tbuckley/cabot-search huggingface dataset:
Prognostic role of circulating tumor cells-CTCs in metastatic renal cell carcinoma.
Authors: Umberto Basso, Antonella Facchinetti, Elisabetta Rossi, Marco Maruzzo, Vincenza Conteduca, Michele Aieta, Francesco Massari, Anna Paola Fraccon, Claudia Mucciarini, Teodoro Sava, Matteo Santoni, Maria Cristina Pegoraro, Emilia Durante, Maurizio Nicodemo, Alessandra Perin, Alessandra Bearz, Felice Pasini, Carlo Gatti, Rita Zamarchi, Vittorina Zagonel
Journal: Journal of Clinical Oncology (2017)

4568 Background: CTCs can be isolated in peripheral blood of cancer pts and have demonstrated to have prognostic role in several metastatic tumors such as breast, colorectal and prostate cancer. Few data are available for Renal Cell Carcinoma-RCC. Methods: We designed a multicenter prospective observational trial aiming to assess the association between CTC counts and PFS of RCC pts treated with an antiangiogenic tyrosine-kinase inhibitors as a first-line regimen for metastatic disease. OS and response rate were secondary objectives. Both basal and sequential counts were enumerated by Cellsearch system at 4 time points: day 0 of treatment, +1 mo, +3 mo, at progression or 12 mo in the absence of progression. Ethics Committee approval was obtained. Results: Among 246 pts, 195 are eligible for the present analysis, 71.4% males, median age 69 yrs (range, 27 to 91), 81% with previous partial/total nephrectomy. Treatment was sunitinib (77.5%), pazopanib (21%) or sorafenib (1.5%). According to Heng criteria there were 24.6% good, 62.6% intermediate and 24.6% poor prognosis pts. After a median follow-up of 31.5 mo, median PFS is 13.6 mo (23% censored), 49.2% of pts are still alive. Investigator-assessed best response was 3.8% complete, 37.3% partial response, 33% stable, 25.9% progression. At baseline 91 pts had 1 or more CTCs, median 2, range 1 to 263. Pts with at least 1 CTC had a significantly shorter PFS compared to negative pts (8.8 vs 16.6 mo, p = 0.03), HR = 1.41 (95%CI 1.02-1.9). Thirty pts had &gt; = 3 CTCs, with a median PFS of 5.8 vs 15 mo in the remaining pts (p = 0.002), HR = 1.99 (CI 1.28-3.03). Percentage of pts with &gt; = 3 CTCs increased from 6.6% of good, 18.4% intermediate and 38.9% poor Heng score pts (p = 0.042). Pts with &gt; = 3 CTCs had a shorter estimated OS of 13.8 mo vs 52.8 mo (p = 0.003), HR = 1.99 (CI 1,17-3.2). Correlation between CTC positivity and response rate was not significant. Conclusions: In this robust multicenter prospective cohort of first-line metastatic RCC pts, the presence of 3 or more CTCs predicts a significantly shorter PFS and OS. Further analyses are ongoing on apoptotic markers of CTCs and concomitant counts of endothelial cells collected in the same cohort.
Prognostic impact of CD3 infiltrating t-cells in the tumor microenvironment with clinical factors for solid organ transplant (SOT) recipients with post-transplant lymphoproliferative disorders (PTLD).
Authors: Ryan Stubbins, Raymond Lai, Jutta Preiksaitis, Neil Sun Chua, James Zhu, Anthea Carmen Peters
Journal: Journal of Clinical Oncology (2016)

e19033 Background: Prognostication in post-transplant lymphoproliferative disorders (PTLD) is limited to clinical factors, with no validated tissue biomarkers. It is suggested that the degree of CD3 positive cytotoxic T-cell infiltrate in the tumor microenvironment is predictive of overall survival (OS) in PTLD, given the role of immune competence in PTLD pathogenesis. Methods: A retrospective analysis of 146 pediatric and adult solid-organ transplant (SOT) recipients diagnosed with PTLD after the year 2000 was performed for clinical prognostic variables and OS. CD3 infiltrate was determined by a blinded pathologist with a standardized scoring system (integer scale 0 – 3), utilizing formalin-fixed paraffin embedded tissue stained for CD3 by immunohistochemistry. Tissue was assessed for 46 patients, with an additional 86 available. Survival analysis was done by Cox regression, including an additional Kaplan-Meier (KM) estimator for CD3 infiltrate, with between group differences tested by Pearson's chi-square test. Results: Median age at diagnosis was 49 years. Histology subtype included early (n = 7), polymorphic (n = 17), monomorphic, (n = 85) Hodgkin, (n = 8) and unknown. (n = 29) Median OS was 41 months, with 71 (49%) deceased. Clinical factors identified by univariate analysis include: age < 18 at transplant (p = 0.017), monomorphic histology (p = 0.010), ECOG 3-4 (p = 0.027), stage 3-4 (p < 0.001), elevated LDH (p = 0.006), extranodal disease (p = 0.035), IPI 3-5 (P < 0.001), marrow involvement (p = 0.017), and leukocytes < 1.0 at diagnosis. (p = 0.004) Dense CD3 infiltrate (score 2-3) was associated with improved OS by KM analysis (p = 0.048) and a trend towards significance by univariate Cox regression. (HR 0.401, p = 0.056) Dense CD3 infiltrate was associated with non-monomorphic histology (p < 0.001), but not EBER status. (p = 0.154) Conclusions: The degree of CD3 infiltrate in the tumor microenvironment shows promise as a potential prognostic biomarker for SOT patients with PTLD. Clinical prognostic factors remain dominant. Further study by expanding the number of patients assessed for CD3 infiltrate is warranted.
A phase 1b study of the safety, pharmacokinetics, and preliminary antitumor activity of citarinostat (ACY-241) in combination with paclitaxel (Pac) in patients (pts) with advanced solid tumors (AST).
Authors: Michael S. Gordon, Geoffrey Shapiro, John Sarantopoulos, Dejan Juric, Brian Lu, Peng Chen, Jamie Connarn, Yvan Le Bruchec, R. Donald Harvey
Journal: Journal of Clinical Oncology (2018)

2547 Background: Citarinostat is an oral, selective histone deacetylase 6 inhibitor that inhibits growth of solid tumor cell lines and exhibits potent synergy with Pac in preclinical studies. We conducted a phase 1b dose-escalation study evaluating the safety and preliminary antitumor activity of citarinostat plus Pac in pts with AST. Methods: Pts with AST, including those who progressed on prior taxane therapy, were enrolled in a 3+3 escalation study. Cohorts: 1) 180 mg, 2) 360 mg, or 3) 480 mg oral citarinostat d1-21, all plus 80 mg/m2 Pac d1, 8, 15 in a 28-day cycle. If no maximum tolerated dose (MTD) was identified, an additional cohort was allowed. Primary endpoints: dose limiting toxicity (DLT), MTD, and citarinostat recommended phase 2 dose (RP2D). Key secondary endpoints: safety, efficacy, and pharmacokinetics (PK). Results: Of 20 pts enrolled (cohort 1 = 3 pts, cohort 2 = 5 pts, cohort 3 = 6 pts, additional 360 mg cohort = 6 pts), 15 had prior taxane therapy. No DLTs were observed; MTD was not identified. Citarinostat RP2D was established at 360 mg/day. At 480 mg, a higher incidence and severity of neutropenia were observed (1 grade 4; 1 grade 3; 1 grade 2) vs 360 mg (1 grade 1). Common (≥ 25%) treatment-emergent adverse events (TEAEs): anemia (50%), alopecia (40%), hypomagnesemia (40%), decreased appetite (35%), fatigue (35%), diarrhea (30%), nausea (30%), leucopenia (25%), dehydration (25%), and vomiting (25%). Peripheral neuropathy was observed in 30% of pts (15% grade 3; 8 Pac-related events, 1 Pac/citarinostat-related). Twelve serious TEAEs were reported in 8 patients. No deaths were observed under treatment. Citarinostat did not modify the overall safety profile of Pac. Two pts had confirmed partial response (PR); of 14 pts with stable disease, 2 had unconfirmed PR. In preliminary PK analysis, citarinostat exposure increased in a dose-proportional manner from 180 mg to 360 mg; however, a decrease in exposure was observed after dosing at 480 mg Conclusions: Citarinostat plus Pac showed acceptable safety in heavily pretreated pts without any unexpected toxicities. Further investigations of efficacy are needed. Clinical trial information: NCT02551185.
Intestinal microbiota to predict lung cancer patients at risk of immune-related diarrhea.
Authors: Tian Liu, Qi Xiong, Yi Hu
Journal: Journal of Clinical Oncology (2018)

3067 Background: Anti-programmed cell death protein-1 (PD-1) antibodies represent an effective treatment for lung cancer. However, previous studies showed that a number of patients treating with anti-PD-1 antibodies experience immune-related diarrhea. Intestinal microbiota plays a vital role in gastrointestinal dysregulation including diarrhea. Nevertheless, The association between intestinal microbiota and immune-related diarrhea is still elusive. Our study aims to identify specific intestinal microbiota as potential biomarkers for immune-related diarrhea in patients treating with anti-PD-1 antibodies. Methods: Fecal samples of 26 advanced lung cancer patients were obtained before the first dose of anti-PD-1 antibodies. Based on whether they develop diarrhea or not, the patients were subgroup into progressed to diarrhea(PtD) group and diarrhea-free(D-F) group. Immune-related diarrhea was graded according to CTC version 4.0. And 16S rRNA sequencing was used to profile fecal bacterial composition.The onset of diarrhea and fecal bacterial composition were retrospectively analyzed. Results: Of the 26 patients, 8 patients experienced diarrhea after the treatment of anti-PD-1 antibodies. Compared to the diarrhea-free patients, patients with diarrhea had similar microbial richness and diversity based on Alpha diversity analysis. While referring to Beta diversity, weighted-UniFrac PCoA analysis demonstrated significant differences in bacterial composition among the two group. Moreover, At the phylum level, Bacteroidetes were significantly richer in D-F group than that in PtD group, and Firmicutes were poorer. Whereas, Veillonella from Proteobacteria phylum was obviously lower in D-F group than that in PtD group. At the genus level, two families of the Bacteroidetes phylum ( Bacteroides and Parabacteroides) and a family of the Firmicutes phylum (Phascolarctobacterium) were more abundant in D-F group. Veillonella from Proteobacteria phylum was lower in D-F group than that in PtD group. Conclusions: Intestinal microbiota variation is associated with the onset of immune-related diarrhea. Identifying these biomarkers may help to diagnose and prevent the side effect earlier.
Complex approach in the treatment of retroperitoneal fibrosarcoma.
Authors: Firdavs Ulmasov, Mirjalol Djuraev, Abrorjon Yusupbekov, Dilshod Makhmudovich Egamberdiev
Journal: Journal of Clinical Oncology (2017)

e22537 Background: to improve the efficiency of the treatment of retroperitoneal fibrosarcomas by developing complex approach with using neoadjuvant endoarterial chemotherapy, surgical intervention followed by radiotherapy. Methods: For material of the study we analyzed treatment results of 34 patients with retroperitoneal giant fibrosarcoma. Depending on the method of treatment patients were divided into 2 groups: 1 main group n = 16, underwent neoadjuvant chemotherapy + surgery + radiotherapy 2 control group n = 18 who underwent surgery + adjuvant chemotherapy. There was performed endoarterial catheter into the close blood vessels feeding the tumor at the preoperative period. Chemotherapy was conducted 3 cycles by CAP regimen. Drugs were administered endoarterially with 48 hours infusion. After receiving chemotherapy for all patients there was performed radical surgery. Postoperatively patients received radiotherapy to the tumor bed with single dose 1.8-2 Gr and up to total dose - 60 Gr. Results: Therewere selected the following criteria: - The effect of chemotherapy on tumor size, extension and traumatizing of surgical treatment, and the duration of relapse-free and metastases-free period. - The effectiveness of postoperative radiotherapy for the duration of disease-free period. Chemotherapy in the preoperative period, led to partial regression of tumors in 9 (58.3%) patients. In 4 (25.0%) patients the process was stabilized, in 3 (16.7% 5 + 15%) observed progression of the process. Study of patients’ survival, which is the main determining factor showed an increase of survival in the main group up to 18.2 +0.4 months, and in the control group 12.4 +0.3 months. (P &lt; 0.05). Recurrence free survival in the main group was 10,2 +0,4 months, and in the control group 7,3 +0,3months (P &lt; 0.05), metastases-free survival consisted 11,4+0,5 months and 9,1+0,4 month, respectively.(P &lt; 0.05). Conclusions: Complex approach in the treatment of retroperitoneal fibrosarcomas significantly increased the overall survival and as well as the relapse-free and metastases-free survival. Using adjuvant continuously endoarterial chemotherapy gives partial effect in 58.3% cases, and thereby leads to more favorable conditions for surgery.
Expression of HER2-neu, SKP2 and HIF-1 and their role in predicting the response of muscle invasive urothelial carcinoma to bladder- preservation chemotherapy
Authors: E.A. Elkhouly, N. Alkady, A. Samir
Journal: Annals of Oncology (2018)

Background: Cystectomy is the prime treatment of muscle-invasive urothelial carcinoma but it is associated with many complications and affects patients' quality of life. Chemotherapy is an alternative modality, but it may not give the expected response. This arouses the need for markers that help to predict the response to chemotherapy. Her2-neu, Skp2 and HIF-1 regulate cell cycle progression, tumor adaptation to hypoxic environment and response to chemotherapy. This study aimed at evaluation of HER2-neu, SKP2 and HIF1 expression in muscle-invasive urothelial carcinoma and investigating the association between their expression and tumor response to chemotherapy. Methods: One hundred specimens of non-metastatic muscle-invasive urothelial carcinoma were collected at the Pathology Department and the selected patients received the treatment and were followed up at the Clinical Oncology Department, Menoufia University. HER2-neu, SKP2 and HIF-1expression were evaluated using immunohistochemical techniques. The patients received chemotherapy followed by cystoscopic examination. Bladder biopsy was examined to determine tumor response. Results: A significant association was found between partial tumor response to chemotherapy and HER2-neu, SKP2 and HIF-1 positive expression (P = 0.004, 0.029 and 0.004,). Skp2 expression was significantly associated with low apoptotic count and high mitotic one (P = 0.008 and 0.01), while HIF-1 expression was significantly associated with necrosis (P = 0.008). A statistically significant association was found between Skp2 and HR2-neu expression (P = 0.018) and between SKP2 and HIF-1 expression as well (P = 0.013). Conclusions: This study showed that HER2-neu, SKP2 and HIF-1expression can predict poor response to chemotherapy in muscle-invasive urothelial carcinoma and helps in selecting patients who will benefit from chemotherapy. In addition, targeted therapy against these markers can be effective in treatment. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
A pilot, phase I clinical trial to determine the biological effects of hydroxychloroquine (HCQ) on par-4 levels in patients with surgically removable solid tumors.
Authors: Peng Wang, Heidi Weiss, Susanne M. Arnold, John L. Villano, Mark Leggas, Vivek Rangnekar
Journal: Journal of Clinical Oncology (2018)

e14555 Background: Prostate apoptosis response-4 (Par-4, also called PAWR) is a tumor suppressor that induces apoptosis in diverse cancer cells but not in normal cells. The baseline levels of Par-4 secreted by normal cells are generally inadequate to cause massive apoptosis in cancer cells. Hydroxychloroquine (HCQ) is a robust inducer of Par-4 secretion in mice. Here, we report the biological effects of two-week neoadjuvant administration of HCQ on Par-4 levels in patients with surgically removable solid tumors. Methods: This was a single-institution, Phase I, open-label, dose finding trial of oral HCQ for 14 days prior to planned surgery. Dose escalation was based on the isotonic regression to model safety and biological effect based on Par-4. A total of 9 patients with early stage solid malignancies were consented and enrolled onto two dose cohorts. Six patients in cohort#1 were treated with oral HCQ 200 mg twice daily; three patients in cohort#2 were treated with oral HCQ 400 mg twice daily. Pre and post HCQ plasma Par-4 levels were measured. Apoptosis analysis and autophagy-inhibition assays from diagnostic biopsies and paired resected tumor specimen were performed. Results: After 14-day administration of HCQ, four from cohort#1 and two patients from cohort#2 showed a 2-fold elevation of plasma levels of Par-4 relative to pre-treatment baseline levels. Furthermore, two patients also showed elevation of plasma levels of Par-4. No toxicities were observed in these dose levels. The resected tumors from patients with elevated plasma Par-4 levels exhibited TUNEL-positivity indicative of apoptosis. By contrast, all tumors, including that from one patient who did not show evidence of Par-4 elevation or tumor cell apoptosis, showed p62 induction indicative of inhibition of autophagy. Conclusions: To our knowledge, this is the first clinical trial indicative of HCQ as a robust inducer of Par-4 in cancer patients. The elevated levels of secreted Par-4 trigger paracrine apoptosis of cancer cells. The regimen of HCQ 200 mg twice daily was chosen for an ongoing adjuvant study. Clinical trial information: NCT02232243.
Patient-reported outcomes (PROs) in patients with urothelial carcinoma (UC) treated with durvalumab (second-line or above) in phase 1/2 dose-escalation study 1108.
Authors: Peter H. O'Donnell, Hendrik-Tobias Arkenau, Srikala S. Sridhar, Michael Ong, Alexandra Drakaki, Alexander I. Spira, Jingsong Zhang, Michael S. Gordon, Arnold Degboe, Ashok Kumar Gupta, Pralay Mukhopadhyay, Wenmei Huang, Shaad Essa Abdullah, Natasha Angra, Terence W. Friedlander
Journal: Journal of Clinical Oncology (2018)

4532 Background: In Study 1108, durvalumab showed meaningful clinical activity in patients with UC, with an objective response rate (ORR) of 17.8% (PD-L1–positive patients: 27.6%) [Powles 2017, JAMA Oncol]. We report PRO results. Methods: Phase 1/2, open-label, dose escalation study 1108 (NCT01693562) enrolled patients with locally advanced/metastatic UC and prior platinum-based treatment. Patients received durvalumab 10 mg/kg Q2W for 12 months, and were asked to complete Functional Assessment of Cancer Therapy-Bladder Cancer (FACT-BL), European Organisation for Research and Treatment of Cancer Quality of Life (QoL) Questionnaire (EORTC QLQ-C30) and a pain questionnaire at baseline (D1) and days 29, 43, 57, 85 and 113 (D113). Changes in PROs were analyzed descriptively. Improvement/deterioration from D1 was based on minimum important difference: ½ baseline standard deviation (SD) for FACT-BL (range 0–156), 10-point difference for EORTC QLQ-C30 (total range 0–100). Results: In the full analysis set (n = 182), overall questionnaire completion rate at baseline was 99% and 81% at D113. Pain total mean (SD) score (range 0–10) tended to decrease over time, from 3.4 (2.8) on D1 to 1.9 (2.4) at D113. Mean (SD) FACT-BL total scores improved over time, from 107.5 (23.0) on D1 to 115.4 (22.6) on D113, with similar increases in bladder cancer subscale (BLCS) and trial outcome index (TOI) mean scores. FACT-BL total score improved over time in 32.6% of patients (48.8% no change, 18.6% deterioration); 34.9% showed an improvement in FACT-BLCS, and 32.6% in FACT-TOI. EORTC QoL mean (SD) score improved from 57.1 (24.8) on D1 to 69.0 (21.4) at D113. Improvements in EORTC QLQ-C30 functional domains were seen in 26.3–37.8% of patients, while 57.6–73.1% showed improvements in symptom domains, with largest responses in pain, fatigue, physical and role domains (improvement: 73.1, 57.6, 37.8 and 32.4%; no change: 0.0, 27.3, 46.0 and 41.2%; deterioration: 26.9, 15.2, 16.2 and 26.5%, respectively). Conclusions: Overall, the mean scores (domain or total) for pain, FACT-BL and EORTC QLQ-C30 improved over time in patients with UC treated with durvalumab in the phase 1/2 study 1108. Clinical trial information: NCT01693562.
TCT-356 Correlation of neuromarkers and brain injury after TAVR – results from CLEAN-TAVI trial
Authors: Stephan Haussig, Norman Mangner, Michael Dwyer, Lukas Lehmkuhl, Christian Luecke, Felix Woitek, David Holzhey, Robert Zivadinov, Axel Linke
Journal: Journal of the American College of Cardiology (2018)
Factors of local immunity in esophageal tumors of various stages.
Authors: Adlan Lechaevich Bazaev, Oleg Ivanovich Kit, Elena Yurievna Zlatnik, Evgeniy N. Kolesnikov, Vladimir Trifanov, Aleksandr V. Snezhko, Roman E. Myagkov, Mikhail A. Averkin, Olesya N. Selyutina, Elena S. Bondarenko, Ekaterina I. Zolotareva, Tanzila Beksultanovna Kazieva, Sergey V. Sanamyants
Journal: Journal of Clinical Oncology (2018)

e16013 Background: The purpose of the study was a comparative assessment of parameters of the local cellular immunity in patients with esophageal tumors of various stages. Methods: We studied tissues of tumors, peritumoral (PT) and resection line (RL) tissues of 35 patients who underwent surgery for esophageal cancer (11 women and 24 men aged 32-76 years). All patients had squamous cell carcinoma: stage I – 7, stage II – 12, and stage III – 16 patients. Subpopulations of lymphocytes were determined in tissue homogenates using the BD FACSCantoII flow cytometer with a panel of antibodies T-, B-, NK (CD45, CD3, CD4, CD8, CD19, CD16/56); levels of T-regs (CD4+CD25+CD127dim) were assessed. Percentages of lymphocytes were calculated from the total lymphocyte number, T-regs – from the number of CD3+CD4+ cells. Tissue levels of TNF-α, IL-1ß, IL-6, IL-8 and IL-10 were determined by ELISA (pg/mL per 1 g of protein). Results: More advanced-stage tumors were characterized by statistically significant changes in lymphocyte and cytokine tumor microenvironment. The СD3+CD4+ content in st. III tumors was lower than in st. I (38.3±3.99 vs. 48±2.4%; p < 0.05); the number of СD19+ cells was 4 times lower in st. II tumors, compared to st. I (2.45±1.2 vs. 9.95±3.0%). Levels of T-regs in tumors were high ( > 20%), starting with st. I, exceeding the values in RL by 6 times and in PT by 4 times. Levels of NK cells in all tumors were 2.7 times lower compared to RL. Specific levels of cytokines in the tumor and partly in PT and LR statistically significantly increased in st. III. IL-10 in st. III tumors was 4.17±0.8 vs. 1.99±0.7 pg/mL/g in st. II, IL-1ß – 70.0±14.4 vs. 38.95±5.0 pg/mL/g, and TNF-α – 5.38±0.90 vs. 3.21±0.4 pg/mL/g, respectively (p < 0.05 in all cases). Conclusions: More advanced-stage tumors were characterized by increasing changes in their immunological microenvironment, including the deepening of T-lymphocytic and cytokine imbalances in tumor tissue with partial involvement of the peritumoral zone and resection line tissues.