tbuckley/cabot-search huggingface dataset:
8q24 and prostate cancer: Association with the risk of disease and meta-analysis.
Authors: N. A. Oskina, U. A. Boyarskikh, A. F. Lazarev, V. D. Petrova, D. I. Ganov, O. G. Tonacheva, G. I. Lifshits, M. L. Filipenko
Journal: Journal of Clinical Oncology (2011)

e15180 Background: Genome-wide association studies and subsequent replication studies have shown that single nucleotide polymorphisms (SNPs) in the chromosomal region 8q24 are associated with prostate cancer (PC) susceptibility. We examined the residents of the West Siberian Region of Russia to assess the contribution of SNPs rs6983267 and rs1447295 in the risk of sporadic PC. The group consisted of 393 Caucasian men with sporadic PC (mean aged 69.1 = 8.5 years). The group was selected from patients of the Altai Affiliated Department of N.N.Blokhin Cancer Research Center, Altai Regional Oncological Center and Krasnoyarsk Regional Oncologic Centre. Control group consisted of 384 Caucasian men (mean aged 61.3 = 16.6 years) without a history of cancer. All participants included in this study provided written informed consent. Methods: Genotyping was carried out by real-time PCR using competitive TaqMan probes. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% C.I.). We considered p-value below 0.05 to indicate statistical significance. We also performed a meta-analysis combining our result with 21 previous studies evaluating the association between rs1447295 and PC risk. The inclusion criteria were: (a) case–control studies evaluating studied SNPs and sporadic PC risk; (b) sufficient data for estimating an OR with 95%C.I. and (c) enough ethnicity information for subgroup analysis. OR and its 95%C.I. were used to evaluate the size effect. Results: The frequencies of genotypes in control DNA samples and in samples from patients with sporadic PC corresponded to the Hardy-Weinberg distribution in both groups. No significant association of rs6983267 polymorphic loci and PC development was detected (OR = 1.04; p=0.68). We observed association with PC for SNP rs1447295: the A-allele was associated with the risk of PC (OR(C.I.95%) = 1.74 (1.26-2.4), p = 0.00078) among men of the West Siberian Region. Meta-analysis of our result with previously reported studies of PC strongly support the association for this SNP (combined OR for rs1447295=1.37, 95%C.I. 1.32-1.43, p<10-6). Conclusions: Our study confirms the association between SNP rs1447295 on chromosome 8q24 and PC risk.
The Q141K single-nucleotide polymorphism impacts the transporter activity of ABCG2.
Authors: Kuniaki Morisaki, Robert W. Robey, Tim Nadjem, Csilla L. Ozvegy, Yasumasa Honjo, Lyn Huff, Alex Sparreboom, Balazs Sarkadi, Susan E. Bates
Journal: Cancer Research (2004)

2463  The ATP-binding cassette half-transporter ABCG2 has been implicated in oncology as a mediator of drug resistance, in pharmacology as an arbiter of drug absorption, and in normal physiology as a marker of stem cell populations. Three nonsynonymous single nucleotide polymorphisms (SNPs) have been described in the ABCG2 gene, V12M, Q141K and D620N. To determine if the SNPs would have an effect on drug transport, human embryonic kidney cells (HEK-293) were stably transfected with ABCG2 coding the SNP mutations V12M, Q141K, or D620N. Northern and immunoblot analysis confirmed expression of ABCG2 mRNA and protein, respectively. Transport and cytotoxicity studies were performed to evaluate the potential impact of the SNPs on protein function. Efflux of both mitoxantrone and Hoechst 33342 inhibitable by fumitremorgin C (FTC) was detected with all three SNP vectors. To detect differences in transport, surface protein expression was quantified using the antibody 5D3. FTC-inhibitable efflux of mitoxantrone was calculated for HEK 293 cells transfected with the SNPs as well as wild-type R482 and the gain-of-function mutants R482G and R482T ABCG2. When FTC-inhibitable mitoxantrone efflux was normalized to cell surface ABCG2 expression, cells transfected with variant Q141K ABCG2 had significantly lower values than wild-type R482 ABCG2 (p=0.0048). Further, in 4-day cytotoxicity assays with mitoxantrone, cells transfected with wild-type R482 ABCG2 had IC50 values 6.0-fold higher than cells expressing comparable levels of Q141K ABCG2, providing support for the observation that the Q141K SNP does impact drug transport. The vanadate-sensitive ATPase activity of ABCG2 in membrane fractions of Sf9 insect cells transfected with recombinant baculoviruses containing wild-type and SNP variants of ABCG2 was subsequently examined, and ATPase activity in the Q141K variant was 1.8-fold lower compared to wild-type ABCG2. The ATPase activities of the V12M and D620N variants were comparable to that of wild-type ABCG2. The results presented suggest that the Q141K SNP affects the transport efficiency of ABCG2 and individuals carrying this ABCG2 variant may be more sensitive to ABCG2 substrate drugs.
Pooled Treatment Analysis of Pediatric Patients with Defibrotide for Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome and Multi-Organ Dysfunction Following Hematopoietic Stem Cell Transplant
Authors: Nancy A. Kernan, Stephan A. Grupp, Kamalika Banerjee, Alison L. Hannah, Robin L. Hume, Bijan Nejadnik, Paul Richardson
Journal: Blood (2015)
Impact of anatomical location of positive lymph node on TNM classification in patients with node positive gastric cancer.
Authors: Masanori Tokunaga, Makoto Hikage, Rie Makuuchi, Yutaka Tanizawa, Etsuro Bando, Taiichi Kawamura, Masanori Terashima
Journal: Journal of Clinical Oncology (2016)

155 Background: In the 7th edition of TNM classification, node positive gastric cancer is subclassified into three categories (N1, 1-2 positive nodes; N2, 3-6 positive nodes; N3, 7 or more positive nodes) according to the number of positive lymph node (LN). However, anatomical location of positive LN is not taken into account in the TNM classification, although Japanese classification for gastric cancer had adopted anatomical location oriented nodal staging system and had shown relevance between location of positive LN and survival outcome. The aim of the present study is, therefore, to clarify the impact of anatomical location of positive LN on numerical number oriented, latest TNM nodal staging system. Methods: The present study included 1047 node positive gastric cancer patients who underwent curative gastrectomy at the Shizuoka Cancer Center between September 2002 and December 2014. Survival outcomes were compared between patients with positive extra-perigastric lymph node (PEPLN) and those with positive perigastric lymph node (PPLN) in each nodal stage according to the 7th edition of TNM classification. Results: The present study included 471 N1 patients, 309 N2 patients, and 267 N3 according to the 7th edition of TNM classification, and 5-year survival rates (5ysr) were 81.8%, 70.5%, and 51.9%, respectively. In the N1 group, 5ysr was 75.4% in patients with PEPLN, while it was 83.2% in those with PPLN, and the difference was not statistically significant (P = 0.105). It was also similar between patients with PEPLN (64.2%) and those with PPLN (73.8%, P = 0.343) in the N2 group. However, in the N3 group, survival outcome was significantly worse in patients with PEPLN (47.9%) than in those with PPLN (63.9%, P = 0.036). Conclusions: In the N1 and N2 group, involvement of extraperigastric LN did not have impact on survival outcome. On the contrary, in the N3 group, patients with PEPLN showed worse survival outcome than those with PPLN, and they could be potential candidates for intense postoperative adjuvant treatment.
Community oncology care delivery staffing model.
Authors: David C. Fryefield, Roberta Kafora, Lori Bradshaw-Hucko, Chris Tribble, Terry Jensen, Tom Chentnik, Roy Beveridge
Journal: Journal of Clinical Oncology (2012)

87 Background: In 2010, the US Oncology Network’s Clinical Advisory Council (CAC), a practice-based clinical leadership team, reviewed the care delivery process at 5 pilot community oncology clinics to determine how licensed and unlicensed clinical resources were used. The Lean Six Sigma methodology, which employs statistical analysis within a structured approach to problem-solving, was used to understand the required clinical activities of the practices within 3 primary areas. The objective of this pilot was to ensure patients receive timely, effective treatment from qualified personal in a cost-efficient model. Methods: A team led by a certified Master Black Belt studied tasks performed by licensed vs. non-licensed staff in the areas of physician services, treatment services and triage services at each practice. Based on the findings, tasks were realigned to maintain quality of care but to deliver care more efficiently. Results: Care Delivery processes comprised 95 tasks at baseline vs. 80 tasks in the redefined model. Within physician services, changes to workflow included rooming and clinic support (vitals, cleaning, and patient comfort) to be provided by Medical Assistants (MAs) instead of RN. RN duties were changed to MA supervision and tasks that require licensure. Changes to triage services included use of RNs to coordinate care and MAs for phone call screening, centralized triage (non-patient facing), and normal lab follow-up. Increased clarity of tasks and re-assignment of responsibilities reduced RN work load by 17% or 16.6 hours/day based on 120 patient visits. Each pilot site realized an annualized labor savings in excess of $100,000. This prospective, patient volume-based Care Delivery Staffing Model was adopted by the CAC as Network standard after completion of the pilot. Conclusions: Using Lean Six Sigma methods, the care delivery process was successfully re-designed such that clinical staff were re-aligned to better utilize each resource’s core competencies. Implementation of this care delivery model resulted in improved cost effectiveness while maintaining quality of care and also enabled prospective staff planning so that costs can be kept competitive in the future.
Evaluating the effects of monoclonal antibody therapies on pro-angiogenic growth factors in individual human colorectal cancer explants
Authors: J. S. Marry, H. Mulcahy, D. Fennelly, J. O'Sullivan
Journal: Journal of Clinical Oncology (2008)

15055 Background: Conventional in-vitro single cell lines cannot adequately assess the cellular effects of molecular targeted therapies since they lack peritumoral stroma and thus a vascular milieu. The monoclonal antibodies bevacizumab (anti-VEGF) and cetuximab (anti-EGFR) are in clinical use, though we lack markers predictive of response. We have developed a colorectal cancer explant model that allows us to assess the effects of anti-angiogenic therapies on individual patient's tumors. Methods: Tumor and matching normal tissue was obtained at surgery from 18 patients and subsequently cultured and treated with bevacizumab and cetuximab for 72 hours. Media from treated explant tissue was screened by ELISA for the secreted factors described above. 7 patients received palliative chemotherapy containing bevacizumab while one received cetuximab. Results: VEGF levels were lower in both tumor (p<0.01) and normal (p<0.01) tissue secretions treated with bevacizumab, while MMP levels were lower in normal (p=0.04), but not tumor media. There was a trend towards higher IL-8 levels in tumor secretions following bevacizumab treatment (p=0.06), but not in normal tissue explants. Cetuximab treatment resulted in reduced EGFR in tumor (p<0.01) and normal (p<0.01) secretions, but cetuximab had no significant effect on other secretion profiles. Normal tissue EGFR secretions were increased (p=0.03) and MMP9 levels reduced (p<0.01) by telomerase inhibition, with no effects seen in tumor secretions. In contrast, tumor co-treatment with telomerase inhibitor and bevacizumab resulted in increased VEGF secretion compared to bevacizumab alone (p<0.01). Serum and peripheral blood mononuclear cells from a subset of patients were assayed for similar markers and results compared with tissue. Individual patient profiles were generated and will be compared with matching clinical data,when mature, to determine any correlations. Conclusions: Ex-vivo tissue explant models have the ability to assess the biological effects of molecular treatments in individual colorectal cancer patients. Combining these results may allow us to develop a profile indicating response/resistance to these expensive treatments. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Merck
The effect of different doses of bevacizumab and irinotecan on tumor growth of nude mice bearing human colon cancer DLD-1.
Authors: Luo Cong
Journal: Journal of Clinical Oncology (2014)

518 Background: Anti-angiogenic therapy is an important therapeutic strategy in advanced colorectal cancer. However, the anti-angiogenic drug,such as bevacizumab(avastin) is expensive. So, clarifying whether different doses of avastin play the same effect in vivo is urgently needed. The aim of the study was to observe the different doses of avastin in combination with irinotecan in human colon tumor growth in nude mice and tumor angiogenesis. Methods: 21 nude mice inoculated with DLD-1 human colon cancer cells were randomly divided into four groups: sterile saline control (group A), 5mg/kg avastin plus irinotecan chemotherapy group (group B), 10mg/kg avastin plus irinotecan group (group C), and irinotecan chemotherapy group (group D). Drugs were administered in the first 1,5,9 days, mice were sacrificed in the 10th day after treatment, the tumor growth inhibitory rate was calculated and the tumor microvessel density (MVD) were detected by immunohistochemistry. Results: The tumor inhibition rate in groups B, C, and D were 62.85%, 47.91%, 39.59% respectively. A, B, C, and D groups’ MVD were 7.000 ± 0.71, 4.940 ± 0.58, 5.080 ± 1.25, 5.557 ± 2.04, The MVD in group B and C were significant different compared with group A by Dunnett's test, and the MVD expression difference between D, A groups and B, C groups did not reach statistical significance (P values were 0.086,0.083). Tissue necrosis was found in each group after HE staining of tumor tissue. Among them, the control group, mostly mild to moderate necrosis, and the necrosis area were increased after drug treatment. But there were no statistical differences of the necrotic area in drug treated groups graded by rank sum test (χ2 = 4.73, P = 0.193). And cell apoptosis was obviously seen in treated groups. Conclusions: Different doses of avastin with irinotecan inhibited the tumor growth on DLD-1 xenografted nude mice, Synergistic effects were observed in combination therapy, From cell morphology changes after staining with HE, we speculated that the mechanism may be related to the inhibition of tumor angiogenesis, and cell apoptosis increasing. The effect of 5mg/kg and 10mg/kg bevacizumab on tumor volume and MVD had no significant differences.
Cost-benefit analysis of AR-V7 testing in patients (Pts) with metastatic castration resistant prostate cancer (mCRPC) eligible for abiraterone (Abi) or enzalutamide (Enza).
Authors: Mark Christopher Markowski, Kevin D. Frick, James R. Eshleman, Jun Luo, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2016)

283 Background: The rising cost of oncology care in the US is an ongoing societal challenge, and identifying biomarkers that inform clinical decisions and reduce the use of ineffective therapies remains elusive. A splice variant of the androgen receptor, AR-V7, was found to confer resistance to Abi and Enza in men with mCRPC, but did not negatively affect responses to taxanes, suggesting that early use of chemotherapy may be a more effective option for AR-V7(+) pts. With the recent development of a CLIA-certified clinical assay for AR-V7 at Johns Hopkins, we hypothesized that AR-V7 testing in mCRPC pts may result in cost savings by avoiding futile treatment with Abi/Enza in men with AR-V7(+) disease. Methods: We calculated the cost savings of performing AR-V7 testing in mCRPC pts prior to starting Abi/Enza (and avoiding these drugs in AR-V7(+) men) versus treating all mCRPC pts with Abi/Enza (without use of the biomarker). We have set the cost of the AR-V7 assay at $1000. The cost of 3 months of Abi/Enza (the minimum time it would take to determine resistance, clinically) was approximated at $20,000. We estimated that 30,000 mCRPC pts per year are eligible for Abi/Enza in the US. Results: In our prior studies, about 30% of mCRPC pts previously treated with Abi/Enza had detectable AR-V7 in CTCs. Assuming an AR-V7 prevalence of 30%, about 9,000 AR-V7(+) mCRPC pts per year would receive ineffective treatment with Abi/Enza, at an estimated cost of $180 Million. The upfront cost of testing all mCRPC pts who are Abi/Enza-eligible for AR-V7 is $30 Million, resulting in a net cost savings of $150 Million. When performing a continuous cost-benefit analysis after assuming other prevalences of AR-V7 (ranging from 4% to 50%) and a range of costs for Abi/Enza ($2000 to $24,000 per 3 months), we determined that AR-V7 testing would result in a cost savings as long as the prevalence of AR-V7 is &gt; 5% (if the cost of 3 months of Abi/Enza remains at $20,000). Conclusions: AR-V7 testing in mCRPC pts (at $1000/test) is cost-beneficial when considering the current price of Abi/Enza, and may reduce the ineffective use of Abi/Enza leading to a net cost savings to the healthcare system.
Activity of fractionated radioimmunotherapy (RAIT) with 90Y clivatuzumab tetraxetan (90Y-hPAM4) plus gemcitabine (Gem) in advanced pancreatic cancer (APC): Final results from a two-part study.
Authors: Allyson J. Ocean, Michael J. Guarino, Kenneth Lee Pennington, Gregory M. Springett, Seza A Gulec, Tanios S. Bekaii-Saab, Alberto J. Montero, Edith P. Mitchell, John S Kauh, Max W. Sung, David V. Gold, Heather Horne, William A. Wegener, David M. Goldenberg
Journal: Journal of Clinical Oncology (2012)

227 Background: A Phase I/II trial was undertaken to evaluate repeated cycles of 90 Y-labeled anti-mucin humanized mAb ( 90 Y-hPAM4) plus Gem as first-line therapy in Stage 3-4 APC. Methods: Pts received Gem once-weekly x 4 with 90 Y-hPAM4 on wks 2, 3 and 4, with cycles repeated until progression or unacceptable toxicity. In Part I, pts were treated in cohorts with escalating 90 Y doses and Gem fixed at a low 200 mg/m 2 dose for radiosensitization. In Part II, the Gem doses were increased up to standard levels, with 90 Y doses fixed for first cycle, but decreased for subsequent cycles. Tumor responses were assessed by CT, FDG/PET and serum CA19-9; safety by NCI-CTCv3. Results: Of 100 untreated pts enrolled, 10 withdrew early, while 90 (73 stage IV) received 1-4 cycles. In Part I, 38 pts received 90 Y-hPAM4 weekly x 3 at 90 Y doses of 6.5 (N=4), 9 (N=12), 12 (N=17) or 15 (N=5) mCi/m 2 , with the same cycle repeated 1-3 times in 13 pts. Grade 3-4 platelets or ANC developed in 20/38 (53%) after cycle 1 (all reversible to Grade 1) and in all retreated pts (irreversible in 4/9 pts at 12 or 15 mCi/m 2 ). There were 3 febrile neutropenias, 4 other infections treated with IV antibiotics, but no major bleeding or other AEs. By CT-RECIST criteria, 6 pts (16%) had PRs and 16 (42%) had stabilization as best response (58% disease control). After cycle 1, 52% (13/25) with PET-avid images became negative or had &gt;25% SUV reduction, and 33% (9/27) with elevated CA19-9 levels decreased by &gt;50%. The median overall survival was 7.7 mo., but 11.8 mo. for retreated pts [46% (6/13) survived ≥1 yr.], with improved efficacy at higher 90 Y doses. In Part II, 52 pts received 12 mCi/m 2 90 Y-hPAM4 x 3 with Gem doses of 200 (N=17), 600 (N=8) or 1000 mg/m 2 (N=27), with 13 pts now retreated at 90 Y doses of 6.5 or 9 mCi/m 2 . Results so far indicate no advantage to giving higher doses of Gem with RAIT. Toxicity, response and survival data for this group will be presented at the conference. Conclusions: Fractionated RAIT with 90 Y-hPAM4 combined with low-dose gemcitabine appears to be a manageable and active first-line therapy for APC. It may provide comparable efficacy yet less toxicity compared to other regimens.
Phase II trial of pegylated liposomal doxorubicin (PLD), rituxan, cyclophosphamide, vincristine, and prednisone in aggressive B-cell non-Hodgkin's lymphoma
Authors: H. Gu, A. Tulpule, N. Berman, C. Duran, S. G. Groshen, L. Buchanan, W. Boswell, B. Nathwani, A. M. Levine
Journal: Journal of Clinical Oncology (2008)

8563 Background: The R-CHOP regimen has become the standard of care for treatment of patients with aggressive B-cell lymphomas. Pegylated liposomal doxorubicin (PLD) has an improved pharmacokinetic profile over conventional doxorubicin with decreased cardiotoxicity. In a phase II study we substituted PLD for conventional doxorubicin in the R-CHOP regimen to define the toxicity profile and obtain data on efficacy Methods: All patients were treated with PLD 40mg/m2, cyclophosphamide, 750 mg/m2; vincristine 2.0 mg; all given IV on day 1. Prednisone, 100 mg was given orally on days 1–5. Rituxan, 375 mg/m2 IV day 1 was added to the regimen starting cycle 2. Chemotherapy cycles were repeated every 21 days. Results: 67 patients with a median age of 53.5 years (range 20–77) have been accrued. All patients had CD20+ positive lymphoma with diffuse large cell in 57, high grade not otherwise specified in 4, and follicular grade 3 in 11. Four patients had both diffuse large cell lymphoma and follicular lymphoma. 51 patients had stage III (9) or IV (42) disease. 43 had elevated serum LDH levels and an intermediate or high risk IPI score. Toxicities have been primarily hematologic with transient grade 3 or 4 neutropenia in 35 patients; grade 3 or 4 anemia in 11 patients; and grade 3 or 4 thrombocytopenia in 5 patients. Eight patients experienced neutropenic fever. Non-hematologic side effects of note are 8 patients with grade 3 or 4 GI side-effect. Ten patients experienced grade 2 or 3 palmer-planter erythrodysesthesia (PPE). Of the 47 patients evaluable for response, 35 have had a complete remission (75%), 11 had a partial remission (23%). Median duration of response was 9.1 months (range 0.7 to 38.8 months). 15 patients were inevaluable for response. Reasons for coming off study prior to response evaluation included PPE in 5, death due to lymphoma in 4, patient refusal to continue treatment in 3, early progression of disease in 1, death from GI perforation in a patient with gastric lymphoma, and ileus due to vincristine in 1 patient. The remaining 5 patients are too early to evaluate. Conclusions: Our results show that PLD substituted for conventional doxorubicin in the R-CHOP regimen is an active regimen for aggressive NHL. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Ortho Biotech Oncology