tbuckley/cabot-search huggingface dataset:
Presence of myeloid-derived suppressor cells (MDSC) in patients with metastatic castration-sensitive and castration-resistant prostate cancer.
Authors: Karen A. Autio, Phillip Wong, Angel Rabinowitz, Jianda Yuan, Lauryn Michelle Slavin, Ryan Brennan, Melineh DerSarkissian, Zhenyu Mu, Howard I. Scher, Alexander M. Lesokhin
Journal: Journal of Clinical Oncology (2015)

222 Background: MDSC contribute to an immune suppressive environment and have been implicated in cancer progression. Measurement (identification and enumeration) is challenged by the lack of analytically valid assays limiting data interpretation between groups. This impacts our understanding of rationale immune targets and design of clinical trials. We employed a novel biomarker based assay in whole blood to enumerate MDSC from patients with metastatic castration sensitive (CSPC) and castration resistant prostate cancer (CRPC). Methods: Whole blood was collected in Cyto-Chex (Streck) tubes. A published computational algorithm-based approach (developed by Memorial Sloan Kettering Cancer Center and commercialized by Serametrix) was employed to determine the %MDSC-monocytic and coefficient of variance (CV=ratio of SD and geometric mean fluorescence intensity) to assess HLA-DR spread on CD14+CD11b cells. Samples were performed in duplicate. Clinical variables including clinical state, past and current treatment, metastatic sites, PSA, and standard prognostic markers were collected. Results: 36 pts with metastatic prostate cancer (29 CRPC; 7 CSPC) were included. Median (SD) %MDSC in 29 CRPC pts was 21.15 (5.33) and median (SD) CV was1.29 (0.25); 7 CSPC demonstrated a median (SD) %MDSC 19.15 (4.86) and median (SD) CV 1.22 (0.25). MDSC did not differ between chemotherapy exposed (n=13) and chemotherapy naive (n=16) CRPC (23.3 vs 19.5, p=ns). MDSC were not significantly higher in those with visceral mets, though a trend existed (20.3 vs 24.0, p=0.076). PSA did not appear to correlate with MDSC or CV. Conclusions: Understanding the distribution and characterization of MDSC in various clinical states in prostate cancer is relevant to the development of immune targets in this disease. MDSC were quantifiable in both CSPC and CRPC. There was a trend for higher MDSC values in patients with visceral metastases, which historically are associated with worse prognoses. Presence of MDSC in metastatic CSPC and CRPC has important therapeutic and trial implications. Further discovery in larger cohorts and earlier disease states is underway.
An audit of relapsed ovarian cancer (OC) management in 9 UK centres
Authors: J. Stewart, R. Allerton, S. Chan, K. Gregory, A. Hughes, S. Awwad, S. Pledge, H. Thomas
Journal: Journal of Clinical Oncology (2005)

5138 Background: Relapsed ovarian cancer has a poor prognosis but in recent years treatment has improved as new agents have been licensed. As the range of available agents becomes wider, the need increases to audit the outcomes achieved with each regimen in real clinical practice. Such audit is increasingly a requirement of UK national guidance on the appropriate use of these agents. However, it is difficult to obtain meaningful results in many centres, when the range of potential regimens is wide, and the number of patients treated for relapsed OC relatively small.Thus it was the aim of this audit to describe the patterns of chemotherapy usage and associated outcomes in patients with relapsed OC, pooling the data from 9 UK centres to provide robust results which could inform future management of the disease. Methods: Ovarian cancer patients in 9 UK hospitals who received treatment for recurrent disease between Aug 2001 and Feb 2004 were included in the analysis using a common data set. End points included response and toxicity to treatments and subsequent treatment-free interval. Results: 320 patient records were analysed. Platinum-based regimens were used in the treatment of 65% of first relapses, 32% of 2nd and 18% of 3rd relapses. Use of topotecan was 17–19% at each relapse, while use of liposomal doxorubicin (LD) increased from 2% at first relapse to 16% at 2nd and 3rd relapses. 5.8% lines of treatment were given as part of clinical trials. Response rates at any relapse were: carboplatin 47%, topotecan 21% and LD18%. Neutropenic sepsis was reported in 1.2% of carboplatin, 17% of topotecan and 3% of LD-treated patients. 27% of LD treated patients developed palmar-plantar erythema. Suspected allergic reactions were reported in 7.3% of carboplatin, 7.4% of topotecan and 3.2% of LD-treated patients. Treatment free intervals were highly variable at all lines of treatment, but the trend was for the mean interval to reduce with each relapse. Conclusions: Pooling data from several centres was a successful means of auditing relapsed OC management. Platinum-based regimens remain the mainstay of treatment, but where platinum resistance develops, topotecan and LD are worthwhile. The incidence of neutropenic sepsis with topotecan was not as high as previously reported. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, GlaxoSmithKline, Merck, Schering-Plough
Phase I dose-escalation study of sorafenib plus S-1 in refractory solid tumors.
Authors: Hui-Jen Tsai, Nai-Jung Chiang, Her-Shyong Shiah, Kwang-Yu Chang, Wu-Chou Su, Jang-Yang Chang, Li-Tzong Chen
Journal: Journal of Clinical Oncology (2016)

745 Background: S-1 is a new oral fluoropyrimidine-derived combo and has been shown activity in patients with various cancers in phase II/III studies. Sorafenib is an oral multikinase inhibitor with anti-proliferative and anti-angiogenesis activities and has been approved for the first-line treatment of advanced HCC, RCC and radioactive iodine-resistant thyroid cancer. In xenograft mouse models, sorafenib showed its activity to enhance the cytotoxicity of chemotherapeutic agents. Therefore, a phase I dose-escalation study to determine the dose-limiting toxicity and maximum dose of S-1 in combination with standard dosing of sorafenib in patients with refractory solid tumors was conducted. Methods: Eligible patients would receive escalating dose (30, 35 and 40 mg/m2, twice daily) of S-1 in a standard 3+3 phase I study design. Treatment was consisted of continuous sorafenib 400 mg bid plus S-1 30-40mg/m2 bid, D1-14, every 21 days per cycle. DLTs were assessed during the first two cycles of treatment, and treatment would be continued until disease progression, the occurrence of unacceptable toxicity or consent withdrawal. Results: A total of 13 patients were included, 7 in 30 mg/m2 dose level and 6 in 35 mg/m2 dose level. DLT occurred in 2 of 6 patients with 35 mg/m2 twice daily, manifested as grade 3 skin rash and prolonged grade 2 hand-foot-skin reaction in one each; while there was no DLT observed in 30 mg/m2 cohort. Seven patients achieved durable tumor control, included one pancreatic neuroendocrine tumor patient who had a sustained PR for 27.9 months, and durable stable diseases (&gt;6 months of progression-free survival) in 3 out of 4 colorectal cancer patients, 2 of 2 biliary tract cancer patients and 1 of 2 pancreatic cancer patients. Conclusions: The recommended dose of S-1 in this combination was 30mg/m2 bid. Preliminary results suggested sorafenib/S-1 combination is feasible and deserves for further exploration in refractory advanced gastrointestinal tract cancers. Clinical trial information: NCT01128998.
Molecular characterization of colorectal tumors in young patients compared with older patients and impact on outcome.
Authors: Arielle Celeste Heeke, Joanne Xiu, Sandeep K. Reddy, Jiji Jiang, Hongkun Wang, John Marshall, Mohamed E. Salem
Journal: Journal of Clinical Oncology (2016)

505 Background: The incidence of colorectal cancer (CRC) among young individuals is rising. The effect of an individual’s age on their tumor molecular profile is unknown. Methods: Molecular profiles of 4,821 tumors obtained from younger and older CRC patients (pts) were reviewed and correlated with pt outcome. Protein expression (IHC), gene amplification (ISH), sequencing (NGS and Sanger), and fragment analysis were performed. T and Fisher’s exact tests determined differences between age groups; Kaplan-Meier methodology estimated survival. Results: Tumors from 1,277 younger (median age 40; range 15-45 yr) and 3,544 older (72; 65-98) pts were studied. Most frequently mutated genes included TP53, APC, KRAS, PIK3CA, SMAD4, and BRCA1/2. Mutation rates for BRAF (14.4% vs. 4.8%, p &lt; 0.001), APC (62% vs. 54%, p = 0.0034), FBXW7 (9.6% vs. 5.5%, p = 0.01), and KRAS (45% vs. 41%, p = 0.02) were higher in older pts; NRAS mutation rates (4.5% vs. 3.9%) were similar in both groups. Younger pts had higher overexpression rates of HER-2/neu (3.2% vs. 1.8%, p = 0.017) and MGMT (64% vs. 58%, p = 0.001). Microsatellite instability (MSI), determined by IHC (MLH1, MSH2, MLH6 and PMS2) and fragment analysis, was similar between cohorts (10.3% vs. 8.1%), but somatic MSI high (determined by concurrent BRAF mutation) was higher in older pts (6% vs. 0%, p &lt; 0.0001). There was no difference in TS (37% vs. 34%), ERCC1 (25% vs. 26%) or TOPO1 (49% vs. 46%) expression between age groups. Older pts showed a trend toward higher PD-L1 expression (2.9% vs. 0.7%, p = 0.0512) but there was no difference in the frequency of PD-1 expression on tumor-infiltrating lymphocytes (39% vs. 43%). Outcome was evaluable for 82 pts (younger, 47; older, 35). Most pts received FOLFOX + Bev as first line Rx. Median OS was worse in younger pts (p = 0.03). Low ERCC1 expression was associated with prolonged survival in older (p &lt; 0.01) but not in younger (p = 0.3) pts. There was no association between TOPO1 expression and OS (p = 0.8). Pts with low TS expression showed a trend toward longer OS (p = 0.08). Conclusions: Young pts with CRC may carry genetic alterations that are distinct from older pts. A better understanding of disease biology may help to identify therapeutic targets for younger pts.
Second primary cancers in young adult colorectal cancer survivors.
Authors: Raji Shameem, Muhammad Saad Hamid, James Luke Godwin, Niket Sonpal, Kevin M. Sullivan
Journal: Journal of Clinical Oncology (2015)

516 Background: Second primary cancers are a major concern for young adult colorectal cancer (CRC) survivors. The impact of treatment with radiation on the risk for second solid and hematological malignancies, as well as the typical latency period before development of a second cancer, requires elucidation. Methods: The Surveillance Epidemiology and End Results (SEER) database was used to detect CRC cases in young adults (aged 20-40 years) diagnosed up to 12/31/2011. The Standardized Incidence Ratio (SIR) was calculated as the ratio of observed to expected cases of second primary malignancy based on incidence data in the general United States population. The latency exclusion period from the date of diagnosis was 5 years. We investigated the possible effect of radiation therapy on risk for a second cancer, and established the typical latency period after initial diagnosis (5-10 years and &gt;10 years). Results: A total of 9,537 cases of CRC in young adults were available for analysis. Radiation was administered in 1,823 (19.1%) patients. Second primary cancers occurred in 798 cases, 754 (94.5%) solid tumors and 44 (5.5%) hematological malignancies respectively. In the latency period 5-10 years after initial diagnosis, “All Solid Tumors” (SIR: 1.85, p&lt;0.05) and female genital tumors (SIR: 3.52, p&lt;0.05) were increased. In the latency period &gt;10 years after initial diagnosis, an increased risk of developing pancreatic cancer (SIR: 1.90, p&lt;0.05) and female genital tumors (SIR: 1.77, p&lt;0.05) was observed. In patients who received radiation the only significantly increased risk was for “All Solid Tumors” (SIR: 1.42, p&lt;0.05). No significant increase in second hematological malignancies was observed in the entire cohort, including cases that received radiation. Conclusions: An increased risk of second primary female genital tumors was seen in both the 5-10 years and &gt;10 years latency periods. Pancreatic cancer risk was increased specifically in the &gt;10 years latency period. Radiation treatment did not pose an increased risk for any specific second primary cancers. Interestingly, young adult CRC survivors did not have an increased risk for hematological malignancies compared to the general population.
First-line treatment with bevacizumab plus capecitabine for elderly patients with metastatic colorectal cancer: BECA trial
Authors: J. Feliú, A. Salut, M. Safont, F. Losa, C. García, C. Bosch, P. Escudero, R. López, M. Bolaños, M. González-Barón
Journal: Journal of Clinical Oncology (2008)

15120 Background: Elderly pts with metastatic colorectal cancer (mCRC) are frequently treated with Capecitabine (Cap) alone if they present comorbidities that make them unsuitable for receiving chemotherapy combinations.In CRC, Bevacizumab (Bev) has demonstrated to improve the efficacy of many chemotherapy regimens regardless of patient´s or tumour´s characteristics. Elderly pts benefits from Bev as well as younger ones, and the toxicity profile keeps manageable regardless of the age. In this study we analize the efficacy and toxicity of Cap (1250 mg/m2 bid, days 1–14 q3w) plus Bev (7,5 mg/kg iv q3w) as first line treatment for elderly pts with mCRC unsuitable for polychemotherapy treatment. Methods: This is a phase II open, multicenter, non controlled trial. Main elegibiligy criteria were: age of at least 70 years, chemotherapy naïve, metastatic and non resectable CRC and ECOG ≤2. The primary objective was to determine the overall response rate (ORR), other objectives were to analyze PFS, OS and toxicity of the combination. Results: Data from 50 out of the 59 pts enrolled are available. Baseline characteristics are: median age 76 years (73–79), male/female 54/46%, 42% of pts presented mild/severe dependence as Lawton activity index and 9% mild/severe disability as Barthel index. 59% of the patients presented HTA at baseline. 49 pts have been included in the toxicity analysis. Most frequent adverse events were: hand-food syndrome 30.6% (G1 8%, G2 14%, G3 8%), diarrhea 30.6% (G1 10.2%, G2 10.2%, G3 8.2% and G4 2%) and asthenia 30.6% (G1 6%, G2 20.4% and G3 4.1%). The most common Bev related adverse event reported so far has been HTA in 14% of pts (G1 4.1%, G2 8.2% and G3 2%). Other toxicities related to Bev were: deep venous thrombosis found in 4 pts (G3), epistaxis in 2 pts (G1) and there was one death due to GI haemorrage. Conclusions: The combination of Bev plus Cap as first-line treatment for elderly patients with mCRC seems to be well tolerated and has a manageable toxicity profile. Updated results will be presented during the congress. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche
Risk of metastatic spread in patients with early-stage, surgically resected pancreatic neuroendocrine tumors.
Authors: J. R. Strosberg, A. Cheema, J. Weber, L. K. Kvols
Journal: Journal of Clinical Oncology (2011)

338 Background: The risk of metastatic spread among patients with early-stage surgically resected pancreatic neuroendocrine tumors has not been well established. Methods: Patients with surgically resected localized or locally advanced pancreatic neuroendocrine tumors treated at the H. Lee Moffitt Cancer Center between 1999 and 2010 were assigned a stage (I-III) based on the new AJCC classification. Recurrence-free survival was measured for each stage. A separate analysis was performed excluding patients who had been referred to Moffitt Cancer Center after metastatic recurrence. Results: 123 patients with nonmetastatic, surgically resected pancreatic neuroendocrine tumors were identified. 5-year recurrence-free survival correlated with AJCC stage (p=0.01; Table). Conclusions: The novel AJCC 7th edition TNM classification for pancreatic neuroendocrine tumors is highly prognostic for recurrence in patients with surgically resected nonmetastatic tumors. [Table: see text] No significant financial relationships to disclose.
Diagnostic accuracy and value of magnetic resonance imaging (MRI) in planning exenterative pelvic surgery for advanced colorectal pelvic cancer.
Authors: P. P. Tekkis, P. A. Georgiou, V. A. Constantinides, U. Patel, A. Antoniou, R. D. Goldin, A. W. Darzi, D. Cunningham, R. Nicholls, G. Brown
Journal: Journal of Clinical Oncology (2011)

370 Background: Exenterative pelvic surgery is challenging and has been used in colorectal surgery to manage patients with advanced colorectal pelvic cancer. Resection of the tumor needs to be performed en-bloc and if feasible, without exposing the tumor, since this can compromise resection margins. This can only be performed through careful pre-operative staging. This study aimed to assess the diagnostic accuracy of MRI in detecting colorectal tumor invasion into seven intrapelvic compartments and its value in planning exenterative pelvic surgery. Methods: Sixty four consecutive patients underwent preoperative MRI planning for exenterative surgery, for locally advanced (n= 23) and recurrent (n= 41) pelvic colorectal cancer. Two radiologists reported tumor invasion for each of the seven anatomic surgical resection compartments and were blinded to histopathology and intraoperative reference standards. Sensitivity, specificity and predictive values were calculated for each compartments. Kaplan-Meier methodology was used to calculate survival rates. Interobserver agreement was assessed using Cohen's Kappa coefficient (k). Results: The sensitivity of MRI was ≥93.3% in all except for the lateral compartment where it was 89.3%. Its specificity for the posterior (82.2%), anterior below (86.4%) the peritoneal reflection compartments was lower compared to the rest of the compartments. MRI diagnosis of lateral (OR= 11.41, p= 0.033), anterior compartment above the peritoneal reflection (OR= 3.14, p= 0.005) and multicompartmental involvement (OR= 1.99, p&lt;0.001) was associated with higher risk of incomplete resection which was subsequently found to be significant factor in predicting overall and disease free survival (p&lt;0.05). The agreement between the two radiologists was found to be either good or very good for all the compartments (k&gt;0.72). Conclusions: MRI is highly accurate in predicting tumor invasion within the intrapelvic compartments and it should be the pre-operative staging modality of choice when considering exenterative surgery for patients with locally advanced colorectal pelvic cancer. [Table: see text]
Carboplatin alone or in combination with epirubicin for stage III and IV endometrial cancer
Authors: U. Barthakur
Journal: Journal of Clinical Oncology (2008)

16577 Background: With current chemotherapy, median survival in advanced endometrial cancer (AEC) is 7–15months. Carboplatin alone (CA) and Epirubicin (CE) offers advantages with respect to toxicity compared to regimens such as adriamycin/ cisplatin, but to date there is no published evidence for CE. The primary aim of this review is to assess CA or CE for AEC with respect to toxicity, progression free survival (PFS) and overall survival(OS), in both the adjuvant setting and for metastatic or relapsed disease. Methods: A retrospective analysis of patients with AEC who received carboplatin AUC5 and epirubicin 50mg/m2, or carboplatin AUC6 alone was undertaken. Common toxicity criteria was used to grade toxicity. The Kaplan-Meier method was usedto estimate PFS and OS. Results: 45 patients wereidentified (median age 66 years).Patients were divided into two groups: group 1 (n=35) had stage III disease or less, with no residual microscopic disease; group 2 (n=10) had metastatic disease or relapse. In group 1, 91% had stage III disease. In group 1 had 97% had optimal surgery and 83% had radical radiotherapy. In group 2, 6 patients(60%) presented with metastatic disease, with the remainder presenting with relapse. 34 patients received CE and 11 received CA with 87% of patients receiving at least the recommended number of chemotherapy cycles. Median follow up was 29 months (range 2- 70). Grade 3 or 4 toxicity was observed in 24% of patients and this proportion was similar for CA (27%) and CE(23%); there were only two hospital admissions. Overall median progression free survival was 54 months (range 8 to 101). In group 1, the risk of being progression free at 2 years was 66% compared to 40% in group 2. Median OS was 62 months.In group 1 the median OS was 62 months with survival at 1,2 and 3 years being 94%, 87% and 59% respectively. In group 2 median OS was 22 months and survival at 1, 2 and 3 years was 70%, 48% and 36% respectively. Conclusions: CE or CA appears successful in terms of toxicity and efficacy. This regimen should be subject to further evaluation. No significant financial relationships to disclose.
Tax Ubiquitylation and Sumoylation Control the Two Distinct Steps of NF-κB Activation.
Authors: Rihab Nasr, Estelle Chiari, Marwan El-Sabban, Renaud Mahieux, Youmna Kfoury, Mohammad M. Abdulhay, Olivier Hermine, Hugues de Thé, Claudine Pique, Ali Bazarbachi
Journal: Blood (2005)
Physician inter-annotator agreement in the Quality Oncology Practice Initiative (QOPI) manual abstraction task.
Authors: Jeremy Warner, Reed Drews
Journal: Journal of Clinical Oncology (2012)

226 Background: The Quality Oncology Practice Initiative (QOPI) relies upon the accuracy of manual abstraction of clinical data from paper-based and electronic medical records (EMR’s). While there is no “gold standard” to measure manual abstraction accuracy, measurement of inter-annotator agreement (IAA) is a commonly agreed-upon surrogate. We quantified the IAA of QOPI abstractions on a cohort of cancer patients treated at Beth Israel Deaconess Medical Center. Methods: The EMR charts of 49 patients (20 colorectal cancer; 18 breast cancer; 11 non-Hodgkin lymphoma) were abstracted by separate physician abstractors in the Fall 2010 and Fall 2011 QOPI abstraction rounds. The Fall 2011 abstractors were unaware that the charts had been previously abstracted. We analyzed data elements that were common to both rounds, had data entry for both rounds, and did not contain information expected to change after the Fall 2010 round. Cohen’s kappa (κ) was calculated for encoded data; raw levels of agreement and magnitude of discrepancies were calculated for numeric and dated data. IRB approval was obtained and all investigators completed appropriate human subjects research training. Results: 109 data elements with 2,035 paired entries met the above criteria; four narrative elements were not analyzed. Overall IAA for 1,496 coded entries was κ=0.75; median IAA for n=85 individual coded elements was κ=0.84 (interquartile range 0.30-1.00). Overall IAA for 421 dated entries was 73%; median IAA for n=17 individual dated elements was 67% (interquartile range 61-86%). The median discrepancy for the 113 discrepant dated entries was +6 days (range -217 to +391 days). Conclusions: This study establishes a baseline level of accuracy for a complex medical abstraction task with clear relevance for the oncology community. Despite the fact that all information was available in the EMR, there was disagreement for objective elements (e.g. cancer stage) as well as subjective elements (e.g. patient wellbeing). Given that the observed κ is considered only fair IAA, and that the rate of date discrepancy is high, caution is necessary in interpreting the results of QOPI and other manual abstractions of clinical oncology data.