tbuckley/cabot-search huggingface dataset:
A phase II trial of 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) chemotherapy plus bevacizumab (bev) for patients (pts) with unresectable stage IV colon cancer and a synchronous asymptomatic primary tumor: Results of NSABP C-10.
Authors: L. E. McCahill, G. A. Yothers, S. Sharif, N. J. Petrelli, S. Lopa, M. J. O'Connell, N. Wolmark
Journal: Journal of Clinical Oncology (2010)

3527 Background: Surgical resection of asymptomatic primary colon tumor for pts presenting with synchronous yet unresectable metastatic disease is controversial. Concerns remain about combining cytotoxic chemotherapy with bev in pts with an intact colon tumor because of risk of perforation. Methods: Eligible pts had ECOG Performance 0 or 1 and an asymptomatic colon tumor with unresectable distant metastases. Primary endpoint (PE) was major morbidity, defined as surgical resection for symptoms from the intact primary tumor or death resulting from intact primary evaluated in a Simon two-step design. Major morbidity rate of 25% was considered acceptable and the trial had 85% power to rule out a rate of 40%. Two secondary endpoints were overall survival and morbidity related to the intact primary requiring hospitalization, transfusion, or interventional procedure. Results: Between March 2006-June 2009, 90 pts were registered and 86 eligible pts with follow-up comprise this analysis. 52% were female and 47% were age 60+. Median follow-up was 20.7 mos. There were 12 (14%) major morbidity events, 10 (11.6%) required surgery: obstruction (8), perforation (1), and pain (1). Two (2.3%) resulted in pt death: perforation (1), obstruction (1). This is fewer than 26 specified for stage II of the Simon design, thus the trial has met its PE. Cumulative incidence of major morbidity at 24 mos was 16.3% (95% CI 7.6%-25.1%). Twelve other primary tumor resections were performed; attempted cure (8), other reasons (4). There were 4 secondary endpoint events: 3 obstructions (2 required stents, 1 resolved with conservative management) and 1 pt required percutaneous abscess drainage. Median survival was 19.9 mos (95% CI 15.0-27.2). Conclusions: The primary endpoint was met: utilizing mFOLFOX6 with bev did not result in an unacceptable rate of obstruction, perforation, bleeding, or death related to the intact primary tumor. Survival is not compromised by leaving the primary colon tumor intact. Majority of pts (72/86; 84%) can be spared an initial non-curative resection of the primary colon tumor. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration University of Pittsburgh
Heart Failure Resulting From Age-Related Cardiac Amyloid Disease Associated With Wild-Type Transthyretin
Authors: Lawreen H. Connors, Flora Sam, Martha Skinner, Francesco Salinaro, Fangui Sun, Frederick L. Ruberg, John L. Berk, David C. Seldin
Journal: Circulation (2015)

Background— Heart failure caused by wild-type transthyretin amyloidosis (ATTRwt) is an underappreciated cause of morbidity and mortality in the aging population. The aims of this study were to examine features of disease and to characterize outcomes in a large ATTRwt cohort. Methods and Results— Over 20 years, 121 patients with ATTRwt were enrolled in a prospective, observational study. Median age at enrollment was 75.6 years (range, 62.6–87.8 years); 97% of patients were white. The median survival, measured from biopsy diagnosis, was 46.69 months (95% confidence interval, 41.95–56.77); 78% of deaths were attributable to cardiac causes. By Kaplan–Meier analysis, 5-year survival was 35.7% (95% confidence interval, 25–46). Impaired functional capacity (mean V o 2 max, 13.5 mL·kg −1 ·min −1 ) and atrial fibrillation (67%) were common clinical features. Multivariate predictors of reduced survival were elevated serum brain natriuretic peptide (482±337 pg/mL) and uric acid (8.2±2.6 mg/dL), decreased left ventricular ejection fraction (50% median; range, 10%–70%), and increased relative wall thickness (0.75±0.19). Conclusions— In this series of patients with biopsy-proven ATTRwt, poor functional capacity and atrial arrhythmias were common clinical features. Elevated brain natriuretic peptide and uric acid, decreased left ventricular ejection fraction, and increased relative wall thickness were associated with limited survival of only 35.7% at 5 years for the group as a whole. These data establish the natural history of ATTRwt, provide statistical basis for the design of future interventional clinical trials, and highlight the need for more sensitive diagnostic tests and disease-specific treatments for this disease.
Robot-assisted Versus Open Radical Prostatectomy: A Contemporary Analysis of an All-payer Discharge Database
Authors: Jeffrey J. Leow, Steven L. Chang, Christian P. Meyer, Ye Wang, Julian Hanske, Jesse D. Sammon, Alexander P. Cole, Mark A. Preston, Prokar Dasgupta, Mani Menon, Benjamin I. Chung, Quoc-Dien Trinh
Journal: European Urology (2016)
Selection of an Immunoresistant Moloney Lymphoma Subline With Decreased Concentration of Tumor-Specific Surface Antigens&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Eva Maria Fenyö, Eva Klein, George Klein, Karol Swiech
Journal: JNCI Journal of the National Cancer Institute (1968)

The ascites form of the Moloney lymphoma YAC is highly sensitive to the cytotoxic action of Moloney-specific antiserum in vitro.and carries a high concentration of Moloney-specific surface antigens, as judged by quantitative absorption and membrane immunofluorescence tests. We attempted to establish an immunoresistant subline by prolonged immunoselection in vitro.and in vivo. Serial exposure to cytotoxic antiserum, in the presence of complement, before each inoculation during 20 passages did not lead to a stable immunoresistant subline, although occasionally cytotoxic sensitivity decreased temporarily. Subsequently, the same subline was subjected to in vivo selection, by inoculation into preimmunized syngeneic mice. A stable immunoresistant subline YAC-IR could be isolated from a preimmunized recipient inoculated with 103 cells. YAC-IR cells were completely resistant to Moloney-specific cytotoxicity but maintained full sensitivity to isoantisera directed against H-2 antigens. Their Moloney-specific surface antigen concentration showed an approximately tenfold decrease in quantitative absorption tests. In the membrane immunofluorescence tests, surface staining with diluted Moloney antisera decreased uniformly, but the proportion of reactive cells, comprising 80–90% of the cell population, remained unchanged. The difference in the antigenicity of YAC and YAC-IR did not appear to be due to a change in cellular localization, with diminished surface expression, since there was an analogous difference when cell homogenates were compared. The decreased antigen concentration and the immunoresistance of the YAC-IR subline were stable and showed no reversion after 13 passages in untreated syngeneic hosts. Two or three passages through hosts neonatally infected with, and immunologically tolerant to, the Moloney virus resulted in partial or full reversion to sensitivity, however. Preliminary absorption experiments indicated that the YAC-IR line has a slightly higher surface expression of H-2a isoantigens than the YAC line. The two lines did not differ in immunogenicity, as judged by their ability to induce the formation of anti-Moloney antibodies.
Human Leukemia Antigens: Partial Isolation and Characterization2
Authors: R. S. Metzgar, T. Mohanakumar, R. W. Green, D. S. Miller, D. P. Bolognesi
Journal: JNCI Journal of the National Cancer Institute (1974)

Human leukemia-associated antigens detected by nonhuman primate antisera were freed from leukemia cells by trypsin digestion, autolytic or spontaneous release, and KCI extraction; the released antigen was sedimented at 100,000×g in 4–6 hours. Electron microscope studies revealed many membrane vesicles in the ultracentrifuged pellets. Of the 3 release methods, trypsinization was most effective. Moreover, the leukemic cells after trypsin digestion were viable and yet refractory to lysis by nonhuman primate antisera to human leukemia cells. The antigenic sites were regenerated within 24 hours at either 37 or 4° C. The regeneration could be blocked by puromycin and cyclohexamide but not by actinomycin D or cytosine arabinoside. The amount of subcellular antigen released by 3.0M KCI never exceeded the amount released spontaneously by autolysis. Papain digestion solubili;zed HL-A antigens from leukemic cells but was ineffective in solubilizing leukemia-associated antigens. High yields of soluble leukemia-associated and HL-A antigens were obtained by pronase treatment. LeUkemia-associated antigens prepared by pronase digestion could not be sedimented at 60,000×g for 16 hours and were detected in the included volume of Sephadex G-200 gel filtration. The Sephadex G-200 fractions possessing the leukemia-associated antigens specific for lymphatic leukemia cells also contained HL-A12 activity. Neuraminidase treatment of leukemic cells resulted in a complete loss of leukemia-associated antigen activity from these cells. However, no antigen activity could be recovered in the supernatant after such enzyme digestion. Neuraminidase treatment of the subcellular membrane antigens isolated by tryptic digestion and the soluble antigens prepared by pronase digestion had no effect on the ability of these preparations to inhibit the leukemia antisera.
A phase III, intergroup, randomized, double-blind, chemoprevention trial of selenium (Se) supplementation in resected stage I non-small cell lung cancer (NSCLC).
Authors: D. D. Karp, S. J. Lee, G. L. Shaw Wright, D. H. Johnson, M. R. Johnston, G. E. Goodman, G. H. Clamon, G. S. Okawara, R. Marks, J. C. Ruckdeschel
Journal: Journal of Clinical Oncology (2010)

CRA7004 Background: Selenium was reported to have possible lung cancer chemopreventive benefits based on a large skin cancer trial secondary observation. (JAMA 1996; 276: 1957-1963). Since that time, research continued to suggest that Se could decrease risk of second primary tumor (SPT) in persons with resected NSCLC. In 2007, a publication from another group suggested an increased association of Se with type 2 diabetes (Annals Int Med 147:217-223). Methods: From Oct 2000-Nov 2009, 6 groups, led by ECOG, carried out a double blind, placebo controlled trial using selenized yeast 200 micrograms daily in a 2:1 randomization vs. placebo for 48 mo in completely resected stage I NSCLC. Participation was 6–36 mo post-op and required a negative mediastinal node biopsy, no excessive vitamin intake, normal liver function, a negative chest x-ray, and no other evidence of recurrence. Planned size of 1,960 participants had been designed to detect a 40% decrease in SPTs with 80% power. Methylation studies of sputum and blood (S. Belinsky) add important biologic correlates to this project. Results: Interim analysis occurred in Oct 2009 after 1,561/1,772 pts reached step 2 (completion of the 4 week (step 1) run-in period requiring at least 75% of the study drug to be taken). Endpoints included SPTs, recurrence, and toxicity. A total of 216 SPTs developed of which 84 (38.9%) were lung cancer. SPT (lung/overall) incidence was 1.36/3.66 per 100 person yrs for placebo vs. 1.91/4.11 for Se (p=.150). 5 yr progression free survival was 78% for placebo vs. 72% for Se. Study was stopped according to futility analysis. Grade 1 or 2 toxicity occurred in 38% of placebo and 39% Se. Grade 3 toxicity was 3% placebo vs. <1% Se. Compliance was excellent (>95% at 2 yrs). Conclusions: No increase in diabetes mellitus or skin cancer was detected. Se was safe but conferred no benefit over placebo. Methylation studies are continuing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer
Elucidating the mechanisms responsible for the previous failure of phase III clinical trials with eniluracil (EU) and development of a novel scheduling approach to optimize the efficacy of EU/5-fluorouracil (5-FU) combination therapy
Authors: V. Guarcello, J. Fourie, M. J. Lawton, W. W. Peters, M. J. Heslin, R. B. Diasio
Journal: Journal of Clinical Oncology (2007)

2557 Background: Irreversible inhibition of dihydropyrimidine dehydrogenase (DPD) by EU blocks 5-FU catabolism allowing for oral 5-FU administration with complete bioavailability. Unfortunately, phase III trials with co-administered EU/5-FU showed inferiority vs. 5-FU/leucovorin, and were discontinued. We recently reported that competitive inhibition of human uridine phosphorylase (UP) and thymidine phosphorylase (TP) 5-FU-anabolic enzymes by EU is an important mechanism potentially responsible for clinical failure of the combined EU/5- FU regimen. We hypothesize that EU inhibition of UP and TP is transient, while that of DPD is prolonged, allowing for novel schedule dependent optimization of EU/5-FU dosing regimens with improved efficacy. Methods: In this phase I study, five patients received a single oral dose (2 mg, 5 mg or 10 mg) of EU 12–14 hours prior to scheduled resection of primary/metastatic colorectal cancer. Dosage was as follows: Two patients received the 2 mg dose, one patient received the 5 mg dose and two patients received the 10 mg dose. Matched normal and tumor tissue biopsies were immediately snap frozen and subsequently UP, TP and DPD activity was measured in vitro via HPLC detection of [6- 14 C]-5-FU catabolites/anabolites. Peripheral blood mononuclear cell (PBMC) DPD activity was determined at baseline prior to EU administration, 30 min prior to surgery (Day 1), and on Days 2, 5 and 14 following EU administration. Results: At 12–14 hours following EU administration, there was an absence of inhibition of UP and TP, while DPD was significantly inhibited in matched tumor and normal tissue. Importantly, PBMC DPD activity was significantly inhibited by EU on Day 1 (12–14 hours after EU administration) and Day 2 (36 hours after EU administration) at 0 ± 0% and 17 ± 11% (mean ± SD) of baseline, respectively. Conclusions: These data demonstrate a differential recovery time of EU mediated inhibition of UP and TP compared to DPD, which permits future schedule dependent optimization of EU/5-FU therapy. No significant financial relationships to disclose.
Cloretazine is an effective induction therapy in elderly patients (pts) with poor-risk de novo AML
Authors: J. E. Karp, D. Rizzieri, N. Vey, G. Mufti, R. Geller, S. O’Brien, F. Giles
Journal: Journal of Clinical Oncology (2006)

6512 Background: The incidence of AML increases with age with a median of 68 years in the US. The treatment of elderly pts (≥60 years) with AML poses challenges related to pt characteristics (age, performance status (PS), comorbidities) and adverse biological features. The majority of elderly pts are not considered for standard induction therapies that incorporate araC + anthracycline, and complete remission rates (CR+CRp), leukemia-free (LFS) and overall survival (OS) are significantly lower than in younger pts. As a result, NCCN guidelines recommend investigational therapy for this population. Cloretazine (C) is a novel DNA alkylating agent that selectively targets the O-6 position in guanine and has been developed in AML, based on phase I data demonstrating activity in refractory hematologic malignancies with acceptable toxicity. Methods: A multi-center trial in elderly pts with untreated poor-risk AML and high risk MDS was performed. Pts received C (600 mg/m 2 ) as a single 30–60 minute infusion. Retreatment for induction was permitted for pts who showed improvement. A consolidation course of C at 400 mg/m 2 was an option for pts who achieved a CR. Results: 105 pts were treated, of whom 45 pts (median age 72, range 60–84) had de novo AML, 44 had secondary AML, and 16 had high-risk MDS. Considering only de novo AML pts, pt characteristics are the following: M/F=25/20; favorable/intermediate/poor/NA cytogenetics =0/28(62%)/15(33%)/2; and PS 0/1/2=8(18%)/21(47%)/16(36%). The CR rate was 49% (N=22). CR was 50% for pts with intermediate cytogenetics and 53% for pts with poor risk cytogenetics. CR remained consistent despite increasing PS (PS0=50%, PS1=48%, PS2=50%). For responders, the median time for ANC≥1000 cells/dl was 31 days (range 27–44) and for plt≥20,000/dl was 22 days (range 14–29). There was no significant non-hematologic toxicity; the early death rate was 20%. Of the 22 pts who achieved CR, 8 remain alive and disease-free at a median of 337 days (range 137–546). At one year, the LFS is 27% and the OS is 22%. Conclusion: C is very well tolerated and has demonstrated impressive response results as a single agent in an elderly pt population with poor risk AML. [Table: see text]
Clonal Origin of Tumors Induced by Ultraviolet Radiation&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: D K Burnham, L C Gahring, R A Daynes
Journal: JNCI Journal of the National Cancer Institute (1986)

Skin tumors were induced in (C3H/HeN X C3H/HeN-PGK-1a)F1 female mice, heterozygous at the X-linked phosphoglycerate kinase-1 (PGK-1) locus, by exposure to the carcinogenic influence of ultraviolet radiation (UVR), 3-methylcholanthrene [(MCA) CAS: 56-49-5], or benz[a]pyrene [(BP) CAS: 50-32-8]. An assessment of the clonal origin of these tumors was accomplished through an analysis of the PGK-1 enzyme phenotype expressed by the transformed cells. In vitro culture was employed as a means of depleting nontransformed cells of host origin from the induced tumors. Cultured lines derived from tumors induced by each of the above agents were found to express only one of the two enzyme forms encoded by the host genotype, consistent with the probability that all the UVR-, MCA-, and BP-induced tumors examined in this study were monoclonal in origin. For further substantiation of the monoclonality of UVR-induced tumors, 2 UVR-induced tumors were enzymatically dissociated immediately following excision from the primary hosts, and the resulting cell suspensions were cloned in soft agar. Upon analysis, each set of clones selected in soft agar expressed only a single PGK-1 enzyme form. To rule out the possibility that the apparent monoclonality of culture-adapted tumor lines was due to in vitro selection, tumors that arose in UVR-treated PGK-1a/b female heterozygote mice were transplanted into PGK-1a and PGK-1b homozygous recipients. These transplanted tumors expressed a single PGK-1 allozyme following growth in recipients that were genetically homozygous for the major PGK-1 enzyme form expressed by the tumor prior to transplantation. These data strongly support the concept that most, if not all, UVR-induced tumors are derived from the progeny of a single transformed cell. This observation is important to the understanding of the nature of tumor-specific transplantation antigens expressed by individual UVR-induced tumors and indicates that such antigens also are clone specific. In addition, the results of this study indicate that polyclonality does not play a significant role in the generation of cellular and phenotypic heterogeneity known to be present within individual UVR-induced tumors.
Bortezomib therapy for prostate specific antigen (PSA)-only relapse after definitive local therapy
Authors: J. S. Turner, C. S. Chen, W. Butler, J. Bearden, E. Garrett-Mayer, G. Onicescu, A. S. Kraft
Journal: Journal of Clinical Oncology (2009)

e16053 Background: We conducted a single arm, phase II trial of single-agent bortezomib, a proteasome inhibitor, in patients with prostate cancer with biochemical recurrence (PSA relapse) after definitive local therapy. Eligible patients had previous radical prostatectomy and/or radiation therapy (including brachytherapy), and a rising PSA over 1 ng/mL without bone scan evidence of metastasis. The primary goal of this study was to determine the PSA response to single agent bortezomib. Secondary goal was to identify the time to PSA relapse after bortezomib therapy defined as time from nadir to PSA &gt;1ng/ml. Methods: Treatment was composed of bortezomib 1.3mg/m2 IV on days 1,4,8,11 then 10 days off for the first two cycles. The third cycle was comprised of weekly bortezomib therapy for three out of four weeks. Sixteen patients were enrolled and treated at 4 sites with13 evaluable patients. Results: Median baseline PSA was 12.0 ng/ml. 3 of 13 patients (23%) achieved complete responses and 1 a partial response (PR) for a response rate of 30% (95% CI: 0.09 –0.61). Median time to PSA relapse in these 3 patients was 6.0 months. Linear longitudinal modeling was used to compare the rate of increase in PSA prior to treatment versus during treatment with bortezomib and found that treatment significantly decreased the slope of log PSA during treatment, slowing PSA rise (p = 0.003). The major toxicity associated with bortezomib therapy was peripheral neuropathy (7 pts, grade 3 in 3 pts) requiring dose reductions in 3 cases and discontinuation of therapy in 4 patients. Other toxicities included non-neutropenic infections (shingles in 2 pts), 1 small bowel ileus (grade 3), and 1 case of thrombocytopenia (grade 3). Conclusions: In a small number of patients there was a 30% PSA response rate to single agent bortezomib therapy. Further investigations using bortezomib as a single-agent or in combination are warranted in this patient population. No significant financial relationships to disclose.
Clinical benefit of second line weekly paclitaxel in advanced urothelial carcinoma (AUC): A GETUG phase II study
Authors: F. Joly, N. Tchen, C. Chevreau, M. Henry-Amar, F. Priou, P. Chinet-Charrot, F. Rolland, J.-P. Droz, V. Journet, S. Culine
Journal: Journal of Clinical Oncology (2004)

4619 Background: There is no standard indication of second line chemotherapy for patients who relapse after prior therapy for AUC. A multicenter phase II trial was designed to assess the benefit [efficacy, toxicity and quality of life (QoL)] of weekly paclitaxel in relapsing AUC patients. Methods: From July 2002 to August 2003, 45 patients were enrolled in the study. Paclitaxel (80 mg/m2 over 1 hour) was administered day 1, 8 and 15 of a 28-day course. 89% of patients had received gemcitabine and platinum as first line chemotherapy (median time since last administration: 5 months). Response was evaluated using RECIST criteria and QoL assessment was made using the FACT-B1 and FACT-Taxane questionnaires. An absolute 5-point change in any scale was considered clinically significant. Results: By December 15 2003, 37 patients (31 males, 6 females) were evaluable for response. Initial characteristics: mean age 63 years; WHO PS 0–1 78%; metastatic disease 94% (2 or more sites: 68%, liver metastases: 40%). The median number of cycles was 2 (1 to 6). Chemotherapy was well tolerated: 2 patients developed grade 3/4 neutropenia, 4 patients grade 3/4 anemia, 10 patients grade 1/2 and 1 patient grade 3 neuropathy. An objective partial response was observed in 2 (5%) patients only (with pulmonary or liver metastases: 1 patient each) and a stable disease in 7 (19%) patients. Median time to progression or death was 3 months and 6.5 months, respectively. Prior to starting chemotherapy, QoL assessment was available in 33 patients. After 2 chemotherapy cycles (16 patients with data available), QoL improved in 6 patients, was unchanged in 8 and worsened in 2 patients. Conclusions: Second line chemotherapy with weekly paclitaxel is associated with poor objective response rate in relapsing patients with advanced urothelial carcinoma. QoL assessment, however, indicates that patients may experience a clinical benefit from this chemotherapy. No significant financial relationships to disclose.