decompensation. MET knockout or simply EGFR-inhibited mice had distinct and signaling-specific alterations in Ser/Thr phosphorylation of mammalian target of rapamycin, AKT, extracellular signal-regulated kinases 1/2, phosphatase and tensin homolog, adenosine monophosphate-activated protein kinase α, etc. In the combined MET and EGFR signaling elimination of MET knockout + EGFR-inhibited mice, however, alterations dependent on either MET or EGFR combined to create shutdown of many programs vital to hepatocytes. These included decrease in expression of enzymes related to fatty acid metabolism, urea cycle, cell replication, and mitochondrial functions and increase in expression of glycolysis enzymes. There was, however, increased expression of genes of plasma proteins. Hepatocyte average volume decreased to 35% of control, with a proportional decrease in the dimensions of the hepatic lobules. Mice died at 15-18 days after hepatectomy with ascites, increased plasma ammonia, and very small livers.MET and EGFR separately control many nonoverlapping signaling endpoints, allowing for compensation when only one of the signals is blocked, though the combined elimination of the signals is not tolerated; the results provide critical new information on interactive MET and EGFR signaling and the contribution of their combined absence to regeneration arrest and liver decompensation. (Hepatology 2016;64:1711-1724).
80% Dose R-CHOP Is Suitable Chemotherapy for Very Elderly Patients with DLBCL
Authors: Anna Takahashi, Yuko Mishima, Norihito Inoue, Yoshiharu Kusano, Tadahiro Gunji, Kyoko Ueda, Noriko Nishimura, Hideaki Nitta, Masahiro Yokoyama, Naoko Tsuyama, Kengo Takeuchi, Yasuhito Terui, Kiyohiko Hatake
Journal: Blood (2015)
Muscular dystrophy drug looks set for commercial success despite clinical doubts
Authors: Owen Dyer
Journal: BMJ (2016)

A newly approved drug to treat Duchenne muscular dystrophy seems likely to be used by most US neurologists, even though its benefit has yet to be proved, treatment costs $300 000 (£230 000; €270 000) a year, and the head of the Food and Drug Administration has said that the main clinical study on which it rests “should probably be retracted by its authors.”

Eteplirsen, made by Sarepta Therapeutics and marketed as Exondys 51, was approved in the United States this month after a long internal battle between FDA scientists who doubted its efficacy and the director of the FDA’s Center for Drug Evaluation and Research, Janet Woodcock. The details of this dispute, which led to formal complaints against Woodcock from several top agency scientists, are laid out in an unusually frank report by the FDA’s commissioner, Robert Califf.1

The drug’s approval has been widely interpreted as a victory for Woodcock’s vision of an FDA that is more responsive to patients’ demands, especially those with …
The peripheral blood TCR repertoire to facilitate patient stratification for immune checkpoint blockade inhibition in metastatic melanoma.
Authors: Simone M. Goldinger, Anais Courtier, Nicoletta F Jaberg-Bentele, Sabrina Schindler, Manuarii Manuel, Nadia Plantier, Bertrand Treillard, Marlene Noel, Thi Dan Linh Nguyen-Kim, Marieke Ineke Geertje Raaijmakers, Pia Kvistborg, John B. A. G. Haanen, Reinhard Dummer, Mitchell Levesque
Journal: Journal of Clinical Oncology (2016)

3026 Background: Anti-PD-1 and/or anti-CTLA-4 antibodies show durable responses in metastatic melanoma. Measuring the diversity of T lymphocytes in pre-treatment liquid biopsies may help stratify patients for immunotherapy. Methods: In this retrospective blinded study, we used a multi-N-plex polymerase chain reaction (PCR) assay to measure TCR combinatorial diversity from genomic DNA in peripheral blood from melanoma patients treated with anti-CTLA-4 (n = 40) or anti-PD-1 (n = 36). A receiver operating characteristic (ROC) curve was used to determine the threshold for dichotomized analysis (i.e. low vs. high diversity) according to RECIST 1.1. Association with benefit in the low vs. high groups was assessed through a Fisher’s exact test. OS, PFS, and ORR were tested with ALC, ANC, LDH, S100 levels, and TCR diversity (DS) in a univariate model. Significant (p < 0.10) candidate prognostic factors from the univariate analysis were included in a multivariate Cox regression to define the added value of each variable on ORR, OS and PFS prediction. Results: A diversity score (DS) < 20% was associated with progressive or stable disease (p = 0.016) in anti-CTLA-4 treated patients. In contrast, a DS < 20% was associated with partial or complete response in 5 of the 12 responders (p = 0.0021) receiving anti-PD-1, and all non-responders (24) had a high DS > 20%. All low DS patients were non-responders in the anti-CTLA-4 cohort (100% negative predictive value), and were all responders in the anti-PD1 cohort (100% positive predictive value). In multivariate analysis with ALC, ANC, LDH, and age, a DS < 20% was an independent predictive marker of response to anti-PD-1 (p = 0.0001), with ALC > 1.4 (p = 0.027) and ANC > 4.8G/L (p = 0.016). A DS < 20% was found to be an independent prognostic marker of PFS (p = 0.040) with ANC > 4.8G/L (p = 0.0071). Conclusions: Patients with low DS did not benefit from anti-CTLA-4. In contrast, low DS patients receiving anti-PD-1 benefitted from the therapy. Thus, the TCR repertoire is a predictive biomarker of response that might help physicians choose best immune checkpoint modulators. Several studies are ongoing to validate these results.
<i>FCGR</i>, Cetuximab, and Colorectal Cancer Survival—Letter
Authors: Francesca V. Negri, Daniela Boggiani, Anita Rimanti, Antonino Musolino
Journal: Clinical Cancer Research (2016)

Some common single-nucleotide polymorphisms (SNP) in the coding regions of the FcγRIIIa and FcγRIIa genes have been associated with differential mAb-binding affinities and clinical outcomes. In their study ([1][1]), Liu and colleagues performed a validation of these polymorphisms in a randomized
Does delaying adjuvant chemotherapy after curative surgery for colorectal cancer impair survival? A meta-analysis.
Authors: B. Uzzan, P. Nicolas, C. Kader, J. F. Morere, G. Des Guetz
Journal: Journal of Clinical Oncology (2010)

e14021 Background: In stage III colorectal cancer (CRC), adjuvant chemotherapy (CT) is usually prescribed within two months after curative surgery. Whether or not delaying initiation of CT affects survival is still debated. Methods: We performed a meta-analysis (MA) of all published studies (full papers or abstracts) comparing delayed CT with standard care. Studies were obtained from a PubMed query (keywords: CRC, adjuvant treatment, delay of CT), a review (Chau et al, 2006), cross-checking references, and abstracts from the proceedings of ASCO, ASCO GI and WCGI annual meetings. We chose a cut off delay of 8 weeks. Risk ratios (RRs) were calculated from the recorded events (deaths, relapses). We used EasyMA software (fixed-effect model). Results: Fourteen studies (including 4 abstracts) were identified (17,645 patients; 5,952 males, 5,151 females, mean age 70 years). Of these, 3 could not be statistically analysed and 3 used another cut off (4, 5 or 6 weeks), leaving 8 studies for main MA (13,158 patients, 3,932 males, 3,644 females, 5,942 missing data; 5,576 colon cancers, 6,677 rectal, 1,265 missing data). Delaying CT more than 8 weeks was associated to worse overall survival (OS) (RR: 1.20; 95% confidence interval [1.15-1.26]). In the MA including all studies whatever their cut off, longer delay was similarly associated to a worse OS but not a worse relapse-free survival (5 studies). Conclusions: Adjuvant chemotherapy should be started within 8 weeks after surgery. Delaying initiation of adjuvant CT more than 8 weeks after surgery significantly decreased OS but not RFS. This discrepancy might be due to factors not directly related to cancer (postoperative complications, social status) or to a more accurate appraisal of death. No significant financial relationships to disclose.
Final results of a phase I study of CTLA-4 blockade in combination with GM-CSF for metastatic castration resistant prostate cancer (mCRPC).
Authors: A. L. Harzstark, L. Fong, V. K. Weinberg, C. J. Ryan, A. M. Lin, J. Sun, E. J. Small
Journal: Journal of Clinical Oncology (2010)

4689 Background: CTLA-4 is an inhibitory molecule expressed on activated T cells. CTLA-4 blockade with ipilimumab augments T cell responses and anti-tumor immunity in animal models. We have previously demonstrated that granulocyte-macrophage colony-stimulating factor (GM-CSF) can induce PSA declines in patients with CRPC, possibly by enhancing antigen presentation. The two agents were combined with the goal of augmenting clinical and immune responses. Methods: Six sequential cohorts of 3-6 patients with mCRPC were treated on a phase I trial with GM-CSF 250 mcg/m2/d SC on days 1-14 of a 28 day cycle with escalating doses (from 0.5 to 10 mg/kg) of ipilimumab, a fully human anti-CTLA-4 antibody, given IV on day 1 of each cycle × 6 cycles. Patients were monitored for toxicity and T cell activation, as well as PSA and radiographic responses. Results: 36 patients were treated. Grade 3 immune-related adverse events included rash (5 pts), panhypopituitarism (1 pt), temporal arteritis (1 pt), and diarrhea (3 pts). Non-immune-related toxicities of note included grade 3 and 4 cerebrovascular events (1 pt each), grade 3 angina (1 pt), grade 3 atrial fibrillation (1 pt), grade 3 fatigue (4 pts), and grade 5 pulmonary embolism (1 pt). Of six patients treated at 3 mg/kg, three (50%) had confirmed PSA declines of ≥50%, with a time to progression (TTP) of 22, 26, and 103 weeks. One of these pts had a partial response in hepatic metastases. One patient treated at 10 mg/kg had a PSA decline of ≥50% with a TTP of 39 weeks. Conclusions: CTLA-4 blockade with ipilimumab in combination with GM-CSF induces clinical responses in CRPC with the highest response proportion observed at a dosage of 3 mg/kg. Further exploration of this regimen is warranted. No significant financial relationships to disclose.
Government urges food industry to cut 20% of sugar and reduce portion sizes
Authors: Gareth Iacobucci
Journal: BMJ (2016)

Food retailers and restaurant chains in England will be expected to remove 20% of the sugar from food they sell and reduce portion sizes as part of government led efforts to reduce the prevalence of childhood obesity. Companies will also be publicly named and shamed if they fail to commit themselves to the reduction and reformulation programme, which was outlined in the government’s childhood obesity plan …