tbuckley/cabot-search huggingface dataset:
Correlation between PD-L1 level and immunotherapy outcome in NSCLC in Lebanon, 2012-2018: A multicenter observational review.
Authors: Ahmad Ghoche, Lewis Nasr, Saada Diab, Fadi Nasr
Journal: Journal of Clinical Oncology (2019)

e20524 Background: Immunotherapy targeting the PD1/PDL1 checkpoint pathway represents an important innovation in lung cancer treatment. In our research, we evaluate the correlation of PD-L1 expression with clinical outcomes (progression free survival, overall survival, objective response rate) in lung cancer patients in 4 centers in Lebanon. Methods: The 57 patients enrolled in this observational study were stage IIIB/IV NSCLC and SCLC who received immunotherapy with nivolumab, pembrolizumab or atezolizumab at any line of treatment, and were recruited between February 2012 and august 2018. Immunotherapy was continued until progression, death or unacceptable toxicity. PD-L1 expression was assessed on tumor samples either on diagnosis or at progression. Patients were divided into 3 categories according to PD-L1 level (&lt; 1, 1-49, &gt; 50%). Progression free survival defines the time from randomization to disease progression after each line of therapy. Overall survival defines time from randomization to death from any cause. Results: 70.18% had adenocarcinoma, 26.32% had squamous cell carcinoma, 1.75% had small cell lung cancer and one pathology was missing from the file. 66.66% were stage IV at diagnosis, 26.31% were stage 3. PD-L1 expression was &gt; 50% in 40.35% of patients, 24.56% had a level between 1 and 50% and the remaining had a value of less than 1%. PD-L1 was missing or not done in 15.79%. Median PFS was 13.9 months. Median OS was 14.2 months. 22.81% received immunotherapy as first line and 75% of the remaining patients upon first progression. PFS1 was 4.2 months. Mean time to first progression on immunotherapy was 3.6 months in patients with PD-L1 &gt; 50%, 10.5 months in PD-L1 between 1 and 50% and 14.3 months in those who had PD-L1 &lt; 1%. At the date of data cutoff, 49.12 % of patients were still receiving immunotherapy. No grade 3 or 4 immune related adverse events were seen during follow-up. Conclusions: The efficacy and safety of anti-PD-1 medications for advanced NSCLC were comparable in real-world and clinical settings. Prediction of treatment response from tumor PD-L1 expression seemed less practical than that was expected
The prognostic role of progesterone receptor in patients with rapidly proliferating, hormone receptor-positive early breast cancer.
Authors: Sara Bravaccini, Giuseppe Bronte, Emanuela Scarpi, Sara Ravaioli, Maria Maddalena Tumedei, Roberta Maltoni, Maurizio Puccetti, Anita Mangia, Dino Amadori, Andrea Rocca
Journal: Journal of Clinical Oncology (2019)

545 Background: The prognostic role of progesterone receptor (PgR) in highly proliferating early breast cancer (BC) is not well established. We retrospectively explored this biomarker in a cohort of patients with highly proliferating tumors enrolled in a phase III trial of adjuvant therapy. Methods: 1066 patients with N- or 1-3 N+ BC were randomized to receive: epirubicin followed by CMF, CMF followed by epirubicin, or CMF alone. Rapidly proliferating tumors were defined by thymidine labeling index (TLI) &gt; 3% or histological grade 3 or S-phase &gt; 10% or Ki67 &gt; 20%. We analyze the subgroup of 466 patients with hormone receptor (HR)-positive tumors treated with sequential epirubicin/CMF regimens followed by tamoxifen and for whom immunohistochemical assessments of estrogen receptor (ER), PgR, HER2 and Ki67 were available. Disease-free (DFS) and overall survival (OS) curves were built with the Kaplan–Meier estimator and compared by logrank test and Cox regression models. Results: PgR expression was significantly associated with ER expression, HER2 status, age and menopausal status, but not with Ki67, tumor size and nodal status. PgR cutoff values of 10% and 20% were chosen based on a Receiver Operating Characteristics analysis and the literature data. DFS and OS figures at 5 and 10 years, as well as the relative hazard ratios, according to the different PgR cutoff values, are reported in the table. Conclusions: Our results confirm the prognostic relevance of PgR expression in a cohort of patients with highly proliferating, HR-positive early BC treated with adjuvant chemotherapy and endocrine therapy. [Table: see text]
Real-world Merkel cell carcinoma outcomes from a tertiary care center.
Authors: Theresa N Canavan, Nicole Adell Doudican, Mary Stevenson, Anna C. Pavlick, John Carucci
Journal: Journal of Clinical Oncology (2019)

e14098 Background: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine carcinoma of the skin that is highly immunogenic. Checkpoint inhibitors (CPI) have recently revolutionized the treatment of advanced MCC. In this study we sought to better understand how CPI are used in an outpatient setting and to better define MCC outcomes associated with their use. Methods: We conducted a retrospective chart review of MCC patients seen in the New York University Hematology and Oncology Department from 2012-2018. Patient characteristics and treatment regimens were compared between those with and without disease progression at any point during follow-up. Results: Fifteen patients were identified, 46.7% of whom presented with nodal or distant disease (Table). Nine patients experienced relapse during follow-up. There were no MCC-specific deaths, and 92.3% of patients were without evidence of MCC at the end of follow-up. Ten patients were treated with one or more CPI (pembrolizumab, nivolumab, ipilimumab) either in the setting of first line systemic therapy (71.4%) or after experiencing disease progression (28.6%). There was a trend toward improved relapse free survival with CPI use (P = 0.054). Conclusions: Although recurrences were common, overall outcomes at the end of follow-up were very good. CPI were well tolerated and were associated with a trend toward improved relapse free survival. Patients with advanced stage MCC would benefit from consideration of CPI as part of their treatment options. [Table: see text]
Abstract 266: Is the Col4a3 <i> <sup>-/-</sup> </i> Alport Mouse a Novel Model for Heart Failure With Preserved Ejection Fraction?
Authors: Keyvan Yousefi, Wen Ding, Jayanti Singh, Lina Shehadeh
Journal: Circulation Research (2016)

Heart failure with preserved ejection fraction (HFpEF) accounts for more than 50% of all HF cases. HFpEF patients manifest normal or mildly reduced left ventricle (LV) ejection fraction (LVEF), LV hypertrophy, diastolic dysfunction, myocardial stiffness, cardiac fibrosis, hypertension, nephropathy and sudden death. There is no appropriate animal model for HFpEF. The Alport Col4a3 -/- mouse, a model of nephropathy, hypertension and early death, develops a cardiovascular pathology that is yet to be well characterized. We elected to analyze the cardiovascular pathology of the Alport mouse and investigate any commonalities with HFpEF. Male Alport and wild type (WT) littermates of mixed background at 2 months of age were subjected to echocardiographic and 2D speckle tracking analyses and heart tissues were used for histopathological examinations (N=6 mice per group). Circulating Galectin-3, a marker of HFpEF, was measured by Elisa in plasma samples. Data are shown as mean±SEM. Normalized heart weight increased in Alport relative to WT mice - p&lt;0.01, indicative of cardiac hypertrophy. Consistently, echocardiography showed interventricular septum (IVS) thickening -p&lt;0.05. Reduced stroke volume p&lt;0.01, and impaired global longitudinal and circumferential strain (GLS and GCS) indicated systolic dysfunction in Alport mice. No significant reduction in LVEF was observed. Alport mice developed diastolic dysfunction evidenced by a prolonged Isovolumetric relaxation time -P&lt;0.05, and a reduced E/A, a marker of LV relaxation and stiffness -p&lt;0.01. Elevated LV filling pressure and pulmonary artery wedge pressure were demonstrated by an increase in E/E’ - p&lt;0.01. Galectin-3 increased in Alport relative to WT plasma (P&lt;0.01). Alport hearts had more Fibronectin protein - P&lt;0.05 and increased number of fibroblasts with “activated” phenotype as demonstrated by increased mass of rough endoplasmic reticulum in EM cross sections. Our study suggests that the cardiovascular pathologies of the Alport mouse are similar to HFpEF, specifically preserved ejection fraction, diastolic dysfunction, hypertension, early death and cardiac stiffness and fibrosis. Further study of this multi-factorial pathology may render the Alport mouse as a useful novel model for HFpEF.
Recurrence-free survival (RFS) and objective response rate (ORR) phase 1/2 study of intralesional (IL) neoadjuvant (neo) anti-PD1 agents (aPD1) for stage IIIB-IV melanoma (MEL).
Authors: Igor Samoylenko, Olga V. Korotkova, Ekaterina Shakhray, Tatiana Zabotina, Sergey Berdnikov, Dmitry Tabakov, Elena Zakharova, Natalia N. Petenko, Lev V. Demidov
Journal: Journal of Clinical Oncology (2019)

e14171 Background: We previously reported that aPD1 agents could be safely administered IL in patients (pts) with metastatic MEL with superficial lesions, providing local and bystander tumor response (Samoylenko, I., et al. (ASCO-SITC 2018)). We present results from an interim 6 mos analysis of RFS and ORR for IL neo aPD1 therapy. Methods: Pts with unresectable stage IIIC/D/IVM1a-c MEL (safety cohort, N = 7) and resectable stage IIIC/D/IVM1a (expansion cohort, N = 18), with ≥ 1 injectable cutaneous, subcutaneous, or nodal lesions ≥ 10 mm were allocated to 6 doses/12 of nivolumab or pembrolizumab before surgery (surg). aPD1 was given at scale-based dosing regimen reported previously. Tumor sampling for biomarker analysis and pCR confirmation (or core-needle biopsy, CNB) was performed prior to treatment and at week 13-18. The analysis was conducted on the ITT basis to estimate RFS at 6 mos and ORR. An RFS event was defined as disease progression or death due to any cause after surg and assessed in the expansion cohort. ORR for the both cohorts was evaluated. Results: Since Apr 2016 to Dec 2018 25 pts were enrolled. Baseline characteristics are summarized in Table. ORR was 47,6% (10/21 pts assessed), with 5 (24%) clinical CR and 4 pathological CR (19%). Among 18 pts considered for surg 2 refused from surg when CNB confirmed no residual tumor. 89% of pts (16/18 pts) from the expansion cohort remained recurrence free at 6 mos FU. Baseline immune phenotype of tumor infiltrating lymphocytes (TILs) was available for 20 of 21 pts assessed. Baseline percent of TILs assessed by flow cytometry (FCT) was higher in responders vs non-responders (7.54±7.51% vs 1.51±2.93, p &lt; .05), whereas CD3 - CD16 + CD56 + and CD4 + CD25 + values were lower in responders vs non-responders (0.94±1.45% vs 7.88±6.84, p &lt; .05, and 6.68±3.46% vs 20.50±16.79, p &lt; 0.05, respectively). PD1, PDL-1 and PDL-2 expression in tumor cells and TILs assessed by FCT did not differ significantly between responders and non-responders. Conclusions: We demonstrated the potential clinical efficacy of IL aPD1 in melanoma pts. Further studies are needed to determine if unsuccessful IL administration could predict failure to adjuvant treatment. Primary analysis of RFS at 1-yr is expected. Clinical trial information: NA. [Table: see text]
Concurrent or layered treatment (Tx) with radium-223 (Ra-223) and enzalutamide (Enza) or abiraterone plus prednisone/prednisolone (Abi/pred): A retrospective study of real-world clinical outcomes in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Neal D. Shore, Oliver A. Sartor, Cora N. Sternberg, Fred Saad, Bertrand F. TOMBAL, Kurt Miller, Jan Kalinovsky, Xiaolong Jiao, Krishna Tangirala, Celestia S. Higano
Journal: Journal of Clinical Oncology (2020)

50 Background: In clinical practice, Ra-223 is often combined with Enza or Abi/pred. ERA 223 (NCT02043678) showed increased fracture risk with concurrent Ra-223+Abi/pred. We assessed real-world symptomatic skeletal events (SSEs) and overall survival (OS) of pts with mCRPC who received concurrent or layered Ra-223+Enza or Abi/pred. Methods: Patients with mCRPC treated with Ra-223 in US cancer clinics from 1/01/2013 to 6/30/2017 were identified from a Flatiron prostate cancer registry of electronic health records. Tx initiation defined subgroups: concurrent (both started within 30 days) or layered (1 started ≥30 days after the other). Baseline (BL) was the first dose of Ra-223. Descriptive analysis was performed for BL characteristics, SSEs, and OS (Kaplan–Meier). Results: Of 625 pts treated with Ra-223, 48% received Ra-223+Enza or Abi/pred. Layered Tx was more common (73%) than concurrent (27%). BL characteristics and clinical outcomes were summarized [Table]. Conclusions: Ra-223+Enza or Abi/pred Tx was mainly layered. SSE rates with layered vs concurrent Ra-223+Abi/pred varied between subgroups; results must be treated cautiously given small pt numbers and a non-randomized study. The ongoing PEACE III trial is investigating concurrent Ra-223+Enza; a Phase III study (ESCALATE) exploring layered Ra-223+Enza is planned. Clinical trial information: NCT02043678. [Table: see text]
Disassociation of ARID1A with genomic ancestry and prognostic impact in an admixed cohort of Brazilian patients with gastric cancer (GC).
Authors: Helano C. Freitas, Diana Noronha Nunes, Thais Fernanda Bartelli, Maria Galli de Amorim, Luiza Ferreira Araujo, Victor Hugo Fonseca Jesus, Maria D. Begnami, Israel Tojal da Silva, Alexandre Defelicibus, Renan Valieris, Bianca Salgado Boneti, Elizabete Maria Pereira de Andrade Caires, Emmanuel Dias-Neto
Journal: Journal of Clinical Oncology (2019)

e15585 Background: Loss of expression of ARID1A, a tumor suppressor gene involved in chromatin remodeling and transcription activation, has been associated with worse prognosis in Asian GC patients (Yang et al. 2016). Mutations in ARID1A have been found in 8-27% of GC, usually leading to gene/protein inactivation. Here we evaluated the possible involvement of ARID1A mutations and clinical characteristics, while considering genomic ancestry and survival, in a cohort of Brazilian GC patients. Methods: We included 112 pts diagnosed with GC and treated at AC Camargo Cancer Center before 2013. The study was approved by local IRB. Genomic DNA was used for capture-based enrichment of a customized gene panel including 99 genes. Libraries were sequenced in the NextSeq 500 platform (Illumina), using paired-end reads (2x75bp). For ancestry inference we used a set of ancestry informative markers, covered by target and off-target reads, described by Elhaik et al. (2014). Results: Median age was 64y (37-91), 63% were male, M:F ratio was 1.73. Most cases were classified as Diffuse (47.3%) followed by Intestinal (41.1%), Mixed (2.7%) and 8.9% were deemed unclassifiable by Lauren´s classification. 22.3% were stage I, 20.5% stage II, 42.9% stage III and 14.3% stage IV. 11.6% were in the GEJ and 80.4% were in corpus/antrum. Five patients were EBV positive (4.5%). Genomic ancestry was as follows: 55.4% European, 27.7% Asian, 8.9% African and 8% were highly admixed ( &lt; 50% of any ancestry). ARID1A was mutated in 19% of cases and showed no association with age at diagnosis (p = 0.21), gender (p = 0.76), tumor location (p = 0.55), staging (p = 0.42), Lauren (p = 0.14) or EBV (p = 0.42). ARID1A had no impact on overall survival (OS) (HR 1.17; 95%CI 0.59-2.31; p = 0.6) or disease-free survival (DFS) (HR 1.24; 95%CI 0.66-2.32; p = 0.5), including the subgroup with Asian genomic background: OS-Asia (HR 1.08; 95%CI 0.31-3.81; p = 0.9), DFS-Asia (HR 1.15; 95%CI 0.32-4.12; p = 0.8). Conclusions: ARID1A is a common driver in GC among Brazilian patients. Unlike in Asians, ARID1A was not prognostic in this Brazilian cohort even in the subgroup with a predominant ( &gt; 50%) Asian genomic ancestry.
Long-term toxicity profile of trastuzumab emtansine (T-DM1): A multicenter real-life study.
Authors: Giuseppe Buono, Alessandra Fabi, Lucia Del Mastro, Katia Cannita, Nicla Maria La Verde, Raffaele Ardito, Ferdinando Riccardi, Filippo Montemurro, Marina Elena Cazzaniga, Ornella Garrone, Alberto Zambelli, Benedetta Conte, Roberta Caputo, Daniela Cianniello, Marta Bonotto, Michele Bartoletti, Sara Parola, Sabino De Placido, Massimo Di Maio, Grazia Arpino
Journal: Journal of Clinical Oncology (2019)

e12507 Background: T-DM1 is widely used in HER2 positive metastatic breast cancer (MBC) patients (pts), often for many cycles until progression. However, little is known about its long term toxicity. The aim of this study was to evaluate the safety profile of T-DM1 when delivered for ≥12 cycles. Methods: HER2 positive MBC pts who had received ≥12 cycles of T-DM1 across 18 Italian cancer centers were enrolled from January 2017 to September 2018. The 12 cycles cut-off was chosen based on the EMILIA trial median PFS (9.6 months), to identify a patient population treated with T-DM1 for longer time. Tumor and clinical characteristics were collected. Standard haematological tests, blood chemistries and side effects (nausea, vomiting, diarrhea, stomatitis, asthenia) were recorded cycle by cycle, according CTCAE criteria version 4. Haematological and laboratory toxicities were available for 86 patients, while other toxicities for all 115 patients. Results: Overall, 115 pts were enrolled. Median age was 54.5 (range 29.6–81.9); median time from diagnosis of metastatic disease to first T-DM1 cycle was 32.5 months. T-DM1 was administered as 2nd line and 3rd line of treatment in 45.2% and 27.8% of pts, respectively. Median number of cycles was 18 (range 12-59). Complete response, partial response and stable disease rates were 11.4%, 43% and 45.6%, respectively. Treatment related side effects are shown in table 1. Interestingly, no increased liver toxicity was observed in pts with liver metastases. Analysis of mean CTCAE grade by cycle showed that no relevant incremental toxicity was observed during long term T-DM1 therapy. Conclusions: T-DM1 is safe and well tolerated in these long responding pts. We found no relevant cumulative toxicity. Patients should be treated with T-DM1 as long as their tumor responds, as no safety issues are related to its long term use. [Table: see text]
Phase I trial of TG02 plus dose-dense or metronomic temozolomide for recurrent anaplastic astrocytoma and glioblastoma in adults.
Authors: Jing Wu, Ying Yuan, Christine Cordova, Orwa Aboud, Marta Penas-Prado, Brett James Theeler, Christine Bryla, Yu-Ting Su, Ewa Grajkowska, Ann McCoy, Lisa Boris, Christine Siegel, Ramya Antony, Nancy Garren, Tracy Lawhon, Terri Armstrong, Mark R. Gilbert
Journal: Journal of Clinical Oncology (2019)

2031 Background: Therapies targeting multiple survival pathways simultaneously may be more effective for high-grade gliomas, a disease highly resistant to treatment. Our preclinical studies have shown potent anti-glioma effects of TG02 and synergy with temozolomide (TMZ) through modulation of transcription and cellular metabolism. A phase I/II trial was launched to test the combination of TG02 and TMZ in recurrent malignant gliomas and herein we report the phase I results. Methods: Adults with recurrent high-grade astrocytoma, KPS ≥ 60, normal organ function, ≤ 2 prior relapses were enrolled. The primary endpoint was dose limiting toxicity (DLT) from the start of the combined treatment to 4 weeks after in each arm. Bayesian optimal interval (BOIN) design was employed to determine the maximum tolerated dose (MTD) with the target DLT rate of 35% and the toxicity profile of the combination of TG02 (starting dose 200mg orally on days 1, 12, 15, and 26) and TMZ, either as a dose-dense (DD; 125mg/m 2 /d, 7on/7off, Arm 1) or metronomic (MN; 50mg/m 2 /d, Arm 2) dosing schedule on a 28-day cycle. Results: Forty patients were enrolled; 38 were evaluable; 70% male; overall median age 50.7; median KPS 90. Of 18 evaluable patients in Arm 1 (DD TMZ), at TG02 dose level 200mg, 1/6 had a DLT: Gr3 diarrhea. At TG02 dose level 250mg, 3/12 had DLTs: Gr4 neutropenia for over 5 days, Gr3 elevated ALT, and Gr3 fatigue. Of 20 evaluable patients in Arm 2 (MN TMZ), at TG02 dose level 200mg, 1/6 had a DLT: recurrent Gr3 neutropenia. At TG02 dose level 250mg, 5/12 had a DLT: Gr3 elevated ALT, Gr3 fatigue, and Gr4 neutropenia. At TG02 dose level 300mg,1 out of 2 had a DLT: Gr4 febrile neutropenia, Gr4 elevated ALT, Gr4 elevated AST, which resulted in hospitalization. Therefore, the TG02 dose level of 250mg was declared as the MTD in both Arm 1 and Arm 2. Conclusions: The combination of TG02 at the MTD of 250mg with DD or MN TMZ has a tolerable toxicity profile. Cohort expansion continues at the MTD in both arms to conduct pharmacokinetics and pharmacogenetics to better elucidate the toxicity profile. Objective responses have been observed, suggesting activity of this regimen and supporting continued investigation with the phase II randomized component. Clinical trial information: NCT02942264.
Clinical efficacy and safety evaluation of nimotuzumab combined with chemotherapy in the treatment of advanced colorectal cancer: A retrospective analysis.
Authors: Sai-xi Bai, Ruo-rong Zhang, Wang-hua Chen, Hongmin Dong, Gang Wang, Xiaokai Li, Ling Wen Wang
Journal: Journal of Clinical Oncology (2019)

e15009 Background: To retrospectively analyze the clinical effects and safety of nimotuzumab combined with chemotherapy as the first-line treatment of advanced colorectal cancer (ACRC). Methods: ACRC patients treated by nimotuzumab combined with chemotherapy (40 cases) or chemotherapy alone (44 cases) were enrolled in this study. Responses were evaluated by Respond Evaluation Criteria in Solid Tumors. Adverse events were evaluated by Common Terminology Criteria for Adverse Events 3.0. Results: The combined treatment group had a slightly higher objective response rate (RR) and disease control rate (DCR) (RR: 55.0% vs 36.4%; DCR: 85.0% vs 75.0%) compared to the chemotherapy alone group, although not statistically significant (P &gt; 0.05). The median progression-free survival (PFS) was 9.89 months in the combined treatment group and 7.86 months in the chemotherapy alone group, respectively. The median survival time was 22.32 months in the combined therapy group and 18.10 months in the chemotherapy alone group, respectively (P = 0.060). There was no statistically significant difference regarding the adverse events between these two groups. Conclusions: The nimotuzumab combined with chemotherapy had similar efficacy and safety to chemotherapy-alone treatment in ACRC. The efficacy and safety of the combined treatment should be further studied with a randomized multicentre trial with a larger number of ACRC patient.