tbuckley/cabot-search huggingface dataset:
Updated overall survival (OS) results for BRF113220, a phase I–II study of dabrafenib alone versus combined dabrafenib and trametinib in patients with <i>BRAF</i> V600 metastatic melanoma (MM).
Authors: Adil Daud, Jeffrey S. Weber, Jeffrey Alan Sosman, Kevin Kim, Rene Gonzalez, Omid Hamid, Jeffrey R. Infante, Jonathan S. Cebon, Lynn Mara Schuchter, Georgina V. Long, Alain Patrick Algazi, Ragini Reiney Kudchadkar, Igor Puzanov, Donald P. Lawrence, Richard Kefford, Amy S. Kline, Heather Lynn Del Buono, Peng Sun, Diane Opatt McDowell, Keith Flaherty
Journal: Journal of Clinical Oncology (2015)

9036 Background: This Phase I—II study evaluated the safety and efficacy of the combination of dabrafenib and trametinib (the combination) compared with dabrafenib alone (monotherapy) in patients (pts) with BRAF V600 MM. Methods: BRAF V600E/K MM pts naive to BRAF and MEK inhibitors were enrolled. Part B (Ph I, n = 77 BRAFi-naive) pts enrolled into escalating dose (mg) cohorts of dabrafenib twice daily (BID)/trametinib once daily (QD) as follows: 75/1, 150/1, 150/1.5 and 150/2. Part C (Ph II, n=162) pts were randomized 1:1:1 to dabrafenib 150 mg monotherapy, 150/1 and 150/2. Crossover from monotherapy to 150/2 combination was allowed post-progression of disease. Primary endpoints were progression-free survival, response rate, duration of response, and safety; secondary endpoints were OS and pharmacokinetics. Results: Previously reported landmark 2-year OS results for pts in Parts B and C with median follow-up of 35 and 34 mo is presented in Table 1.In Part C, median OS rate for 150/2 combination pts was 25 mo (HR = 0.79 vs monotherapy; p = 0.3341). OS rate for monotherapy was confounded by crossover to the 150/2 arm; 45 (83%) pts crossed over at time of analysis. In the 150/2 arm, 16 (30%) pts continued to receive combination beyond progressive disease. Subsequent systemic therapies were similar across arms; 39 (24%) pts received ipilimumab, 17 (10%) received anti-PD-1/PD-L1 therapies, and 21 (13%) received vemurafenib. Conclusions: Landmark 2-year OS rate was 51% for Part C 150/2. Further follow-up is ongoing. Landmark 3-year OS rate and safety data with 12 mo additional follow-up will be presented. NCT01072175 Clinical trial information: NCT01072175. Treatment Deaths, n (%) Med. OS, mo (95% CI) HR (95% CI) p-value 12-mo OS rate (%) 24-mo OS rate (%) Part B 150/2 combination (n = 24) 10 (42) 27.4 (12.9, NR) NA 72 60 Part C dabrafenib monotherapy (n = 54) 36 (67) 20.2 (14.5, 27.1) NA 70 44 Part C 150/2 combination (n = 54) 32 (59) 25.0 (17.5, NR) 0.79 (0.49, 1.27) 0.3341 80 51 NA: not applicable; NR: not reached
Contracting is a recipe for inefficiency
Authors: A M Will
Journal: BMJ (1995)

strategies but have little or no leverage with general practice fundholders to implement them.The emphasis on general practice fundholders as purchasers is a move away from population based purchasing, which took into account the major influences on health.'It is not clear how a local population perspective of health and health care needs developed by health authorities will be able to influence general practice fimdholders.Furthermore, if health authorities are to become the new "regulators" of general practice fundholders4 all their resources will be taken up with this time consuming task, which will increase the transaction costs inherent in the internal market.
Necrotic and Ulcerated Plaques Over Face and Extremities
Authors: Sandeep Gera, V. Ramesh
Journal: JAMA Dermatology (2015)

Aman in his 30s had ulceration of the skin of the soles, legs, hands, elbow joints, and face of 15 days’ duration. It had started as swelling of the feet, followed by erythematous acral lesions. Numbness of the hands and feet had begun 11⁄2 years previously, spreading gradually to the forearm and legs. He had no history of fever, jointpains, orepistaxis.Blackescharandulcerationwith purulent discharge was seen over the soles and elbows.Thereweretriangularandbizarrepurpuricandnecrotic lesions over the legs, thighs, and dorsum of the hands (Figure, A) with necrosis of pinnae and nasolabial folds. The scrotum was also affected. There was diffuse infiltration of the face andmadarosis of the lateral half of theeyebrows.Healsohadhypoesthesia over the palms, proximal forearms, feet, and legs. Peripheral nerve examination revealed thickening of the right radial cutaneous and both ulnar nerves. Bilateral inguinal lymphadenopathywas present. Findings from the rest of the general physical and systemic examination were normal. Punch biopsy specimens were obtained (Figure, B-D). Quiz at jamadermatology.com Patient photograph A
Lung function and -inflammation after short term exposures to traffic related air pollution and physical activity
Authors: Nadine Kubesch, Audrey de Nazelle, David Martinez, Stefano Guerra, Mark Nieuwenhuijsen
Journal: European Respiratory Journal (2013)

Background: Traffic air pollution exposure is associated with adverse respiratory outcomes. Exercise in polluted air increases pollutant uptake. We aimed to assess respiratory responses in healthy subjects following short term exposures to traffic air pollution and the role of moderate physical activity as a potential effect modifier. Methods: Controlled crossover study design comparing lung function and the fraction of exhaled Nitric Oxide (FeNO) at baseline with measures repeated up to 6h post exposure to traffic air pollution. Healthy non-smoking subjects were exposed for 2 hours to contrasting pollution levels (high vs. low exposure) while cycling or resting (n=31). Each volunteer was to undergo all 4 conditions. On-site exposure monitoring included particulate matters [Ultrafine PM (UFP), PM 2.5, PM10], nitrogen oxides (NOx), and elemental carbon (EC). Data were analyzed using mixed effect models for repeated measures. Results: Physical Activity was associated with a significant increase in FEV1 (0.034,p=0.000). These associations were robust and insensitive to adjustment for pollutants. Similarly consistent associations were seen with FeNO (0.880,p=0.047). Interquartile increases in UFP (-0.004,p=0.001), EC (-0.004,p=0.003), NOx (-0.004,p=0.002), PM2.5 (-0.005,p=0.001), and PM10 (-0.003,p=0.002) were significantly associated with a decrease in the ratio of FEV1/FVC. Conclusions: Moderate physical activity is slightly increasing lung function but also lung inflammation. The decreasing ratio of FEV1 and FVC indicates a lung obstruction after traffic air pollution exposure. The implications of these immediate subclinical responses remain to be further explored.
Predictors Of Response To Rigosertib In Patients With a Myelodysplastic Syndrome (MDS) Or Acute Myeloid Leukemia (AML) Relapsing After Or Refractory To Hypomethylating Agents
Authors: Shyamala C. Navada, Rosalie Odchimar-Reissig, E. Premkumar Reddy, Erin P Demakos, James F Holland, Francois Wilhelm, Lewis R. Silverman
Journal: Blood (2013)
Management for Doctors: Handling the conflicting cultures in the NHS
Authors: J. Drife, I. Johnston
Journal: BMJ (1995)

St Duncan's and St Kenneth's United Hospitals Trust, like other hospitals, is now funded by contracts which specify how much work is to be undertaken in each specialty or subspecialty. Like many hospitals in the real world outside London, the trust has only one major purchasing authority. In the case of one specialty, ontological surgery, the volumes set for the contract are reasonable but tight. The ontological surgeons (all men, incidentally) have always run an excellent service, including giving dates for admission within a few months to outpatients. During the year they have improved on their already impressive performance, and waiting times for admission are now a matter of weeks. The problem with this is that the hospital is now well ahead of contract and the health authority can afford to pay only for the agreed contract volumes. The health authority has also said that if it did have more money it would want to use it in specialties that were having difficulty with waiting lists.

The managerial culture requires, broadly, that the contract numbers are adhered to, and the consultants have been required to restrict their activities. The doctors, however, know that there are patients waiting for treatment. They want to treat them and they believe that the health authority's problems are not theirs. They feel that if other specialties have excessive waiting lists they should be required to get their house in order before being given extra funds. The managers and the doctors have reached an impasse.

The NHS is a multicultural society. Each profession—medical, nursing, management, and many others—has its own identity, culture, and subcultures. Within medicine there are various specialty groupings, such as surgeons, psychiatrists, or general practitioners, with different characteristics and aims. The potential for conflict arising from cultural differences is almost limitless—a problem not, …
Biomarker analysis from completely resected NSCLC patients enrolled in an adjuvant erlotinib clinical trial (RADIANT)
Authors: F. Richardson, K. Richardson, G. Sennello, D. Young, S. Orlov, Z. Pápai-Székely, S. Keshavjee, J. Kim, R. Cerfolio, F. A. Shepherd
Journal: Journal of Clinical Oncology (2009)

7520 Background: RADIANT is a phase III trial comparing erlotinib 150 mg daily vs. placebo (2:1) in stage IB-IIIA NSCLC patients with EGFR-positive tumors (IHC and/or FISH), following complete surgical resection. Planned accrual is 945 patients. Correlative biomarker studies on primary tumor tissue, whole blood, and serum are key components of the study. Methods: Tumor tissue was evaluated by IHC for protein expression of EGFR (PharmDx Kit, Dako with + ≥ 1% positive tumor cells), by FISH for gene expression of EGFR (Vysis, Abbott), and by Wave HS for EGFR and Kras mutations. Results: Among 655 tissue samples analyzed, 96% were EGFR IHC+ and 74% EGFR FISH+. Of the 476 tissue samples analyzed to date for mutations (mut), 12% had activating EGFR and 19% had Kras mut. Preliminary comparisons suggest that EGFR mut rate increased while Kras mut rate decreased with tumor stage. EGFR mut occurred in 29/178 (16%) females (F) vs. 23/271 (8%) males (M), 19/57 (33%) Asians (A) vs. 33/392 (8%) non-Asians (NA), and 29/66 (44%) never smokers (NS) vs. 23/383 (6%) current or former smokers (S). The differences between A vs. NA and NS vs. S were significantly different (P &lt;0.0001) for all comparisons made. Kras mut occurred in 40/180 (22%) F vs. 48/280 (17%) M, 4/57 (7%) A vs. 84/403 (21%) NA, and 3/68 (4%) NS vs. 85/392 (22%) S. The difference between A vs. NA and NS vs. S were significantly different (P ≤0.0389) for all comparisons made. In adenoca, 51/254 (20%) had EGFR and 79/261 (30%) had Kras mut, and in SCC, 0/157 (0%) had EGFR and 3/162 (2%) had Kras mut. One tumor sample demonstrated both an activating EGFR and Kras mut. Conclusions: Ongoing comprehensive biomarker assessment in the RADIANT population indicates successful sample collection and analysis. FISH positivity rates are greater than observed in late-stage tumors. Remaining results in this early-stage population are consistent with those observed in advanced-stage disease. Once complete, this study will provide a robust biomarker dataset on which to evaluate predictive and prognostic response markers, which may help determine who may benefit from treatment with erlotinib in the adjuvant setting. [Table: see text]
A first-in-human phase I study to evaluate the pan-PI3K inhibitor GDC-0941 administered QD or BID in patients with advanced solid tumors
Authors: A. J. Wagner, D. H. Von Hoff, P. M. LoRusso, R. Tibes, K. E. Mazina, J. A. Ware, Y. Yan, M. K. Derynck, G. D. Demetri
Journal: Journal of Clinical Oncology (2009)

3501 Background: The PI3K-PTEN-AKT signaling pathway is deregulated in a wide variety of cancers. GDC-0941 is a potent and selective oral inhibitor of the class I PI3K with 3 nM IC50 for the p110-alpha subunit in vitro and 28 nM IC50 in a cell-based pAKT assay and demonstrates broad activity in breast, ovarian, lung, and prostate cancer models. Methods: A Phase I dose escalation study using a 3+3 design was initiated in patients (pts) with solid tumors. GDC-0941 was given on d1, followed by 1 wk washout to study single-dose PK and PD markers. GDC-0941 was then administered qd on a 3 wk on, 1 wk off, schedule. Steady-state PK and PD were evaluated after 1 wk of continuous dosing. A separate concurrent dose-escalation arm with bid dosing was initiated after the third qd cohort. Results: Nineteen pts have been enrolled in 5 successive dose-escalation cohorts in the qd arm with dose levels up to 80 mg daily. Seven pts were enrolled in 2 cohorts in the bid arm at total daily doses of 60 and 80 mg. The most frequently reported drug-related AEs were Grade 1/2 nausea, fatigue, diarrhea, peripheral edema, and dysgeusia; no drug related grade &gt;3 events have been reported. PK data suggest dose-proportional increases in Cmax and AUC. Potential signs of anti-tumor activity have been observed with a soft tissue sarcoma pt on-study for &gt;176 days with stable disease (30 mg qd), an ovarian cancer pt with an on-study 2.8-fold decrease in CA-125 response to normal levels (30 mg bid) and a pt with endometrial cancer with a decrease in tumor FDG-PET uptake (80 mg qd). Conclusions: GDC-0941 is generally well-tolerated with potential signs of anti-tumor activity. Preliminary PK data suggest dose-proportional increases in exposure over the dose levels evaluated. Dose-escalation on both the qd and bid schedules continues with updated data to be presented. [Table: see text]
Drug points: Interaction of thyroxine sodium with antimalarial drugs
Authors: Y Munera, F C Hugues, C Le Jeunne, J F Pays
Journal: BMJ (1997)

Objective: To study the comparative importance of environment and genes in the development of islet cell autoimmunity associated with insulin dependent diabetes mellitus.Design: Population based study of diabetic twins.Setting: Danish population.Subjects: 18 monozygotic and 36 dizygotic twin pairs with one or both partners having insulin dependent diabetes.Main outcome measures: Presence of islet cell antibodies, insulin autoantibodies, and autoantibodies to glutamic acid decarboxylase (GAD65) in serum samples from twin pairs 10 years (range 0-30 years) and 9.5 years (2-30 years) after onset of disease.Results: In those with diabetes the prevalence of islet cell antibodies, insulin autoantibodies, and autoantibodies to glutamic acid decarboxylase in the 26 monozygotic twins was 38%, 85%, and 92%, respectively, and in the dizygotic twins was 57%, 70%, and 57%, respectively.In those without diabetes the proportions were 20%, 50%, and 40% in the 10 monozygotic twins and 26%, 49%, and 40% in the 35 dizygotic twins. Conclusion:There is no difference between the prevalence of islet cell autoantibodies in dizygotic and monozygotic twins without diabetes, suggesting that islet cell autoimmunity is environmentally rather than genetically determined.Furthermore, the prevalence of islet cell antibodies was higher in the non-diabetic twins than in other first degree relatives of patients with insulin dependent diabetes.This implies that the prenatal or early postnatal period during which twins are exposed to the same environment, in contrast with that experienced by first degree relatives, is of aetiological importance.
A Balanced Data Archiving Policy for Long-Term Studies
Authors: Michael C. Whitlock, Judith L. Bronstein, Emilio M. Bruna, Aaron M. Ellison, Charles W. Fox, Mark A. McPeek, Allen J. Moore, Mohamed A.F. Noor, Mark D. Rausher, Loren H. Rieseberg, Michael G. Ritchie, Ruth G. Shaw
Journal: Trends in Ecology & Evolution (2015)
FDA Approval: Blinatumomab
Authors: Donna Przepiorka, Chia-Wen Ko, Albert Deisseroth, Carolyn L. Yancey, Reyes Candau-Chacon, Haw-Jyh Chiu, Brenda J. Gehrke, Candace Gomez-Broughton, Robert C. Kane, Susan Kirshner, Nitin Mehrotra, Tiffany K. Ricks, Deborah Schmiel, Pengfei Song, Ping Zhao, Qing Zhou, Ann T. Farrell, Richard Pazdur
Journal: Clinical Cancer Research (2015)

Abstract On December 3, 2014, the FDA granted accelerated approval of blinatumomab (Blincyto; Amgen, Inc.) for treatment of Philadelphia chromosome–negative relapsed or refractory precursor B-cell acute lymphoblastic leukemia (R/R ALL). Blinatumomab is a recombinant murine protein that acts as a bispecific CD19-directed CD3 T-cell engager. The basis for the approval was a single-arm trial with 185 evaluable adults with R/R ALL. The complete remission (CR) rate was 32% [95% confidence interval (CI), 26%–40%], and the median duration of response was 6.7 months. A minimal residual disease response was achieved by 31% (95% CI, 25%–39%) of all patients. Cytokine release syndrome and neurologic events were serious toxicities that occurred. Other common (&amp;gt;20%) adverse reactions were pyrexia, headache, edema, febrile neutropenia, nausea, tremor, and rash. Neutropenia, thrombocytopenia, and elevated transaminases were the most common (&amp;gt;10%) laboratory abnormalities related to blinatumomab. A randomized trial is required in order to confirm clinical benefit. Clin Cancer Res; 21(18); 4035–9. ©2015 AACR.
Lapatinib in Gastric Cancer: What Is the LOGiCal Next Step?
Authors: Yelena Y. Janjigian
Journal: Journal of Clinical Oncology (2015)

2–Positive Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Adenocarcinoma) trial, which tested the activity of capecitabine and oxaliplatin with or without lapatinib in the firstline setting in HER2-positive esophagogastric cancer. LOGiC is a well-designed study, with appropriate end points, enrollment criteria, chemotherapy backbone, and toxicity management schema. Two-drug chemotherapy backbones are the preferred approach due to the excessive toxicity (and potential lack of benefit) from three-drug regimens when combined with targeted agents. Initially, the primary end point in LOGiC was progression-free survival. However, during the conduct of the trial, ToGA results showed that trastuzumab improved OS (13.8 v 11.1 months; hazardratio, 0.74;P 5.0046). Therefore, the primary endpointinLOGiCwaschangedtoOS,andthestudywaspowered for a hazard ratio of 0.74 in the experimental arm. Although the trial results will be considered negative because the primary end point of a statistically significant improvement in OS was not met (12.2 v 10.5 months; hazard ratio, 0.91; 95% CI, 0.73 to 1.12; P 5 .3492), the response rate was significantly higher in the lapatinib arm(53%v39%;P5.0031).Inaddition,apreplanned exploratory subgroup analysis demonstrated robust OS benefit in Asian patients (16.5 v 10.9 months; hazard ratio, 0.68; 95% CI, 0.48 to 0.96;P5.0261) and inyounger patients (12.9v9.0 months; hazard
Major Response to Cyclophosphamide and Prednisone in Recurrent Castration-Resistant Prostate Cancer
Authors: Nicolas Batty, Naveen Yarlagadda, Roberto Pili
Journal: Journal of the National Comprehensive Cancer Network (2013)

Prostate cancer is the most common noncutaneous cancer among men. This case report describes a 43-year-old man with rapidly progressing castration-resistant prostate cancer (CRPC) that responded initially to docetaxel and did not tolerate cabazitaxel. He subsequently received a third line of chemotherapy with cyclophosphamide and prednisone, and experienced a dramatic clinical and radiographic response in his liver metastases. This therapeutic intervention led to a significant clinical benefit and confirms the potential use of cyclophosphamide in patients with CRPC, particularly those with liver metastases.
Are you pharmiscuous? Take our quiz!
Authors: Christopher AKY Chong
Journal: BMJ (2015)

The general public is blessed to have Cosmo quizzes and their ilk, but medical magazines seem oddly uninterested in publishing similar fare. I remedy this problem with the following quiz, “Are you pharmiscuous?” Pharmiscuity is characterised by eagerly assuming multiple, casually indiscriminate financial relationships with industry.
Phase I Study of Fludarabine Plus Cyclophosphamide in Patients With Previously Untreated Low-Grade Lymphoma: Results and and Long-Term Follow-Up—A Report From the Eastern Cooperative Oncology Group
Authors: Howard S. Hochster, Martin M. Oken, Jane N. Winter, Leo I. Gordon, Bruce G. Raphael, John M. Bennett, Peter A. Cassileth
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To determine the toxicity and recommended phase II doses of the combination of fludarabine plus cyclophosphamide in chemotherapy-naive patients with low-grade lymphoma. PATIENTS AND METHODS: Previously untreated patients with low-grade lymphoma were entered onto dosing cohorts of four patients each. The cyclophosphamide dose, given on day 1, was increased from 600 to 1,000 mg/m 2 . Fludarabine 20 mg/m 2 was administered on days 1 through 5. The first eight patients were treated every 21 days; later patients were treated every 28 days. Prophylactic antibiotics were required. RESULTS: Prolonged cytopenia and pulmonary toxicity each occurred in three of eight patients treated every 3 weeks. The 19 patients treated every 28 days, who were given granulocyte colony-stimulating factor as indicated, did not have undue nonhematologic toxicity. Dose-limiting toxicity was hematologic. At the recommended phase II/III dose (cyclophosphamide 1,000 mg/m 2 ), grade 4 neutropenia was observed in 17% of all cycles and 31% of first cycles. Grade 3 or 4 thrombocytopenia was seen in only 1% of all cycles. The median number of cycles per patient was six (range, two to 11) for all patients enrolled. The response rate was 100% of 27 patients entered; 89% achieved a complete and 11% a partial response. Nineteen of 22 patients with bone marrow involvement had clearing of the marrow. Median duration of follow-up was more than 5 years; median overall and disease-free survival times have not been reached. Kaplan-Meier estimated 5-year overall survival and disease-free survival rates were 66% and 53%, respectively. CONCLUSION: The recommended dosing for this combination in patients with previously untreated low-grade lymphoma is cyclophosphamide 1,000 mg/m 2 day 1 and fludarabine 20 mg/m 2 days 1 through 5. The regimen has a high level of activity, with prolonged complete remissions providing 5-year overall and disease-free survival rates as high as those reported for other therapeutic approaches in untreated patients.
Anterior Myocardial Infarction With Acute Percutaneous Coronary Intervention and Intracoronary Injection of Autologous Mononuclear Bone Marrow Cells
Authors: Ketil Lunde, Svein Solheim, Kolbjørn Forfang, Harald Arnesen, Lorentz Brinch, Reidar Bjørnerheim, Asgrimur Ragnarsson, Torstein Egeland, Knut Endresen, Arnfinn Ilebekk, Arild Mangschau, Svend Aakhus
Journal: Journal of the American College of Cardiology (2008)