tbuckley/cabot-search huggingface dataset:
Phase II trial of concurrent chemoradiation with consolidation pembrolizumab in patients with unresectable stage III non-small cell lung cancer: Hoosier Cancer Research Network LUN 14-179.
Authors: Greg Andrew Durm, Sandra K. Althouse, Ahad Ali Sadiq, Shadia Ibrahim Jalal, Salma Jabbour, Robin Zon, Goetz H. Kloecker, William B. Fisher, Karen L. Reckamp, Ebenezer A. Kio, Robert M. Langdon, Bamidele Adesunloye, Ryan D. Gentzler, Nasser H. Hanna
Journal: Journal of Clinical Oncology (2018)

8500 Background: Concurrent chemoradiation (CRT) has been the standard Rx for pts with unresectable stage III NSCLC. A recent phase III trial (PACIFIC) of consolidation durvalumab [PDL-1 inhibitor] demonstrated improved median PFS vs. placebo (16.8 vs. 5.6 mo, HR 0.52, p < 0.001). 12-mo (55.9% vs. 35.3%) and 18-mo (44.2% vs. 27%) PFS were also improved. Toxicity was manageable with a grade 3-4 pneumonitis rate of 3.4%, and 4 patients experienced grade 5 pneumonitis. We report the results of a phase 2 trial of consolidation pembrolizumab [PD-1 inhibitor] following concurrent CRT in patients with unresectable stage III NSCLC. Methods: After completion of CRT with carbo/pac, cis/etop, or cis/pemetrexed + 59-66.6 Gy XRT, those pts w/o PD after 4-8 weeks off CRT received pembro 200 mg IV q3wk for up to 1 yr. The primary endpoint was time to metastatic disease or death [TMDD]. Key secondary endpoints included PFS, OS, and toxicity. Results: 93 pts enrolled [92 eligible for efficacy analysis]. Median f/u was 16.4 mo and median age 66 (45-84). 64.1% male and 35.9% female. Stages were 59.8% IIIA and 40.2% IIIB. 55.4% non-SqCC and 43.5% SqCC with 1 mixed histology. 94.6% were current/former smokers. Chemo regimens included carbo/pac (71.7%), cis/etop (26.1%), cis/pemetrexed (2.2%). Median number of cycles of pembro was 13.5 [1-19]. 16% received < 4 cycles; 84% received ≥ 4 cycles; 37% completed 1 yr pembro. Median TMDD was not reached (95% CI 18.7-NR), but the estimates of 1-yr and 2-yr OS were 80.5% and 68.7% respectively. Median PFS was 15.4 months (95% CI 10.4-NR). 12, 18, and 24-month PFS were 59.9%, 49.5%, and 45.4% respectively. 16 (17.2%) pts developed G≥2 pneumonitis, 5 (5.4%) had G3-4 pneumonitis. There was 1 pneumonitis-related death. In those developing pneumonitis, the median time was 8.4 wks [1.1-48.2]. No other G 3/4 toxicities exceeded 5% except dyspnea (5.4%). Conclusions: Consolidation pembrolizumab following CRT substantially improves TMDD and PFS compared with historical controls. Prelim OS data is promising and suggests a substantial gain in outcomes of patients with stage III NSCLC is possible with consolidation pembrolizumab. Clinical trial information: NCT02343952.
Cisplatin/UFUR/irinotecan triple combination therapy for recurrent/metastatic head and neck squamous cell carcinoma: A phase I/II clinical study.
Authors: San-Chi Chen, Peter Chang, Muh-Hwa Yang
Journal: Journal of Clinical Oncology (2016)

e17508 Background: The response to treatment and prognosis is poor in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Triple combination therapy may increase tumor response and disease control.Methods: This phase I/II prospective trial tested the recommended dose of irinotecan with added cisplatin and UFUR (tegafur/uracil). Irinotecan was supplied at doses of 40, 50, 60, and 70 mg/m2 in each 3 patients step, then escalated with 5 mg/m2 until the dose-limiting toxicities occurred. In phase II, the maximum tolerated dose of irinotecan was administered intravenously (IV) over 90 min on day 1, with cisplatin 50 mg/m2 IV over 60 min also on day 1, and oral UFUR 200 mg twice a day for 5 days every 2 weeks a cycle.Results: In phase I study, the dose level of 60 mg/m2 was defined as the recommended dose. Among 43 patients in phase II, objective response rate (ORR) was 27.9% and disease control rate (DCR) 39.5%. Subgroup analysis of patients who did not receive chemoradiotherapy in the preceding 6 months, ORR of 40.7% and DCR of 59.3% were observed. The median PFS was 3.2 months and OS 6.7 months, and those who did not receive chemoradiotherapy in the preceding 6 months had a longer median PFS at 3.8 months and longer OS at 8.4 months. Neutropenia developed in 12 patients (27.9%), and only 1 patient experienced febrile neutropenia. Among non-hematological events, grade 1/2 nausea (46.5%) and vomiting (39.5%) were common, but only few of them (16.3%) developed grade 3/4 toxicity. Quality of life was improved in patients who had response to this treatment.Conclusions: Cisplatin/UFUR/irinotecan triple combination therapy is tolerated and effective for selected patients. Individualized choice of treatment will influence prognosis and quality of life in R/M HNSCC patients. Clinical trial information: ISRCTN17533723.Phase II response. Response No previous CCRT in < 6 m (n=27) Previous CCRT in < 6 m (n=16) All (n=43) n (%) n (%) n (%) Complete response 2 7.4 0 0 2 4.7 Partial response 9 33.3 1 6.3 10 23.3 Stable disease 5 18.5 0 0 5 11.6 Progression 11 40.7 15 93.8 26 60.5 Objective response 11 40.7 1 6.3 12 27.9 Disease control 16 59.3 1 6.3 17 39.5 Abbreviation: CCRT, concurrent chemoradiotherapy.
Safety and immunologic activity of anakinra in HER2-negative metastatic breast cancer (MBC).
Authors: Joyce O'Shaughnessy, Robyn R. Young, Maren K Levin, Jeanine Baisch, Roxana Timis, Luz Stella Muniz, Jacob Turner, Virginia Pascual, Karolina Palucka
Journal: Journal of Clinical Oncology (2016)

e14565 Background: Higher intratumoral IL-1b levels correspond with advanced stages of MBC. We hypothesized that anakinra (Ank), an IL-1R antagonist, may decrease tumor inflammation and improve outcomes in MBC patients (pts). Methods: Eleven pts with HER2– MBC received nab paclitaxel (n = 3), eribulin (n = 5) or capecitabine (n = 2) along with Ank daily following 2 week treatment with Ank only. One pt had progressive MBC prior to chemotherapy and received Ank for 14 days. Blood was collected prior to Ank treatment, then at 2 weeks, then monthly for 6 months (mos). 11 healthy controls were included. Whole blood mRNA transcripts were captured and hybridized to 579 immune-related probes and 15 housekeeping genes using the Nanostring nCounter Human Immunology V2 panel. A linear mixed model was used to query differences in gene expression between baseline, post Ank treatment and at each time point in pts vs controls while accounting for the longitudinal study design. Differentially expressed transcripts were annotated using a modular framework analysis strategy (Chaussabel, Immunity 29:150, 2008). Results: Median age: 44 yrs; Median number of prior cytotoxic regimens for MBC: 1; Sites of metastases: bone 91%; liver 27%; lung 46%. Median duration on Ank: 4 mos (range: 11-179 days); 8/11 pts had grade 1-2 Ank injection site reactions. Gene expression analyses revealed down-regulation of T cell/cytotoxic-related transcripts and upregulation of PD-L1 and innate myeloid inflammation-related transcripts at baseline compared to controls. At month 1 post-initiation of Ank treatment, a transcriptional program characterized by down-regulation of IL1- and TLR-related transcripts and upregulation of dendritic cell differentiation transcripts was evident. This profile, together with progressive upregulation of cytotoxic/NK cell-related transcripts, was maintained at 1-6 mos follow-up. Conclusions: Ank given during chemotherapy is safe and effective at down-modulating innate inflammation and upregulating cytotoxic/NK cell transcriptional pathways in MBC pts. Further evaluation of anakinra in MBC is warranted. Clinical trial information: NCT01802970.
Analysis of immune infiltrates in a genomically characterized clinical cohort of head and neck squamous cell carcinoma (HNSCC) patients (pts).
Authors: Nicole Grace Chau, Yvonne Y Li, Yin P. Hung, Peter S. Hammerman, Scott J. Rodig, Jonathan Daniel Schoenfeld, Danielle Nina Margalit, Jochen H. Lorch, Guilherme Rabinowits, Roy B. Tishler, Robert I. Haddad, Vickie Y. Jo
Journal: Journal of Clinical Oncology (2016)

6052 Background: Characterization of immune infiltrates and correlation with clinical and genomic alterations in HNSCC may facilitate the discovery of prognostic or predictive biomarkers to better select pts for immune checkpoint therapy. Methods: We previously reported the clinical utility of targeted next-generation sequencing of tumor DNA derived from 213 HNSCC pts treated at our center (Chau/Li CCR 2016). In this same cohort, we performed immunohistochemical analysis on formalin-fixed paraffin embedded tumor samples to determine PD-L1, PD-L2, PD-1, FOXP3, LAG3, GITR, TIM3, CD3, CD4, and CD8 expression. Survival estimates were obtained by Kaplan-Meier method. Differences in progression free and overall survival (PFS, OS) between pts with high or low PD-L1, PD-L2, PD-1, GITR, TIM3 expression, which was scored semiquantitatively by staining intensity (0, negative; 1+, weak; 2+, moderate; 3+, intense) and extent ( < 5%, 5-25%, 25-50%, 50-75%, > 75%), and absolute average number per 4 HPF for GITR, FOXP3, LAG3, CD3, CD4, CD8 tumor infiltrating lymphocytes, were assessed by univariate and multivariate survival analyses using Cox proportional hazards model. Immune marker expression was correlated with clinical and genomic factors. Results: Initial analysis (n = 36 pts) revealed expression of PD-L1 (50%, 18/36), PD-L2 (31%, 11/35), PD-1 (37%, 13/35), GITR (30%, 10/33), TIM3 (76%, 26/34), and lymphocyte expression (absolute number > 40) was identified for FOXP3 (26%), LAG3 (20%), CD3 (68%), CD4 (21%), CD8 (86%). Poorer OS appeared to be associated with PD-1+ (p = 0.06), TIM3+ (p = 0.26) and GITR+ (p = 0.17). CD8+ alone was not predictive of survival, but if CD8+ T-cells displayed exhaustion markers (TIM3, PD-1) and the tumor was PD-L1+, the outcome was worse. No significant correlations were observed between presence of immune infiltrates and tumor site, stage, age, sex, smoking, p16 status, somatic alterations, copy number variations, PFS or OS. Conclusions: Initial analysis reveals co-expression of CD8+/TIM3+/PD-1+ T-cells and PD-L1+ tumors may be associated with poorer survival outcomes, suggesting that targeting of multiple checkpoints in these tumors may be warranted.
Thrombopoietin level predicts response to treatment with eltrombopag and romiplostim in immune thrombocytopenia
Authors: Hanny Al‐Samkari, David J. Kuter
Journal: American Journal of Hematology (2018)

Thrombopoietin receptor agonists (TPO-RAs) are used to treat immune thrombocytopenia (ITP), but predicting clinical response to TPO-RAs before initiation is not possible. To determine whether endogenous TPO levels predict treatment response to TPO-RAs we performed a retrospective analysis of ITP patients with known baseline TPO levels who received TPO-RAs. Data was collected for ITP patients with a baseline TPO level treated with eltrombopag or romiplostim. Multiple logistic regression was used to model the probability of 3 classes of treatment response (overall, moderate, and superior) based on TPO level; receiver operating characteristic (ROC) analysis was performed to identify optimal TPO thresholds for response; correlations between TPO level and various response characteristics were analyzed. A total of 67 patients (37 receiving eltrombopag and 46 receiving romiplostim) were included. Logistic regression models demonstrated a significant predictive relation between TPO level and probability of all classes of response; per 10 pg/mL TPO increase, odds ratio for overall response to eltrombopag was 0.524 (95% CI 0.327, 0.837) and romiplostim was 0.905 (95% CI, 0.844, 0.970). TPO level was inversely correlated with all classes of response; for overall response, r = -0.719 (P < .001) for eltrombopag and r = -0.584 (P < .001) for romiplostim. ROC analysis identified TPO thresholds of ≤136 pg/mL (eltrombopag) and ≤209 pg/mL (romiplostim) as optimally discriminating between responders and nonresponders. Most non-responders had high TPO levels but did respond after addition of low-dose prednisone. In conclusion, TPO levels predict response to eltrombopag and romiplostim in ITP patients, with lower levels predicting improved probability and magnitude of response.
Computer-extracted features relating to spatial arrangement of tumor infiltrating lymphocytes to predict response to nivolumab in non-small cell lung cancer (NSCLC).
Authors: Cristian Barrera, Priya Velu, Kaustav Bera, Xiangxue Wang, Prateek Prasanna, Monica Khunger, Arjun Khunger, Vamsidhar Velcheti, Eduardo Romero, Anant Madabhushi
Journal: Journal of Clinical Oncology (2018)

12115 Background: Immune checkpoint inhibitors are now approved for use as therapy in advanced stage NSCLC. These drugs can decrease risk of progression by up to 60% when compared to standard chemotherapeutic regimens, but only about 20% of treated patients show significant benefit. The current gold standard for predicting response is increased tissue expression of PD-L1, but recent studies have shown this measure to be inadequate. TILs are correlated with PD-L1 levels and with antigen-induced anti-tumor immune pressure, with increased TILs associated with treatment response and longer survival. Recent work suggests that the spatial arrangement of TILs may be prognostic of outcome in several different cancer types. Here we evaluate whether computer-extracted features relating to spatial arrangement of TILs on digitized H&E images could predict response to Nivolumab in NSCLC. Methods: The study included fifty-six NSCLC patients with diagnostic tumor biopsies who were treated with Nivolumab. Responders and non-responders were classified according to clinical improvement and radiologic assessment by RECIST criteria on the first post-treatment CT scan. Two expert pathologists manually delineated tumor regions on digitized H&E images of the biopsies. Computerized algorithms automatically identified TILs within these regions, defined TIL clusters based on TIL proximity, and utilized network graph concepts to capture measurements relating to arrangement of these TIL clusters. Results: The top five features determined by a statistical feature selection method reflected the area and density of TIL clusters and the spatial proximity of the TILs to each other and to tumor cells. A machine learning classifier trained on these top 5 features had an AUC of 0.76 on the training set (n = 32) and an AUC of 0.64 on an independent validation set from another institution (n = 24). Conclusions: Computer extracted features relating to spatial arrangement of TIL clusters on digitized H&E images distinguished between patients who did and did not respond to Nivolumab. These findings need to be validated on in larger, multi-site validation sets.
Overall survival (OS) in patients (pts) with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP): A real-world retrospective study.
Authors: Kristin L. Hennenfent, Allicia C. Girvan, Aafia Chaudhry, Paolo Abada, Kristin Sheffield, Catherine K Herren, Aditya Raju, Eileen Farrelly, Lee Bowman, Pamela Landsman-Blumberg
Journal: Journal of Clinical Oncology (2017)

e15658 Background: HCC is associated with a worse prognosis in pts with high baseline AFP levels. The relationship between elevated baseline AFP and survival benefit with systemic HCC treatments in the real world setting is poorly characterized. Methods: A retrospective analysis of clinical outcomes among newly diagnosed advanced HCC pts treated in US community-based oncology practice settings was conducted. Pts treated with sorafenib or best-supportive care (BSC) between 10/1/2007 and 12/31/2013 were identified in the International Oncology Network electronic medical record (EMR) database and were followed until date of death, date of last visit, or 06/30/2014 (end of study). Baseline demographics, clinical characteristics, and AFP (≤ or &gt; 400 ng/mL), plus date of death were extracted from the EMR and physician progress notes. Treatment differences in OS were evaluated and stratified by AFP, AST/ALT, and bilirubin using unadjusted Cox proportional hazards regression models. Results: A total of 370 advanced HCC pts receiving sorafenib (217) or BSC (153) were identified. The mean age was 65.6 years and 77.0% were male. Cirrhosis (38.4%), hepatitis C (36.8%), and alcoholic liver disease (22.4%) were common hepatic-related comorbidities. 45.1% of pts had elevated AFP ( &gt; 400 ng/mL) at baseline. The sorafenib cohort had significantly longer median OS time than the BSC cohort (29.6 vs 19.7 weeks, p= 0.048). OS for sorafenib vs BSC cohorts with AFP≤400 ng/mL and AFP &gt; 400 ng/mL were 45.1 vs 25.3 weeks ( p= 0.128) and 25.3 vs 13.1 weeks ( p =0.197), respectively. Cox models revealed a consistent effect of sorafenib vs. BSC, regardless of AFP level (AFP ≤400ng/mL: HR = 0.79 (95% CI 0.55-1.13), p= 0.200; AFP &gt; 400 ng/mL: HR = 0.80 (95% CI 0.53-1.52), p= 0.297). Conclusions: This study supports the poor prognosis for advanced HCC pts with baseline AFP levels &gt; 400 ng/mL compared to baseline AFP ≤400 ng/mL. Limitations with retrospective, real-world studies require caution in interpretation, but this analysis suggests an OS benefit with sorafenib treatment compared to BSC. There remains an unmet need for effective therapies for advanced HCC associated with elevated AFP levels.
Adenoviral shRNA vector targeting ribonucleotide reductase M1 (RRM1) has a strong antitumor activity and decrease the drug resistance to GEM in RRM1-overexpressing bladder cells.
Authors: Xia Zhang, Dage Liu, Rikiya Taoka, Mikio Sugimoto, Yoshiyuki Kakehi
Journal: Journal of Clinical Oncology (2018)

e24237 Background: Ribonucleotide reductase large subunit (RRM1) is the main enzyme responsible for synthesis of the deoxyribonucleotides and involved in cell proliferation. It is also the primary cellular target for gemcitabine (GEM). Overexpression of RRM1 is reported to be associated with the resistance to GEM and the poor prognosis for many types of malignant tumors. We performed this experimental study in order to establish the gene therapy against RRM1-overexpressing tumors. Methods: Two RRM1-overexpression human bladder tumor cell lines, RT112 and J82 cell were used. An adenoviral vector expressing short hairpin siRNA targeting RRM1 gene (Ad-shRRM1) was constructed. The gene and protein expression of RRM1 were evaluated by quantitative RT-PCR and Western blotting. The drug sensitivity to GEM was assessed by MTT. A human tumor xenograft model in nude mice was prepared by the implantation of RRM1-overexprssing tumors derived from RT112 cells. Results: The infection of Ad-shRRM1effectively downregulated the mRNA and protein expression of RRM1 in both RRM1-overexpressing tumor cells. Regarding the in vitro experiment, MTT assays demonstrated the infection of Ad-shRRM1 to significantly inhibit cell growth in RT112 and J82 cell (p < 0.01 and p < 0.05 respectively). Regarding in vivo experiments, the Ad-shRRM1treatment was found to have a strong antitumor effect against the RRM1-overexpressing tumor xenografts (p < 0.05). Moreover, combined treatment of Ad-shRRM1 and GEM exerted a significantly greater inhibition on cell proliferation than Ad-shRRM1 or GEM treatment alone in both cell lines (p < 0.005 and p < 0.01 respectively). Conclusions: The cancer gene therapy using the adenoviral vector expressing shRNA against RRM1 has a strong antitumor effect against RRM1-overexpressing tumors. Combination therapy with Ad-shRRM1and GEM may become a new treatment option for patients with GEM-resistant.
Acupuncture to improve circadian health in breast cancer survivors (BCS): An RCT.
Authors: Oxana Palesh, Michelle Moore, Lonnele Ball, Melissa Packer, Benjamin Smarr, Eric Neri, Nadia Haddad, Rachel Manber, Lance Kriegsfeld
Journal: Journal of Clinical Oncology (2016)

10066 Background: Acupuncture is a popular complementary modality frequently used by cancer patients and survivors for management of side effects associated with cancer treatments. Circadian rhythm disruption (CRD) is prevalent among cancer patients and survivors. CRD may hinder the maintenance of host defenses against cancer and has been shown to be associated with earlier mortality. A marker of CRD is circadian power. Greater circadian power is an indicator of better health, including increased consolidation/regularity of circadian rhythm. Methods: 68 BCS (54 years, SD = 9) experiencing insomnia symptoms were randomized to receive 12 sessions over 6 weeks of either acupuncture for improving sleep (n = 34) or sham (n = 34; using the Streitberger device, a retractable needle). CRD data were collected through an actigraphy ambulatory device (Actiwatch 2; Phillips Respironics) worn by participants for at least 42 days. To calculate circadian power wavelet decomposition, signal processing of actigraphy data was used during 3 timepoints: the week before, 1 week after, and 5 weeks after acupuncture or sham treatments. Results: At 5 weeks after treatment initiation, a significant increase in circadian power relative to baseline measurements was found in the acupuncture group (p= 0.02) but not in the sham group (p > 0.05). Interestingly, this group difference did not emerge at 1 week post acupuncture but was found after 5 weeks of acupuncture treatment. Conclusions: Acupuncture holds the potential for improving CRD among BCS. The current study is one of few studies showing acupuncture’s effectiveness objectively through biomedical measurement rather than primarily through self-report. Our findings support the need for additional research on acupuncture’s effectiveness using objective measures. If these results are replicated, a possible dosage of bi-weekly acupuncture sessions over at least 5 weeks should be considered for managing CRD. Clinical trial information: NCT01162018.
Lipid peroxidation in tissues of ovarian tumors after neoadjuvant chemotherapy.
Authors: Oksana E. Kravtsova, Galina Andreevna Nerodo, Vera P. Nikitina, Ekaterina V. Verenikina, Ivan Nikitin, Alla V. Pustovalova
Journal: Journal of Clinical Oncology (2017)

e17036 Background: The purpose of the study was to analyze neoadjuvant chemotherapy (NACT) effect on parameters of monoaminergic, free radical and hydrolytic systems in tissues of malignant ovarian tumors. Methods: Activity of parameters of monoaminergic, free radical and hydrolytic systems was determined in ovarian tissue of 92 patients with ovarian cancer. Tissues of tumorous and contralateral (non-tumorous) ovaries were studied, and results were compared to the data in 30 patients with uterine fibroids and other benign tumors. Results: Tumorous ovaries showed the decrease in vitamins E and A by 2.6 and 4.1 times, respectively, compared to the norm. The levels in contralateral ovaries were 5 and 2.8 times lower than the norm, respectively. SOD in tumor tissue exceeded the norm by 46%. Content of copper-zinc-SOD amounted to 15.7% of the total activity in healthy ovaries, while in tumorous ones – 8.2%. Diene conjugates in tumors were increased by 42% compared to the healthy ovaries. Contralateral ovaries showed 2.1 times increase in SOD activity compared to the norm; catalase activity was decreased by 35% which was similar to the value in tumor tissue. Diene conjugates in contralateral ovaries were increased by 38% compared to the healthy ovaries and did not differ from the value in tumor. MDA level was decreased by 4.1 times and did not differ from the value in tumor. Tumorous ovaries after NACT showed an increase in vitamins A and E by 1.8 and 3.2 times, respectively, compared to the levels before treatment; copper-zinc-SOD activity increased by 40.3%. Lipid peroxidation changed as well: diene conjugates level increased by 24.7% and MDA decreased by 47.7% compared to the values before treatment. Levels of the main antioxidant enzymes – SOD and catalase – in contralateral ovaries after NACT were similar to the normal ones; diene conjugates were close to the norm, vitamin E decreased by 40%, vitamin A – by 30%, MDA content did not change. Conclusions: Morphologically healthy tissue of the contralateral ovary in the organism affected by malignant tumor demonstrates signs of imbalance in antioxidant factors similar to those in the tumorous ovary. NACT results in normalization of metabolism indices in both tumorous and contralateral ovaries.