tbuckley/cabot-search huggingface dataset:
Outcomes to first-line pembrolizumab in patients with PD-L1-high (≥50%) non-small-cell lung cancer and a poor performance status.
Authors: Joao Victor Machado Alessi, Biagio Ricciuti, Elizabeth Jimenez Aguilar, Fangxin Hong, Zihan Wei, Mizuki Nishino, Andrew J. Plodkowski, Peter Sawan, Jia Luo, Hira Rizvi, Brett W. Carter, John Heymach, Mehmet Altan, Matthew David Hellmann, Mark M. Awad
Journal: Journal of Clinical Oncology (2020)

9568 Background: Patients with non-small cell lung cancer (NSCLC) and a poor Eastern Cooperative Oncology Group performance status (ECOG PS) have been excluded from immunotherapy clinical trials. We sought to evaluate clinical outcomes to first-line pembrolizumab in patients with advanced NSCLC, a PD-L1 tumor proportion score (TPS) of ≥50%, and an ECOG PS of 2. Methods: We performed a multicenter retrospective analysis of patients with metastatic NSCLC and a PD-L1 tumor proportion score (TPS) of ≥50% (negative for genomic alterations in EGFR and ALK) who received treatment with first-line commercial pembrolizumab. Clinical outcomes were compared in patients based on ECOG PS. Results: Among 234 patients, 83.3% (N = 195) had an ECOG PS of 0 or 1, and 16.7% (N = 39) had an ECOG PS of 2. The baseline clinicopathological characteristics were balanced between the ECOG PS 0-1 vs 2 groups in terms of age, sex, tobacco use, histology, KRAS mutation status, presence of other potentially targetable driver mutations ( BRAF, MET, HER2, RET), history of central nervous system (CNS) disease, and PD-L1 TPS distribution. Compared to patients with an ECOG PS of 0-1, patients with an ECOG PS of 2 had a significantly lower objective response rate (ORR 43.1% vs 25.6%; P = 0.04), a numerically shorter median progression free survival (mPFS 6.6 months vs 4.0 months; P = 0.09), and a significantly shorter median overall survival (mOS 20.3 months vs 7.4 months; P &lt; 0.001). Upon disease progression, patients with an ECOG PS of 2 were significantly less likely to receive second-line systemic therapy compared to patients with an ECOG PS of 0-1 (55.5% vs 14.3%, P &lt; 0.001). Conclusions: Although a subset of patients with an ECOG PS of 2 can respond first-line pembrolizumab, clinical outcomes in this population are poor, and use of second-line systemic therapy is infrequent.
The impact of a multidisciplinary approach (MA) in the management of pancreatic disease (PD).
Authors: Brunella Di Stefano, Giuseppe Quero, Cinzia Bagalà, Claudio Fiorillo, Maria Bensi, Roberta Menghi, Caterina Cina, Gian Carlo Mattiucci, Riccardo Manfredi, Francesco Cellini, Maria Gabriella Brizi, Francesca D'Aversa, Vincenzo Perri, Alberto Larghi, Fabia Attili, Frediano Inzani, Sergio Alfieri, Giampaolo Tortora, Lisa Salvatore
Journal: Journal of Clinical Oncology (2020)

e19196 Background: The management of PD is very insidious, mainly due to the often difficult differential diagnosis between benign and malignant diseases, and, in case of pancreatic ductal adenocarcinoma (PDCA), to the frequently hard differentiation among resectable/borderline PDCA susceptible to upfront surgery, locally advanced PDCA susceptible to a neoadjuvant approach and never resectable or metastatic PDCA in which a palliative treatment is the only option. A correct PD evaluation and the subsequent choice of the most appropriate treatment strategy, thus, need a MA, involving surgeons, oncologists, radiologists, radiation oncologists, endoscopists, gastroenterologists and pathologists. On the basis of such considerations, we investigate the impact of the multidisciplinary meeting (MM) in the management of PD at our Institution. Methods: We retrospectively evaluated all the cases discussed by surgeons at our MM. We collected data, both pre- and post-MM, regarding diagnosis (cyst vs pancreatitis vs IPMN vs PDCA), and, in case of PDCA, tumor burden at baseline (resectable vs border-line resectable vs locally advanced vs metastatic disease) and disease response to treatment (disease control vs progression). Primary endpoint was the overall rate of discrepancy in diagnosis and/or PD evaluation between pre- and post-MM. Results: From October 2018 to December 2019, a total of 139 cases were presented by surgeons. After MM, a total of 38 diagnosis and/or PD evaluation were modified, for an overall discrepancy rate of 27%. In particular, of the 38 discordant cases, 9 (24%) were initial diagnosis, 24 (63%) baseline tumor burden assessments and 5 (13%) were PDCA response evaluations. Among the 24 cases of tumor burden evaluations, treatment strategy changed in 17 out of 24 cases. More specifically, of the 19 cases, evaluated as borderline/resectable before the MM, 15 were defined as locally-advanced or metastatic disease after the MM; of the 5 cases, evaluated as not resectable before the MM, 2 were considered border-line/resectable after the MM. Similarly, out of 9 cases of discrepant initial diagnosis, 5 cases, considered as malignant disease before MM, were assessed as benign after the MM. Conclusions: Our analysis demonstrates a significant rate of discrepancy in diagnosis and/or PD evaluation between pre- and post-MM. Our results show that a MA allows a considerable modification in PD diagnosis and evaluation, maximizing the treatment strategy, in particular avoiding unnecessary and detrimental pancreatic surgery.
Real-world patterns of molecular testing in advanced melanoma (advMel): adherence to guidelines.
Authors: Anthony J. Olszanski, Jeffrey M. Farma
Journal: Journal of Clinical Oncology (2020)

e22031 Background: National guidelines (eg, NCCN and ESMO) recommend BRAF mutation testing to inform treatment (tx) decisions in high-risk stage III or IV cutaneous melanoma, but few studies have evaluated its implementation in a real-world setting. Here we report the testing patterns for BRAF and other mutations in advMel via an electronic health record (EHR)–derived database, to assess guideline adherence and implications for patient (pt) care. Methods: This retrospective observational study used Flatiron Health’s nationwide longitudinal database comprising de-identified EHR structured and unstructured data, curated via technology-enabled abstraction. Pts with stage III or IV cutaneous melanoma at initial diagnosis, or a locoregional or distant recurrence, with ≥ 2 clinic encounters starting January 1, 2011 were included in the advMel cohort. Data through October 2019 were analyzed. Results: A total of 9333 pts from 160 US cancer clinics were in the advMel cohort. Overall, 21% of pts had no evidence of BRAF testing. In the adjuvant setting, the percentage of pts with known BRAF status before initiation of systemic tx increased from 34% prior to the year 2018 to 56% post approval of adjuvant targeted tx in 2018. The rate of known BRAF status before initiation of first line (1L) metastatic tx declined from 80% in 2012 to 62% in 2018. Notably, within 30 days after tx initiation, BRAF status was reported in an additional 17% of pts in 1L metastatic setting. Next-generation sequencing (NGS) overtook polymerase chain reaction (PCR) as the most common assay (40% NGS vs 22% PCR in 2018, whilst 8% vs 53% in 2012). Of the 35-day (NGS) or 27-day (PCR) median turnaround time from sample collection to results, 21-25 days occurred from specimen collection to receipt in the lab. Despite this turnaround time, 35% of pts with known BRAF status before tx initiation had NGS testing. Of all pts tested for BRAF, 30% were also tested for NRAS and 32% for KIT. Among pts with a BRAF mutation, concomitant NRAS (1.1%) or KIT (0.6%) mutation was rare. Conclusions: Our real-world analysis shows that BRAF mutation status is known in ≈60% of pts with advMel before initiation of adjuvant or 1L metastatic tx. NGS and PCR are the most common testing platforms, with the use of NGS on the rise. Notably, a prolonged time was observed between collection and lab receipt of the specimen. These results indicate an opportunity for physicians to conduct earlier molecular testing at workup per the guidelines, and for improved logistical efficiency to facilitate timely receipt of genomic results to better inform individualized tx plans.
从一位肝硬化患者的诊疗过程看全科医生的角色和临床思维
Authors: 金世红, 周仲华
Journal: BMJ (2011)

一位23岁的未婚女性,海南人,她的父亲及哥哥都是我们全科门诊的老患者,但她自己一直在温州及广州打工,半年前才第一次在哥哥的介绍下来全科就诊.来诊时自述没有任何不适,只是因家人发现她面色苍白才来看病。
老年股骨颈骨折患者不同术式疗效比较
Authors: 范国强, 武瑞星, 刘江
Journal: BMJ (2004)

收治60岁以上新发生的股骨颈骨折患者118例,分别行内固定术(包括加压空心螺钉、动力髋)与人工髋关节置换术(包括人工股骨头置换术、全髋关节置换术).内固定组较人工髋关节置换术组手术打击小、恢复快,但关节功能恢复较差,再手术率高(均P<0.05)。
DREAMM-9: Phase III study of belantamab mafodotin plus VRd versus VRd alone in transplant-ineligible newly diagnosed multiple myeloma (TI NDMM).
Authors: Saad Zafar Usmani, Evangelos Terpos, Wojt Janowski, Hang Quach, Sarah West, Danae Williams, Elisha J. Dettman, Geraldine Ferron-Brady, Katarina Luptakova, Ira Gupta
Journal: Journal of Clinical Oncology (2020)

TPS8556 Background: Bortezomib, lenalidomide, and dexamethasone (VRd) is the standard of care for transplant-eligible and TI NDMM, but relapse is usually inevitable. The median progression-free survival (PFS) is ~3 years for patients with TI NDMM, and with each relapse, the duration of response (DoR) diminishes, highlighting the need for novel, effective, targeted agents. Single-agent belantamab mafodotin is a first-in-class B-cell maturation antigen–binding, humanized, afucosylated, monoclonal immunoconjugate, showing deep and durable responses in heavily pretreated patients with relapsed/refractory multiple myeloma ( Lancet Oncol2020). Preclinical work suggests belantamab mafodotin plus bortezomib or lenalidomide enhances anti-myeloma activity. Therefore, studying clinical activity of belantamab mafodotin in combination with these agents is warranted. Methods: DREAMM-9 (NCT04091126) is a two-part, open-label study to determine efficacy and safety of single-agent belantamab mafodotin with VRd vs. VRd alone in patients with TI NDMM. Patients aged ≥18 years with ECOG status 0–2 and adequate organ system functions will be eligible. Part 1 (dose selection) will evaluate safety/tolerability of belantamab mafodotin with VRd administered by single (Day 1) or split dosing (Days 1 and 8) in ≤5 cohorts (n = 12/cohort): 1.9 mg/kg, 2.5 mg/kg split and single, and 3.4 mg/kg split and single. Six more patients may be added to cohort(s) most likely to be selected as recommended Phase III dose (RP3D). Dose-limiting toxicities and adverse events (AEs) will be assessed, and belantamab mafodotin RP3D determined through modified toxicity probability interval criteria. Part 2 (randomized Phase III) will determine efficacy and safety of belantamab mafodotin at RP3D with VRd vs. VRd alone (n = 750) in two arms randomized 1:1. Dual primary endpoints will be rate of minimal residual disease (MRD) negativity and PFS. Secondary endpoints will be response rates (overall response, complete response, very good partial response or better, sustained MRD negativity), DoR, time to progression, and overall survival. Safety assessment will include AEs, serious AEs and ocular findings. In both parts, belantamab mafodotin will be given with VRd for eight induction cycles and then with Rd for maintenance until disease progression or unacceptable toxicity. Funding: GlaxoSmithKline (209664). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT04091126 .
Porokeratosis: clinical analysis of seven cases
Authors: Hui Chen, Ruifeng Sun, Chen Zhao, Yuying Lin, Shi Lian
Journal: BMJ (2017)

The clinical data of 7 patients with porokeratosis (PK) were analyzed retrospectively. In 7 PK patients, 4 cases were disseminated superficial actinic porokeratosis (DSAP), 1 case was disseminated superficial porokeratosis (DSP), 1 case was giant porokeratosis (GP) and 1 case was hypertrophic porokeratosis (HP). The characteristic cutaneous manifestations were annular well-circumscribed keratotic plaques with slightly atrophic center and elevated border. All patients shared a common histological hallmark, the cornoid lamella. Four cases of DSAP patients had family medical history, consistent with autosomal dominant inheritance. DSP, GP and HP patients denied family medical history. Diagnosis of PK should be based on clinical manifestations, family medical history and histopathological examination.


Key words: 
Porokeratosis; Pathological conditions, signs and symptomes; Prognosis
Disease-associated CTNNBL1 mutation impairs somatic hypermutation by decreasing nuclear AID
Authors: Marcel Kuhny, Lisa R. Forbes, Elif Çakan, Andrea Vega-Loza, Valentyna Kostiuk, Ravi K. Dinesh, Salomé Glauzy, Asbjorg Stray-Pedersen, Ashley E. Pezzi, I. Celine Hanson, Alexander Vargas-Hernandez, Mina LuQuing Xu, Zeynep H. Coban Akdemir, Shalini N. Jhangiani, Donna M. Muzny, Richard A. Gibbs, James R. Lupski, Ivan K. Chinn, David G. Schatz, Jordan S. Orange, Eric Meffre
Journal: Journal of Clinical Investigation (2020)

Patients with common variable immunodeficiency associated with autoimmune cytopenia (CVID+AIC) generate few isotype-switched B cells with severely decreased frequencies of somatic hypermutations (SHMs), but their underlying molecular defects remain poorly characterized. We identified a CVID+AIC patient who displays a rare homozygous missense M466V mutation in β-catenin–like protein 1 (CTNNBL1). Because CTNNBL1 binds activation-induced cytidine deaminase (AID) that catalyzes SHM, we tested AID interactions with the CTNNBL1 M466V variant. We found that the M466V mutation interfered with the association of CTNNBL1 with AID, resulting in decreased AID in the nuclei of patient EBV-transformed B cell lines and of CTNNBL1 466V/V Ramos B cells engineered to express only CTNNBL1 M466V using CRISPR/Cas9 technology. As a consequence, the scarce IgG+ memory B cells from the CTNNBL1 466V/V patient showed a low SHM frequency that averaged 6.7 mutations compared with about 18 mutations per clone in healthy-donor counterparts. In addition, CTNNBL1 466V/V Ramos B cells displayed a decreased incidence of SHM that was reduced by half compared with parental WT Ramos B cells, demonstrating that the CTNNBL1 M466V mutation is responsible for defective SHM induction. We conclude that CTNNBL1 plays an important role in regulating AID-dependent antibody diversification in humans.
Naxitamab, a new generation anti-GD2 monoclonal antibody (mAb) for treatment of relapsed/refractory high-risk neuroblastoma (HR-NB).
Authors: Jaume Mora, Godfrey Chi-Fung Chan, Daniel A. Morgenstern, Karsten Nysom, Melissa K Bear, Lene Worsaae Dalby, Steen Lisby, Brian H. Kushner
Journal: Journal of Clinical Oncology (2020)

10543 Background: NB is a rare cancer but represents the most common extracranial solid tumor of childhood. Most HR-NB patients present with or develop metastatic disease typically in bone or bone marrow (BM). Despite advances in frontline multimodal therapy ~50% of patients relapse. Refractory or relapsed disease represents an unmet medical need. GD2 is an adhesion molecule abundantly expressed in NB. Naxitamab is a humanized anti-GD2 mAb with high receptor affinity. Methods: We evaluated naxitamab in HR-NB patients with disease in bone and/or BM, who were refractory to initial treatment(s) or who had insufficient response to therapy for progressive/relapsed disease. Patients were treated in an outpatient setting with naxitamab as a planned 30-minute i.v. infusion and s.c. granulocyte-macrophage colony-stimulating factor (GM-CSF). Patients received 3 infusions of naxitamab 3 mg/kg/dose during the first week of a treatment cycle repeated initially every 4 weeks. Patients were evaluated for safety (CTCAE V4.0) and efficacy (INRC, Park et al. 2017). Results: We report on 24 patients recruited from April 2018 with a data cut off in June 2019. At diagnosis, 21 patients were stage 4, 1 was stage 3, 2 were unknown. At study entry, 11 patients had metastases in bone, 1 in BM and 12 in both bone and BM. Overall objective response was 75% (18/24), with complete response (CR) in 67% (16/24) and partial response in 8% (2/24). Of the 13 patients with BM involvement at enrollment, 12 achieved CR in BM during trial therapy. 6 treatment-related SAEs were reported in 5 patients (anaphylactic reaction, pyrexia, and respiratory depression). Conclusions: Naxitamab is an anti-GD2 mAb under development for HR-NB. In addition to a high CR rate of 67% and an overall objective response rate of 75% in a high-risk patient population, naxitamab offers an unique option for treatment of patients in the outpatient setting. These data and convenience to patients are strongly supportive of further drug development. Clinical trial information: NCT03363373.
Final survival analysis of NSGO-AVANOVA2/ENGOT-OV24: Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer—A randomized controlled chemotherapy-free study.
Authors: Mansoor Raza Mirza, Gitte-Betina Nyvang, Bente Lund, Rene dePont Christensen, Theresa Louise Werner, Susanne Malander, Line Bjørge, Michael J. Birrer, Maarit Anttila, Gabriel Lindahl, Sakari Hietanen, Maria Dimoula, Ulla Peen, Kristine Madsen, Anja Knudsen, Synnove Staff, Nicole Buchner Vinum, Maj Kamille Kjeldsen, Elisabeth Avall-Lundqvist, Johanna Unelma Maenpaa
Journal: Journal of Clinical Oncology (2020)

6012 Background: We previously reported significantly improved progression-free survival (PFS) with the chemotherapy-free regimen of niraparib and bevacizumab compared to niraparib alone, in women with platinum-sensitive relapsed ovarian cancer (PSROC), regardless of homologous recombination deficiency (HRD) status (MyChoice HRD), duration of chemotherapy-free interval (CFI) and number of previous lines of therapy (Mirza MR et al, Lancet Oncol 2019). We now present the updated PFS, overall survival (OS) and other efficacy and safety endpoints. Methods: In this randomized, open-label, phase 2 study, women with measurable/evaluable, high-grade serous or endometrioid PSROC were randomized to niraparib 300mg once daily or the combination of niraparib 300mg once daily and bevacizumab 15mg/kg IV every 3 weeks until disease progression (1:1 randomization). The primary endpoint was PFS. Stratification was according to HRD status and CFI (6-12months (mo) vs. &gt; 12mo). First-line maintenance bevacizumab was permitted. Results: Of 97 enrolled patients, 48 were randomized to niraparib monotherapy and 49 to the chemotherapy-free combination. The combined treatment significantly improved PFS compared to niraparib alone: updated median PFS 12.5 mo vs. 5.5 mo; hazard ratio (HR) adjusted for stratification factors 0.34; 95% confidence interval (CI) [0.21 to 0.55]; P &lt; 0.0001. Preplanned exploratory subgroup analyses: patients with HRD-positive tumors (n = 54) HR 0.41 (CI, 0.23-0.76); HRD-negative disease (n = 43) HR, 0.40 (CI, 0.20-0.79); Time to First Subsequent Therapy (TFST) (n=97) HR, 0.4 (CI, 0.25-0.64); PFS2 (n=97) HR 0.55 (CI, 0.35-0.88); Time to Second Subsequent Therapy (TSST) (n=97) HR, 0.56 (CI, 0.35-0.90); OS (49 events only) HR, 0.77 (CI, 0.42-1.41). There was no difference in treatment-emergent grade 3-4 adverse events except for the rate of hypertension (22.9% vs. 0%) and neutropenia (8.3% vs. 2.0%). Patient-reported outcomes measured using EORTC QLQ-C30 and OV28 were similar for both treatment arms. Conclusions: Updated PFS consistently demonstrates that the niraparib-bevacizumab combination had clinically and statistically meaningful activity in PSROC. This phase 2 study was not powered to detect differences in OS or any other efficacy endpoints however TFST, PFS2 &amp; TSST are significantly improved while there is a trend towards OS improvement with niraparib-bevacizumab combination. Clinical trial information: NCT02354131.
Survival of patients with aneurysm subarachnoid hemorrhage and its related factors
Authors: Guo-hou He, Ting Yang
Journal: BMJ (2009)

Objective To describe survival of patients with aneurysm subarachnoid hemorrhage (aSAH) and its related factors. Methods Data of 88 patients with aSAH were analyzed retrospectively, including their age, gender, past medical history, therapeutic measures, complications and prognosis, and so on. Their survival and its related factors were identified by Kaplan-Meier method and COX proportional hazard regression model. Results Eighty-eight patients were followed-up for a total of 141. 9 person-year,with an average of (1.6 ?.0) years, and the longest of 5. 6 years. Survival was 78 percent, 73 percentand 68 percent in the first month, first year and 2. 5 - 5. 6 years after onset, respectively. Administration ofnimodipine (RR = 0. 981, 95 % CI = 0. 965 - 0. 997, P = 0. 023) was potential protective factor for deaths caused by aSAH. Compared with conservative medical treatment, both surgical occlusion (RR =0. 147, 95% CI = 0. 041 - 0. 532, P = 0. 003) and intervention embolotherapy (RR = 0. 221, 95% CI = 0. 060-0. 823, P= 0.024) were also protective factors. However, complications such as hyponatremia, pulmonary infection, alimentary tract hemorrhage (RR = 1. 965, 95% CI - 1. 404 - 2. 748, P ＜ 0. 05) and cerebral vasospasm (RR = 2. 951, 95% CI = 1. 473 - 5. 911, P = 0. 002) were independent risk factors for aSAH.Conclusions Prognosis in patients with hyponatremia, pulmonary infection, alimentary tract hemorrhage and cerebral vasospasm is unfavorable, and aneurysm occlusion by surgical operation, embolotherapy andadministration of nimodipine all can decrease fatality caused by aSAH.

Key words: 
Subarachnoid hemorrhage;  Aneurysm;  Risk factor;  Survival rate