tbuckley/cabot-search huggingface dataset:
Safety outcomes of darolutamide versus apalutamide and enzalutamide in nonmetastatic castration-resistant prostate cancer (nmCRPC): Matching-adjusted indirect comparisons.
Authors: Shan Jiang, Emi Terasawa, Viviana Garcia Horton, Rajeev Ayyagari, A. Reginald Waldeck, Susan Halabi, Neal D. Shore
Journal: Journal of Clinical Oncology (2020)

5561 Background: Randomized nmCRPC trials comparing darolutamide (D), apalutamide (A) and enzalutamide (E) have not been reported. Safety of these therapeutics has important implications in assessing patient risk-benefit concerns. Matching-adjusted indirect comparison (MAIC) is a method to perform indirect treatment comparisons adjusting for cross-trial heterogeneity. Objective: To compare the safety outcomes of D vs. A or E using MAIC. Methods: Data from the ARAMIS (D vs. placebo [PBO]), SPARTAN (A vs. PBO) and PROSPER (E vs. PBO) trials were used. Key safety outcomes including adverse events (AEs) that have central nervous system relevance were compared using anchored MAIC. Individual patient level data (IPD) from ARAMIS were selected and re-weighted to match the inclusion criteria and baseline characteristics published in SPARTAN and PROSPER (no access to their IPD). The Benjamini-Hochberg approach was applied to adjust for multiplicity. The D vs A MAIC matched on 7 covariates: age, prostate-specific antigen (PSA) level and doubling time, Eastern Cooperative Oncology Group (ECOG), Gleason score, bone-sparing agent use and prior surgery. Sensitivity analyses were conducted matching on different sets of covariates. D vs. E were matched on age, region, PSA level and doubling time, ECOG, Gleason score and bone-sparing agent use. Risk difference (RD) ([DARO – PBO ARAMIS ] – [ENZA – PBO PROSPER ]) and odds ratio (OR) (OR ARAMIS /OR PROSPER ) were calculated. RD&lt;0 or OR&lt;1 indicate lower AE risk for D. Results: For D vs. A, the effective sample sizes (ESS) of D and its placebo (PBO) arm were 604 and 391 after matching. Fall, fracture, and rash were statistically significantly lower for D vs. A (Table). For D vs. E, the ESS of D and PBO arm were 580 and 395, respectively. Fall, dizziness, mental impairment, hypertension, fatigue and severe fatigue were statistically significantly lower for D vs. E. Conclusions: After adjusting for trial differences, D showed favorable safety profile in fall, dizziness, mental-impairment, hypertension, rash, fatigue, and fracture. [Table: see text]
HANNA: Real-world outcomes from an observational study with nivolumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck in Germany.
Authors: Andreas Dietz, Manfred Welslau, Dennis Hahn, Christine Langer, Ulrike Bockmühl, Harald Müller-Huesmann, Chia-Jung Busch, Jorge Riera-Knorrenschild, Jens Büntzel, Boris Kubuschok, Jens von der Grün, Thomas Christoph Gauler, Daniela Waldenberger, Eyck von der Heyde
Journal: Journal of Clinical Oncology (2020)

6532 Background: Nivolumab has demonstrated efficacy in clinical trials of recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). As only limited real-world data are available, we describe the use of nivolumab and its outcomes in routine clinical practice. Methods: HANNA is a prospective, observational study of patients with R/M SCCHN treated with nivolumab in 56 hospitals and practices in Germany. In total, 385 patients will be followed for ≤ 5 years from treatment initiation until death, withdrawal of consent, loss of follow-up/record, or end of study. The primary objective is overall survival (OS). Secondary objectives include baseline characteristics, safety profiles, and quality of life (QOL) assessment. Results: By November 2019, data from 311 patients were available. Median follow-up was 3.5 months. Baseline characteristics were male, 81.7%; median age, 63 years; history of smoking, 73.3%; Eastern Cooperative Oncology Group performance status (ECOG PS) 0/1, 60.8%; ECOG PS 2/3, 29.6%. Location of primary tumor was oropharynx, 38.3%; hypopharynx, 20.9%; oral cavity, 22.8%; larynx, 11.6%; others, 6.4%. 55.6% of R/M SCCHN patients progressed ≤ 6 months after platinum-based therapy, whereas 43.4% were platinum-sensitive (progressed &gt; 6 months after platinum-based therapy). Nivolumab was received by 25.1% of patients as first therapy after platinum-based chemo- or radiochemotherapy, by 62.1% as second therapy, and by 12.9% as later line therapy. Median treatment duration was 4.6 months. OS at 1 year was 43.3%. 1-year OS for patients with ECOG PS 0 was 75.9%; ECOG PS 1, 41.2%; and ECOG PS 2, 27.3%. Platinum-sensitive patients had higher 1-year OS probability (51.6%). Drug-related adverse events (grade 1/2) and serious adverse events (grade 3/4) were observed in 28.9% and 10.0% of patients, respectively. Interim QOL data (per FACT-H&amp;N and EQ-5D questionnaire) indicated a tendency toward stabilization or slight improvement. We will present an update of the data with longer follow-up (data cut March 2020). Conclusions: HANNA represents one of the largest real-world datasets for nivolumab in R/M SCCHN and comprises a more diverse set of patients than the phase 3 CheckMate 141 trial, including patients with higher ECOG PS, age, and platinum sensitivity. Outcomes from HANNA show that the improved OS, safety, and QOL seen with nivolumab in the real-world setting are consistent with the outcomes from CheckMate 141. Clinical trial information: NCT03114163 .
Ovarian cancer clinical trials: Study the studies to terminate the terminations.
Authors: Daniel Spinosa, Elizabeth Howell, D'Erryl Williams, Catherine Watson, Tomi F. Akinyemiju, Rebecca A. Previs
Journal: Journal of Clinical Oncology (2020)

6069 Background: Clinical trials safely expand the arsenal of treatments available to future patients while providing hope to current patients, particularly ovarian cancer patients who often have poor prognoses. Trial termination for lack of efficacy or unacceptable toxicity are consistent with the aim of protecting patients in the pursuit of knowledge, but those are not the only reasons trials terminate early. Understanding why some clinical trials do not achieve their stated goals may aid in the design of future trials. Methods: Data were gathered from clinical trials registered to ClinicalTrials.gov. Included trials were interventional (as opposed to observational), were closed between 2004 and 2019, enrolled ovarian cancer patients, had submitted results, and were open at one or more domestic sites. For each trial, data were captured regarding study completion, reason for non-completion (if applicable), sites, phase, sponsor (defined as the study initiator, not necessarily the funder), and intervention type. Results: A total of 313 trials were examined, of which 262 met inclusion criteria. Of the 262 evaluable trials, 189 (72%) were completed and 72 (27%) terminated early. The most common reasons for early termination were low accrual (27 trials, 38%), lack of efficacy (15 trials, 21%), or insufficient funding (9 trials, 13%). Five trials (7%) were terminated early due to toxicity. Early phase trials are less likely to complete enrollment, with 11 out of 16 (65%) phase 1 trials, 135 out of 180 (75%) phase 2 trials, and 15 out of 16 (94%) phase 3 trials completed. Trials initiated by an academic center were twice as likely to be terminated early (41/103, 40%) as those initiated by industry (16/80, 20%), with remaining trials initiated by consortia, NCI, or non-academic oncology practices. Terminated trials were open at an average of 11 sites (range 1-317), while completed trials were open at an average of 27 sites (range 1-632). Trials that had multiple types of interventions, for instance a drug and a procedure, had a 34% early termination rate which was higher than the rate for trials with any single type of intervention. Conclusions: More than one in four ovarian cancer clinical trials are terminated early, rarely due to treatment efficacy or tolerability. Trials terminated for reasons other than patient outcomes represent a misallocation of resources or a missed opportunity for innovation. Further research is needed to understand the circumstances that allow for clinical trial completion such that available resources maximize patient benefit.
蛋白尿的临床解读
Authors: 姜群
Journal: BMJ (2008)

正常人24 h尿蛋白总量小于150 mg,青少年可略高,但不超过300 mg/d,用常规方法不能检测出.尿蛋白50%～70%来源于血浆蛋白,另30%～50%是泌尿系统分泌的蛋白,如肾小管髓袢升支及远端能分泌少量黏蛋白、Tamm-Horsfall蛋白等,这些构成了每日尿中极微量蛋白,当尿中蛋白总量超过上述界限检出时,即称为蛋白尿.是肾脏疾病常见临床表现。
The value of B-type natriuretic peptide in diagnosis and prognosis of coronary heart disease study
Authors: 叶舟, 牛丽丽
Journal: BMJ (2011)

目前有关B型钠尿肽(BNP)与冠状动脉性心脏病(冠心病)关系的临床研究很多,在此对其进行一简要综述. 自1988年BNP被提取成功后,在人体多处组织器官中检出,其中以心脏含量最高.BNP基因定位于1号染色体短臂远端,分泌后以BNP原(含108氨基酸)形式储存在心室肌细胞内.当心室肌细胞受到异常牵拉和所受压力改变刺激时分泌BNP原,随后被水解成一份有活性的BNP(32个氨基酸)、一份无活性的氨基末端B型钠尿肽原(NT-pro BNP,含76个氨基酸).人体正常血浆BNP＜10 n/L.BNP的生理作用有[1]:扩张血管;利尿排钠作用;保护心肌细胞和改善心肌重塑,抗纤维化作用;抑制肾素血管紧张素醛固酮轴及交感神经兴奋性。
Investigating macrophage function as a mechanism of resistance to daratumumab in relapsed refractory multiple myeloma patients.
Authors: Swetha Kambhampati, Kwun Wah Wen, Victoria Sung, Sandy Wai Kuan Wong, Thomas G. Martin, Jeffrey Lee Wolf, Nina Shah, Arun Wiita
Journal: Journal of Clinical Oncology (2020)

e20547 Background: Daratumumab (Dara), an anti-CD38 antibody, has a variety of Fc-dependent immune effector mechanisms of action including macrophage-mediated antibody-dependent cellular phagocytosis (ADCP). However, it remains unclear which mechanism, when disrupted, drives in vivo resistance. Given widespread use of this agent for treatment of multiple myeloma, identifying how to overcome Dara resistance has become an urgent clinical need. We hypothesized that inhibiting macrophage activity, via increased plasma cell surface expression of the CD47 “don’t eat me” signal, could be a mechanism of acquired Dara resistance. Methods: We retrospectively identified 11 patients with relapsed refractory multiple myeloma who progressed on Dara and had sequential bone marrow core biopsies before and after Dara with both samples containing &gt; 20% plasma cells. Nine patients had sufficient material for analysis. Core biopsy slides were stained and analyzed for expression of CD47 (H-scoring for total intensity on plasma cells, as well as annotation of membrane vs. cytosolic localization), CD68 (cell counts of macrophages), and CD4/CD8/FOXP3 triple stain (cell counts of CD4 and CD8 effector and regulatory T-cells). Results: Median age was 57 years. Median R-ISS stage was 2. Two patients had high-risk cytogenetics at diagnosis. Median time from diagnosis to progression on Dara was 56.3 months (95% CI 37.43 – 88.92). Median overall survival was 69.5 months (95% CI: 46.5 – 97.1). Plasma cells in all samples expressed CD47 (H-score median = 96, range 43 - 290). However, in contrast to our hypothesis, there was no significant change in CD47 H-score at progression on Dara (H-score median = 100, range 29 – 140). Furthermore, we observed no significant change in CD68+ macrophage counts nor CD68+ localization at Dara progression. We did note a trend toward CD47 expression shifting from membrane to cytosol at Dara resistance ( p = 0.14). Consistent with prior studies, in our cohort we observed no influx in Tregs but a markedly increased CD8/CD4 ratio at resistance ( p = 0.01). Conclusions: In vitro and murine studies have proposed ADCP as an important mechanism of Dara efficacy. However, we did not observe signatures of resistance in patients being driven by this pathway. Our work suggests that anti-CD47 therapy, leading to activation of macrophages to eliminate tumor cells, will potentially be efficacious for both the Dara-naïve and Dara-refractory settings.
Atezolizumab (atezo) therapy for locally advanced/metastatic urinary tract carcinoma (mUTC) in patients (pts) with poor performance status (PS): Analysis of the prospective global SAUL study.
Authors: Daniel Castellano, Craig Gedye, Giuseppe Fornarini, Andre P. Fay, Jens Voortman, Michal Mego, Aristotelis Bamias, Jason Francis Lester, Robert A Huddart, Michaela Matouskova, Howard Gurney, Begona Mellado, Michael Ong, Filipa Carneiro, Florian Seseke, Laura Milesi, Shahrokh F. Shariat, Simon Fear, Sabine de Ducla, Cora N. Sternberg
Journal: Journal of Clinical Oncology (2020)

5035 Background: Pts with PS &gt; 1 have a poor prognosis and are often excluded from clinical trials. The single-arm SAUL study (NCT02928406) evaluated atezo in a ‘real-world’ population. Overall, safety and efficacy were consistent with prior trials. However, ECOG PS 2 pts had worse overall survival (OS) but fewer adverse events (AEs) than ECOG PS 0/1 pts [Sternberg, 2019], likely reflecting shorter treatment duration and warranting exploration. Methods: Pts with mUTC received atezo 1200 mg q3w until loss of clinical benefit or unacceptable toxicity. The primary endpoint was safety. Post hoc analyses compared baseline factors, AEs and efficacy in pts with ECOG PS 2 vs 0/1. In this analysis, AE incidences were restricted to the first 45 days of atezo to adjust for differing treatment exposure. Results: None of the baseline factors explored was significantly associated with worse OS or disease control rate (DCR) in ECOG PS 2 pts. However, pts with visceral metastases and ECOG PS 2 had particularly poor outcomes. Safety appeared similar between subgroups. Conclusions: ECOG PS 2 pts have a dismal prognosis. The higher proportion with poor prognostic factors despite similar age in ECOG PS 2 vs 0/1 pts may suggest that poor PS was related to disease rather than comorbidities. Risk/benefit should be considered especially carefully when treating pts with ECOG PS 2 due to high-burden/visceral disease. Clinical trial information: NCT02928406 . [Table: see text]
大肠癌误诊155例分析
Authors: 王世和, 梁海清, 祝莹
Journal: BMJ (2004)

总结分析155例大肠癌的误诊原因,提出掌握大肠癌的流行病学特点、大肠常见疾病的特点、重视肛门指诊等一些简便易行的检查方法、熟练结肠镜检查操作、正确利用放射学检查等是提高大肠癌诊断水平需注意的问题。
Successful oral desensitization and reintroduction in selected glioma patients with procarbazine‐mediated hypersensitivity
Authors: Hester Van der Valk, Hilda Dijkstra, Annemiek Walenkamp, Marie L.A. Schuttelaar, Hanneke N.G. Oude Elberink, Annick A. J. M. Van de Ven
Journal: Allergy (2020)
Impact of interim PET on Hodgkin lymphoma treatment outcome and survival in clinical practice.
Authors: Serena Zheng, Kanika Gupta, Piyush Goyal, Reiko Nakajima, Laure Michaud, Connie Lee Batlevi, Paul A. Hamlin, Steven M. Horwitz, Anita Kumar, Matthew J. Matasar, Alison J. Moskowitz, Craig H. Moskowitz, Ariela Noy, Maria Lia Palomba, David J. Straus, Heiko Schöder, Joachim Yahalom, Andrew David Zelenetz, Anas Younes, Erel Joffe
Journal: Journal of Clinical Oncology (2020)

e20017 Background: FDG avidity above liver on interim PET (PET2) during frontline ABVD is considered a marker of impending treatment failure and an indication to switch to an intensified regimen. However, in clinical practice the utility of PET2 for treatment decisions is less clear. We describe outcomes of patients with positive PET2 who continued treatment with ABVD in the clinical setting. Methods: A retrospective study of all patients with newly diagnosed advanced-stage Hodgkin lymphoma treated with frontline ABVD at Memorial Sloan Kettering Cancer Center between 2008-2017. Eligibility criteria were set to correspond with the RATHL inclusion criteria (stage IIB - IV, or IIA bulky or ≥ 3 involved sites). We identified all PET2 reports indicating suspected residual uptake. All positive PET2 images were then reviewed by a single study radiologist. To increase reproducibility and avoid selection of borderline cases, we defined as PET2 positive only those cases with a lesion-to-liver (mean) SUV ratio ≥ 1.3. We also used a recently published stringent criterion of lesion-to-liver (max) ratio ≥ 1.4 (mPET2+). Progression-free and overall survival (PFS, OS) were calculated from the date of initial treatment until progression or death of any cause. Consolidative radiation was not considered a PFS event, and all progressions were verified by biopsy. Results: We identified 227 patients fitting RATHL inclusion criteria treated with ABVD. Median age was 34, with 25% (58) ≥ 45 years, 12% (26) had an IPS ≥ 4; 28% (64) stage II (5% II-X) and 38% (87) with extranodal involvement. 57 (25%) patients had a PET2 report indicating suspected residual lymphoma (PET2+), however, only 32 (14%) met the more stringent mPET2+ criterion. Most patients with PET2+ continued ABVD (84%, 48), and 9 switched to escBEACOPP (this subset of patients had substantially worse disease and are not the focus of this analysis). 21 (9%) patients received consolidative radiation. With a median follow-up of 47 months (42-54m), PET2+ patients who continued ABVD had a 3yPFS of 70% (58-85%, n = 48); mPET+ had a 3yPFS of 71% (55-92%, n = 24). Overall survival was excellent regardless of PET2 status (5yOS 97%). Conclusions: The outcome of PET2+ patients in this analysis was better than previously reported and the continuation of ABVD was appropriate for most patients. Use of a confirmatory biopsy is important for identifying true progressions. Patients with PET2+ had an excellent OS. Evaluation of the superiority of alternative regimens in PET2+ patients requires an ABVD comparator arm.
Effect of early blood counts on overall survival (OS) following glasdegib + LDAC in newly diagnosed AML: BRIGHT AML 1003 post hoc analysis.
Authors: Eunice S. Wang, Michael Heuser, Mikkael A. Sekeres, Cristina Papayannidis, Anna Candoni, Akil Merchant, Andrew Brown, Ashleigh O'Connell, Wendy Ma, Geoffrey Chan, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2020)

7525 Background: Addition of glasdegib (GLAS) to LDAC approximately doubled OS without significant worsening of myelosuppression-related complications, ostensibly by targeting leukemic stem cells dependent on the hedgehog pathway, which is not involved in normal adult hematopoiesis. We assessed potential association of early blood counts and OS. Methods: In BRIGHT AML 1003, patients (pts) with newly diagnosed AML were randomized to GLAS + LDAC (n = 78) or LDAC alone (n = 38). GLAS was given once daily continuously and LDAC on days 1–10 of a 28-day cycle. We evaluated peripheral blood counts measured early in the study (cycle 2 day 1 [C2D1]), approximately 1 month before the first bone marrow assessments. OS was compared for GLAS+LDAC vs LDAC alone subgroups meeting thresholds of absolute neutrophil count (ANC; ≥1000 or 500/µL), hemoglobin (Hb; ≥10 or 9 g/dL) or platelets (≥100,000 or 50,000/µL). Data cut-off was Apr 2019. Results: Among all pts regardless of baseline values, achievement of ANC, Hb and platelet thresholds at C2D1 was associated with improved OS with GLAS+LDAC (table, left side). Notably, in pts who did not meet ANC, Hb or platelet thresholds (table, right side), OS benefit with GLAS+LDAC was also observed (table, all p≤0.05). Among pts below threshold at baseline, C2D1 recovery of platelets ≥50,000 or 100,000 and Hb ≥9 or 10 was associated with improved OS (not shown). Clinical trial information: NCT01546038 . Conclusions: In pts with newly diagnosed AML, improved OS was associated with various blood count thresholds after 1 cycle of GLAS+LDAC vs LDAC alone. In pts with baseline measurements below threshold, recovery of specific thresholds was associated with improved OS. These exploratory results are consistent with the hematopoiesis-sparing mechanism of GLAS, and merit further evaluation. [Table: see text]
Development of a circulating tumor cell-based RNA classifier for patients with castration-resistant prostate cancer: CTC-PCS/PAM50.
Authors: Pai-Chi Teng, Yu Jen Jan, Minhyung Kim, Jie-Fu Chen, Junhee Yoon, Jasmine Jiemei Wang, Pin-Jung Chen, Nu Yao, Yi-Te Lee, Amber Lozano, Ruslan Gadilov, Michael Freeman, Sungyong You, Hsian-Rong Tseng, Edwin Melencio Posadas
Journal: Journal of Clinical Oncology (2020)

e17509 Background: Genomic profiling has strongly impacted the contemporary understanding of prostate cancer (PCa). Clinical trials are now testing the utility of genomic classifiers such as the PCS (You, Ca Res 2016) and PAM50 (Zhao, JAMA Onc 2017) systems to optimize therapy selection. As contemporary tissue is not always readily available, especially in metastatic, castration-resistant PCa (mCRPC), a blood-based test would be better suited for assessing patients and predicting treatment response. Methods: The CTC-RNA assay combines the Thermoresponsive (TR)-NanoVelcro system with the NanoString nCounter platform. This allows for CTC purification and RNA analysis. Using a novel bioinformatics approach that accounts for differences in background signals between tissue and blood, we reconstructed the PCS and PAM50 panels to recapitulate both classifiers in this blood-based assay. A weighted Z-score and nearest centroid classifier were used to calculate gene expression and to assign PCS and PAM50 subtypes. Performance of the revised signatures and CTC-RNA assay was benchmarked on simulated spiked-blood specimens. An initial clinical test was performed using clinically annotated, banked blood specimens within the Translational Oncology Program Blood and Biospecimen Bank. Results: CTC-RNA profiles of C4-2B AR signaling inhibitor (ARSI)-resistant sublines were compared to parental C4-2B. C4-2B ARSI-resistant cells had significantly higher PCS1 Z scores, PCS1 probability, and basal probability compared to the parental C4-2B cells. Blood samples from 34 mCRPC patients prior to initiation of therapy with ARSIs (abiraterone, enzalutamide, or apalutamide) were then analyzed. Samples were classified as PCS1 (n = 3), PCS2 (n = 20), and PCS3 (n = 11); luminal A (n = 12), luminal B (n = 11), and basal (n = 11). The biochemical progression-free survival (bPFS) on ARSI and overall survival (OS) for PCS1/Basal vs. other are shown in the table. Conclusions: The CTC-RNA assay is capable of generating luminal-basal classifications such as those in the PCS and PAM50 systems. Given early data of these classifiers and their potential to guide therapeutic decisions, this approach may be useful as an alternative to biopsy to facilitate such decisions. Larger prospective studies will be needed to confirm and validate its clinical utility. [Table: see text]