tbuckley/cabot-search huggingface dataset:
Subsequent endocrine therapy after resistance to ethinylestradiol treatment for the late-stage metastatic breast cancer: A retrospective cohort study.
Authors: Toshinari Yamashita, Yutaka Yamamoto, Mutsuko Ibusuki, Touko Inao, Mitsuhiro Hayashi, Aiko Sueta, Takashi Takeshita, Katsumasa Kuroi, Hirotaka Iwase
Journal: Journal of Clinical Oncology (2014)

148 Background: Aromatase inhibitor (AI) is a most commonly used as the endocrine therapy in postmenopausal hormone-dependent breast cancer. Paradoxically, estrogen additive therapy using ethinylestradiol can be useful after long-term estrogen deprivation therapies with AI. Furthermore, there is a possibility of the beneficial effect of AI or fulvestrant as a subsequent endocrine therapy after EE2 failure. Methods: Ethinylestradiol (EE2; 3mg/day, TID) therapy was performed in 20 patients with metastatic breast cancer (median; 62 years-old, the mean observation time: 13.6 months.), who were heavily treated by sequential endocrine therapies (3rd or more line) including cytotoxic chemotherapies. We examined the efficacy of a subsequent endocrine therapy of AI or fulvestrant after becoming resistance to the EE2 therapy in the patients who got the disease control by the prior EE2 therapy. The primary endpoint was clinical benefit rate (CBR) and the secondary endpoint was time to treatment failure (TTF). (Registration number; UMIN 000002831, additional analysis). Results: Median TTF of EE2 treatment was 46 weeks (23-62+, 2 cases were ongoing). The response rate was 41% (9/22), the clinical benefit rate was 50% (11/22). The stable disease (&lt; 6 months) was 18% (4/22) and another 3 cases were judged as progressive disease. Four cases withdrew due to nausea, fatigue and muscle-skeletal pain. In 20 cases progressed after disease control (SD or more) of EE2, a subsequent endocrine therapy, fulvestrant for 10 cases and AI for 10 cases, was performed. Fulvestrant group showed 50% (3 in 6) of CBR and 15 weeks (5-55+) of TTF, and AI-treated group showed 43% (3 in 7) of CBR and 19 weeks (5-33+) of TTF. Two in three cases, who became resistance to anti-estrogen treatment, got long SD by further EE2 re-therapy. Conclusions: Some cases showed clinical benefits of a subsequent therapy by AI or fulvestrant after becoming to EE2 failure. Taken together, sequential use of estrogen and anti-estrogen therapy (vice versa) could be one of the options as a salvage endocrine therapy for the patients with end-stage breast cancer.
Antibody-dependent cellular cytotoxicity (ADCC) in COG ANBL0032: A phase III randomized trial of chimeric anti-GD2 and GM-CSF/IL2 in high risk neuroblastoma following myeloablative therapy and autologous stem cell transplant (ASCT)
Authors: A. L. Yu, A. Batova, R. Gribi, M. Diccianni, L. Bridgeman, D. Geske, W. London, A. Gilman, F. Ozkaynak
Journal: Journal of Clinical Oncology (2004)

2582 Background: ADCC plays an important role in the efficacy of anti-cancer monoclonal antibody therapy. We monitored ADCC activities of neuroblastoma patients enrolled on COG ANBL0032. Methods: High risk neuroblastoma patients who achieved a complete or very good partial response after induction therapy, myeloablation with carboplatin + etoposide + melphalan, ASCT, and local radiation according to COGA3973, were eligible for this study. After engraftment, they were randomized to 13-cis-retinoic acid (RA) x 6 courses or RA + immunotherapy with 5 courses of Ch14.18 and alternating cycles of GM-csf and IL2. Results: So far, 27 patients have been evaluated before treatment on day 76 ± 9 (62∼93) post-ASCT. The mononuclear cells of all 27 patients displayed ADCC which averaged 43.2 ± 28.3 LU20 (11.7∼138). Granulocytes of all 23 patients evaluated pre-treatment also showed ADCC with an average of 18.7 ± 17.9 LU20(3.4∼67.5). ADCC of both cell types were significantly less than that observed for 5 normal donors who had a mean of 145.7 ± 58.3 LU20 (P=0.001) for mononuclear cells and 26.7 ± 7.1 (P=0.0168) for granulocytes. ADCC mediated by both cell types in patients did not change significantly subsequently: before 4th course of RA/ immunotherapy on day 163, and before last course of RA/ immunotherapy on day 196. Although impaired chemotaxis of granulocytes has been reported during IL-2 therapy, we found no significant changes in granulocyte mediated ADCC, right before and after ch14.18 + IL2. Conclusions: These findings suggest that ADCC mediated by mononuclear cells and granulocytes are present shortly after ASCT and persist throughout the course of immunotherapy, albeit at lower levels than normal controls, which is consistent with the reported decreased ADCC in cancer patients. The preliminary findings so far indicated that there is residual ADCC following ASCT, which may allow the monoclonal antibody to be efficacious. No significant financial relationships to disclose.
Randomized phase II trial of the multi-kinase inhibitor sorafenib versus interferon (IFN) in treatment-naïve patients with metastatic renal cell carcinoma (mRCC)
Authors: B. Escudier, C. Szczylik, T. Demkow, M. Staehler, F. Rolland, S. Negrier, T. E. Hutson, U. J. Scheuring, B. Schwartz, R. M. Bukowski
Journal: Journal of Clinical Oncology (2006)

4501 Background: Sorafenib, an oral multi-kinase inhibitor that targets tumor growth and vascularization, significantly prolonged PFS in a Phase III trial with previously treated mRCC patients. This randomized Phase II trial investigated the efficacy and tolerability of sorafenib compared with IFN in first-line therapy of patients with clear-cell RCC. Methods: Untreated patients with mRCC were stratified by MSKCC prognostic score and randomized to receive continuous oral sorafenib 400 mg bid or IFN 9 million units tiw, with an option of dose escalation (600 mg bid sorafenib) or crossover from IFN to sorafenib upon disease progression. The study assessed PFS at 99 events as primary objective, best response (RECIST), overall survival, health-related quality of life, and adverse events (AEs). Results: Baseline characteristics of 188 patients (sorafenib n=97; IFN n = 91) were: median age 62.0 years; MSKCC score: 57% low, 41% intermediate, 1% high; prior nephrectomy: 82%; ECOG 0:1, 55.3%:44.7%. As of January 6, 2006, PFS events have been reported for 64 (34%) patients. Preliminary data showed drug-related AEs of any severity (sorafenib vs IFN) in 50.5% vs 51.6% of patients (≥grade 3: 8.2% vs 11.0%), including diarrhea (24.7% vs 5.5%), fatigue (14.4% vs 20.9%), fever (2.1% vs 18.7%), hypertension (13.4% vs 0%), nausea (5.2% vs 13.2%), flu-like syndrome (1.0% vs 6.6%), hand-foot skin reaction (6.2% vs 0%), and rash/desquamation (4.1% vs 0%). Drug-related metabolic/laboratory abnormalities at grade 3 (no grade 4) comprised hypophosphatemia (21.7% vs. 0%), lipase elevation (5.6% vs. 11.1%), anemia (0% vs. 5.3%) and hypoalbuminemia (0% vs. 3.6%). Five patients receiving IFN withdrew from treatment due to AEs, whereas only one patient withdrew from sorafenib. Conclusions: Sorafenib was generally well tolerated in RCC patients in the first-line setting, with relatively infrequent drug-related AEs ≥grade 3. Full PFS data will be presented at the meeting. [Table: see text]
Adjuvant chemotherapy (AC) initiation and early discontinuation in elderly patients (EPs) with stage III colon cancer (CC).
Authors: Jenny J Ko, Hagen F. Kennecke, Howard John Lim, Sharlene Gill, Ryan Woods, Caroline Speers, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2012)

6014 Background: Research suggests that EPs with cancer are commonly undertreated, but the precise reasons for this observation are unclear. Our aims were to 1) evaluate the impact of advanced age on AC use (none vs capecitabine vs FOLFOX) for stage III CC, 2) determine the specific reasons for selecting and discontinuing a particular regimen, and 3) examine if the effect of AC on outcomes is modified by age. Methods: Patients diagnosed with stage III CC from 2006 to 2008 and referred to any 1 of 5 cancer centers in British Columbia, Canada were identified. Descriptive statistics were used to summarize treatment patterns in young patients (YPs) aged &lt;70 vs EPs aged &gt;/=70 years. Logistic regression was used to evaluate the association between AC and cancer-specific survival (CSS) in YPs and EPs. Results: We identified 810 patients: 51% men, 52% YPs and 48% EPs, and 74% received AC in the entire cohort. When compared to YPs, EPs had worse ECOG and more comorbidities (both p&lt;0.01). EPs were less likely than YPs to receive AC (57 vs 91%, p&lt;0.01). Frequent reasons for no treatment included age, comorbidities and perceived minimal benefit from AC. Among those treated with AC, EPs were less likely to receive FOLFOX (32 vs 74%, p&lt;0.01) in favor of capecitabine due to patient preference, age and comorbidities. Once started on AC, EPs had similar rates of early treatment discontinuation as YPs (70 vs 62%, p=0.08). Reasons for early discontinuation were comparable between EPs and YPs (Table). Receipt of either FOLFOX or capecitabine was correlated with improved CSS, compared to surgery alone. Age did not modify CSS, irrespective of AC choice (interaction p for capecitabine and age=0.26; interaction p for FOLFOX and age=0.40). Conclusions: EPs with stage III CC frequently received either no adjuvant treatment or capecitabine monotherapy due to advanced age and comorbidities. The treatment effect of AC on CSS is similar across age groups, with comparable side effects and rates of discontinuation between EPs and YPs. AC should not be withheld from CC patients based on advanced age alone. [Table: see text]
Association of SNPs in ABCC1 gene with overall survival in stage IV pancreatic adenocarcinoma patients treated with gemcitabine monotherapy
Authors: H. Ueno, Y. Sato, T. Okusaka, J. Furuse, H. Ishii, A. Sekine, Y. Nakamura, N. Kaniwa, J. Sawada, N. Saijo
Journal: Journal of Clinical Oncology (2008)

14504 Background: Gemcitabine (Gem) is an anti-cancer drug effective against solid tumors. However, genetic polymorphisms associated with overall survival time (OS) or the antitumor effect of Gem have not yet been identified. We investigated the association between genetic polymorphisms and OS in Japanese patients with stage IV pancreatic adenocarcinoma receiving Gem monotherapy. Methods: Sixty-eight Japanese patients with metastatic pancreatic ductal adenocarcinoma (Stage IV) who had previously received neither radiation therapy nor Gem were given a 30-min i.v. infusion of the drug at either 800 or 1000 mg/m2. DNA samples were extracted from peripheral blood leukocytes, and 5,438 SNPs in 219 genes encoding a wide category of drug-metabolizing enzymes or transporters were analyzed in RIKEN (SNP list available at http://gemdbj.nibio.go.jp). Survival analysis was performed using the log-rank test and multiple Cox proportional hazards model with adjustment for CA19–9 and CRP as prognostic factors. Written informed consent was obtained from each patient, and the study was approved by the ethics committee of each institution. Results: A non-synonymous missense SNP of ABCC1 (rs4148335) with a minor allele frequency of 0.06 in the Japanese population was significantly associated with short OS (median for TG+GG and TT, 76.5 and 196 days, P=2.3×10-5, HR=6.6 (2.8–15.8)) even after multiple comparison adjustment. Multivariate analysis identified CRP and rs4148335 SNPs as significant variables for OS (P<0.001 for all). Additionally, all of the 8 patients with TG or GG for rs4148335 SNPs had progressive disease, compared with a quarter of the patients with TT (15/60 patients). These results may be explained by the function of the ABCC1 gene, which is involved in the transport of a wide range of drugs and resistance to them. Conclusions: ABCC1 gene polymorphism could be a new prognostic biomarker for patients with stage IV pancreatic adenocarcinoma receiving Gem monotherapy. Result of multiple Cox proportional hazards model analysis Variables HR CI P-value ABCC1 TG+GG/TT 8.95 3.59-22.3 0.000015 CA19-9 >1000/≤1000 (U/mL) 1.49 0.90-2.47 0.12 CRP >5/≤5 (mg/dL) 3.69 1.83-7.48 0.0003 No significant financial relationships to disclose.
AlteRCC phase I-II trial: Alternating radiotherapy and chemotherapy plus cetuximab in advanced head and neck cancer (HNC)
Authors: M. C. Merlano, G. Numico, I. Colantonio, O. Garrone, M. Gasco, E. Russi, R. Vigna Taglianti, C. Granetto, G. Di Costanzo
Journal: Journal of Clinical Oncology (2006)

15515 Background: Pfister (ASCO 2003) added Cetuximab (C) to CT/RT to evaluate toxicity and activity of this combination in advanced HNC. The trial was early stopped due to an excess of toxicity including on treatment deaths. However, the treated pts achieved an excellent long term. Results: 76% of them were alive and disease free at 24 months. Therefore, a new, less toxic scheduling of CT/RT and C is highly attractive. Alternating CT/RT (ACR) may be less toxic than concurrent CT/RT (Haffty 2000; Merlano 2003). Therefore we designed a phase I-II trial, scheduling finding, combining ACR and C. Methods: The ACR regimen consists of cisplatin 20 mg/m 2 and 5FU 200 mg/m 2 days 1 to 5, weeks 1, 4 and 7; and RT, 2 Gy/day, days 1 to 5, weeks 2–3, 5–6, 8–10 to a total dose of 66 Gy. ACR remains unchanged during both phase I and phase II part of the study, whereas C is given to the first 6 pts (phase I, step I) weekly only in the weeks when RT is delivered. If no limiting toxicity is observed, C is combined also with CT, in a second group of six pts (phase I step II). If again no limiting toxicity is recorded, the trial will be continued as a phase II study (optimal two-stage design, 21+24 pts, Simon 1989). Results: At the time of the present report, the phase I step I is completed and 3 pts in phase I step II are on-going. All the pts had HNC stage IVa (8 pts) or stage III (1 pt). Two pts had disease recurrence after prior surgery, while the others had previously untreated cancers. All the tumors over-expressed EGFr (+++), but the percentage of cells expressing EGFr ranges between 10 to 100% (median 70%), One episode of neutropenic fever occurred in one pt enrolled in phase I step II. All the pts developed chemoradiation expected toxicities, including stomatitis and dysphagia requiring TPN. The only unexpected toxicity was a moist desquamation occurring within the irradiated field which was observed in all but one pts at a cumulative RT dose of 50–66 Gy. This toxicity did not interfere with ACR treatment but C was stopped until recovery. Recovery occurred in 5–7 days. Four pts out of the 6 evaluable for response, reached a complete response; the two remaining achieved a PR. One of them underwent surgical removal of a residual nodal mass without complications. Conclusions: The update of the AlteRCC trial will be presented. [Table: see text]
Economic implication of outcomes complicating hematopoeitic stem cell transplant (HSCT) for multiple myeloma (MM), Hodgkin’s (HD) and non-Hodgkin’s lymphoma (NHL)
Authors: J. A. Jones, M. H. Qazilbash, Y. T. Shih, S. B. Cantor, C. D. Cooksley, L. S. Elting
Journal: Journal of Clinical Oncology (2005)

6012 Background: HSCT is the standard of care for MM and lymphoma in the first-line and salvage settings, respectively. Recent studies suggest that the morbidity attributable to HSCT has declined over the last decade. We studied the outcomes for a population-based sample of HSCT recipients and estimated the economic consequences of these outcomes. Methods: A retrospective cohort, consisting of 8275 HSCT recipients with MM, HD, or NHL treated in U.S. hospitals between 2000–2001, was extracted from the National Inpatient Sample. Patients were characterized by transplant type and conditioning regimen. Outcomes were identified from ICD-9 codes, including stomatitis (STOM), febrile neutropenia (FN), parenteral nutrition (TPN), bacteremia (BACT), intubation (INT), and death. Mean hospital charges were examined by outcome and transformed into costs (2003 US$) using state-specific Medicare cost-to-charge ratios for urban centers, with proper weighting procedures to account for sampling design. Results: Outcomes were similar to published reports and did not differ significantly between HD and NHL. TPN, BACT, and STOM were more frequently reported among allograft recipients. A significant proportion of TPN pts was found to have STOM (p=0.04) and/or BACT (p=0.001). Presence of any adverse outcome increased the cost of HSCT by 27–46%. TPN, BACT, and particularly INT each predicted substantially higher costs. Mean costs were three times greater for HSCT recipients who died compared to pts without adverse outcomes, regardless of diagnosis or transplant type. Conclusions: Interventions that prevent the most serious outcomes (TPN, BACT, INT, death) could substantially decrease the morbidity and costs associated with pts hospitalized for HSCT. Systematic assessment of outcomes as well as their economic consequences should guide future research in both the inpatient and ambulatory settings. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, McNeil, MGI Merck Amgen
Abstract 19581: Embryonic Lethality of Mice Deficient for IRF2BP2: An Essential Ischemia-Inducible Transcriptional Coactivator of VEGFA
Authors: Tiffany V Ho, Nida Yap, Naif Almontashiri, Alexandre F Stewart
Journal: Circulation (2012)

Background - VEGF (vascular endothelial growth factor) is a master regulator of angiogenesis is a major player in ischemic heart disease. In 2010, we found that IRF2BP2 (interferon regulatory factor-2 binding protein-2) coactivates VEGFA expression in muscle. IRF2BP2 protein levels show a 7-fold increase is ischemic muscle whereas its mRNA expression is not increased, indicating that IRF2BP2 is translational repressed in normoxic tissues and becomes translationally derepressed during ischemia. Methods - To characterize the mechanisms repressing translation of IRF2BP2 mRNA in normoxic conditions and enabling derepression during ischemia, luciferase reporter plasmids were transiently transfected in cultured cells. In addition, we generated transgenic mice with targeted deletion of the IRF2BP2 gene and others with a floxed IRF2BP2 allele enabling tissue specific ablation by Cre-transgene expression. Results - In the 3’UTR of IRF2BP2 mRNA, microRNAs miR-17 and -20a were found to differentially regulate translation. A common 9 nucleotide deletion polymorphism (rs3045215) disrupted the miRNA target sequence in IRF2BP2 mRNA and associated with coronary artery disease risk in the Ottawa Heart Genomics study (p&lt;0.0045). The RNA binding protein Staufen-1 (Stau1) binds to the 3’UTR of IRF2BP2 mRNA and inhibits its translation. Stau1 levels increased during C2C12 skeletal muscle differentiation, coincident with the downregulation of IRF2BP2 protein levels. Of interest, IRF2BP2 knockout mice died during embryonic development. Out of 11 litters from hemizygous matings, 42 offspring were born: 15 wild type (35.7%), 25 hemizygous (59.5%), and 2 homozygous null (4.8%) mice, deviating from the expected Mendelian ratio of 25% wild type:50% hemizygous: 25% null. The 2 surviving IRF2BP2 null mice displayed severe growth retardation. We are currently characterizing the phenotype of embryonic lethality in these mice. Conclusion - Translational derepression enables expression of IRF2BP2 protein in ischemic tissues, an emerging mechanism of gene regulation. Our data show the IRF2BP2 gene is critical for mouse development. These transgenic models will enable the elucidation of IRF2BP2 function in angiogenesis and the response to ischemia.
Inspecting the Colon from inside and Out to Solve Pyrexia of Unknown Origin
Authors: A D Dwarakanath, E Chua, Jonathan M Rhodes, M J Hershman
Journal: Journal of the Royal Society of Medicine (1995)

A man with longstanding intermittent symptoms of abdominal pain, diarrhoea and pyrexia of unknown origin was diagnosed with the novel technique of laparoscopic-assisted colonoscopy. At subsequent laparotomy, a longstanding perforation of sigmoid diverticular disease was resected, with resolution of his symptoms.
FDG PET/CT (FDG PET) in evaluation of response in patients with multiple myeloma (MM) treated with bortezomib, pegylated liposomal doxorubicin, and dexamethasone
Authors: N. Pandit-Taskar, R. L. Comenzo, H. Hassoun, E. Hoover, S. Borkar, E. Reidel, A. Cohen, C. Surti, S. D. Nimer, H. J. Landau
Journal: Journal of Clinical Oncology (2009)

8533 Background: In a high risk population of pts with newly diagnosed or primary refractory MM, we prospectively studied FDG PET imaging to determine the value of PET/CT in assessing therapeutic response. Methods: Forty pts with high-risk MM defined as ISS II, ISS III or presence of extramedullary plasmacytoma have been enrolled on study and treated using a combination of bortezomib, pegylated liposomal doxorubicin hydrochloride (Doxil), and dexamethasone (BDD) for 3 cycles followed by 2 cycles of thalidomide and dexamethasone for patients achieving at least PR. Pts were assessed using serial FDG PET imaging: at baseline (BL), after 3 cycles of BDD and at end of study (EOS). FDG PET response was determined using European Organization for research and treatment of cancer (EORTC) recommendations. MM disease response was assessed according to the International Myeloma Working Group (IMWG) criteria. Results: Median age of pts enrolled was 59 yrs (range 41–80), 62% male, 38% ISS II, 47% ISS III, and 15% ISS I with soft-tissue disease. Thirty-five percent (14/40) had soft-tissue involvement with MM. At completion of protocol therapy, the ORR was 79%, with 44% of pts achieving CR/nCR and 59% ≥ VGPR. Ninety FDG PET scans were performed in 40 pts; 25 pts were evaluable for FDG PET response. The other pts are as follows: 2 had negative FDG PET at BL, 6 were taken off study (5 for toxicity and 1 with CR), 1 FDG PET was unable to be compared due to technical differences and 6 pts have not completed treatment. Seventeen of the 25 pts had PR by FDG PET, 5 had SD and 3 PD; none of the pts had CR. There was little agreement between MM disease response and FDG PET responses (Kappa statistic, 0.05). Three pts with PD by FDG PET, had PR (n=2) or CR (n=1) by IMWG criteria. One had granulomatous disease rather than MM at biopsy. In 1 pt with progression of disease with a progressive skull-based plasmacytoma, FDG PET was scored as PR by EORTC criteria. Conclusions: There was poor agreement between FDG PET response and MM disease response by IMWG criteria. Serial FDG PET did not provide additional information for therapeutic response assessment in pts with newly diagnosed or primary refractory MM. [Table: see text]