tbuckley/cabot-search huggingface dataset:
Adjuvant chemotherapy for gastric cancer patients with mismatch repair deficiency or microsatellite instability.
Authors: Run-Cong Nie, Shu-Qiang Yuan, Jin Won Kim, Yun Wang, Guoming Chen, Jie Zhou, Yingbo Chen, Yingbo Chen, Zhiwei Zhou, Muyan Cai, Yuanfang Li
Journal: Journal of Clinical Oncology (2021)

e16004 Background: Mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) serves as a predictor poor response to adjuvant chemotherapy in stage II colon cancer patients. Our objective was to investigate the efficacy of adjuvant chemotherapy in dMMR/MSI-H gastric cancer (GC). Methods: We searched literatures through December, 2020 to identify clinical studies that reported survival comparing adjuvant chemotherapy with surgery alone in dMMR/MSI-H GCs. Two approaches were used to pool the hazard ratio (HR) of survival: (1) If Kaplan-Meier curves and number at risk were provided, individual patient data were extracted. Cox models were used to calculate the HR with 95% confidence interval (CI); (2) for study-level data, pooled HR was estimated using fixed/random-effects models. Results: Six clinical studies were identified. For dMMR/MSI-H versus mismatch repair proficient (pMMR)/microsatellite stable (MSS)/microsatellite instability-low (MSI-L), the estimated 5-years DFS were 74.2% versus 51.5% (HR, 0.44; 95% CI, 0.32-0.62; P &lt; 0.001); the estimated 5-years OS were 60.8% versus 50.1% (HR, 0.72; 95% CI, 0.60-0.88; P = 0.001). At study-level data, the pooled HRs were 0.42 for DFS (95% CI, 0.31-0.57; P &lt; 0.001) and 0.66 for OS (95% CI, 0.32-1.38; P = 0.268). For adjuvant chemotherapy versus observation in dMMR/MSI-H, the estimated 5-years DFS were 76.1% versus 73.3% (HR, 0.72; 95% CI, 0.45-1.15; P = 0.171); the estimated 5-years OS were 74.9% versus 60.2% (HR, 0.60; 95% CI, 0.44-0.83; P = 0.001). Significant survival differences were also observed at study-level. Conclusions: This study further suggested adjuvant chemotherapy could be beneficial even in dMMR/MSI-H GC patients.
Safety assessment of niraparib individualized starting dose in patients with platinum-sensitive recurrent ovarian cancer: A randomized, double-blind, placebo-controlled, phase III NORA trial.
Authors: Jing Wang, Xiaohua Wu, Jianqing Zhu, Rutie Yin, Jiaxin Yang, Qidan Huang, Lingying Wu, Ziling Liu, Yunong Gao, Danbo Wang, Ge Lou, Hongying Yang, Qi Zhou, Beihua Kong, Yi Huang, Lipai Chen, Guiling Li, Ruifang An, Tao Tan, Juan Dong
Journal: Journal of Clinical Oncology (2021)

5535 Background: To present the safety profile of niraparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer (PSROC) included in the NORA trial. Methods: The double-blind, randomized, placebo-controlled, multicenter, phase III NORA trial (NCT03705156) included adult (≥18 years) Chinese women with PSROC who received ≥2 prior lines of platinum-based chemotherapy. Post ≤8 weeks of the last chemotherapy, patients were randomized (2:1) to receive oral niraparib (300 mg/day or 200 mg/day for patients with bodyweight &lt;77 kg or platelet count &lt;150 × 10 3 /µL) or matched placebo. The primary endpoint was progression free survival, reported previously. Safety was assessed in terms of treatment emergent adverse events (TEAEs) related to hematologic toxicity (anemia/platelet count decreased and neutrophil count decreased) and non-hematologic toxicity (nausea/vomiting/constipation/insomnia/palpitations/hypertension). Adverse events (AEs) were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.03. The data cutoff was February 1, 2020. Results: Of 265 patients included, the first 16 patients were given oral niraparib or matched placebo at a fixed starting dose of 300mg while 249 patients received individualized starting dose of niraparib (n = 166) or matched placebo (n = 83) based on baseline bodyweight and platelet count. The incidence of any TEAEs and grade ≥3 TEAEs was 100% and 50.8%, respectively in niraparib group, while 95.5% and 19.3%, respectively in placebo. Incidence of all grades of hematologic toxicity, gastrointestinal adverse events (nausea, constipation and vomiting), insomnia, palpitation and hypertension were highest in the first month after treatment with a gradual decrease in the further months. The median time to onset of grade ≥3 anemia, decreased neutrophil count and decreased platelet count were 87, 28, and 22 days, respectively, in the niraparib group. In niraparib group, any TEAEs that lead to dose reduction was observed in 59.9% of patients. Only 2 (1.1%) patients discontinued the treatment due to platelet count decreased and no patients discontinued niraparib treatment due to anemia or neutrophil count decreased. Overall, only 4% of patients in the niraparib group and 5.7% in the placebo group discontinued the treatment due to TEAEs. Conclusions: The lower incidence of TEAEs and the discontinuation rates indicate improved safety profile of niraparib with individualized starting dose in PSROC. Clinical trial information: NCT03705156.
The common gamma-chain cytokines IL-2, IL-7 and IL-15 impact on proliferation of lymphocytes in vitro in breast cancer patients.
Authors: Sofia V. Timofeeva, Anastasia O. Sitkovskaya, Elena Yu. Zlatnik, Svetlana Yu. Filippova, Tatiana V. Shamova, Irina V. Mezhevova, Inna A. Novikova, Larisa N. Vashchenko, Emma E. Kechedzhieva, Irina R. Dashkova, Tatiana V. Ausheva, Elena A. Andreyko, Natalya S. Saforyan, Oleg I. Kit
Journal: Journal of Clinical Oncology (2021)

e13060 Background: Monotherapy with low doses of cytokines does not provide significant therapeutic results, while treatment with high doses leads to a number of side effects, for example, cytokine release syndrome, etc. Therefore, it is necessary to study the effect of cytokines on immune cells which are involved in the regulation of pro- and antitumor immune response. Thus, the aim of this study was to analyze the dynamics in the proliferation of the total fraction of lymphocytes after expansion and exposure to γc-cytokines: IL-2, IL-7 and IL-15 and their combinations in vitro in patients with diagnosed breast cancer. Methods: The study included 10 patients with locally advanced stage I-III breast cancer. Peripheral blood mononuclear cells (PBMC, ficoll-hypaque) were used as material. After density separation the cells were cultured at a dose of 500 thousand cells / ml in 6-well plates (Biofil, China) in RPMI 1640 (Gibco, USA) supplemented with 10% FBS (HyClone, USA) at 37° C, 5% CO2. Expansion of lymphocytes was performed by kit with anti-biotin magnetic particles MACSiBead to CD2, CD3 and CD28 (Miltenyi Biotec, Germany), according to the manufacturer's protocol. Stimulation of lymphocyte proliferation was performed on days 4, 8 and 12 by introducing recombinant cytokines - IL-2, IL-7, IL-15 (Miltenyi Biotec, Germany) and their combinations. Cytokines were introduced at a concentration of 40 ng / ml each in the following variants: IL-2; IL-2 / IL-15; IL-2 / IL-15 / IL-7; IL-15; IL-15 / IL-7. Plates with cell suspension were cultured at 37 ° C, 5% CO2 for 15 days. Results: The data obtained on the 11th day of incubation demonstrated statistically significant differences in cell viability in samples with the addition of interleukin IL-7 / IL-15 combination (778%) compared to control samples by 1.5 times (p &lt; 0.05). The proportion of lymphocytes in samples with the addition of only IL-15 (702%) and IL-7 / IL-15 (756%) combination was 1.47 and 1.6 times higher, respectively, compared with the control (p &lt; 0.05) at the 12th day of co-cultivation. Conclusions: Stimulation of lymphocyte proliferation by the IL-7 / IL-15 combination results in a high frequency of viable cell production. Despite the only culture stage, the results of the study may be important for optimizing the use of γc-cytokines in the treatment of patients with breast cancer.
Isatuximab plus carfilzomib and dexamethasone versus carfilzomib and dexamethasone in elderly patients with relapsed multiple myeloma: IKEMA subgroup analysis.
Authors: Thierry Facon, Philippe Moreau, Thomas G. Martin, Ivan Spicka, Albert Oriol, Youngil Koh, Andrew Lim, Gabor Mikala, Laura Rosiñol, Münci Yağci, Michele Cavo, Kwee Yong, Marie-Laure Risse, Gaëlle Asset, Sandrine Schwab, Gracia Martinez
Journal: Journal of Clinical Oncology (2021)

8026 Background: A prespecified interim efficacy analysis of the Phase 3 IKEMA study (NCT03275285) demonstrated that isatuximab (Isa) plus carfilzomib (K) and dexamethasone (d) (Isa-Kd) significantly improved progression-free survival (PFS) compared with Kd in patients (pts) with relapsed multiple myeloma (RMM) (HR 0.531; 99% CI, 0.318–0.889; P=0.0007), with a clinically meaningful increase in minimal residual disease negativity (MRD-) (29.6% vs 13.0%) and complete response (CR) (39.7% vs 27.6%) rates, and a manageable safety profile. This subgroup analysis of IKEMA examined efficacy and safety in pts aged &lt;70 and ≥70 years. Methods: Pts with 1–3 prior lines of therapy were randomized 3:2 to receive Isa-Kd (n=179) or Kd (n=123). The primary end point was PFS, as assessed by an independent response committee. We compared outcomes in pts &lt;70 vs ≥70 years; division into different or additional age groups resulted in smaller sample sizes. Results: Of the 302 randomized pts, 71.5% were aged &lt;70 years (Isa-Kd: 70.9%; Kd: 72.4%) and 28.5% were aged ≥70 years (Isa-Kd: 29.1%; Kd: 27.6%). Consistent with the significant improvement of PFS in the overall population, the addition of Isa to Kd resulted in improved PFS independently of age (Table). The CR, ≥very good partial response (VGPR), and MRD- rates were higher with Isa-Kd vs Kd. Within the Isa-Kd arm, CR rate and ≥VGPR rate were similar in elderly and younger pts. MRD- was observed in 32.3% of younger pts and 23.1% of elderly pts with Isa-Kd. In both arms, Grade ≥3 and serious treatment-emergent adverse events (TEAEs) were more frequently reported in elderly pts vs pts &lt;70 years old (Table). For both age groups, the incidence of Grade ≥3 TEAEs was higher whereas the incidence of serious TEAEs was similar between Isa-Kd and Kd. In the elderly subgroup, 3 (5.9%) pts receiving Isa-Kd and 1 (2.9%) receiving Kd had fatal TEAEs (Isa-Kd, infection; Kd, general health deterioration due to progressive disease). The most common Grade ≥3 TEAEs in pts aged &lt;70 and ≥70 years treated with Isa-Kd vs Kd were hypertension (18.3% vs 17.0% [&lt;70 years] and 25.5% vs 26.5% [≥70 years]) and pneumonia (14.3% vs 9.1% [&lt;70 years] and 21.6% vs 20.6% [≥70 years]). Conclusions: The addition of Isa to Kd improved PFS and quality of response in elderly pts, with a manageable safety profile, consistent with the benefit observed in the overall IKEMA study population. Isa-Kd provides a potential new treatment option for elderly pts with RMM. Funding: Sanofi. Clinical trial information: NCT03275285. [Table: see text]
Efficacy of AI and palbociclib in ER+ HER2- advanced breast cancer patients relapsing during adjuvant tamoxifen: An exploratory analysis of the PADA-1 trial.
Authors: François-Clément Bidard, Florence Dalenc, Thibault De La Motte Rouge, Barbara Pistilli, Caroline Cheneau, Catherine Delbaldo, Olfa Derbel, Claire Garnier Tixidre, Nathalie Marques, Sandrine Marques, Lionel Moreau, Frederique Berger, J Lemonnier, Anne-Claire Hardy-Bessard, Suzette Delaloge, Thomas Bachelot
Journal: Journal of Clinical Oncology (2021)

1070 Background: In PADA-1 (NCT03079011), a phase III trial testing the clinical utility of ESR1 mut detection, ER+ HER2- advanced breast patients (ABC pts) received Aromatase Inhibitor (AI) and Palbociclib (Pal) +/- LHRH agonist as first line therapy. PADA-1 was open to “AI-sensitive” pts, including those with de novo stage IV disease or metastatic relapse after adjuvant endocrine therapy but also pts with metastatic relapses during adjuvant tamoxifen (TAM). In this subsidiary analysis, we report the efficacy of AI+PAL as first line therapy in patients relapsing on adjuvant TAM. Methods: Main inclusion criteria in PADA-1 are: pre- or post-menopausal pts with ER+ HER2- ABC, who did not receive any prior therapy for ABC and who had no adjuvant AI or completed adjuvant AI for &gt; 12 months or who had disease recurrence while on adjuvant TAM. Results: From 04/2017 to 01/2019, 1017 ABC pts have been included in PADA-1, of which 115 (11.3%) had a metastatic relapse while on adjuvant TAM (TAM only (N = 112) or TAM+GnRH agonist (N = 3)). Median age at inclusion was 46 years (range 25-81), and 58 (50.4%) patients had visceral disease. The median PFS under AI+PAL was 20.4 months (95%CI16.1;27.8) in patients relapsing during adjuvant TAM. In contrast, median PFS in patients with de novo metastatic disease and metastatic relapses after the completion of adjuvant endocrine therapy were 30.6 months (95%CI26.7;Not reached) and 27.8 months (95%CI24.1;30.)], respectively. A subgroup analysis among patients relapsing on adjuvant TAM showed that those relapsing during the first two years of adjuvant TAM had a shorter PFS (11.4 months 95%CI[8.7;20.7]) than those relapsing after 2 years of adjuvant TAM (23.8 months 95%CI[20.2;Not reached]). Conclusions: To our knowledge, these are the first data on first line AI+CDK4/6 inhibitor in patients relapsing on adjuvant TAM. While PFS on AI + PAL appears primarily driven by endocrine resistance status, our data show that AI+PAL is a valuable option also in patients relapsing during adjuvant TAM. Clinical trial information: NCT03079011 .
Improvement of pneumococcal pneumonia diagnosis using quantitative real-time PCR targeting lytA in adult patients: a prospective cohort study
Authors: Lucía Boix-Palop, Meritxell Obradors, Mariona Xercavins, Ester Picó-Plana, Lydia Canales, Beatriz Dietl, Josefa Pérez, Javier Garau, Esther Calbo
Journal: Clinical Microbiology and Infection (2021)
A phase II trial cohort of nivolumab plus ipilimumab in patients (Pts) with recurrent/metastatic salivary gland cancers (R/M SGCs).
Authors: Bharat Burman, Eric Jeffrey Sherman, Lara Dunn, James Vincent Fetten, Loren S. Michel, Luc G.T. Morris, Irina Ostrovnaya, Sofia Haque, David G. Pfister, Alan Loh Ho
Journal: Journal of Clinical Oncology (2021)

6002 Background: R/M SGCs are a diverse group of malignant neoplasms arising from the major or minor salivary glands and have no standard treatment. The impact of combining PD-1/CTLA-4 checkpoint blockade in R/M SGCs is unknown. Methods: In a Simon's two-stage minimax phase II trial, pts with progressive R/M SGCs (any histology except adenoid cystic carcinoma (ACC)) were enrolled and treated with nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (1 cycle = 6 weeks). Imaging, using RECIST v1.1 response assessment, was scheduled to be performed approximately every 12 weeks. The primary endpoint was best overall response (BOR = complete response [CR]+partial response [PR]) per RECIST v1.1. To detect a difference between an unacceptable BOR of 5% and a desirable BOR of 20% (one-sided type I error of 10%, power of 90%), at least 1 in the first 18 pts required an observed response. At least 4 responses of 32 total pts were needed to meet the primary endpoint. Treatment beyond progression of disease (PD) was allowed at the discretion of the investigator. A second cohort of pts with ACC was analyzed and reported separately. Results: From 7/25/2017-7/16/2020, 32 pts were enrolled and evaluable for the primary endpoint. There was 3 confirmed PRs in the first 18 pts, therefore enrollment of the second stage continued. BOR rate was 16% (5/32). Seven pts never reached a first disease assessment and were classified as non-responders: 5 due to clinical PD, 1 due to toxicity, and 1 pt withdrew. Four pts discontinued the trial for toxicities: pancytopenia (1), blurry vision (1), cardiomyopathy/hyperglycemia (1), and neutropenic sepsis (1), and mucositis (1). The 5 confirmed responders had regressions ranging from -66% to -100% in target lesions, with a duration of therapy ranging from 15.7 to 29.5 months (treatment ongoing for one as of 2/6/20). Conclusions: This cohort met its primary endpoint, and the responses observed were dramatic and durable. Paired biopsy and peripheral blood samples will be analyzed to elucidate insights into mechanisms of response and resistance to dual checkpoint blockade. Clinical trial information: NCT03172624.
The Pulmonary Circulation and Congenital Heart Disease
Authors: Abraham M. Rudolph, Alexander S. Nadas
Journal: New England Journal of Medicine (1962)

CARDIOPULMONARY function in the mammalian organism is subjected to a major transformation after birth. The elimination of the utero-placental circulation and the establishment of the pulmonary circulation are associated with a series of stresses and adjustments; changes in the pulmonary circulation are of utmost importance in the successful adaptation to extrauterine existence.The pulmonary circulation has been increasingly recognized to have a very important role in patients with congenital heart disease. It is interesting not only that the pulmonary circulation has a major effect in determining the clinical picture, the natural history, the prognosis and the decision for surgery in . . .
A Distinction Without a Difference—Does It Matter Whether Fractures Are Nontraumatic or Traumatic?
Authors: Anne L. Schafer, Dolores M. Shoback
Journal: JAMA Internal Medicine (2021)

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NBE-002: A novel anthracycline-based antibody-drug conjugate (ADC) targeting ROR1 for the treatment of advanced solid tumors—A phase 1/2 clinical trial.
Authors: Anthony W. Tolcher, Funda Meric-Bernstam, Meredith McKean, Roger R Beerli, Lorenz Waldmeier, Rémy Gebleux, Ina Hellmann, Pawel Chrom, Ulf Grawunder
Journal: Journal of Clinical Oncology (2021)

TPS1108 Background: The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is highly expressed during embryonic development, but is minimally present or absent on post-partum healthy tissues. ROR1 is expressed in a variety of hematological and solid tumors and is associated with aggressive cancer phenotype and poor clinical outcomes. NBE-002 is an ADC targeting ROR1, obtained by site-specific, enzymatic conjugation of the anthracycline-derivative PNU-159682, modified with a non-cleavable linker to a humanized recombinant IgG1 monoclonal antibody, based on a novel anti-human ROR1 monoclonal antibody XBR1-402 (Peng et al. (2017) J. Mol. Biol. 429: 2954-73). Direct anti-tumor activity of NBE-002 was evaluated in immunodeficient, ROR1 expression-low/-intermediate/-high PDX models of several carcinoma and sarcoma subtypes. The most pronounced anti-tumor effect was achieved in triple-negative breast cancer (TNBC), at doses as low as 0.033 mg/kg, suggesting a best-in-class therapeutic index in light of the high tolerability in preclinical toxicology models. Administration in a fully immune competent setting (EMT6/ROR1 orthotopic breast cancer model) led to a strong anti-tumor response and a long-lasting anti-tumor immune protection dependent on CD8 T cells. Methods: NBE-002-01 (NCT04441099) is a first-in-human, open-label, multi-center, phase (Ph) 1/2 study of NBE-002 in adult patients with advanced solid tumors. Ph 1 of the study consists of a Dose Escalation Cohort (DEC), utilizing an accelerated titration design, followed by a traditional 3+3 design, and an optional Safety Expansion Cohort (SEC). Ph 2 will include two parallel Expansion Cohorts (EC), enrolling patients with advanced TNBC (EC1) or other solid tumors (EC2), with Simon’s two-stage design. Key eligibility criteria include Eastern Cooperative Oncology Group performance status of 0-2 (Ph 1) or 0-1 (Ph 2), adequate organ function defined as: hemoglobin ≥9.0 g/dL, neutrophils ≥1500 /µL, platelets ≥100000/µL, aspartate and alanine aminotransferases ≤2.5x the upper limit of normal (ULN), total bilirubin ≤1.5x ULN, creatinine ≤1.5x ULN, left ventricular ejection fraction ≥50%. The primary objectives are to assess safety and tolerability and to establish the recommended dose for further development (Ph 1), and to evaluate anti-tumor activity of (Ph 2). Secondary and exploratory objectives include characterization of immunogenicity as well as pharmacokinetic and pharmacodynamic profiles. NBE-002 is given intravenously once every three weeks until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-specific criteria are met. Ph 1 dose escalation was initiated on 17 JULY 2020 and is still recruiting in the US. Ph 2 is planned to be initiated in 2022. Clinical trial information: NCT04441099 .