tbuckley/cabot-search huggingface dataset:
A phase Ib/II study of olutasidenib in patients with relapsed/refractory IDH1 mutant solid tumors: Safety and efficacy as single agent.
Authors: Robin Lewis Jones, Teresa Macarulla, John A. Charlson, Brian Andrew Van Tine, Lipika Goyal, Antoine Italiano, Christophe Massard, Mark Rosenthal, Macarena Ines De La Fuente, Patricia Roxburgh, Madappa N. Kundranda, Jean-Yves Blay, Changhoon Yoo, Kate Lipford, Sanjeev Forsyth, Sylvie Mireille Guichard, Yelena Mikhailov, Blythe Thomson, Patrick Francis Kelly, Florence Duffaud
Journal: Journal of Clinical Oncology (2020)

e16643 Background: Isocitrate dehydrogenase 1 mutations (mIDH1) are present in a variety of solid tumors resulting in production and accumulation of (R)-2-hydroxyglutarate causing DNA hypermethylation and promoting tumorigenesis. Olutasidenib is an oral, potent and selective inhibitor of mutated IDH1 protein. We report preliminary results from the ongoing, first-in-human, Phase 1, open-label, single-arm study of olutasidenib in non-CNS solid tumors. Methods: Patients with advanced relapsed/refractory (R/R) mIDH1 solid tumors received olutasidenib 150 mg BID, orally. Following a dose confirmation cohort (Phase 1b), patients with intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma (CS), or unspecified mIDH1 solid tumors (Other) were enrolled in a Phase 2 efficacy evaluation (NCT: 03684811). Results: As of 31-Oct-2019, 44 patients with relapsed or refractory mIDH1 solid tumors were treated with olutasidenib. Diagnosis included: IHCC (n = 26), CS (n = 13), and Other (n = 5). The median age was 58 years (range: 29-81) and 43% were male. Median number of prior treatments was 2 (1-10). mIDH1 status was locally determined (IHC, NGS or PCR): R132C (61%), R132G (7%), R132S (7%), R132H (2%), R132L (2%), Others (2%) &amp; unspecified (18%). Fourteen patients discontinued treatment (disease progression [n = 6; 3 IHCC, 2 CS, 1 Other], AE [n = 4; 3 IHCC, 1 CS], PI decision [n = 3; IHCC] &amp; withdraw consent [n = 1; IHCC]). Treatment emergent adverse events (all grades, regardless of attribution) that occurred in &gt; 15% of pts were: nausea (43%), fatigue (25%), decreased appetite (22%), AST increase (18%), ALT increase (16%), and constipation (16%). No protocol-defined DLTs occurred. Best responses by tumor type are shown in the table. Conclusions: Single agent olutasidenib at 150 mg BID demonstrates acceptable safety and tolerability with preliminary clinical activity in patients with R/R mIDH1 solid tumors. Updated safety and clinical activity, as well as exploratory evaluations of PK/PD will be provided. Clinical trial information: 03684811 . [Table: see text]
Covid-19: Frontline doctors continue PPE fight
Authors: Alison Shepherd
Journal: BMJ (2020)

Intradermal inoculation of rats at the tail base with Mycobacterium butyricum led to the gradual development of an arthritic swelling of the limbs which peaked at 3 weeks and subsided thereafter. Arthritic rats displayed a loss of body weight, hypophagia, and hypodipsia in addition to a disruption of the diurnal rhythms of ingestive behavior and of core temperature. The activity of adenohypophyseal beta- endorphin-(beta-EP) secreting corticotrophs, in contrast to prolactin- (PRL) secreting lactotrophs, was increased in arthritic rats. Indeed, hypertrophy of the adrenal glands was seen. Arthritic rats also showed an elevation in spinal cord levels of immunoreactive dynorphin (DYN), an endogenous ligand of the kappa-opioid receptor. The paws and tail of arthritic rats showed lower thresholds in response to noxious pressure (hyperalgesia), higher thresholds in response to noxious heat (hypoalgesia), and no change in their response to noxious electrical stimulation. Neither naloxone nor ICI-154, 129 (a preferential delta- receptor antagonist) modified the responses of the paw or tail to pressure. However, MR 2266 (an antagonist with higher activity at kappa- receptors) decreased thresholds to pressure in arthritic, but not control, rats; that is, it potentiated the hyperalgesia. This action was stereospecific. None of the antagonists modified the response to heat. MR 2266 did not affect the response to pressure in rats with acute inflammation produced by yeast. Thus, the potentiation of pressure hyperalgesia by MR 2266 in chronic arthritic rats is highly selective. Arthritic rats showed a reduced response to the analgesic effect of a kappa-agonist (U-50,488H), whereas the response to a mu- agonist (morphine) was enhanced. These effects were specific to nociception in that their influence upon endocrine secretion (PRL and beta-EP) was otherwise changed. The secretion of beta-EP and PRL was stimulated by both morphine and U-50,488H, and the influence of U- 50,488H upon the release of beta-EP (from the adenohypophysis) was enhanced in arthritic rats. It is suggested that polyarthritis is a complex condition entailing many changes, both behavioral and endocrinological. Further, arthritic rats cannot simply be described as “hyperalgesic”: of critical importance is the nature of the nociceptive stimulus applied. The parallel alterations in spinal cord pools of DYN and kappa-receptors (see also Millan et al., 1986) and the changes in the influence on nociception of kappa-agonists and kappa-antagonists suggest an increased activity of spinal DYN. Thus, spinal kappa- receptors may play a role in the modulation of nociception under chronic pain.(ABSTRACT TRUNCATED AT 400 WORDS)
Limited significance of frozen section analysis in nephron sparing surgery
Authors: Lei Shan, Tian-zhong Yan, Xiang-yang Wang, Qi-zhong Li
Journal: BMJ (2010)

One hundred sixty-three cases with a mean age of 58 years (range 21 to 87) underwent nephron sparing surgery due to suspected renal tumors.Mean tumor size was 2.8 cm (range 1.0 to 4.0 cm).Frozen section analysis was routinely performed during surgery,positive tumor margins in frozen section analysis were found in 5 cases (3.1%),and immediate radical nephrectomy was followed.Among 158 cases,in which frozen section analysis showed negative margins,paraffin sections disclosed positive tumor margins in 6 cases (3.8%).Our results suggest that frozen section analysis during nephron sparing surgery has limited clinical significance and hence routine incorporation in urological practice should be reconsidered.

Key words: 
Carcinoma,renal cell; Nephrectomy
Weekly chemotherapy instead of best supportive care alone must be considered for patients of small cell lung cancer with poor performance status.
Authors: Gunjan Shrivastav, Alok Gupta, Neha Sonthwal, Suhas Kirti Singla, Tarun Mohindra, Harit Kumar Chaturvedi, Nitesh Rohatgi
Journal: Journal of Clinical Oncology (2020)

e21102 Background: Many patients of Small Cell Lung Cancer (SCLC) present with advanced age &amp; comorbidities. Although chemotherapy may benefit these patients, therapy is denied due to treatment toxicities. We studied tolerability and efficacy of weekly Etoposide with carboplatin in patients unfit for 3-weekly regimen to analyze the hypothesis if small dose weekly chemotherapy can replace the current standard of care of best supportive care (BSC) alone in patients with poor performance status (PS). Methods: We retrospectively studied consecutive patients of SCLC treated between January 2015- December 2017. Based on team’s assessment, patients received either Etoposide100 mg/m 2 (Day 1,2,3) + Cisplatin25 mg/m 2 (Day 1,2,3) (or Carboplatin AUC5 Day 1) q 21 days OR Etoposide100 mg/m 2 + Carboplatin(AUC2)q weekly OR BSC. Responses at 6-9 weeks of therapy and toxicities were studied according to RECIST 1.1 and CTCAEv4 criteria respectively. Results: 66 patients were diagnosed with SCLC. 24 patients received 3-weekly chemotherapy regimen (Group A). Of the 42 unfit patients, 21(50 %) received weekly chemotherapy regimen (Group B). Median age was higher in Group B ( 66 vs 61 yrs ) and Co-morbidities (≥ 2)were also more in Group B, 53 vs 33 %. Furthermore, Group B had more brain metastases (38 vs 21 %) but there was equal distribution of liver metastases and SVCO (4 patients each group). Altogether Group B had worse prognostic patients. In Group A the median number of chemotherapy cycles received were 4.5 (1-8) over a median duration of 3.37 months (0.75 - 6) while in group B the median number of chemotherapy cycles were 2 (1-5) over 1.5 months (0.5 - 3.75). G-CSF was required in 22(92%) in Group A and 15(71%) in Group B. Grade 3-4 toxicity and Febrile neutropenia were seen in 11(46%) and 7(29%) patients in Group A respectively and 8(38.1%) and 7(33%) patients in Group B respectively. Progressive disease was seen in 3(13%) and 6(29%) patients in group A and B respectively. Objective response was seen in 14(59%) and 9(43%) in Group A and B respectively. Clinical benefit rate (CBR) (Objective response + Stable disease) was 75% in Group A and 57% in Group B. Among patients with brain metastasis, CBR was 60% in Group A and 50% in Group B. This was better than most patients that are not offered treatment. Conclusions: Although 3 weekly doublet remains a better regimen, weekly etoposide and platinum is a valid option for patients unfit for standard regimen with no excess toxicity. Clinical benefit is seen irrespective of poor prognostic features.
Intraoperative Detection of Hyperplastic Parathyroid Gland With Positron Emitter 18F-Fluorocholine and Handheld Probe
Authors: Anja Tea Golubić, Frano Poljak, Boris Bumber, Dražen Huić
Journal: Clinical Nuclear Medicine (2020)

Abstract We present the first intraoperative detection of a hyperplastic parathyroid gland with a positron emitter 18 F-fluorocholine and handheld probe, with the estimation of the absorbed dose to the surgeon and surgical staff. Intraoperative positron emitter detection enabled the resection of a small parathyroid gland, resulting in normal postoperative values of PTH and serum calcium in a 69-year-old woman. Calculated whole-body dose to the surgical staff and surgeons’ fingers is well below the annual limits for exposed workers and the general public. Intraoperative 18 F-FCH detection with handheld probe is a safe and feasible method for localizing small parathyroid glands.
关于社区医生对《阻塞性睡眠呼吸暂停与糖尿病专家共识》提问的答复
Authors: 高雪梅, 何权瀛
Journal: BMJ (2010)

问:对诊断为阻塞性睡眠呼吸暂停综合征的患者,其下颌后缩、小下颌畸形、咽腔狭窄如何判定? 阻塞性睡眠呼吸暂停低通气综合征(obstructive sleep apnea and hypopnea syndrome,OSAHS)患者常常伴有以下体征:下颌后缩、小下颌畸形、咽腔狭窄、舌体软腭肥大、舌骨低位等.OSAHS的诊断以症状加多导睡眠监测来得出,体征和OSAHS之间没有主要关系,也就是说,OSAHS不一定都有下颌后缩、小下颌畸形、咽腔狭窄等,下颌后缩、小下颌畸形、咽腔狭窄也并非必然导致 OSAHS。
Defining the tumor cell: CA-MSC interactions which mediate ovarian cancer metastasis.
Authors: Ester Goldfeld, Huda Atiya, Leonard Frisbie, Lan Gardner Coffman
Journal: Journal of Clinical Oncology (2020)

e18072 Background: Carcinoma-associated mesenchymal stem cells (CA-MSCs) are mesenchymal stem cells (MSCs) within the tumor microenvironment (TME). We demonstrated that CA-MSCs promote ovarian cancer chemotherapy resistance through paracrine signaling with ovarian cancer cells, interact with ovarian cancer cells to form mixed-cellularity complexes which enhance metastasis, and arise from cancer cell and TME reprogramming of normal tissue MSCs. To identify mediators of the CA-MSC:tumor cell interaction, we investigated the role of tetraspanins, which are membrane-spanning proteins that have been implicated in cancer development and metastasis by influencing cell adhesion and cell-cell interactions. The tetraspanins CD9, CD81, CD151, and CD63 were identified as potential mediators of cell surface interactions between ovarian cancer cells and CA-MSCs through homo- and heterodimerization. Methods: Td-labeled OVCAR3 cancer cells were co-cultured with 3 patient-derived MSC (derived from normal tissue) and 3 patient-derived CA-MSC (derived from malignant tissue) cell lines. Flow cytometry was performed to measure surface protein expression of the tetraspanins CD9, CD81, CD151, and CD63, and was compared to control cells (not co-cultured) and their median fluorescence intensity (MFI). We next separated OVCAR3 cells co-cultured with MSCs or CA-MSCs using fluorescent activated cell sorting (FACS) based on Td expression. Following FACS, tetraspanin expression in OVCAR3 cells, MSCs, and CA-MSCs was assessed via qRT-PCR and western blotting, and compared to cell lines that were not co-cultured. Results: Flow cytometric analysis revealed an increase in MFI of CD9 and CD151 in co-cultured OVCAR3 cells, as well as CD81 and CD63 in co-cultured CA-MSCs and MSCs when compared to non-co-cultured matched cells. Increased RNA expression of CD9, CD151, and CD63 was seen in OVCAR3 cells that were co-cultured with CA-MSCs or MSCs when compared to non-co-cultured OVCAR3 cells. Increased RNA expression of CD81 and CD63 was noted in both co-cultured CA-MSCs and MSCs compared to non-co-cultured cells. Lastly, western blotting demonstrated increased protein expression of CD9 and CD151 in co-cultured OVCAR3 cells, as well as CD81 and CD63 in co-cultured CA-MSCs and MSCs compared to non-co-cultured matched cells. Conclusions: These results indicate that direct interactions between OVCAR3 cells and CA-MSCs or MSCs lead to overexpression of specific tetraspanins at the RNA and protein levels, implying that they may be facilitating tumor cell:CA-MSC and tumor cell:MSC binding.
Abstract 10894: Cerebral Energy Metabolism and Pools of Neurotransmitters Related to the Use of Deep Hypothermic Circulatory Arrest in Infant Piglets
Authors: Masaki Kajimoto, Dolena R Ledee, Aaron K Olson, Nancy G Isern, Christine Des Rosiers, Michael A Portman
Journal: Circulation (2015)

Introduction: Complex congenital cardiac defect repair in infants often requires deep hypothermic circulatory arrest (DHCA). As immediate or late neurological complications still occur, adjunctive selective cerebral perfusion (SCP) theoretically provides superior neural protection by supplying oxygen and substrate and maintaining energy metabolism. Hypothesis: SCP preserves glucose utilization, energy metabolism, and glutamate cycling in comparison to DHCA alone. Methods: Fourteen male Yorkshire piglets (age 34-44 days) were assigned randomly to 2 groups (DHCA or SCP for 60 minutes at 18°C). Cerebral perfusion through 1st branch of aorta was maintained at 40 ml/kg/min during SCP. After the completion of rewarming, 13-Carbon-labeled glucose ( 13 C-glucose) was infused through common carotid artery for 1 hour under continuous cardiopulmonary bypass support and then cerebral tissue was extracted. Gas chromatography-mass spectrometry and nuclear magnetic resonance were used for cerebral metabolic analysis in the frontal cortex of brain. Results: There were no operative or technical complications in any groups. Cerebral rSO 2 in simple DHCA dropped substantially to ~ 25% during DHCA, but maintained over 80% in SCP. Apoptosis by TUNEL assay was significantly less in SCP at 2.5 hours after DHCA. ATP levels in the extracted cerebral tissue were similar between 2 groups but glycogen store were higher in SCP. Absolute levels of lactate and citric acid cycle intermediates and their 13 C-enrichment were similar in the cerebral tissue between the 2 groups. However, SCP increased absolute and 13 C-enrichment for glutamate and compared to DHCA, while gamma aminobutyric acid (GABA) increased in DHCA. Conclusions: SCP added to DHCA does not provide additional ATP preservation or modify glucose oxidation. However, SCP does alter glucose cycling into alternate pathways, leading to preservation of glycogen, and shifts flux away from GABA, a major inhibitory neurotransmitter, and towards glutamate. These flux changes suggest that SCP decreases synaptic inhibition, which may relate to the reduced neural apoptosis.
Experience on general practitioner training in community health care center
Authors: Ting Li, Yaqin Cheng, Yikai Mi, Fulai Shen, Chuntao Yi
Journal: BMJ (2017)

General practitioner represents the core competency of community health care center and also the key for sustainable discipline development.Talent developing is regard as critical issue for both discipline construction and community health service development.Community health care center, as a platform for internship, practice and continue medical education of medical professionals, plays an important role in career development of general practitioner.We clearly defined the role and responsibility of community health care center in general practicing talent development, and built an excellent career development platform.We integrated project-talent-discipline three-in-one to promote clinical research and talent development; applied two-factor theory to set up effective talent plan and incentive mechanism.This article summarized our approach and experience in talent development as a reference for colleagues in other community centers.


Key words: 
Community health care; General practice; Talent development
ASPEN: Results of a phase III randomized trial of zanubrutinib versus ibrutinib for patients with Waldenström macroglobulinemia (WM).
Authors: Constantine Si Lun Tam, Stephen Opat, Shirley D'Sa, Wojciech Jurczak, Hui-Peng Lee, Gavin Cull, Roger G. Owen, Paula Marlton, Bjorn E. Wahlin, Alessandra Tedeschi, Jorge J. Castillo, Tanya Siddiqi, Christian Buske, Veronique Leblond, Wai Y. Chan, Jingjing Schneider, Sunhee K. Ro, Aileen Cohen, Jane Huang, Meletios A. Dimopoulos
Journal: Journal of Clinical Oncology (2020)

8007 Background: Bruton tyrosine kinase (BTK) inhibition is an emerging standard of care for WM. ASPEN is a randomized phase 3 study comparing zanubrutinib (ZANU), a potent and selective BTK inhibitor, versus ibrutinib (IBR), a first generation BTK inhibitor, in WM patients. Methods: Patients with WM and MYD88 mutation were randomly assigned 1:1 to receive ZANU (160 mg twice daily) or IBR (420 mg once daily). Patients without MYD88 mutations were assigned to a separate cohort, received ZANU, and are reported separately. Randomization was stratified by CXCR4 mutational status and the number of lines of prior therapy (0 vs 1-3 vs &gt;3). The primary end point was the proportion of patients achieving a complete response or very good partial response (CR+VGPR). Sample size was calculated to provide 81% power to detect a difference in CR+VGPR rate of 35% vs 15% in the subset of patients with relapsed or refractory (R/R) WM. Primary analysis was planned to occur at ~ 12 months after last patient enrolled. Results: In total, 201 patients were randomized from Jan 2017 to Jul 2018. The treatment groups were well balanced for important baseline factors, except in the ZANU arm there were more elderly patients (aged &gt;75 years, 33.3% vs 22.2%) and more anemia (hemoglobin ≤110 g/L, 65.7% vs 53.5%). At a median follow-up of 19.4 months, the rate of CR+VGPR was 28.4% vs 19.2% with ZANU vs IBR, respectively (2-sided P=0.09). Rates of atrial fibrillation, contusion, diarrhea, edema peripheral, hemorrhage, muscle spasms, pneumonia, and adverse events (AEs) leading to discontinuation or death were lower with ZANU. The rate of neutropenia was higher with ZANU (Table); however, grade ≥ 3 infection rates were similar (17.8% vs 19.4%). Conclusions: ASPEN is the largest phase 3 trial of BTK inhibitors in WM and the first head-to-head comparison of BTK inhibitors in any disease. Although not statistically significant, ZANU was associated with a higher CR+VGPR response rate, and demonstrated clinically meaningful advantages in safety and tolerability compared to IBR. Clinical trial information: NCT03053440 . [Table: see text]
Status of general practice residency training and career choice of trainees in Henan Province
Authors: Xiaoyu Liu, Bing Li, Yudong Miao, Shuyi Wang, Hongwei Xu, Liuyi Wang
Journal: BMJ (2020)

Objective
To survey the status general practice residency training and career choice of trainees in Henan Province.


Methods
From December 2017 to February 2018, 332 trainees from the first general practice residency training program (2014-2017) were enrolled in the study. The self- administered questionnaire included the demographic information and the current career status. The logistic regression model was used to analyze the influencing factors of the career choice when their completed the training.


Results
Of 332 participants, there were 167 participants designated by the institutions and the others were directly enrolled by the program. The designated participants were from the 56 medical institutions in Henan. The percentage of participants from the tertiary hospitals was 75.5% (126/167), which was much higher than that from the secondary hospitals (24.5%,41/167). There were 24 participants who did not have a work six months after graduation. Of the 308 employed participants, there were only 111 (36.0%, 111/308) working in the department of general practice, and 197 (64.0%, 197/308) working in other departments. The participants designated by the institutions and with the post-graduate degrees preferred to choose other specialties, instead of the general practice. The reasons were that there was no department of general practice in their institutions or the participants had been designated to the other departments (57.9%, 114/197).


Conclusion
The survey suggests that the general practice residency training program should enroll trainees mainly from the medical graduates in order to improve the effectiveness of general practitioner residency training and the allocation of health resources in Henan Province.


Key words: 
Inservice training; Employment; General practitioner
Fatigue trajectories in long-term non-Hodgkin lymphoma survivors.
Authors: Matthew Roger LeBlanc, Sheryl Zimmerman, Mariam Kayle, Thomas William LeBlanc, Kathryn Elizabeth Hudson, Sophia Kustas Smith
Journal: Journal of Clinical Oncology (2020)

e20053 Background: Fatigue is a common and distressing effect of cancer and its treatment. Prior research suggests fatigue persists long after diagnosis and treatment in non-Hodgkin lymphoma (NHL) survivors. This study aimed to identify distinct trajectories of fatigue in NHL survivors and predictors of trajectories that could inform clinical care. Methods: Our secondary analysis used data from a longitudinal study of NHL survivors (n = 886) at least 2 years post-diagnosis. Fatigue was measured using the SF-36 vitality subscale across three time points. Prior literature informed the selection of baseline demographic (e.g. age, gender, race) and disease characteristics [e.g. NHL type, comorbidities, post-traumatic stress disorder (PTSD)] explored as possible predictors of fatigue trajectories. We used group-based trajectory modeling to identify distinct groups of patients experiencing similar patterns of fatigue. Variables significant in bivariate analysis were included in a stepwise multinomial logistic regression to identify factors predictive of group membership. Results: We identified four distinct trajectories that suggest levels of fatigue persist unchanged over time. The Low Fatigue Group (15.6%) experienced less fatigue than the general population. The Population Norm Group (42.5%) experienced a similar level of fatigue to the general population mean. The Significant Fatigue Group (27.5%) experienced fatigue levels almost one standard deviation worse than the general population. The Worst Fatigue Group (14.3%) experienced fatigue almost two standard deviations worse than the population norm. PTSD symptoms and comorbidity scores were predictive of levels of fatigue over time. Greater age at diagnosis increases the odds survivors experienced worse fatigue than the population mean (Table). Conclusions: Levels of fatigue experienced early in an NHL patients’ disease trajectory may persist for many years. Higher levels of PTSD symptoms and comorbidities were predictive of worse fatigue over time. Early interventions addressing PTSD symptoms and comorbidities may improve long term fatigue outcomes. [Table: see text]