tbuckley/cabot-search huggingface dataset:
Reduced intensity conditioning regimen (RIC) followed by allogeneic stem cell transplantation (ASCT): Low related transplant mortality and high survival probability in patients with advanced solid tumors in a multicenter trial
Authors: D. Blaise, J. O. Bay, C. Faucher, M. Michallet, J. M. Boiron, J. Y. Cahn, M. Mohty, D. Maraninchi, P. Viens
Journal: Journal of Clinical Oncology (2004)

2551 Background: ASCT is associated with high treatment related mortality (TRM): RIC for treatment of hematological malignancies has decreased TRM. In ST the low number of pts reported in each single center series has not allowed so far to obtain this information. Methods: In a prospective and multicenter trial we have investigated whether ASCT after RIC might represent a potential treatment for patients suffering from ST with acceptable toxicity and potent antitumoral effect. From 06/98 until 11/03 we treated 79 pts with ST (RCC: 33; Breast Ca: 20; Ovarian Ca: 8; melanoma: 5; Sarcoma: 5; others: 8) (Age: 45 (17–61) and Male: 44%). All pts had measurable disease according to RECIST criteria (Progressive (PD)/Stable (SD) disease: 70%/30%). RIC included Fludarabin (30 mg/m2/d over 5 to 6 days), Bu (4mg/kg/d over 2 days) and ATG (Thymoglobuline: 2.5 mg/kg/d for 4 to 0 days)) followed with ASCT from a HLA identical sibling. Results: All pts engrafted. Grade 2–4 aGVHD cumulative incidence (CI) was 31% (17–39) and cGVHD CI was 50% (38–62). 5 pts died from TRM (all related to GVHD) (6% (95% CI: 1–11%)) at 118 (68–252) days post transplant. All these 6 pts were 50 years or older (TRM: age <50: 0%; age >= 50: 20% (4–36; p=.005). 5 of these 6 pts had PD prior ASCT. 21 pts remain alive at a median follow-up of 272 (54–819) days for a 1 year survival probability of 32% (21–44). At time of abstract, 61 pts had a 1-year minimal follow-up and have been fully analyzed for response and outcome: 69 % had PD and 31% SD at time of ASCT. 9 of the 19 SD pts vs. 2 of the 42 PD pts achieved a PR or CR (objective response: OR) (OR CI: SD: 47% (20–64); PD: 5% (0–12%); p=.0004). No difference between diagnoses was found. In this subpopulation 1 year-survival probability was 56% (35–76) for SD and 17% (9–31) for PD (p=0.001). Conclusion: RIC ASCT is associated with a low TRM especially in younger patients: This information is of importance for further developments. Secondly we confirm that pre-graft tumor kinetics is a major factor predictor for survival inviting cautious selection of pts. No significant financial relationships to disclose.
Chronologic changes in the clinicopathologic findings and survival of gastric cancer patients.
Authors: K Kitamura, T Yamaguchi, K Sawai, S Nishida, K Yamamoto, K Okamoto, H Taniguchi, A Hagiwara, T Takahashi
Journal: Journal of Clinical Oncology (1997)

To determine the chronologic changes in the clinicopathologic features of gastric cancer patients.The clinicopathologic findings of 1,795 patients with gastric cancer were examined retrospectively from hospital records obtained between 1969 and 1995. The patients were divided into three generations on the basis of chronologic order. The first generation included patients treated over the period 1969 to 1977; the second generation, 1978 to 1986; and the third generation, 1987 to 1995.The chronologic changes in the clinicopathologic findings for all gastric cancers included increases in the superficial type based on macroscopic appearance (P < .005), small-sized tumor (P < .025), superficial depth of invasion (P < .005), and earlier histologic stages (P < .005), in addition to a decrease in lymph node metastasis (P < .005). Overall, the postoperative survival rate has improved over time in gastric cancer patients, with 5-year survival rates of 36.0%, 53.3%, and 68.6% in the first, second, and third generations, respectively. In stages 1,2, and 3, the survival rate in the third generation was the highest of the three generations, whereas in stage 4, the survival rate did not differ between the three generations. Patients who underwent a D2 dissection showed a higher survival rate than those with D1 or D3 dissections, but there was no statistical difference in the survival of patients with D1, D2, and D3 dissections when stage 4 patients were excluded.The chronologic changes in gastric cancer patients over the past 27 years have included an increase in the incidence of earlier-staged gastric cancers, which has had a significant impact on the improved postoperative survival rate.
Pharmacogenetic study in patients (pts) with metastatic breast (BC) and colorectal cancer (CRC) treated with Capecitabine (C)
Authors: N. Ribelles, A. Sánchez, J. López Siles, E. González, M. J. Sánchez, F. Carabantes, P. Sánchez Rovira, A. Márquez, I. Sevilla, E. Alba
Journal: Journal of Clinical Oncology (2005)

2005 Background: Different polymorphisms (P) of the enzymes involved in C metabolism could be responsible of the different efficacy and toxicity in patients treated with C. Carboxylesterase (CES) and Cytidine Deaminase (CDD) are involved in hepatic transformation of C to 5’dFUrd. Thymidilate Synthase (TS) and Dihydropyrimidine Dehydrogenase (DPD) P have been related to 5FU efficacy and toxicity. Our objective was to correlate the efficacy and grade 3–4 toxicity of C with genetic P of CES, CDD, TS and DPD. CES and CDD P have not been previously studied. Methods: Metastatic BC and CRC pts treated with C 1250 mg/m2 PO bid d1–14 every 3 weeks, with evaluable or measurable disease, no dermatological disease and normal hepatic function were prospectively included. PCR and sequencing methods were used to analyze CES exon 3 (5841 G>A, 6046 G>A, 6174 G>A, 6320 G>A); CES UTR (823 C>G, 854 G>C); CDD (575 C>T, 771 C>G, 794 G>A, 942 C>G, 943 insC, 1052 A>C); TS genotype (2R/2R, 2R/3R, 3R/3R) and DPD (IVS14+1 G>A). Fisher’s exact test was used for comparisons. Results: 93 pts (45 BC/48 CRC) previously treated were included, median age 67 yrs (38–90). 31 pts experienced grade 3–4 toxicity: hand-foot syndrome (HFS) 15%, asthenia 6.4%, diarrhea 4.3%, vomiting 3.2%, mucositis 2% and anorexia 2%. Nearly significant correlation was detected between heterozygous (HT) and homozygous (HM) P of CDD gene (943 insC) and greater incidence of HFS than in the wild type (WT) (21.3%, 14.2% and 3.5% respectively) (p=0.055), and HM P of CES exon 3 (6046 G>A) and greater diarrhea rate than in the HT or WT (100%, 0% and 3.4% respectively) (p=0.08). 56 pts were evaluable for response (1 CR/23 PR/14 SD/18 PD). 92% of pts with HT and 100% with HM CES UTR (823 C>G) P obtained clinical benefit (CR+PR+EE) compared with 58% of patients with WT (p=0.04). 60% of pts with 2R/2R variant of TS and 87% with 2R/3R had clinical benefit compared with 47% of 3R/3R form (p=0.01). Conclusions: The occurrence of a single nucleotide P in CES UTR gene and some TS variants are associated with improved efficacy of C and can be useful to select patients for this treatment. The lack of statistical significance for grade 3–4 toxicity may be due to the low number of events. The study is ongoing No significant financial relationships to disclose.
Assessment of PI3 kinase as a druggable target in melanoma
Authors: S. A. Aziz, E. Pick-Golan, M. M. McCarthy, K. T. Flaherty, R. L. Camp, D. L. Rimm, H. M. Kluger
Journal: Journal of Clinical Oncology (2007)

8521 Background: PI3 (phosphatidylinositol-3) kinase is central to a major intracellular signal transduction pathway that influences numerous cellular functions, including growth, differentiation and survival. Drugs that target PI3 kinase have demonstrated preclinical activity, and are undergoing further development. The PI3 kinase inhibitor, SF1126 is expected to enter clinical trials in 2007. The hallmarks for a valuable drug target include differential expression between normal and malignant cells and an association with disease progression. PI3 kinase expression has not been thoroughly evaluated in melanoma. We sought to determine the expression and prognostic value of PI3 kinase in a large cohort of primary and metastatic melanomas and to compare the expression with that of benign nevi. Methods: Tissue microarrays containing 548 melanomas and 540 benign nevi were employed to assess PI3 kinase expression. We used a novel method of in situ automated quantitative analysis (AQUA) of protein levels. We applied S100 conjugated to Cy3 to identify a melanoma tumor mask within a histospot, and measured PI3 kinase expression levels using Cy5 conjugated antibodies within the mask. Continuous AQUA scores were correlated with clinical and pathological variables. Results: PI3 kinase expression was higher in melanomas than in nevi by unpaired t-tests (p &lt; 0.0001), and was significantly higher in metastatic than in primary specimens (p &lt; 0.0001). High PI3 kinase scores were associated with Clark levels of IV-V (p = 0.0126), Breslow thickness &gt; 2mm (p = 0.044) and absence of tumor infiltrating lymphocytes (p = 0.014). High PI3 kinase expression strongly correlated with decreased survival by Cox univariate analysis (p = 0.0024), but was not independent of disease stage. Conclusions: PI3 kinase expression is remarkably higher in malignant melanocytes than in benign nevi. Moreover, high PI3 kinase expression is associated with disease aggression, making PI3 kinase an attractive drug target for melanoma. This is the first large study assessing PI3 kinase levels in melanoma in a quantitative fashion. Assessment of the association between PI3 kinase levels and response to therapy is warranted. No significant financial relationships to disclose.
Clinical experience with fulvestrant in pretreated patients with advanced breast cancer.
Authors: S. Menjon Beltran, J. Garcia Garcia, E. Gonzalez Flores, V. Conde Herrero, E. Gonzalez Jimenez, V. Gutierrez Lomas
Journal: Journal of Clinical Oncology (2010)

e11511 Background: Considering the efficacy and tolerability of fulvestrant (F) in previous clinical trials with metastatic breast cancer, monitor the effectiveness of F in daily practice and to determine F clinical benefit (CB) in pretreated patients (pts) with hormone-receptor positive advanced breast cancer (ABC). Methods: 70 ABC pts treated with F 250 mg i.m. monthly were included. 46 pts with objective response assessment have been evaluated. Histology: 68.6% ductal, 24.3% lobular, 7.1% others. Median age: 62 (41-83). Hormone receptor status: RE+ RP+: 56 pts (80.0%), RE+ RP-: 11 pts (15.7%), RE- RP+: 3 pts (4.3%). Non visceral metastases 53 pts (75.7%) and visceral metastases: 17 pts (24.3%). Median chemotherapy and/or endocrine previous therapies 1.0 (0-7). Results: The mean of F doses was 10 (1-37). 36 pts (51.4.5%) experienced CB: 18 pts CR (25.7%), 7 pts PR (10.0%) and 11 pts SD ≥ 24 weeks (15.7%). There was a nonsignificant statistical trend to greater CB in first- and second-line treatments and patients with nonvisceral metastases. The median time to progression (TTP) was 25.17 months in pts with CB vs. 8.9 months in pts without CB (p<.0001). 33 pts (47.1%) experienced toxicity: pain at injection site not flushes 7 pts (10%), musculoskeletal disorders 6 pts (8.6%), gastrointestinal disturbances 4 pts (5.7%), and urinary infection 1 pt (1.4%). Conclusions: Fulvestrant showed an important clinical activity and time to progression even in heavily pretreated patients with ABC with a good toxicity profile. No significant financial relationships to disclose.
Preclinical evaluation of PARP inhibition as a treatment for endometrioid endometrial carcinomas.
Authors: K. J. Dedes, D. Wetterskog, A. M. Mendes-Pereira, R. Vatcheva, R. Natrajan, M. B. Lambros, C. J. Lord, A. Ashworth, J. S. Reis-Filho
Journal: Journal of Clinical Oncology (2010)

5065 Background: Loss of function of PTEN is the most common genetic defect in endometroid endometrial carcinomas (EEC). PTEN plays a pivotal role in the regulation of the AKT and mTOR signalling pathways and is reported to be inactivated in up to 80% of EECs. PTEN loss of function has recently been shown to cause genetic instability through defects in homologous recombination (HR) DNA repair of double strand breaks. Cancer cells with defective HR have an exquisite sensitivity to inhibitors of the poly(ADP) ribose polymerase (PARP) inhibitors. Recent data suggest PTEN deficiency may also lead to sensitivity to PARP inhibition. Methods: PTEN expression was tested in a panel of eight EEC cell lines by western blotting. Cells were tested for their ability to elicit phospho-γ-H2AX foci (a marker of induction of DNA damage) and RAD51 foci (a marker of competent HR DNA repair) when challenged with ionising radiation. The sensitivity of these cell lines to the PARP inhibitor KU0058948 was tested in vitro. PTEN was silenced and re-expressed in cell lines by generating stably transfected cell lines with either two short hairpin-RNAs against PTEN or with a pBABE retroviral PTEN expression vector, respectively. Results: Out of the 8 EEC cell lines, two cell lines expressed PTEN (Hec-1b, EFE-184). ECC cells lacking PTEN expression (Nou-1, Ishikawa, RL95-2, EN, AN3-CA, Hec-59) were unable to elicit HR DNA repair. PTEN deficient EEC cells showed a significantly greater sensitivity to KU0058948 than PTEN wild-type EEC cells (IC50 10−8M vs 10−4M, respectively). PTEN silencing in Hec-1b cells resulted in a reduced RAD51 foci formation and in increased sensitivity to PARP inhibition. PTEN re-expression in Ishikawa and Nou-1 cells resulted in enhanced RAD51 foci formation and in a lower sensitivity to KU0058948. Conclusions: Given that most EECs lack PTEN expression and that EEC cell lines lacking PTEN expression show an exquisite sensitivity to KU0058948, our results suggest that PARP inhibitors may constitute a novel therapeutic approach for the majority of EECs. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Merck AstraZeneca, Pfizer AstraZeneca
Incidence and outcomes associated with brain metastases (BM) in a three-arm phase III trial of gemcitabine in combination with carboplatin (GC) or paclitaxel (GP) versus paclitaxel plus carboplatin (PC) for advanced non-small cell lung cancer (NSCLC)
Authors: M. J. Edelman, C. P. Belani, M. A. Socinski, R. Ansari, C. K. Obasaju, M. J. Monberg, R. Chen, J. Treat
Journal: Journal of Clinical Oncology (2009)

8076 Background: A limited number of randomized phase III studies of advanced or metastatic NSCLC have included a mixed population of patients (pts) with and without BM at presentation. Analyses of pts with lung cancer from the 1970s and 1980s indicated that the incidence of BM at the time of diagnosis was approximately 10%. Methods: 1135 chemonaïve pts with stage IIIB or IV NSCLC were randomized to receive: G 1000 mg/m 2 d 1, 8 plus C AUC 5.5 d 1; or G 1000 mg/m 2 days 1 and 8 plus P 200 mg/m 2 d 1; or P 225 mg/m 2 plus C AUC 6.0 d 1. Stratification was based on stage, baseline weight loss, and presence or absence of BM. Cycles were repeated every 21 d up to 6 cycles or disease progression. Pts who developed BM as the only evidence of progression were able to be treated with whole brain radiation and steroids and remained on study. Results were retrospectively analyzed in by presence or absence of BM at study entry. Results: BM rates by subgroup were as follows (%): overall (17.1), nonsquamous (19.3), squamous (6.9), &lt;70 y (21.3), ≥ 70 y (7.1), female (19.2), male (15.7), Caucasian (16.7), African American (18.8%), Hispanic (22.2), PS 0 (12.9), PS 1 (19.7), weight loss &lt;5% (18.3), weight loss ≥ 5% (15.1), and stage IV (19.0). Among pts with (N=194) and without (N=941) BM, response rates=28.9% and 29.1%, median survival = 7.7 mos (95% CI: 6.7, 9.3) and 8.6 mos (95% CI: 7.9, 9.5), and median time to progression = 4.3 mos (95% CI: 3.4, 5.6) and 4.6 mos (95% CI: 4.2, 5.1), respectively. Rates of grade 3 or 4 adverse events were not different among pts with and without BM. Median survival among pts with BM was 7.6 mos for GC (N=66, 95% CI: 6.3, 10.1), 8.2 mos for GP (N=64, 95% CI: 4.6, 10.5), and 7.7 mos for PC (N=64, 95% CI: 6.1, 10.2). Conclusions: 1) The higher incidence of BM (17.1%) observed in this trial may be related to the increasing incidence of adenocarcinoma, or to the increasing sensitivity of imaging modalities. 2) There was no difference in response, time to progression or survival for pts with or w/o BM. [Table: see text]
Delay in conventional breast cancer treatment associated with alternative therapy usage
Authors: C. McNeil, F. Collinson, K. Smith, R. Dunleavey, J. Boyages, R. Kefford
Journal: Journal of Clinical Oncology (2004)

593 Background: Alternative therapies are used by between 28% and 83% of women with breast cancer, but their impact in causing deleterious delay in commencing empirically validated conventional therapies has been poorly documented. Methods: A retrospective qualitative study examined the clinical and psychological profiles of women presenting to Westmead and Nepean Hospitals (WNH) with breast cancer, over a 4 year period, after initially refusing conventional treatment in favor of alternative therapies. Results: Six patients were identified, aged 38 to 53 years, all with operable stage I-II breast cancer at initial presentation. Three patients had tertiary educational qualifications, one was a qualified oncology nurse. Elevated anxiety levels were noted in four patients, however only one had a significant past psychiatric history. All declined conventional therapy at initial presentation, choosing instead alternative therapies including high dose vitamin C, urine therapy and laetrile. One patient received prolonged alternative therapy from a registered medical practitioner. Reasons elicited for refusal of conventional management included perceived loss of personal control, dissatisfaction and lack of confidence in conventional treatments, and denial. At subsequent presentation all had advanced breast cancer with extensive fungating chest wall disease. The delay in commencement of conventional therapy was 6 to 24 months. Five patients accepted salvage conventional therapy, and responded for variable periods of up to 43 weeks. Three patients have so far died from their disease. Conclusions: Alternative therapy was used in isolation for potentially curable breast cancer by six women. Poor outcomes have been observed in all patients. The dangers of delay caused by ineffective alternative therapies may have been underestimated in a medico-political climate that favors accommodation of non-traditional adjuncts to cancer therapy. No significant financial relationships to disclose.
A phase 1 study evaluating the safety, pharmacokinetics, and efficacy of ABT-263 in subjects with refractory or relapsed lymphoid malignancies
Authors: W. H. Wilson, M. S. Czuczman, A. S. LaCasce, J. F. Gerecitano, J. P. Leonard, K. Dunleavy, A. P. Krivoshik, H. Xiong, Y. Chiu, O. A. O’Connor
Journal: Journal of Clinical Oncology (2008)

8511 Background: ABT-263 is a novel BH3 mimetic that binds with high affinity (Ki 1 nanoM) and inhibits multiple antiapoptotic Bcl-2 family proteins. ABT-263 displays potent mechanism-based cytotoxicity (EC50 1 microM) against human cell lines derived from lymphoid and small cell lung cancers. The anticipated ABT-263 associated toxicities are mechanism based, in particular, Bcl- XL mediated decrease in circulating platelet survival, Bcl-w mediated testicular toxicity, and Bcl-2 mediated effects on lymphocytes. Methods: The safety and pharmacokinetic (PK) profile of ABT-263 were studied in patients with relapsed or refractory lymphoid malignancies. For each 21-day cycle, subjects received ABT-263 orally QD for 14 consecutive days followed by 7 days off drug. The drug dose was doubled in each cohort until a grade 3 toxicity occurred, after which escalations were in 40% increments. Results: Currently, 30 patients have been enrolled in the lymphoma study completing the 10, 20, 40, 80, 160, 225 and 315 mg cohorts. One grade 3 dose limiting toxicity (DLT) occurred in each of the 160 and 315 mg cohorts (a URI and an ALT, respectively) resulting in expansion of those cohorts. Responses include: two patients with bulky CLL in the 40 mg cohort had 99% and 36% tumor reductions after cycles 8 and 7, respectively, one patient with bulky CLL/SLL in the 60 mg cohort had a 75% reduction at cycle 4, one patient with follicular lymphoma in the 80 mg cohort had a 20% tumor reduction after cycle 7 and one patient with NK/T cell lymphoma at 315 mg had a 75% reduction at cycle 2. These subjects remain on study with intrapatient dose escalation of the 40 mg patients. The PK profile of ABT-263 was linear and the average terminal half-life was 14 to 20 hours. ABT-263 reduced platelet levels in a dose-dependent manner. Grade 3 thrombocytopenia was observed in 5 patients without any bleeding. Conclusions: ABT-263 is a novel, orally bioavailable and active small molecule Bcl-2 family protein inhibitor that shows early evidence of activity in lymphoid malignancies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories
An animal model for chemotherapy-associated steatohepatitis (CASH) and its prevention by the oral administration of fatty acid bile acid conjugate (FABAC)
Authors: D. Keizman, N. Maimon, M. Ish-Shalom, D. Buchbut, M. Inbar, B. Klein, J. Bernheim, I. Goldiner, A. Leikin- Frenkel, S. Shpigel, F. Konikoff
Journal: Journal of Clinical Oncology (2009)

4098 Background: Preoperative chemotherapy (irinotecan and oxaliplatin), used in patients undergoing hepatic resection of colorectal liver metastases, is associated with the development of CASH. This hepatic injury increases the risk of perioperative morbidity and mortality. An animal model for CASH has not yet been described. Fatty acid bile acid conjugates (FABACs) are novel synthetic lipid molecules that were shown to prevent the formation of diet induced fatty liver. The present study was designed to establish an animal model of CASH and to use it to study the effect of FABAC on its occurrence. Methods: C57B1/6 mice were given different doses of intraperitoneally injected oxaliplatin and irinotecan. Once weekly administered oxaliplatin at a dose of 6mg/m 2 for a total dose of 24mg/ m 2 , was best tolerated and most consistently associated with CASH in comparison to higher doses of oxaliplatin or different irinotecan regimens. Thus it was chosen as the induction model for CASH. Subsequently, 32 mice were divided into a control group (no treatment, n=6), oxaliplatin group (n=14), and a CASH prevention group (n=12) treated by oxaliplatin and C20-FABAC (arachidyl-amido-cholanoic acid) at a dose of 150 mg/kg/day administered by gavage. The animals were sacrificed after 28 days. Their livers were homogenized and analyzed for fat content (measured as mg lipid/g liver tissue). Results: There were no significant differences in animal or liver weights between the groups. Liver fat content, was significantly lower (P&lt;0.0001) among the control (51.63 mg/g) and prevention (62.13 mg/g) groups versus the oxaliplatin group (95.35 mg/g). The difference between the control and prevention groups was not significant. To the best of our knowledge this is the first description of a model and a potential preventive treatment for CASH. Conclusions: C57B1/6 mice treated by intraperitoneal injection of weekly oxaliplatin at a dose of 6mg/m 2 for a total of 24mg/m 2 , can be used as a model for CASH. Oral FABAC therapy reduces the development of chemotherapy associated steatohepatitis in animals treated with oxaliplatin. No significant financial relationships to disclose.