tbuckley/cabot-search huggingface dataset:
Molecular profiling of metastatic breast cancer (MBC) and target-based therapeutic matching in an Asian tertiary phase I oncology unit.
Authors: Robert John Walsh, Natalie Ngoi, Rebecca Jia Min Ong, Samuel Guan Wei Ow, Andrea Wong, Lim Siew Eng, Yi Wan Lim, Valerie Heong, Raghav Sundar, Ross A. Soo, Wei-Peng Yong, Cheng Ean Chee, Boon Cher Goh, Soo-Chin Lee, David Shao Peng Tan, Joline Si Jing Lim
Journal: Journal of Clinical Oncology (2020)

3561 Background: Somatic profiling of MBC has highlighted actionable mutations and driven trials of matched targeted therapy (tx). Previous phase I studies have reported improved outcomes following matched therapies with tumour molecular profiles. Here, we review next generation sequencing (NGS) and treatment outcomes of Asian MBC patients (pts) in the phase I unit of a tertiary centre. Methods: Pts with MBC referred to a phase I unit underwent NGS (n = 152). Tumour tissue was sequenced via the amplicon based Ion Ampliseq Cancer (IAC) v2 (50 genes) platform from 2014-2017 prior to institutional change to Foundation Medicine 1 (FM1) (324 genes) 2017-2019. Patients were counselled on findings and enrolled onto matched therapeutic trials where available. Results: NGS was successfully performed in 107 pts (IAC 46%, FM1 54%) of which tumour subtypes include hormone receptor positive 63%, triple negative breast cancer (TNBC) 28% and Her2 positive 19%. Median lines of prior tx for MBC was 4 (range 0-12). 89% had prior chemotherapy (CT), 57% prior endocrine therapy (ET). 72/107 (67%) sequenced patients had further treatment and 18 (25%) were matched to tx based on NGS findings (15 clinical trial, 3 off trial). Matching rates on both NGS platforms were similar (IAC 22% vs FM1 28%). Mutated pathways with potential matched tx included PIK3CA/AKT/PTEN (52%), DNA damage response (DRR) (15%), and FGFR (11%) pathways. PIK3 mutations were seen in 43% and associated with higher number of metastatic sites (p = 0.03); most prevalent aberrations were PIK3CA H1047R (41%) and PIK3CA E542K (13%). Matched cases were more heavily pretreated (mean lines of prior tx 5.3 matched vs 3.7, unmatched p = 0.05), and showed a median progression free survival (mPFS) of 24 weeks [w] and clinical benefit rate (complete/partial response or stable disease ≥ 12 weeks) of 53% on matched tx. Comparison by NGS platform showed improved mPFS for matched vs unmatched pts sequenced on FM1 vs IAC (FM1: 26 vs 19w, HR = 0.76 [95% CI: 0.3-1.9]; IAC: 8 vs 12w; HR = 1.21 [95% CI: 0.5-2.8]). Interestingly, 1 pt with SMARCB mutation, reportedly associated with the FGFR pathway, had a PFS of 70w on tx with a pan-FGFR inhibitor after progressing on 3 prior lines of tx (ET and CT). Conclusions: Molecular profiling of MBC in a phase I unit led to matched tx in 25% of cases. Matched pts showed encouraging mPFS with a suggestion of benefit in those matched after sequencing on a broader gene panel (FM1).
Phase Ib study of BI 836880, a VEGF/Ang2-blocking nanobody, in combination with BI 754091, an anti-PD-1 antibody: Initial results in patients (pts) with advanced non-small cell lung cancer (NSCLC).
Authors: Nicolas Girard, Martin Wermke, Fabrice Barlesi, Harald Timotheus Landsteiner, Girish Jayadeva, Juergen Alt, Björn Hackanson
Journal: Journal of Clinical Oncology (2020)

9566 Background: Preclinical studies show that combining anti-VEGF/Ang2 with anti-PD-1 therapy promotes an immunopermissive state supportive of T-cell-mediated tumor cell destruction. BI 836880 is a humanized bispecific nanobody that targets VEGF and Ang2, and BI 754091 is an anti-PD-1 antibody. Each has shown manageable safety and preliminary activity as monotherapy. Here, we report initial results from a Phase Ib study assessing BI 836880 in combination with BI 754091. Methods: In Part 1 (dose escalation), pts with locally advanced or metastatic (m) non-squamous NSCLC who progressed during/after completion of ≥2 cycles of platinum-based chemotherapy (CT) ± a checkpoint inhibitor (CPI) were enrolled. Pts received BI 836880 (cohorts of 360, 500 and 720 mg intravenously [iv] 3-weekly [q3w]) plus fixed-dose BI 754091 (240 mg iv q3w). Dose escalation was guided by Bayesian logistic regression models with overdose control. Primary endpoint in Part 1 was maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), based on dose-limiting toxicities (DLTs) in Cycle 1. Initial safety and efficacy results of Part 1 are reported here. Part 2 will assess safety and efficacy in 6 expansion cohorts: mNSCLC after CPI monotherapy; mNSCLC after CT + CPI; mSCLC after CT ± CPI; immunotherapy-resistant m-melanoma; recurrent glioblastoma after 1 st -line CT; and hepatocellular carcinoma after prior sorafenib or lenvatinib ± subsequent CPI. Results: 12 pts received BI 836880 plus BI 754091 (8 male; median age 59.5 years; 8 had received prior CPI). 4 pts remain on treatment (including 1 treated for 15 cycles). 1 pt had a DLT during Cycle 1 (360 mg; G3 pulmonary embolism). All pts experienced an adverse event (AE; any-cause; safety data cut-off Nov 2019), most commonly (all%/G3%) hypertension (58/25), vomiting (42/0), nausea (33/0), and asthenia (33/0). Hypertension was transient. No G4 AEs were reported; one G5 AE occurred (general physical health deterioration). 5 pts had immune-related AEs (G2 hypothyroidism in 2 pts; G2 pruritus, G1 papular rash, and G2 vomiting). To date (Jan 2020), 2 pts have achieved partial response; 1 pt (500 mg dose; CPI-naïve) had 58% target lesion reduction, and 1 (720 mg; prior CPI) had 35% target lesion reduction. 8 pts had stable disease. Conclusions: MTD/RP2D was BI 836880 720 mg plus BI 754091 240 mg q3w. The combination had a manageable safety profile, and preliminary anti-tumor activity was observed. Expansion cohorts are ongoing. Equal contribution: JA and BH Clinical trial information: NCT03468426 .
A community oncology practice financial experience in oncology care model pilot (OCM).
Authors: Adil Jamal Akhtar, Jeffrey H. Margolis, Karna Sheth, Karma Maxwell, Andrew A. Muskovitz, Richard Philip Zekman, George Howard, Samer Ballouz, Yusuf Qamruzzaman, Savitha Balaraman, Mohammed Ibrahim, Maria Fabbiano, Mitchell Folbe, Mohammed S. Ogaily, Lexi Stortz, Shehnaz Pancholi, Anoosha Maria Tauquir
Journal: Journal of Clinical Oncology (2020)

e19379 Background: Oncology Division of Michigan Health Professionals (MHP) participates in OCM, which requires effort from all MHP OCM providers to coordinate care at same or lower cost to Medicare. Palliative Care, Care Management, and End of Life Care programs established by MHP, in collaboration with Premiere Hospice and Integra Connect, have shown cost and quality benefits in the OCM patients. Quality improvement initiatives included monthly OCM provider meetings to review OCM results, identify cost &amp; quality opportunities, and to design training and education sessions. In order to assess the impact of such a concerted initiative, this study aims to evaluate MHP OCM provider impact in OCM total cost of care relative to historical period. Methods: Retrospective review of reconciliation results provided by Centers for Medicare and Medicaid Innovation (CMMI) for OCM performance periods 1-4 (pp1-4). Total cost of care (ACTUAL) and cost categories were the summarized and adjusted expenditures during 6-month OCM period as reported by CMMI. ACTUAL and cost category experience was compared by OCM performance period to the trended-mean of matched historical OCM-eligible patients (Baseline Episodes from CMMI). Patients were matched by cancer type, comorbidity count, age group, radiation, surgery, and low-intensity/-risk cancer sub-type for prostate, bladder and breast cancers. Results: The largest pp1-4 cost category reductions were acute inpatient ($2.2M), physician services excluding drug-cost, imaging and labs ($1.2M), skilled nursing facility ($0.5M), ancillary which consists of imaging and lab ($0.5M), inpatient rehab ($0.3M), home health agency ($0.3M), radiation oncology ($0.1M). The largest pp1-4 increase in OCM expense relative to historical was Part D Drugs ($1.7M). Conclusions: MHP decreased non-drug costs by $5.1M compared to historical cost for matched patients. OCM costs were lower in facility (hospital and SNF) and physician sites of care. Drug costs increased by $1.7M. Study was limited by OCM claims available as of December 2019. Results may be refreshed as more data becomes available. [Table: see text]
The spectrum of cancer in adolescents and young adults (AYAs): An observational study in a single institution from 2015-2019.
Authors: Wei Lin Goh, Jiancheng Hong, Evelyn Wong, Victoria Wong, Daniel Quah, Yee Pin Tan, Yung Ying Tan, Selene Chan, Jason Yongsheng Chan, Nagavalli Somasundaram, Mohamad Farid Rin Harunal Rashid, Eileen Yi Ling Poon
Journal: Journal of Clinical Oncology (2020)

e13629 Background: Cancer in adolescents and young adults (AYAOs) refers to patients diagnosed with a malignancy between 16 and 39 years old. This is thought to be 5% in the Western population. The exact incidence and distribution in Asia is uncertain although the WHO estimated 650 000 AYAs to be newly diagnosed in this part of the world in 2018. There is limited data on the incidence and epidemiology on AYAs in Asia, but it is known from the western literature that the distribution of cancer types, clinico-pathological features and outcomes in this population is very different. We therefore, sought to evaluate the pattern of cancer types among the different age groups of the AYA population seen in a high-volume single Asian tertiary cancer centre. Methods: We undertook a retrospective observational study of all patients diagnosed with cancer between 16 and 39 years old who presented to the National Cancer Centre Singapore (NCCS) from 1 January 2015 to 31 December 2019. Results: A total of 2583 cases was observed during the 5-year period. The male: female ratio was 1:1.75. The majority of the patients were between of 35-39 years (y) ( n= 1128, 44.0%). The most common cancer across the different age groups in females were sarcoma (16-19 y), hematologic malignancies (20-24 y) and breast cancer (25-29 y, 30-34 y and 35-39 y). The most common cancer across the different age groups in males were hematologic malignancies (16-19 y), germ cell tumours (20-24 y), germ cell tumours, hematologic malignancies and sarcoma (25-29 y), hematologic malignancies (30-34 y) and colorectal cancers (35-39 y). The majority of the patients presented were localized disease (38.3%), while 19.4% presented with lymphatic involvement. Amongst 507 (19.6%) patients presenting with metastatic disease, 126 patients have deceased. Conclusions: This population has unique characteristics compared to their geriatric and pediatric counterparts. With an increased incidence and expected longer survivals, more efforts are needed to better understand the clinicopathological features of the AYA population. This will enable us to better survival rates and long-term treatment outcomes.
Real-world outcomes of venetoclax refractory multiple myeloma patients.
Authors: Kathryn T. Maples, Jonathan L. Kaufman, Vikas Anand Gupta, Nisha Joseph, Leonard T. Heffner, Craig C. Hofmeister, Madhav V. Dhodapkar, Shannon M. Matulis, Lawrence Boise, Sagar Lonial, Ajay K. Nooka
Journal: Journal of Clinical Oncology (2020)

e20524 Background: The BELLINI trial investigated the efficacy and safety of venetoclax (ven)/bortezomib (bort)/dexamethasone (dex) vs placebo/bort/dex in patients with bort-sensitive, early relapsed myeloma. The median PFS favored the ven arm (22.4 vs 11.5 months); however, a higher death rate in the ven arm led to study discontinuation. A subgroup of patients with t(11;14) not only had improved PFS but a positive trend in OS with ven, suggesting biomarker-driven patient selection may mitigate the safety concern. BELLIINI results raised concern regarding the natural history of myeloma progressing on ven. We aimed to investigate the clinical outcomes of ven refractory myeloma patients. Methods: We identified 70 refractory myeloma patients at our institution prescribed ven alone or in combination between 03/2014 -11/2019. Our group has published the functional profiling of BCL2 family members to predict responses to ven (Matulis, S et al. Leukemia), and most patients had functional profiling available prior to starting ven. Demographic and outcomes data were obtained from our IRB approved myeloma database and responses were evaluated per IMWG criteria. Results: Patients received a median of 3 (1-13) lines of therapy (LOT), with 37% receiving ≥4prior LOT and 86% had t(11;14) by FISH/CTG. Most patients received ASCT (86%) and were refractory to len and bort (97%), dara (41.4%), car (43%), or pom (53%). The most common combinations with ven were dex (83%), PI and dex (8.5%), or dara and dex (8.5%). At a median follow up of 16.8 months, 38 patients progressed on ven. Median duration of therapy was 9.5 (1-63) months. Median PFS for the entire cohort was 13 (7.9-18.2) months. Use of ven as an early LOT provided PFS benefit ( &lt; 3 vs &gt; 3 LOT: 23.2 vs 10.4 months). Notably, patients who received &gt; 6 LOT also had a PFS benefit of 7.23 (0-15.6) months, and ‘penta-refractory’ patients had a PFS of 7.2 (0-17.2) months. Among the 38 patients that progressed on ven, dara-based combinations (30%) and clinical trials (24%) were the most common subsequent LOT. At a median follow up of 15.4 months, the median OS for the cohort from the time of ven refractoriness was 31.4 months. Patients who received &gt; 6 LOT had an OS of 15.1 (0-14.2) months and ‘penta-refractory’ patients at ven refractoriness had an OS of 13.7 (0-30.6) months. Conclusions: Patients with ven refractory myeloma can still experience good long term outcomes, and our experience does not support the hypothesis that ven resistance leads to a more refractory myeloma phenotype. These data support the early use of ven or ven combinations in the t(11;14) cohort of patients.
缺血性心脏病患者六分钟步行试验的临床研究
Authors: 杨靖, 何劲松, 杨小英
Journal: BMJ (2005)

对6分钟步行试验用于缺血性心脏病患者医疗体操中的负荷强度测定进行了研究.160例缺血性心脏病伴慢性心力衰竭的男性患者随机分为训练组、对照组.通过对训练组增加6分钟步行试验训练,显示该运动可以改善患者心力衰竭症状,增强运动耐力,对患者在恢复心功能方面有重要意义。
Myasthenia gravis complicated with polymyositis: a report of three cases and literature review
Authors: Zhao Yuyue, Peng Linyi, Fei Yunyun, Zhang Fengchun
Journal: BMJ (2016)

Three female patients admitted with elevated creatine kinase, impaired muscle on electromyogram, and positive repetitive nerve stimulation and neostigmine tests were diagnosed as polymyositis (PM) with myasthenia gravis (MG). Twenty five more cases were retrieved by literature search, and the clinical data of total 28 cases were analyzed. There were 10 males and 18 females with an average age of 56 years. The clinical manifestations include dyspnea(43%), dysphagia(43%), ptosis(43%), dysarthria(29%), diplopia(18%), cough after drinking(14%), myalgia(11%). Thirteen out of 26 cases (50%) had positive results in repetitive nerve stimulation (RNS) and 10/11 showed positive reaction in neostigmine test. Serum positive anti-acetylcholine receptor was detected in 21 out 23 patients (91%).


Key words: 
Polymyositis; Myasthenia Gravis
Lifelong disease burden of chemotherapy in Hodgkin lymphoma (HL): A simulation study from the St. Jude Lifetime (SJLIFE) Cohort and HL International Study for Individual Care (HoLISTIC).
Authors: Susan K. Parsons, Nickhill Bhakta, Angie Mae Rodday, Carlton Scharman, Marc André, Massimo Federico, Jonathan W. Friedberg, Debra L. Friedman, Andrea Gallamini, Annette E. Hay, Brad S. Kahl, Frank G. Keller, Kara M. Kelly, Ralph M. Meyer, John Raemaekers, Leslie L. Robison, Melissa M. Hudson, Joshua T. Cohen, Andrew M. Evens, F. Lennie Wong
Journal: Journal of Clinical Oncology (2020)

12068 Background: Current emphasis for childhood and young adults with HL is to maintain high cure rates while concurrently identifying regimens to reduce excess long-term mortality/morbidity. Thus, understanding the late effects (LE) of contemporary clinical trials (CCT) for HL is critical. Methods: We used simulation to estimate the projected life expectancy (LExp), quality adjusted life-expectancy (QALE) &amp; cause of death (COD) in a large cohort of HL CCT patients (pts) in the recently established HoLISTIC consortium by linking long-term risk models from the SJLIFE cohort. Individual patient data (IPD) on bleomycin, alkylating agents and anthracycline were extracted &amp; harmonized for 982 HL pts in 5 prospective CCT (mean diagnosis age 19y, range 3-30y; 51% male; all treated with chemotherapy only; progression-free survival [PFS] &gt;5y) in the HoLISTIC database. LExp, QALE &amp; COD were projected using a previously developed microsimulation model (Bhakta, Blood [Supplement], 2019) that incorporated mortality &amp; incidence of LEs by diagnosis age, sex, race, treatment exposures &amp; attained age estimated from 5,522 adult 10-y survivors of childhood cancers in the SJLIFE cohort (56% male; mean age at last follow-up 35y, range 19-68). Microsimulation was applied to 10,000 randomly selected survivors of HL CCT cohort, from 10y after HL diagnosis until death to project the LExp, QALE &amp; COD. Results: Assuming 10-y PFS, LExp and QALEs projected for the HL CCT cohort using adjusted US general population rates linked with the SJLIFE microsimulation model, COD and trial-specific exposures are shown in the Table. Conclusions: A novel lifetime simulation approach was used to project LExp, QALE &amp; COD by linking together IPD from CCTs with the long-term risk model of the SJLIFE survivorship cohort. Despite differences in PFS, reflecting in part the variation in risk/stage status, the projected long-term outcomes were similar. Our approach highlights a new opportunity to inform future clinical trial design and aid provider &amp; patient decision-making. [Table: see text]
阿尔茨海默病与血管性痴呆的关系和鉴别
Authors: 黄明生, 李进, 况伟宏
Journal: BMJ (2006)

痴呆是一个较为常见的获得性临床综合征,是指在意识清楚的背景下呈现的一种以记忆障碍为主的全面认知功能损害状态[1].老年(≥65岁)和老年前期(55～64岁)人群是痴呆的高发人群.临床上,可以导致痴呆发生的疾病有许多,阿尔茨海默病(AD)和血管性痴呆(vascular dementia,VD)最为常见,约占90%.目前,这两大疾病的临床诊断均基于操作性定义的诊断标准,病理活检和尸检是确诊的惟一途径,但对临床工作的具体开展帮助不大。
Method improvement of the medial plantar pedicled flap transplantation to cover the defect of the foot heel
Authors: Gong-lin Zhang, Ming Zhang, Ao Guo, Wen-zheng Zhang, Yu-xiang Hu, Fa-ming Ding
Journal: BMJ (2008)

The article presents a method improvement of the medial plantar pedicled flap transplantation to cover the defect of the foot heel.Since 2002,6 patients with soft tissue defects on the foot heel underwent reconstruction with the medial plantar pedicled flap transplantation of excluding the plantar fascia and 3 patients used conventional flap of the medial plantar pedicled flap transplantation.They ranged in age from 18 to 52 years(mean,32 years).All the flaps had survived completely without major complication with satisfactory clinical results.Follow-up period ranged from 1.5 to 6 years(mean,3.8years)postoperatively.There was no remarkable donor site morbidity.Patients with flap of excluding the plantar fascia had good appearance in recipient site.Injury to donor site was reduced.Skin of the instep area can be raised as an island fasciocutaneous flap based on medial plantar vessels,with the branch of medial plantar nerve supplying the instep skin to provide the sensation.The flap is thin and suitable for repairment of soft tissue defect on the foot heel.

Key words: 
Reconstructive surgical procedures;  Foot diseases
Blood-based gene expression profiling to reveal potential response biomarkers for immunotherapy in advanced lung cancer.
Authors: Jie Wu, Weihua Huang, Changhong Yin, Yee Him Cheung, Debra Abrams, John T Fallon, Nevenka Dimitrova, Michael Paul Fanucchi
Journal: Journal of Clinical Oncology (2020)

e15155 Background: Novel immunotherapies are becoming a viable option for advanced lung cancer treatment. High-throughput gene expression profiling (GEP) has enabled better understanding of patient responsiveness to targeted immunotherapy. However, non-invasive blood-based signatures are needed to monitor and predict response. Methods: To evaluate the predictive and prognostic role of blood-based GEP, we designed a longitudinal study by enrolling 15 patients with advanced lung cancers. A total of 65 samples were collected for RNA sequencing, ~4 blood specimens per patient, before and during anti-PD-1 treatment. We used multiple analyses, including time-course differential gene expression, principal component, lymphocyte compartment deconvolution, and genetic mutation, to search for and assess potential predictive and prognostic aspects. Results: Of 15 patients, 11 were classified as Responders (partial responders) and four were Non-Responders (one stable and three progressive diseases). Our analyses demonstrated: 1) By comparing baseline GEPs from Responders vs. Non-Responders before the first treatment, we identified potential markers (e.g., LY6E is significantly lower expressed in Responders, with Log2 Fold change = -3.44 and p = 1.83E-04) that can be used as predictors of responsiveness of the patients; 2) Immunoglobulin subunits- and T cell receptor complex-related genes were differentially expressed in Responders (DAVID analysis, p = 6.7E-3 and 2.1E-2, respectively), but not in Non-responders; 3) γδ T cells in the lymphocyte compartment were relatively increased in Responders; 4) Despite a different set of genes differentially expressed at different time points, the biggest GEP changes were at ~ week 6, after the second treatment. Additionally, we observed certain genes consistently up- or down-regulated through the whole course of treatment. Furthermore, after the first treatment, genes in the immune response pathway were regulated to different directions in Responders and Non-Responders. For example, interleukin receptor genes, such as IL18R1 and IL18RAP, and CD24 were down-regulated in Responders, but up-regulated in Non-Responders (p = 0.042, 0.023 and 0.044 respectively, t-test for the differential expression in these two groups). Conclusions: The utility of blood GEP to identify predictive and prognostic factors for precision immunotherapy is encouraging. Nevertheless, these results, predictive of the anti-PD-1 clinical response, are preliminary and need to be validated in a larger cohort.
Covid-19: UK government’s defence of senior aide has damaged public and NHS confidence, say experts
Authors: Elisabeth Mahase
Journal: BMJ (2020)

Persistent viral infections and inflammatory syndromes induce the accumulation of T cells with characteristics of terminal differentiation or senescence. However, the mechanism that regulates the end-stage differentiation of these cells is unclear. Human CD4<sup>+</sup> effector memory (EM) T cells (CD27<sup>−</sup>CD45RA<sup>−</sup>) and also EM T cells that re-express CD45RA (CD27<sup>−</sup>CD45RA<sup>+</sup>; EMRA) have many characteristics of end-stage differentiation. These include the expression of surface KLRG1 and CD57, reduced replicative capacity, decreased survival, and high expression of nuclear γH2AX after TCR activation. A paradoxical observation was that although CD4<sup>+</sup> EMRA T cells exhibit defective telomerase activity after activation, they have significantly longer telomeres than central memory (CM)-like (CD27<sup>+</sup>CD45RA<sup>−</sup>) and EM (CD27<sup>−</sup>CD45RA<sup>−</sup>) CD4<sup>+</sup> T cells. This suggested that telomerase activity was actively inhibited in this population. Because proinflammatory cytokines such as TNF-α inhibited telomerase activity in T cells via a p38 MAPK pathway, we investigated the involvement of p38 signaling in CD4<sup>+</sup> EMRA T cells. We found that the expression of both total and phosphorylated p38 was highest in the EM and EMRA compared with that of other CD4<sup>+</sup> T cell subsets. Furthermore, the inhibition of p38 signaling, especially in CD4<sup>+</sup> EMRA T cells, significantly enhanced their telomerase activity and survival after TCR activation. Thus, activation of the p38 MAPK pathway is directly involved in certain senescence characteristics of highly differentiated CD4<sup>+</sup> T cells. In particular, CD4<sup>+</sup> EMRA T cells have features of telomere-independent senescence that are regulated by active cell signaling pathways that are reversible.