tbuckley/cabot-search huggingface dataset:
Changes in platelet/lymphocyte ratio after CRT to predict oncologic outcome in patients with rectal cancer.
Authors: In Hee Lee, Soyoon Hwang, Dong Won Baek, Soo Jung Lee, Byung Woog Kang, Yee Soo Chae, Hye Jin Kim, Jong Gwang Kim
Journal: Journal of Clinical Oncology (2017)

539 Background: Previous studies have shown that the neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) are potential prognostic markers in many different cancers. However, the relationship between the changes of these ratios after concurrent chemoradiotherapy (CRT) and clinical outcome in rectal cancer patients was not reported yet. Accordingly, the aim of this study was to evaluate the prognostic relevance of the changes in NLR and PLR in patients with rectal cancer who treated with CRT followed by surgery. Methods: We enrolled 296 patients with histologically confirmed rectal adenocarcinoma who have received preoperative CRT at Kyungpook National University Medical Center (Daegu, Korea) between January 2006 and December 2015. We analyzed full hematological data both pre CRT (initial visit) and post CRT (before surgery) and oncologic outcomes including pathologic complete response (pCR), relapse-free survival (RFS), and overall survival (OS). An NLR≥5 and PLR ≥235 were considered to cut-off values according to previous studies. The ratio of change in NLR and PLR were calculated by following formula: ratio of change in NLR = (post NLR-pre NLR)/ pre NLR *100, ratio of change in PLR = (post PLR-pre PLR)/pre PLR *100. Significant cut-off value for ratio of change in NLR and PLR were calculated by simulation analysis (SAS Institute Japan, Tokyo, Japan). Results: Of the 296 patients, the majority were male (69.6%), with a median age of 59.1 years (range 25~88). Of these patients, 41 (13.9%) obtained pCR after CRT. Sixty-one patients (20.6%) had high PLR before CRT, which significantly correlated with pCR (p = 0.014) and RFS (p = 0.026), while high NLR was associated with pCR (p = 0.012) only. The optimal cut-off value for the ratio of change in PLR was 200 for RFS. The patients who had relatively higher ratio of change in PLR (ratio of change in PLR ≥ 200) showed better RFS compared to lower ratio of change (ratio of change in PLR &lt; 200) (3-year RFS 90.9% vs. 69.7%, p = 0.05). Changes in NLR did not correlate with oncologic outcomes. Conclusions: Changes in platelet/lymphocyte ratio could also be a potential clinical biomarker in predicting oncologic outcome in rectal cancer patients treated with preoperative CRT.
Chimeric antigen receptor T cells: a novel therapy for solid tumors
Authors: Shengnan Yu, Anping Li, Qian Liu, Tengfei Li, Xun Yuan, Xinwei Han, Kongming Wu
Journal: Journal of Hematology & Oncology (2017)

The chimeric antigen receptor T (CAR-T) cell therapy is a newly developed adoptive antitumor treatment. Theoretically, CAR-T cells can specifically localize and eliminate tumor cells by interacting with the tumor-associated antigens (TAAs) expressing on tumor cell surface. Current studies demonstrated that various TAAs could act as target antigens for CAR-T cells, for instance, the type III variant epidermal growth factor receptor (EGFRvIII) was considered as an ideal target for its aberrant expression on the cell surface of several tumor types. CAR-T cell therapy has achieved gratifying breakthrough in hematological malignancies and promising outcome in solid tumor as showed in various clinical trials. The third generation of CAR-T demonstrates increased antitumor cytotoxicity and persistence through modification of CAR structure. In this review, we summarized the preclinical and clinical progress of CAR-T cells targeting EGFR, human epidermal growth factor receptor 2 (HER2), and mesothelin (MSLN), as well as the challenges for CAR-T cell therapy.
Acquired resistance to macrolides in<i>Pseudomonas aeruginosa</i>from cystic fibrosis patients
Authors: Muhammad-Hariri Mustafa, Shaunak Khandekar, Michael M. Tunney, J. Stuart Elborn, Barbara C. Kahl, Olivier Denis, Patrick Plésiat, Hamidou Traore, Paul M. Tulkens, Francis Vanderbist, Françoise Van Bambeke
Journal: European Respiratory Journal (2017)

Cystic fibrosis (CF) patients receive chronic treatment with macrolides for their antivirulence and anti-inflammatory properties. We, however, previously showed that Pseudomonas aeruginosa, considered as naturally resistant to macrolides, becomes susceptible when tested in a eukaryotic medium rather than a conventional broth.We therefore looked for specific macrolide resistance determinants in 333 CF isolates from four European CF centres in comparison with 48 isolates from patients suffering from hospital-acquired pneumonia (HAP).Minimum inhibitory concentrations (MICs) of macrolides and ketolides measured in eukaryotic medium (RPMI-1640) were higher towards CF than HAP isolates. Gene sequencing revealed mutations at three positions (2045, 2046 and 2598) in domain V of 23S rRNA of 43% of sequenced CF isolates, but none in HAP isolates. Enzymes degrading extracellular polymeric substances also reduced MICs, highlighting a role of the mucoid, biofilm-forming phenotype in resistance. An association between high MICs and chronic azithromycin administration was evidenced, which was statistically significant for patients infected by the Liverpool Epidemic Strain.Thus, ribosomal mutations are highly prevalent in CF isolates and may spread in epidemic clones, arguing for prudent use of oral macrolides in these patients. Measuring MICs in RPMI-1640 could be easily implemented in microbiology laboratories to phenotypically detect resistance.
Phase Ib/II study of INNO-206 (EMCH-doxorubicin) in patients with soft tissue sarcoma.
Authors: Sant P. Chawla, Victoria S Chua, Andrew Hendifar, Doris Quon, Sandeep Nagre, Kristen N. Ganjoo, Kamalesh Sankhala, Scott Wieland, Daniel Levitt
Journal: Journal of Clinical Oncology (2012)

10036 Background: The safety and preliminary tumor response of a doxorubicin conjugate, INNO-206, was evaluated primarily in patients with metastatic STS who progressed on prior chemotherpy. INNO-206 consists of doxorubicin attached to an acid-sensitive linker that binds covalently to cysteine-34 in circulating albumin. Methods: INNO-206 was administered IV at doses of either 230, 350 and 450 mg/m 2 (165, 260 and 325 mg/m 2 dox. eq.) every 21 days for up to 8 consecutive cycles. Subsequent dose levels were administered if &lt; 2/5 or 4/8 patients experienced a non-hematological dose-limiting toxicity during Cycle 1. Tumor response was monitored every other month and treatment continued until tumor progression or unacceptable toxicity. Standard safety monitoring was performed and cardiac function was followed periodically using MUGA or cardiac ultrasound. Results: As of January 11, 2012, 25 patients were entered in the study. 21/25 patients had STS of various types. Of the 5 patients treated at 230 mg/m 2 INNO-206, 1 subject had grade 3 fatigue and acid reflux. Of the initial 5 patients entered at the 350 mg/m 2 dose, no individuals experienced a grade 3 or 4 non-hematological toxicity during cycle 1. 2 patients treated at the 450 mg/m 2 dose developed grade 3 oral mucositis during cycle 1. No patient exhibited cardiotoxicity as determined by MUGA or cardiac ultrasound. The MTD was determined to be 350 mg/m 2 INNO-206 (260 mg/m 2 dox.eq.). 15 more patients were entered at this dose (total of 20 patients). Of the 16 patients with STS, 3 objective partial responses (one of whom received prior doxorubicin) are ongoing as well as 10 patients with stable disease (range 2-7 months). 1 patient had progressive disease at the first evaluation. 2 patients died within the first cycle, one due to progressive disease and the other due to sepsis. Conclusions: INNO-206 is an active drug for the treatment of patients with advanced STS who have failed prior chemotherapy. Cumulative doses of 2000 mg/m 2 of doxorubicin equivalents have been achieved, which is over 3 1/2 x the peak cumulative dose of standard doxorubicin. Adverse events are primarily hematological and no cardiotoxicity has been observed.
Phase I trial of autologous CD19-targeted CAR-modified t cells as consolidation after purine analog-based first-line therapy in patients with previously untreated CLL.
Authors: Jae Hong Park, Isabelle Riviere, Xiuyan Wang, Shirley Bartido, Michel Sadelain, Renier J. Brentjens
Journal: Journal of Clinical Oncology (2014)

7020 Background: In order to address the previously recognized limitation of autologous T cells modified to express chimeric antigen receptor (CAR) targeting CD19 in patients (pts) with chemotherapy refractory and relapsed CLL (Brentjens RJ et al., Blood 2011), we designed a phase I trial wherein CLL pts with residual disease following the first-line chemotherapy will receive the CD19-targeted CAR+ T cells as a consolidative therapy. Methods: Pts with CLL who have achieved either partial (PR) or complete response (CR) with detectable minimal residual disease (MRD) to the first-line therapy consisting of 6 cycles of pentostatin, cyclophosphamide and rituximab (PCR) were enrolled. Autologous T cells were transduced with a retroviral vector encoding the anti-CD19 scFv linked to CD28 co-stimulatory and CD3ζ signaling domains (19-28z). Pts received cyclophosphamide conditioning therapy followed by 3 escalating doses of CAR+ T cells. Response was assessed at 3 months according to the NCI-WG criteria. Results: 7 pts have received the CAR+ T cells in 3 dose cohorts (3x106 - 3x107 CAR+ T cells/kg). 6 pts had unmutated IgHV and 2 pts had del11q. All 7 pts achieved PR following the PCR chemotherapy. 4 pts had palpable lymphadenopathy (1 pt with bulky lymph nodes) prior to the T cell infusion. Median follow-up was 11 months (range, 3 – 17 mos). No DLT was observed. Mild and self-limiting cytokine release syndrome (CRS) was observed in 3 pts, and there was a positive correlation between the development of CRS and the CAR+ T cell persistence. 1 pt achieved CR; 2 pts achieved CR in the bone marrow (1 MRD negative CR) but had progressive disease in lymph node only; 3 pts achieved PR; and 1 pt had progressive disease but this pt had rapidly rising ALC at the time of T cell infusion. Conclusions: Autologous CD19-targeted CAR+ T cells appear to be safe and have promising anti-tumor efficacy in pts with high-risk CLL undergoing first-line chemoimmunotherapy. Our findings suggest that the CD19-targeted CAR+ T cells are more effective in eradicating disease in the marrow versus lymph nodes, and further studies are being conducted to better understand the mechanism of resistance. Clinical trial information: NCT01416974.
Meta-analysis of chemotherapy in nasopharyngeal carcinoma (MAC-NPC): An update on 4,798 patients.
Authors: Pierre Blanchard, Anne W. M. Lee, Julie Leclercq, Sophie Marguet, Wai Tong Ng, Jun Ma, Anthony T. C. Chan, Peiyu Huang, Guopei Zhu, Daniel TT Chua, Hai Qiang Mai, Joseph Wee, Dora LW Kwong, James Moon, Kwan Hwa Chi, George Fountzilas, Masuto Hareyama, Li Zhang, Jean Bourhis, Jean-Pierre Pignon
Journal: Journal of Clinical Oncology (2014)

6022 Background: In a previous MAC-NPC individual patient data (IPD) meta-analysis, the addition of chemotherapy (CT) to radiotherapy improved overall survival (OS) in nasopharyngeal carcinoma (NPC; Baujat IJROBP 2006). There was an interaction between the timing of CT and treatment effect, with an OS benefit restricted to the concomitant (+/- adjuvant) timing. Since other trials have been conducted, this meta-analysis was updated. Methods: Trials of radiotherapy (RT) with or without CT in patients with non-metastatic NPC were identified and updated IPD obtained. Both Western and Chinese medical literatures were searched. OS was the main endpoint. The fixed-effect model was used. All analyses were pre-specified. Results: Overall 19 trials and 4,798 pts were included. One 2x2 trial was counted twice and 5,020 pts were analyzed. Patients characteristics were well balanced (60% < 50 years, 75% male, 60% PS 0, 90% stage III-IV and 96% WHO grade 2-3). Median follow-up was 7.1 years. There was a significant benefit in favor of CT regarding OS (hazard ratio (HR) [95% confidence interval]: 0.79 [0.72;0.86], p <0.0001; absolute benefit at 5 years=6.4%). There was a significant interaction between treatment effect on OS and the timing of CT (p=0.01) in favor of concomitant CT (without adjuvant CT: HR 0.79 [0.68;0.92]; with adjuvant CT: HR 0.65 [0.56;0.76]) compared to induction CT (HR 0.96 [0.80;1.16]) or adjuvant CT (HR 0.93 [0.70;1.24]), which explained the statistical heterogeneity. Restriction of the analysis to trials with a control arm with RT alone led to similar results. The benefit of the addition of CT was consistent for all endpoints: progression-free survival (HR 0.76 [0.70;0.82], p<0.0001), loco-regional control (HR 0.74 [0.65;0.85], p<0.0001), distant control (0.68 [0.60;0.76], p<0.0001) and NPC related mortality (0.73 [0.66;0.81], p<0.0001). There was no significant interaction between treatment effect on OS and patient covariate (age, sex, tumor stage). Conclusions: The addition of concomitant chemotherapy, with or without adjuvant CT, significantly improves survival in patients with locally advanced nasopharyngeal carcinoma. Supported by PHRC and LNCC
Open-label, multicenter, single-arm phase II study (DeCOG-Trial) to further evaluate the efficacy and safety of ipilimumab in patients with cutaneous melanoma and rare subgroups.
Authors: Lisa Zimmer, Thomas K. Eigentler, Julia-Marianne Vaubel, Peter Mohr, Zeinab Jradi, Felix Kiecker, Jochen Utikal, Carola Berking, Eckhart Kämpgen, Axel Hauschild, Edgar Dippel, Rainer Rompel, Michael Fluck, Rudolf Stadler, Rudolf Herbst, Patrick Terheyden, Claus Garbe, Carmen Loquai, Dirk Schadendorf
Journal: Journal of Clinical Oncology (2014)

9031 Background: Ipilimumab is a recently approved immunotherapy that has shown an overall survival benefit in previously treated and treatment-naïve patients with metastatic melanoma in two phase III trials. However, results of registrational trials might not address all questions regarding safety and efficacy of ipilimumab in advanced melanoma patients seen in daily routine. We performed a multicenter, phase II clinical trial of ipilimumab in patients with different subtypes of metastatic melanoma. Methods: Pretreated patients with unresectable stage III or stage IV with cutaneous, mucosal, ocular or unknown primary melanoma (MUP) were included into this study (CA184-137; supported by BMS). Treatment-naïve patients with metastatic ocular melanoma were eligible, too. Four cycles ipilimumab should be administered at a dose of 3 mg/kg 3 weeks apart. Tumor assessments according to RECIST 1.1 version were conducted at baseline, weeks 12, 24, 36 and 48. Adverse events (AEs), including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria v.4.0. Primary endpoint was the overall survival (OS) rate at 12 months. Results: Between May 2011 to December 2013, 156 patients were enrolled in 25 German centers and received at least one dose of ipilimumab, including 83 cutaneous, 7 mucosal, 53 ocular melanomas and 13 MUP. After a median follow-up of 7 months (range 0.1-26.4), 12-month OS rates were 37% for cutaneous, 14% for mucosal, and 22% for ocular melanomas and 27% for MUP. The median OS from the first dose of ipilimumab was 6.9 months (95% CI 5.7-8.1). The overall response rates among 104 evaluable patients were 16% for cutaneous, 17% for mucosal, 9% for ocular melanomas and 11% for MUP. There were one patient with complete response (1%), 13 patients with partial response (13%), and 23 patients with stable disease (22%). Treatment-related AEs were observed in 106 patients (68%), including 39 grade 3-4 events (25%). There was a drug-related death due to pancytopenia. Conclusions: Ipilimumab is a treatment option for patients with cutaneous, ocular, mucosal and unknown primary melanoma with manageable toxicity. Clinical trial information: NCT01355120.
Multidisciplinary management and use of neoadjuvant cisplatin combination chemotherapy in patients with muscle-invasive urothelial bladder cancer.
Authors: Jean H. Hoffman-Censits, Jianqing Lin, Costas D. Lallas, Timothy Norman Showalter, Robert Benjamin Den, Ellen Doubet, Jillian Brown, Jaspreet Singh, Adam Dicker, Leonard G. Gomella, William Kevin Kelly, Edouard John Trabulsi
Journal: Journal of Clinical Oncology (2012)

e15012 Background: Although randomized data support neoadjuvant cisplatin-based chemotherapy prior to cystectomy for muscle invasive bladder cancer (MIBC), a recent retrospective study of 14 academic centers demonstrated only 12% of patients eligible for cystectomy received neoadjuvant chemotherapy. We reviewed utilization of neoadjuvant chemotherapy in a cohort of patients with MIBC seen at the Genitourinary Multidisciplinary Cancer Clinic (GUMDCC) of the Kimmel Cancer Center at Thomas Jefferson University (TJU). Methods: With IRB approval, records were reviewed for patients seen in the GUMDCC by urologists, radiation and medical oncologists with MIBC expertise from August 2009 to August 2011. Results: Of the201 patients with bladder or urothelial carcinoma, 46 (23%) with T2-T4 MIBC were identified and evaluated for neoadjuvant chemotherapy prior to radical cystectomy. 14 of 46 (30%) had renal, cardiac or other comorbidities rendering them unfit for cisplatin or cystectomy, and 2 were never referred to medical oncology. Of the 30 patients eligible for cisplatin and cystectomy, 2 were treated at outside institutions, 4 were recommended for treatment but were lost to follow up, and 4 who had refused neoadjuvant chemotherapy had adverse pathology at cystectomy and received adjuvant chemotherapy. Twenty eligible patients (66%) initiated neoadjuvant chemotherapy at TJU, 8 of those (40%) on clinical trial. 100% of patients treated with neoadjuvant chemotherapy at TJU received cisplatin based regimens, and 17 of 20 patients received at least 3 cycles. Chemotherapy was initiated in an average of 29.8 days of multidisciplinary evaluation. Conclusions: Multidisciplinary evaluation and management of patients with MIBC leads to improved compliance with evidence based guidelines and higher rates of cisplatin based neoadjuvant chemotherapy administration compared with historic data.
A pilot, open-label phase II study of sorafenib combined with cisplatin plus gemcitabine for the treatment of patients with advanced renal collecting duct carcinoma.
Authors: Xi Nan Sheng, Chuan Liang Cui, Zhihong Chi, Lu Si, Si Ming Li, Li Li Mao, Bin Lian, Bi Xia Tang, Xuan Wang, Yan Kong, Xiaodong Xie, Fang-Jian Zhou, Jian-lin Yuan, Qiang Wei, Jun Guo
Journal: Journal of Clinical Oncology (2014)

e15554 Background: Collecting duct carcinoma (CDC) of the kidney is a rare and aggressive neoplasm without any approved treatment. The anti-VEGF drugs can produce definite efficacy on renal clear cell carcinoma, but it is limited for advanced CDC. This study was designed to evaluate the efficacy and safety of sorafenib combined with cisplain plus gemcitabine in patients with advanced CDC without prior systemic chemotherapy or anti-VEGF therapy. Methods: This study is an open-label, multicenter, single-arm phase II trial. Up to 20 adult patients with metastatic, recurrent, or unresectable RCC of any MSKCC prognosis and histological confirmation of CDC, ≥1 measurable baseline lesion as per RECIST criteria, ECOG PS ≤2, and adequate liver, renal, and bone marrow function are targeted for enrollment. All patients received sorafenib (400mg Bid) combined with cisplatin plus gemcitabine (cisplatin: 25mg/m2, D1-3; gemcitabine: 1000 mg/m2, D1-8, for 4 cycles) until disease progression, unacceptable toxicity, or study discontinuation for any other reason. The primary study endpoint is PFS. Overall survival, disease control rate, and safety will also be assessed. Results: The first patient visit was June 1, 2012; 12 patients have entered the study to date. 11 patients received prior nephrectomy. The sites of metastases included lung (5/12), mediastinal lymph node(4/12), local recurrence (4/12), retroperitoneal lymph node (4/12), skeleton(2/12) and peritoneum (2/12). The overall objective response rate was 33.3% (95% confidence interval [CI, 6.6% to 59.9%]), with 0(0%) complete response (CR) and 4 (33.3%) partial responses (PRs). 6 (50.0%) had stable disease (SD), and 2(16.7%) had progression disease (PD). The disease control rate was 83.3%. The median progression-free survival was 10 months. The therapy was well tolerated with grade 3-4 toxicities: neutropenia (4/12), thrombocytopenia (3/12), hand-foot syndrome (3/12). Conclusions: Sorafenib combined with cisplatin plus gemcitabine may benefit patients with advanced CDC. More patients will enroll in the next years. Clinical trial information: NCT01762150.
Phase I study of neoadjuvant bevacizumab, 5-fluorouracil, and radiation therapy followed by surgery for patients with primary rectal cancer
Authors: C. G. Willett, D. Chung, D. Sahani, M. Mino, J. Clark, D. Ryan, A. Zhu, L. Blaszkowski, G. Lauwers, R. Jain
Journal: Journal of Clinical Oncology (2004)

3589 Background: Vascular endothelial growth factor (VEGF) is over expressed in rectal cancer and is associated with disease progression and inferior survival. Based on our pre-clinical studies, inhibition of VEGF may enhance radiation and chemotherapy response in patients with rectal cancer. To test this hypothesis, we initiated a phase I clinical trial in collaboration with the National Cancer Institute to evaluate the feasibility of integrating Bevacizumab (BV - a recombinant, humanized antibody against VEGF) into a contemporary treatment program of preoperative chemotherapy and radiation therapy followed by surgery for patients with primary and non-metastatic rectal cancer. Methods: Nine patients with clinical stage T3 or T4 NX M0 rectal cancer have completed a treatment program of preoperative BV (5mg/kg - 6 patients) or (10 mg/kg -3 patients) on day 1 followed by concurrent administration of BV (5 mg/kg or 10 mg/kg; days 15, 29, 43) with 5-fluorouracil (5-FU) chemotherapy (225 mg/m2 q24 hrs: days 15 –52) and radiation therapy (50.4 Gy in 28 fractions: days 15–52). Surgery is performed 7 weeks after completion of BV, 5-FU, and radiation therapy. Results: All six patients at dose level 1 of 5 mg/kg BV completed the protocol without dose limiting toxicity (DLT) and underwent resection without complication. Three patients have completed dose 2 of 10 mg/kg BV without DLT and one patient has undergone resection without complication. Two patients are scheduled for surgery. Endoscopic responses (just prior to surgery) have shown no visible macroscopic tumor in 6 of 7 evaluable patients. Similarly, pathological evaluation has demonstrated limited microscopic disease in the surgical specimens of 6 of 7 evaluable patients. Conclusions: Preliminary data (i) indicate safety of BV in combination with neoadjuvant 5-FU and radiation and surgery in the treatment of patients with locally advanced rectal cancer and (ii) significant clinical activity. (Supported by R21 CA099237 (Willett)). Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech