tbuckley/cabot-search huggingface dataset:
Prevalence of BRCA1 and BRCA2 founder mutations in Ashkenazi Jewish (AJ) families with breast cancer (BC) and pancreatic cancer (PC)
Authors: M. C. Marcotrigiano, E. Wadsworth, L. Balistreri, A. Schluger, K. Offit, M. Robson
Journal: Journal of Clinical Oncology (2005)

9549 Background: Germline mutations in BRCA2 have been associated with an increased risk for PC. Breast-pancreas (BP) families with BRCA1 mutations have also been observed. The purpose of this study was to evaluate the prevalence of germline BRCA mutations in BP families. Methods: Clinical databases were reviewed to identify AJ families meeting the following criteria: 1) proband or at least one individual in kindred with BC before age 50, ovarian cancer (OC) at any age, or both, 2) proband or a first-, second- or third degree relative (FDR, SDR, TDR) with PC, and 3) affected proband tested for the 3 common AJ founder BRCA mutations (BRCA1 185delAG or 5382insC, BRCA2 6174delT). Results: 57 families met the above criteria. BRCA1 or BRCA2 mutations were identified in 25 of 57 families (43.9%). BRCA1 mutations (12 - 185delAG, 2 - 5382insC) were observed in 14 of 25 families with mutations (56% of families with mutations; 24.6% of all families). BRCA2 6174delT was observed in 11 families (44% of families with mutations; 19.3% of all families). Mutations were found in 15 of 44 (34.1%) families with BC and PC but no OC (9 - BRCA1, 6 - BRCA2). Mutations were found in 10 of 13 (76.9%) families with OC and PC, with or without BC (5 - BRCA1, 5 - BRCA2). Conclusions: A family history of PC appears to increase the likelihood of identifying a BRCA founder mutation in AJ probands with early-onset BC or with OC. Furthermore, BRCA1 mutations are as common as BRCA2 mutations, suggesting that BRCA1 mutations are associated with an increased risk for PC. No significant financial relationships to disclose.
Presence of Unbalanced Chromosomal Translocations Independently Predicts for Treatment Failure, Short Treatment-Free (TFS) and Overall Survival (OS) in B-Cell Chronic Lymphocytic Leukemia (B-CLL) Patients Treated with Cladribine.
Authors: Eric W. Van Den Neste, Valérie Robin, Julie Francart, Anne Hagemeijer, Michel Stul, Andre Delannoy, Anne Sonet, Sabrina Costantini, Augustin Ferrant, Véronique Deneys, Annie Robert, Lucienne Michaux
Journal: Blood (2006)
Phase I study of LY573636-sodium, an acylsulfonamide anti-cancer compound with a novel mechanism of action, administered as 2-hour IV infusion in patients with advanced solid tumors
Authors: R. L. Ilaria, G. R. Simon, M. Sovak, M. K. Burton, A. L. Cleverly, A. K. Sykes, D. P. De Alwis, M. M. Wagner, D. R. Spriggs
Journal: Journal of Clinical Oncology (2007)

2515 Background: LY573636 -sodium (hereafter referred to as LY573636 ) is a novel anti-cancer compound that induces apoptosis by a mitochondrial-mediated mechanism. Methods: A phase I study was conducted to determine the maximum tolerated dose (MTD) and pharmacokinetic (PK) profile of LY573636 administered as an intravenous infusion over 2 hours every 21 days. Results: 53 patients (pts) were enrolled on study, 16 males, 37 females, with a median age of 58 (range: 18–83). LY573636 was dose-escalated using a flat dosing paradigm in the first 34 patients (range 100 mg to 2400 mg). PK analysis of this cohort revealed that LY573636 had a low total plasma clearance (CL = 0.02L/hr) and terminal elimination half-life of approximately 340 hours due to high-albumin binding (∼99%). The dose limiting toxicity (DLT) for the flat dose escalation was bone marrow (BM) suppression, which included CTC (ver2) grade 3/4 thrombocytopenia/neutropenia. In some patients, significant BM suppression occurred in cycle 2 and later, attributed to the accumulation of albumin-bound drug with repeated flat dosing. Based on these findings, the dose-finding strategy was modified to an idealized dosing paradigm which calculated LY573636 doses based on pt lean body weight, and used a loading/maintenance dose regimen to achieve a specific Cmax target value. All 3 pts in the first 400 μg/mL Cmax cohort completed at least 2 cycles and no DLTs were reported. Of the 16 pts enrolled to the 420 μg/mL targeted dose group: 1 pt reported a DLT, a transient grade 3 elevation of ALT/AST which did not recur in subsequent cycles; 8/16 pts received 4 or more cycles prior to disease progression and 2 remain on treatment. Overall, 23/53 pts had stable disease (SD) after 2 or more cycles. Seven pts received &gt;8 cycles (SD &gt; 6 mos), including heavily pre-treated pts with ovarian cancer, non-small cell lung cancer, soft tissue sarcoma, and thymoma. Conclusions: LY573636 is a novel anti-cancer compound with a unique mechanism of action. The most common DLT was BM suppression. The individualized, target Cmax dose of 420 μg/mL has been taken forward into phase II clinical trials. No significant financial relationships to disclose.
Radioimmunotherapy (RIT) of refractory or relapsed Hodgkin’s lymphoma with 90Yttrium-labeled antiferritin antibody
Authors: D. Decaudin, J. Kadouche, R. Levy, M. Belhamiche, P. Arnaud, J. L. Alberini, F. M. Lokiec, A. P. Pecking
Journal: Journal of Clinical Oncology (2006)

2534 Background: The aims of this study were to evaluate (1) the tumor targeting of 111 Indium-labeled rabbit polyclonal antiferritin antibody (Ab) and (2) the therapeutic efficacy of 90 Yttrium-labeled antiferritin Ab in relapsed or refractory Hodgkin’s lymphoma (HL) patients (pts). Methods: After obtention of the patients’ consent, the protocol included a first intravenous injection of 2 mg of antiferritin Ab labeled to 111 MBq (3 mCi) of 111 Indium followed by immunoscintigraphy at time 24 and 48 hours and, in case of tumor targeting, one or more intravenous injections of 90 Yttrium-labeled antiferritin Ab at various activities. Results: Ten patients were included in the study: median age 32 years (range: 18–43 years); sex ratio M/F 9; stages III and IV at the time of RIT 1 and 9 pts, respectively; median number of chemotherapy regimens 3 (range: 2–4); number of autografted pts 8; number of previously irradiated pts 9; response to last chemotherapy: 6 PR and 4 progressions. All immunoscintigraphies showed a tumor targeting by 111 Indium-labeled antiferritin Ab. Nine patients were treated, one case died of HL evolution. Five pts received one 90 Yttrium-labeled antiferritin Ab injection, three pts 2 injections (0.5, 5 et 14 months after the first one), and one pt 4 injections (3, 9 et 16 months after the first one). Median injected activity was 13 MBq/kg (0.35 mCi/kg)(range: 7–15 MBq). Among the 9 treated pts, 1 CR, 6 PR, 1 stable disease, and 1 tumor progression were observed (ORR 78%). The median duration of responses were 8 months (range: 7–12 months). Toxicity was mainly hematological, with neutropenia and anemia of grades 1 or 2, and thrombopenia of grades 2 and 3; one pt presented a generalized convulsive crisis 24 hours after the therapeutic injection, without etiologic evidence. Conclusion: These results confirmed those that have been reported by Vriesendorp and Quadri and showed that rabbit polyclonal antiferritin Ab targeted HL tumor sites and had an important therapeutic potential in this discrepancy situation. They warranted therefore further multicentric prospective trials. [Table: see text]
Luring the vocationally trained back
Authors: J. M Chapman
Journal: BMJ (1995)

due to adhesions as a result of mesh being in contact with viscera are unknown.This contrasts with the low long term recurrence rate of less than 0-5-2%, minimal complications, and no deaths after many thousands of elective open repairs in unselected patients reported from many centres.If comparative trials are to be carried out then it is important that local anaesthesia is used for the open repair.Payne et al,3 Brooks,4 and Rudkin and Maddern5 have done so, and the latter two papers favoured the open mesh technique.Cost effectiveness must be considered.Taylor and Loosemore report on 700 laparoscopic pro- cedures.Laparoscopic disposables cost up to about ,C450 a case, so C315 000 would be required.Disposables for a mesh repair are £35 and would thus amount to £24 500 for 700 repairs.This difference in costs cannot be justified.Training surgeons in the laparoscopic technique is associated with a long learning curve and extra indirect costs.There are about 2500 general surgeons in England and Wales.I have taught experienced general surgeons the mesh techniques in a day.Brooks concluded that the open mesh repair (with local anaesthesia) is a "minimally invasive procedure, is appropriate for the greatest number of patients, is the least expensive and has the fewest short-and long-term complications."4Already three major hospitals in California have banned the laparoscopic hernia operation.
Use of a thoracic oncogeriatric assessment (TOGA) to predict surgical outcomes.
Authors: T. Weigel, A. Kothari, T. Bretl, K. Block, A. Munoz-del-Rio, N. K. LoConte
Journal: Journal of Clinical Oncology (2010)

e19528 Background: Surgery remains the primary therapy for most thoracic malignancies yet evidence exists that elderly patients often are not offered curative surgeries. No concise, assessment tool currently exists to easily and objectively quantify risk in geriatric patients considering thoracic surgery. The goal of our study was to develop a pre-operative thoracic onco-geriatric assessment (TOGA) which could be administered by providers during a routine preoperative visit and would successfully estimate surgical risk in geriatric patients undergoing thoracic surgery. Methods: Patients ≥70 years old were recruited to participate in a prospective study that involved preoperative administration of a panel of validated functional and cognitive screening tests including: Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), Geriatric Depression Screen (GDS), Brief Fatigue Inventory (BFI), Eastern Cooperative Oncology Group Performance Status (ECOG PS), Mini Mental State Exam (MMSE), and Mini Nutritional Assessment (MNA). Total sample size was set at 60 pre-operatively, with the option to increase accrual if analysis was underpowered due to unexpectedly low patient outcomes. Results: Interim analysis was conducted on first 60 patients: 20 with esophageal, 33 with lung, and 7 with metastatic lesions between August, 2007 and February, 2009. Overall thirty day and overall mortality was 1.6% (1/63) and 4.8% (3/63). Increasing ECOG PS score was significantly correlated to incidence of major complications (r=0.34, p=.03). Mean IADL was .14 in patients discharged to a location other than their home, compared to .04 in those discharged to their home (p=.02). Patients who had impaired cognition or nutritional status, based on the MMSE or MNA scores, had longer length of stays than those with normal scores (MMSE: 7 vs. 4, p=.08; MNA: 5 vs. 3; p=.04). Conclusions: An abbreviated TOGA comprised of the ECOG PS, ASA, IADL, MNA, and MMSE may help predict outcomes and place of discharge for geriatric patients being considered for thoracic surgery. Future studies will focus on this abbreviated TOGA in hopes that it will enable geriatric patients and their physicians to make more informed treatment choices. No significant financial relationships to disclose.
Abstract 12940: Clinical Outcome of Drug-Eluting Stents Implantation for In-Stent Restenosis of Sirolimus-Eluting Stent
Authors: Masako Misaki, Akira Sato, Kentarou Yoshida, Daisuke Abe, Noriyuki Takeyasu, Kazutaka Aonuma
Journal: Circulation (2012)

Background: Treatment of in-stent restenosis (ISR) is a challenging clinical problem. The aim of the present study was to evaluate the clinical outcomes after treatment with drug-eluting stent (DES) implantation in patients with ISR of Sirolimus-eluting stent (SES). Methods: A total of 4261 patients who underwent percutaneous coronary intervention (PCI) were registered in Ibaraki coronary assessment study (ICAS) multi-center registry from 2007 to 2011. Among these patients, 430 patients (69.3±10.3 year-old, 78%male) were enrolled for treatment with DES implantation with either SES (n= 153), Paclitaxel-eluting stent (PES) (n=131), Zotarolimus-eluting stent (ZES) (n=45), or Everolimus-eluting stent (EES) (n=101) for treatment of SES-ISR. Major adverse cardiac event (MACE) was defined as all cause death, myocardial infarction (MI), or target lesion revascularization (TLR). Results: MACE was significantly higher in PES group than SES group and EES group (12.9 vs 5.2%, p=0.022, 12.9 vs 8.9%, p=0.018). There we...
Decitabine therapy in patients with AML or MDS and chromosome 5, 7, or 8 abnormalities.
Authors: S. R. Mohan, M. A. Sekeres, Y. Saunthararajah, J. P. Maciejewski
Journal: Journal of Clinical Oncology (2010)

6555 Background: Though cytogenetic abnormalities have a major prognostic impact in MDS and related myeloid malignancies, the IPSS and other classification systems have been derived using patients (pts) who received supportive care only. However, most pts receive 1 or more forms of treatment and prognostic scoring is likely to be affected by modern therapies. Regardless of their role in IPSS and related schemes, high-risk cytogenetic lesions likely convey a risk of refractoriness to most therapies, but specific modalities may be more or less effective in pts with certain chromosomal abnormalities, as shown, for example, with del5q and lenalidomide. DNA methyltransferase inhibitors, now FDA-approved for use in MDS, lead to responses in a significant minority of pts but predictive markers of response are not yet known. Specific chromosomal lesions could constitute such markers, as suggested by recent reports that del7/7q pts may show favorable response rate to hypomethylating agents. Methods: To identify prospective chromosomal markers of responsiveness or refractoriness to hypomethylating agents, we retrospectively evaluated by combined regression analysis 3 clinical trials of decitabine in 243 pts with advanced-stage MDS or AML; 104 pts had cytogenetic abnormalities of chromosomes 5, 7, and/or 8. Results: Of 62 pts with del5q who received decitabine, no difference in objective response rate (ORR) was found compared to 181 pts without this lesion (21% vs. 18%, p = 0.57). Consistent with the known poor prognostic impact of del5q in AML/MDS this defect was associated with poor overall survival (OS) (274 d vs. 489 d, p < 0.0001). Of 66 pts with del7/7q who received decitabine, no difference in ORR was observed compared to 177 pts without del7/7q (20% vs. 18%, p = 0.77) but carriers of this defect showed decreased OS (319 d vs. 485 d, p = 0.0002). For 64 pts with chromosome 8 abnormalities, there was no difference in ORR to decitabine vs. 179 pts without (22% vs. 17%, p = 0.42) and no difference in OS (289 d vs. 442 d, p = 0.07). Conclusions: We conclude that recurrent chromosomal abnormalities including del5q, del7/7q and tri-8 do not constitute selective markers of responsiveness to decitabine and hypomethylating therapy does not alter their impact on OS. No significant financial relationships to disclose.
Effect of zoledronic acid combined with cisplatin and paclitaxel on inhibition of non-small cell lung cancer cell lines
Authors: Z. Gao, B. Han, J. Teng
Journal: Journal of Clinical Oncology (2009)

e19095 Backgrounds: Recent studies reported that zoledronic acid, a biphosphonate with proposed apoptotic activity, could cause a direct antitumor effect. Our prior study [J Clin Oncol 26: 2008 (May 20 suppl; abstr 19116)] reported that Zoledronic acid combined with Cisplatin shows significantly synergistic antitumor effects on lung cancer cell line A549 and subcutaneous implanted tumor on nude mice. Investigate whether zoledronic acid, augmented the cytotoxicity of cisplatin and/or paclitaxel in A549 lung cancer cell line. Methods: This cell line was subjected to different concentrations of the above chemotherapeutic agents and zoledronic acid. Cytotoxicity was assessed by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide) assay. Flow cytometry was used to examine cell cycle,cell apoptosis rate. Results: Zoledronic acid in in 50 micromolar (mM) concentration augmented the cytotoxicity by cisplatin in 10μmol/L and paclitaxel in 5μmol/L. Zoledronic acid could inhibit the proliferation of lung cancer cells in vitro,which was associated with arresting of G1 phase and inducing apoptosis by a time-dependent and dose-dependentmanner. The apoptosis rate of cell increased after zoledronic acid combined with cisplatin and/or paclitaxel. Conclusions: Zoledronic acid can induce apoptosis and block cell cycle of lung cancer cells. Zoledronic acid has also shown synergistic antitumor effects when combined with cisplatin and/or paclitaxel. The clinical potential of this finding should be further studied. No significant financial relationships to disclose.
Distribution of <i>UGT1A1</i> (TA) polymorphisms in Caucasian and Asian subjects
Authors: J. Liu, K. Qu, Y. Ren, A. Sferruzza, R. A. Bender
Journal: Journal of Clinical Oncology (2006)

2063 Background: The hepatic isoform 1A1 of uridine diphosphate glucuronosyltransferase (UGT) is responsible for glucuronidation and detoxification of SN-38, the active metabolite of irinotecan. The presence of an additional TA repeat in the TATA sequence of the UGT1A1 gene is a common polymorphism, leading to a significant decrease in SN-38 glucuronidation. Patients with the UGT1A1 (TA) 7 allele (either [TA] 6/7 or [TA] 7/7 ) are more likely to experience severe neutropenia and diarrhea following irinotecan chemotherapy. We assessed the distribution of the UGT1A1 (TA) polymorphism in Caucasian and Asian subjects. Methods: We used a fluorescent PCR-based assay to detect UGT1A1 (TA) polymorphisms in 129 healthy subjects (52 Caucasian, 34 Chinese, 36 Filipino, and 7 Japanese). The chi-square test was used to assess between-group differences in the distribution of UGT1A1 (TA) genotypes. Results: UGT1A1 (TA) genotype distribution differed significantly between Caucasian and Asian subjects (P = 0.003). The UGT1A1 (TA) 6/7 and (TA) 7/7 genotypes were more common in Caucasians than Asians. Genotype distributions did not differ significantly between men and women in either group ( Table ). Conclusions: The frequency of the deleterious UGT1A1 (TA) 7 polymorphism was greater in Caucasians than in Asians; genotype frequencies were consistent with previous reports. In both groups, UGT1A1 (TA) genotype distributions were similar in men and women. [Table: see text] No significant financial relationships to disclose.
Serum lactate dehydrogenase (LDH) changes during sunitinib treatment in patients with renal cell carcinoma (RCC)
Authors: M. Mego, T. Salek, K. Rejlekova, Z. Sycova-Mila, J. Obertova, J. Mardiak
Journal: Journal of Clinical Oncology (2008)

16086 Background: Increase in serum LDH levels predicts a poor outcome in a spectrum of neoplastic diseases. Based on a clinical observation that several RCC patients receiving sunitinib developed transient increase of LDH, we perfomed retrospective, observational study to describe LDH changes and correlate them with clinical outcome in this patient population. Methods: 41 consecutive patients (26M/15F) with RCC were treated from November 2005 to October 2007, with sunitinib at our Institution. Median age was 59 years (range 45–69 years). Data regarding LDH level, treatment response and time on therapy were recorded. Additionally, medical data regarding other causes of LDH elevation were reviewed. Patients with known causes of LDH elevation not related to sunitinib were excluded. Results: After initiating the therapy with sunitinib we observed the elevation of LDH that was more than 1.5 times of initial level in 76% of patients (Table 1). Median time to peak elevation of LDH was 4 weeks (range 2–10 weeks). The difference between initial and peak level of LDH was significant (p=0.0001). Mean peak elevation of LDH was 2.5-times above initial level (range 1.2–25). Subsequently during treatment we observed decrease of LDH level. Median time to nadir LDH level from start of therapy was 12 weeks (range 10–23 weeks). We didn’t find correlation between LDH elevation, response or toxicity. Conclusions: This is the first study to document the common occurrence of sunitinib-associated transient LDH elevation in RCC patients in the beginning of therapy. Because LDH, VEGF and VEGFR are regulated by hypoxia inducible factor, we suppose that this elevation could be mediated by feed-back due to inhibition of VEGFR by sunitinib. Another explanation is sudden tumor and/or tissue hypoxia induced by inhibition of VEGFR soon after starting therapy with sunitinib. Based on this observation we suggest that physicians should be aware of transient elevation of LDH since it could be misinterpreted as expression of disease activity. LDH changes during sunitinib therapy. mean ± SE** range initial level of LDH (μkat/L)* 6.0 ± 0.62 2.4 - 19.6 peak level of LDH (μkat/L) 16.4 ± 2.82 3.5 - 69.5 nadir level of LDH (μkat/L) 5.3 ± 0.66 2.0 - 21.0 * institutional range of LDH is 1.67–4.0 ukat/L;** standard error No significant financial relationships to disclose.
The unique molecular signatures of nodular and superficial spreading melanoma
Authors: A. E. Rose, J. Wang, A. Pearlman, N. Doudican, E. Hernando, S. J. Orlow, D. Polsky, H. Ostrer, I. Osman
Journal: Journal of Clinical Oncology (2009)

9047 Background: Primary nodular melanoma (NM) patients have a relatively poor prognosis compared to superficial spreading melanoma (SSM) patients. The disparity is generally attributed solely to NM's advanced thickness at presentation. In this study we attempted to define molecular signatures of NM and SSM that may explain their clinical differences. Methods: We performed an in silico gene expression analysis of 2 public data sets consisting of 36NM and 54 SSM primary melanoma tissues (CCR 2007;13 and JNCI 2006;98). We then utilized DNA microarray to generate gene expression profiles of a panel of 22 melanoma cell lines (2SSM, 4 NM, 12 met, 4 melanocytes). Differentially expressed genes and over-represented pathways in NM and SSM were identified based on a pooled analysis of the 3 data sets. We then used SNP array to define genomic alterations unique to NM and SSM but not altered in normal melanocytes. Finally, we correlated SNP array with gene expression. Results: Genes significantly overexpressed (p&lt;0.05) in NM showed over-representation of pathways related to MAPK signaling (p=0.05) and cytoskeleton organization (p=0.02), while SSM showed over-representation of cell communication (p=0.05) and primary metabolic processes (p=0.002). Notable correlations between gene expression and copy number alteration in NM include increased copy number/overexpression of SOX5 (transcription factor related to embryonic development and cell fate) and the downregulation/deletion of ST14 (suppression of tumorigenicity 14). SSM demonstrated concordance of increased copy number/overexpression of EZR (cell adhesion protein implicated in human cancer) as well as PALLD (a protein related to motility, adhesion, and extracellular matrix interactions). Notable SSM genes showing correlation between downregulation/deletion include BNIP3 (a pro-apoptotic protein) and MTAP (often co- deleted with tumor suppressor p16). Conclusions: Simultaneous integration of gene expression with SNP array revealed molecular signatures characteristic of NM and SSM. These results suggest that NM and SSM are distinct biologic entities and that molecularly targeted adjuvant therapy may be more effective if tailored to the molecular signatures of melanoma subtypes. Validation is necessary to draw further conclusions. No significant financial relationships to disclose.