tbuckley/cabot-search huggingface dataset:
Evaluating variability in fluorouracil (FU) exposure in obese and non-obese patients with colorectal cancer using full weight-based dosing.
Authors: Jai Narendra Patel, Allison Mary Deal, Howard L. McLeod, Bert H. O'Neil, Christine Marie Walko
Journal: Journal of Clinical Oncology (2013)

409 Background: Approximately 30% of cancer patients are obese. Controversy exists on how to best use body weight to safely and effectively dose chemotherapy. Additionally, body surface area (BSA)-based dosing is associated with high pharmacokinetic (PK) variability and is a poor indicator of optimal drug exposure. Methods: We estimated FU exposure post cycle 1, as indicated by area under the curve (AUC), in 58 colorectal cancer patients receiving mFOLFOX6 (FU 2400 mg/m 2 [BSA calculated using actual body weight (ABW)] over 46 hours) +/- bevacizumab. AUCs were determined using an immunoassay at Myriad Laboratories. The primary objective was to identify variability in FU exposure in obese and non-obese patients using body mass index (BMI), BSA, and ABW. Groups were compared using two group t-tests. Results: No significant difference in AUC was observed between obese (BMI ≥ 30 kg/m 2 ) and non-obese (&lt; 30 kg/m 2 ) patients. A significantly lower AUC was observed in patients with a BSA ≥ 2.0 m 2 compared to those &lt; 2.0 m 2 (p=0.02). The AUC for obese and non-obese patients ranged from 7-34 and 12-38 mg*hr/L, respectively. Only 32% and 28% of obese and non-obese patients, respectively, were within the previously reported therapeutic target AUC 20-25 mg*hr/L. Males had significantly lower AUCs compared to females (mean 18.7 v 22.4, p=0.03). FU AUC was not strongly correlated with BMI, BSA, or ABW (Pearson correlation of -0.03, -0.26, and -0.15, respectively). Conclusions: BSA-based dosing is associated with variable FU exposure. Lower AUCs in patients with a BSA ≥ 2.0 m 2 supports both ASCO recommendations for full-weight-based dosing in obese patients and the value of dosing assessment across patient populations. Further study of AUC-based dosing is warranted as our data do not support a reduction in variable exposure based on BMI, BSA, or ABW dosing. [Table: see text]
Rectal adenocarcinoma: Surveillance and timing of surgical resection after neoadjuvant chemoradiotherapy in a retrospective cohort.
Authors: Vanessa Pachón Olmos, Pablo Reguera Puertas, Cristina Saavedra Serrano, Reyes Ferreiro Monteagudo, Federico Longo, Carmen Guillén Ponce, Ana Gómez Rueda, Mercedes Rodríguez Garrote, María Ángeles Vaz Salgado, Maria Gion Cortés, Alfonso Cortes Salgado, Jacobo Muñoz del Toro, Silvia Patricia Cortez Castedo, Asunción Hervás Morón, Cayetano Sempere Ortega, Javier Die Trill, Juan Carlos García Pérez, Irene Moreno Montes, Estela Tobaruela de Blas, Alfredo Carrato
Journal: Journal of Clinical Oncology (2016)

737 Background: There is some evidence relating delay of surgery (DS) by more than 8 weeks after the end of chemoradiotherapy and achievement of complete pathological response (ypCR). However, the relationship with overall survival (OS) seems to be negative. Methods: Records of 171 patients diagnosed from January 2003 to December 2011 with rectal adenocarcinoma T3/T4 and/or positive node staged by ultrasound or MRI were collected retrospectively from the Pathology Department database. Results: Of the 171 patients, 62% were male, median age at diagnosis 69.3 years (31.3 years -85.3 years). All of them received 50.4 Gy with different concomitant regimens (capecitabine, continuous infusion of fluoracil or bolus of fluoracil-leucovorin). 72.5% of the cohort received adjuvant chemotherapy. 13% of patients achieved ypCR, independently of DS (13.7% in DS vs 11.8%, p 0.722). OS was significantly worse among DS patients (67.9 months vs 54.8 months, p 0.016). In addition, more sphincter preservations (SP) were not achieved (60.8% in DS vs 57.1%, p 0.881). Conclusions: In contrast with published literature, in our cohort DS failed to show higher rates of ypCR. Neither an improvement in OS or SP was observed with DS. It is recommended that clinical trials be designed in order to establish ideal surgical timing.
A phase I/II study combining tosedostat with capecitabine in patients with metastatic pancreatic ductal adenocarcinoma (PDAC).
Authors: Andrea Wang-Gillam, Lingling Du, Andrea S. Teague, Rama Suresh, Kian-Huat Lim, Manik A. Amin, Katrina Pedersen, Benjamin R. Tan, Jess Huffman, Albert C. Lockhart
Journal: Journal of Clinical Oncology (2017)

410 Background: Recent advances in front-line therapy have improved survival in patients with advanced PDAC. A fluorouracil-based regimen is recommended for patients who progress on a gemcitabine-based therapy. Tosedostat is an oral aminopeptidase inhibitor that disrupts the cleavage of amino acids from peptides downstream of proteasomal degradation. It prevents the recycling of free amino acids, leads to intracellular depletion of amino acids, and triggers an amino acid deprivation response that subsequently results in apoptosis. Because PDAC cells frequently upregulate expression of these aminopeptidases, tosedostat offers therapeutic promise, particularly in combination with fluoropyrimidines. Methods: This is a single institution phase I/II trial to evaluate the safety and toxicity of tosedostat plus capecitabine in patients with metastatic PDAC progressed on a gemcitabine-based therapy. The phase I portion is being conducted in a dose de-escalation fashion, with two dose levels of tosedostat (120 mg or 60 mg) p.o. daily on days 1 to 21 with capecitabine 1000 mg/m 2 p.o. BID on days 1 to 14 of a 21-day cycle. If more than one out of 6 patients in the tosedostat (120 mg) cohort experience a dose limiting toxicity (DLT), then 6 more will be enrolled to the tosedostat (60 mg) cohort. The primary objective of the phase I portion is to determine the optimal phase II dose. The primary objective of the phase II portion is to determine the progression-free survival at 3 months. Secondary objectives include the overall response rate, overall survival and CA 19-9 response. To avoid futility, interim analysis is planned after 10 evaluable patients enrolled. Results: Up to date, a total of 11 patients have been enrolled in the study, and 10 patients are evaluable. No DLT have been observed. Tosedostat at a dose of 120 mg with capecitabine is extremely well tolerated. Prolonged stable disease has been observed in 4 (40%) patients with a time on treatment of 10 months, 7.5 months, 5.5 months and 4 months, and 3 of the 4 patients remain on the trial. Conclusions: The combination of tosedostat and capecitabine is a well-tolerated regimen with impressive clinical activity in the subset of patients studied thus far. Clinical trial information: NCT02352831.
What leads to better quality of life at the end of life?
Authors: M. E. Nilsson, B. Zhang, E. Reitschuler-Cross, A. A. Wright, X. Gao, J. S. Temel, T. A. Balboni, H. G. Prigerson
Journal: Journal of Clinical Oncology (2011)

9040 Background: When curative treatments are no longer options for dying cancer patients, the focus of care turns from prolonging life to promoting the best possible quality of life (QOL). Determining the factors that most enhance or detract from advanced cancer patients’ QOL will help to identify targets for interventions to improve patients’ QOL at the end-of-life (EOL). Methods: Coping with Cancer (CwC) is an NCI/NIMH-funded multi-site, prospective longitudinal study of advanced cancer patients. Baseline interviews with 393 patients and 393 caregivers assessed patients’ medical status, psycho-social characteristics, mental health, treatment preferences and patient-oncologist relationships. Post-mortem caregiver and clinician assessments conducted within one month of the patient’s death captured the QOL and care received by patients in the last week of life. Multiple regression models estimated associations between patient QOL and baseline characteristics and types of EOL care received. Akaike’s Information Criteria, which balances model fit and parsimony, determined the best model in the prediction of QOL in the last week of life. Results: In the final adjusted model, younger patients, White patients, patients with caregivers with generalized anxiety disorder, patients without a DNR order, and patients who stayed in the ICU during the last week of life were significantly (p<.05) more likely to have worse QOL in the last week of life. Patients who at baseline reported a sense of inner peace and harmony and who thought their oncologist saw them as a whole person were significantly (p<.05) more likely to have better QOL. Conclusions: Avoiding aggressive treatments in the last week of life (e.g., by completing a DNR order), having oncologists whom patients perceive as caring about them, promoting patients’ peacefulness and reducing anxiety among afflicted family caregivers are practical ways to improve patients’ EOL outcomes.
Lack of Correlation between CD 52 Expression and Treatment Outcome in PTCL Patients Treated with CHOP Chemotherapy Plus Campath-1h (CHOP-C) as First Line Treatment.
Authors: Andrea Gallamini, C. Campidelli, F. Zaja, A. Billio, L. Gargantini, A. Manna, V. Secondo, A. Levis, L. Rigacci, P. Mazza, E. Iannitto, A. Pinto, A. Tucci, C. Patti, V. Zoli, P. Torchio, S. Ascani, S. Pileri
Journal: Blood (2006)
Feasibility of docetaxel-prednisone (DP) in frail elderly (age 75 and older) patients with castration-resistant metastatic prostate cancer (CRMPC): GERICO10-GETUG P03 trial led by Unicancer.
Authors: Loic Mourey, Gwenaelle Gravis, Emmanuel Sevin, Frank Priou, Emmanuelle Bompas, Corinne Sarda, Nadine Houede, Elisabeth Carola, Sophie Abadie Lacourtoisie, Igor Latorzeff, Christine Orsini, Thomas Filleron
Journal: Journal of Clinical Oncology (2014)

152 Background: Chemotherapy with docetaxel-prednisone (DP) is one of the standard treatment of castration-resistant metastatic prostate cancer (CRMPC). However little is known about feasibility of DP in frail elderly patients seen in daily practice. Methods: Randomized phase II study evaluating prospectively the feasibility of DP administered either q3w (Arm A: 60 mg/m² cycle one then 70 mg/m²) or weekly (Arm B: 35 mg/m² D1 D8 q3w) in patients age 75 or older, assessed through comprehensive geriatric assessment (CGA) and classified according to the International Society of Geriatric Oncology (SIOG) as vulnerable (SIOG group 2) or frail (SIOG group 3). Failure was defined as: (1) stop or delay of chemotherapy more than 2 weeks, (2) need for dose reduction more than 25%, (3) febrile neutropenia or NCI CTC grade 3 non-haematological toxicity (excluding alopecia), and (4) decrease of activities of daily living (ADL) scoring two or more points. The study was based on a Simon’s optimum two-stage design for each group (α = 5%, 1-β = 90 %, p0 = 0.70 and p1 = 0.90). An interim analysis was planned after enrolment of 15 patients per arm, with continuation of the program if at least 12 patients met the feasibility criteria. Results: From December 2010 to August 2012, 21 centers have included 66 CRMPC patients, 45 and 21 in SIOG groups 2 and 3 respectively, based on investigators evaluation. The planned interim analysis primary endpoint is based on group allocation by a steering committee (per-protocol [PP] population). The enrolment in group 3 was prematurely closed on October 2012 after inclusion of 19 PP patients (Arm A/B, n=9/10) on recommendation of a safety committee due to an excess of toxic deaths. In this group, only four patients completed six cycles of DP in each arm. In group 2, the planned interim analysis was performed after inclusion of 30 PP patients (Arm A/B n=15/15): 11 and 10 patients in Arm A and B did not meet the predefined criteria for feasibility (73.3%; 95%CI=[44.9; 92.2] and 66.6%; 95%CI=[38.4; 88.2], respectively, and only nine and seven respectively completed six cycles of DP. Conclusions: Chemotherapy with DP given q3w or weekly is not feasible in CRMPC patients age 75 and older classified in SIOG group 2 and 3, according to our study criteria. Patients age 75 and older shouldn’t be offered DP without a CGA. Clinical trial information: NCT01254513.
Inhibition of cardiomyocytes late <i>I</i><sub>Na</sub> with ranolazine blunts anthracyclines-cardiotoxicity in experimental models in vitro and in vivo.
Authors: Nicola Maurea, Carmela Coppola, Domenica Rea, Giovanna Piscopo, Gennaro Riccio, Antonio Barbieri, Giuseppe Palma, Marianna Gala, Antonio Luciano, Aldo Giudice, Immacolata Capasso, Stefania Scala, Rosario Vincenz Iaffaioli, Claudia De Lorenzo, Claudio Arra, Carlo G. Tocchetti
Journal: Journal of Clinical Oncology (2012)

e13539 Background: Anthracyclines produce a well-known cardiomyopathy through multiple mechanisms, which also include, among many, Ca2+ overload due to reduced SERCA2a activity and inappropriate opening of the RyR2, and impaired myocardial energetics. Anthracyclines generate Reactive Oxigen and Nitrogen Species (ROS and RNS), posing the heart at increased demand for oxygen, thus setting the stage for a metabolic ischemia that also activates late I Na , the target of ranolazine (RAN). Here, we aim at assessing whether RAN, diminishing intracellular Ca2+ through its inhibition of late I Na, and enhancing myocardial glucose utilization (and/or reverting impairment of glucose utilization caused by chemotherapy) blunts anthracyclines cardiotoxicity. Methods: To assess for toxicity in vitro, rat H9C2 cardiomyoblasts were pretreated with RAN (0.1-1mM) for 72 hours and then treated with doxorubicin (DOX, 0.1 mM) for additional 24 hours. Cells counts were assessed by Trypan exclusion test. To evaluate cardiac function in vivo, fractional shortening (FS) and ejection fraction (EF) were measured by echocardiography in C57BL6 mice, 2-4 mo old, pretreated with RAN (370mg/kg/day, a dose comparable to the one used in humans) per os for 3 days. RAN was then administered for additional 7 days, together with DOX (2.17mg/kg/day ip), according to our well established protocol. Results: After DOX, only 68% of the cells were viable. RAN alone did not affect cell survival, but blunted DOX toxicity, rescuing % cell survival to 87% (p=.01 vs DOX alone). In our in vivo studies, after 7 days with DOX, FS decreased to 50±2%, p=.002 vs 60±1% (sham), and EF to 81±2%, p=0.0001 vs 91±1% (sham). RAN alone did not change FS (59±2%) nor EF (89±1%). Interestingly, in mice treated with RAN and DOX, the reduction in cardiac function was milder: FS was 57±1%, EF was 89±1%, p=0.01 and 0.0009 respectively, vs DOX alone. Conclusions: RAN blunts DOX cardiotoxic effects in 2 different models, in vitro and in vivo. We plan to test RAN as a cardioprotective agent with other antineoplastic cardiotoxic drugs in our experimental models, and to better characterize the cardioprotective mechanisms of RAN in all these settings.
Bortezomib plus DA-EPOCH-rituximab followed by bortezomib maintenance versus observation in previously untreated mantle cell lymphoma (MCL).
Authors: C. Grant, K. Dunleavy, M. Tweito, S. M. Steinberg, S. Pittaluga, E. S. Jaffe, A. Wiestner, W. H. Wilson
Journal: Journal of Clinical Oncology (2011)

8022 Background: Bortezomib (B) is a proteasome inhibitor that appears to work in MCL by causing cell cycle arrest and induction of apoptosis through oxidative and ER stress-mediated up-regulation of NOX. Phase II clinical trials of B in relapsed/refractory MCL have shown durable responses in up to 58% of patients. DA-EPOCH-R is an effective platform regimen in MCL and we set out to investigate the efficacy of DA-EPOCH-RB and maintenance B in newly diagnosed MCL. Methods: All patients received Part A and Part B. Part A was B alone (1.5 or 1.3mg/m2) for 1 cycle on d 1, 4, 8, 11 and Part B was DA-EPOCH-R for 6 cycles with B on d 1, 4. Due to excessive neurotoxicity in the first 5 patients on study (all required reduction or discontinuation of B), the dose of B with DA-EPOCH-R was reduced from 1.5 to 1.3 mg/m2. Patients with a CR or PR to Part B (and without significant neurotoxicity) were randomized to maintenance B (1.3mg/m2 d 1, 4, 8 and 11 q 8 wks for 18 mos) or observation (Part C). Results: Patient (n=38) characteristics: median (range) age 58 (41-73); male sex 29 (76%); stage IV disease 100%. Responses: Part A: PR in 4 (11%) and NR in 34 (89%); Part B: CR in 24 (63%), PR in 11 (29%) and NR in 3 (8%). PFS and OS at 36-month follow-up are 47% and 84% respectively. For 11 patients randomized to B maintenance, PFS at 36 months is 48% compared to 63% for patients (10) randomized to observation (2-tailed log-rank p-value=0.66). 50% of patients had ≥ grade 2 neurotoxicity and at the 1.3mg/m2 dose of B, 33% of patients required a dose reduction or discontinuation of B. Other significant toxicities were neutropenic fever/infection in 8% of cycles and grade 3 or 4 thrombocytopenia in 34% of cycles. Conclusions: B does not appear to add to the efficacy of DA-EPOCH-R in MCL. This may be related to scheduling – B may put cells into cycle arrest and reduce the efficacy of DA-EPOCH-R. In an early analysis, maintenance B following induction therapy does not appear to improve PFS compared to observation alone, suggesting that maintenance B may not be a useful strategy in MCL. However, accrual continues. Ongoing translational studies on biopsied tissue taken before and after B (during Part A) will attempt to elucidate the mechanism of action of B in MCL.
Predicting adherent perinephric fat with preoperative clinical and radiological factors in partial nephrectomy: Development and validation of a risk score.
Authors: Leonardo Daniel Borregales, Mehrad Adibi, Arun Z. Thomas, Rodolfo B. Reis, Lisly J Chery, Catherine E Devine, Xuemei Wang, Aaron M. Potretzke, Theodora Potretzke, Robert S. Figenshau, Tyler M. Bauman, Surena F. Matin, Jose A. Karam, Christopher G. Wood
Journal: Journal of Clinical Oncology (2016)

497 Background: The decision to perform a partial nephrectomy (PN) relies largely upon the complexity of the renal mass and its surrounding anatomy. An often encountered intraoperative challenge in PN is the adherent perinephric fat (APF). The anticipation of this feature may improve preoperative risk assessment and aid in decision-making for the surgical approach. We sought to develop and externally validate a score that predicts for APF based on preoperative clinical and radiological prognostic factors. Methods: We retrospectively analyzed 495 consecutive patients that underwent open or minimally invasive PN. APF was defined as the presence of “dense”, “adherent”, or “sticky” perinephric fat at time of dissection by the surgeon and this did not required subcapsular dissection for tumor isolation. A score model was developed using multivariate logistic regression analysis. This score was further validated using an external data set with 285 patients. Discrimination and calibration were assessed by calculating the area under the receiver operating characteristic curve (AUC) and the Hosmer–Lemeshow statistic, respectively. Results: Among the 495 patients, 95 (19%) patients presented with APF. On multivariate analyses, diabetes mellitus (p = 0.009), perinephric fat thickness (p &lt; 0.001) and perinephric stranding (p &lt; 0.001) were predictors of encountering APF in PN. A risk score ranging from 0 to 4, was developed based on these three variables to predict for APF. Among the 285 patients in the validation cohort, 41(14.3%) presented with APF. The score demonstrated good discrimination of 0.82 and 0.84 for the development and validation cohort, respectively. The model did not show a statistically significant lack of calibration (p-values = 0.98, 0.35). Moreover, predicted probabilities of APF based on a 0.5 threshold yielded a specificity of 92.3 and 92.2 in the development and validation cohorts, respectively. Conclusions: The score can accurately predict the presence of APF in patients with small renal mass planning to undergo PN. This score could aid current algorithms of preoperative risk assessment and impact surgical approach.
Abstract 2670: Intracoronary Bone Marrow Cell Transfer After Myocardial Infarction: 5-Year Follow-up of the BOOST Trial
Authors: Gerd P Meyer, Kai C Wollert, Joachim Lotz, Ulrike Rager, Jens Pirr, Arnold Ganser, Helmut Drexler
Journal: Circulation (2008)

The BOOST study (BOne marrOw transfer to enhance ST-elevation infarct regeneration) was the first randomized controlled clinical trial to investigate the effects of intracoronary bone marrow cell (BMC) transfer after ST-elevation myocardial infarction (STEMI). 60 patients with STEMI and successful percutaneous coronary intervention (PCI) with stent implantation were randomized 1:1 to a control (CON) or BMC group. Baseline mean left ventricular ejection fraction (LVEF) as assessed by cardiac magnetic resonance imaging (MRI) 4 days after PCI was 51.3% and 50.0% in the CON and BMC groups, respectively. As previously reported, BMC transfer led to a mean improvement of LVEF by 6.0 percentage points at 6 months (P=0.003) and 2.8 percentage points at 18 months (P=0.27) as compared to the CON group. Five years (61±11 months) after PCI, we have now assessed the clinical status and have repeated cardiac MRI in all surviving patients. 2 CON patients and 2 BMC patients had died after 5 years. The composite endpoint of death, recurrent MI, or hospitalization with heart failure occurred in 6 CON and 5 BMC patients. As compared to baseline, LVEF at 5 years had decreased by 3.3±9.5% in the CON group and by 2.5±11.9% in the BMC group (mean difference between BMC and CON, 0.8 percentage points; P=0.75). As compared to baseline, LV end-diastolic and end-systolic volume indices had increased and LV mass index had decreased at 5 years, with no significant differences between both groups. In patients with a higher baseline infarct transmurality (MRI late enhancement), BMC therapy prevented a deterioration of LVEF as compared to the CON group even at the 5-year time point (P&lt;0.04). In conclusion, a single intracoronary application of bone marrow cells does not appear to promote a sustained improvement of LVEF in patients with STEMI and relatively preserved systolic function. It remains possible that BMCs are effective long-term in patients with more impaired systolic function and/or with preconditioning of the cells.