tbuckley/cabot-search huggingface dataset:
Pharmacogenomic (PG) analysis of Japan-SWOG common arm study in advanced stage non-small cell lung cancer (NSCLC): A model for testing population-related pharmacogenomics
Authors: D. R. Gandara, T. Kawaguchi, J. J. Crowley, J. Moon, M. Kawahara, S. Teramukai, S. K. Williamson, K. Furuse, H. L. McLeod, P. C. Mack
Journal: Journal of Clinical Oncology (2007)

7500 Background: We have previously reported differences in outcomes (increased survival, neutropenia &amp; febrile neutropenia) in Japanese versus US patients (pts) treated with a paclitaxel-carboplatin “common arm” in a prospectively designed fashion in 3 phase III trials (FACS, LC03, S0003) in advanced NSCLC (Gandara, ASCO 05 &amp; Crowley, ASCO 06). We hypothesized that these findings were due in part to PG alterations in paclitaxel disposition. Methods: Genomic DNA was prospectively collected from pts in 2 of these phase III trials (LC03 [N=78, 37 on common arm] &amp; S0003 [N=78]) with identical eligibility, staging, treatment plan (paclitaxel 225 mg/m 2 &amp; carboplatin AUC 6), response &amp; toxicity criteria. Analysis for genotypic variants of CYP3A4, CYP3A5, CYP2C8, NR1I2–206, ABCB1, ERCC2 was performed by pyrosequencing, and results assessed by Cox model for survival/PFS &amp; logistics regression for response/toxicity. Results: There was a significant difference between Japan &amp; US pts in genotypes: CYP3A4*1b (p=0.01), CYP3A5*3c (p=0.03), ERCC2 k751q (p &lt;0.001), and CYP2C8 r139k (p=.01). Genotypic correlations were observed between CYP3A4*1b for PFS (HR 2.75, 1.06–7.08, p=0.04) &amp; ERCC2 k751q for response (HR 0.33, 0.13–0.84, p=0.02). There were no other statistically significant associations, although for grade 4 neutropenia, the HR for ABCB1 3425c-&gt;T was 1.84 (0.77–4.48), p=0.19. The low number of events for febrile neutropenia within this data set precluded assessment of this parameter. Additional PG testing is ongoing &amp; will be presented. Conclusions: 1) Differences in allelic distribution for genes involved in paclitaxel disposition or DNA repair were observed between Japanese &amp; US pts. 2) Statistically significant genotype-associated correlations were present for PFS (CYP3A4*1b) &amp; response (ERCC2 k751q), but not for neutropenia (p=0.19). 3) The small sample size limits interpretation of these data. Further studies based on this common arm approach are warranted for the prospective study of population-related PGs where ethnic/racial differences in anti-neoplastic drug disposition are anticipated. [Table: see text]
Effects of intravenous hyperalimentation during treatment in patients with small-cell lung cancer.
Authors: R S Weiner, B S Kramer, G H Clamon, R Feld, W Evans, E M Moran, R Blum, L M Weisenthal, D Pee, F A Hoffman
Journal: Journal of Clinical Oncology (1985)

One hundred nineteen patients were entered onto a randomized trial of the role of intravenous hyperalimentation (IVH) in patients with small-cell lung cancer. IVH was given during the first 30 days of induction chemotherapy to 54 patients. IVH did not effect any improvement in response or survival from therapy. In view of the lack of benefits from IVH, an analysis was made of the toxicities suffered by the 54 patients receiving IVH as well as any effects IVH might have made on chemotherapy-induced toxicity. Toxicities observed included mechanical difficulties with the catheter leading to temporary or permanent discontinuation of the IVH (11 patients), subclavian vein thrombosis (one patient), sepsis in nine patients v none of the 62 control patients, fluid overload (27 patients), hyponatremia (25 patients), and hyperglycemia requiring insulin (13 patients). Patients receiving IVH had higher granulocyte counts on days 14 and 21 of the first cycle of chemotherapy. Analysis shows that this difference is likely caused by fever and infection associated with IVH rather than any nutritional effect on granulopoiesis. In this population of patients, IVH had significant complications but did not ameliorate chemotherapy-induced toxicity and it did not effect any clinical benefit. Future studies of adjunctive nutritional therapy must consider the significant risk in this older population and must limit IVH volume or exclude patients with even mild compromise in cardiovascular functions. Further, any new trial must have a significant rationale for adjunctive use to justify the potential risks.
Drug sensitivity associated mitochondrial (MT) ultrastructure in ovarian cancer
Authors: S. Isonishi, M. Saitou, T. Tachibana, H. Ishikawa, M. Yasuda, T. Tanaka
Journal: Journal of Clinical Oncology (2005)

5122 Background: Morphological features found in ovarian carcinoma after chemotherapy have been reported (Silverberg SG; Int J Gynecol Pathol. 2000), however, there is no established correlation between morphological change and biochemical response (McCluggage WG; J Clin Pathol 2002). Based on our report documenting the platinum-resistant cell specific MT function and ultrastructure (Isonishi S; Human Cell 2001), tumor responsiveness to chemotherapy is analyzed in association with MT ultrastructure. Methods: Ultrathin sections of 200 MTs prepared from tumor cells of 20 cases with ovarian cancer were examined by electron microscopy. Platinum-sensitive ovarian carcinoma cell line 2008 and its 15-fold resistant variant C13 were used as control cells. On a bases of the finding in control cells, 1 Size of MT determined by maximal diameter, 2 Pattern of cresta structure, 3 MT electron density, 4 MT distribution density, 5 MT distribution pattern, 6 Ratio of minimal/maximal diameter were examined and each of these characteristics were assigned a score of between 0 and 2 to describe the extent of change. The results were independently compared with clinical diagnosis of drug sensitivity based on GOG criteria. Results: All 20 cases were advanced stage III (18 cases) or IV (2 cases) ovarian cancer at initial diagnosis. MTs in 2008 cells (score; 0) were characterized by large size, clear typical cresta structure, low electron density, high density distribution, located in perinuclear space, and short ovoid morphology, whereas MTs in C13 cells (score; 12) were characterized by small size, destroyed cresta structure, high electron density, dispersed in whole cytoplasmic area, and long ovoid morphology. Total score of 10 clinical sensitive cases was 3.25 ± 1.44 (M ± SD) points and was 9.40 ± 0.27 in 8 resistant cases (P < 0.05; 95% Confidence Interval, 0.074–0.189). Scores of 2 intermediate cases were 6 and 7 point. Conclusions: This MT scoring system was consistent with the clinical diagnosis of drug sensitivity in 90% of the samples. This strongly suggests that MT might be of great value as biomarker in predicting drug sensitivity in ovarian carcinoma. No significant financial relationships to disclose.
Long-Term Brain Status and Cognitive Functioning In Children With Acute Lymphoblastic Leukemia Treated According To ALL IC-BFM 2002
Authors: Olga Zajac-Spychala, Mikolaj Pawlak, Katarzyna Karmelita-Katulska, Jakub Pilarczyk, Katarzyna Derwich, Jacek Wachowiak
Journal: Blood (2013)
Pilot evaluation of a stellate ganglion block for the treatment of hot flashes.
Authors: D. R. Pachman, D. L. Barton, P. E. Carns, P. J. Novotny, S. L. Wolf, B. Linquist, S. Kohli, D. R. Smith, C. L. Loprinzi
Journal: Journal of Clinical Oncology (2010)

9104 Background: Hot flashes are a significant problem in breast cancer patients, especially because the most effective therapy, estrogen, is often contraindicated. Recent pilot data from a single investigator support the use of a stellate ganglion block (SGB) for the treatment of hot flashes. This pilot trial was done to further evaluate the hypothesis that SGB may be a safe and effective therapy for hot flashes. Methods: In this prospective pilot trial, a SGB was performed after one week of baseline hot flash data collection. The main efficacy measures were the change from baseline in hot flash frequency and hot flash score during the sixth week. Major eligibility criteria included: women who reported bothersome hot flashes that were present ≥1 month, age ≥18 years, life expectancy ≥6 months, ECOG PS ≤1, and no concurrent antineoplastic chemotherapy or hormonal therapy, except that concurrent therapy with tamoxifen, raloxifene, or aromatase inhibitors was permitted. Descriptive summary statistics including means, standard deviations and percentages formed the basis of analysis for the study. Results: Ten patients were enrolled between 4/23/2009 and 7/10/2009. One patient canceled prior to starting the study and one patient had incomplete hot flash information. Thus, 8 patients were evaluable in the current analysis. After the SGB, the mean hot flash frequency and score at week 6 decreased from baseline values by 44% and 45% respectively (Table). There were no significant adverse events clearly attributed to SGB. Conclusions: The results of this pilot trial suggest that SGB is a promising therapy for hot flashes in breast cancer patients. A prospective placebo-controlled clinical trial should be done to confirm these preliminary findings. Mean percent hot flash reduction from baseline by study week Week Baseline 1 2 3 4 5 6 Frequency 0% 50% 62% 56% 52% 39% 44% Score 0% 52% 64% 61% 57% 42% 45% No significant financial relationships to disclose.
Clinical and pharmacological study of CPT-11 and VM-26/VP-16 for patients with recurrent malignant primary brain tumors
Authors: L. G. Feun, A. Marini, H. Landy, A. Markoe, D. Heros, N. Savaraj
Journal: Journal of Clinical Oncology (2005)

1558 Background: CPT-11 is a potent inhibitor of topoisomerase I (topo) and has shown antitumor activity in brain xenografts and in early clinical trials in recurrent/progressive malignant glioma. VM-26 and VP-16 are topo II inhibitors and have also shown activity in phase II trials. In glioma cell lines and primary culture we have found that they express higher topo I levels when compared to topo II, however, upon treatment with topo I inhibitor CPT-11 or SN-38 (active metabolite of CPT-11), topo II levels increased and cells became more sensitive to topo II inhibitor (VP-16). Therefore, we theorize that administering CPT-11 followed by VM-26 or VP-16 may increase their antitumor activity in malignant glioma. Methods: Patients (pts) with progressive or recurrent malignant glioma after cranial radiotherapy were treated with CPT-11 at a starting dose of 125 mg/m2 iv followed 24 h later with VM-26 125 mg/m2. Due to drug shortage, VP-16 at 125 mg/m2 was given if VM-26 was not available. For pts on anti-convulsants, the starting dose of all drugs was 150 mg/m2. Drugs were given weekly(wk) x 3 wk with 1 wk rest. CT/MRI scans were repeated q 8 wk. Results: 28 pts were treated. 3 pts (11%) had improvement in CT/MRI scans. Myelosuppression, including grade 3–4 leukopenia and thrombocytopenia, were the main toxicities. Conclusions: The combination of the topo I inhibitor, CPT-11, followed by the topo II inhibitor, VM-26 or VP-16 has shown modest antitumor activity comparable to that reported for each drug singly. Myelosuppression may be increased by adding topo I and II inhibitors together. No significant financial relationships to disclose.
Abstract 13764: Clinical Outcomes of Percutaneous Coronary Intervention (PCI) at Hospital With or Without Onsite Cardiac Surgery Backup in Japan
Authors: Tomonori Akasaka, Seiji Hokimoto, Hisao Ogawa, Kics investigators
Journal: Circulation (2013)

Background:  Primary PCI is reasonable in hospitals without onsite cardiac surgery. Elective PCI might be considered in hospitals without onsite cardiac surgery, provided that appropriate planning for program development has been accomplished therefore rigorous clinical and angiographic criteria should be used for proper patient selection(2011 ACCF/AHA/SCAI PCI Guideline). However, it is not clear whether or not there is the difference in performance of PCI at hospitals between with or without onsite surgery backup in Japan. The aim of this study was to examine the impact of with or without onsite surgery on clinical outcomes following PCI in Japan.   Methods:  From Aug 2008 to March 2011, subject (n=5830) were enrolled from the Kumamoto Intervention Conference Study (KICS), which is a physician’s initiated, non-company sponsored, multicenter registry ,and enrolling consecutive patients, undergoing PCI in 16 centers in Japan. Patients were assigned to two groups treated in hospitals with or without onsite cardiac surgery (with backup [[Unable to Display Character: ]] n=5059[[Unable to Display Character: ]] male72%[[Unable to Display Character: ]] age69.6ys: without backup [[Unable to Display Character: ]]n=771 [[Unable to Display Character: ]]male69% [[Unable to Display Character: ]]age70.8ys). We examined the clinical events between two groups. Clinical endpoints were in-hospital death, cardiovascular death, myocardial infarction,stent thrombosis, and stroke.   Results:  In demographic data, high age,acute coronary syndrome (ACS), and single vessel were more frequently seen in hospitals without onsite surgery than with onsite surgery. At the overall endpoint, there was no significant difference in hospitals without onsite surgery or in those with onsite surgery (4.3% vs 5.3%,NS). Ratios of in-hospital death,cardiovascular death,myocardial infarction,and stroke were no significant difference between with and without onsite surgery backup (1.8% vs 1.2%,2.7% vs 3.1%,0.7% vs 1.2%,0.8% vs 0.4%,NS),however, Ratio of stent thrombosis was significantly higher in hospitals without onsite surgery than with onsite surgery (0.6% vs 0.1%, P   Conclusions:  There is no significant difference in clinical outcome between with and without onsite surgery backup.
The efficacy of oxaliplatin (Ox) when added to 5-fluorouracil/leucovorin (FU/L) in stage II colon cancer.
Authors: G. A. Yothers, C. J. Allegra, M. J. O'Connell, T. J. George, S. Sharif, N. J. Petrelli, S. Lopa, N. Wolmark
Journal: Journal of Clinical Oncology (2011)

3507 Background: The use of adjuvant chemotherapy in patients (pts) with stage II colon cancer who lack "high-risk" features ([HiR] perforation, T4 disease and/or less than 12 lymph nodes examined [LNEx]) is highly controversial. We investigated the addition of Ox to FU/L in pts with stage II colon cancer as well as in subsets without HiR ("low/intermediate-risk" [LoR]) and those with HiR. Methods: Our analysis includes 4,883 pts with stage II and III colon cancer (2009 with stage II disease) treated using FU/L regimens, and 3,788 pts with stage II and III colon cancer (991 with stage II disease) treated with FU/L + Ox. Pts from 4 NSABP trials were included: C-05, C-06, C-07, C-08. Only in C-07 was there random assignment to Ox. Analyses controlled for stage, race, age, gender, LNEx, T-stage, bevacizumab (bev) treatment, and the bev-time interaction as appropriate. Results: Overall, there was a highly significant benefit of Ox for DFS and OS in pts with stage II and III disease combined. A test for a stage-Ox interaction was not significant for DFS (p=0.20) or OS (p=0.38), suggesting that the relative effect of Ox did not differ by stage. The effect of Ox remained significant for DFS and OS in stage III. For stage II, Ox did not significantly improve outcomes. A further exploratory analysis in LoR and HiR stage II disease demonstrates 5-year DFS of 0.80 for LoR pts treated without Ox, and 0.83 for those treated with Ox (3% absolute difference). For pts with HiR features these same estimates were 0.76 without Ox and 0.81 for those treated with Ox (5% absolute difference). 5-year OS estimates for the LoR group were 0.89 and 0.91, and for the HiR pts, 0.87 and 0.90 treated without and with Ox, respectively. Conclusions: Regardless of risk status, we were unable to show a statistically significant benefit for the addition of Ox to FU/L in 3,000 pts with stage II colon cancer participating in NSABP clinical trials in this exploratory pooled analysis. The observed 2-3% increase in 5-year OS with Ox for LoR and HiR stage II colon cancer may not outweigh the substantial risk of adverse events including persistent neuropathy. Funded by grants U10-CA-37377, U10-CA-69974, U10-CA-12027, U10-CA-69651, with support from Brystol-Myers Squibb, sanofi-aventis, and Genentech.
Phase I dose-escalation trial investigating the safety and tolerability of EPO906 plus estramustine in patients with advanced cancer
Authors: M. Wojtowicz, J. D. Rothermel, J. Anderson, M. Todd, E. H. Rubin, R. S. Dipaola
Journal: Journal of Clinical Oncology (2004)

4623 Background: Estramustine in combination with taxanes has demonstrated synergistic antitumor activity in patients (pts) with hormone-refractory prostate cancer. However, taxanes are associated with hematologic toxicity and the development of drug resistance. EPO906 is a novel epothilone that induces microtubule polymerization and has demonstrated clinical cytotoxic activity in taxane-sensitive, -resistant, and -refractory tumors. Phase I studies show EPO906 has a favorable safety profile compared with docetaxel. Methods: We investigated the MTD of EPO906 plus estramustine in pts with advanced cancer. Pts with stage III/IV solid tumors and a performance status ≤ 2 were eligible. DLT was defined as grade (gr) 4 neutropenia and thrombocytopenia, febrile neutropenia, ≥ gr 3 nonhematologic toxicity, or gr 2 renal toxicity. Pts received weekly oral estramustine 280 mg BID days 1 - 3 and EPO906 starting at 0.5 mg/m2 via 5-min IV infusion weekly on day 2 for 3 wk followed by 1 wk of rest. EPO906 was escalated by 0.5-mg/m2 increments to 2.5 mg/m2 in cohorts of 3 - 6 pts. Results: Thus far, 14 pts have been enrolled. Tumor types are predominantly prostate and breast cancer. All pts except 1 had received prior taxane therapy. Median age was 61 yrs (range, 40 - 75 yrs). Three pts were treated in cohort 1 (0.5 mg/m2), 3 in cohort 2 (1.5 mg/m2), 4 in cohort 3 (2.0 mg/m2), and 4 in cohort 4 (2.5 mg/m2). One pt in cohort 3 experienced a DLT (gr 3 diarrhea). Eight pts experienced gr 3 and 1 pt experienced gr 4 adverse events, including fatigue, vomiting, and diarrhea. The most frequent gr 1 and 2 toxicities were diarrhea and nausea (most likely associated with estramustine). One pt experienced gr 3 anemia; no other pts had severe hematologic toxicity. Preliminary tumor assessment showed 1 pt with PR and 8 pts with SD (3 for 4 months; 5 for 2 months). The MTD of EPO906 in combination with estramustine is 2.5 mg/m2. Conclusion: Preliminary results suggest that EPO906 plus estramustine is generally well tolerated in pts with advanced cancer. Future studies will fully characterize the role of EPO906 in combination with estramustine in the treatment of advanced cancers. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceuticals Corp. Nevada Cancer Institute; Novartis Pharmaceuticals Corp.; Vertex Novartis Pharmaceuticals Corp. Alza Novartis Pharmaceuticals
PWE-055 Characterisation of serum proteins in biliary tract cancer, primary sclerosing cholangitis and immunoglobulin G4-associated cholangitis using 2-dimensional difference gel electrophoresis and tandem mass spectrometry
Authors: N S Sandanayake, J Sinclair, F Andreola, M H Chapman, S Camuzeaux, G J Webster, I D Norton, R C Smith, J F Timms, S P Pereira
Journal: Gut (2010)

<h3>Introduction</h3> Distinguishing biliary tract cancer (BTC: cholangiocarcinoma and gallbladder carcinoma) from benign biliary disease such as pre-malignant primary sclerosing cholangitis (PSC) or immunoglobulin G4-associated cholangitis (IAC) can be difficult. Serum markers such as CA19.9 and immunoglobulin G4 lack sensitivity and specificity. There is a need for better biomarkers to differentiate these clinically similar diseases. We aimed to perform serum immunoaffinity depletion, 2-dimensional difference gel electrophoresis (2-DIGE) and liquid chromatography tandem mass spectrometry to identify differential biomarkers in benign and malignant biliary disease and healthy volunteers. <h3>Methods</h3> Blood was prospectively collected from 37 patients with BTC, 11 with PSC, 7 with IAC and 30 healthy volunteers. Serum was pooled into the four clinical groups and immunoaffinity depleted via fast protein liquid chromatography to remove highly abundant proteins. Following 2-DIGE using minimal labelling Cy-dyes, gels were scanned then analysed with DeCyder software. Protein spots with a &gt;2-fold differential expression (p&lt;0.01, Student t test) were picked, trypsin digested and subjected to nanoflow reversed-phase liquid chromatography coupled to electrospray ionisation tandem mass spectrometry for protein identification. <h3>Results</h3> The median age of BTC, PSC, IAC and healthy groups were similar at 68 (range 27–93), 47 (range 22–76), 63 (range 43–71) and 64 (range 40–79) years, respectively. The median serum bilirubin in the BTC, PSC and IAC groups was 40 (range 8–616), 20 (range 7–457) and 12 (range 5–40) μmol/l, respectively. 30/37 BTC, 4/11 PSC and 1/4 IAC patients, had elevated (&gt;37 IU/ml) CA 19.9 levels. 61 protein spots were picked, of which 34 were upregulated and 13 downregulated in BTC vs healthy, 32 upregulated and 9 downregulated in BTC vs PSC, and 7 upregulated and 12 downregulated in PSC vs IAC. Leucine-rich glycoprotein, apolipoprotein A-IV and E, MASP2, CLEC3B, RAD1 and vimentin were upregulated and Hsp90, C4BPA and SERPIND1 downregulated in BTC vs PSC. Carbonic anhydrase 1, lumican and twinfilin-2 were upregulated and IgG4 chain C region and MASP2 were downregulated in PSC vs IAC, respectively. Serum validation of putative markers is underway. <h3>Conclusion</h3> Differentially expressed serum proteins in benign and malignant biliary disease were identified using this proteomic approach. These putative markers may be useful in monitoring patients with PSC who are at increased risk of BTC.