tbuckley/cabot-search huggingface dataset:
Outcomes of patients with unresectable stage III non-small cell lung cancer treated with durvalumab and subsequent therapies after disease progression.
Authors: Franco Adjei-Baffour Dickson, Luis E. Raez, Katerine Dumais, Herman W. Powery, Damaal Walker
Journal: Journal of Clinical Oncology (2021)

e20531 Background: The PACIFIC trial demonstrated that durvalumab improved 3-year overall survival in unresectable Stage III non-small-cell lung cancer (NSCLC) following chemoradiotherapy (CRT). However, there is no consensus on the preferred therapy after patients progress on durvalumab. This study aimed to determine the real-world outcomes of patients treated with durvalumab and subsequent therapies after disease progression. Methods: Forty-five NSCLC patients previously treated in a large multi-site community cancer center with concurrent CRT followed by durvalumab were evaluated for progression-free survival (PFS). Subsequent lines of therapy for patients who progressed on durvalumab were also evaluated. Treatment characteristics of the patients were also reviewed. PFS was reported using the Kaplan-Meier method using a p-value of &lt; 0.05 for statistical significance. Results: Baseline characteristics of patients included a median age of 65 years (46-90), 99% with ECOG 0 or 1, and 89% with PDL-1&gt;50%. The median duration between the end of CRT and initiation of durvalumab was 1.3 months and the median treatment duration was 8.1 months the A total of 13 patients (29%) progressed on durvalumab; the 12-month PFS was 65.9% (49-79.7) and the 18-month PFS was 59.1% (36.7-76.1). The median PFS observed was 38.4 months (Table 1). The subsequent lines of therapy for the 14 patients that progressed were as follows: 8(62%). immunotherapy/chemotherapy combination, 2(15%) chemotherapy only, 2(15%) targeted therapy, and 1(8%) radiation therapy. Conclusions: Evaluation of consolidation durvalumab in patients with locally advanced NSCLC finds PFS in clinical practice to be consistent with trial data. Subsequent lines of therapy were consistent with guideline recommendations for newly diagnosed stage IV NSCLC. Longer follow-up will be needed to determine the PFS associated with the different subsequent therapies and how immunotherapy failure could potentially affect outcomes of subsequent chemo/immunotherapy combinations.[Table: see text]
CHIP and hips: clonal hematopoiesis is common in patients undergoing hip arthroplasty and is associated with autoimmune disease
Authors: Judith S. Hecker, Luise Hartmann, Jennifer Rivière, Michèle C. Buck, Mark van der Garde, Maja Rothenberg-Thurley, Luise Fischer, Susann Winter, Bianka Ksienzyk, Frank Ziemann, Maria Solovey, Martina Rauner, Elena Tsourdi, Katja Sockel, Marie Schneider, Anne S. Kubasch, Martin Nolde, Dominikus Hausmann, Alexander C. Paulus, Jörg Lützner, Andreas Roth, Florian Bassermann, Karsten Spiekermann, Carsten Marr, Lorenz C. Hofbauer, Uwe Platzbecker, Klaus H. Metzeler, Katharina S. Götze
Journal: Blood (2021)
Association between cancer stem cell marker ALDH1 and clinical and morphological factors of colorectal cancer prognosis.
Authors: Elena A. Dzhenkova, Inna A. Novikova, Oleg I. Kit, Elena Yu. Zlatnik, Elena P. Ulianova, Anastasia O. Sitkovskaya, Oksana G. Shulgina, Yuriy A. Gevorkyan, Natalya V. Soldatkina, Vladimir E. Kolesnikov, Maksim K. Aleksandrovich, Andrey V. Dashkov, Sergey I. Poluektov, Dmitry O. Kaymakchi, Ellada A. Mirzoyan, Vladislav K. Pavlov, Maksim A. Vereshchak, Oksana V. Katelnitskaya, Dmitriy A. Savchenko, Roman E. Tolmakh
Journal: Journal of Clinical Oncology (2021)

3522 Background: Cancer stem cells (CSCs) capable of self-sustaining and multipotent differentiation are considered among the most important factors limiting treatment effectiveness. ALDH1 is a marker of colorectal cancer (CRC) CSCs; it is involved in cell differentiation and proliferation, determines resistance to alkylating chemotherapeutic agents, and also induces epithelial-mesenchymal transition (EMT), which increases the invasive and metastatic potential of tumors. The purpose of the study was to assess the association between the expression of the ALDH1 CSC marker in tissues of CRC of different stages and clinical and morphological factors of the disease prognosis. Methods: The study included 299 patients (aged 42-86 years, mean age 64.2±1.7) with stage II-IV CRC T1-4N0-2M0-1; histologically verified G1-G3 adenocarcinoma in all patients. Tissues of surgically removed tumors were studied with IHC analysis using mouse monoclonal anti-ALDH1 antibodies (clone B-5, Santa Cruz Biotechnology) diluted 1:1800 and the Reveal Polyvalent HRP-DAB Detection System. The percentage of cells positively stained for ALDH1 among all tumor cells was assessed. Statistical analysis was performed using the STATISTICA 13.0 program (StatSoftInc., USA). Results: Positive ALDH1+ expression was registered in 52.5% of all patients, negative expression – in 47.5%. Statistically significant association was observed between the ALDH1 expression and the CRC stage, since the ALDH1+ expression increased from stage II to stage IV (p = 0.003). The ALDH1 expression was statistically significantly associated with the depth of tumor invasion (p = 0.018) and the presence of distant metastases (p &lt; 0.001). No significant relationship was observed between the ALDH1 expression and regional lymph node metastasis (p = 0.788). Statistically significant association was registered between the ALDH1 expression and the tumor grade (p &lt; 0.001), perineural invasion (p = 0.010) and lymphocytic infiltration (p &lt; 0.001). No significant relationship was observed between the tumor histological structure (p = 0.979), lymphovascular invasion (p = 0.772) and ALDH1 expression. Tumor site was not statistically significantly associated with ALDH1 expression (p = 0.349). Conclusions: The study demonstrated statistically significant association between the ALDH1 expression and clinical and morphological characteristics of CRC, determining invasive and metastatic potential of the tumor, and ALDH1 may be an independent prognostic factor and a new therapeutic target for the regulation of the progression process.
Human Kidney Spheroids and Monolayers Provide Insights into SARS-CoV-2 Renal Interactions
Authors: Dorit Omer, Oren Pleniceanu, Yehudit Gnatek, Michael Namestnikov, Osnat Cohen-Zontag, Sanja Goldberg, Yehudit Eden Friedman, Nehemya Friedman, Michal Mandelboim, Einat B. Vitner, Hagit Achdout, Roy Avraham, Eran Zahavy, Tomer Israely, Haim Mayan, Benjamin Dekel
Journal: Journal of the American Society of Nephrology (2021)

Although coronavirus disease 2019 (COVID-19) causes significan t morbidity, mainly from pulmonary involvement, extrapulmonary symptoms are also major componen ts of the disease. Kidney disease, usually presenting as AKI, is particularly severe among patients with COVID-19. It is unknown, however, whether such injury results from direct kidney infection with COVID-19's causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or from indirect mechanisms.
A phase 2, two-stage study of avelumab and axitinib in patients with mismatch repair proficient (MMR-P) recurrent or persistent endometrial cancer (EC).
Authors: Elizabeth Katherine Lee, Niya Xiong, Nabihah Tayob, Carolyn N. Krasner, Mary K. Buss, Susana M. Campos, Alexi A. Wright, Joyce F. Liu, Meghan Shea, Oladapo O. Yeku, Cesar Martin Castro, Rebecca L Porter, Elizabeth Stover, Sara Bouberhan, John William Moroney, Stephen A. Cannistra, Richard T. Penson, Gini F. Fleming, Ursula A. Matulonis, Panagiotis A. Konstantinopoulos
Journal: Journal of Clinical Oncology (2021)

TPS5609 Background: Despite significant strides in understanding the molecular pathogenesis of EC, there remain few effective therapies for recurrent disease. Deeper insight into the roles of disordered tumor vasculature and HIF1α- and VEGF-mediated immunosuppressive effects on myeloid-derived suppressor cells, T-cells, and PD-L1 expression contributed to the development of new targeted regimens. Activity of pembrolizumab and lenvatinib was demonstrated in a phase 2 trial in MMR-P EC (NCT02501096). By inhibiting VEGF receptor (VEGFR) and PD-L1 signaling, immunologically “cold” tumors may become inflamed. However, there are concerns regarding the toxicity of pembrolizumab/lenvatinib and alternatives are sought. The combination of the anti-PD-L1 antibody avelumab with axitinib, an inhibitor of VEGFR 1-3 and PDGFR with more potent IC 50 inhibitory activity than lenvatinib, has also shown synergistic activity and is FDA approved as first line treatment for patients with renal cell cancer. We therefore hypothesized that this combination would be well tolerated and efficacious in recurrent MMR-P EC. Methods: This is an investigator-initiated, phase 2, two-stage single cohort trial evaluating avelumab with axitinib in recurrent or persistent EC. Participants must have MMR-P EC of any histology and have received at least one chemotherapeutic regimen, with no upper limit on the number of prior lines received. Prior use of immune checkpoint (IC) inhibitors is excluded. Treatment consists of avelumab 800mg IV every 2 weeks and axitinib 5mg orally twice daily. Co-primary endpoints are progression-free survival at 6 months (PFS6) and objective response rate by RECIST 1.1. Translational objectives include characterization of tumor-infiltrating lymphocytes, infiltrating myeloid cells, expression of IC markers, and whole exome sequencing to evaluate mutations in genes related to DNA repair and immunologic response. This is a two-stage design in the method of Sill et al, with 16 participants anticipated in stage 1 and 19 participants in stage 2, for a total of 35 participants. Accrual is ongoing. Clinical trial information: NCT02912572.
Abstract 14803: Primary Prevention of Sudden Cardiac Death in Hypertrophic Cardiomyopathy, Data From the French Society of Cardiology Hospital-Based Register
Authors: Mariana Mirabel, Erwan Donal, Offredo Lucile, Xavier Jeunemaitre, Patricia Reant, Albert A Hagege
Journal: Circulation (2019)

Introduction: Risk assessment of sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HCM) remains subject of debate. Hypothesis: Use of implantable cardioverter defibrillator (...
Daratumumab (DARA) maintenance therapy following DARA + cyclophosphamide, bortezomib, and dexamethasone (CyBorD) induction therapy in multiple myeloma (MM): End-of-study analysis of LYRA.
Authors: Robert M. Rifkin, Jason M. Melear, Edward Faber, William I. Bensinger, John M. Burke, Mohit Narang, Don A. Stevens, Kathleen Gray, Yana Lutska, Padma Bobba, Keqin Qi, Ming Qi, Thomas S. Lin, Habte Aragaw Yimer
Journal: Journal of Clinical Oncology (2021)

8035 Background: LYRA is a community practice-based, phase 2, single-arm study (NCT02951819) evaluating DARA + CyBorD as an immunomodulatory drug-sparing regimen in MM. The primary analysis demonstrated the safety and efficacy of DARA + CyBorD in newly diagnosed MM (NDMM) and relapsed MM (RMM), and an update showed that DARA maintenance therapy deepened responses. We present the final end-of-study analysis of LYRA. Methods: US pts aged ≥18 years with MM per IMWG criteria and ≤1 prior line of therapy received 4-8 induction cycles of DARA + CyBorD (cyclophosphamide 300 mg/m 2 PO weekly [QW]; bortezomib 1.5 mg/m 2 SC on Days [D] 1, 8, and 15; dexamethasone 40 mg PO or IV QW every 28 days; DARA IV 8 mg/kg on D1 and D2 of cycle [C]1, 16 mg/kg QW C1D8-C2, 16 mg/kg Q2W C3-6, and 16 mg/kg Q4W C7-8). After induction, eligible pts could receive autologous stem cell transplantation (ASCT). Pts received up to 12 maintenance cycles with DARA 16 mg/kg IV Q4W and were followed for up to 36 months after induction. Results: In total, 101 (NDMM, n = 87; RMM, n = 14) pts were enrolled; 36% of pts had high-risk cytogenetics. NDMM and RMM pts received a median of 6 and 8 induction cycles, respectively. Among NDMM pts, 44.8% (39/87) underwent ASCT and 72.4% (63/87) completed 12 months of maintenance. Rates of ≥VGPR and ≥CR were 82.1% and 48.7% in NDMM pts who underwent ASCT, and 70.2% and 29.8% in NDMM pts who did not (Table). With a median follow-up of 35.7 months, median progression-free survival (PFS) and overall survival (OS) were not reached for NDMM pts. Estimated 36-month PFS rates were 69.3% and 72.6% for NDMM pts who did and did not receive ASCT, respectively; estimated 36-month OS rates were 94.9% and 84.3% (Table). Among RMM pts, 7.1% (1/14) underwent ASCT and 50.0% (7/14) completed 12 months of maintenance; efficacy outcomes are shown in the Table. Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 62.0% of all pts, with the most common (≥10%) being neutropenia (14.0%). Serious TEAEs occurred in 33.0% of pts, the most common being pneumonia (4.0%) and pulmonary embolism (3.0%). TEAEs led to death in 2.0% of pts, all unrelated to study treatment. Infusion-related reactions occurred in 56.0% of pts; the majority were mild (4.0% of pts had grade 3/4 events). Conclusions: DARA used for induction with CyBorD and maintenance as monotherapy resulted in durable, deep responses in pts with NDMM or RMM, with a 3-year PFS rate of 70% in NDMM irrespective of ASCT status. With longer follow-up, no new safety concerns were identified. Clinical trial information: NCT02951819. [Table: see text]
<i>NTRK</i> fusion positive colorectal cancer as a unique subset of CRC with high tumor mutation burden and microsatellite instability.
Authors: Hui WANG, Qiuxiang Ou, Xue Wu, Misako Nagasaka, Sai-Hong Ignatius Ou, Yang Shao
Journal: Journal of Clinical Oncology (2021)

3544 Background: Neurotrophin receptor tyrosine kinase ( NTRK) gene fusions are rare but actionable oncogenic drivers that are present in a wide variety of solid tumors. This study aims to identify the frequency and the clinicopathologic and genetic features of NTRK-driven colorectal cancers (CRC). Methods: Colonic and rectal tumor DNA specimen from colorectal cancer patients submitted for molecular profiling at a CLIA-certified genomics laboratory in China that performed NTRK1/2/3 fusion detection by hybridization-based targeted next generation sequencing (NGS) were retrospectively reviewed. Patients’ demographic, clinical characteristics, and treatment history were retrieved from the database for further evaluation. Results: A total of 2,519 unique Chinese colorectal cancer cases were profiled from April 2016 to May 2020, and 17 NTRK+ fusion events were identified (0.7%, 17/2,519) consisting of 14 cases of NTRK1+ and 3 cases of NTRK3+ fusions. Furthermore, thirteen out of 17 NTRK+ CRC tumors (76%) were microsatellite instability-high (MSI-H) tumors, a much higher rate than that of the molecularly unselected CRC population (8%) or NTRK+ non-CRC tumors ( &lt; 1%). NTRK+ CRC patients also had increased tumor mutation burden (median TMB = 65 mut/MB) compared to that of non- NTRK+ CRC (median TMB = 7.7 mut/MB) or NTRK+ non-CRC tumors (median TMB = 4 mut/MB). POLE/POLD1 mutations were also enriched in NTRK+ CRC (8/17, 47%) relative to molecularly unstratified CRC patients (8%) with over half carrying concurrent POLE and POLD1 mutations. TPM3 was the most common fusion partner of NTRK1 (78%, N = 14), followed by LMNA and TRP. Three NTRK3+ CRC were identified (ETV6-NTRK3, RUNX1-NTRK3, CSNK1G1-NTRK3). RNF43 (71%) was the most frequently mutated gene and the aberrations of RNF43 and ARID1 were significantly enriched in MSI-positive NTRK+ tumors as compared to the MSS NTRK+ subgroup. TP53 (53%) and APC (35%) aberrations frequently co-occurred with NTRK fusions, whereas the majority of the NTRK+ cohort were RAS/BRAF wildtype, except in one case that an oncogenic KRAS Q61R variant co-occurred with RUNX1-NTRK3. Conclusions: NTRK+ colorectal cancer is rare. In addition to the absence of canonical driver mutations, NTRK+ tumors demonstrated increased tumor mutation burden, higher frequency of microsatellite instability, and an enrichment of POLE/POLD1 mutations relative to molecularly unselected CRC population.
Comorbidity: Chronic neurogenic pain affects malignant growth and changes balance of neurosteroids in brain of rats.
Authors: Yulia A. Pogorelova, Ekaterina I. Surikova, Elena M. Frantsiyants, Valeria A. Bandovkina, Irina V. Kaplieva, Irina V. Neskubina, Natalia D. Cheryarina, Inga Movlievna Kotieva, Elena V. Shalashnaya, Lidia K. Trepitaki, Viktoria V. Pozdnyakova
Journal: Journal of Clinical Oncology (2021)

e23516 Background: Sex steroids in the brain regulate neurogenesis and the body's response to stress. Chronic neurogenic pain (CNP) and the tumor growth are stress factors that often accompany each other. The purpose of the study was to analyze levels of sex steroid hormones in white matter of the brain of rats with tumor development in presence of CNP. Methods: The study included white outbred male rats (n = 74). In the main groups, a CNP model was created by bilateral sciatic nerve ligation, and after 45 days, M1 sarcoma was transplanted subcutaneously (n = 11) or into the subclavian vein (n = 11). Two comparison groups (each n = 13) included sham operated animals with M1 sarcoma transplanted subcutaneously or into the subclavian vein. Control groups (each n = 13) included animals with CNP or sham operated rats. Levels of testosterone (T), estrone (E1), estradiol (E2), estriol (E3) and progesterone (P4) were measured by ELISA (Cusabio, China) in the brain tissues obtained on day 21 of the tumor growth. Results: Tumors transplanted subcutaneously with and without CNP grew in 100% of animals. Tumor volumes were 1.5 times (p&lt;0.05) greater in animals with CNP, compared with rats without CNP, while the survival in the groups was similar. Levels of all studied hormones, except for E1, in the brain tissue in subcutaneous sarcoma growth were lower in presence of CNP than without it: T and E3–on average by 1.4 times (p&lt;0.05), E2 and P4–by 3.5 times (p&lt;0.05). In rats with intravenous transplantation of M1, tumor nodes in the lungs were registered only in rats with CNP, and the survival of animals was 36 days shorter (p&lt;0.05) than in rats of the corresponding control group. Such specificity of selective neoplastic growth in the pulmonary tissue was combined with lower cerebral T and E3 levels than in the corresponding control–on average by 1.4 times (p&lt;0.05), E2–by 7.2 times, and higher levels of E1–by 1.3 (p&lt;0.05) and P4–by 2.0 times, compared to animals which did not develop the neoplastic process in the lungs without pain. Conclusions: The presence of CNP stimulates the growth of M1 sarcoma in standard subcutaneous inoculation and allows the development of tumors in the lung in intravenous inoculation. The specificity of malignant growth in presence of CNP is accompanied by changes in the brain levels of neurosteroids in rats.
Dynamics of circulating tumor DNA in patients with advanced solid tumors treated with cediranib and olaparib.
Authors: Yiduo Hu, Azeet Narayan, Julia Wolfe, Dennis Vu, Trinh Thi, Chaitanya Kantak, S. Percy Ivy, Joseph Paul Eder, Patricia LoRusso, Joseph W. Kim, Abhijit Patel
Journal: Journal of Clinical Oncology (2021)

3035 Background: Circulating tumor DNA (ctDNA) has emerged as a potential biomarker to monitor treatment response in solid tumors. Our group previously showed that changes in ctDNA levels were predictive of radiographic response and survival in NSCLC patients receiving immunotherapy. Here we evaluated whether ctDNA dynamics could similarly be used to assess response in a PARP inhibitor-based therapy. Methods: A total of 122 patients with NSCLC, TNBC, PDAC or SCLC received cediranib (C) 30mg daily and Olaparib (O) 200mg twice daily in a phase II study NCI9881. Using a multigene NGS assay, ctDNA was measured longitudinally at baseline (T 0 ), after 3 to 7 days of C monotherapy (T 1 ), after 1 week of C+O combination (T 2 ), after 4 weeks of C+O (T 3 ), and every 4 weeks (T 4+ ) thereafter. The first radiographic assessment was done after 8 weeks of C+O and every 8-12 weeks thereafter. CtDNA was quantified by determining the allele fraction of cancer-associated somatic mutations in plasma. We defined an early ctDNA response (e-ctDNA-R) as a &gt;10% decrease in mutant allele fraction from T 0 to T 2 , and an early ctDNA progression (e-ctDNA-P) as a &gt; 10% increase; otherwise, it was stable ctDNA (e-ctDNA-S). Results: In total, 493 samples were analyzed from 94 patients, and 40 unique patients had both T 0 and T 2 ctDNA measurements, as well as corresponding radiographic assessments. These included 10 NSCLC, 17 TNBC, 3 SCLC and 10 PDAC. Of these patients, 4, 21, and 15 patients had PR, SD, and PD as best overall radiographic response respectively. Twenty-three (57.5%) patients had either e-ctDNA-R (17, 42.5%) or e-ctDNA-S (6, 15.0%), 18 (78.3%) of whom subsequently had either radiographic partial response (PR) or stable disease (SD). Seventeen (42.5%) patients had e-ctDNA-P, 10 (58.8%) of whom then had PD. A fair agreement was observed between e-ctDNA-R/S or e-ctDNA-P and radiographic PR/SD or PD with Cohen’s k 0.38 (70% agreement). The correlation between early ctDNA changes and PFS/OS are summarized in the table. All 25 patients with PR/SD eventually progressed. Of these, 17 (68%) had &gt;10% increase in ctDNA from the nadir prior to disease progression (median 94.6%, 95%CI 38.2%-389.1%). The time between ctDNA progression and ctDNA nadir was significantly shorter (median 21 days, 95%CI 21-28) than the time between radiographic/clinical progression and initial PR/SD (median 107 days, 95%CI 56-204, P=0.0015). Conclusions: Longitudinal ctDNA measurements could enable early assessment of treatment response, resistance, and disease progression in patients treated with PARP inhibitor-based therapy. However, in this study, tumor responses and ctDNA changes were generally not as robust as have been observed with other classes of therapy.[Table: see text]