tbuckley/cabot-search huggingface dataset:
Comparative characteristics of the genes expression of cancer-testis antigens in tumor and non-tumor breast tissues.
Authors: Khava A. Mogushkova, Dmitriy I. Vodolazhsky, Denis S. Kutilin, Oleg I. Kit
Journal: Journal of Clinical Oncology (2017)

e23085 Background: Breast cancer (BC) is the most common cancer among women. The development of immunotherapy which targets cancer-testis antigens (CTA) is needed for the decreasing in breast cancer mortality. Therefore, the aim of this work was the study of specific CTA of breast cancer tissue among CTA-family, role of which has been previously mentioned. Methods: The paired surgical biopsies of tumor and non-tumor breast tissue of 25 patients (50 samples) residing in the South of Russia and treated in Rostov Research Institute of Oncology were included in the present study. Total RNA was extracted from tissue samples by P. Chomczynski and N. Sacchi (2006) method. cDNA library was synthesized using reagent kit "Reverta-L» (Russia, "InterLabService"). Primers were designed using the NCBI GenBank database. The relative expression of 17 genetic loci ( MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-B1, MAGE-B2, GAGE1, GAGE3, GAGE4, MAGE-C1, BAGE, CTAG-1B, XAGE3, NY -ESO1, SSX2, SYCP1, PRAME1) was determined by Real-Time qPCR (reference gene - GAPDH) using CFX96 thermal cycler (Bio-Rad, USA). Statistical analysis was performed using nonparametric Mann-Whitney U-test. Results: The expression of CTA genes MAGE-A4, MAGE-B1, MAGE-B2 and GAGE3 was found to be significantly (p &lt; 0.05) increased by 1.4; 9.5; 4.0 and 9.8 fold, respectively, in tumor tissue compared with non-tumor breast tissue. The expression of other CTA genes were not differed between tumor and non-tumor samples. Conclusions: Detected increasing of the expression levels of MAGE-A4, MAGE-B1, MAGE-B2 and GAGE3 genes evidences that these CTA may serve as the effective immunotherapeutic targets in breast cancer.
Single-agent LV305 to induce anti-tumor immune and clinical responses in patients with advanced or metastatic sarcoma and other cancers expressing NY-ESO-1.
Authors: Neeta Somaiah, Matthew Stephen Block, Joseph W. Kim, Geoffrey Shapiro, Khanh Tu Do, Patrick Hwu, Joseph Paul Eder, Robin Lewis Jones, Sacha Gnjatic, Hailing Lu, Jan Ter Meulen, Frank J. Hsu, Seth Pollack
Journal: Journal of Clinical Oncology (2016)

3093 Background: Immune approaches that stimulate specific anti-tumor cytotoxic T cells (CTLs) can have single agent activity, be synergistic with check point inhibitors (CPIs) and enhance adoptively transferred T cells. LV305 is a replication-incompetent, integration-deficient, hybrid viral vector based on the ZVex platform. It is designed to target dendritic cells in vivo and induce the expression of NY-ESO-1 in order to potently generate and expand anti-cancer CTLs. In this first-in-human study, the safety, immunogenicity and efficacy of LV305 were examined in patients (pts) with sarcoma or carcinoma. Methods: Pts with previously treated, advanced or metastatic malignancies expressing NY-ESO-1 (IHC) were eligible. In Part 1, Dose Escalation, 3 pts enrolled into each of 4 cohorts to receive 3 or 4 intradermal injections every 3 weeks of 108, 109 or 1010 vector genomes (vg) per dose. Cohort advancement followed a 3+3 design and safety was reviewed with a DSMB. In Part 2, additional pts were treated at the max dose/MTD. Results: In Part 1, no DLT or SAEs were observed in the 12 sarcoma patients; all related AEs were grade 1/2. In Part 2 (1010 vg dose), only 1 grade 3 AE was reported in 27 pts (12 sarcoma, 5 melanoma, 9 ovarian and 1 NSCLC). Of evaluable sarcoma pts, NY-ESO-1 specific CD4 12/23 (52%), CD8 12/23 (52%) and CD4 and/or CD8 16/23 (70%) were induced by LV305. Clinical responses included: sarcoma, 1 PR (recent SD to PR change {Study Day 579}, 606+ days), 13 SD (defined as > 84 days, range 136 – 585+ days); melanoma 4 SD; ovarian, 2 SD; and NSCLC 1 SD. In sarcoma pts, median PFS was 140 days and 7/10 pts with pretreatment PD had SD or PR following LV305. Conclusions: LV305 demonstrated acceptable safety up to 1010 vg and induced significant anti-NY-ESO-1 T cell responses in advanced malignancies. Clinical benefit (PR/SD) was seen in 14/24 pts with sarcoma, have been durable > 1 year in 5 pts and includes a late conversion of SD to PR. The median PFS for sarcomas was similar to that of trabectedin as reported in a recent US Ph3 study. The induction of immune responses, favorable safety profile and clinical activity indicate LV305 is an active agent that warrants further investigation. Clinical trial information: NCT02122861.
Missense polymorphism in HSD3B1 in Japanese men treated with primary androgen-deprivation therapy for metastatic prostate cancer.
Authors: Masaki Shiota, Naohiro Fujimoto, Kenjiro Imada, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Katsunori Tatsugami, Shunichi Kajioka, Masatoshi Eto
Journal: Journal of Clinical Oncology (2018)

e17051 Background: Recently, genetic polymorphism in HSD3B1 has been shown to be associated with oncological outcome when treated with androgen-deprivation therapy (ADT) for prostate cancer, and rises during progression to castration-resistant prostate cancer. However, its impact on prognosis among different ethnicities remains unclear. Then, we aimed to investigate the significance of missense polymorphism in HSD3B1 gene encoding 3β-hydroxysteroid dehydrogenase among men treated with primary ADT for metastatic prostate cancer and in castration-resistant prostate cancer (CRPC) tissues. Methods: This study included 104 Japanese patients with metastatic prostate cancer treated with primary ADT. The association of HSD3B1 (rs1047303, 1245C) with clinicopathological parameters and prognosis, including progression-free survival and overall survival, was examined. As well, genotype in HSD3B1 (rs1047303, 1245C) was examined in CRPC tissues. Results: Clinicopathological parameters were comparable between men with homozygous wild-type and men with heterozygous and homozygous variant types in HSD3B1 gene. Men carrying heterozygous and homozygous variant types in HSD3B1 gene showed higher progression risk [hazard ratio (95% confidence interval), 2.34 (1.08–4.49), P = 0.033], but not any-caused death risk [hazard ratio (95% confidence interval), 1.36 (0.52–2.92), P = 0.50], compared with men carrying homozygous wild-type. Among 8 CRPC tissues, variant types in HSD3B1 gene were identified in 4 (50%) cases, where, de novo mutation in somatic cells occurred in at least one case. Conclusions: This study confirmed the finding that HSD3B1 genetic variation is associated with high risk of progression in Japanese men treated with primary ADT for metastatic prostate cancer, suggesting universal significance among different ethnicities. De novo mutation was suggested to contribute to CRPC progression.
HIV-Specific, Ex Vivo Expanded T Cell Therapy: Feasibility, Safety, and Efficacy in ART-Suppressed HIV-Infected Individuals
Authors: Julia A. Sung, Shabnum Patel, Matthew L. Clohosey, Lauren Roesch, Tamara Tripic, JoAnn D. Kuruc, Nancie Archin, Patrick J. Hanley, C. Russell Cruz, Nilu Goonetilleke, Joseph J. Eron, Clio M. Rooney, Cynthia L. Gay, Catherine M. Bollard, David M. Margolis
Journal: Molecular Therapy (2018)

Adoptive T cell therapy has had dramatic successes in the treatment of virus-related malignancies and infections following hematopoietic stem cell transplantation. We adapted this method to produce ex vivo expanded HIV-specific T cells (HXTCs), with the long-term goal of using HXTCs as part of strategies to clear persistent HIV infection. In this phase 1 proof-of-concept study (NCT02208167), we administered HXTCs to antiretroviral therapy (ART)-suppressed, HIV-infected participants. Participants received two infusions of 2 × 107 cells/m2 HXTCs at a 2-week interval. Leukapheresis was performed at baseline and 12 weeks post-infusion to measure the frequency of resting cell infection by the quantitative viral outgrowth assay (QVOA). Overall, participants tolerated HXTCs, with only grade 1 adverse events (AEs) related to HXTCs. Two of six participants exhibited a detectable increase in CD8 T cell-mediated antiviral activity following the two infusions in some, but not all, assays. As expected, however, in the absence of a latency reversing agent, no meaningful decline in the frequency of resting CD4 T cell infection was detected. HXTC therapy in ART-suppressed, HIV-infected individuals appears safe and well tolerated, without any clinical signs of immune activation, likely due to the low residual HIV antigen burden present during ART.
Association of Ki-67 expression in CTCs with disease relapse in patients with early breast cancer (BC) and affect by the administration of adjuvant chemotherapy.
Authors: Dimitrios Mavroudis, Sofia Agelaki
Journal: Journal of Clinical Oncology (2016)

e23243 Background: The assessment of Ki67 in the primary tumor represents a prognostic marker in early BC. We evaluated Ki67 expression in CTCs from patients (pts) with early BC and assessed the effect of adjuvant chemotherapy as well as Ki67 expression in the primary tumor. Methods: Ki67 was evaluated in CTCs of 166 pts with early BC pre- and post- adjuvant chemotherapy by the use of immunofluorescence analysis. Cytospins of peripheral blood mononuclear cells were double stained with A45-B/B3 cytokeratin and Ki67 antibodies. Ki67 staining of the primary tumor was also performed for 20 CTC-positive pts. The proliferation index (PI) of CTCs was defined as the ratio of Ki67-positive CTCs/total CTCs. A PI of ≤ 14% and > 14% was defined as ‘low’ and ‘high’, respectively. Results: CTCs were detected in 53 (32%) pts before and/or after chemotherapy. Ten (19%) of 53 CTC(+) and 9 (8%) of 113 CTC(-) pts relapsed (p = 0.039). Ki67(+) CTCs were identified in 42 (79%) of 53 pts, whereas in 13 (25%) and 11 (21%) pts, exclusively Ki67(+) and Ki67(-) CTCs, respectively, were detected. Five (38.5%) of 13 pts with exclusively Ki67(+) CTCs relapsed compared to none among 11 pts with exclusively Ki67(-) CTCs (p = 0.041). The PI among the total CTCs detected pre- and post-chemotherapy was 59% and 55%, respectively. Among pts with detectable CTCs at both time points, the PI remained high in 67%, turned to high in 17% and turned to low in 17%. A concordance in Ki67 staining between the primary tumor and corresponding CTCs was recorded in 15 (75%) out of the 20 pts evaluated. Conclusions: Adjuvant chemotherapy fails to decrease the proliferation index of CTCs in pts with BC. Ki67 expression of CTCs seems to reflect Ki67 expression of the primary tumor and is predictive of patient outcome.
Impact of modified Glasgow prognostic score and neutrophil/platelet-lymphocyte ratio on survival metastatic colorectal cancer (mCRC).
Authors: Fernando Namuche, Claudio J. Flores, Jorge Leon, Alfredo Aguilar
Journal: Journal of Clinical Oncology (2018)

e15557 Background: Modified Glasgow Prognostic Score (mGPS), was reported as a good prognostic factor for OS, in other neoplasms, however its role in mCRC it’s still being studied. High circulating neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) appears to be prognostic in metastatic colorectal cancer (mCRC), they have been suggested as important inflammatory markers and potential predictors of long-term outcomes in patient with colorectal cancer (CRC). In developing countries, the impact of biomarkers that could better approach the evaluation process is critical. Methods: We retrospectively reviewed the electronic medical files of 248 patient with mCRC. Patients were diagnosed and treated at a specialized cancer center between 2012-2017. We divided the population according to mGPS (mGPS0, 1 or 2), NLR cut-off (low≤3.8, high > 3.8) and PLR (low≤172, high > 172), the number of patients were similar in each group. Between-group comparison was performed using a stratified Cox’s proportional hazard model for OS. Chi square was used to evaluate association between NLR/PLR cut-offs and mGPS. Results: A total of 248 pts with mCRC were included. Independent prognostic factors for poor OS were high PLR and mGPS2. Overall five-year survival rates were 56.2% in mGPS0, 42.3% in mGPS1 and 18.5% in mGPS2, it was significantly worse in mGPS2. Overall five-year survival rates were 53.3% in low NLR and 24.6% in high NLR. Multivariate analysis for OS showed that high NLR (p = 0.034), PLR (p = 0.039) and mGPS (p = 0.002) were independent prognostic factor. There was an association between mGPS - NLR and mGPS - PLR (p = 0.032 and 0.022 respectively) Conclusions: The impact of elevated mGPS, NLR and PLR were found to be prognostic factors for survival in patients with mCRC. There was association between mGPS - NLR and mGPS - PLR. This data is valuable, specially in scenarios that can’t afford other biomarkers due to its prohibitive cost.
TERT promoter mutations and telomerase expression in melanoma in adolescents and young adults.
Authors: Brittani Seynnaeve, Seungjae Lee, Yongseok Park, Alberto S. Pappo, John M. Kirkwood, Armita Bahrami
Journal: Journal of Clinical Oncology (2016)

9561 Background: Melanoma incidence in adolescents and young adults (AYAs) (between the ages of 15 and 29 years) is increasing more rapidly than other cancers in the U.S. Progression of melanoma to distant sites in this age group is not reliably predicted by clinicohistologic criteria at diagnosis. Thus, understanding genomic features associated with aggressive behavior is crucial. It has been shown that TERT promoter mutations are acquired early in melanoma tumorigenesis and correlate with poor patient outcomes. We investigated telomerase expression in a clinicopathologically well characterized cohort of AYA melanomas of the University of Pittsburgh and its correlation with TERT promoter mutations and clinical outcome. Methods: Formalin-fixed paraffin-embedded sections of 28 AYA melanomas, including 20 conventional melanomas (CM), 2 nevoid melanomas (NM), and 6 spitzoid melanomas (SM), were analyzed for the presence of hotspot mutations in BRAF, NRAS, and the TERT promoter. Telomerase expression levels were analyzed by using real-time quantitative reverse transcriptase polymerase chain reaction (RT-qPCR). Results: Twenty melanomas (71%) carried a BRAF V600E mutation (18/20 CMs, 2/2 NMs, and 0/6 SMs) and none carried an NRAS mutation. Eleven of 20 CMs (55%), but none of NMs or SMs, carried a TERT promoter mutation [-146C > T (n = 7); -124C > T (n = 4)]. RT-qPCR was successful in 14 CMs, 1 NM, and 4 SMs. TERT mRNA in CMs was expressed at higher levels than those in SMs and NM, with a 4- to 1814-fold (median, 100-fold) increase relative to the control value. Thirteen of 20 patients (65%) with CM had an unfavorable clinical course (2 recurrences, 11 distant metastases; 10 DOD), whereas all SM and NM patients had a favorable clinical course (median follow-up, 87 months). All clinically unfavorable CMs with expression data had high TERT mRNA expression levels, of which 7 (54%) had a TERT promoter mutation. Conclusions: Telomerase expression by RT-qPCR is a better indicator of aggressive behavior in AYA melanoma than TERT promoter mutations alone, and may be an important prognostic marker. Studies of alternative mechanisms of TERT upregulation in AYA melanoma and its therapeutic exploitation are warranted.
Oxidative processes in the blood during chemotherapy and lethality of patients with multiple myeloma.
Authors: Irina A. Goroshinskaya, Oleg I. Kit, Natalia Zuderman, Nadezhda D. Ushakova, Irina B. Lysenko, Ludmila A. Nemashkalova, Nadezhda V. Nikolaeva, Elena A. Kapuza, Olga N. Shatokhina
Journal: Journal of Clinical Oncology (2018)

e20027 Background: Our aim was a comparative analysis of the intensity of lipid peroxidation, the activity of antioxidant enzymes, the functional state of albumin, and indices of endogenous intoxication in the blood of patients with multiple myeloma (MM) during multi-course chemotherapy. Methods: Plasma content of malondialdehyde (MDA), the activity of superoxide dismutase (SOD) and catalase in erythrocytes, total and effective concentrations of albumin (TCA and ECA), level of medium mass molecules (MMM), toxicity index (TI = TCA / ECA – 1) and intoxication factor (IF = MMM254 / ECA • 1000) were determined in 26 patients with primary revealed secreting multiple myeloma during multi-course chemotherapy (CT) under the VCD scheme, as well as in 24 people without cancer. The data were analyzed using Statistika 6.0 programs and Student's t-test. Results: MM patients before the start of treatment had an increase in plasma MDA level by 46.9% (p < 0.01) compared with the group without oncological pathology. This was accompanied by an increase in the SOD / catalase ratio in erythrocytes by 42.3% (p < 0.01), which indicated a violation of the balanced work of antioxidant enzymes. There was a decrease in ECA by 56% (p = 0.000000), an increase in TI by 6.3 times and IF by 3.4 times (p < 0.001). In most patients, after 4 cycles of CT, complete normalization of MDA and SOD / catalase ratio was observed, ECA increased by 37.6%, TI and IF decreased by 68.7% and 44.4% (p < 0.05) compared to values before treatment. While 5 deceased patients had an increase in MDA level (by 106.4% above the norm, by 45% relative to the values before treatment and by 119.3% compared with successfully treated patients, p < 0.01-0.001), the SOD / catalase ratio exceeded the norm and the value for successful treatment by 53.7-59.1%. ECA, IT and CI did not differ from the initial values and were statistically different from the level in patients with successful treatment (by 29.7%, 176%, and 59.9%, respectively, p < 0.05-0.01). Conclusions: The results suggest the relationship of free radical oxidation, conjugated operation of the main antioxidant enzymes, associated with them detoxification capacity of albumin with the success of CT treatment in patients with multiple myeloma.
Mesenchymal Stromal Cells Use Extracellular Vesicle-Mediated Mitochondrial Transfer to Modulate Human Macrophage Phenotype Through Enhancement of Oxidative Phosphorylation in the In Vitro and In Vivo Models of the Acute Respiratory Distress Syndrome
Authors: Thomas Morrison, Megan Jackson, Danny McAuley, Adrien Kissenpfennig, Cecilia O'Kane, Anna Krasnodembskaya
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Labeling recommendations based on exposure-response relationships to minimize musculoskeletal related adverse reactions of a Hedgehog inhibitor.
Authors: Stacy Shifflett Shord, Ping Zhao, Liang Zhao, Hong Zhao, Denise Casey, Suzanne Demko, Patricia Keegan, Brian Booth, Nam Atiqur Rahman
Journal: Journal of Clinical Oncology (2016)

e14121 Background: On July 24, 2015, FDA approved Odomzo (sonidegib) for the treatment of patients with locally advanced basal cell carcinoma. At the recommended dose of 200mg once daily, 68% of patients experienced musculoskeletal-related adverse events (MRAE) and 61% of patients experienced creatine kinase (CK) elevation. Methods: Data was obtained from 336 cancer patients and 50 healthy subjects following daily doses of 200mg to 800mg. Exposure-response relationships for safety endpoints were evaluated by logistic regression analyses. Drug-drug interaction (DDI) trials were simulated using Simcyp. Results: More patients receiving 800mg experienced grade 3-4 CK elevation compared to those receiving 200mg (16% vs. 6%). A steep exposure-safety curve suggested that the mean probability of grade 3-4 CK elevation increased with increasing sonidegib trough concentrations; no covariates affecting this relationship were identified. Sonidegib demonstrated non-linear pharmacokinetics (PK); the mean steady-state exposure (AUC0-24h ) with an 800mg dose was 2.3-fold higher compared to the 200mg dose. Co-administration of ketoconazole increased sonidegib AUC0-10d by 2.2-fold following a single 800mg dose in healthy subjects. Population PK analysis suggested that sonidegib apparent oral clearance was 3-fold lower in cancer patients compared to healthy subjects. Simulated DDI trials in cancer patients suggested that sonidegib steady-state exposure would increase by 1.8-3.5 fold following co-administration of a moderate or a strong CYP3A inhibitor for 14 days or 120 days. Conclusions: These analyses along with the observed safety data suggest that co-administration of CYP3A4 inhibitors would likely increase sonidegib exposure to levels shown to be associated with MRAE. These data and analyses support FDA's recommended dose and labeling to avoid co-administration of strong and moderate CYP3A inhibitors with Odomzo, except co-administering moderate CYP3A4 inhibitors for 14 days or less.
Patient preferences for clinical attributes of metastatic melanoma treatment with targeted therapy and immunotherapy.
Authors: Carol Mansfield, Briana Ndife, Joyce S. Chen, Kathleen Gallaher, Sameer R. Ghate
Journal: Journal of Clinical Oncology (2018)

e21511 Background: Patients with metastatic melanoma (MM) have more options for treatment, including targeted therapy and immunotherapy. Treatments differ in efficacy, adverse events (AE), and administration mode. This study assessed patients’ preferences for treatment’s clinical attributes. Methods: We administered an online, discrete-choice experiment (DCE) survey to respondents with self-reported MM. Respondents answered 9 DCE questions offering a choice between 2 hypothetical treatments defined by 6 attributes, each with 3 levels: progression-free survival (PFS, 4, 7, 13 months), mode and frequency of administration (pills 2xday, infusion 30 minutes every 3 weeks, or infusion 60 minutes every 2 weeks), fever (none, mild-to-moderate, severe), risk of colitis and risk of hormone-gland problems (0%, 10%, 30%), and risk of extreme sensitivity to the sun (0%, 4%, 20%). Analyzed using random-parameters logit, the results were used to calculate the relative importance of changes in attributes and additional months of PFS respondents would require to accept worse AEs. We analyzed preferences for 2 subgroups based on stage at initial diagnosis (stage 4 vs. earlier) and time since diagnosis (≥ 5 years ago vs. < 5 years ago). Results: The respondents (N = 200, 30% diagnosed ≥ 5 years ago, 43% initially diagnosed stage 4 disease), on average, ranked the attributes as follows: avoiding a 30% risk of colitis and hormone-gland problems and avoiding a severe fever were more important than avoiding a 20% risk of extreme sun sensitivity. Differences in mode of administration were least important. Avoiding a 30% chance of hormone problems and avoiding severe fever required the largest increase in PFS (~13 months) to offset the disutility of these AEs. Respondents with an initial stage 4 diagnosis and, separately, those diagnosed ≥ 5 years ago placed more value on longer PFS than other respondents. Conclusions: Respondents valued PFS and were willing to trade the risk of AEs such as hormone-gland problems, colitis, and severe fever for a longer PFS benefit. Working with patients to find treatments that reflect preferences may help them achieve full benefits from the growing number of therapeutic options for MM.