bluuebunny/crossref_metadata_2025_split huggingface dataset:
Time interval between final protocol approval (FPA) and inclusion of the first patient into randomized clinical trials (RCTs) performed by the Central European Cooperative Oncology Group (CECOG): A 10-year experience
Authors: Brodowicz T. , Steiner I. , Beslija S. , Ciuleanu T. E. , Inbar M. , Krzakowski M. , Kahan Z. , Tzekova V. , Vrbanec D. , Zielinski C. C. 
Published: August 2020

6546 Background: CECOG has been formed in 1999 to unite centers of clinical oncology from Central and Southeastern Europe and Israel in order to conduct and coordinate multicenter oncology RCTs. Based on the European legislation passed in 2001 (Directive 2001/20/EC), clinical trials must get ethical approval and approval from the competent authorities (CA). However, the duration of these regulatory procedures to initiate a clinical trial is a factor determining the competitive position in clinical research. Methods: Within the last 10 years, CECOG conducted trials in breast, colorectal, esophago-gastric, NSCLC, pancreatic, prostate cancer and GIST. We analyzed the dates of FPA, the approvals by Ethics Review Boards (ERB) and CAs, the letters of agreement between sponsor and site (LoA), the site initiation and the inclusion of the first patient in a total of 6 multicenter trials in 25 CECOG study centers in Austria, Bosnia, Bulgaria, Croatia, the Czech Republic, Hungary, Israel, Poland, Romania, Serbia, and Slovakia. Results: The average time interval from FPA to the inclusion of the first patient was 18.4 ± 9.4 months. Most of this time has been spent for regulatory procedures, i.e. the approval by ERBs (9.6 ± 7.2 months) and CAs (10.0 ± 6.6 months). The LoA were signed 11.5 ± 9.4 months after FPA. The time interval from approval by the CAs to site initiation was 3.3 ± 3.7 months and the interval between site initiation and the inclusion of the first patient was 4.2 ± 4.5 months. Conclusions: The ‘paper to patient process‘ - the time interval between the approval of the final study protocol and the inclusion of the first patient - required 18.4 months on average in 6 multicenter trials conducted by CECOG. As the regulatory procedures used up more than 50% of duration of the whole process, optimization is necessary and realistic in order to make novel therapies available to patients more quickly. No significant financial relationships to disclose.
Factors associated with contralateral prophylactic mastectomy use among breast cancer patients in a metropolitan hospital system
Authors: Arrington A. K. , Jarosek S. L. , Virnig B. A. , Habermann E. B. , Tuttle T. M. 
Published: August 2020

6558 Background: A recent population-based study reported the proportion of women with unilateral breast cancer who underwent contralateral prophylactic mastectomy (CPM) increased by 150% between 1998 and 2003. This study evaluated all patients undergoing breast cancer surgery in a metropolitan-based hospital system to identify factors not available from tumor registries that may be associated with increased CPM rates. Methods: We reviewed the records of all patients who underwent breast cancer surgery in 2006 and 2007 in a single health care system in the Twin Cities, including one university, two suburban, and three smaller rural hospitals. Exclusion criteria included bilateral breast cancer, stage IV disease, and prior breast cancer. We recorded patient and tumor characteristics, surgery and surgeon characteristics. Logistic regression models were used to determine predictors of CPM use. Results: Of 571 eligible patients, 276 (48.3%) underwent lumpectomy, 130 (22.8%) underwent unilateral mastectomy, and 165 (28.9%) underwent mastectomy and a CPM. Among mastectomy patients, 55.9% underwent CPM. Young patients (<40 v. >55), larger tumors (>5cm v. <2cm), positive family history, lobular histology, multicentric disease, and surgeon gender (female) were independent predictors of increased CPM rates. Body mass index (BMI), tumor grade, estrogen receptor status, and preoperative breast magnetic resonance imaging were not associated with increased CPM rates. Conclusions: This cohort of patients has a much higher CPM rate than reported from population-based studies. We confirmed the role of patient age, tumor size and lobular histology as factors associated with CPM. Interestingly, factors not available through cancer registries, including positive family history and surgeon gender, are also independent predictors of CPM use. Since this study includes patients from diverse surgical practices, our findings are generally reflective of CPM use in metropolitan areas. [Table: see text] No significant financial relationships to disclose.
Average length of stay in hospice for five cancers
Authors: Kinzbrunner B. , Tanis D. 
Published: August 2020

6593 Background: Factors which influence average length of stay (ALOS) for terminally ill cancer patients who choose hospice include patient and family preferences, availability of services, demographics, specialty, and experience of referring physician, advances in treatment options, and especially type of cancer. In this paper, we examined differences in ALOS for the top five cancers in patients who utilized a large, national hospice provider between 2000 and 2007. Methods: We reviewed the records of 73,263 patients with prostate, colorectal, breast, lung, or pancreatic cancer who were admitted to one of 45 hospice programs and died on service between January 2000 and December 2007. The top five cancers accounted for 58% of all cancer deaths in the hospice programs. The effect of type of cancer and year on ALOS was evaluated using analysis of variance. Pair-wise differences were compared using the Bonferroni correction. Results: Overall ALOS was 40.0 days (yearly range 37.8–41.1). ALOS for prostate, colorectal, breast, lung, and pancreas was 46.8, 44.9, 44.2, 37.3, and 31.4 days, respectively. Prostate, colorectal, and breast ALOS were not significantly different from one other; lung ALOS was less than the top three but greater than pancreas ALOS (p < 0.001); and pancreas ALOS was significantly lower than all others (p < 0.001). The interaction between year and type of cancer was not significant (p > 0.05). Conclusions: The longer ALOS for patients with prostate, colorectal and breast cancer may be related to differences in natural history and effectiveness of anti-neoplastic therapies when compared to cancers of the lung and pancreas. Given the remarkable stability of ALOS over the last eight years and the lack of a statistical interaction between year and type of cancer, ALOS differences also suggest a steeper rate of decline for patients with cancers of the lung and pancreas following admission to hospice. No significant financial relationships to disclose.
The role of iron chelation activity of wheat grass juice in patients with myelodysplastic syndrome
Authors: Mukhopadhyay S. , Basak J. , Kar M. , Mandal S. , Mukhopadhyay A. 
Published: August 2020

7012 Background: A pilot study with wheat grass juice in major thalassaemia patients was done by a group of clinicians in IPGMR, Chandigarh, India. We performed a study of 200 patients of intermediate thalassaemia with wheat grass juice and found 80% patients becoming transfusion independent. During the study in majority of the patients, serum ferritin level was significantly less as compared to pretreatment values. The aim of our study was to see the effect of wheat grass juice in reducing Ferritin level in myelodysplastic syndrome and also do the biochemical analysis of the wheat grass juice. Methods: During period from January 2003 to December 2007 we selected 20 patients of transfusion dependent myelodysplastic syndrome in the oncology department of Netaji Subhash Chandra Bose Cancer Research Institute. The age range of the patients was 42 years to 72 years (median 55 years). The fresh leaves of 5–7-day-old wheat grasss including stems were made fresh juice and had given 30 mL of juice daily to all 20 patients for continuous 6 months. Wheat grass juice was analyzed by column chromatography and found to be rich in oxalic and malic acid which might have some role in dietary absorption of iron from intestine. Beside that the wheat grass juice was found to contain two unique active ingredients with iron chelating property which was performed by deoxyribose degradation assay. We compared aqueous soluble extract of 5–7-day-old plant and dose-dependent study showed a significant iron chelating activity of crude extract in comparison to known standard iron chelator desferroxamine (DFO). The active compounds of crude extract of wheat grass may chelate catalytic iron in iron overload disorders when taking systematic dose. Result: The mean serum Ferritin level of the patients was 2,250 (range 650–4,800) before wheat grass treatment. The mean reduced to 950 (range 68–1680) (p < 0.0001). The performance status was improved from 60% to 80% (Karnofsky) after wheat grass treatment. The mean interval between transfusions was found increased. Conclusions: Wheat grass juice is an effective iron chelator and its use in reducing serum ferritin should be encouraged in myelodysplastic syndrome and other diseases where repeated blood transfusion is required. No significant financial relationships to disclose.
A nine-gene predictor of therapy response in adult Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL)
Authors: Zuo Z. , Jones D. M. , Thomas D. A. , O'Brien S. , Ravandi F. , Kantarjian H. M. , Medeiros L. J. , Luthra R. , Chen S. S. 
Published: August 2020

7014 Background: Ph+ ALL in adults shows a poor response to therapy and high frequency of relapse. This study utilized a meta-analysis of previous genome-wide gene expression studies to define and validate a nine-gene predictor of outcome in Ph+ ALL patients. Methods: Normalized gene expression data from previously published studies of 672 ALL patients were analyzed to identify genes associated with therapy response. Expression of the selected genes was assessed using Applied Biosystems low density reverse transcription quantitative PCR (RT-qPCR) arrays in bone marrow (BM) samples from 27 adult Ph+ ALL patients treated with standard chemotherapy plus a tyrosine kinase inhibitor. Therapy responses were defined at the molecular level by monitoring BCR/ABL1 levels, and categorized into 3 groups: optimal, persistent and relapse. Median follow up was 6 months (range 4–15). Median disease-free survival among the optimal and relapse groups were 12 and 5 months respectively (p = 0.002). There was no statistical difference in age, initial peripheral blood white cell and BM blast counts, and initial normalized BCR/ABL1 levels between groups. Differentially expressed genes were selected using the significance analysis of microarrays (SAM). Hierarchical clustering and principal component analysis were applied to assess the correlation between gene expression pattern and therapy response. A predictive model was built using support vector machines. Differences in survival among groups were compared by Kaplan-Meier analysis. Results: Data mining and pathway analysis of the published data identified 46 genes in 7 pathways potentially associated with therapy response (p < 0.001). RT-qPCR results from a 15 case training set, 5 in each outcome group, identified 9 genes that classified the cases with 100% accuracy. Validation using an additional 12 cases showed 91.7% prediction accuracy (ROC error = 0.056). Compared with the initial diagnostic samples, gene expression pattern in relapsed samples shifted to that resembling the persistent group. Conclusions: Using data-trimming of whole genome expression studies, we defined and validated a nine-gene signature that is an independent predictive marker for therapy response in adult Ph+ ALL patients. No significant financial relationships to disclose.
A phase I dose-escalation study of the novel KSP inhibitor ARRY-520 in advanced leukemias
Authors: Estrov Z. , Cortes J. , Borthakur G. , Faderl S. , Garcia Manero G. , Ravandi F. , Khoury J. , Ptaszynski M. , Kantarjian H. 
Published: August 2020

7022 ARRY-520 is a potent, selective KSP inhibitor that arrests cells in mitosis with the subsequent onset of apoptosis. ARRY-520 has shown potent activity in preclinical models of hematological cancers and is being evaluated in a phase I trial in patients with advanced or refractory leukemias. The primary objectives of this study are to establish the safety and the MTD of ARRY-520 given as a single dose each cycle. Secondary objectives are to characterize the pharmacokinetics (PK) of ARRY-520, to assess evidence of preliminary clinical activity, and to explore biomarkers of KSP inhibition. ARRY-520 is administered as a 1-h IV infusion as a single dose per cycle in a “3 + 3 phase I design”. Dose escalations are following a prespecified schema. PK analyses for ARRY-520 are performed on plasma samples collected during cycle 1 and cycle 2. Pretreatment and post-treatment peripheral blood samples are collected for analysis of markers of KSP activity. To date, 15 patients, with a median age of 69 yrs (range 44–84 yrs), have been enrolled in the single dose schedule, 3 patients each at doses of 2.5 mg/m2, 3.75 mg/m2, and 5.6 mg/m2 and 6 patients at 4.5 mg/m2 per cycle. All patients had disease refractory to, and/or relapsed from, 1 or more prior therapies with a median of 3 prior regimens (range 1–10). Two patients at 5.6 mg/m2 experienced a DLT of gr3 mucositis. ARRY-520 was well tolerated at doses below 5.6 mg/m2. 4.5 mg/m2 has been determined to be the MTD. ARRY-520 has shown promising signs of clinical activity at doses of 3.75 mg/m2 and above. 2 patients had a complete reduction in their peripheral blasts on day 5 of cycle 1. Of these, one patient experienced a 70% reduction in bone marrow blasts while on study. One patient without peripheral blood blasts at baseline had a 43% reduction in bone marrow blasts and four additional patients had marked reductions in WBC counts. This is the first reported use of a KSP inhibitor in refractory and/or relapsed leukemias. ARRY-520 has been well tolerated in patients on a single dose schedule. Mucositis was observed as the DLT at 5.6 mg/m2. At doses 3.75 mg/m2 and above, ARRY-520 has shown signs of clinical activity. Based on these data, an alternative dose schedule is being explored. Updated data including safety, PK, PD, and preliminary activity of ARRY 520 from this study will be presented. [Table: see text]
Chronic myeloid leukemia (CML) with e1a2 BCR-ABL fusion transcript type: Analysis of characteristics, outcomes, and prognostic significance
Authors: Verma D. , Kantarjian H. , Jones D. , Borthakur G. , Garcia-Manero G. , Thomas D. A. , Verstovsek S. , Rios M. , Cortes J. 
Published: August 2020

7030 Background: The most common BCR-ABL fusion transcripts in CML are e13a2 (b2a2) and e14a2 (b3a2). Rarely, other transcripts like e1a2 are seen. Currently, there is no published series of data on efficacy of imatinib or other tyrosine kinase inhibitors (TKIs) in CML with e1a2. Methods: We analyzed records of 1,292 CML patients treated with TKI at our institution between January 2000 and November 2008. Results: 14 CML patients with e1a2 transcripts were identified, 9 in chronic phase (CP), 1 in accelerated phase (AP), and 4 in blast phase (BP). Median age at diagnosis was 60 (range 28–86) years, median follow-up 39.5 (range 2–109) months. Of the 9 in CP, 3 received interferon and then imatinib after interferon failure, 6 received TKI as first-line therapy (5 imatinib, 1 nilotinib): 5 achieved CHR only, 1 CCyR, 1 MCyR, 1 PCyR, and 1 did not respond to imatinib. 5 patients (2 post-interferon failure - 1 in CHR, 1 in PCyR; 3 frontline imatinib - 1 in CHR, 1 in CCyR, 1 non-responder) progressed to advanced phases (3 myeloid BP, 1 lymphoid BP, 1 AP) at a median 48 (range 4–92) months after CML diagnosis; with only 1 alive and in CMR after allogeneic SCT. AP patient received various TKIs sequentially and achieved only CHR with disappearance of clonal evolution. BP patients received Hyper-CVAD+imatinib/dasatinib or idarubicin+Ara-C; 2 did not respond, 1 had CCyR lasting 12 months with Hyper-CVAD+Imatinib and 1 had CMR after allogeneic SCT lasting 2 months. In all 14 patients, cytogenetic responses lasted 1–9 months before being lost and none (except 2) achieved MMR or CMR on imatinib or other TKI therapy. Six patients (5 CP, 1 AP) were alive at a median 39 (range 2–85) months after initial diagnosis: 4 with CHR (2 on imatinib, 1 nilotinib, 1 bosutinib), 1 with MCyR on imatinib, and 1 with CMR after allogeneic SCT. Conclusions: CML with e1a2 BCR-ABL fusion transcripts is rare and is associated with an inferior outcome to therapy with TKI, with responses being usually short-lived. These patients need to be identified as high-risk patients and monitored closely for efficacy during therapy with TKI. No significant financial relationships to disclose.
Phase I/II study of oxaliplatin, fludarabine, cytarabine, and rituximab in patients (OFAR2) with Richter's syndrome (RS), and relapsed or refractory B-cell chronic lymphocytic leukemia (CLL)
Authors: Tsimberidou A. M. , Wierda W. G. , Plunkett W. K. , O'Brien S. , Lerner S. , Smith S. C. , Kantarjian H. M. , Keating M. J. 
Published: August 2020

7031 Background: The first Phase I-II clinical trial of oxaliplatin, fluradabine, Ara-C, and rituximab (OFAR1) demonstrated significant activity in refractory CLL and RS (Tsimberidou et al, J Clin Oncol, 2008;26:196). To enhance the response rate with a decrease in myelosuppression, the dose of oxaliplatin was increased to 30 mg daily, the dose of Ara-C was decreased to 0.5g/m2 daily and the optimal number of days of fluradabine and Ara-C administration was explored (OFAR2). Methods: The OFAR2 regimen consisted of oxaliplatin 30mg/m2, D1–4; fludarabine 30mg/m2, Ara-C 0.5 g/m2; rituximab 375mg/m2, D3; and pelfigrastim 6mg D6. Fludarabine and Ara-C were given on D2–3 (dose level 1) D2–4 (dose level 2) or D2–5 (dose level 3); courses were repeated every 4 wks. Prophylaxis for tumor lysis, DNA viruses, and PCP was given. Results: A total of 55 pts have been treated to date: 12 pts enrolled in phase I (dose level 1, n=3; dose level 2, n=6; and dose level 3, n=3). DLTs were noted in 2/3 pts in dose level 3 (G4 diarrhea, 1; G4 neutropenic sepsis, 1), therefore level 2 was the MTD. Forty-three pts were treated in the Phase II portion of the study (relapsed CLL, 35; RS, 8). The median age was 64 yrs (range, 40- 81); 50 (91%) had β2-microglobulin > 3 mg/L; platelets were < 100 x109/L in 22 pts; and 44 pts had > 1 prior therapies. FISH results were: 17p deletion, n=15; 11q del, n=7; trisomy 12, n=12; 13q del, n=8; normal, n=2; unknown, n=11. Overall, 33 pts had unmutated and 7 mutated IgVH gene; ZAP70 was positive in 30, and negative in 14. Six (46%) of 13 pts with 17p del by FISH responded to OFAR2 (nPR, 2; PR, 4). Eleven pts underwent stem cell transplantation as postremission or salvage therapy. The most common toxicity was myelosuppression. Conclusions: Preliminary results demonstrated that OFAR2 resulted in an overall response rate of 63%, had antileukemic activity in pts with 17p del and clinical outcomes appeared to be superior to those of OFAR1. Accrual is ongoing. [Table: see text] [Table: see text]
Long-term follow-up of metastatic renal cancer patients undergoing reduced-intensity allografting
Authors: Bregni M. , Bernardi M. , Servida P. , Pescarollo A. , Crocchiolo R. , Treppiedi E. , Corradini P. , Ciceri F. , Peccatori J. 
Published: August 2020

7037 Background: Stem cell transplantation from a HLA-compatible sibling donor is an adoptive immunotherapy for cytokine-refractory, metastatic clear-cell renal cell cancer (RCC). However, the recent introduction of targeted therapy compounds has reduced the interest in this therapeutic strategy. We have reanalyzed our series with the aim to assess long-term benefit from allografting. Methods: Twenty-five RCC patients (Table) received a reduced-intensity allograft from an HLA-identical sibling donor after a thiotepa, fludarabine, and cyclophosphamide conditioning regimen, and a cyclosporine-based GVHD prophylaxis. Allogeneic peripheral blood hematopoietic cells were collected by apheresis after filgrastim treatment of the donor. Results: Best response to allograft was evaluable in 24 patients: 1 complete remission, 4 partial remissions, 12 minor response or stable disease, 7 progressive disease. Six patients died because of transplant related mortality (TRM) at day +12, +71, +86, +151, +259, +478. Cause of death was infection in four cases, GVHD in one case, and acute renal failure in one case. Fourteen patients died for progressive disease at median 415 (36–958) days from transplant. One-year survival was 48%, and 5-yr survival was 20%. At a median observation time of 65 months, 5 patients are alive, one in CR, one in PR, and three with stable disease. At multivariate analysis, CRP value before transplant, number of CD34+ infused cells and disease status at +90 significantly correlated with survival. Survival of patients at favourable/intermediate-risk according to the MSKCC score that underwent allografting was better in comparison to the survival predicted by historical controls. Conclusions: Transplantation is able to induce long-term disease control in a fraction (20%) of relapsed RCC patients. Identifying patients who could benefit from allografting, and incorporating molecularly targeted drugs in the transplant regimen, could further decrease progression and prolong overall survival. [Table: see text] No significant financial relationships to disclose.
A phase II randomized study comparing pegfilgrastim (PEG) versus filgrastim (FIL) after high-dose chemotherapy (HDC) and autologous peripheral blood stem cell support (PBSC)
Authors: Castagna L. , Bramanti S. , Levis A. , Michieli M. , Anastasia A. , Mazza R. , Sarina B. , Todisco E. , Giordano L. , Santoro A. 
Published: August 2020

7038 Background: The aim of this study was to demonstrate the non-inferiority of one fixed dose of PEG compared to daily FIL, in patients (pts) receiving HDC and PBSC. Methods: Criteria for elegibility were: HDC for haematological or solid tumors; at least 3 x10^6/kg CD34+ reinfused; age >18 years; normal cardiac, renal, liver and pulmonary function; signed written informed consent. Pts were randomized to receive on day+1 subcutaneously(sc) PEG (6mg) or 5 mcg/kg/d sc of FIL until ANC >1.0 x 10^9/L. Primary end points were: absolute neutrophil count (ANC) < 0.5 x 10^9/L and the number (no.) of days to achieve an ANC > 0.5 x 10^9/L from day +1. Secondary end points were: no. of days to achieve an ANC > 1.0 x 10^9/L; no. of days with fever > 38 °C; duration of antibiotic therapy; and no. of documented infections. Results: 80 pts were enrolled (40 pts for group). The duration of ANC < 0.5 x 10^9/L, the time to reach an ANC > 0.5 x 10^9/L and the time to reach an ANC > 1.0 x 10^9/L were superimposable in the two groups (mean days 6, 11, 12 respectively ). No. significant differences between FIL versus PEG group were observed in incidence of fever (24 vs 22), no. of documented infections (12 vs 10), no. of days with fever (1.7 vs 0.97 days), duration of antibiotic therapy (5.7 vs 3.5 days). No. differences in terms of extra-hematological toxicities and time to discharge between the two groups (16 vs 14). Time to reach a platelets count > 20 x 10^9/L was significantly shorter in PEG group compared to FIL group (15 vs 11 days, p value 0.05). Conclusions: This study shows that PEG was not inferior to FIL in terms of hematological reconstitution. Additionally PEG significantly shortened duration of thrombocytopenia <20 x 10^9/L. Consequently, PEG could be safely used after PBSC infusion. No significant financial relationships to disclose.