tbuckley/cabot-search huggingface dataset:
An open-label, multicenter, phase Ib/II study of rebastinib in combination with paclitaxel in a dose-expansion cohort to assess safety and preliminary efficacy in patients with advanced or metastatic endometrial cancer.
Authors: Filip Janku, Erika Paige Hamilton, Christina Chu, Debra L. Richardson, Rebecca Christian Arend, Keisuke Kuida, Haroun Achour, Rodrigo Ruiz-Soto, John L. Hays
Journal: Journal of Clinical Oncology (2020)

6085 Background: Rebastinib is a switch control inhibitor targeting tunica interna endothelial cell kinase (TIE2). TIE2 is primarily expressed in endothelial cells playing a role in angiogenesis. TIE2 is also expressed in a subset of macrophages with pro-metastatic and immunosuppressive properties and linked to chemo-resistance. This study is a 2-part open-label, phase Ib/II, multicenter study of rebastinib orally administered, in combination with paclitaxel. In Part 1, we observed encouraging antitumor activity of rebastinib with 5 PRs in 24 patients (pts) at 50 mg BID and 3 PRs in 19 pts at 100 mg BID from a heavily pretreated heterogeneous patient population. Here we summarize preliminary results from the endometrial cancer (EC) cohort of Part 2. Methods: Part 2 of this study has four disease-specific cohorts (TNBC, inflammatory breast cancer, ovarian cancer and EC). Pts were evaluated for safety (CTCAE v5.0) and efficacy (RECIST v1.1). According to the Simon 2-stage design of this study, for each cohort, 15 additional pts will be enrolled if more than 4 PRs are observed. Results: As of Jan 21, 2020, 19 EC pts were enrolled with a median age of 66 years. All pts received at least one prior line of paclitaxel and 12 (63%) pts received &gt;3 prior anti-cancer therapies. Sixteen pts were treated with rebastinib starting dose 100 mg BID (reduced to 50 mg BID due to a higher frequency of muscular weakness) and 3 pts with 50 mg BID, in combination with 80 mg/m 2 weekly paclitaxel with a median duration of treatment 85 days (6, 225). In 15 evaluable pts, there were 5 PRs (4 confirmed) and 6 SD 8 weeks for an ORR of 33% and clinical benefit rate of 73%. Treatment-emergent AEs (&gt;20%) were mostly ≤ grade 2: constipation, fatigue (each n=9); alopecia, peripheral edema (each n=8); dysgeusia, peripheral sensory neuropathy, arthralgia (each n=6); diarrhea, hypomagnesaemia, vomiting, dry mouth (each n=5); anemia, decreased appetite, dyspnea, nausea, and muscular weakness (each n=4). Serious AEs possibly related or related to rebastinib included muscular weakness (n=2, at 100 mg BID), head discomfort (n=1) and increase troponin (n=1) which resolved after dose interruption. Conclusions: Preliminary activity of rebastinib in combination with paclitaxel was encouraging in heavily pretreated EC pts, all of whom received prior paclitaxel. The safety profile of rebastinib at 50 mg BID was generally well tolerated. The EC cohort is enrolling at 50 mg BID in stage 2 of the study. Clinical trial information: NCT03601897.
Primary analysis of KAITLIN: A phase III study of trastuzumab emtansine (T-DM1) + pertuzumab versus trastuzumab + pertuzumab + taxane, after anthracyclines as adjuvant therapy for high-risk HER2-positive early breast cancer (EBC).
Authors: Nadia Harbeck, Seock-Ah Im, Carlos H. Barrios, Herve R. Bonnefoi, Julie Gralow, Masakazu Toi, Paul Ellis, Luca Gianni, Sandra M. Swain, Young-Hyuck Im, Michelino De Laurentiis, Zbigniew Nowecki, Jigna Shah, Thomas Boulet, Haiying Liu, Harrison Macharia, Peter Trask, Chunyan Song, Eric P. Winer, Ian E. Krop
Journal: Journal of Clinical Oncology (2020)

500 Background: The standard of care for HER2-positive EBC is chemotherapy plus one year of HER2-directed therapy. However, recurrence—particularly in high-risk populations—remains a problem, as does systemic chemotherapy-associated toxicity. In KAITLIN, we aimed to improve efficacy and reduce toxicity by replacing taxanes and trastuzumab with T-DM1. Methods: KAITLIN (NCT01966471) is a phase 3, randomized, open-label study that enrolled 1846 patients with adequately excised, centrally confirmed HER2-positive EBC either node-positive (LN+); or node-negative, HR-negative, and tumor size &gt; 2.0 cm. Within 9 weeks of surgery, patients were randomized 1:1 to 3-4 cycles of anthracycline-based chemotherapy followed by 18 cycles of T-DM1 3.6 mg/kg + pertuzumab 420 mg q3w (loading dose [LD] 840 mg) (AC-KP) or taxane (3-4 cycles) + concurrent trastuzumab 6 mg/kg (LD 8 mg/kg) + pertuzumab 420 mg q3w (LD 840 mg) (AC-THP). Patients were stratified by world region, nodal status, HR status, and anthracycline type. Adjuvant radiotherapy and/or endocrine therapy was administered after 4 cycles of HER2-targeted therapy when indicated. The co-primary endpoints were invasive disease-free survival (IDFS) in the LN+ and in the ITT populations applying a hierarchical testing procedure. Secondary endpoints included overall survival (OS), patient-reported outcomes (PROs), and safety. Results: KAITLIN did not meet its co-primary endpoints. In LN+ patients (n = 1658), there was no significant difference between arms in IDFS event risk (stratified hazard ratio = 0.97; 95%CI 0.71–1.32). Three-year IDFS was 94.1% with AC-THP and 92.7% with AC-KP. Results were similar in the ITT population (stratified hazard ratio = 0.98; 95%CI 0.72–1.32; 3-year IDFS: 94.2% vs 93.1%). OS data are immature with an event rate of ~4%–5% in each arm. During the study overall, there was a similar incidence of grade ≥3 AEs (55.4% vs 51.8%) and SAEs (23.3% vs 21.4%) with AC-THP and AC-KP, respectively. More patients receiving AC-KP than AC-THP discontinued T-DM1 or trastuzumab, respectively, because of AEs (26.8% vs 4.0%). PRO data will be presented. Conclusions: Replacing adjuvant taxane and trastuzumab with T-DM1 did not result in significantly improved efficacy or overall safety. Nonetheless, in this high-risk population, a favorable IDFS outcome was achieved in both study arms. HP + chemotherapy remains the standard of care for patients with high-risk HER2-positive EBC. Clinical trial information: NCT01966471 .
Prophylactic anticoagulation for pregnant women with high risk of thrombosis
Authors: Suhan Lin, Caiyun Song, Rongying Ou
Journal: BMJ (2016)

Pregnant women are usually in a hypercoagulable state; if it is complicated with high risk conditions of thrombosis, such as obesity, pregnancy-induced hypertension, mechanical heart valve replacement, systemic lupus erythematosus and antiphospholipid syndrome, prophylactic anticoagulation therapy with heparin/warfarin will be required. Due to pros and cons of heparin/warfarin, there is a controversy about how to choose anticoagulants. This article reviews the current status and progress of drug prophylaxis for thrombosis disease, and related issues particularly for administration of heparin and warfarin.


Key words: 
Pregnant women; Thrombophilia; Protective agents
Advances in clinical use of pamidronate disodium
Authors: 钟永祥, 张祥斌
Journal: BMJ (2005)

帕米膦酸二钠(pamidronate disodium)为第二代双膦酸盐类药物,是破骨细胞性骨溶解抑制剂,能牢固地吸附在骨小梁表面,形成一层保护膜,选择性地阻挡破骨细胞的骨溶解作用,并有抑制破骨细胞发育成熟,抑制其向骨表面移动的作用,其抗骨溶解效力为羟乙双膦酸盐的100倍,氯甲双膦酸盐的10倍,是目前常用的有修复骨溶解病灶作用的双膦酸盐制剂,具有较广泛的临床适应证.作者对帕米膦酸二钠新的临床应用及不良反应加以综述。
A phase II randomized trial of RAdium-223 dichloride and SABR versus SABR for oligomEtastatic prostate caNcerS (RAVENS).
Authors: Matthew Pierre Deek, Hamza Hasan, Ryan Phillips, Robert F Hobbs, Ana Ponce Kiess, Hao Wang, Elizabeth D Thompson, Jonathan Powell, Curtiland Deville, Stephen C. Greco, Danny Song, Steven P. Rowe, Samuel R. Denmeade, Mark Christopher Markowski, Emmanuel S. Antonarakis, Michael Anthony Carducci, Mario A. Eisenberger, Kenneth J. Pienta, Channing Judith Paller, Phuoc T. Tran
Journal: Journal of Clinical Oncology (2020)

TPS5586 Background: Metastasis directed therapy (MDT) is able to prolong progression free survival (PFS) and forestall initiation of androgen deprivation therapy (ADT) in men with hormone-sensitive, oligometastatic prostate cancer (HSOPCa) compared to observation. While MDT appears to be effective in HSOPCa, a large percentage of men will have disease recurrence. Patterns of failure demonstrate patients tend to recur in the bone following MDT, raising the question of sub-clinically-apparent osseous disease. Radium-223 dichloride is a radiopharmaceutical with structural similarity to calcium, allowing it to be taken up by bone where it emits alpha particles, and therefore might have utility in the treatment of micrometastatic osseous disease. Therefore, the primary goal of the phase II RAVENS trial is to evaluate the efficacy of Stereotactic ablative radiation (SABR) + radium-223 dichloride in prolonging PFS in men with HSOPCa. Methods: Patients with HSOPCa and 3 or less metastases with at least 1 bone metastasis (by conventional imaging) will be randomized 1:1 to SABR alone vs. SABR + radium-223 dichloride. Eligibility criteria include PSA doubling time of &lt; 15 months and ECOG performance status of &lt; 2. Patients cannot be on ADT and must have normal testosterone levels at the time of randomization. Patients randomized to the combination arm will receive six doses of Radium-223 dichloride at four week intervals. A sample size using a 1:1 randomization scheme of 30 patients per arm will provide 80% power to detect an increase of median PFS from 10 months to 20 months with type I error = 0.1, using a one-sided log-rank test. To account for 5% early drop out, we will randomize a total of 64 patients (32 per arm). The primary end point is PFS with a primary hypothesis that SABR + radium-223 dichloride will increase median PFS from 10 months in the SABR arm to 20 months in the SABR + radium-223 dichloride arm. Progression is a composite endpoint including PSA progression per Prostate Cancer Working Group 2 (PCWG2), symptomatic progression, radiologic progression per RECIST 1.1 criteria, initiation of ADT, or death due to any cause. Secondary clinical endpoints include toxicity and quality of life assessments, local control at 12 months, locoregional progression, time to distant progression, time to new metastasis, and duration of response. Biological correlates will be evaluated including changes in circulating tumor cells following therapy, deep sequencing of circulating tumor DNA, and T-cell repertoire profiling before and after therapy. Clinical trial information: NCT04037358 .
Just-in-Time Teaching (JiTT) screencasts for the resident inpatient oncology service: A pilot study evaluating feasibility and effectiveness.
Authors: Patrick Kuhlman, Donna Williams, Amy Amornmarn, Joshua Harbaugh, Thomas Lycan
Journal: Journal of Clinical Oncology (2020)

11025 Background: Just-in-Time Teaching (JiTT) screencasts have been viewed positively in some undergraduate and graduate medical settings. JiTT screencast effectiveness has not yet been evaluated for medical trainees in the inpatient adult hematology/oncology setting. Objectives: Our pilot study’s goal was to identify relevant learning objectives, to assess feasibility of screencast development, and to optimize screencast delivery. Methods: To identify key clinical topics, a mixed methods approach first utilized institutional retrospective data (6/1/2018-6/30/2019) to determine the most common inpatient medical problems followed by qualitative interviews of teaching faculty and senior residents. The following six topics were identified for inclusion: 1. Metastatic disease to spine 2. Brain metastases 3. Oncologic emergencies 4. Cancer associated venous thromboembolism 5. Hematologic emergencies 6. Sickle cell disease: inpatient management For each topic, a literature review was performed to develop teaching points which were then refined with input from clinician experts. Each screencast went through several rounds of edits by faculty and trainees prior to submission to the instructional design team for final editing. Screencast length ranged from 13 – 25 minutes (mean of 18 minutes). Qualitative and quantitative feedback was obtained from residents by structured focus group session and online surveys. Results: All residents reported that educational content was “just right.” The series of 6 screencasts was completed within 2 months of dedicated fellow research time. Preferred screencast length was 10-20 minutes and preferred viewing speed was 1.5x original speed (7/10). All residents reported that a screencast database would be a helpful resource for future clinical rotations. All residents (n = 10) reported that screencasts improved medical oncology knowledge base and will improve care provided to cancer patients. Conclusions: Creation of a screencast series was feasible for a hematology-oncology fellow. Systematic identification of key clinical topics led to materials which were confirmed by faculty and trainees to be important for internal medicine medical education on inpatient oncology services. This pilot data indicate that JiTT screencasts may be an effective educational intervention and directly informed a randomized educational research study which is currently enrolling participants.
Multiomics profiling of longitudinal melanoma specimens unravels molecular mechanisms of resistance to sequential targeted and cancer immunotherapies.
Authors: Jinho Lee, Marilyne Labrie, Gen Yong, Todd Camp, Hongli Ma, Megan Grout, Wei Xu, Georgia Beasley, Lynn Mara Schuchter, Suzanne McGettigan, Donald M. O'Rourke, Meenhard Herlyn, Christopher L. Corless, Gordon B. Mills, Gao Zhang
Journal: Journal of Clinical Oncology (2020)

e22015 Background: We evaluated spatially-resolved protein profiling of longitudinal tumor specimens derived from two patients with metastatic melanoma who progressed on sequential therapies including targeted therapy (TT) and immune checkpoint blockade (ICB) therapy targeting T cell-surface antigens (CTLA-4 and PD-1). The purpose of this study was to identify molecular determinants of resistance to sequential TT and ICB therapies. Methods: We performed multiplexed and multidimensional spatial protein profiling using NanoString’s GeoMx Digital Spatial Profiling (DSP) platform and single-cell level imaging analysis with Cyclic Immunofluorescence (CycIF) to simultaneously determine dynamic changes in tumor intrinsic signaling pathways and immune response in the tumor microenvironment (TME). Results: The first patient presented with a BRAF V600E -positive brain metastasis. This patient was sequentially treated with ipilimumab (Ipi), the combination of dabrafenib and trametinib, and pembrolizumab (Pembro) and progressed despite of high expression of CD56 NK cell after all treatments. In addition, CycIF analysis revealed drug resistance in a subpopulation of cells that had continued activation of mTOR (pS6) and EGFR pathways. The second patient presented with dermal metastases on the flank with NRAS Q61K mutation. This patient was sequentially treated with Pembo, Talimogene Laherparepvec, the combination of Ipi plus nivolumab, and two different investigational agents combined with Pembro. This patient displayed stable disease (SD) on Pembro but eventually progressed on the subsequent therapies. DSP analysis demonstrated CD68/CD40 myeloid cell infiltrates as well as HLA-DR and CD44 in the TME after the last treatment. CycIF analysis revealed dynamic changes in tumoral characteristics including DNA damage and proliferation during treatment. Furthermore, the analysis suggested that there might be a resistant subpopulation in the last tumor biopsy, which is in line with progression of the disease. Conclusions: In this study, we conducted detailed analyses on serial specimens from two patients to precisely define the spatial distribution of immune responses and cancer signaling pathways. The findings propose that concurrent proteomics analysis and immune monitoring of longitudinal tumor biopsies can be informative in clinical evaluation in order to identify salvage therapies to overcome drug resistance.
老年糖尿病患者肺部感染的临床特点和病原学分析
Authors: 刘成国, 阮连生, 郭琼瑶
Journal: BMJ (2007)

将2001年至2005年收治的老年2型糖尿病合并肺部感染者78例作为感染组,同期无肺部感染的2型糖尿病者307例.结果 表明,2型糖尿病患者合并肺部感染情况与病程、血糖控制及慢性并发症相关;肺部感染以革兰阴性杆菌为主,对亚胺硫霉素、头孢曲松较为敏感;革兰阳性球菌对万古霉素敏感.积极控制血糖及正确使用抗生素,是治疗2型糖尿病合并肺部感染的关键。
IBI310 monotherapy or in combination with sintilimab in patients with advanced melanoma: An open-label phase Ia/1b study.
Authors: Bin Lian, Chuanliang Cui, Lu Si, Xinan Sheng, Zhihong Chi, Lili Mao, Bixia Tang, Xuan Wang, Xieqiao Yan, Siming Li, Xue Bai, Li Zhou, Jun Guo, Hui Zhou, Huan Xia
Journal: Journal of Clinical Oncology (2020)

e15111 Background: IBI310 is a humanized IgG1 monoclonal antibody against CTLA-4. The study evaluates the safety and tolerability of IBI310 alone or in combination with sintilimab, a PD-1 inhibitor, in patients (pts) with advanced melanoma. Methods: This phase 1a/1b study contained three parts: Part A, Part B and Part C (NCT03545971). In Part A, pts with advanced melanoma were treated in an accelerated titration design with 0.3 mg/kg IBI310 (Q3W, IV), or a 3+3 escalation design with 1, 2 or 3 mg/kg IBI310 (Q3W, IV), up to 3 cycles. In Part B, pts with advanced melanoma were administrated in a 3+3 escalation design with 1, 2 or 3 mg/kg IBI310 (Q3W, IV) plus sintilimab (200 mg, Q3W, IV) for 4 cycles, followed by sintilimab maintenance therapy (200 mg, Q3W, IV). Part C was dose expansion of the combination therapy. The primary objective was to determine dose-limiting toxicity (DLT) of IBI310 monotherapy and the second was efficacy of the combination therapy. Tumor evaluation was based on RECIST 1.1. Results: As of Nov 12, 2019, 10 pts were enrolled in Part A (median age 55.5), 6 were mucosal melanoma, 3 were acral melanoma and 1 was non-chronic sun damaged (NCSD) melanoma; 17 pts were enrolled in Part B and C (median age 47.0), only 1 (5.9%) was chronic sun damaged (CSD), and 16 (94.1%) were other melanoma types, including 12.5% (2/16) acral, 31.3% (5/16) mucosal and 56.3% (9/16) NCSD melanomas. No DLTs were observed in both Part A and B. In Part A, 9 pts occurred treatment-related adverse events (TRAEs), most commonly pruritus (4 pts), blood thyroid stimulating hormone increased (2 pts), and asthenia (2 pts). No AEs of ≥ grade 3 were reported. Five pts had stable disease (SD). In Part B and C, 13 pts reported TRAEs, only 1 pt occurred grade 3 TRAE (aspartate aminotransferase increased in 3mg dose level), and others reported grade 2, most commonly pruritus (8 pts), rash (7 pts) and alanine aminotransferase increased (6 pts). No AEs leading to death. In evaluable pts in combination with sintilimab, 1 (NCSD melanoma) of 7 pts (3 NCSD, 1 acral, 2 mucosal and 1 CSD melanoma) reached confirmed partial response (PR) in 2 mg group, and 1 (acral melanoma) of 3 pts (1 acral, 1 mucosal and 1 NCSD melanomas) reached confirmed PR in 3 mg group. Five pts had SD. Part C is currently ongoing. Conclusions: IBI310 monotherapy or in combination with sintilimab were well-tolerated without unanticipated AEs in pts with advanced melanoma. The data preliminarily demonstrate an antitumor activity of the combination therapy in previously treated advanced melanoma (acral and NCSD melanomas). Clinical trial information: NCT03545971 .
STAT6 expression and trastuzumab resistance in HER2+ breast cancer.
Authors: Melody A. Cobleigh, Molly DiScala, Matthew S. Najor, Timothy Yung, Abde M. Abukhdeir
Journal: Journal of Clinical Oncology (2020)

e13006 Background: Approximately 20% of breast cancers are HER2-positive. Trastuzumab has improved patient outcomes significantly for these cancers. However, acquired resistance occurs in almost all patients with metastatic breast cancer. Therefore, identifying molecular changes that are associated with trastuzumab resistance is worthwhile. STAT6 is a transcription factor that regulates a variety of genes involved in cell cycle regulation, growth inhibition, and apoptosis. STAT6 expression is lost in approximately 3% of breast cancers, but little work has been done in the context of trastuzumab resistance in breast cancer. Methods: In isogenic cell line pairs, we observed that trastuzumab-resistant cells expressed significantly lower levels of STAT6 compared to trastuzumab-sensitive cells. Therefore, in order to study the consequences of STAT6 loss in HER2+ breast cancer, we knocked out both alleles of the STAT6 gene using somatic cell gene targeting. Results: We observed that loss of STAT6 resulted in resistance to trastuzumab treatment in HER2-over-expressing cells. Additionally, loss of STAT6 resulted in anchorage-independent growth and changed expression of several genes involved in epithelial to mesenchymal transition. Functional studies revealed that STAT6 loss caused a non-tumorigenic human breast cell line to form tumors in mice. Conclusions: Loss of STAT6 in breast cells results in enhanced growth properties and resistance to trastuzumab. This study suggests that STAT6 may play a role in the pathophysiology of HER2+ human breast cancer. Disclaimer: The work herein was completed while AMA was a faculty member at Rush University. AMA is currently an employee with the U.S. Food and Drug Administration. The views and data in this publication do not reflect the opinions of the U.S. Government or The U.S. Food and Drug Administration.
妊娠和产后甲状腺疾病诊治指南(节选一)
Authors: 中华医学会内分泌学分会, 中华医学会围产医学分会
Journal: BMJ (2012)

[前言]妊娠期甲状腺疾病是近十年来内分泌学界和围产医学界研究的热点领域之一.其起因是20世纪80年代末期荷兰学者Vulsma等首次发现甲状腺激素合成障碍和无甲状腺新生儿的脐带血中存在甲状腺激素,从而推翻了母体甲状腺激素不能通过胎盘的传统观点。
Cytotoxic effect of unclassified group K rotaviruses on T98G and U87MG glioblastoma cells in vitro.
Authors: Anastasia O. Sitkovskaya, Oleg I. Kit, Sergey A. Kolpakov, Elena P. Kolpakova, Elena Yu. Zlatnik, Svetlana Yu. Filippova, Irina V. Mezhevova, Elena S. Bondarenko, Eduard E. Rostorguev, Sergey N. Ignatov, Natalya S. Kuznetsova, Dmitriy P. Atmachidi, Sergey E. Kavitskiy, Inna A. Novikova, Liubov Yu Vladimirova
Journal: Journal of Clinical Oncology (2020)

e15597 Background: Oncolytic virotherapy is developing intensively in modern oncology. Viruses demonstrate the ability to the direct oncolysis and to the stimulation of antitumor immune activity; this experiment was aimed at solving the question of the prevalence of one of them. Glial tumors are the most common brain tumors; oncolytic viruses show certain prospects in their treatment due to the ability to penetrate the blood-brain barrier. The aim of the study was to determine the possible oncolytic effect of new unclassified group K rotaviruses (RVK) on T98G and U87MG glioblastoma cells in vitro. Methods: T98G and U87MG cell cultures were received from Russian banks of cell lines of human and animal tissues. Standard culturing was performed with attenuated apatogenic RVK strains No. 100 and No. 228 at a concentration of 10 8 , 10 7 , 10 6 and 10 5 particles/mL. The cytotoxic effect was determined with MTT and Annexin V assays, cell morphology was evaluated by the light-optical method. Results: Both RVK strains demonstrated a dose-dependent cytotoxic activity; the maximal effect was observed in strain No.100 at a dose of 10 8 particles/mL on U87MG cells (predominantly apoptosis). Studies of cell morphology showed a pronounced effect of RVK on the cell culture: significant degenerative changes in cells, a tendency to a decrease in cluster size, a change in their shape and granularity. Cluster formation in culturing in the serum-free medium is considered in the literature as a property of cancer stem cells responsible in vivo for tumor recurrence and its chemo- and radio-resistance. T98G cells demonstrated morphological changes: nuclear segmentation, diffused cytoplasm, indistinct cell borders with signs of syncytium formation. Conclusions: The established oncolytic effect of RVK strain No. 100 in vitro on glioma cells, presumably with tumor stem cells, indicates a significant potential for the use of these rotaviruses in treatment of glial tumors.