tbuckley/cabot-search huggingface dataset:
Graft versus leukemia effect may overcome therapeutic resistance of chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy chain gene status
Authors: M. Ritgen, A. Humpe, S. Stilgenbauer, H. Dãhner, P. Dreger, M. Kneba
Journal: Journal of Clinical Oncology (2004)

6525 Background: Although allogeneic SCT (allo-SCT) can result in long-term disease control in CLL, to date it is unknown to what extent graft-versus-leukemia activity (GVL) plays a role espescially in VH unmutated cases. We investigated whether the therapeutic resistance of unmutated CLL can be overcome by GVL in the context of allo-SCT following reduced-intensity conditioning (RIC) with fludarabine and cyclophosphamide. Methods: We prospectively measured the kinetics of residual disease (MRD) by real-time IgH PCR and donor chimerism in peripheral blood in 9 patients with unmutated CLL after RIC allo-SCT and compared to that of 29 unmutated patients who had undergone autologous SCT (auto-SCT). Results: After auto-SCT median MRD decreased immediately from 1.0E-2 pretransplant to 2.6E-4 at +3 months (p=0.0002) followed by a stable phase of about two years. Failure to achieve MRD negativity was associated with subsequent clinical relapse in 9 of 29 patients, with a median progression-free survival of 48 months post auto-SCT. Conditioning for allo SCT provided a moderate reduction of the median MRD level (5.4E-2 pretransplant vs. 5.0E-3 at +3 months). With reduction of immunosuppression, however, MRD levels progressively declined to 8.5E-5 at +6 months (p=0.005) and to MRD negativity at +12 months in 7 of 9 patients. With a median follow-up of 21 (11–35) months, these 7 patients remain in continuing clinical and molecular remission, althoug one patient shows still mixed chimerism. One patient died from progressive nodular disease with MRD levels at 1E-4, another patient with slowly increasing MRD-level presents still subclinical CLL. Conclusion: A progressive decline of MRD levels to negativity can be obtained after RIC allo-SCT but not after auto-SCT for unmutated CLL, suggesting a crucial role of GVL-mediated immunotherapy for complete disease eradication in this high-risk subset. No significant financial relationships to disclose.
Phase II study of dose-dense docetaxel (T) and epirubicin (E) as neoadjuvant treatment for locally advanced breast cancer (LABC). An ONCOPAZ Cooperative Group study
Authors: A. Lorenzo, C. Madroñal, J. J. Sanz, M. Centelles, M. Ruiz López, A. Casas, V. G. Pérez, C. González de la Puente, M. J. García López, P. Borrega
Journal: Journal of Clinical Oncology (2005)

779 Background: The combination of E and T has demonstrated clinical objective response rates (ORR) up to 81% as neoadjuvant therapy for operable BC. Dose-dense chemotherapy may achieve superior clinical outcomes over conventionally administered chemotherapy in BC. The aim of this study is to evaluate the ORR of neoadjuvant dose-dense T and E in LABC. Secondary objectives were pathological response rate, safety profile, and correlation between molecular markers (MM) and response. Methods: Patients with histologically confirmed LABC and ECOG PS ≤ 2, age ≥ 18 years and adequate bone marrow, renal, hepatic and cardiac functions, were eligible. Diagnosis of invasive bilateral BC and prior systemic therapy or radiotherapy for BC were not allowed. Treatment: E at 75 mg/m2 and T at 75 mg/m2 iv, day 1, every 14 days for 6 cycles, followed by surgery. G-CSF (5 mcg/kg/day, s.c.) was started 48 hours after chemotherapy and maintained for 5 days. Expression of MM (ER, PR, Her-2) was determined by immunohistochemistry. Results: Sixty-one patients were evaluated. Median age was 51 years (29–77), 98% had ECOG PS 0–1, 43% were stage IIIA, and 56% IIIB. MM expression: ER+ 59%, PR+ 41%, HER-2+ 52%. A total of 333 cycles (median 6, range 1–6) were administered. Median RDI was 98% for both T and E. All patients were evaluable for toxicity. Main grade 3–4 toxicities per patient were neutropenia 13%, leukopenia 10%, and anaemia 3%. Febrile neutropenia was reported in 2 patients (3%), 1 cycle each. Efficacy: Six patients (10%) were not evaluable (3 no efficacy evaluation; 2 early withdrawal;1 protocol deviation); 13 patients achieved CR (21%), 27 PR (44%), 15 SD (25%) for an ORR of 65% (95%CI: 54–78). Of the 56 patients who had surgery, 6 achieved a pCR (11%). Logistic analysis suggested that neither hormone receptor status nor HER-2 status correlated with clinical response. Conclusions: T and E every 14 days for 6 cycles is an active and well-tolerated neoadjuvant chemotherapy regimen for LABC. No significant financial relationships to disclose.
A randomized phase 2 trial comparing efficacy of the combination of the PARP inhibitor olaparib and the antiangiogenic cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer.
Authors: Joyce Liu, William Thomas Barry, Michael J. Birrer, Jung-min Lee, Ronald J. Buckanovich, Gini F. Fleming, Bj Rimel, Mary K. Buss, Sreenivasa R. Nattam, Jean Hurteau, Weixiu Luo, Philippa Quy, Elizabeth Obermayer, Christin Whalen, Hang Lee, Eric P. Winer, Elise C. Kohn, S. Percy Ivy, Ursula Matulonis
Journal: Journal of Clinical Oncology (2014)

LBA5500 Background: PARP inhibitors and anti-angiogenics are clinically active in recurrent ovarian cancer (OvCa). Preclinical studies suggest these agents can synergize, and a phase 1 study showed that the combination of cediranib (ced) and olaparib (olap) is well-tolerated. We therefore compared the activity of olap alone (Olap) to combined ced and olap (Ced/Olap) in treatment of recurrent platinum-sensitive (plat-sens) high-grade serous (HGS) or BRCA-related OvCa (NCT 01116648). Methods: Patients (pts) across 9 centers were randomized 1:1 in this Ph 2 open label study to Olap (olap 400 mg capsules BID) or Ced/Olap (olap 200 mg capsules BID; ced 30 mg daily), stratified by BRCA status and prior anti-angiogenic therapy. Eligibility included pts with recurrent plat-sens HGS or BRCA-related OvCa. Pts had measurable disease by RECIST 1.1, PS 0 or 1, and the ability to take POs. No prior anti-angiogenics in the recurrent setting or prior PARP inhibitor was allowed. Progression-free survival (PFS) was defined as time from randomization to radiographic progression or death. With a target N=90 pts, the study was powered to detect a hazard ratio (HR) of 1.75 (median PFS 6 vs 10.5 mo). Results: Pts were enrolled from Oct 2011 to Jun 2013: 46 to Olap, 44 to Ced/Olap. 48 pts were known BRCA carriers (25 Olap; 23 Ced/Olap). At a planned interim analysis the DSMB recommended release of data. As of Jan 7, 2014, 41 pts had a PFS event. Median PFS was 9.0 mos for Olap and 17.7 mos for Ced/Olap (HR 2.9, 95% CI 1.5-5.6, p = 0.001). There were 2 complete responses (CR) and 21 partial responses (PR) in pts on Olap (56% objective response rate, ORR) and 3 CRs and 33 PRs in pts on Ced/Olap (84% ORR, p = 0.008). The overall rate of Gr3/4 toxicity was higher for pts on Ced/Olap (70%) than on Olap (7%). Differentially occurring toxicities included fatigue (27% Ced/Olap vs 7% Olap), diarrhea (23% vs 0%), and hypertension (39% vs 0%). Updated efficacy and exploratory subgroup analyses will be presented. Conclusions: Combined Ced/Olap significantly extended PFS and ORR compared to Olap in plat-sens OvCa. Further studies of this oral combination in plat-sens OvCa are warranted. Clinical trial information: NCT01116648.
Ciliary beat frequency in nasal and bronchial epithelial cells in patients with cystic fibrosis
Authors: Samra Alikadic, Friedrich Horak, Thomas Frischer, Edith Nachbaur, Sabine Renner, Saskia Gruber
Journal: European Respiratory Journal (2011)

Background: The extent to which altered ciliary function plays a role in the decrease in mucociliary clearance in cystic fibrosis (CF) patients is unclear.

Objective: To study ciliary beat frequency (CBF) in nasal and bronchial epithelial cells of children with CF.

Methods: Nasal and bronchial brushings were performed on 11 CF children (mean age: 8.86±4.54) undergoing bronchoscopy. In 15 healthy controls (mean age: 11.47±4.7) undergoing endoscopic procedures, nasal brushings were performed. The biopsies were performed using an Olympus BC-202D-2010 disposable brush. The samples were transported in a Medium 199 HEPES buffer and immediately analyzed. Slides were put into a climate chamber preheated to 37°C and viewed through an inverted phase contrast video microscope (Olympus IX-51). Short videos of ciliated cell groups were filmed with a high-speed video camera (Olympus i-Speed 2) at 300 frames/sec. The videos were then played back and the ciliary beat frequencies of on average 5 to 10 cell conglomerates per patient were determined. Mean values were used for further analysis.

Results: Nasal CBF in CF patients was higher when compared to that of healthy controls (mean/SD: 15.4±3.03 vs. 12.92±2.37, p<0.05). Furthermore, nasal CBF in CF patients was found to be higher than bronchial CBF (mean/SD: 13.23±2.38, p<0.01), and the values were found to correlate (r=0.7, p<0.01).

Conclusion: Our results indicate that CF patients indeed have altered nasal ciliary function. Whether these findings could have therapeutic implications requires further study.
DAB(389)IL2 (denileukin diftitox) suppresses growth of melanoma metastases
Authors: J. Chesney, J. Guarnaschelli, S. Telang, D. Miller
Journal: Journal of Clinical Oncology (2006)

18010 Background: CD4+CD25 high regulatory T (Treg) cells have been found to suppress the activation of anti-tumor effector T cells. Depletion of Treg cells using anti-CD25 antibodies can induce a CD8+ T cell dependent rejection of melanoma in mice. Furthermore, Treg cells are increased in human lymph nodes containing melanoma metastases relative to adjacent benign lymph nodes. Taken together, these observations provide rationale for an examination of the effect of Treg cell depletion on the progression of metastatic melanoma in humans. Recombinant interleukin 2/diphtheria toxin conjugate (DAB[389]IL2; also termed ONTAK or denileukin diftitox) binds to CD25 and, following internalization, causes cell death. DAB(389)IL2 was recently reported to selectively deplete peripheral blood Treg cells in patients with renal cell carcinoma. Methods: The effect of DAB(389)IL2 on tumor growth was examined in 4 patients with Stage IV melanoma who had either progressed after biochemotherapy and/or high dose IL-2 or were ineligible for these treatments. DAB(389)IL2 (9 or 12 μg/kg) was administered daily x 4 days every three weeks for two cycles. FDG-PET/CT imaging was obtained just prior to DAB(389)IL2 administration and within 2 weeks of completion of the second cycle. In the setting of stable disease or tumor regression, DAB(389)IL2 was continued for two more cycles and a subsequent FDG-PET/CT imaging study was obtained. Results: Two patients received 9 μg/kg DAB(389)IL2 and, after two cycles, experienced overt progression consisting of a combination of tumor growth and newly detectable tumors. Two patients received 12 μg/kg DAB(389)IL2 and, after two cycles, experienced a combination of stable disease and marked regression of several metastatic tumors. In one patient, tumor volume of right and left axillary metastases shrunk by 33% and 43%, respectively, after two cycles of DAB(389)IL2. The second responding patient experienced resolution of several dermal metastases, reduction in the tumor volume of a left adrenal mass, and the complete regression of two hepatic metastases. Conclusions: We conclude that DAB(389)IL2 may provide a safe and effective treatment for stage IV melanoma. A phase II clinical trial is now underway to examine the efficacy of DAB(389)IL2 in this patient population. No significant financial relationships to disclose.
Do Asian breast cancer patients younger than age 40 have more aggressive biologic characteristics than their western counterparts? A comparison between Shanghai and Vienna.
Authors: M. M. Tea, L. Fan, Z. Shao, C. F. Singer
Journal: Journal of Clinical Oncology (2010)

1573 Background: Breast cancer (BC) is the most common cancer in women under the age of 40. About 7% of all breast cancers are diagnosed in this young age group. Breast cancer in younger women is biologically more aggressive than that in their older counterparts. The incidence of BC is rising in Asia. Unlike the Caucasian population, where BC peaks between the ages of 45 and 55, Breast neoplasma in Chinese women peaks at the age of 40, much earlier than in the western population. The aim of this study was to investigate the biological characteristics of Chinese BC compared to their European/Austrian counterparts. Methods: Histo-pathological findings of 30 Austrian women with operable breast cancer and aged 40 and younger seen during 2005 and 2007 were recorded for our weekly tumor board. The results were compared with 60 Chinese patients (date and age matched) obtained from the Breast Cancer Database of the Department of Breast Surgery, Cancer Institute, in Shanghai. Results: The mean patients' age in both study groups were 36.5 years. In Austria and China the breast-conserving surgery rate was 76.7% and 26.7%, respectively. The total breast immediate reconstruction-rate (silicon implants only or latissimus dorsi flap only or both combined) was similar in these compared departments (Vienna 13.33%, Shanghai 10%). No differences were found in BC subtypes, hormonreceptor (Estrogen receptor and Progesteron receptor) expressions (p = 0.442) and axillary lymphnode involvements (p = 0.083), whereas in Austria sentinel lymphnode biopsy was performed in 10 out of 30 and in China in only 2 out of 60 cases. Interestingly, more grade 3 breast cancers were detected (p = 0.006) in Austrian women, whereas in the Chinese population more triple negative BC were found (p = 0.004). Conclusions: Chinese women present with a higher percentage of triple-negative breast cancer, which is a negative prognostic factor. However, Chinese women present with a lower rate of grade 3 breast malignancies. As expected, a higher mastectomy rate was noted in China. Ethnic-specific screening protocols may benefit this young Asian population, especially Asian women in western countries. No significant financial relationships to disclose.
Diagnostic Accuracy of 320-Slice Multi-Detector Row Computed Tomography to Detect Coronary Artery Disease: A Direct Comparison to Invasive Coronary Angiography
Authors: Jonathan Chan, Sheryar Sarwar, Faisal Khosa, Milliam Kataoka, Marie-Claire Paicopolis, Roger Laham, Melvin E. Clouse
Journal: Journal of the American College of Cardiology (2009)
Abstract 18607: Prevalence, Outcome, and Predictors of Cardio-Renal Syndrome in Children with Dilated Cardiomyopathy
Authors: Ahmad Kaddourah, Stuart Goldstein, Jeffrey Towbin, John Jeffries
Journal: Circulation (2012)

Background: Cardio-renal syndrome (CRS) describes variety of acute or chronic conditions where the primary failing organ can be either the heart or kidney. The prevalence, predictors and outcome of CRS has not been reported in children with dilated cardiomyopathy (DCM). Methodology: Data from patients &gt; 1 year of age with DCM enrolled in the Pediatric Cardiomyopathy Registry (PCMR) was assessed. CRS was defined as glomerular filtration rate &lt;90 ml/min/1.73m 2 estimated by modified Schwartz formula (eGFR). Patients with eGFR&gt;150 ml/min/1.73m 2 were excluded. CRS prevalence was determined by cross-sectional design in patients newly diagnosed with DCM using the baseline PCMR data. Survival analysis compared patients with vs. without CRS using annual PCMR data. Regression models were applied on both baseline and annual data to study the interactions between eGFR and different echocardiographic measures. Results: The baseline data had 484 children with DCM. Serum Cr data to calculate eGFR were available for 92 patients. Fifty six (62.0%) patients had eGFR &lt; 90 ml/min/1.73m 2 , which is greater than the 48% prevalence published in 3256 healthy historical controls (P&lt;0.001). CRS patients had a mean eGFR of 61 (±22.6) vs. 108 (±14) (P&lt;0.001). Death occurred in 8 (14%) of CRS patients compared to no deaths in patients without CRS (P=0.052) after 7 years follow-up. Univariate regression models showed a significant positive correlation between fractional shortening (FS) and eGFR (P= 0.0013, r 2 = 0.09). No correlation was observed between eGFR and ejection fraction (EF), left ventricular end-diastolic dimension (LVEDD) and LVEDD Z-scores. Conclusion: This is the first study to show that CRS is common in children newly diagnosed with DCM and is associated with higher risk of subsequent death. Worsening FS was associated with decreasing eGFR which suggests that patients with poor FS might have significant CRS. We suggest kidney functions should be evaluated systematically in children with DCM to assess for chronic kidney disease and direct potential management.
Aromatase inhibitors and radiation-induced lung fibrosis
Authors: N. S. Bese, A. Y. Altinok, E. M. Ozsahin, S. Yildirim, N. Sut, T. Altug, A. Ober, D. Azria
Journal: Journal of Clinical Oncology (2008)

614 Background: In experimental and clinical trials, tamoxifen (TAM) has been shown to increase radiation-induced lung fibrosis (RILF). Aromatase inhibitors (AI) are superior to TAM in the adjuvant setting, and preclinical data suggest that letrozole (LET) sensitizes breast cancer cells to ionizing radiation. However, poor data are available regarding the toxicity of concurrent use of AI and radiation therapy (RT). In this experimental study, we evaluated whether AI have any impact on the development of RILF in rats. Methods: 60 female wistar- albino rats were divided into 6 groups: control (group A), RT alone (group B), RT + TAM (group C), RT + anastrozole (ANA group D), RT + LET (group E), and RT + exemestane (EXE, group F). RT consisted of 30 Gy in 10 fractions to both lungs with an anterior field at 2-cm depth. Equivalent doses for 60 kg adult dose per day of TAM, ANA, LET, and EXE i.e. 20 mg, 1 mg, 2.5 mg, 25 mg, respectively, were calculated according to the mean weight of rats which was 200 gr and orally administrated with a feeding tube. Administration started at the first day of RT and given once daily including the week-ends until the animals were sacrificed at 16th week following the last day of RT. Percentage of lung with fibrosis was quantified with image analysis of histologic sections of the lung. The mean score values were calculated for each group. One way ANOVA test and Tukey HSD post-hoc test were used to calculate the significance of the differences among groups. Results: Mean values of fibrosis were 1.7, 5.9, 6.7, 2.5; 2, and 2.2 for groups A, B, C, D, E, and F, respectively (p = 0.000). TAM increased RT-induced lung fibrosis but without statistical significance probably due to sample size. Groups treated with RT + AI showed significantly less lung fibrosis than groups treated with RT alone or RT + TAM (p = 0.000). RT + AI groups showed nearly similar RT-induced lung fibrosis than control group. Conclusions: In this model, we found that AI decreased RT-induced lung fibrosis to the control group level suspecting protective effect. No significant financial relationships to disclose.
A randomized phase II study of sapacitabine in MDS refractory to hypomethylating agents.
Authors: Guillermo Garcia-Manero, Selina M. Luger, Stuart Goldberg, Jessica K. Altman, Martha Lucia Arellano, Meir Wetzler, Karen Seiter, Judy H. Chiao, Hagop Kantarjian
Journal: Journal of Clinical Oncology (2012)

6520 Background: Sapacitabine is an orally administered nucleoside analogue which causes single-strand DNA breaks and induces G2 cell cycle arrest. A multi-center, randomized phase 2 study was conducted to evaluate 3 dose regimens in older patients with MDS refractory to hypomethylating agents. The primary endpoint is 1-year survival. Secondary endpoints include the rate of CR, CRp, PR, major hematological improvement (HI) or stable disease and their corresponding durations. The study uses a selection design to identify a dose regimen which produces a better 1-year survival rate in the event that all three dose regimens are active. The planned sample size is 60 patients (20 patients in each arm). Methods: Eligible patients must be ≥ 60 years with intermediate-2 or higher risk MDS previously treated with hypomethylating agents and 6 - &lt; 20% blasts in bone marrow, ECOG 0-2, adequate renal and hepatic functions. Patients were randomized 1:1:1 to receive sapacitabine every 4 weeks at 200 mg b.i.d. x 7 days (Arm G), 300 mg q.d. x 7 days (Arm H), or 100 mg q.d. x 5 days per week x 2 weeks (Arm I). The number of cycles is not limited. Results: As of January 2012, 61 patients were enrolled and 56 had ≥ 30 days of follow-up. Mean follow-up was 173 days. Median age was 71. Two or 3 cytopenias were present in 42 patients and 14 have received both azacitidine and decitabine. Baseline bone marrow had 6-10% blasts in 31 patients and 11-19% blasts in 25 patients. Median number of cycles was 2 and 18 patients received ≥ 4 cycles. To date, 8 patients have responded (2 CRs, 2 CRp, and 4 major HIs): 15% (Arm G), 16% (Arm H) and 12% (Arm I). Time to response is 1-3 cycles. Additionally, 6 patients achieved stable disease lasting longer than 16 weeks. More than 50% of patients have lived 16 weeks or longer. Three deaths occurred within 30 days of randomization and 1 death was considered to be related to sapacitabine. Common adverse events (all grades, regardless of causality) included fatigue, nausea, diarrhea, constipation, edema, dyspnea, pyrexia, pneumonia, febrile neutropenia, anemia, neutropenia and thrombocytopenia, most of which were mild to moderate. Conclusions: Sapacitabine appears to be safe and active across all 3 dose regimens. Updated data will be presented at the meeting.
Multicentric study to evaluate reduced glutathione (GSH) activity on prevention of oxaliplatin chronic cumulative neurotoxicity
Authors: C. Saggia, G. Forti, G. Biaggi, M. E. Negru, I. Romaniello, E. Castiglioni, G. Porcile, G. Ferrero, R. Manfredi, O. Alabiso
Journal: Journal of Clinical Oncology (2005)

8177 Background: Oxaliplatin dose-limiting toxicity (DLT) is the chronic cumulative neurotoxicity; it can be moderate (grade 2) or severe (grade 3 - NCI criteria). Grade 3 neurotoxicity leads to functional limitation that forces us to stop the treatment. Grade 3 toxicity involves 3% of the patients treated with 510–765 mg/m2 of oxaliplatin, 15–28% of those treated with 765-1020 mg/m2 and 50% of those treated with over 1020 mg/m2(Gamelin E, Semin Oncol, 29: 21–33, 2002). We conduced a multicentric study to evaluate GSH activity to prevent chronic cumulative neurotoxicity of oxaliplatin. Methods: From 01/2003 to 11/2004 we evaluated 92 patients (58 males, 34 females) whose median age was 65 (range 33–78). They were affected by: colorectal carcinoma (77 pts), cholangio or pancreatic carcinoma (10 pts), gastric carcinoma (3 pts), NHL (2 pts). These patients were submitted to chemotherapy containing oxaliplatin as adiuvant or as first, second, third or fourth line therapy as per following schedules: monochemotherapy, FOLFOX 4, FOLFOX 6, GEMOX, capecitabine plus oxaliplatin. We gave all these patients GSH (1500 mg/m2 in 500 ml saline solution) 30 minutes before oxaliplatin infusion. According to NCI criteria Neurotoxicity was evaluated at every therapy cycle. Results: chronic cumulative neurotoxixity incidence is reported in the following table. Conclusions: Our experience is still limited and preliminary, but GSH seems to be able to prevent oxaliplatin chronic cumulative neurotoxicity, reducing grade 3 toxicity percentage in comparison with that expected; thus chemotherapy can go on without delay or therapy stop. Anyway further randomized and controlled studies are necessary. No significant financial relationships to disclose.
Antibiotics for otitis media.
Authors: B P Gardner, P T Doyle
Journal: BMJ (1976)

with central retinal vein thrombosis reported by Kohner and associates'0 failed to detect any difference in the visual out- come.Nevertheless, the work of Ring and associates5 suggests that further evaluation might show that it has a role in treating this condition.I Sorsby, A, The Incidence and Causes of Blindness in England a-4 TV'zles