tbuckley/cabot-search huggingface dataset:
A phase I study of bi-weekly administration of 24-hr gemcitabine (GEM) followed by 24-hr irinotecan (CPT-11) in patients with solid tumors
Authors: M. W. Saif, S. Sellers, M. Li, W. Wang, L. Cusimano, H. Wang, R. Zhang
Journal: Journal of Clinical Oncology (2005)

2102 Background: Combination of GEM and CPT-11 is attractive as both agents have widespread antitumor activity, synergy, no overlapping mechanisms of action and non-hematologic toxicities. Antitumor activity of GEM is not dose-response related but schedule-dependent. Prolonged infusion of CPT-11 is pharmacologically more efficient and better-tolerated than 30–90 min infusions, especially lesser acute and delayed diarrhea. This prompted a phase I trial to determine MTD (maximum tolerated dose), DLT (dose-limiting toxicity) of combination of GEM/24-hr and CPT-11/24-hr every 2 wks,and pharmacokinetics of two agents on this novel schedule. Methods: Eligible pts had advanced, evaluable cancer, any # prior therapy and PS ≤ 2. Pts received GEM on days 1,15 and CPT-11 on days 2,16 on a 4-wk cycle. Incremental doses of both drugs were explored until MTD was reached.Once MTD would be reached, 6 additional pts would be enrolled to that dose. Pharmacokinetic parameters of CPT-11 and GEM were estimated by using noncompartmental Methods: Results: To date, 15 pts [12M/3F; median age 57; PS \(\frac{1}{2}\): 10/5] have been treated with > 35 cycles. CPT-11 was administered at 3 doses (70–140 mg/m2) with fixed dose of GEM (75mg/m2). Then GEM was escalated in 3 cohorts up to 150 mg/m2. DLT was observed in 1 of 6 pts at CPT-11/GEM 110/100 mg/m2 [grade 4 neutropenia]. No DLT has been seen so far at CPT-11/GEM 110/125 mg/m2. No pt developed acute cholinergic symptoms at any dose. Other toxicities were ≤ grade 2 N,V, and fatigue. One pt had CR (cholangio), 2 PR (SCLC; NE), and 3 SD (2 CRC; 1 CUP). Both CRC pts had prior CPT-11. Preliminary PK analysis showed Tmax 23.75 hr, Cmax 216.55 ng/mL, t1/2 11.11 hr, and AUClast of 4844.48 ng.hr/mL for CPT-11; ratio of AUC of CPT-11 to SN-38 = 158.9; Tmax20.03 hr, Cmax2.25 ug/mL, AUC 73.68 ug.hr/mL and t1/2 33.89 hr for dFdU. High dose of dFdC seems to increase t1/2 of CPT-11. Accrual continues as planned. Conclusions: MTD and DLT will be presented. No pt experienced acute cholinergic symptoms likely due to lower Cmax levels vs. 125 mg/m2/90-min. This schedule and combination appears safe both in pretreated and chemonaive pts, demonstrated activity in a variety of solid tumors, and merits further evaluation. No significant financial relationships to disclose.
Association of CR/VGPR with progression-free survival in rituximab-naïve WM patients undergoing rituximab-based therapy, as predicted by polymorphisms in FcγRIIIA-158.
Authors: Z. R. Hunter, G. Yang, L. I. Ioakimidis, C. A. Hanzis, R. J. Manning, C. J. Patterson, P. S. Sheehy, P. Gong, L. Xu, S. P. Treon
Journal: Journal of Clinical Oncology (2010)

8108 Background: The incorporation of rituximab into various regimens has improved depth of response in Waldenstrom's macroglobulinemia (WM), though the impact of achieving better responses remains to be determined, as also are determinants including Fcγ receptor polymorphisms. Methods: We examined the impact of categorical responses on progression free survival (PFS) in 159 rituximab-naïve WM patients who received rituximab-based therapy. Baseline characteristics: median age 62 years; serum IgM 3,670 mg/dL; hematocrit 31.7%; serum B2M ≥3.0 g/L (52%); previously untreated 67.3%. All patients received a rituximab containing regimen with either cyclophosphamide, fludarabine, bortezomib, or an immunomodulatory agent. The median follow-up was 33.5 months, and categorical responses were as follows: CR (8.8%); VGPR (13.2%); PR (50%); MR (18.9%); Non-Responders (8.8%). Sequencing for polymorphic variants at FcγRIIA, FcγRIIB, and FcγRIIIA was performed for 75 patients for whom genomic DNA was available, and impact on categorical responses determined. Results: Achievement of better categorical responses was incrementally associated with improved PFS (p<0.0001). No separation was observed between VGPR and CR, and minor responses showed improved PFS over non-responders. Median TTP for CR/VGPR patients was 71.8 versus 38.6 months for MR/PR patients (p=0.03). Neither age, baseline serum IgM level, hematocrit, platelet count, serum B2M level, WM ISS score, and treatment group predicted for CR/VGPR. In contrast, polymorphisms at FcγRIIIA-158, FcγRIIIA-48, and FcγRIIA-131 were associated with improved categorical responses, particularly attainment of CR/VGPR (p≤0.03). A clear linkage between these polymorphisms was also detected, with the presence of at least one valine at FcγRIIIA-158 serving as the primary determinant of CR/VGPR responses. Conclusions: The attainment of CR/VGPR is associated with significantly longer PFS in rituximab-naïve WM patients undergoing rituximab-based therapy, and is predicted by the presence of at least one valine (V/V or V/F) at FcγRIIIA-158. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Biogen Idec, Celgene, Genentech, Millennium Biogen Idec, Celgene, Millennium Celgene, Millennium
Identifying avoidable terminal oncology ICU hospitalizations.
Authors: Robert Michael Daly, Andrew Hantel, Blase N. Polite
Journal: Journal of Clinical Oncology (2016)

56 Background: Eight percent of cancer patients expire in the ICU. There is no association between spending on aggressive end of life (EOL) care and survival outcomes. This aggressive care is also associated with reduced quality of life for patients and families. The National Quality Forum endorses the number of patients admitted to the ICU in the last 30 days of life as a quality of care measure. Our hypothesis is that a significant number of oncology patients suffer avoidable terminal ICU hospitalizations. Methods: Using data from the University of Chicago (UCM) Cancer Registry, we identified patients who died in UCM adult ICU’s in FY2013. Of the 1,388 oncology deaths, 115 were in the ICU. Of those, 72 were established patients having had at least one visit with a UCM oncologist. A physician from oncology, critical care, and hospital medicine directly reviewed the electronic medical record of each patient from 3 months prior to index hospitalization until death. Using a standardized assessment tool, these physicians then determined whether the terminal hospitalization was clinically avoidable through different medical management. The primary outcome was the proportion of terminal oncology ICU hospitalizations identified as potentially avoidable by two or more reviewers. Results: Seventy-one percent of this patient population had a solid malignancy and 53% of those had metastatic disease. The ECOG performance status was ≥ 2 prior to admission in 51% of patients. Eighty-two percent had at least one prior hospitalization. During the index hospitalization, 81% were intubated, 39% had resuscitation, and 22% had hemodialysis. Two or more physician reviewers identified 34 (47%) of terminal oncology ICU hospitalizations as clinically avoidable. All three specialty physicians agreed about the avoidability 43% of the time. Conclusions: A review of terminal oncology ICU hospitalizations demonstrates that most of these patients had an advanced malignancy and poor clinical status and underwent aggressive EOL interventions. A significant number of these hospitalizations were identified as clinically avoidable by two or more physician reviewers. By identifying avoidable terminal oncology ICU hospitalizations, we can design interventions to prevent them.
Fludarabine and Oral Busulfan: A Low Toxicity Conditioning Regimen When Plasma Level Targeting and Intravenous Busulfan Is Not Available. A Brazilian Experience.
Authors: Belinda P. Simoes, M. Souza, Marcos Mauad, Eduardo J.A. Paton, Fabiano Pieroni, Ana B.P.L. Stracieri, Maria C. Oliveira, Daniela Moraes, Marina Coutinho, Julio C. Voltarelli, Vergilio R. Colturato
Journal: Blood (2005)
Quality of care among breast cancer (BC) survivors in the University of California (UC) Athena Breast Health Network.
Authors: Patricia A. Ganz, Erin E. Hahn, Laura Petersen, Michelle E. Melisko, John P. Pierce, Marlene Marie Von Friederichs-Fitzwater, Karen Lane, Robert A. Hiatt
Journal: Journal of Clinical Oncology (2012)

164 Background: Post-treatment cancer care needs improvement (IOM 2006), including use of treatment summaries (TS) and survivorship care plans (SCP). ASCO BC surveillance guidelines (2006) suggest only 1 provider needs to see patients 3 to 4 times a year in first 2 years, and every 6 to 12 months thereafter. Athena is a collaborative project designed to drive innovation in BC care among the five UC cancer centers. Interviews with Athena MDs and RNs noted visit redundancy and poor guideline adherence (Hahn ASCO Breast 2011). Methods: BC patients diagnosed in 2008-09 were recruited from UC hospital tumor registries. With UC-wide IRB approval, patients were invited to participate in a mailed survey on post-treatment care starting September 2011. A 30-page survey collected information on post treatment care including number and type of provider visits, discussion of key topics, satisfaction with care, and quality of life. We targeted 100 completed questionnaires from each site. Results: Data from the first 194 respondents are reported. Most were white, college graduates, with mean age 61 yrs, and mean time from diagnosis 3.2 ± 0.6 years. Treatments: surgery (S) only=33; S and radiation (XRT)=66; S and chemotherapy (C)=25; S, C, XRT=70. Mean number of BC follow-up care providers (2.3±1) was not related to treatment received (p=0.3). S-only treatment resulted in fewer BC specific clinic visits than C-treatment (33% vs. 45% to 58%). Of 80% who attended UC clinics, most received follow-up care every 3 to 4 months. The providers seen were: oncologists (66%), surgeon (38%), radiation oncologist (47%), primary care (40%). There were no differences in visit frequency by &lt;3 or &gt;=3 years since diagnosis. 68% had copies of medical records; 40% had received a TS; 57% had a SCP (61% at UC vs. 41% not at UC, p=0.03). The presentation will update data with a larger sample and multivariable models. Conclusions: Patient reports confirm that multiple providers are delivering BC specific follow-up care. Visit frequency may exceed guideline recommendations, and does not reflect risk of recurrence or treatment intensity. Less than half of patients received TS, but more than half had SCP. There is room to improve the coordination of post-treatment BC care.
Outcomes by schedule and line of therapy in patients (pts) with metastatic breast cancer (MBC) treated with <i>nab</i>-paclitaxel (<i>nab</i>-P): A U.S. retrospective, community-based, real-world cohort analysis.
Authors: Debra A. Patt, Sotirios G. Stergiopoulos, Rick Hippert, Robyn K. Harrell, Janet L. Espirito, Peg Squier, Amy Ko
Journal: Journal of Clinical Oncology (2016)

86 Background: In a phase III study in MBC, nab-P showed activity across lines of therapy. nab-P is approved for MBC at 260 mg/m2 every 3 weeks (q3w). This analysis evaluated outcomes with use of nab-P in MBC by schedule and line of therapy in a U.S. community setting. Methods: A multicenter, retrospective cohort analysis was conducted using iKnowMed electronic health record data and electronic medical chart review of women with ≥ 5 visits to a site in the US Oncology Network. Vital status was supplemented by the Social Security Death Index. Pts with MBC treated with nab-P between April 1, 2011, and February 1, 2013, were followed through August 1, 2013. Pts diagnosed with another primary cancer or with prior nab-P use were excluded. Data were analyzed by line (first [1L] vs ≥ second [≥2L]) or schedule (weekly [qw] vs q3w) based on the first therapy (index therapy) received in the study period. The usage pattern of index therapy was described by pt demographics and baseline characteristics. Effectiveness of index therapy was assessed by adjusted duration of treatment (DOT; time from first to last date of treatment + 6 days for qw and 20 days for q3w [to reflect true treatment duration]), time to new treatment (TTNT; time from start of index therapy), and overall survival (OS; time from start of index therapy). Analyses of other efficacy/safety endpoints, healthcare utilization, and corresponding costs will be performed. Results: 766 pts were included; 333 and 433 initiated index therapy as 1L and ≥ 2L, and 650 and 116 received index therapy qw and q3w. 76% received nab-P monotherapy. Most pts were < 65 years (64%), HER2− (76%), ER+ (76%), ER+/HER2− (60%), and postmenopausal (79%). 16% had triple-negative MBC. No notable differences in pt characteristics between the 1L/≥ 2L or qw/q3w groups were seen. Sensory neuropathy rates were 35% vs 39% for the 1L and ≥ 2L and 36% vs 45% for qw vs q3w. Conclusions: This analysis of a community-based cohort indicated that nab-P was primarily used as monotherapy on a qw schedule and in the ≥ 2L setting. nab-P 1L nab-P ≥ 2L nab-P qw nab-P q3w DOT, median mos 4.3 3.6 4.1 3.2 OS, median mos >27 19.5 23.2 >27 TTNT, median mos 6.4 5.9 6.2 5.3
Calpain Drives Megakaryopoiesis by Targeting the 7SK snRNP Complex: A Connection to Down Syndrome Megakaryocytic Neoplasia
Authors: Kamaleldin Elagib, Jeremy D. Rubinstein, Lorrie L. Delehanty, Peter A. Greer, Shuran Li, Jae K. Lee, Ivailo S. Mihaylov, Zhe Li, Stuart H. Orkin, Adam Goldfarb
Journal: Blood (2011)
ERCC1 expression and activity of PELF regimen as first-line treatment of metastatic gastric cancer patients.
Authors: G. Natoli, T. Ranalli, F. Nelli, D. Arduini, L. Moscetti, D. Giuliana, M. Chilelli, D. Padalino, V. Gomes, E. Ruggeri
Journal: Journal of Clinical Oncology (2010)

e14603 Background: The role of the excision repair cross-complementing 1 (ERCC1) is well documented in a large number of tumor types with cisplatin-based chemotherapy. The aim of this study was to determine whether ERCC1 expression predict clinical outcome in patients affected by metastatic gastric cancer (MGC) treated with cisplatin (P), epirubicin (E), leucovorin (L), 5-fluorouracil (F) chemotherapy (PELF). Methods: The study population included 33 MGC patients (median age 62 years, 24 male) treated from 2001 to 2008 in our center. Patients were treated with cisplatin (40 mg/m2, day 1), epirubicin (30 mg/m2, day 1), 5-fluorouracil (400 mg/m2 bolus, followed by 600 mg/m2, 22 h continuous infusion, day 1 and 2) and leucovorin (100 mg/m2, 2-h infusion, day 1 and 2). Treatment was repeated every 14 days. The expression of ERCC1 of primary tumors was examined by immunohistochemistry and then analysed by semiquantitative H-score method. Results: The positive rate of ERCC1 was 42%. Median overall survival (OS) was significantly longer in patients with low ERCC1 expression than those with high ERCC1 expression (13 months vs. 9 months, log- rank p = 0.018), likewise 1-year survival rate (62% vs. 21%, Fisher's exact p = 0.033). Of note a stepwise logistic regression analysis comparing 1-year survivors and non-survivors showed that ERCC1 expression unfavourably impacted on OS (odds ratio 0.62; 95% CI = 0.010- 0.78; p = 0.03). Conclusions: Immunohistochemical studies for ERCC1 might be useful to predict the clinical outcome in MGC patients treated with PELF regimen. No significant financial relationships to disclose.
Phase II trial of <sup>177</sup>lutetium radiolabeled anti-PSMA antibody J591 (<sup>177</sup>Lu-J591) for metastatic castrate-resistant prostate cancer (metCRPC): Survival update and expansion cohort with biomarkers.
Authors: Scott T. Tagawa, Naveed Hassan Akhtar, Joseph Osborne, Paul J. Christos, Shankar Vallabhajosula, Stanley J. Goldsmith, Renee Kahn, Caryn Ecker, Himisha Beltran, Michael J. Morris, Matthew I. Milowsky, Neil Harrison Bander, David M. Nanus
Journal: Journal of Clinical Oncology (2013)

121 Background: A phase II trial in men with progressive metCRPC receiving a single dose of 177 Lu-J591 at 65 mCi/m 2 (15 pts) or 70 mCi/m 2 (phase I MTD, 17 pts) was performed without selection for PSMA expression, suggesting a larger than expected dose-response (13 vs 47% &gt;30% PSA decline respectively), leading to an expansion cohort to validate the response rate at 70 mCi/m 2 . Methods: Endpoints: to validate the PSA and/or measurable disease response at 70 mCi/m 2 , evaluate circulating tumor cell counts (CellSearch) and pre-treatment PSMA imaging with 111 In-J591 in the expansion cohort, and examine overall survival (OS) for all pts. Results: 15 additional pts were treated. Expansion cohort demographics were similar to the initial cohorts, and PSA responses and toxicity were similar to the initial cohort treated at 70 mCi/m 2 (see Table), with myelotoxicity improving in all following nadir at 1 month. More PSA declines and longer OS were seen at 70 mCi/m 2 . 12 of 15 pts had baseline and follow up CTC counts at 4-6 weeks: 66.7% had &gt;50% decline and 25% were unchanged at 0 or 1 (one declined 27%). Although 93.3% had accurate targeting (imaging) of known sites of disease, as seen in initial analysis, a trend for fewer &gt; 30% PSA declines was seen with less intense PSMA imaging. Conclusions: Single dose 177 Lu-J591 at70 mCi/m 2 was generally well tolerated, with predictable, reversible myelosuppression, and demonstrates anti-tumor activity in pts with progressive metCRPC. A dose-response relationship was confirmed for both toxicity and activity, with improved response and OS at 70 mCi/m 2 . CTC declines are demonstrated. Selection of pts based upon non-invasive testing (PSMA imaging) may improve the therapeutic profile. Clinical trial information: NCT00195039. [Table: see text]
Impact of number of lines of therapy following docetaxel (D) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Guru Sonpavde, Menaka Bhor, Daniel Hennessy, Debajyoti Bhowmik, Liji Shen, Ian D. Schnadig
Journal: Journal of Clinical Oncology (2014)

223 Background: The impact of number of lines of therapy on outcomes following docetaxel (D) in metastatic castration-resistant prostate cancer (mCRPC) is unclear. We examined outcomes with cabazitaxel (C) and/or abiraterone acetate (A), following D during a period when all three therapies were available. We previously reported that most patients received only two of these three therapies. Among patients who received all three, DCA was administered more commonly and exhibited better overall survival (OS) than DAC after controlling for prognostic factors. Here, we report the impact of number of lines of therapy following D. Methods: A retrospective analysis of the U.S. Oncology network electronic health records (EHR) was conducted of post-D patients with mCRPC who received C and/or A from April 2011 to May 2012. Median OS was analyzed by Kaplan-Meier method. Cox proportional hazard models were used to evaluate impact on OS of number of therapies administered, age, Prostate Cancer Working Group (PCWG2) subtype, Charlson comorbidity index, prostate-specific antigen (PSA), alkaline phosphatase, hemoglobin, narcotic use, and treatment duration. Results: Multivariate analysis showed significantly lower mortality in the three-drug group compared to the two-drug group (HR 0.209 95% CI: 0.092-0.476, p&lt;0.05). 113 patients received three drugs (DCA=77, DAC=36) and 237 received two drugs (DA=183, DC=54). The three-drug cohort was significantly younger than the two-drug group (median age 69 vs. 73). Other significant covariates (p&lt;0.05) for mortality were narcotic use (HR 2.010 [1.240-3.259]), PSA (HR 1.014 [1.001-1.027] and alkaline phosphatase (HR 1.001 [1.000-1.001]. Conclusions: In men with mCRPC receiving C and/or A post-D, patients receiving all three therapies were younger and exhibited significantly better OS after controlling for clinical factors. In those receiving only two therapies, there appeared to be no difference in outcomes for second-line C versus A. Given the favorable impact of receiving all three therapies, more frequent administration of DCA in the three-drug group and better OS for DCA compared to DAC, we hypothesize that DCA may be a more optimal sequence. These results are exploratory and prospective validation is necessary.
Prognostic and predictive values of APC and WNT pathway mutations in MSS colorectal cancers.
Authors: Nishi Kothari, Binglin Yue, Jamie K. Teer, Michael J. Schell, Richard D. Kim
Journal: Journal of Clinical Oncology (2015)

652 Background: WNT signaling is abnormal in many inherited and acquired colorectal cancers, through mutations in APC and other components of the pathway including beta catenins and AXINs. Aspirin and other COX-2 inhibitors have been hypothesized to decrease WNT pathway activity in preclinical models, potentially leading to improved survival. We evaluated APC and WNT pathway mutations as potential prognostic and predictive biomarkers for ASA use in a cohort of colorectal cancer patients. Methods: We analyzed tumor samples collected from 468 CRC patients diagnosed between 1998 and 2010 as part of a multi-institutional observational study. We performed targeted exome sequencing using the Illumina NGS platform with 50-100X coverage of mutations. The BWA/GATK pipeline was used to identify variants and indels. Matched normal samples were not available for comparison to identify somatic mutations, so filtering of normal variants was performed using 1000 Genomes. One or 2 mutations in the APC gene were counted as mutant. Additional WNT pathway mutations included AXIN1, AXIN2, CTNNB1, WNT1, and WNT2. Variants identified in 1000 Genomes with an MAF &lt;0.01 were filtered. ASA use data was collected through retrospective chart review. Results: MSI-H tumors were excluded. 356 patients were eligible for analysis. 258 patients had APC mutations and 20 patients had other WNT pathway mutations including CTNNs, WNTs, AXINs, and TCF7L2. 140 patients had metastatic disease. Aspirin users had a median age of 70 compared to non-users at 63. Patients with APC mutations had improved overall survival compared to wild type patients for early stage disease (p = 0.03) with a trend towards improvement in survival for metastatic patients. Additional WNT pathway mutations did not strengthen this relationship. ASA use was not associated with improved OS in the APC or WNT pathway mutant patients. Conclusions: In this population, APC mutations had positive prognostic value, which was more pronounced in early stage disease. There was limited predictive value for ASA use in APC mutant patients. However, aspirin users tended to be older which might have confounded the association.