tbuckley/cabot-search huggingface dataset:
A phase II study of ribociclib in men with unresectable, incurable teratoma with recent progression.
Authors: Daniel E. Castellano, David I. Quinn, Darren R. Feldman, Karim Fizazi, Xavier Garcia del Muro, Jourik A. Gietema, Richard C. Lauer, Mary Elizabeth Ising, Mehreteab Aregay, Adam Samuel Crystal, David J. Vaughn
Journal: Journal of Clinical Oncology (2019)

517 Background: Most patients with teratoma are managed by surgery and no standard medical therapy exists for progressive and/or unresectable teratoma. Teratomas have functional expression of retinoblastoma protein and clinical activity was observed with CDK4/6 inhibition (Vaughn DJ, et al. Cancer. 2015). Here, we report results with the CDK4/6 inhibitor ribociclib (RIBO) for unresectable teratoma. Methods: This multicenter, double-blind study enrolled patients (pts) ≥ 15 years old with unresectable, progressive teratoma without malignant transformation, ECOG PS 0-1, and ≥ 1 line of prior chemotherapy. Pts were randomized (2:1) to receive RIBO (600 mg/day, 3 weeks on/1 week off) or placebo (PBO). Crossover to RIBO was permitted following progressive disease (PD) on PBO. The primary endpoint was progression-free survival (PFS). Secondary endpoints included additional efficacy measures, safety, and tolerability. Results: The trial was closed prematurely in the setting of slow accrual. Ten pts were randomized (8 to RIBO, 2 to PBO). Median age was 33 years (range, 21-53). All pts received study treatment, and both pts in the PBO arm crossed over to RIBO following PD. Median exposure was 385 days for RIBO and 166 days for PBO. The PFS rates at 24 months were 71% and 0% in the RIBO and PBO arms, respectively. All 8 pts in the RIBO arm had stable disease (SD) as best response at first evaluation. In the PBO arm, 1 pt had best response of PD and the other SD with durations of treatment of 78 and 254 days, respectively. After crossover, both pts received RIBO, with a best response of SD, and durations of treatment of 943 and 133 days, respectively; the former entered a rollover protocol and the latter discontinued treatment due to an adverse event. The most common reason for discontinuation in both groups was PD. Grade ≥ 3 adverse events in the RIBO group included neutropenia and non-cardiac chest pain in 2 pts, and headache, decreased appetite, asthenia, fatigue, vomiting, and increased blood creatinine in 1 pt each; all but non-cardiac chest pain were suspected to be drug related. Conclusions: In this rare clinical setting, with a limited small sample size, RIBO prolonged PFS as compared to PBO and no new safety signals emerged. Clinical trial information: NCT02300987.
GP who failed to act on red flags for cauda equina syndrome breached duty
Authors: Clare Dyer
Journal: BMJ (2019)

A GP breached his duty to a 35 year old out-of-hours patient in failing to note red flag warning signs for cauda equina syndrome and to refer her urgently to hospital, a High Court judge has ruled.1

Andrew Stead could not remember his consultation with Kerry Shaw in 2013 but had written “no red flags” in his notes. But Mrs Justice Yip accepted the evidence of Shaw and her husband that she did have red flag symptoms or signs that the GP should have elicited.

Cauda equina syndrome is a rare and severe narrowing of the spinal canal usually caused …
Discovery of targetable mutational signatures in advanced prostate cancer (aPC) using machine learning and next-generation sequencing (NGS) of circulating tumor DNA (ctDNA).
Authors: Edwin Lin, Andrew W Hahn, Guru Sonpavde, Michael B. Lilly, Roberto Nussenzveig, Elisa Ledet, Sumanta K. Pal, Petros Grivas, Thereasa A. Rich, Victoria M. Raymond, A. Oliver Sartor, Mark Yandell, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2019)

226 Background: Alterations (alts) of the AR gene are common in aPC and are associated with reduced responses to AR-axis inhibitors; optimal treatment is unknown. Genomic sequencing of ctDNA from aPCs may recapitulate truncal and branching alts across metastatic sites in heavily pretreated progressive aPC and facilitates identification of AR and other alts that contribute to aPC progression. Such data could lead to better understanding of aPC molecular biology and guide development of novel treatments. Methods: Two unsupervised machine learning algorithms, hierarchical clustering and principal components analysis, were used to evaluate mutational profiles of 2,679 plasma samples from 2,309 men with aPC. Samples were assessed by a validated ctDNA NGS panel that sequences 73 clinically relevant cancer genes (Guardant360, Redwood City, CA). Indels, amplifications, and fusions are evaluated in a subset of genes with high sensitivity and specificity. Chi-squared residual analysis and gene ontology enrichment were used to identify significantly co-altered molecular pathways. Results: Distinct, non-overlapping mutational signatures were observed in tumors with only AR amplification (amp) vs. only AR mutation (mut). Tumors with only AR amp, and those with both AR amp and mut, were strongly enriched for amps in the MAPK pathway (P = 3.62E-10, 4.92E-05, resp.). Tumors with only AR mut, and those with no AR alts, were strongly enriched for muts in negative regulators of cell proliferation (P = 1.09E-05, 3.30E-09, resp.). Muts further stratified to oxidative stress response in AR mut (P = 4.37E-05), and cell aging in no AR alts (P = 8.31E-07). Conclusions: In men with aPC, machine learning of ctDNA NGS data revealed recurrent mutational signatures that stratified according to the type of AR alts. These hypothesis-generating data require external validation but suggest that aPC may progress due to distinct mechanisms dependent on AR status. Future efforts to develop novel therapeutic approaches for aPC may need to consider the impact of the type of AR alt present and explore the interplay of AR with other altered pathways identified in this analysis.
Advance Care Planning Codes—Getting Paid for Quality Care
Authors: Ankita Mehta, Amy S. Kelley
Journal: JAMA Internal Medicine (2019)

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
Collection of grade 3/4 adverse event (AE) data in a subgroup of patients in cancer clinical trials supporting supplemental indications: A comprehensive analysis.
Authors: Rajeshwari Sridhara, Huanyu Chen, Yun Wang, Sirisha Mushti, Sean Khozin, Virginia Ellen Maher, Richard Pazdur
Journal: Journal of Clinical Oncology (2015)

e17640 Background: Comprehensive collection of safety data in clinical trials provides a complete AE profile of therapies at a significant cost. Kaiser et al (JCO 2010; 28:5046-5053) proposed a sample-based safety data collection approach to collect Grade 3/4 AE data in a subgroup of patients in supplemental indications. We conducted analyses to evaluate sample-based estimates of AE rates compared to observed overall (“true”) AE rates in treated patients. Methods: We identified 38 randomized clinical trials (RCTs) in non-hematologic malignancies that were submitted to the USFDA for supplemental indication approval of products with established safety profiles from their initial approval. We examined the impact of five different sample selection methods (two random and three purposive) and a range of sample sizes on estimation of AE rates. Sample selection methods included simple random sampling of patients (SRS), simple random sampling of accruing site (RSS), sampling by randomization date (SRD), sampling from largest and smallest accruing sites (LSS), and sampling from largest accruing sites (LS). We examined samples sizes of 100, 150, 200, 250 and 300 each in treatment and control arms. Repeated samples were obtained using SRS and RSS. Results: A total of 70,748 grade 3/4 AEs were analyzed. Trial sizes of 38 RCTs ranged from 2219 to 403 subjects with true grade 3/4 AE rates of 0% to 70%. The sample-based AE rates were closer to true AE rates as sample sizes increased with each method. SRS and RSS estimates were close to the true AE rates with sample size of 100 in each of the treatment and control arms. However, with purposive sampling using SRD, LSS or LS, at least 300 per arm was necessary to get reasonable estimates of true AE rates, except when the overall study size was < 600. SRS performed the best and LS the worst in estimating true AE rates. Conclusions: A random sampling approach can give reasonable estimates of true AE rates in RCTs. However, this approach may not significantly reduce cost as data on all patients are needed to select a random sample. Selecting the first ≥ 300 patients randomized per treatment arm (SRD) gives reasonable estimates of true AE rates.
A good response of refractory mantel cell lymphoma to haploidentical CAR T cell therapy after failure of autologous CAR T cell therapy
Authors: Tongjuan Li, Yuanyuan Zhang, Dan Peng, Xia Mao, Xiaoxi Zhou, Jianfeng Zhou
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> The aggressive form of Mantle cell non-hodgkin B cell lymphoma (MCL) has a dismal prognosis. Dual targeting BTK and BCL2 with ibrutinib and venetoclax has improved outcomes in MCL patients who were predicted not to respond to conventional therapy, but it is unlikely to be curative. Chimeric antigen receptor-modified T (CAR T) cells exhibit very effective function in elimination of relapsed/refractory B-cell lymphoid malignancies, we investigated their use in a patient with relapsed MCL. <h3>Case presentation</h3> Here, we report a case of a refractory MCL in a patient who had relapsed after conventional chemotherapy and autologous CAR T cell therapy. The patient received multiple molecularly targeted therapies, including targeting BTK and BCL2, and haplo-identical CAR T (haplo-CAR T) cells from her daughter without previous allo-hematopoietic stem cell transplantation. Haplo-CAR T cells could effectively proliferate in vivo and had a clinically significant antitumor activity without serious side effects. The patient achieved a partial remission, with minimal residual disease. <h3>Conclusions</h3> This case suggests that haplo-CAR T cell therapy can be effective in controlling lymphoma that failed to respond to autologous CAR T cell therapy and overcome limitation of autologous CAR T cells, thus may be one possible regimen before the era of off-the-shelf "universal" CAR T cell therapy. <h3>Trial registration</h3> ChiCTR-OPN-16008526. http://www.chictr.org.cn/showproj.aspx?proj=13798; ChiCTR1800019385. http://www.chictr.org.cn/showproj.aspx?proj=32805; ChiCTR1800019449. http://www.chictr.org.cn/showproj.aspx?proj=32778.
The green tea polyphenol EGCG blocks H. pylori-induced scattering of gastric carcinoma cells, a process dependent on the activation of PI3K, p38 MAPK, and Rac1 pathways
Authors: Jared L. Snider, Bryan Bellaire, James Cardelli
Journal: Cancer Research (2004)

1852  Helicobacter pylori has been implicated in gastric cancer, although the signaling pathways altered by this bacterium remain to be determined. Virulent strains (Type I) inject the cytotoxin-associated gene (Cag) A protein into gastric epithelial cells, causing them to become motile and scatter, a change important for invasive tumor cells. In order to determine which signaling components were involved in H. pylori-induced scattering, phospho-specific antibodies were used to probe western blots of lysates of AGS cells exposed to Type I H. pylori. As early as 30 minutes following exposure to bacteria, the levels of phosphorylated Erk, JNK, Akt, and p38 significantly increased. Additionally, induced levels of Erk-P, JNK-P, and Akt-P were sustained for 12 hours. Next, a pharmacological approach was used to determine which pathways were necessary for H. pylori-induced scattering. AGS cells pretreated with the inhibitors LY294002 or SB203580 prior to the addition of Type I H. pylori did not scatter, indicating that PI3-kinase and p38 MAP kinase pathways are necessary for this event to occur. Inhibition of the MAPK pathway using U0126 did not prevent bacterially-induced scattering.To determine if Rho family GTPases regulated scattering, AGS cells were transiently transfected with dominant negative (DN) or constitutively active (CA) forms of RhoA, Rac1, and Cdc42. Only expression of DN-Rac1 prevented H. pylori-induced scattering, demonstrating that this GTPase was necessary for scattering, although expression of CA-Rac1 was not sufficient to induce scattering in the absence of bacteria. The Met receptor has previously been shown to play an important regulatory role in tumor progression and metastasis. Exposure of AGS cells to Type I H. pylori induced Met phosphorylation by 30 minutes after the addition of bacteria, and high levels of phosphorylated Met were observed for at least 12 hours. In addition, the level of Met protein increased, beginning 6 hours after the addition of bacteria. Met phosphorylation is associated with scattering and invasion of other cancer cells, including DU145 prostate cancer cells. Interestingly, DU145 cells were induced to scatter by H. pylori in a protein synthesis-independent manner, while the Met ligand, HGF, induced scattering dependent on protein synthesis; HGF does not induce scattering in AGS cells. These results suggest that H. pylori- and HGF-induced scattering occur through distinct pathways. Finally, a large number of animal and epithelial studies support a role for the green tea polyphenol epigallocatechin 3-gallate (EGCG) in the prevention of cancer progression. Pretreatment of AGS cells with physiologically relevant levels of EGCG blocked H. pylori-induced scattering. Current studies are designed to study the nature of the bacterially induced pathways contributing to scattering inhibited by EGCG.
Impact of surgeon volume on outcomes of older stage I lung cancer patients treated via video-assisted thoracoscopic surgery.
Authors: Cardinale B. Smith, Andrea S Wolf, Grace Mhango, Juan P. Wisnivesky
Journal: Journal of Clinical Oncology (2015)

e17630 Background: Surgeon procedure volume has been shown to influence patient outcomes for several types of cancer operations. Limited data is available however, for the volume-outcome relationship for video-assisted thoracic surgery (VATS) for the treatment of non-small cell lung cancer (NSCLC). In this study, we used population-based data to evaluate the extent to which surgeon volume is associated with postoperative and long-term oncologic outcomes following VATS resection for older patients with early stage NSCLC. Methods: We identified 2,295 patients with stage I NSCLC patients > 65 years treated with VATS lobectomy, segmentectomy or wedge resection from the Surveillance, Epidemiology, and End Results registry linked to Medicare claims. Surgeon volume was ascertained based on the number of Medicare cases resected within each year and grouped into tertiles (low, intermediate, and high). Overall and lung cancer-specific survival of patients treated with VATS vs. open segmentectomy was compared after adjusting patients based on their propensity score. We performed secondary analyses evaluating perioperative complications, need for intensive care unit (ICU) admission, extended length of stay, and perioperative mortality. We then repeated these comparisons adjusting for physician characteristics. Results: Overall (hazard ratio [HR]: 0.73, 95% CI: 0.62-0.87) and lung cancer-specific (HR: 0.76, 95% CI: 0.58-0.99) survival was significantly better among those treated by high volume surgeons after adjusting for propensity scores. Patients treated by high volume surgeons had lower rates of ICU admission (p = 0.02), thromboembolic complications (p = 0.03) and respiratory complications (p = 0.002). The distribution of all postoperative complications, requirement for ICU admission, extended length of stay, and perioperative mortality was not significantly different across groups after adjusting for surgeon characteristics. Conclusions: Elderly stage I NSCLC patients undergoing VATS by high-volume surgeons have better survival outcomes compared to those undergoing surgery by lower volume surgeons.
Communication with children and adolescents about the diagnosis of a life-threatening condition in their parent
Authors: Louise Dalton, Elizabeth Rapa, Sue Ziebland, Tamsen Rochat, Brenda Kelly, Lucy Hanington, Ruth Bland, Aisha Yousafzai, Alan Stein, Theresa Betancourt, Myra Bluebond-Langner, Catherine D'Souza, Mina Fazel, Kim Fredman-Stein, Emily Harrop, Daniel Hochhauser, Barbara Kolucki, Aoife C Lowney, Elena Netsi, Linda Richter
Journal: The Lancet (2019)
Somatic Mutations in T Cells As Possible Regulators of Immunodeficiency
Authors: Paula Savola, Timi Martelius, Matti Kankainen, Yrjö Koski, Samuli Eldfors, Jani Huuhtanen, Tiina Kelkka, Sofie Lundgren, Pekka Ellonen, Panu Kovanen, Soili Kytölä, Mikko Seppänen, Satu Mustjoki
Journal: Blood (2018)
Thyroid atrophy in patients receiving sunitinib or pazopanib for the treatment of advanced renal cell carcinoma: A common but under-reported toxicity.
Authors: James Albert Bennett, Eirini Vrentzou, Georgina Elizabeth Wood, Arnold Eric Conrad Drury, Thomas Richard Geldart
Journal: Journal of Clinical Oncology (2015)

e15577 Background: Sunitinib (Su) and Pazopanib (Pa) represent standard first line treatment options for patients with metastatic Renal Cell Carcinoma (mRCC). Hypothyroidism is commonly reported but the incidence of thyroid atrophy is unknown and is rarely reported. Methods: We retrospectively reviewed case notes and serial CT images from all patients undergoing at least 6 months first line treatment for mRCC with Su or Pa between 1.5.07 and 31.5.14, for whom thyroid volume (mm3) could be assessed. Thyroid volumes were evaluated using Livewire segmentation on a single 1 mm slice at a matched level for all scans and change in size over time was estimated. Baseline demographics, Heng prognostic group and outcomes were collated. Results: 66 patients were identified that met all study entry criteria. 49/66 (74%) were male, 17/66 (26%) female, median age 67 (range 36-78 yrs). 13/66 (20%) had good (G), 35/66 (53%) intermediate (I) and 18/66 (27%) poor (P) prognostic disease by Heng criteria at initiation of treatment. 53/66 (80%) received Su and 13/66 (20%) Pa. At data cut-off, 20/66 (30%) remain on first line treatment. 37/66 (56%) have died. Median time on treatment was 20 months (range 6-NR); median overall survival was 39 months (range 7-NR), with survival estimates in the G, I and P groups of 63, 31 and 28 months respectively by Kaplan-Meier analysis. Changes in thyroid volume were grouped into stable (S; +20% to -20% compared to baseline), moderate atrophy (Mo; > 20-50%) and major atrophy (Ma; > 50%). Overall, 25/66 (38%) developed Mo (12/66; 18%) or Ma (13/66; 20%) reduction in thyroid volume (range 21-82%). Median treatment duration in the Ma group was over 2.5 times that of the S group (48 v 18 months; p = 0.01), with maximal atrophy seen late in the course of treatment (69% of patients had received > 80% delivered treatment). Further statistical analysis evaluating outcomes related to thyroid atrophy in association with other prognostic factors will be reported. Conclusions: Thyroid atrophy is common and is seen in more than one-third of patients receiving first line treatment with Su or Pa for over 6 months. There is an increased incidence of thyroid atrophy with longer exposure to treatment.
Effectiveness of Kuska Tele-Wasi, a home blood-pressure telemonitoring system for hypertension control in Lima, Peru: a randomised controlled trial
Authors: Renzo Calderon-Anyosa, Mabel Raza Garcia, Cesar Carcamo Cavagnaro, Patricia Garcia
Journal: The Lancet Global Health (2019)

BackgroundHypertension is one of the leading causes of death worldwide, yet despite this disease being a known public health challenge, fewer than a third of patients with hypertension achieve blood-pressure control. In this study, we describe an easy to use and affordable home blood-pressure telemonitoring system —Kuska Tele-Wasi, from the Quechuan words for "working together" and "home". We aimed to compare hypertension control in patients using this blood-pressure telemonitoring system with that in a control group.MethodsWe recruited adult patients with hypertension from a primary health-care centre in Lima, Peru, to participate in our study. We included participants with uncontrolled blood pressure and who were taking pharmacological treatment for hypertension. Participants were randomly allocated to either an intervention group or control group. Patients in the intervention group used a home blood pressure telemonitoring device that sends readings via short messaging service (SMS) to primary care centres for health providers to use for decisions about treatment, office visits, and follow-up. Patients in the intervention group used the system for 2 weeks and were followed up for 2 more weeks at the primary care centre. In the control group, patients continued with the usual monitoring (clinic visits or patient-initiated monitoring at pharmacies) for 4 weeks. Primary outcome was the change in systolic and diastolic blood pressure from baseline to the end of the study period. The trial is registered at ClinicalTrials.gov (NCT03524456).FindingsWe included data from 19 patients in the intervention group and 19 in the control group; 26 were women and the mean age was 68·1 years (SD 10·8). There was a difference in the change of systolic blood pressure values between the control and intervention group (–7·2 mm Hg [SD 14·9] vs −16·3 mm Hg [16·7]; p=0·09, respectively), and a difference in the change of diastolic blood pressure values (–1·2 mm Hg [6·4] vs −7·2 mm Hg [9·8]; p=0·03, respectively).InterpretationA home blood pressure telemonitoring system based on SMS is effective in reducing blood pressure by working in conjunction with primary care centres. Our findings show that an intervention of this type can work in primary health care centres in an upper-middle income country, and could be an important strategy for the control of arterial hypertension.FundingRunachay: Information and Communication Technologies for Global Health (NIH: 1R25TW009710-01) Masters Program in Biomedical Informatics in Global Health Thesis Funding (UPCH-FondeCyT).