tbuckley/cabot-search huggingface dataset:
Safety and pharmacokinetics of crizotinib in patients (pts) with hepatic impairment (HI) and advanced cancer.
Authors: Anthony B. El-Khoueiry, John Sarantopoulos, Cindy L. O'Bryant, Kristen Keon Ciombor, Huiping Xu, Melissa T O'Gorman, Jayeta Chakrabarti, Tiziana Usari, Bassel F. El-Rayes
Journal: Journal of Clinical Oncology (2017)

2552 Background: Crizotinib is a kinase inhibitor approved for treating ALK+ and ROS1+ advanced non-small cell lung cancer. Since crizotinib undergoes hepatic metabolism, this phase 1 study evaluated the pharmacokinetics (PK) and safety of crizotinib in pts with liver dysfunction. Methods: Crizotinib-naïve pts with different types of advanced cancer (ALK and ROS1 status unknown), ≥ 18 yr old, and ECOG PS 0–2 were enrolled. Pts were assigned to groups A1 – D based on liver function: normal (A1/A2) = both AST and TB ≤ the upper limit of normal (ULN); mild impairment (B) = AST &gt; ULN and TB ≤ ULN, or TB &gt; 1.0 – 1.5 × ULN; moderate (C1/C2) = TB &gt; 1.5 – 3 × ULN; severe (D) = TB &gt; 3 × ULN. Starting dose was based on HI. Pts in A1 and A2 were matched for weight, age, gender, race and ECOG PS to pts in B and C2, respectively. Study objectives included PK, safety and antitumor activity. Results: 88 pts were enrolled in A1 (n=11), A2 (n=15), B (n=20), C1 (n=10), C2 (n=16) and D (n=16). The geometric means of PK parameters at steady-state (Cycle 2 Day 1) are shown below. 75% of pts experienced treatment-related AEs (TRAEs), 9 (81.8%), 14 (93.3%), 15 (75.0%), 6 (60.0%), 11 (68.8%) and 11 (68.8%) in groups A1, A2, B, C1, C2 and D, respectively. 25% of pts experienced Grade 3/4 TRAEs, 3 (27.3%), 3 (20.0%), 3 (15.0%), 1 (10%), 7 (43.8%), 5 (31.3%) in groups A1, A2, B, C1, C2 and D, respectively. Three (3.4%) pts, all in A2, experienced treatment-related SAEs. Two pts (10%) in B and 1 (6.3%) in C2 required dose reductions for TRAEs. TRAEs associated with permanent discontinuation of treatment occurred in 1 pt in A1, A2, C2 and D. Overall, 3 pts had partial responses with durations of 96, 17 and 17 wks; 25 pts had stable disease. Conclusions: Systemic exposures of crizotinib in pts with mild HI receiving 250 BID and in pts with moderate HI receiving 200 mg BID are comparable with that of pts with normal hepatic function at 250 mg BID. All TRAEs were manageable across the various levels of hepatic function. Clinical trial information: NCT01576406. [Table: see text]
Telemedicine Eyed for Mental Health Services
Authors: Mike Mitka
Journal: JAMA (2003)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
TERT promoter mutations in progressive treatment-resistant meningiomas.
Authors: Tareq A. Juratli, Christian Thiede, Dietmar Krex, Priscilla Kaliopi Brastianos, Hiroaki Wakimoto, Gabriele Schackert, Matthias Kirsch, Daniel P. Cahill
Journal: Journal of Clinical Oncology (2017)

2047 Background: Recurrent meningiomas often undergo a grade-progression to become atypical or malignant upon recurrence. Detailed study of progressive meningioma has been hampered by the lack of available paired specimens. Here, we sequenced the TERT promoter ( TERTp) in a large series of patients with treatment-resistant meningiomas at initial diagnosis as well as their sequential recurrences. Methods: We scored 77 meningiomas from 36 patients for TERTp mutations. All patients in this study developed recurrences during the median follow-up of 13.3 years (range 6.4 - 25.5 years) and underwent three surgeries on average (range 2-8). Additionally, we screened geographically distinct sites of all TERTp-mutant meningiomas to interrogate intratumoral heterogeneity. Results: TERTp mutations were detected in 18 tumor samples (18/77 = 23.3%) from 12 patients, but not in any of the matched blood sample DNAs, excluding germline mutations. Notably, the TERTp mutations were absent in the initial lower-grade tumor and were present in the subsequent recurrent tumors. Moreover, we observe emergent spatial heterogeneity in the form of mixed populations of recurrent tumor cells containing different mutation status of the TERT promoter gene in three cases. Patients with emergence of TERTp -mutant meningiomas had a significantly shorter overall survival than their TERTp wild-type counterparts, when measured from the time of initial diagnosis (2.4 vs 11.1 years, 95% CI 0.25-4.54 vs 9.3- 16.8 years p = 0.007). Conclusions: Our data confirm the high frequency of TERTp mutations and the emergence of TERT promoter mutation in recurrent progressive meningiomas, strongly indicating the presence of ongoing evolution impacting the natural history of these tumors. TERTp mutations are mostly associated with poor outcome. Finally, our study provides important insight into the complexity of tumor heterogeneity and has important implications for targeted therapy in treatment-resistant meningiomas.
Traitement endoscopique des patients présentant une polypose duodénale sévère dans le cadre de la polypose adénomateuse familiale
Authors: D Moussata, B Napoleon, B Parmentier, MJ Lapalus, S Nancey, JC Cenni, C Partensky, T Ponchon, JA Chayvialle, JC Saurin
Journal: Endoscopy (2005)

Rationnel Dans la polypose adénomateuse familiale (PAF), le traitement de référence d'une polypose duodénale sévère (stade IV de la classification de Spigelman) est la duodénopancréatectomie céphalique. La morbidité et la mortalité de cette approche justifient l'évaluation d'alternatives, en particulier le traitement endoscopique. Le but de notre travail a été d'évaluer l'efficacité et les risques d'une prise en charge endoscopique multimodale de patients présentant un polypose duodénale sévère.
Neoadjuvant cisplatin and doxorubicin in locally advanced triple negative breast cancer.
Authors: Abdul Mateen, Allah Rakha Adil, Rab Nawaz Maken, Quratul Ain Hashmi, Famya Abdullah, Arif Moin Duraishi
Journal: Journal of Clinical Oncology (2016)

e12511 Background: Triple negative breast cancer (TNBC) is common in Pakistan and presents in advanced stage due to aggressive behavior. Neoadjuvant chemotherapy (NACT) is usual therapy before local surgical treatment. Choice of chemotherapy (CT) is in a process of refinement for these patients. Platin based CT has shown promising results. Due to limited resources, cost of drugs does matter for treating poors. We have tested inexpensive CT with cisplatin and doxorubicin to see outcome in this population. Methods: All patients had biopsy proven locally advanced invasive TNBC without evidence of metastatic disease on imaging (CT chest, abdomen and bone scan). All patients were planned for treatment with cisplatin (60 mg/m2) and doxorubicin (50 mg/m2) every three weekly for six cycles. The patients were evaluated after every two cycles for response using Response Evaluation Criteria in Solid Tumors (RECIST). A patient showing progressive disease (PD) or having developed grade III or IV toxicity (according to Common Toxicity Criteria Version 3.0) was excluded from study and shifted to other CT. After completion of planned CT , patients underwent surgical treatment followed by locoregional radiation therapy. The primary end point was to assess response rate and disease free survival (DFS). Complete response (CR), partial response (PR), stable disease (SD) and PD were assessed using RECIST criteria. The patients with recurrent disease during the follow up were offered further CT regimen. As a secondary end point overall survival (OS) was also assessed. Results: A total of 143 patients were enrolled. 13 patients (9%) progressed during NACT and were excluded. 130 patients were evaluable for response assessment, DFS and OS. 23 (18%) patients showed CR, 72 (55%) showed PR and 35 (27%) showed SD. Five year DFS and OS were 34% and 52% respectively. Mean and median DFS (year) were 3.55±0.14 (95% confidence interval [CI] 3.28 to 3.83) and 3.13±0.19 (95% CI 2.76 to 3.51) respectively. Mean OS was 4.40±0.13 (95% CI 4.15 to 4.65). No grade III or IV acute toxicity was observed during CT. Conclusions: NACT with cisplatin and doxorubicin is effective in locally advanced TNBC. A larger randomized trial is warranted to clearly define its role in routine practice.
TCT-703 Comparison of 5 Years Clinical Outcome of Drug-Eluting Stent Implantation in High-Angled (≥70°) Bifurcation and Lower-Angled (≤70°) Bifurcation Lesion of Unprotected Left Main Coronary Arteries
Authors: Sunao Nakamura, Shotoro Nakamura, Hisao Ogawa, Jang-Ho Bae, Yeo Cahyadi, Wasan Udayachalerm, Damras Tresukosol, Sudaratana Tansuphaswadikul
Journal: Journal of the American College of Cardiology (2012)
Uric acid promotes vascular stiffness, maladaptive inflammatory responses and proteinuria in western diet fed mice
Authors: Annayya R. Aroor, Guanghong Jia, Javad Habibi, Zhe Sun, Francisco I. Ramirez-Perez, Barron Brady, Dongqing Chen, Luis A. Martinez-Lemus, Camila Manrique, Ravi Nistala, Adam T. Whaley-Connell, Vincent G. Demarco, Gerald A. Meininger, James R. Sowers
Journal: Metabolism (2017)
Endoscopie oeso-gastro-duodénale (EOGD): analyse de pratique médicale concernant la qualité de l'information notifiée sur la feuille de prescription de l'EOGD
Authors: B Kaliszan, J Soulé, T Vallot, S Matheron, J Lucet, M Mignon
Journal: Endoscopy (2005)

Tant la charge de travail des Gastroentérologues hospitaliers que les exigences concernant la qualité des soins ne cessent de croître. Pour améliorer la qualité des informations fournies lors d'une prescription d'EOGD, une feuille standardisée, élaborée par le SHGE et CED, validée par la CE locale, a été distribuée aux Services cliniques du CHU-BCB début 2002.
KEYNOTE-119: A randomized phase III study of single-agent pembrolizumab (MK-3475) vs single-agent chemotherapy per physician's choice for metastatic triple-negative breast cancer (mTNBC).
Authors: Eric P. Winer, Thao Dang, Vassiliki Karantza, Shu-Chih Su
Journal: Journal of Clinical Oncology (2016)

TPS1102 Background: Pembrolizumab is a humanized monoclonal antibody against PD-1 that blocks the PD-1–ligand interaction, allowing activation of antitumor immune response. In the phase 1b KEYNOTE-012 study, pembrolizumab showed promising antitumor activity and manageable safety in heavily pretreated patients with mTNBC, supporting further evaluation of pembrolizumab in these patients. The randomized, global phase III KEYNOTE-119 study (NCT02555657) was designed to compare the efficacy and safety of pembrolizumab monotherapy with those of investigator’s choice chemotherapy in patients receiving second-line or third-line treatment for mTNBC. Methods: Eligible patients must have centrally confirmed TNBC, have received 1 or 2 prior systemic treatments for metastatic breast cancer, have documented progression on most recent therapy, and have been previously treated with an anthracycline and/or a taxane. Patients are randomly assigned 1:1 to receive pembrolizumab 200 mg Q3W or single-agent chemotherapy per investigator’s choice: capecitabine, eribulin, gemcitabine, or vinorelbine. Randomization is stratified by PD-L1 tumor status and history of prior neo/adjuvant treatment versus de novo metastatic disease at initial diagnosis. Treatment will continue for 35 cycles or until progressive disease (PD), unacceptable toxicity, or patient/investigator decision. Response will be assessed every 9 wk up to 1 yr after randomization, and every 12 wk thereafter, based on RECIST v1.1 per central review and RECIST adapted for immunotherapy response patterns. Clinically stable patients may continue treatment until PD confirmation at least 4 wk after initial evidence of progression. AEs will be assessed throughout treatment and for 30 d thereafter (90 d for serious AEs) and graded per NCI CTCAE v4.0. After progression, patients will be followed for survival every 3 mo. Primary end points are OS and PFS based on RECIST v1.1 by central review; secondary end points include safety, ORR, duration of response, and disease control rate. Enrollment in KEYNOTE-119 will continue until ~600 patients have enrolled. Clinical trial information: NCT02555657.
IMpassion130: a Phase III randomized trial of atezolizumab with nab-paclitaxel for first-line treatment of patients with metastatic triple-negative breast cancer (mTNBC).
Authors: Leisha A. Emens, Sylvia Adams, Sherene Loi, Andreas Schneeweiss, Hope S. Rugo, Eric P. Winer, Carlos H. Barrios, Veronique Dieras, Juan de la Haba-Rodriguez, Luca Gianni, Stephen Y. Chui, Peter Schmid
Journal: Journal of Clinical Oncology (2016)

TPS1104 Background: Treatment for mTNBC is limited, with chemotherapy the mainstay (bevacizumab is approved in > 80 countries). Atezolizumab (atezo; MPDL3280A), a humanized anti-PDL1 antibody, inhibits PD-L1 binding to PD-1 and B7.1 but leaves PD-L2/PD-1 binding intact. mTNBC has high levels of tumor-infiltrating immune cells, increased PD-L1 expression and high mutation rates that may generate immunogenic neoantigens, making it a good candidate for PD-L1–targeted therapy. It is hypothesized that atezo's single-agent activity in TNBC could be enhanced with chemotherapy by exposing the immune system to high levels of tumor antigens and modulating T-cell and NK cell functions. Nab-paclitaxel (pac) has high antitumor activity that may favorably alter the immune microenvironment, and atezo + nab-pac resulted in promising activity and tolerable safety. A Phase III multicenter, randomized, double-blind, placebo-controlled trial (IMpassion130) has been initiated to evaluate atezo + nab-pac in first-line mTNBC. Methods: Patients (pts) will be randomized 1:1 to receive atezo (840 mg) or placebo on days 1 and 15 plus nab-pac (100 mg/m2) on days 1, 8 and 15 of a 28-day cycle. Stratification factors include presence of liver metastases and prior taxane therapy. Pts will have histologically documented locally advanced TNBC or mTNBC, no prior systemic therapy for advanced TNBC, ECOG PS 0–1 and measurable disease (RECIST v1.1). Pts with known CNS disease (except asymptomatic treated metastases), autoimmune disease or prior immune checkpoint blockade therapy are excluded. Coprimary endpoints include progression-free survival (PFS) and overall survival (OS). Other endpoints include response rate and duration and safety. Tumor biopsies will be obtained at baseline and progression to assess biomarkers of response and immune escape. PD-L1 expression will be centrally evaluated using the SP142 IHC assay. PFS and OS will be compared between study arms using the stratified log-rank test. Hazard ratios for progression or death will be estimated with a stratified Cox proportional hazards model. This trial will enroll 900 pts at > 270 sites globally. Clinical trial information: NCT02425891.
Treatment Outcomes and Prognostic Factors of Patients with Relapsed Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Yunsuk Choi, Jung-Hee Lee, Kyoo-Hyung Lee, Han-Seung Park, Eunji Choi, Sun-Hye Ko, Miee Seol, Young-Shin Lee, Young-Ah Kang, Mijin Jeon, Je-Hwan Lee
Journal: Blood (2016)
Discussing human papilloma virus vaccination
Authors: Yan Ling Quah, Ieera Madan Aggarwal
Journal: BMJ (2017)

#### What you need to know

A mother and her 15 year old daughter come to your clinic. The mother’s other daughter, who is 12 years old, recently received the human papilloma virus (HPV) vaccine at school. The mother wants to know whether her 15 year old daughter who missed her HPV vaccination should receive it now.

HPV is sexually transmitted. Infection is often asymptomatic. In some people, however, HPV infection persists and over time leads to genital warts or cancer, mainly cervical, but also anal, penile, oral, and throat cancers (fig 1⇓). The HPV types 16 and 18 together cause 70% of cervical cancers.1234



Fig 1  Sequelae of HPV infection and preventive strategies



Prophylactic vaccines against HPV are offered as part of the national immunisation programme in many countries including in the UK.1 These vaccines generate HPV-specific antibodies that bind to the virus and prevent cervical infection. Table 1⇓ shows the three types of vaccines available.

View this table:

Table 1 
Types of HPV vaccines2



Vaccination coverage globally has been variable. Surveys among parents find that the most common reasons for not vaccinating their child include lack of knowledge about the vaccine, a belief that it is not needed, their child is not sexually active, and concerns about safety.678 A healthcare provider’s recommendation is an important factor in parents’ …
Universal BRCA testing of TNBC and HGSOC and active family outreach to increase identification of at-risk relatives for cascade testing.
Authors: Kimberly I. Muse, Erica Bednar, Trisha S Emborgo, Holly D. Oakley, Jennifer Keating Litton, Susan K. Peterson, Karen H. Lu, Banu Arun
Journal: Journal of Clinical Oncology (2016)

1590 Background: Triple negative breast cancer (TNBC) and high grade serous ovarian cancer (HGSOC) are cancer types highly enriched for BRCA germline mutations. Universal BRCA testing of these patients allows for targeted therapies and the identification of at-risk relatives (ARR) who may benefit from cascade testing (predictive testing) and cancer prevention. Recognizing the importance of disseminating positive genetic test results, we developed the REACH (Research, Education, and Awareness of Cancer family History) registry and report on the number of ARR. Methods: The REACH registry began enrollment in 2014. BRCA positive TNBC and HGSOC probands were asked to provide contact information for ARR. Study personnel initiated the family outreach module (FOM) through the use of questionnaires and an interactive web-based platform. The FOM allowed participants to access educational videos, connect to ARR, and find resources to undergo cascade testing. Pedigree data for each proband was used to identify all living ARR eligible for cascade testing and the REACH registry. Descriptive statistics were used to summarize the data. Results: 195 probands were enrolled in the REACH registry: 106 TNBC, 82 HGSOC, and 7 with both. 149/195 (76.4%) agreed to participate in the FOM. 94 probands provided contact information for 224 ARR: 189 1st degree relatives (FDR) and 35 2nddegree relatives (SDR). Of the 224 ARR, 60 enrolled in the REACH Registry. Study personnel conducted pedigree review for probands and identified 1,345 ARR: 611 FDR and 734 SDR. Probands reported an average of 2.4 ARR, while the pedigree review identified an average of 9.0 ARR. Conclusions: The REACH registry FOM revealed a four-fold increase of identified ARR, suggesting that proband report was not sufficient in determining ARR. Active outreach and pedigree review identified more ARR eligible for cascade testing and ultimately cancer prevention. Coupled with universal testing, our FOM has the potential to be applied to other patient care settings and reduce the incidence of breast and ovarian cancer in BRCA positive families.
Quantifying the benefit of chemotherapy and radiation in low-grade glioma: A systematic review and meta-analysis of numbers needed to treat.
Authors: Timothy J Brown, Daniela Annenelie Bota, Elizabeth A. Maher, Dawit Gebremichael Aregawi, Linda M. Liau, Paul D. Brown, Jan C. Buckner, Michael Weller, Martin J. Van Den Bent, Mitchel S. Berger, Michael J. Glantz
Journal: Journal of Clinical Oncology (2017)

2057 Background: The optimal role of chemotherapy and radiation (RT) in adult low-grade glioma (LGG, WHO grade 1 &amp; 2) is unclear. We conducted a systematic review and study-level meta-analysis of the literature on overall survival (OS) and progression free survival (PFS) in patients with LGG. Methods: Pubmed was queried with MeSH terms. All comparative studies of adults with newly diagnosed, supratentorial LGG were included. Comparisons of interest were OS and PFS at 2, 5, and 10 years in chemotherapy versus no chemotherapy and early RT versus delayed or no RT. Data were extracted from studies and synthesized with a random effects model. Quality of evidence was determined by American Academy of Neurology criteria and further analysis was performed, separating high quality (class I and II) from low quality (class III and IV) evidence. Numbers needed to treat (NNT) were determined from the risk difference. Results: 1531 articles were screened; 18 studies were included. Chemotherapy was not associated with a significant survival advantage compared to control. However, an analysis of high quality data revealed a survival advantage at 10 years associated with chemotherapy compared to control with NNT 5 (relative risk death chemo vs control 0.69 [0.56-0.86] p = 0.0006). Furthermore, NNT to prevent one progression with chemotherapy at 5 and 10 years was 6 and 3, respectively. Early RT was not associated with an OS advantage compared to control. However, early RT had progression benefit at all time points, with NNT of 10, 6, and 5 at 2, 5, and 10 years. Conclusions: Further study will be needed to confirm the optimal role of chemotherapy and RT. Caution must be used in interpretation as much of the literature consists of low-quality studies. [Table: see text]