tbuckley/cabot-search huggingface dataset:
A phase 1 study to evaluate the safety and tolerability of MEDI4736, an anti–PD-L1 antibody, in combination with tremelimumab in patients with advanced solid tumors.
Authors: Margaret K. Callahan, Patrick Alexander Ott, Kunle Odunsi, Stephane V. Bertolini, Linda S. Pan, Ralph Rudolph Venhaus, Joyson Joseph Karakunnel, F. Stephen Hodi, Jedd D. Wolchok
Journal: Journal of Clinical Oncology (2014)

TPS3120^ Background: MEDI4736 (M) is a human IgG1 monoclonal antibody that binds specifically to programmed cell death ligand 1 (PD-L1), expressed on immune cells and tumor cells, preventing binding to PD-1 and CD80, expressed on T cells. Tremelimumab (T) is a human IgG2 monoclonal antibody directed against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Both PD-1 and CTLA-4 are regulators, or checkpoints, of T cell activation. The mechanisms of activation for these checkpoints are non-redundant, suggesting that targeting both pathways may have additive or synergistic activity. Data from mouse models of transplantable solid tumors support synergistic antitumor activity of combination immunotherapy. Methods: This open-label phase I study (NCT01975831) is designed to evaluate the safety of the combination of M and T in patients (pts) with advanced solid tumors. Eligible pts include those with histologically confirmed non-small cell lung, cervical, head and neck, colorectal, ovarian cancers, or renal cell carcinoma with adequate performance status and organ function who are not eligible for, have declined, or have failed standard treatment. The dose escalation phase uses a 3+3 design: M is administered at escalating doses starting at 0.3 mg/kg every 2 wks and T is administered at escalating doses starting at 3 mg/kg (up to 10 mg/kg) every 4 wks for the first 6 cycles, then every 12 wks. An expansion phase will evaluate the combination therapy at the maximum tolerated doses in each tumor type. Treatment may continue for up to 12 months or until progressive disease or unacceptable toxicity. The primary study end points are safety/tolerability and identification of the maximum tolerated dose of the combination. Secondary objectives include pharmacokinetics, immunogenicity, and clinical activity, as assessed by tumor response (RECIST v1.1 and Immune-related Response Criteria), progression-free survival, and overall survival. Exploratory objectives include the evaluation of tumor and serum PD-L1 levels, immune cell phenotypes, and tumor microenvironment. Recruitment is ongoing to a target enrollment of 102 pts. Clinical trial information: NCT01975831.
Is multiparametric MRI able to characterize margin for focal brachytherapy in low-grade prostate cancer?
Authors: Soleakhena Ken, Pierre Graff-Cailleaud, Jean-Marc Bachaud, Richard Aziza, Sandra Arnault, Amellie Lusque, Francois-Xavier Arnaud, Thomas Brun, Daniel Portalez, Bernard Malavaud
Journal: Journal of Clinical Oncology (2017)

e555 Background: Focal brachytherapy is proposed in our institute as an alternative treatment to active surveillance for low-grade prostate cancer (PCa). This study aims at characterizing the tumor focus and its margin with multiparametric Magnetic Resonance Imaging (mpMRI). Methods: Patients pre-qualified for this study were positive for PCa (Gleason 3+3) on a previous standard biopsy series. New series of mp-MRI-guided and ultrasound-targeted biopsies were performed and in total, 17 patients with confirmed tumor and diameter &lt; 20mm were included in this phase II clinical trial (NCT01902680). mpMRI were acquired on a 1.5T Magnetom Aera Siemens scan. Anatomic imaging consists in Fast Spin Echo T2-weighted MRI (T2-MRI) and functional Diffusion Weighted MRI (DWI-MRI) and Dynamic Contrast Enhanced MRI (DCE-MRI) were also performed. After mpMRI registration, tumor volumes of interest (VOI) were drawn on anatomic T2-MRI. VOI and VOI+2mm were reported on functional DWI-MRI and DCE-MRI. Extracted parameters were Apparent Diffusion Coefficient (ADC) and KTrans. All parameters distributions were analyzed with Olea Sphere v3.0 and compared to contralateral normal appearing tissue. Focal brachytherapy was then delivered to all patients with linked 125 I seeds with a dose prescription of 152 Gy on the Planning Target Volume (PTV = VOI+2mm). Results: ADC parameters (mean, meadian, 25th and 75th percentiles) are found to be significantly lower in tumor volume (VOI) compared to contralateral normal tissue (p &lt; 0.012 for all ADC parameters), confirming diffusion tumor mass restriction. Different distributions of ADC and KTrans were observed among patients: majority (66.66%) of low ADC and abnormal KTrans values were included in the VOI but interestingly, the 2mm margin allows us to treat additional abnormal ADC and KTrans volumes on 1/3 of the patients. Conclusions: This study confirms that mpMRI is a non-invasive technique able to characterize tumor margin for focal brachytherapy in low-grade PCa. Target volume margin definition is a hot topic when focal treatments (e.g. cryotherapy or HIFU) are considered and mpMRI can bring quantitative answers. Clinical trial information: NCT01902680.
The role of postoperative adjuvant treatment in stage IB2 and IIA2 cervical cancer patients without pathological risk factor after neo-adjuvant treatment followed by radical surgery.
Authors: Lingying Wu, Ning Li, Binbin Tu, Xiaoguang Li, Rong Zhang, Bin Li, Hongwen Yao
Journal: Journal of Clinical Oncology (2015)

e16591 Background: Bulky local tumor ( ≥ 4cm) is a poor prognostic factor for early stage cervical cancer patients. Most of the locally advanced cervical cancer patients need postoperative radiotherapy. However, some tumors shrink obviously after neo-adjuvant treatment. Whether this subgroup of the patients needs postoperative therapy remains unclear. Our study is aim to evaluate the role of postoperative adjuvant treatment in stage IB2/IIA2 cervical cancer patients without pathological risk factors after neo-adjuvant treatment followed by radical surgery. Methods: Between Jan 1st, 2000 and Dec 31st, 2010, one hundred and three patients with stage IB2/IIA2 cervical cancer who underwent neo-adjuvant chemotherapy±brachytherapy followed by radical surgery were retrospectively assessed. All the patients had no risk factor according to pathological findings after surgery. Results: Median age at diagnosis was 42. Histological type of 95.1% (98/103) patients was squamous cell carcinoma, and 4.9% was adenocarcinoma or adenosquamous carcinoma. 84.5% (87/103) patients were of stage IB2. Seventeen patients received postoperative external pelvic radiotherapy (RT). Fifteen patients received postoperative chemotherapy (CT) for 2-4 cycles, and the remaining 71 cases received no postoperative treatment (OB). The median duration of follow-up was 54 (45-82) months. Seven patients had recurrence (2 RT; 2 CT; 3 OB). Two-year and 5-year OS were 98.0% and 96.8%, respectively. The overall 5-year recurrence rate was 6.8%. Five-year recurrence rates of 3 groups OB, RT and CT were 4.2%, 11.8% and 13.3%, respectively. The difference among the recurrence rates of the 3 groups were not statistically significant (P> 0.05). Conclusions: Stage IB2/IIA2 cervical cancer patients without pathological risk factors after neo-adjuvant therapy followed by radical surgery had a relatively good prognosis. This subgroup of cervical cancer patients might get no benefit from postoperative treatment.
Late gastrointestinal (GI) complications in patients with stage I-II testicular seminoma treated with radiotherapy (RT).
Authors: Christopher Leigh Hallemeier, Brian Davis, Thomas Michael Pisansky, Richard Choo
Journal: Journal of Clinical Oncology (2012)

4595 Background: For stage I-II testicular seminoma, RT is highly effective at eradicating disease in the abdominopelvic lymph nodes, but results in unnecessary exposure to normal tissues including the GI tract. The purpose of this study was to define the incidence and risk factors for late GI complications in this patient population. Methods: A retrospective review was performed of 251 patients with stage I-II testicular seminoma treated with curative intent RT at our institution from 1974-2009. All patients underwent orchiectomy and postoperative external beam RT to the involved and/or at-risk nodal basins. Potential late GI complications that were assessed included endoscopically-confirmed gastric or duodenal ulceration, small bowel obstruction (SBO), and biopsy-confirmed malignancy of the GI tract. Risks were estimated using the Kaplan-Meier (KM) technique and univariate/multivariate analyses were performed using the Cox proportional hazards model. Results: Median age at diagnosis was 36 years (range 18 – 80). Clinical stage was I (n=199) or II (n=52). Median abdominopelvic RT dose was 26 Gy (interquartile range 25 – 30). Median follow-up was 15 years (range 0.1 – 38). KM estimates for any GI complication (ulcer, SBO, or GI malignancy) at 10, 20, and 30 years were 7, 10 and 24%, respectively. Four patients died as result of a GI complication. KM estimates for ulcer at 10, 20, and 30 years were 4, 7, and 9%, respectively. Age at RT (Hazard Ratio [HR] 1.05, 95% Confidence Interval [CI] 1.00 – 1.10, p=0.03) and RT total dose (per Gy, HR 1.20, 95% CI 1.09 – 1.31, p&lt;0.01) were associated with risk of ulcer. KM estimates for SBO at 10, 20, and 30 years were 2%, 2%, and 3%, respectively. History of inflammatory bowel disease was associated with risk of SBO (HR 43, 95% CI 7-325, p&lt;0.01). KM estimates for GI malignancy at 10, 20, and 30 years were 0.5, 3 and 16%, respectively. Age at RT was associated with risk of GI malignancy (HR 1.07, 95% CI 1.02-1.14, p=0.01). Conclusions: In patients with stage I-II testicular seminoma treated with RT, late GI complications were a relatively uncommon, but clinically significant source of late morbidity. Use of low dose, limited field, and/or proton RT may reduce these risks.
Quantifying copy number variations in cell-free DNA for potential clinical utility from a large prostate cancer cohort.
Authors: Ekkehard Schütz, Mohammad R Akbari, Julia Beck, Howard B. Urnovitz, William Zhang, William M. Mitchell, Robert Nam, Steven Narod
Journal: Journal of Clinical Oncology (2013)

5072 Background: Prostate cancer (PrCa) is the most frequent non-dermatological malignancy in the male population. Genomic instability resulting in copy number variation (CNV) is a hallmark of malignant transformation. CNV traces from tumors in cell-free DNA (cfDNA) of prostate cancer patients may be identified through massive parallel sequencing (MPS) of serum DNA. These CNV traces may be biomarkers of cancer with clinical applications for screening and follow-up. Methods: DNA was extracted from serum of 205 PrCa patients (Gleason 2 to10), 207 age matched male controls (HC), 10 men with benign hyperplasia (BPH) and 10 with prostatitis (PiS). DNA was amplified using random primers, tagged with a unique molecular identifier per sample, sequenced on a SOLiD system and aligned to the human genome (Build 37). Hits were counted in sliding 100kbp intervals and normalized. Using a random-resampling procedure, genomic regions showing copy number variations in cfDNA that distinguish PrCa from HC were selected. A model using 20 cfDNA regions was cross-validated and used as cfDNA biomarker. Receiver operator characteristics (ROC) curves were calculated for assessment of diagnostic performance by means of area under the curve (AUC). Results: To assess whether CNVs in cfDNA are indicative of PrCa, the number of regions with significant CNV deviation was counted in a first subset of 82 PrCa. Using only the number of regions as measure resulted in an AUC of 0.81 (0.7 – 0.9, p&lt;0.001). Therefore, all samples were used to select regions (n=80) in random resampling (50/50). These regions were used to define a highly significant 20-regions model using five rounds of 10-fold cross-validation (AUC: 0.85±0.7; p&lt; 10 -7 ). This final model discriminated between PrCa and HC with an AUC of 0.92 (0.87 – 0.95) reaching a calculated accuracy of 83%. Both BPH and PiS could be distinguished from PrCa using the cfDNA CNV biomarker with a predicted accuracy of 90%. Conclusions: MPS revealed that only a limited number of chromosomal regions showing CNVs are necessary to achieve statistical separation between prostate cancer and controls. This technique may prove to be clinically useful for screening and follow up of men with prostate cancer.
Global analysis of transcription reveals BCSC-1 as a melanoma tumor suppressor that downregulates MITF
Authors: R. Correa-Rocha, S. I. Anghel, E. Budinska, K. F. Boligan, S. Abraham, S. Colombetti, L. Fontao, A. Mariotti, D. Rimoldi, G. E. Ghanem, D. E. Fisher, L. Bracco, F. Levy, M. Delorenzi, V. Piguet
Journal: British Journal of Dermatology (2011)

Reference EPFL-CONF-171519View record in Web of Science Record created on 2011-12-16, modified on 2017-05-12
Anemia and functional disability in older adults with cancer.
Authors: Cynthia Owusu, William P. Tew, Molly Hardt, Supriya Gupta Mohile, Heidi D. Klepin, Cary P. Gross, Ajeet Gajra, Stuart M. Lichtman, Rupal Ramani, Vani Katheria, Laura Zavala, Arti Hurria
Journal: Journal of Clinical Oncology (2012)

9109 Background: While anemia is associated with functional disability in older adults in general, this relationship has not been well characterized in older adults with cancer. We sought to examine the association between anemia and functional disability and to identify other factors associated with functional disability in patients (pts) age ≥65 with cancer. Methods: We conducted a secondary analysis of a multi-center prospective study of 500 pts ≥ age 65 that identified predictors of chemotherapy (chemo) toxicity (Hurria et al, JCO, 2011). The primary outcome of this analysis was functional disability, defined as need for assistance with ≥1 instrumental activities of daily living. Data collected prior to initiation of a new chemo regimen included: age, tumor/treatment variables, labs [including hemoglobin (Hb)], and geriatric assessment (functional status, comorbidity, social support, psychological, cognitive, and nutritional status). Anemia (World Health Organization criteria) was defined as Hb &lt;12g/dl (women) and Hb &lt;13g/dl (men). Bivariate analysis and logistic regression were used to examine the association between functional disability, anemia, and other pre-treatment variables. Results: Among 500 pts [median age 72 years (range 65-91), 56% female, 61% stage IV], the prevalence of functional disability and anemia was 43% and 51%, respectively. The mean Hb was 11.7g/dl and 12.6g/dl among pts with and without functional disability. Pts with anemia were more likely to report functional disability (53% vs. 46%, p&lt;0.01). On multivariate analysis, factors associated with functional disability included anemia [Odds Ratio (OR)= 2.06, 95% confidence interval (CI)= 1.39-3.05], increased age (OR= 1.04, 95% CI = 1.00-1.07), increased comorbidity (OR= 1.23, 95% CI = 1.09-1.39), advanced stage (OR= 1.85, 95% CI = 1.22-2.80), and unintentional weight loss (OR= 2.02, 95% CI = 1.37-3.00). Conclusions: Anemia was highly prevalent and was associated with functional disability. Prospective studies that further examine the relationship between anemia and functional disability and randomized-controlled trials that evaluate the correction of anemia as a modifiable strategy to improve functional status in older pts with cancer are warranted.
Comparative study of the perceptions of continuity of care of CRC survivors transitioned to primary care.
Authors: Jeffrey James Sisler, Zoann Nugent, Tara Carpenter-Kellett, Joel Roger Gingerich
Journal: Journal of Clinical Oncology (2017)

96 Background: Colorectal cancer (CRC) patients are increasingly being discharged to a primary care provider (PCP) for follow-up care. This study used a pre-post design to evaluate the impact of the Moving Forward After Cancer(MFAC) program at CancerCare Manitoba on patient perceptions of continuity of care. Methods: The MFAC program was introduced in 2010 to support transfer of care to primary care and includes transitional appointments (TAs) and survivorship care plans. The pre-implementation (PRE) group was a random sample of patients on the provincial cancer registry diagnosed in 2008/09 with Stage II / III CRC. The post-implementation (POST) group was recruited in oncology clinics after their TA over four years starting in 2010. Both groups completed the same mailed survey. Respondents were asked to identify the main provider(s) of their follow-up care. Those indicating a PCP completed the Patient Continuity of Care Questionnaire (PCCQ) which assesses continuity upon discharge with scoring between 5 and 25. Quality of life, disease, treatment, and demographic data were collected. Results: There were 246 responses in the PRE group (rate of 68.3%) and 83 (66%) in the POST. The POST group was significantly younger, more urban and further from diagnosis. It included more Stage III and rectal cancer patients who received more treatment. Comparing the subset of both groups (106 vs 65) who described a PCP as a main provider, the POST group demonstrated higher scores on the PCCQ (24.0 v 22.8, p=0.0065) and on two of its subscales. This finding persisted when tested for the impact of differences between the two groups in stage, site, age and treatment. The most common pattern of provider involvement in follow-up was the “FP alone,” which rose from 19% in the PRE group to 54% in the POST (p&lt;0.0001). The proportion of participants who felt “adequately prepared” for their transfer of care was significantly increased (71 vs 91%, p=0.003). Conclusions: A formal information sharing process with CRC patients at time of transition to primary care follow-up improved their evaluation of continuity of care. Significant shifts were seen in the locus of care from oncology to primary care settings consistent with the intent of the MFAC program.
A phase II trial of weekly docetaxel for second-line treatment of urothelial carcinoma.
Authors: Young Saing Kim, Moon Ki Choi, Jung Yong Hong, Chi Hoon Maeng, Soonil Lee, In Gyu Hwang, Sang-Cheol Lee, Jong-Mu Sun, Se Hoon Park, Jeeyun Lee, Ho Yeong Lim
Journal: Journal of Clinical Oncology (2013)

e15613 Background: Despite high response rates (RRs) with first-line platinum-based chemotherapy in advanced urothelial carcinoma (UCC), treatment after first-line failure remains unclear. The present multi-center phase II trial evaluated the tolerability and efficacy of weekly docetaxel as second-line chemotherapy for UCC. Methods: Between Aug 2010 and Sep 2012, 31 patients with measurable UCC, progressive after one prior platinum-based chemotherapy for advanced disease, were treated with docetaxel 30 mg/m 2 on days 1 and 8. Treatment was repeated every 21 days until disease progression or unacceptable toxicity. The primary endpoints were the RR, progression-free survival (PFS), and safety. To detect a 20% difference in RR (6% vs. 26%), 28 eligible patients were required. Results: All 31 patients were previously treated with gemcitabine/platinum and had Bellmunt risk of one or more. The patients’ median age was 64 years (range, 40 to 79) and 31 (100%) patients had an ECOG performance status of 1. A total of 106 (median, 2; range, 1 to 16) chemotherapy cycles were delivered. Although fatigue (13%) and anorexia (6%) were the most frequently observed grade 3 or 4 toxicities, safety profiles were generally mild and manageable. One patient developed prolonged thrombocytopenia which led to treatment discontinuation but was resolved thereafter. In an intent-to-treat analysis, two (6%) patients achieved objective response, which maintained for 3.0 to 7.8 months. Eight patients experienced disease stabilization, resulting in a disease control rate of 32%. The median PFS and overall survival were 1.4 (95% CI, 1.3 to 1.6) and 9.6 (95% CI, 7.8 to 11.4) months, respectively. Conclusions: Second-line chemotherapy with weekly docetaxel was well tolerated but demonstrated modest antitumor activity in patient with advanced UCC who had progression after first-line platinum-containing regimen and poor prognostic factors. Clinical trial information: NCT01711112.
Phase I trial of tivantinib in combination with carboplatin and pemetrexed as first-line treatment in patients with advanced nonsquamous non small cell lung cancer or malignant pleural mesothelioma.
Authors: Paolo Andrea Zucali, Matteo Simonelli, Fabio De Vincenzo, Giuseppe Fatuzzo, Monica Bertossi, Matteo Perrino, Chiara Miggiano, Laura Giordano, Cristiana Bonifacio, Federica Mrakic Sposta, Armando Santoro
Journal: Journal of Clinical Oncology (2015)

2549 Background: Tivantinib (T) is a selective non-ATP competitive oral inhibitor of MET receptor. Preclinical data showed that MET inhibition blocks Malignant Pleural Mesothelioma (MPM) and Non Small Cell Lung Cancer (NSCLC) cell growth and migration. Adding T to standard first-line chemotherapy may improve efficacy. Methods: Patients (pts) with advanced MPM or non-squamous NSCLC were eligible to receive escalating doses of T combined with carboplatin (C) AUC 5 i.v. d1-q21 and pemetrexed (P) 500 mg/m2 i.v. d1-q21 as first-line treatment. After 6 cycles of CP, T is continued as maintenance therapy until progression. Pts must be chemo-naïve with ECOG Performance Status (PS) < 2 and adequate bone marrow, liver, and kidney functions. A standard 3+3 dose-escalation design was employed starting from dose level 0 (T 240 mg BID). The primary endpoint of the phase I study was to assess the maximum tolerated dose (MTD), defined as the highest dose level at which no more than 1 of 6 pts experiences a dose limiting toxicity (DLT) during the first cycle. To evaluate the anti-tumor activity (MPM pts: 3-month PFS%; NSCLC pts: 5-month PFS%) and the pharmacokinetics of the combination, a phase Ib trial is still ongoing. Results: From April 2013 to September 2014, 12 pts were enrolled in the phase I study; mean age was 69 years (range, 37-73 years), M/F: 9/3, ECOG PS 0/1: 5/7, MPM/NSCLC: 6/6. The MTD was reached at dose level 0 (T 240 mg BID). DLTs (2 neutropenia G4, 1 thrombocytopenia G4) were observed in 2 pts, both at dose level 1 (T 360 mg BID). The most common all-grade toxicities were nausea/vomit (67%), anemia (58%), neutropenia (50%), and asthenia (50%). G3/4 treatment-related AEs were reported in 6 pts (50%) and all were hematological (neutropenia, thrombocytopenia, anemia). All pts received 6 cycles of CT. Among 12 evaluable pts, 1 had CR, 4 PR, and 7 SD as best response. Conclusions: Adding T to CP is safe with preliminary evidence of antitumor activity. T 240 mg BID in combination with C AUC 5 i.v. d1-q21 and P 500 mg/m2 i.v. d1-q21 represents the recommended dose for phase II trials. Clinical trial information: NCT02049060.