tbuckley/cabot-search huggingface dataset:
A pharmacokinetic-based test to predict the risk of life-threatening 5-fluorouracil toxicities in cancer patients
Authors: G. Bocci, C. Barbara, F. Vannozzi, A. Di Paolo, A. Melosi, M. Battistoni, G. Barsanti, G. Allegrini, A. Falcone, M. Del Tacca
Journal: Journal of Clinical Oncology (2004)

2052 Background: The extensive use of 5-fluorouracil (5-FU) has attracted a great attention on dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for detoxification of 5-FU to 5-fluoro-5,6-dihydrouracil (5-FDHU). The incidence of DPD deficiency is estimated to be around 3% and thus the related 5-FU life-threatening toxicity has significant clinical implications. Methods: In order to (1) investigate the clinical pharmacokinetics (PK) of 5-FU/5-FDHU in cancer patients administered with a 5-FU single low dose, (2) predict the systemic impairment of 5-FU catabolism and (3) prevent severe drug-related toxicity, 112 patients received 5-FU 250 mg/m2 as i.v. bolus before starting the planned 5-FU treatment (i.v. bolus of 370 mg/m2/day 5-FU for 5 days, or continuos infusion of 3800 mg/m2 5-FU for 48 h). HPLC analysis was performed on plasma (from 0 to 1.5 h after 5-FU) and peripheral blood mononuclear cell samples to calculate 5-FU/5-FDHU PK parameters and DPD activity, respectively. Adverse events were graded according to WHO scale. Results: The single 5-FU dose did not cause side effects in all tested patients. The 5-FU/5-FDHU PK parameters (mean±SD) are shown in Table 1. A significant correlation between 5-FU AUC and 5-FDHU AUC was found, whereas no correlations between DPD activity and 5-FU/5-FDHU PK were identified. Three patients had marked alterations of 5-FU/5-FDHU PK (e.g. 5-FU t1/2β>5 h; CLTB<1 L/h/m2; 5-FDHU Tmax≥45 min) and were excluded from 5-FU treatments. After the first cycle of 5-FU-based therapy, only 4 of the 100 evaluated patients experienced a grade 3 toxicity. Conclusions: PK analysis of plasma 5-FU/5-FDHU after a test dose provides reliable information on the risk of developing toxicities due to impaired 5-FU catabolism and encourages its application to patients candidates to receive 5-FU chemotherapy (e.g. adjuvant treatment of colorectal cancer). No significant financial relationships to disclose.
Correlation of the Oncotype DX recurrence score with a composite index comprised of ER, PR, HER2, and breast tumor grade.
Authors: J. Geradts, S. M. Bean, R. C. Bentley, W. Barry
Journal: Journal of Clinical Oncology (2010)

10647 Background: The Oncotype Dx recurrence score (RS) has been widely adopted by oncologists to guide adjuvant chemotherapy in patients with ER-positive breast carcinomas. The majority of genes included in the Oncotype assay are components of the ER/PR and HER2 pathways or reflect proliferative potential, which is correlated with tumor grade. Methods: 177 consecutive samples of ER-positive primary breast carcinomas treated at Duke University Medical Center were submitted to Genomic Health at the clinicians' request. From the corresponding pathology reports we extracted the following information: ER and PR (Allred scores), HER2 status (negative, borderline, positive), and the three components of the Nottingham tumor grade. For 160 cases, the specific blocks submitted to Genomic Health were centrally typed and graded by the study pathologist (JG). A multivariate linear regression model was used to generate a new index from the 6 parameters, named the breast cancer prognostic score (BCPS). Results: RS ranged from 0 to 71 (median 18). 85 cases were in the low (< 18), 74 in the intermediate, and 18 in the high (> 30) category. The RS was negatively correlated with the Allred score for ER and PR, and positively correlated with HER2, architectural grade (AG), nuclear grade (NG), mitotic grade (MG), and combined Nottingham grade. The multivariate linear model yielded the following formula: BCPS = 33.1 – 2.88[ER] – 1.48[PR] + 7.05[HER2] + 1.27[AG] + 1.32[NG] + 3.54[MG]. The BCPS predicted the RS with an R2 of 0.42 (p < 10−15). Setting thresholds at 17.8 and 28.1, there was complete categorical concordance between BCPS and RS in 56% of cases (weighted kappa = 0.46). When the RS was categorized as in the TailorX trial (cutoffs 11, 25) and the BCPS cutoffs adjusted accordingly, the complete concordance rate increased to 68%. Central grading did not improve the correlation between BCPS and RS. Conclusions: A composite index incorporating routinely reported ER, PR, HER2, and tumor grade data is strongly correlated with the Oncotype RS but does not involve added expense. Whether the BCPS has similar or better prognostic/predictive value compared to the RS, can be tested in appropriate breast cancer cohorts with outcome data. No significant financial relationships to disclose.
The effect of a novel small molecule inhibitor of FAK on viability of human colon cancer cells.
Authors: M. Heffler, Y. Zhao, W. G. Cance, V. Golubovskaya, K. Bullard Dunn
Journal: Journal of Clinical Oncology (2010)

e13635 Background: Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that is overexpressed of a variety of human malignancies including colon cancer. As such, FAK represents a potential target for inhibiting colon cancer growth and progression. We have recently developed a novel small molecule inhibitor of FAK (1,2,4,5-Benzenetetraamine tetrahydrochloride; Y15) that blocks the Y397 autophosphorylation site of FAK, and we therefore hypothesized that Y15 would inhibit the viability of human colon cancer cells. Methods: Two related human colon cancer cell lines were utilized: SW480 (primary tumor) and SW620 (lymph node metastasis). Cells were screened for FAK production and Y397 autophosphorylation by Western blot analysis. An MTT assay was used to assess cell viability in the presence of different concentrations of Y15 alone (1, 10, 100 mcM), and 5-fluorouracil (5-FU; 1, 5, 25 mcM) alone or in combination with Y15 (1mcM). DMSO was used as a negative control and the FAK kinase inhibitor TAE226 used as a positive control. Results: FAK protein was detected in both cell lines, however the metastatic cells (SW620) expressed more FAK than did the primary tumor cells (SW480). In addition, the metastatic cells had greater amount of phosphorylated Y397 FAK. DMSO did not affect cell viability, while TAE226 did, as expected. Y15 inhibited viability in a dose dependent manner. 5FU did not affect viability at doses < 25 mcM. Interestingly, although 1mcM Y15 had no effect on viability, the addition of 1mcM Y15 to all doses of 5FU decreased viability dose dependently, thus sensitizing cells to 5FU. FAK expression and phosphorylation of Y397 were decreased by Y15 and mirrored the viability results. Conclusions: FAK protein is expressed in SW480 and SW620 colon cancer cells, but the metastatic SW620 cell express higher levels than their primary tumor counterparts. The novel small molecule inhibitor of FAK Y397 autophosphorylation (Y15) inhibits viability of both cell lines and does so in a dose dependent manner. In addition, Y15 increases cell sensitivity to 5FU. Taken together, these data suggest that Y15 may be a useful therapeutic agent for treating patients with colon cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration CureFAKtor Pharmaceuticals
Molecular distinctions between variant and classic hairy cell leukemia
Authors: E. Arons, T. Suntum, J. Sunshine, A. Orthwein, I. Margulies, M. Stetler-Stevenson, R. J. Kreitman
Journal: Journal of Clinical Oncology (2008)

18002 Background: 10–20% of patients with hairy cell leukemia (HCL) have a variant (HCLv) that presents with high tumor burden in spleen and peripheral blood, and is less responsive to purine analogs. HCLv cells lack CD25 and sometimes CD103. Differentiating HCLv from classic HCL (HCLc) is often difficult and it is unclear whether HCLv and HCLc are different disorders. Detailed molecular distinctions between HCLv and HCLc have not been reported. Methods: Patients with HCL were studied by flow cytometry and PCR to sequence the monoclonal immunoglobulin heavy chain rearrangements. Differences were analyzed by Fisher's exact and Wilcoxon non-parametric tests. Results: 50 and 21 VH-D-JH rearrangements were obtained from 49 HCLc and 19 HCLv patients, respectively. All rearrangements except 2 each for HCLc and HCLv were productive with no premature termination codons. The incidence of VH4 usage was higher in HCLv than in HCLc (57% vs 20%, p=0.0041). VH4–34 was the most common VH gene in HCLv and was more common in HCLv than in HCLc (33% vs 8%, p=0.012). The percentage of rearrangements which were unmutated (defined as < 2% somatic mutations) was higher in HCLv than in HCLc (43% vs 18%, p=0.038), but % homology was similar in both groups by rank order (median 94.9 vs 94.3% p=0.22). However, in comparing 11 VH4–34 with 60 other rearrangements, homology was higher with VH4–34 (median 99.2 vs 95.2%, p < 0.0001). In fact, the higher frequency of unmutated rearrangements in HCLv vs HCLc was due to VH4–34 cases alone, since the 7 HCLv VH4–34 rearrangements were all unmated and had higher homology than the other 14 HCLv rearrangements (median 99.6 vs 94.2%, p=0.006). Moreover, unmutated rearrangement incidence was similar between HCLv and HCLc for non-VH4–34 cases (14 vs 13%, p=1.0, median homology 94.2% vs 95.3%, p=0.5). Of the 4 VH4–34+ HCLc (CD25+) patients, 3 (75%) had unmutated rearrangements, and these 3 all had clinical features of HCLv, including presenting with lymphocytosis, large splenomegaly, absent cytopenias, and primary failure of purine analog treatment. Conclusions: No molecular distinctions between HCLv and HCLc were observed in VH4–34-negative patients. Our data suggest VH4–34-positive HCL is itself a variant of HCL affecting ∼15% of our patients. Such patients have features of HCLv, but their HCL cells can be CD25+. No significant financial relationships to disclose.
A study to determine whether the subclassification of DLBCL (using immunohistochemical (IHC) markers with tissue microarray (TMA)) is better than international prognostic index (IPI) to predict prognosis and survival
Authors: M. F. Jawad, A. M. Noonan, E. Watson, G. Avalos, M. Keane, C. E. Connolly
Journal: Journal of Clinical Oncology (2008)

22153 Background: Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkins lymphoma, accounting for 30–40% of new diagnoses. Although combination chemotherapy has improved the outcome, many patients do not achieve complete remission and they ultimately relapse. There is therefore a need to identify parameters that predict high risk of relapse and survival. Gene expression profiling studies (GEP) have been shown to accurately stratify patients with DLBCL into 3 groups: Germinal Centre B cell (GCB), Activated B- cell like (ABC), Mediastinal type, with ABC group having a significantly lower 5 year survival rate. TMA techniques using key IHC markers (Bcl- 2, Bcl-6, Mum1, CD10, Cyclin D) have been shown to be an alternative practical method to do the same. IPI is the current best tool to predict survival but not relapse. This study is designed to assess which method is the best in predicting survival and relapse in patients with DLBCL. Methods: 50 patients with DLBCL presenting form 1999–2006 were identified. TMA samples were stained with Bcl-2, Bcl-6, CD10, MUM 1, Cyclin D. The patients were classified by IHC expression into 2 groups (GCB, non-GCB) according to the method suggested by Hans et al and Amen et al. IPI score at diagnosis, relapse details and survival data were recorded. IPI score and IHC expression were then compared to assess relative prognostic strength with respect to survival and relapse. Results: In this cohort of DLBCL, IPI proved a significant prognostic factor for survival (p= 0.049). However, IPI was not a prognostic factor for relapse (p= 0.496). IHC as suggested by both Hans classification and Amen classification, was not a prognostic factor for survival (p= 0.952 and p=0.917 respectively) or relapse (p=0.932 and p= 0.448 respectively). Conclusions: Our findings confirm that IPI is an important tool in prognosis in DLBCL but IHC alone was not powerful enough to evaluate accurately prognosis in DLBCL. Therefore we have to consider more advanced tools such as GEP to evaluate pathological prognostic factors. No significant financial relationships to disclose.
Interim report of the JROSG99–1 multi-institutional randomized trial, comparing radiosurgery alone vs. radiosurgery plus whole brain irradiation for 1–4 brain metastases
Authors: H. Aoyama, H. Shirato, K. Nakagawa, M. Tago
Journal: Journal of Clinical Oncology (2004)

1506 Background: Stereotactic radiosurgery (SRS) is effective treatment for brain metastases when the number is 4 or less, however the role of upfront whole brain irradiation (WBI) combined with SRS has not been well known. Methods: Eligibility criteria include pathologically confirmed systemic cancer, number of brain metastases 4 or less, and size of brain metastases 3 cm or less. Patients were randomly assigned to either SRS alone arm or SRS+WBI arm after the stratification according to the primary tumor site (lung vs. others), extracranial tumor status (active vs. inactive), and number of brain metastases (1 vs. 2–4). Primary endpoint is survival rate. Secondary endpoint includes cause of death, free from new brain metastases rate, KPS preservation (≥ 70%) rate, local tumor control, and late radiation morbidity (RTOG score). Results were analyzed according to the intention-to-treat basis. Results: The planned accrual number of each arm was 85 patients. The reported accrual number for this interim analysis was 61 patients in SRS alone arm and 59 patients in SRS+WBI arm. The median follow-up duration was 6 months (range, 1–40). The mean marginal radiation dose of radiosurgery was 21.8 Gy in SRS alone arm and 16.6 Gy in SRS+WBI arm. The schedule of WBI was 30 Gy in 10 fractions. The actuarial 1-year survival rate was 26% in SRS alone arm and 39% in SRS+WBI arm(log-rank, p=0.58).Death was attributed to neurologic causes in 9 patients in SRS arm and 6 patients in WBI+SRS arm(χ-square, p=0.48). Actuarial 1-year KPS-preservation (KPS ≥ 70%) rate were 25% in SRS alone arm and 37% in WBI+SRS arm(log-rank, p=0.54). Actuarial 6-months free from new brain metastases rate was 49% in SRS alone arm and 82% in SRS+WBI arm(log-rank, p=0.003). Actuarial 1-year local tumor control rate was 70% in SRS alone arm and 88% in SRS+WBI arm(log-rank, p=0.019). Grade 3,4 late radiation morbidity was observed in 1 patient in each arm. Conclusions: Although survival benefit was not confirmed, the use of upfront WBI combined with SRS is superior to SRS alone regarding the free from new brain metastases rate and local tumor control rate. No significant financial relationships to disclose.
Should attribution be considered when interpreting adverse event data: A North Central Cancer Treatment Group (NCCTG) evaluation of a phase III placebo controlled trial
Authors: S. L. Hillman, S. J. Mandrekar, B. M. Bot, E. A. Perez, J. W. Kugler, A. A. Adjei, J. C. Buckner, D. J. Sargent
Journal: Journal of Clinical Oncology (2006)

6006 Background: In March 1998, the Common Toxicity Criteria version 2.0 was implemented and introduced the collection and reporting of attribution of adverse events to study treatment. Collection and reporting of attribution adds time and cost to the clinical trial process, and its use while reporting adverse events (AE) in the literature has varied. We investigate whether attribution adds value to the interpretation of AE data. Methods: Patients on the placebo arm of trial 97–24–51 (CAI vs. Placebo) were chosen since the true relationship of the event to the study treatment is known (“unrelated”). Attribution was collected per CTCv2.0 and categorized as “not related” (not related or unlikely) and “related” (possible, probable, or definite). All reported AEs and the maximum severity for a given AE were evaluated. Patterns were evaluated using generalized estimating equations adjusting for multiple events per patient. Changes in attribution over time for the same event were computed. Results: 84 patients on the placebo arm experienced a total of 1013 AEs. 47% of AEs were reported as “related” with 36% reported as possibly related. Known CAI AEs were more likely to be reported as “related” (p = 0.005). Pulmonary AEs were more likely to be reported as “not related” (p = 0.0006). No patterns were observed by gender, age, PS, severity or treatment cycle of AE. When the same event was reported on the same patient in multiple cycles, the attribution category changed at least once 36% of the time with 25% changing from “related” to “unrelated” or vice versa. Conclusion: Almost 50% of events on a placebo arm of a phase III trial were reported as being attributed to study treatment and 25% of the time the same event was not consistently attributed. These data suggest that attribution is difficult to determine, unreliable, and thus its value in large phase III trials is questionable. [Table: see text] No significant financial relationships to disclose.
A double-blind, randomized, prospective, phase II trial of capecitabine (Cap) plus enzastaurin (Enz) versus cap plus placebo in patients (pts) with advanced breast cancer (BrCa) and prior anthracycline and taxane treatment.
Authors: M. Clemons, K. A. Gelmon, J. Lynch, M. L. Kotliar, A. Joy, J. P. Jordaan, L. L. Han, J. M. Blair, N. A. Iscoe
Journal: Journal of Clinical Oncology (2010)

1054 Background: This international trial studied the efficacy and safety of Cap plus Enz in treating advanced BrCa. Methods: Eligible pts (advanced BrCa, prior anthracycline and taxanes, ≤2 prior chemotherapy regimens and performance status ≤2) were randomized to 1250 mg/m2 Cap (days 1 to 14) and a loading dose of 1125 mg Enz on day 1 of Cycle 1 preceding daily 500 mg Enz (Cap-E) or daily placebo (Cap-P) as continuous oral 21-day cycle treatment. Pts discontinued due to progression, death, or adverse event (AE). Response was assessed before alternate cycles. The primary endpoint, progression-free survival (PFS), was compared between arms using log-rank test. Planned enrollment of 60 pts/study arm provided 80% power to detect a 40% PFS improvement with Cap-E over Cap-P (1-sided type-I error=0.20). Results: Prespecified efficacy and safety conditions were not met in a planned interim analysis and the study was terminated. All data from study enrollment to termination were analyzed. 85 pts were randomized (Cap-E, n=42; Cap-P, n=43; median age, 54.2 years) and received ≥1 study drug dose. There were no statistically significant differences between Cap-E and Cap-P, respectively, in PFS (median [95% CI]=2.8 months [2.1, 4.6] versus 4.3 months [2.9, 6.2]; log-rank p=0.237), overall survival (median [95% CI]=9.9 months [7.0, 16.6] versus 14.9 months [9.9, 19.3); log-rank p=0.181), best overall response (11.9% versus 11.6%; Fisher's Exact p=1.00) or duration of response (median [95% CI]=4.3 months [2.2, 4.3] versus 3.5 months [2.8, N/A]; log-rank p=0.812). More Cap-E than Cap-P pts, respectively, experienced ≥1 drug-related (d-r) Grade 3/4 toxicity (42.9% versus 32.6%), d-r serious AE (16.7% versus 14.0%) and d-r hospitalization (14.3% versus 9.3%). Fewer Cap-E (9.5%) than Cap-P pts (11.6%) discontinued due to d-r AEs. There were 4 study d-r deaths (Cap-E, n=2; Cap-P, n=2) on therapy or within 30 days of study treatment discontinuation. Conclusions: When compared with Cap-P, Cap-E did not improve survival outcomes and increased d-r toxicity. These data do not support use of Cap-E in this patient population. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly Lilly Lilly Lilly, Roche Lilly
A SEER database analysis of conditional survival for prostate cancer patients
Authors: J. Y. Luh, S. J. Wang, C. D. Fuller, C. R. Thomas
Journal: Journal of Clinical Oncology (2006)

14506 Background: Survival probability changes for patients who have already survived one or more years following diagnosis, and is more accurately represented by conditional survival. The specific aims of this study were to determine the 5-year conditional survival rates for prostate cancer patients. Methods: Using the Surveillance, Epidemiology, and End Results (SEER 11) database from the NCI, we analyzed 66,822 prostate cancer patients diagnosed between 1988 and 1994 that were staged using the SEER-modified AJCC staging system (3rd edition). Using the life table method, we computed observed 5-year conditional survival, stratified by stage, age, and race, for patients who had already survived 0 to 5 years after diagnosis. Results: For each category, we compared baseline 5-year observed survival at diagnosis with 5-year observed conditional survival after having already survived 5 years. Survival decreased from 79% to 67% for Stage I, decreased from 80% to 71% for Stage II, decreased from 83% to 75% for Stage III, but increased from 38% to 49% for Stage IV patients. Survival rates did not change for patients &lt;70 years (79–80%), but decreased from 61% to 55% for patients &gt;70 years old. Although blacks (60–62%) had lower survival than whites (69–71%), no race had any appreciable change in their conditional survival for those who had survived 5 years from diagnosis. Conclusions: For prostate cancer patients who have already survived some time after diagnosis, the expected 5-year conditional survival increases for Stage IV patients, but decreases for other stages and for older patients. Conditional survival can provide more accurate longer term prognostic information for prostate cancer patients who have already survived a number of years after diagnosis. No significant financial relationships to disclose.
Carcinogen Chemistry. I. Reactions of Protonated Dialkylnitrosamines Leading to Alkylating and Aminoalkylating Agents of Potential Metabolic Significance
Authors: G A Olah, D J Donovan, L K Keefer
Journal: JNCI Journal of the National Cancer Institute (1975)

Three distinct modes of protolytic dialkylnitrosamine fragmentation were observed when we followed the time dependence of the nuclear magnetic resonance (NMR) spectra of seven nitrosamines in superacid solution: 1) In equimolar HSO3F: SbF5 ("magic acid"), dimethylnitrosamine was cleaved to the protonated Schiff base of formaldehyde and methylamine, and diethylnitrosamine was similarly converted to the protonated acetaldehydeethylamine Schiff base.2) By contrast, of the five dipropyl-and dibutylnitrosamines were studied, all cleaved nonoxidatively under these conditions (with loss of nitrogen gas) to the corresponding propyl or butyl cations. The carbocations thus produced underwent condensation and fragmentation to form the tert-butyl cation as the principal product ultimately observable by NMR. 3) Thethird fragmentation mechanism, which involved denitrosation to the dialkylammonium ion, was observed only as a minor pathway in the sulfuric or fluorosulfuric acid protolysis of dimethylnitrosamine. The mechanisms that are postulated for these cleavage reactions, if functioning in vivo, could account for several metabolic observations that have proved difficult to reconcile with previous conceptions of nitrosamine metabolism.