tbuckley/cabot-search huggingface dataset:
Molecular features of gliomas with high tumor mutational burden.
Authors: Joanne Xiu, Kyle M Walsh, Manjari Pandey, Emil Lou, Ekokobe Fonkem, Herbert B. Newton, Erin M. Dunbar, Macarena Ines De La Fuente, Michael J. Glantz, Sandeep Mittal, David M. Ashley, Wolfgang Michael Korn, Ashley Love Sumrall
Journal: Journal of Clinical Oncology (2020)

2549 Background: TMB-H in gliomas is caused by molecular alterations or alkylator treatment- induced genomic changes characterized by a large number of G:C&gt;A:T transitions. Our study describes the molecular features of TMB-H gliomas. Methods: Gliomas were tested with NextGen sequencing (592 genes), MGMT promoter methylation (MGMT-m) fragment analysis and IHC at Caris Life Sciences. Microsatellite instability (MSI) was test by NGS, FA/IHC. The GC:AT transition rate was calculated as the prevalence of G:A and C:T changes seen in each tumor and &gt; 80% was regarded as high transition(TR-H). TMB values were compared using Wilcoxon Rank Sum. TMB-H was defined as the top quartile of all TMB values (TMB&gt;9). Results: TMB in the 3129 gliomas ranged from 0 to 372 mutations/MB (mean: 8.5, median: 6). TMB-H was observed in 31% of glioblastomas, 16% of astrocytomas (astro) (22% of grade III, 7% of grade I/II) and 22% of oligodendrogliomas (oligo) (32% of grade III and 15% of grade I/II). MGMT-m (58% vs. 47%; p=0.0001), pathogenic (p) or likely p (lp) EGFR (14% vs 10%, p=0.004) and PIK3CA mutations (13% vs. 9%, p=0.002), as well as p/lp in 30 other genes were more prevalent in TMB-H cases (p&lt;0.01). In the 613 TMB-H tumors, TR-H was seen in 12% (73) and was strongly associated with increased TMB (median TMB 52 in TR-H vs. 9 in TR-L,) and MSI-H (7.3% vs. 1.1%), both p&lt;0.0001. Tumors with both TR-H and MSI-H had a mTMB of 114 vs. 49 in TR-H /MSS tumors. MSI-H and TR-L tumors had an mTMB of 23 vs. 9 in MSS /TR-L tumors (p&lt;0.0001). All 5 POLE-MT tumors had TMB of &gt;100 (median 264) and TR-L; 4 of the 5 were also MSI-H. PDL1 IHC had no correlation with TMB, MSI or transition rates. In 89 paired samples taken &gt;150 days apart (regardless of intervening treatment), acquisition of TMB-H was seen in 11 pairs: 8 glioblastomas, 2 grade II/III astro and 2 oligo. In the paired tumors that acquired TMB-H status compared to those that did not, a significantly higher prevalence of MGMT-m (82% vs. 37%, p=0.008) and IDH mutation (64% vs. 19%, p=0.004) were seen. 10 of the 11 recurrent tumors with acquisition of TMB-H had TR-H while none in the other 78 pairs. Conclusions: TMB varies significantly in gliomas and associates with POLE, TR-H and MSI-H, but not with an increase of PD-L1. POLE-mutated tumors had the highest TMB levels. TR-H, an indicator of alkylator-induced phenotype, is associated with a higher TMB than MSI-H, however, TR-H may synergize with MSI-H to further increase TMB. Tumors with an IDH mutation and MGMT-m are more prevalent in tumors with high TMB gain. Further understanding of molecular and immune profile of the TMB-H may facilitate more individualized treatment planning.
Frontline brentuximab vedotin in Hodgkin lymphoma and CD30-expressing peripheral T-cell lymphoma for older patients and those with comorbidities.
Authors: Christopher A. Yasenchak, Rodolfo Eduardo Bordoni, Victor Y. Yazbeck, Dipti Patel-Donnelly, Tim Larson, Robert Brownell Sims, Matthew Genyeh Mei
Journal: Journal of Clinical Oncology (2020)

TPS8069 Background: Older patients and those with significant comorbidities have not attained outcomes seen in younger patients with classical Hodgkin lymphoma (cHL) and CD30-expressing peripheral T-cell lymphoma (PTCL). Five-year progression-free survival (PFS) was 30%–45% in older HL patients treated with combination chemotherapy versus 75%–80% in younger patients (Evens 2008; Proctor 2009). Similarly, when adjusted for age, a Charleston Comorbidity Index ≥2 was independently associated with worse overall survival (HR=1.63) and PFS (HR=1.54) (Ellin 2018). Brentuximab vedotin (BV, ADCETRIS), a CD30-directed antibody-drug conjugate, has robust activity in cHL patients refractory to several lines of chemotherapy. BV monotherapy in 27 cHL patients aged ≥60 years had a 92% objective response rate (ORR) and 73% achieved complete remission (Forero-Torres, 2015). BV was also active and well-tolerated in CD30-expressing PTCL patients with relapsed or refractory disease (Horwitz 2014). Frontline BV monotherapy may have the potential to be an active and well-tolerated treatment for cHL and PTCL patients who are older or have significant comorbidities, which are populations with high unmet need. Methods: This phase II, open-label study, SGN35-015 (NCT01716806), has added 2 cohorts to evaluate the efficacy and tolerability of BV monotherapy in treatment naive patients with cHL, (Part E), or CD30-expressing PTCL (Part F, n~50 each) who are unsuitable for conventional combination therapy due to comorbidity-related factors as determined by a Cumulative Illness Rating Scale (CIRS) score ≥10 or dependence on others for any instrumental activities of daily living. Eligible patients must also have an Eastern Cooperative Oncology Group (ECOG) performance status ≤3 and measurable disease ≥1.5 cm per radiographic techniques. BV (1.8 mg/kg) will be administered as a single intravenous infusion on day 1 of each 2-day cycle. Patients achieving a complete remission, partial remission, or stable disease will receive up to 16 cycles of treatment. Response will be assessed by blinded independent central review of spiral CT and PET scans at Cycles 2, 6, 11, and at end of treatment to be graded per Lugano 2014. The primary objective of these cohorts is to assess ORR of frontline therapy with single-agent BV in patients who have significant comorbidities. Clinical trial information: NCT01716806 .
Efficacy of revascularization in oldest-old patients with acute ischemic stroke
Authors: Yuhui Chen, Lei Xu, Jun Lu, Peng Qi, Juan Chen, Tao Gong
Journal: BMJ (2020)

Objective
To analyze the efficacy of revascularization in oldest-old patients with acute ischemic stroke (AIS).


Methods
The clinical data of AIS patients receiving recanalization therapy in Beijing Hospital from January 2010 to July 2018 were retrospectively reviewed. Among 141 patients, there were 34 cases aged ≥80 years (oldest-old group) and 107 cases aged<80 years (old group).The clinical characteristics and outcomes of two groups were analyzed and compared.


Results
The proportions of patients with atrial fibrillation and coronary heart disease in oldest-old group were high than those in the old group [61.8% (21/34) vs. 33.6%(36/107), χ2=8.47, P 0.05). The National Institute of Health Stroke Scale Score (NIHSS) was higher in the oldest-old group than that in old group [16 (13,21) vs. 11 (6,16), Z=3.74, P 0.05]. The 3-month independent (modified Rankin score ≤2) rate was lower in the oldest-old group than that in the old group [35.3% (12/34) vs. 56.1%(60/107), χ2=4.46, P 0.05].


Conclusion
The conditions of AIS patients aged ≥80 years are more serious than those of patients aged<80 years, with higher mortality and lower functional improvement rate after recanalization treatment.


Key words: 
Stroke, ischemic; Thrombolytic therapy; Thrombolysis; Endovascular procedures; Aged, 80 and over
Early rehabilitation for severely burned patients in intensive care unit
Authors: Xiaolin Cui, Jie Zhu
Journal: BMJ (2014)

Objective
To evaluate the efficacy of early rehabilitation for severely burned patients in intensive care unit (ICU).


Methods
One hundred and eighty two severely burned patients were enrolled in the study, including 97 patients receiving early rehabilitation in ICU (rehabilitation group) and 85 patients without early rehabilitation (control group). There were no significant differences in burned surface area, depth and locations between two groups.After one year's treatment, patients were evaluated by the Vancouver Scar Scale (VSS).


Results
The mean VSS score of rehabilitation group was significantly lower than that of control group (3.1±1.2 vs. 5.2±1.3, P<0.05).


Conclusion
Early rehabilitation therapy is beneficial for severely burned patients in ICU.


Key words: 
Burns; Intensive care units; Rehabilitation
Effectiveness of home service in rehabilitation of post-stroke patients on recovering period
Authors: Weiping Xu, Yulan Qiu, Yuchang Liu, Haihua Jin, Meirong Ji
Journal: BMJ (2017)

One hundred and fifty eight post-stroke patients in the recovering period were divided into intervention group (78 cases) and control group (80 cases). Patients in intervention group received home rehabilitation service provided by general practitioners (GP) for 6 months, while patients in control group received routine rehabilitation. After 6-months, the scores of self-rated health measurement scale (SRHMS) in intervention group were significantly higher than those of control group (P<0.01); the visiting time and frequency, medical costs and time of caregiving were decreased (P<0.01); and the satisfaction score of the patients in intervention group was 97%. The results show that home rehabilitation service can improve effectiveness of rehabilitation for post-stroke patient in recovering period.


Key words: 
Physicians, family; Rehabilitation, home care service; Stroke
Cancer types applicable to efficacy assessment using real-world data analyzed from PMDA-approved data.
Authors: Yuka Kato, Chikara Hirase, Ken Hatogai
Journal: Journal of Clinical Oncology (2020)

e19272 Background: Clinical development of anti-cancer agents has been accelerated due to emergence of new therapies. Although randomized comparative trials are the gold standard for the evaluation of clinical utility, it is often impossible to conduct such trials. At ASCO 2019, 89 real-world data (RWD) studies were presented. These studies highlighted the increasing awareness of the value of RWD. We here investigated for which cancer types RWD could be applicable to efficacy assessment based on the previous reviews of Pharmaceuticals and Medical Devices Agency, Japan (PMDA). Methods: Review reports and Summaries of submitted documents publicly available on the website of PMDA and research articles of trials included in the new drug applications of anti-cancer agents approved in Japan between 2006 and 2019 were reviewed. Results: Among 209 anticancer-agents approved for a new indication based on clinical trial (CT) data, 42 agents and 167 agents were approved based on results of single-arm CTs and those of comparative trials, respectively. The numbers of agents for hematological malignancies and solid tumors were nearly same. Among agents approved based on single-arm CT results, most of them (85.7%) were designated for orphan drug (OD), and 1/3 of them were specified for a biomarker (BM), such as ALK fusion gene in non-small cell lung cancer (35.7%). Among 42 single-arm CT-based approvals, a threshold for efficacy endpoint was set at least in one pivotal trial in 30 items based on the following references: (i) results of CTs for the same population (11), (ii) no standard therapy (10), (iii) clinical trial plans of other agents for the same population (7), (iv) others such as values defined by the investigators’ discretion (14). Regardless of BM, only 1/4 had a pre-defined threshold for efficacy evaluation in the pivotal trial based on the results of CTs for the same population. Among 15 BM-related agents, most of them (93.3%) had been designated for OD. Meanwhile, among the agents without biomarker and OD, the setting was (ii) or (iv). Conclusions: RWD could be applicable for efficacy evaluation of BM-related agents with OD designation, agents for BM-unrelated tumor types with no established standard treatment, and agents for those in which drug development has not been advanced enough to set a threshold for efficacy evaluation.
Affording Immune Checkpoint Inhibitors (ICI) in the treatment of advanced non-small cell lung cancer (NSCLC): Argentinean National Cancer Institute (ANCI) perspective.
Authors: Carolina Gabay, Santiago Pesci, Johana Caldano, Maria Celeste Diaz
Journal: Journal of Clinical Oncology (2020)

e19404 Background: ICI agents proved clinical effectiveness in metastatic NSCLC; irrespectively PDL1 expression, but they increase costs considerably. Thus its cost-effectiveness (CE) needs to be established in low and middle-income countries. We aimed to assess CE of Pembrolizumab plus carboplatin and pemetrexed (PCP) vs. carboplatin and pemetrexed (CP) in the first-line setting for non-squamous NSCLC, according to PDL1expresion, in Argentinian public healthcare system (APHS). Methods: Clinical outcomes, utilities, and transition probabilities were collected from the available literature (Keynote 189/024) after a systematic review. The certainty of evidence according to GRADE methodology was qualified as high. A Markov model was developed. Model outcomes were measured in quality adjusted-life-years (QALY) and CE was estimated as the incremental cost-effectiveness ratio (ICER) over a 20 years time horizon. Only direct costs were considered from a public price database of the drugs accounted in the model. The WHO ICER threshold, defined as 1-3 GDP per capita, was selected to established CE. Sensitivity analyses were performed to assess the robustness of results. Results: In PDL1≥ 50 % subgroup, PCP increased life expectancy of patients by 1.06 QALY for an incremental cost of USD 71.551 vs. CP with an ICER of 67.352 per QALY. An indirect comparison of PCP vs. Pembolizumab monotherapy found no differences in QALY estimates, however, it was associated with an incremental cost of USD 5.516. QALY estimate for PDL1 1-49% was 0.73 with an ICER of USD 85.984/ QALY gained. PDL1 &lt; 1% obtained a QALY of 0.42 related to the largest ICER (USD 97.095) for the same comparison. The sensitivity analyses using a threshold between 1- 3 Argentinian GDP per capita in 2018 (USD 11.8602) found that PCP has no chance of being considered CE in untreated NSCLC patients. If a 6 GDP threshold is adopted in PDL1≥ 50 %, PCP would have a 50% possibility of being CE. Conclusions: This model was part of the decision-making process in the development of treatment guidelines for metastatic NSCLC in the ANCI. PCP cannot be considered acceptable for the APHS. Strategies to reduce costs are mandatory to improve affordability in our region.
CANOPY-A: A phase III, multicenter, randomized, double-blind, placebo-controlled trial evaluating canakinumab as adjuvant therapy in patients (pts) with completely resected non-small cell lung cancer (NSCLC).
Authors: Edward B. Garon, Andrea Ardizzoni, Fabrice Barlesi, Byoung Chul Cho, Pedro De Marchi, Yasushi Goto, Dariusz M. Kowalski, Shun Lu, Luis G. Paz-Ares, David R. Spigel, Alexander I. Spira, Michael Thomas, Mimi Leung, Jason Baum, Zewen Zhu, Maria do Socorro Oliveira Portella, James Chih-Hsin Yang
Journal: Journal of Clinical Oncology (2020)

TPS9075 Background: In the CANTOS study, canakinumab (selective IL-1β inhibitor) treatment was associated with reduced incidence and mortality from NSCLC in pts with stable post-myocardial infarction with elevated high-sensitivity C-reactive protein (hs-CRP) levels. In CANOPY-A study, we investigate the therapeutic role of canakinumab in NSCLC. Methods: The CANOPY-A study (NCT03447769) is evaluating the efficacy and safety of canakinumab as adjuvant therapy in adult pts with completely resected NSCLC. Pts with AJCC/UICC v.8 stages II–IIIA and IIIB (T &gt; 5 cm, N2), any histology, completely resected (R0) NSCLC who completed adjuvant cisplatin-based chemotherapy (≥2 cycles) and radiotherapy (if applicable) are eligible. Pts must not have had prior neoadjuvant chemotherapy or radiotherapy. Pts (~1500) are randomized 1:1 to receive canakinumab (200 mg Q3W, SC) or placebo (Q3W, SC) for 18 cycles or until disease recurrence as determined by investigator, unacceptable toxicity, treatment discontinuation at the discretion of the investigator or patient, start of a new antineoplastic therapy, death, or loss to follow-up. Randomization is stratified by AJCC/UICC v.8 stage (IIA vs IIB vs IIIA vs IIIB with T &gt; 5 cm, N2 disease), tumor histology (squamous vs non-squamous), and region (western Europe and North America vs eastern Asia vs rest of the world). Primary objective: disease-free survival (DFS) per local investigator assessment. Secondary objectives: overall survival (OS), lung cancer specific survival, safety, pharmacokinetics, immunogenicity, and patient reported outcomes. Adult pts with stage IIA–IIIA, IIIB (N2 disease only) NSCLC who are candidates for complete resection surgery (and therefore prospective candidates for the main study) will be asked to participate in a biomarker sub-study to understand how resection may impact biomarkers involved in the IL-1β inflammatory pathway and mutations present in blood. In the sub-study, the levels of hs-CRP, other cytokines, and additional biomarkers in blood will be assessed at pre- and post-surgery (endpoint: summary statistics of hs-CRP and other pharmacodynamics [PD] biomarkers). For pts who will enroll in the main study, possible associations between pre- and post-surgery biomarker levels with canakinumab efficacy will be assessed (endpoint: DFS and OS by hs-CRP and other PD biomarkers). The CANOPY-A study is currently enrolling. As of Jan 13, 2020, there are 307 study locations. Clinical trial information: NCT03447769.
应用导管给药预防乳房假体包膜挛缩的临床观察
Authors: 李保锴, 张艳清, 王立荣, 吴鲁波, 王春梅, 侯贺宪
Journal: BMJ (2007)

自2002年1月至2005年12月应用软组织扩张器注射壶及导管制成给药导管,于58例110侧乳房假体植入术中将导管一端植入乳房假体的顶端,注射壶端植于腋窝皮下,分别于术后4、7、10、13周和4、6个月从注射壶注入糖皮质激素(每侧3 ml,含曲安奈德25 mg)预防乳房假体包膜挛缩,其中首次隆乳者于术后4、7、10和13周给药4次,假体隆乳术后包膜挛缩松解假体再次植入者和聚丙烯酰胺水凝胶注射隆乳术后注射物取出同时硅胶假体植入隆乳者共给药6次.术后6～12个月根据J.Baker假体包膜挛缩分型标准进行评价,Ⅰ型85侧乳房,Ⅱ型24侧乳房,Ⅲ型1侧乳房,与同期对照相比获得良好的效果.
胸腺类癌致异位促肾上腺皮质激素综合征一例
Authors: 张学军, 朱显军, 杨艳, 吕月婵, 李蓬秋
Journal: BMJ (2007)

患者男,44岁,因反复咳嗽、咳痰10年,复发伴下肢水肿半个月,于2006年4月15日收入呼吸科,因发现血糖升高2 d后转入内分泌科.10年前,患者进行性体重增加伴打鼾,1年前性欲减退,半年前始全身皮肤色素沉着,以面部明显,半个月前四肢水肿、口渴、多饮、夜尿增多、嗜睡,无头昏、头痛,无腹泻、胸痛、胸闷、乏力.有痛风、脂肪肝病史.吸烟史20年,40支/d.母亲患高血压。
The correlation between clinical benefit and financial cost of cancer drugs.
Authors: Aaron Philip Mitchell, Sara Tabatabai, Pranammya Dey, Jennifer Ohn, Michael A. Curry, Peter Bach
Journal: Journal of Clinical Oncology (2020)

7071 Background: The cost of many cancer drugs is very high, but it is unclear if these costs are associated with commensurate improvement in outcomes. We aimed to assess the association between the cost of cancer treatments and their clinical benefit, using the NCCN Evidence Blocks value assessment framework. Methods: The NCCN Evidence Blocks include 4 measures of clinical benefit: Efficacy, Safety, Quality of Evidence, and Consistency of Evidence. The NCCN assigns scores on each measure ranging from 1 (least favorable) to 5 (most favorable). We obtained the NCCN Evidence Blocks scores as of December 31, 2018 for all recommended cancer treatments for the 30 most prevalent cancers in the US. For each treatment, we calculated total treatment costs (including drugs, administration fees, and supportive care medications) using Medicare reimbursement rates. We categorized treatments as either “time-limited” or “time-unlimited” according to whether their costs are best reflected as per full treatment course (often, adjuvant/neoadjuvant treatments) (time-limited) or per month of therapy (often, treatments for advanced disease) (time-unlimited). We used generalized estimating equations, with clustering within treatment indications, to estimate the association between Evidence Blocks scores and treatment costs, modeling the expected change in cost associated with a one-unit increase in the score on an Evidence Blocks measure. Results: There were 541 time-unlimited and 845 time-limited treatments. Among time-unlimited treatments, monthly treatment cost ranged from $4 to $64,630. Monthly treatment cost was positively associated with Efficacy ($3,036, 95%CI: $1,782, $4,289) and Quality of Evidence ($1,509, 95%CI: $171, $2,847) but negatively associated with Safety (-$1,470, 95%CI: -$2,790, -$151) and Consistency of Evidence (-$2,003, 95%CI -$3,420, -$586). Among time-limited treatments, cost per course of therapy ranged from $0 to $775,559, and no measure was significantly associated with cost. Evidence Blocks scores accounted for little of the variation in treatment cost (linear model R-squared = 0.10 for time-unlimited, and &lt; 0.01 for time-unlimited). Conclusions: The association between NCCN Evidence Blocks measures and treatment cost was inconsistent, and accounted for little of the cost variation among treatments for the same indication. The clinical benefit of cancer treatments does not appear to be a primary determinant of treatment cost, suggesting that current pricing models may be inadequate to incentivize the development and utilization of high-value treatments.
Assessment of scalp cooling to prevent chemotherapy-induced alopecia using standard infusion room documentation and patient surveys.
Authors: Dina Hagigeorges, Mimi Bartholomay, Maryanne M Senna, Steven J. Isakoff
Journal: Journal of Clinical Oncology (2020)

e24106 Background: Chemotherapy induced alopecia (CIA) is one of the most distressing reported side-effects of cancer treatment, with patients (pts) reporting negative impacts on self-image and quality of life. Scalp cooling (SC) devices can prevent CIA. SC efficacy varies by chemotherapy regimen and dose, and taxane-based therapies report better outcomes. Here we report the efficacy of SC with the Paxman SC system using a standard infusion room nursing assessment and patient surveys. Methods: Pts using SC at the MGH Cancer Center between 4/2018 and 12/2019 were included in the analysis. Routine infusion room nursing assessments included CTCAE 4.0 grading for alopecia. A retrospective review of SC pts with documented CTCAE grades was conducted with success defined as grade (Gr) 0 or 1 alopecia at the final infusion. CTCAE results were compared to patient surveys of self-assessed success. Additional data include disease type, regimen and SC discontinuation details. Results: 64 pts who initiated SC and had CTCAE grade recorded were included. The most common chemotherapy regimens were docetaxel/cyclophosphamide (33%), docetaxel/carboplatin/trastuzumab/pertuzumab (19%), paclitaxel/trastuzumab (16%) and paclitaxel weekly/pertuzumab/trastuzumab (6%). Breast cancer was the most common disease type (92%). 77% of pts had successful hair retention (Gr 0 = 23 (36%), Gr 1 = 26 (41%)). 3 pts received anthracycline-based therapy and 1 successfully retained hair. Among 11 pts who completed post-treatment surveys, patient reported outcome and CTCAE were concordant in 9 (82%) pts. 13 (20%) pts terminated SC early; 9 (69%) after 2 treatments (tx), 2 (15%) after 3 tx, 1 (8%) after one tx and 1 (8%) after 5 tx. The most common reason for early dc was extent of alopecia (10, 77%). Other factors in the decision were time and discomfort. Of the 51 pts who completed SC for the entire chemotherapy tx, 48 (94%) received a taxane-based regimen and 46 (90%) had successful hair retention. Conclusions: In this single institution experience, we observed a high success rate of scalp cooling to prevent chemotherapy induced alopecia in a population of mostly breast cancer patients receiving taxane-based regimens. Concordance between patient reported outcome of success and routine standard of care nursing CTCAE documentation in the electronic medical record provides a simple and accurate method to monitor outcomes with scalp cooling. Despite high success, 20% discontinued SC, suggesting further studies to improve outcomes and tolerability are needed.