tbuckley/cabot-search huggingface dataset:
Quantitative Kinetics of Development of N-2-Fluorenylacetamide-Induced, Altered (Hyperplastic) Hepatocellular Foci Resistant to Iron Accumulation and of Their Reversion or Persistence Following Removal of Carcinogen23
Authors: Gary M. Williams, Kenshi Watanabe
Journal: JNCI Journal of the National Cancer Institute (1978)

For study of the behavior of previously described carcinogen-induced foci of hepatocytes refractory to iron accumulation, iron deposition was induced in all hepatocytes of rat livers by feeding 8-hydroxyquinoline and ferrous gluconate to the animals for 3 months. The kinetics of development of the altered foci of hepatocytes free of stainable iron was then quantified for each lobe of liver for as long as 13 weeks of feeding of the carcinogen N-2-fluorenylacetamide and for 6 months following cessation of carcinogen exposure. The foci increased slowly in number and size for the first 12 weeks of carcinogen administration and then grew rapidly between weeks 12 and 13. At week 13, they corresponded to altered foci that have been observed in sections stained with hematoxylin and eosin, and they also displayed abnormal glycogen storage. After the carcinogen was discontinued, the foci disappeared by a reversion back to iron storage while temporarily retaining the nuclear abnormalities of altered cells. Over 95% of altered foci at this stage underwent reversion by 6 months following removal of the carcinogen. More advanced lesions developed in the lobes that displayed the greatest incidence and persistence of foci.
Selumetinib with and without erlotinib in KRAS mutant and KRAS wild-type advanced nonsmall-cell lung cancer
Authors: C.A. Carter, A. Rajan, C. Keen, E. Szabo, S. Khozin, A. Thomas, C. Brzezniak, U. Guha, L.A. Doyle, S.M. Steinberg, L. Xi, M. Raffeld, Y. Tomita, M.J. Lee, S. Lee, J.B. Trepel, K.L. Reckamp, S. Koehler, B. Gitlitz, R. Salgia, D. Gandara, E. Vokes, G. Giaccone
Journal: Annals of Oncology (2016)

KRAS mutations in NSCLC are associated with a lack of response to epidermal growth factor receptor inhibitors. Selumetinib (AZD6244; ARRY-142886) is an oral selective MEK kinase inhibitor of the Ras/Raf/MEK/ERK pathway.Advanced nonsmall-cell lung cancer (NSCLC) patients failing one to two prior regimens underwent KRAS profiling. KRAS wild-type patients were randomized to erlotinib (150 mg daily) or a combination of selumetinib (150 mg daily) with erlotinib (100 mg daily). KRAS mutant patients were randomized to selumetinib (75 mg b.i.d.) or the combination. The primary end points were progression-free survival (PFS) for the KRAS wild-type cohort and objective response rate (ORR) for the KRAS mutant cohort. Biomarker studies of ERK phosphorylation and immune subsets were carried out.From March 2010 to May 2013, 89 patients were screened; 41 KRAS mutant and 38 KRAS wild-type patients were enrolled. Median PFS in the KRAS wild-type arm was 2.4 months [95% confidence interval (CI) 1.3-3.7] for erlotinib alone and 2.1 months (95% CI 1.8-5.1) for the combination. The ORR in the KRAS mutant group was 0% (95% CI 0.0% to 33.6%) for selumetinib alone and 10% (95% CI 2.1% to 26.3%) for the combination. Combination therapy resulted in increased toxicities, requiring dose reductions (56%) and discontinuation (8%). Programmed cell death-1 expression on regulatory T cells (Tregs), Tim-3 on CD8+ T cells and Th17 levels were associated with PFS and overall survival in patients receiving selumetinib.This study failed to show improvement in ORR or PFS with combination therapy of selumetinib and erlotinib over monotherapy in KRAS mutant and KRAS wild-type advanced NSCLC. The association of immune subsets and immune checkpoint receptor expression with selumetinib may warrant further studies.
A randomized, multicenter, open-label, phase III study of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) versus ofatumumab in patients (pts) with relapsed or refractory (RR) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): RESONATE.
Authors: John C. Byrd, Jacqueline Claudia Barrientos, Stephen Devereux, Jennifer R. Brown, Neil E. Kay, Nishitha M. Reddy, Susan Mary O'Brien, Thomas J. Kipps, Richard R. Furman, Stephen J. Schuster, Adrian Bloor, Devinder Singh Gill, Patrick Thornton, Claire E. Dearden, Ulrich Jäger, Christine Barker, Jennifer Lin, Lori A. Kunkel, Danelle Frances James, Peter Hillmen
Journal: Journal of Clinical Oncology (2013)

TPS8619 Background: Chemoimmunotherapy (CIT) treatment approaches such as FCR have markedly improved outcomes for CLL pts when administered as initial or second-line therapy. Despite this progress, virtually all pts relapse and effective salvage regimens that induce durable remissions or can be administered safely to elderly pts or those with comorbidities are lacking. BTK, an essential mediator of B-cell receptor signaling, is a novel target in CLL. Ibrutinib, a first-in class inhibitor of BTK, promotes apoptosis and inhibits proliferation, migration and adhesion in CLL cells. Phase II data of ibrutinib monotherapy in RR CLL demonstrated an estimated PFS and OS of 75% and 83% respectively at 26 months (Byrd Abst #189 ASH 2012). These findings confirmed BTK as an important target in CLL and supported initiation of a pivotal phase III study in pts with RR CLL/SLL. Methods: PCYC-1112-CA is an ongoing international Phase 3 randomized controlled study of ibrutinib versus ofatumumab for treatment of pts with RR CLL/SLL. The study is enrolling 350 planned pts in 9 countries. Pts are randomized 1:1 to receive ibrutinib 420 mg orally once daily or ofatumumab per the package insert at 300 mg for the first dose, then 2000 mg for a total of 12 doses over 24 weeks. Pts are stratified based on del 17p and disease refractory to purine analogs. Key inclusion criteria include RR CLL/SLL with &gt;= 1 prior line of therapy including pts who experienced a short remission duration to purine analog based CIT, pts who are older or have comorbidities, and pts with del 17p. Pts must have active disease meeting criterion for requiring therapy and measurable nodal disease by CT. Key exclusion criteria include Richter’s transformation, stem cell transplantation within 6 months, GVHD or immunosuppression, platelet count &lt;30,000 cells/ul or use of warfarin The primary objective of the study is PFS evaluated by an IRC. Other outcomes include ORR, OS, hematologic improvement, and safety. An independent DMC is monitoring the study. Clinical trial information: NCT01744691.
Intent to receive influenza A (H1N1) 2009 monovalent influenza vaccines - two counties, North Carolina.
Authors: Z. Moore, N. Standberry, D. Bergmire-Sweat, J. M. Maillard, J. Horney, P. D. M. MacDonald, A. T. Fleischauer, N. J. Dailey
Journal: MMWR Morbidity and Mortality Weekly Report (2009)
Abstract 259: Histone Deacetylase1 and 2 Are Increased in Myofibroblasts/Fibroblasts After MI
Authors: Hikmet Nural, Liudmila Zakharova, Diego Mastroeni, Mohamed Gaballa
Journal: Circulation Research (2012)

Myofibroblast activation after myocardial infarction (MI) is one of the major mechanisms of myocardial fibrosis and subsequent heart failure. Elucidating the mechanisms of myofibroblast activation will provide a strategy to treat heart failure. Histone Deacetylases (HDAC) were reported to regulate myofibroblast differentiation and extracellular matrix deposition in idiopathic pulmonary fibrosis. Furthermore, HDAC inhibitors were shown to retards myocardial remodeling and improve cardiac function after MI. Therefore, here we examined whether HDAC1/2 are up-regulated after MI, and identify which myocardial cell type is predominately expressing HDAC. MI was created in rats by ligation of the left coronary artery. First, we assessed expression of HDAC 1 and 2 following MI in heart sections. Both HDACs uniformly expressed in myocardium in right ventricular (LV) and left ventricular (LV) in sham hearts. On the other hand, we observed up-regulation of both HDAC1 and 2 in the infarcted LV following MI. In addition, HDAC1 and 2 were co-localized with fibroblast marker Vimentin in the infarcted area. Next, we performed western blot analysis to investigate protein levels of HDAC1 and HDAC2 in right ventricular (RV), septum (S) and LV (infarcted and remote area). We found up-regulation of HDAC1 and HDAC2 only in the infarcted area compared to sham rats. Altogether these results suggest HDAC1 and 2 play a role in fibrosis following MI.
Phase I trial of the sequential administration of pemetrexed (P) and docetaxel (D) in patients (pts) with advanced solid tumours
Authors: A. Lopez-Martin, R. Cubedo, I. Garcia-Rivas, D. Castellano, A. Perez-Romero, C. Savulsky, R. Rodriguez, P. España, H. Cortes-Funes, L. Paz-Ares
Journal: Journal of Clinical Oncology (2005)

2108 Background: Pemetrexed and docetaxel have shown activity in a broad range of solid tumours. Combined in vitro administration of both drugs results in synergistic effect if P is given before taxane. Previous phase I trials (Mackay et al, 2002; Fyfe et al, 2003) revealed DLT at low doses of P and D given concomitantly. The current trial was designed to evaluate the toxicity profile and feasibility of a sequential schedule of P follows by D. Methods: Protocol design allowed 2 sequential schedules for dose escalation. In the first, pts received increasing doses of P (300–600 mg/m2, day 1) with a fixed dose of D (60 mg/m2, day 8). If MTD appeared, as happened at level 1(L1), a second escalation started at the same doses with a biweekly sequence of both drugs. Pts received in-label premedication with corticosteroids, folic acid and vitamin B12. Results: To date, 17 pts have received treatment (14 M, 3 F; PS 0–1). Cancer diagnoses were NSCLC (3), urothelial carcinoma (2), melanoma (3), unknown primary (3), and others (6). Two out of 5 pts in Level 1 (P 300 mg/m2 day 1, D 60 mg/m2 day 8) experienced DLT: 1 died from septicaemia, and 1 had grade 3 asthenia. As per protocol, schedule was modified to sequential biweekly administration starting at the same doses. 13 pts have been treated with this schedule: 3 in L1 (P 300/D 60); 6 in L2 (P 400/D 60); 3 in L3 (P 500/D 60); and 1 in L4 (P 600/D 60). One DLT (febrile neutropenia) occurred at L2. Other G3/4 toxicities included: neutropenia (7 pts), anaemia (2 pts), hepatic toxicity (2 pts), vomiting (2 pts), asthenia (1 pt), and rash (1 pt). Tumour response has been evaluated in 12 pts (7 stable disease, 5 progressive disease). Conclusions: Sequential administration of P (day 1) and D (day 15) is feasible and can be safely administered. At present, MTD has not been reached. Study enrolment is ongoing at the P 600/D 60 dose level. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis, Sanofi, Eli Lilly
US Food and Drug Administration Approval of Flibanserin
Authors: Steven Woloshin, Lisa M. Schwartz
Journal: JAMA Internal Medicine (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Continuing medical education: Changes in health care and continuing medical education for the 21st century
Authors: A. Towle
Journal: BMJ (1998)

A revolution in health care is occurring as a result of changes in the practice of medicine and in society. These include changing demographics and the pattern of disease; new technologies; changes in health care delivery; increasing consumerism; patient empowerment and autonomy; an emphasis on effectiveness and efficiency; and changing professional roles. These are the challenges which will face the medical profession in the 21st century and to which continuing medical education must respond.

### Demographics and the pattern of disease

In 20 years' time the proportion of most rich countries' populations aged 65 and over will have doubled to around 20-25%. Old people today consume about a third of total health care spending; if present trends continue, by the year 2000 they will be consuming half.1 The consequences will be a shift in the need for preventive and curative health care in the direction of the chronic health problems of older people and a large increase in demand for care of very frail or ill dependent elderly patients. There will be even greater pressures to cap spiralling healthcare costs.

#### Summary points

The education system must be better able to respond to rapid changes in the outside world and involve employers and users of health services

The culture of the education system, now largely shaped by performance in examinations and emphasis on factual content, must be changed to one which values self directed learners and problem solvers

There is a need to improve the effectiveness of continuing medical education, such as developing better programmes on doctor-patient communication and interprofessional continuing education

No major changes in overall patterns of morbidity are expected, but some health problems will increase. Health loss areas will include the widening of social class disparities, increasing alcohol consumption and drug addiction, and increasing numbers of cases of senile …
Incidence and survival of patients with T0N1 breast cancers.
Authors: Shoko Emily Abe, Kendall W. Carpenter, Yimei Han, Teresa Flippo, Terry Sarantou, Joshua S. Hill, Richard L. White
Journal: Journal of Clinical Oncology (2014)

56 Background: As imaging modalities have improved, breast cancers are increasingly detected at earlier stages. Patients rarely present with axillary disease but no mammographically evident breast tumor. Based on analysis of Surveillance, Epidemiology and End Results (SEER) data, we determined that there has been an increase in incidence of T1aN1 breast cancers. In response, we hypothesize that T0N1 breast cancer incidence has decreased with increased MRI use. Moreover, SEER analysis showed that T1aN1 patients have worse survival than T1bN1 patients. We thus hypothesize that T0N1 patients have worse survival than T1N1 patients. Methods: We identified 36,093 female patients diagnosed with T0-1 N1 invasive breast cancer from the SEER database. We compared patient and tumor characteristics: age, race, histology, hormone receptor status, and diagnosis year group (1990-1994, 1995-1999, 2000-2005, 2006-2010) – by TN category (T0N1/T1aN1/T1bN1/T1cN1) using chi-square test and ANOVA. Kaplan-Meier method was used to estimate disease specific survival (DSS) for each TN category and diagnosis year group separately. Adjusted hazard ratios were estimated using Cox proportional hazards models. Results: Stage distribution was: T0N1=129, T1aN1=1294, T1bN1=6731, and T1cN1=27942 patients. Median ages were 59.6, 56.3, 59.1, and 58.1, respectively. Time trend analysis of T0N1 cancers showed an increase in incidence from 1990 to 1999 and stability after 2000. Five-year DSS was significantly worse for patients with T0N1 tumors than T1aN1 tumors (84.5% versus 94.1%, HR 0.513, p &lt; 0.0001). T0N1 tumors were more likely to be ER negative than T1b-cN1 tumors (23% versus 16%, p &lt; 0.0001). T0N1 tumors were also more likely to be ER negative than T1aN1 tumors, but did not reach statistical significance (23% vs. 20%, p = 0.09). The proportion of lobular cancers was significantly higher in T0N1 than T1aN1 or T1b-cN1 patients (18% versus 8%, p &lt; 0.0001). Conclusions: Our analysis suggests that T0N1 tumors may differ biologically from T1N1 tumors. Although the incidence of T0N1 tumors did not decrease, it remained stable after 2000 when the use of MRI for occult breast cancers became widely accepted. Our second hypothesis that survival is worse in patients with T0N1 tumors was confirmed by our analysis.
Timing of failure of resected rectal cancer: What is the appropriate duration of postoperative imaging?
Authors: K. Fischkoff, J. Juan, L. Saltz, E. Riedel, M. R. Weiser, G. Nash, L. K. Temple, P. Paty, W. D. Wong, J. G. Guillem
Journal: Journal of Clinical Oncology (2010)

3633 Background: Guidelines for the appropriate duration of imaging after a curative resection for rectal cancer are lacking. Current ASCO and NCCN guidelines conflict and are limited as the data to support the rectal cancer-specific guidelines do not include patients with locally advanced rectal cancer (LARC) who receive neoadjuvant therapy. Methods: 935 stage I through III rectal cancer patients who underwent an R0 resection from 1993 to 2003 were reviewed. Patients with metastatic disease at presentation or undergoing a local excision were excluded. Neoadjuvant therapy (primarily 50.4 Gy and 5-FU based chemotherapy) was delivered to LARC patients. Results: At a median follow-up of 76 months (13-198), 23.9% had a recurrence (6.2% local, 20.6% distant). While early rectal cancer had better recurrence-free survival than LARC (p<0.0001), the timing of the recurrences were similar. Nearly 80% of all recurrences occurred within the first three postoperative years (see Table). Only 1.3% of patients were identified as having a recurrence by routine imaging after three years. Of those few that had a recurrence after 3 years, approximately one-third, or 1.7% of all patients, were salvageable with an R0 resection. Moreover, only 10% of all local failures, or 0.6% of all patients, were salvageable with an R0 resection. Conclusions: Our data support routine surveillance for the first three years following curative rectal cancer resection. Furthermore, since local recurrence is very low and is rarely salvageable beyond the first three postoperative years, the appropriateness of routine postoperative pelvic surveillance beyond this point is questionable. Overall, local, and distant recurrence rates at each time interval Years Overall (n) Local (n) Distant (n) 0-3 19% (178) 4.8% (45) 16.7% (156) 3-5 2.9% (27) 0.7% (7) 2.4% (22) 5-7 1.4% (13) 0.4% (4) 1.2% (11) 7-10 0.5% (5) 0.2% (2) 0.4% (4) No significant financial relationships to disclose.
Microsatellite Instability as a Biomarker for PD-1 Blockade
Authors: Jonathan C. Dudley, Ming-Tseh Lin, Dung T. Le, James R. Eshleman
Journal: Clinical Cancer Research (2016)

Abstract Initial results by Le and colleagues, which were published in the June 25, 2015 issue of the New England Journal of Medicine, report significant responses of cancers with microsatellite instability (MSI) to anti–PD-1 inhibitors in patients who failed conventional therapy. This finding fits into a broader body of research associating somatic hypermutation and neoepitope formation with response to immunotherapy, with the added benefit of relying on a simple, widely used diagnostic test. This review surveys the pathogenesis and prognostic value of MSI, diagnostic guidelines for detecting it, and the frequency of MSI across tumors, with the goal of providing a reference for its use as a biomarker for PD-1 blockade. MSI usually arises from either germline mutations in components of the mismatch repair (MMR) machinery (MSH2, MSH6, MLH1, PMS2) in patients with Lynch syndrome or somatic hypermethylation of the MLH1 promoter. The result is a cancer with a 10- to 100-fold increase in mutations, associated in the colon with poor differentiation, an intense lymphocytic infiltrate, and a superior prognosis. Diagnostic approaches have evolved since the early 1990s, from relying exclusively on clinical criteria to incorporating pathologic features, PCR-based MSI testing, and immunohistochemistry for loss of MMR component expression. Tumor types can be grouped into categories based on the frequency of MSI, from colorectal (20%) and endometrial (22%–33%) to cervical (8%) and esophageal (7%) to skin and breast cancers (0%–2%). If initial results are validated, MSI testing could have an expanded role as a tool in the armamentarium of precision medicine. Clin Cancer Res; 22(4); 813–20. ©2016 AACR.
Stromal Cell Supported High-Throughput Drug Testing Of Primary Leukemia Cells For Comprehensive Assessment Of Sensitivity To Novel Therapies
Authors: Riikka Karjalainen, Tea Pemovska, Bhagwan Yadav, Muntasir Mamun Majumder, Mika Kontro, Kimmo Porkka, Olli Kallioniemi, Tero Aittokallio, Krister Wennerberg, Caroline A Heckman
Journal: Blood (2013)
A Retrospective Study of Weekly Paclitaxel as Second-Line Treatment for Advanced or Recurrent Esophageal Cancer
Authors: Takeshi Sakamoto, Naoki Takegawa, Saeko Kushida, Hidetaka Tsumura, Takuya Mimura, Kazutoshi Tobimatsu, Nobuyoshi Yamamoto, Ikuya Miki, Masahiro Tsuda, Hideto Inokuchi
Journal: Annals of Oncology (2014)
To determine the acquired resistance of mycobacterium tuberculosis by culture to 1st line anti-tuberculous drugs in non responding smear positive patients who have taken category 1
Authors: Saifullah Baig, Nadeem Rizvi, Nausheen Saifullah
Journal: European Respiratory Journal (2011)

Background:  The strongest risk factor for drug resistance is previous history of tuberculous treatment. Currently the national tuberculosis control program recommends drug susceptibility testing in failures of retreatment cases. This study is being conducted to see the drug resistance pattern in failures and defaulters of initial treatment before starting a retreatment regime   Material and methods:  Study Design: Descriptive case series   Setting:  This study was conducted in the OPD of Thoracic Medicine JPMC Karachi.  Sampling technique: Non probability purposive sampling.   Results:  Among 60 selected patients of category 1 sputum smear positive, 14 (23.3%) were defaulter, 38 (63.3%) relapse and 8 (13.3%) patients were of treatment failure.  Culture sensitivity has shown 58 (96.7%) positive patients and only two (3.3%) were negative.  Multidrug resistance was found in 15 (25%) patients. MDR cases were 6 (42.9%) among 14 defaulters, 4 (10.5%) among 36 relapsed and 5 (62.5%) among 8 treatment failure patients.  Rifampicin resistance was found in 20 (34.5%) patients. Isoniazid was resistant in 19 (32.8%) patients. Ethambutol was resistant in 21 (36.2%) patients. Pyrazinamide was resistant in 17 (29.3%) patients. Streptomycin was resistant in 10 (17.2%) patients. None of antitubercolous drug was resistant among two culture negative patients. Multidrug resistance (MDR) was observed in 15 (25.9%) patients.   Conclusion:  We conclude that levels of MDR-TB is very high in patients not responding to CAT1 anti tuberculous drugs in our community.