tbuckley/cabot-search huggingface dataset:
Phase II trial of biweekly CPT-11 plus CDDP for patients with unresectable or recurrent gastric cancer refractory to S-1.
Authors: Y. Rino, T. Oshima, N. Yukawa, R. Yamada, T. Sato, M. Takahashi, H. Matsukawa, Y. Yamamoto, R. Shiraishi, M. Masuda, T. Imada
Journal: Journal of Clinical Oncology (2011)

e14515 Background: Chemotherapy (CT) has been widely used against advanced gastric cancer (AGC), however, the best treatment has not been confirmed. In 2007, S- 1 showed the potential to be the standard treatment for AGC and stage II/III gastric cancer (Narahara et al. 2007 ASCO Abst.4514, Sasako et al. 2007 ASCO-GI Abst.8). CPT-11therapy has many reports showing the effectiveness as the 2nd line treatment, and the combination therapy of CPT-11+CDDP available for outpatients is promising (Koizumi et al, Anticancer Res. 25:1257-62, 2005). Therefore, we performed a phase II study to evaluate CPT-11+CDDP as the second line following S-1 single agent or S-1+CDDP failure. Methods: Eligible patients (pts) had AGC which became ineffective in S-1 as previous, an oral possible, an ECOG PS of 0-2, an age of 20-79 years and adequate organ functions. The following treatment, CPT-11 60 mg/m2+CDDP 30 mg/m2 iv on day 1, was repeated every 2 weeks until disease progression or appearance of unacceptable toxicity. Primary endpoint was response rate. Main secondary endpoints included toxicity, overall survival and progression free survival, and performance rate of third-line CT. Results: A total of 18 pts were enrolled in this trial between November 2006 and May 2009. The male/female was 16/2. The median age was 73 years (range 54-79 yeas). All pts were evaluated for effectiveness and safety. The overall response rate was 16.7%, including 2 CR, 1 PR, 7 SD, 6 PD, and 2 NE. The most common grade 3/4 toxicities were: neutropenia (22.2%), leukopenia (22.2%), anemia (11.1%), anorexia (11.1%), diarrhea (11.1%), and fatigue (5.6%). The median overall survival was 282 days at present. Third-line CTs were performed in 13 of 18 pts (72.2%). Conclusions: The combination treatment of CPT-11 and CDDP is feasible and effective. Accordingly, this regimen can be one of the second-line standard treatments for gastric cancer.
Gemcitabine in combination with Oxaliplatin in Pancreatic (PAN-02) tumor bearing mice
Authors: A. Moschidis, A. Papageorgiou, D. Tsavdaridis, K. Atmatzidis, K. Tsalis, E. Chrysogelou, P. Oustabasidis, G. Geromichalos, N. Charlaftis
Journal: Journal of Clinical Oncology (2004)

4153 Background: Combination chemotherapy is routinely used for many cancer patients to enhance the antitumor efficacy of single agents and reduce overall toxicity. Single agents Gemcitabine (Gem) and Oxaliplatin (Ox) have clinical antitumor activity and act at the DNA level by different mechanism of action. The aim of this study was to optimize scheduling of both drugs in PAN-02 tumor, since in previous in vivo studies with several other tumor types no effective combination schedule of both compounds was found. Methods: In this study the pancreatic ductal adenocarcinoma PAN-02 was used which was purchased from the DCTD, NCI, Frecerick, MD, USA. Tumor was grown in female C57 BL. The tumor was implanted subcutaneously in the axillary region with puncture in the inguinal region. The amount of the transplantation graft is 40–50 mg fragment. Experiments were initiated on day 0 by implanting the mice. Drug administration was begun 24 hours later either as a single dose or on days 1, 9. Experiments were terminated on day 58. Results: The summary of the antitumor activity of Gem-Ox and GemOx in PAN-02 is presented in the Table. Conclusions: The results presented here give further insight in the in vivo interaction between Gem and Ox. This study shows that the schedule dependency between both compounds plays an important role in antitumor response which is of major interest for the treatment of tumors in the clinic. No significant financial relationships to disclose.
The degree of segmental aneuploidy measured by total copy number abnormalities to predict survival and recurrence in superficial gastroesophageal adenocarcinoma.
Authors: Jon M. Davison, J. Michael Krill-Burger, Melissa K. Yee, Tyler J. Foxwell, Maureen A. Lyons-Weiler, James D. Luketich, Katie S. Nason, George K. Michalopoulos, William A LaFramboise
Journal: Journal of Clinical Oncology (2014)

62 Background: Prognostic biomarkers are needed for superficial gastroesophageal adenocarcinoma (EAC) to predict clinical outcomes and select therapy. Although recurrent mutations have been characterized in EAC, little is known about their clinical and prognostic significance. Aneuploidy is predictive of clinical outcome in many malignancies but has not been evaluated in superficial EAC. SNP arrays offer the opportunity to evaluate segmental aneuploidy at high resolution throughout the genome. Methods: We quantified copy number changes in 41 superficial EAC using Affymetrix SNP 6.0 arrays. We identified recurrent chromosomal gains and losses and calculated the total copy number abnormality (CNA) count for each tumor as a measure of aneuploidy. We correlated CNA count with overall survival and time to first recurrence in univariate and multivariate analyses. Results: Recurrent segmental gains and losses involved multiple genes, including: HER2, EGFR, MET, CDK6 , KRAS (recurrent gains); and FHIT, WWOX, CDKN2A/B, SMAD4, RUNX1 (recurrent losses). There was a 40-fold variation in CNA count across all cases. Tumors with the lowest and highest quartile CNA count had significantly better overall survival (p=0.032, log rank test) and time to first recurrence (p=0.010, log rank test) compared to those with intermediate CNA counts. In multivariate Cox analysis, there was a 3.4-fold (95% CI, 1.1–10.4) increased hazard of death among cases with intermediate CNA counts after adjusting for other predictors of survival (N stage, angiolymphatic invasion and tumor size). Similarly, there was a 7.3-fold (95% CI, 1.5-34) increased risk of recurrence for these patients. Conclusions: SNP arrays facilitate the assessment of recurrent chromosomal gain and loss and allow high resolution, quantitative assessment of segmental aneuploidy (total CNA count).The non-monotonic association of segmental aneuploidy with survival has been described in other tumors such as breast and ovarian carcinoma. The degree of segmental aneuploidy is a promising prognostic biomarker in a potentially curable form of EAC.
The pattern of somatic mutations and chromosomal copy number variations (CNV) in young breast cancer (BC) patients (pts).
Authors: Hatem Abdel Azim, Bastien Nguyen, Sylvain Brohee, Martine J. Piccart-Gebhart, Christos Sotiriou
Journal: Journal of Clinical Oncology (2015)

579 Background: Young age at diagnosis is associated with poor prognosis, different distribution of BC subtypes and unique gene expression patterns. Yet, it is unknown whether young pts have different prevalence of somatic mutations or CNV. Methods: This analysis was performed on The Cancer Genome Atlas dataset. We divided pts according to their age into; young ( < 45 years) and old ( ≥ 45 years). We evaluated the association between age as a continuous variable and number of somatic mutations, CNV (amplification, gain, or deletions) using the chi-square test. We examined the genes showing somatic mutations or CNV in young pts and compared it to older pts using t-test. Results: 959 (138 < 45y) and 788 (124 ≥ 45y) pts were included in the somatic mutation and CNV analyses, respectively. Young age at diagnosis was associated with less number of somatic mutations, mainly in ER- BC (r = 0.21, p = 0.002). Within young ER+ pts, mutations in PIK3CA (32.6%), GATA3 (16.8%) and TP53 (16.8%) were the most common with prevalence highly comparable in older pts. Of relevance, higher rates of mutations in NTRK2 (5% vs.0%, p < 0.0001) and ARID1A (7% vs.2%, p = 0.03) were observed in young compared to old ER+ patients. No major differences were observed in the pattern of somatic mutations in ER- BC according to age, with mutations in TP53 (67.5%), RYR2 (13.5%) and CSMD2 (10.8%) being the most common in young pts. We found more chromosomal amplifications in young pts with amplification events decreasing as a function of age, but only in ER+ BC (r = -0.13, p = 0.007). 22% of young pts showed AXIN2 amplification vs. 4% in older patients (p < 0.0001). No other relevant associations were observed between CNV and age at diagnosis. Conclusions: This is the first analysis to interrogate the impact of young age at BC diagnosis on the pattern of somatic mutations and CNV. We observed that young age at diagnosis is associated with 1) less number of somatic mutations, and 2) more chromosomal amplifications, the latter observed only in ER+ disease. AXIN2, which regulates the Wnt/B-catenin pathway appear to be more amplified in young pts and if further validated could represent a potential treatment target in these women.
Use of gene expression profiling to identify responsive patients treated with carboplatin (Carb), paclitaxel (Pac), and everolimus as first-line treatment for cancer of unknown primary (CUP): NCCTG N0871 (Alliance).
Authors: Matthew P. Goetz, Nathan R. Foster, Jeffery P. Meyers, Preston D. Steen, Daniel W. Visscher, Harry H. Yoon, Raji Pillai, Debra M. Prow, Christopher M. Reynolds, Benjamin T. Marchello, Rex B. Mowat, Bassam Ibrahim Mattar, Charles Erlichman
Journal: Journal of Clinical Oncology (2013)

2562 Background: Empiric chemotherapy (taxane/platinum) is standard for CUP. Because prognosis is poor, novel approaches are needed. The PI3K/mTOR pathway is frequently dysregulated in cancer. Everolimus (E), an mTOR inhibitor, is approved for multiple malignancies. We performed a phase II study of Pac + Carb + E as first-line therapy in metastatic CUP patients (pts). We additionally determined if a gene expression profiling (GEP) test that identifies tissue of origin (Pathwork Tissue of Origin) could identify responsive pts. (NCT00936702) Methods: Newly diagnosed, untreated CUP pts were eligible. Central pathology review confirmed CUP prior to registration; GEP was performed on formalin fixed tumor tissue. Pac (200 mg/m 2 ), Carb (AUC=6) and E (30 mg once weekly) were delivered every 3 wks until progression or intolerable adverse events (AEs). The primary endpoint was confirmed response, with ≥11 of 50 responses (22%) needed for trial success. Secondary endpoints were OS, progression-free survival (PFS) and AEs. Results: 46 pts (median age 61) received a median 4 cycles (range: 1-33). 39 (85%), 21 (46%) and 1 (2%) experienced ≥1 grade (gr) 3+, 4+, or 5 (sepsis) AE, with gr 3+ hematologic AE most common (74%). Of 44 evaluable pts, 15 had a confirmed response (RR 34%, 95% CI: 21-50%), with a median PFS and OS of 4.1 and 10.1 mos, respectively. Adequate tissue for GEP was available in 36 pts and predicted 10 different sites of origin. In pts with a predicted tissue of origin in which taxane/platinum is standardly used, higher RR and significantly longer PFS and OS were observed compared with pts whose GEP identified a malignancy where taxane/platinum is not standard (Table). Conclusions: In pts with untreated CUP, Carb +Pac +E demonstrated promising antitumor activity. The GEP test identified patients clinically responsive to Carb/Pac/E therapy, and may be useful to select CUP pts for specific antitumor regimens. Clinical trial information: NCT00936702. [Table: see text]
Doppler-Ultrasonography with perfusion software and contrast medium injection as a tool for early evaluation of gastro-intestinal stromal tumors (GIST) treated with Imatinib
Authors: N. Lassau, M. Lamuraglia, L. Chami, J. Leclere, S. Bonvalot, T. Tursz, J. Y. Blay, A. Le Cesne
Journal: Journal of Clinical Oncology (2005)

3057 Background: To evaluate Doppler-Ultrasonography with perfusion software and contrast agent injection (DUPSCA) as a predictor of tumor response to imatinib (Gleevec) in c-Kit-positive GIST. Methods: Patients with advanced GIST treated with imatinib (French BFR14 trial) were prospectively included in a monocentric imaging trial. DUPSCA was performed with an Aplio sonograph using a new perfusion software (Vascular Recognition Imaging, Toshiba) and injection of Sonovue (Bracco) before imatinib administration (d0) on days 1, 7, 14, 60, and then every 3 months up to 24 months. The percentage of contrast uptake was evaluated at each tumor site by two radiologists. DUPSCA results were compared to CT scan Results: Results: A total of 288 DUPSCA were performed in 37 patients with a total of 70 lesions (37 at d0, 37 at d1, 36 at d7, 35 at d14, 32 at 2 months, 29 at 3 months, 30 at 6 months, 14 at 9 months, 16 at 12 months, 11 at 15 months, 8 at 18 months, 2 at 21 months and 1 at 24 months). At 2 months, a total of 63 lesions in 32 patients were completely evaluated: 27 patients had a good CT scan response (according to tumor volume and necrosis) and 5 patients had a poor response. There was no significant difference between the 2 groups in tumor volume modification but a strong correlation was found according to the decrease in tumor contrast uptake at d1, d7, d14 and d60. A decrease of more than 20% in contrast uptake at d7 was predictive of a good response (p<10−4). Resumption of contrast uptake, before any increase in tumor volume was depicted at 12, 15 and 15 months in 3 patients with recurrence. Conclusions: DUPSCA is a new functional non invasive imaging technique that allows early and accurate evaluation of imatinib activity and might be predictive of secondary resistance to (Gleevec). The final results will be presented during the next ASCO. No significant financial relationships to disclose.
Association between elevated blood pressure and clinical response in patients treated with anti-vascular endothelial growth factor (anti-VEGF) therapy in phase I clinical trials.
Authors: Mehmet Asim Bilen, Aung Naing, David S. Hong, Gerald Steven Falchook, Siqing Fu, Sijin Wen, Jennifer J. Wheler, Jean-Bernard Durand, Michael Ewer, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2012)

e13506 Background: Relationship between elevated blood pressure and clinical response in patients with advanced cancers treated with anti-VEGF treatment was evaluated. Methods: We performed an analysis of 438 consecutive patients from 19 clinical trials treated with therapy that included an anti-VEGF agent starting January, 2006. Clinical response was determined by RECIST 1.0. Blood pressures (BP) were scored as shown in Table. BP scores were calculated from an average mean BP of all BP readings for each patient, taken at each visit, and then divided into time points: baseline, 4, 8 and 12 months. Other factor included number of medication. Scores at each time point were compared to baseline value and divided into: increasing, decreasing and stable. Chi-square was used to correlate increased BP scores with clinical response. Additional analysis was also done by using CTCAE v4.02 for grading of BP. Results: The median age was 57 years (13 to 88) and 54% were male; 10% of patients received more than one anti-VEGF therapy. The median number of anti-VEGF therapies was 2 (1 to 3). Within the first four months, 52% of patients who achieved partial response (PR) had increased BP scores from baseline compared to 18% of those with progressive disease (PD) and 25% of those with stable disease (SD) (p &lt;0.0001) (CTCAE; p=0.004) but there was no difference between SD and PD (p = 0.11) (CTCAE; p=0.31). The elevation in BP scores was significantly higher in the PR+SD group (31%) compared to PD group (18%) within 4 months (p=0.008) (CTCAE; p=0.07). There is a significant difference in increased BP scores among PR to SD groups within 8 months and 12 months (p=0.04 and p=0.028) (CTCAE; p=0.04 and p=0.107). Conclusions: Increasing BP scores is a positive prognostic indicator for favorable clinical response in patients who received anti-VEGF treatment. [Table: see text]
Battle scars: global conflicts and environmental health; the price of preparing for war
Authors: Valerie J. Brown, C. W. Schmidt
Journal: Environmental Health Perspectives (2004)

The nature and weapons of war have changed radically in the last century, bringing conflict off the battleground and into city streets, and thereby magnifying its environmental health consequences. Age-old problems still follow war---lack of food, shelter, water, and sanitation, risk of infectious disease, and psychological trauma. But modern war also saddles populations with new threats from industrial and military chemicals, pesticides, and radiation, and humanitarian aid systems designed to help people after natural disasters cannot function properly in combat environments. A few encouraging strides are being made, such as the overall reduction in landmine production and use. It remains to be seen what further progress can be made in alleviating the environmental health disaster that is war.
Diagnostic strategy based on preoperative serum CEA levels in clinical stage IA NSCLC
Authors: N. Sawabata, M. Okada, M. Higashiyama, K. Nakagawa, M. Miyake, H. Maeda, A. Matsumura, A. Matsumura, M. Okumura, T. Taki, K. Kodama
Journal: Journal of Clinical Oncology (2006)

17011 Background: Following surgery, clinical stage IA NSCLC diagnosed using non-interventional examinations is occasionally pathological stage III or IV. The level of carcinoembryonic antigen (CEA) in serum has been reported to be a predictor of up-staging to advanced stages, however, there are few multi-center studies of serum CEA that utilized a short accrual period. Methods: A multi-center retrospective study was performed to assess serum CEA level as a predictor of advanced stage in 862 consecutive patients with clinical stage IA NSCLC from 2002 to 2004. The subjects were 493 males with a mean age of 65.2 years old, 460 of whom were smokers, who had a total of 689 adenocarcinomas with a mean tumor size of 19.5 cm. They were divided into 4 groups by smoking status and adenocarcinoma histology, after which AUC was calculated using an ROC curve, which provided an estimate of the probability efficiency of pathological diagnosis of stage III or stage IV. When AUC was greater than 0.7, sensitivity, specificity, and positive predictive values were calculated, and multivariate Cox regression analysis was performed to confirm independence. Results: There were 72 cases (8.1%) in an advanced stage. AUC was greater than 0.7 in the group of non-smokers with an adenocarcinoma (n = 413), in which the sensitivity, specificity, and positive predictive values were 0.14, 0.97, and 0.64, respectively, with a CEA cut-off level of 20 ng/ml. Thus, serum CEA level was shown to be an independent predictive factor. Conclusions: In smokers with an adenocarcinoma, a high level of CEA in serum was frequently found in those with pathologically advanced disease, thus intervention should be mandated in such cases. [Table: see text] No significant financial relationships to disclose.
A prospective randomized multicenter gene expression study of docetaxel vs doxorubicin/cyclophosphamide preoperative trial in primary breast cancers
Authors: A. Makris, S. G. Hisenbeck, D. Yee, K. C. Osborne, R. M. Elledge, M. Harrison, P. J. Ostler, S. Mohsin, C. M. Gutierrez, J. C. Chang
Journal: Journal of Clinical Oncology (2005)

544 Introduction: Previously, we had identified a 92-gene expression pattern that predicted response to neoadjuvant Taxotere in primary breast cancers. In this prospective, randomized, multicenter trial we set out to validate this profile, and to compare it with the molecular patterns for response to AC. We report here the clinical results of this study. Methods: Patients were randomized to either 4 cycles of Taxotere 100mg/m2 (T), or 4 cycles of Adriamycin 60mg/m2 and Cytoxan 600mg/m2 (AC), prior to surgery. Core biopsies were obtained before chemotherapy and stored at −80C for subsequent gene expression array analysis. After surgery, T-treated patients received x4 AC, while AC-treated patients received x4 T, as adjuvant CT. Radiation and hormonal therapy were given after CT, as clinically indicated. Results: A total of 107 patients have been recruited. Of these, 91 have completed the neoadjuvant phase and 82 have had surgery. Results on the 91 women (T-treated: 45 AC-treated: 46), with median age of 49 yrs (range 31–74) are presented below. A trend towards higher pathological complete response was observed with T: 12.5% vs. 4.8% (p=0.2). Clinical response rates (CR + PR) were similar in both arms, 62% and 59% respectively. A trend towards higher rate of breast conserving surgery was seen with T, 48% vs. 34% (p=0.2). Higher non-significant grade 3 and 4 toxicities were observed with T: febrile neutropenia (22% vs. 14%), and GI toxicity (11% vs. 5%). Conclusions: In this randomized prospective study, a trend towards higher pathologic complete responses and breast conserving surgery was observed with neoadjuvant T than AC, with acceptable toxicity in both arms. We will undertake gene expression array analysis of the pretreatment specimens to refine and validate gene expression patterns for T response and to determine AC patterns, in order to better select the most appropriate treatment for individual patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis Aventis
Can multidetector computed tomography replace coronary angiography in the preoperative evaluation of patients undergoing valve surgery
Authors: Anne-Catherine Pouleur, Agnes Pasquet, Jean-Louis Vanoverschelde, Bernhard Gerber, Jean-Benoit de Polain de Waroux, Céline Goffinet
Journal: Circulation (2006)

Background.  Pre-operative identification of significant coronary artery disease (CAD) in patients scheduled to undergo valvular surgery still requires invasive coronary angiography. Multidetector-CT (MDCT) is a promising new technique in the evaluation of such patients. The aim of this study was to evaluate the ability of MDCT to detect significant CAD prior to surgery.   Methods.  Seventy-three patients (47 males, mean age: 60±13 yrs) scheduled to undergo aortic root surgery (n=23), mitral valve repair (n=23) or aortic valve replacement (n= 27) underwent 40-slice-MDCT before scheduled invasive coronary angiography. Diagnostic accu-rary of MDCT to identify >50% luminal diameter stenosis in coronary arteries was assessed on both per vessel and per patient basis.   Results.  According to invasive data, 27 coronary vessels had > 50% stenosis. Fifty-nine pts were free of any CAD and 14 patients had CAD (4 1-vessel, 7 2-vessels and 3 3-vessels disease). On a per-vessel basis, MDCT correctly identified CAD in 26/27 (sensitivity 96%) vessels, and excluded it in 174/192 vessels (specificity 91%). Positive and negative predictive values and overall diagnostic accuracy on per-vessel basis were respectively 57%, 100% and 93%. On a per patient basis, all 14 patients with CAD were correctly identified (sensitivity 100%). On the other hand, MDCT correctly excluded CAD in 50/59 patients without CAD by invasive angiography (specificity 85%). Positive and negative predictive values of MDCT were 61% and 100%. Selecting patients to undergo invasive angiography only in pts with an abnormal MDCT would have saved invasive angiography in 50/73 (68%) patients prior to cardiac sugery.   Conclusion.  MDCT could be potentially useful in the preoperative evaluation of pts with valvular disease. By selecting only those patients with coronary lesions to undergo invasive coronary angiography, it could avoid cardiac catheterization in a large number of patients without CAD.