bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hematologic toxicities in cancer patients treated with the multityrosine kinase sorafenib: A meta-analysis of clinical trials.
Authors: Schutz F. A. , Je Y. , Choueiri T. K. 
Published: February 2017

352 Background: Sorafenib is a vascular endothelial growth factor receptor tyrosine-kinase inhibitor currently used in several malignancies. While not a traditional cytotoxic chemotherapeutic agent, hematological toxicities have been reported with this drug but the incidence and risk have not been formerly assessed. We performed a meta-analysis to determine the incidence and risk of hematologic toxicities associated with sorafenib use. Methods: The databases of Medline were searched for articles from 1966 to May 2010. Abstracts presented at the American Society of Clinical Oncology meetings were also searched. Eligible studies include randomized trials with sorafenib, and adequate safety data profile reporting anemia, neutropenia, lymphopenia or thrombocytopenia. Statistical analyses were conducted to calculate the summary incidence, RR and 95% confidence intervals (CI). Results: A total of 3,221 patients were included. The incidence of sorafenib-associated all- grade anemia, neutropenia, thrombocytopenia and lymphopenia were 43.9%, 18.0%, 25.3% and 34.1%, respectively. The incidences of high-grade events were 2.0%, 5.1%, 4.0% and 13.1%, respectively. Sorafenib was associated with a decreased risk of high-grade anemia (RR=0.62; 95% CI 0.39-0.98), an increased risk of all-grade (RR=1.69; 95% CI 1.33-2.17) and high-grade (RR=1.61; 95% CI 1.02-2.57) neutropenia, all-grade (RR=2.56; 95% CI 1.37-4.80) and high-grade (RR=3.63; 95% CI 1.98-6.66) thrombocytopenia, and high-grade lymphopenia (RR=1.84; 95% CI 1.22-2.78). Stratified analysis by the presence or not of concomitant chemotherapy demonstrated similar risks. Conclusions: Independent of cytotoxic chemotherapy, sorafenib has significant hematologic toxicities, with a decreased risk of anemia and increased risk of neutropenia, thrombocytopenia and lymphopenia. [Table: see text]
Likelihood of high volume renal surgeons to offer elective partial nephrectomy in high complexity tumors as classified by the nephrometry scoring system.
Authors: Weight C. J. , Kim S. P. , Crispen P. L. , Breau R. H. , Boorjian S. A. , Thompson R. H. , Leibovich B. C. 
Published: February 2017

354 Background: Partial nephrectomy (PN) has demonstrated equivalent cancer control to radical nephrectomy (RN) and has been associated with lower rates of all-cause mortality. Nevertheless, there continues to be wide variability in practice pattern in the treatment of renal masses. Specifically, the decision to perform PN or RN often depends on patient, surgeon and renal mass characteristics. By quantifying the renal tumor using the R.E.N.A.L. nephrometry scoring system, collecting surgeon information, and providing defined clinical scenarios we attempt to evaluate factors important in surgeon decision-making. Methods: In June 2009, all members of the American Urological Association with a listed email address were invited to participate in a survey evaluating the management of renal masses. Respondents were asked their preferred treatment for 8 clinical scenarios. Each of these renal masses was given a nephrometry score (NS). The propensity to offer PN was evaluated by NS and surgical volume. High volume was defined as > 50 renal cases per year and low volume was defined as £ 10 cases per year. Results: 764 attending level urologic surgeons responded to each of the 8 scenarios providing 6112 evaluable clinical scenarios. NS ranged from 4-10; each unit increase was associated with 2-fold increased odds of a surgeon offering radical nephrectomy (OR 1.99, 95% CI: 1.93,2.06). PN was the preferred treatment for approximately 95% of patients with low complexity tumors (NS < 8) regardless of surgical volume. However, proposed treatment of high complexity tumors (NS ³ 8) demonstrated considerable heterogeneity in treatment choice. Controlling for all patient characteristics, high surgical volume significantly predicted whether PN would be offered to patients with high complexity tumors (OR 3.04 95% CI: 2.34,9.95), but not those with low complexity tumors (OR 1.95 95% CI: 0.87,4.38) compared to low volume surgeons. Conclusions: Increasing NS correlated with increased use of radical nephrectomy, particularly after a score of 8 among all surgeons. As renal surgical volume increased, surgeons were more willing to offer PN in high complexity tumors. No significant financial relationships to disclose.
Effect of an individualized dose/schedule strategy for sunitinib in metastatic renal cell cancer (mRCC) on progression-free survival (PFS): Correlation with dynamic microbubble ultrasound (DCE-US) data.
Authors: Bjarnason G. A. , Khalil B. , Williams R. , Hudson J. M. , Lloyd B. , Milot L. M. , Atri M. , Kiss A. , Burns P. 
Published: February 2017

356 Background: Sunitinib area under the curve (AUC) correlates with response and PFS (Houk et al). Current recommendations for dose modification do not take this into account. Methods: A single center retrospective review identified mRCC patients (pts) where individualized (individ) sunitinib dose/schedule modifications (DSM) were used to maximize dose and minimize time off therapy (Rx). Pts were started on 50 mg 28 days (d) on/14 d off. DSM were done to keep toxicity (fatigue, skin, GI) at ≤ grade-2. DSM-1 was 50 mg 14 d/7 d with individ increases in d on Rx based on toxicity. DSM-2 was 50 mg 7 d/7 d with individ increases in d on Rx. DSM-3 was 37.5 mg continuously with individ 7 d breaks. DSM-4 was 25 mg continuously with individ 7 d breaks. Results: In 171 pts; median age was 60y; 20% good, 60% intermediate, 20% poor prognosis by Heng criteria; 80% had nephrectomy; 79% clear cell histology; 60% were previously untreated. At a median follow-up of 10.7 months (mo), overall median PFS was 7.9 mo. Of 39 pts still on therapy, 37 were on a DSM Rx. Pts were allocated to three groups based on the dose/schedule used for the longest time. The PFS/response% (PR+SD) for each group was 4.4 mo/65.6% (standard 50 mg 28 d/14 d; 43 pts), 8.0 mo/78.2% (DSM-1/DSM-2; 69 pts) and 10.4 mo/81.3% (DSM-3/DSM-4; 59 pts) with improved PFS (p=0.001) in both DSM groups vs. the standard schedule but no difference in response. 30 pts were studied by DCE-US at baseline, and after 7 d and 14 d on Rx or after 14 d and 28 d on Rx. In responding pts, tumor blood volume decreased at d 7 and again at d 14 vs. baseline but was stable or increased at d 28 vs. d 14. A rebound was seen after 14 d off Rx. Conclusions: Based on the U.S. data, previous pharmacokinetic data (steady state at 10-14 d) and this clinical data, starting pts on 50 mg 14 d/7 d followed by individ DSM may be safe and active. This DSM strategy, was associated with a favorable toxicity profile, apparent improvement in PFS and a good PR+SD rate in a group of unselected mRCC pts, warranting confirmation in a prospective trial. Pts that tolerate 50 mg 28 d/14 d with minimum toxicity may need dose escalation and/or less time off therapy to optimize PFS. [Table: see text]
Population-based analysis of the rising incidence of renal cancer: Evaluation of age-specific trends (1975-2006).
Authors: Nepple K. G. , Strope S. A. 
Published: February 2017

357 Background: Multiple studies show an increasing incidence of renal cancer, possibly related to the rising use of cross sectional imaging. We explored if the increase in renal cancer incidence differs across age groups. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) cancer registry data for the years 1975-2006, we ascertained incident cases of renal cancer. Urothelial histology was excluded. Yearly incidence rates of renal cancer were calculated, age-adjusted to the United States 2,000 standard adult population, and stratified by age group (20-39, 40-49, 50-59, 60-69, 70-79, 80+). Age-specific trends in renal cancer diagnosis over time were evaluated with Poisson regression. Results: 63,843 incident renal cancer cases were identified in 544,684,745 person-years of observation. From 1975 to 2006, overall age-adjusted renal cancer incidence rose 238% from 7.4 to 17.6 per 100,000 adults. The mean age at diagnosis was 61.7 years in 1975, increased to 64.7 years in 1991, and then declined to 62.7 years by 2006. Using 1991 (the year of peak renal cancer age at diagnosis) as the dividing point, the average annual percentage increase in renal cancer incidence was 3.6% from 1976-1990 and 2.9% from 1991- 2006. The age-specific incidence rates of renal cancer increased in all age groups from 1975 to 2006; however the age-specific incidence rates changed at different rates (p<0.0001). Younger age groups showed a more rapid increase in renal cancer incidence over the second half of the study than did the older age groups. For example, for patients age 20-39 years the annual percentage change increased from 4.5% in 1975-1990 to 5.2% in 1991-2006 while annual percentage change decreased from 6.7% in 1975-1990 to 0.9% in 1991-2006 in those over 79 years old. The proportion of patients diagnosed younger than age 65 increased from 45.9% in 1991 to 55.3% in 2006. Conclusions: The incidence of renal cancer has risen steadily since 1975 and continues to increase in all age groups. In the last 15 years, mean age at diagnosis of renal cancer has decreased driven by an increased incidence in younger patients with proportionally less increase in older patients. No significant financial relationships to disclose.
Hand–foot skin reaction, an anticipated dermatologic toxicity to pazopanib, with an unexpected low incidence: A systematic review of literature and meta-analysis.
Authors: Balagula Y. , Wu S. , Su X. , Lacouture M. E. 
Published: February 2017

365 Background: Pazopanib is a novel multikinase inhibitor that has been approved for the treatment of advanced renal cell carcinoma (RCC). It shares a similar spectrum of target receptors with sorafenib and sunitinib, including VEGFR, PDGFR, and c-kit tyrosine kinases. We have performed a systematic analysis to investigate the risk of HFSR to pazopanib. Exploring the differences in the incidence of HFSR between sorafenib, sunitinib, and pazopanib may offer additional insights into underlying mechanisms of this toxicity. Methods: Relevant studies were identified from PubMed (1998-2010) and abstracts presented at the American Society of Clinical Oncology Conferences between 2004 and 2010. Eligible studies were limited to prospective phase II-III clinical trials in which cancer patients were treated with pazopanib 800 mg orally once daily. Incidence, relative risk (RR), and 95% confidence intervals were calculated using random-effects or fixed-effects models based on the heterogeneity of included studies. Results: A total of 942 patients from 10 prospective clinical trials were included in the analysis. The overall incidence of all-grade and high-grade HFSR was 4.5% (95% CI: 2.5-7.9%) and 1.5% (95% CI: 0.7-3.1 %), respectively. The relative risks of all-grade and high-grade HFSR to pazopanib monotherapy in comparison with controls were increased, reaching statistical significance for all-grade (RR=6.05, 95% CI: 1.11-33.12, p=0.038), but not for high-grade (RR=2.51, 95% CI: 0.12-51.9, p=0.55). The incidence of all-grade HFSR was significantly higher in patients with RCC as compared to patients with non-RCC malignancies (7.8% vs. 2.4%, p value=0.015). Conclusions: Despite sharing the same spectrum of target receptors with sorafenib and sunitinib, pazopanib is associated with an unexpectedly low risk of HFSR. Further investigations are needed to elucidate HFSR pathogenesis. [Table: see text]
First-line sunitinib in patients with renal cell carcinoma (RCC) and von Hippel-Lindau syndrome (VHL).
Authors: Roma A. , Basso U. , Brunello A. , Maruzzo M. , Zagonel V. , Nardin M. , Bezzon E. , Zovato S. , Opocher G. 
Published: February 2017

373 Background: VHL is a rare hereditary condition caused by germline alteration of VHL gene predisposing to multiple renal and other tumors. Since acquired dysregulation of VHL-dependent pathways is often present in patients with sporadic RCC treated with first-line sunitinib (SUN), there is a strong rationale to use the same drug in VHL patients with progressive disease in the kidneys or other sites. Methods: We performed a retrospective analysis of SUN therapy in genetically confirmed VHL patients treated at our Institution for multifocal or advanced RCC. Results: From February 2007 to October 2010, 9 VHL patients were proposed first-line SUN for RCC, mean age 44 yrs (26-60), F:M ratio 2:1. SUN was administered for a mean of 9 cycles (1-20). Eight of 9 pts received at least two cycles and were considered for response evaluation: all 8 were stable according to RECIST criteria, but decrease in radiological density of lesions was observed in 7 of 8 pts (87.5%). Density decrease was noted not only in renal and hepatic lesions but also in some pancreatic nodules; all CNS haemangioblastoma lesions remained stable (see table). Preliminary median PFS is > 13 months (8 censored, 1 deceased). Conclusions: SUN treatment in VHL patients appears to achieve good disease control not only in renal tumors but also in synchronous VHL-related lesions, especially pancreatic solid nodules whose exact nature (metastatic RCC or neuroendocrine tumor) cannot be ruled out without invasive biopsies. [Table: see text] No significant financial relationships to disclose.
Surgical outcomes of gasless single port retroperitoneal radical nephrectomy for dialysis patients: A comparative analysis with nondialysis patients.
Authors: Okada Y. , Masuda H. , Saito K. , Iimura Y. , Yokoyama M. , Komai Y. , Numao N. , Koga F. , Fujii Y. , Kihara K. 
Published: February 2017

376 Background: Gasless single port retroperitoneal radical nephrectomy is minimally invasive, curative and cost effective operation which we have developed since 1998 (Eur Urol Suppl 2009; 8: 392), and covered by the Japanese universal insurance system from April, 2008. Patients necessitating dialysis are considered high risk operative candidates because of their multiple comorbidities. We compared surgical outcomes of dialysis patients with non-dialysis patients to evaluate this operation as treatment for high risk group. Methods: We reviewed 304 consecutive patients including 59 (19.4%) dialysis patients who underwent CO2 gasless single port retroperitoneal radical nephrectomy at our institute between 2000 and 2009. Complications within the first 30 days after the surgery were graded retrospectively according to the modified Clavien classification system. Patient demographics, operative outcomes, and complications were compared between dialysis and non-dialysis patients. Results: In all patients, the median patient age and body mass index were 60 years and 23.0 kg/m2. The median length of surgical incision, operative time (OT) and estimated blood loss (EBL) were 6.5 cm, 189 minutes and 214 mL, respectively. The transfusion rate was 3.3%. The intra and postoperative complication rate were 3.9% and 10.1%. Two grade 3a (ureteral obstruction, 1; diverticulitis, 1), three grade 3b (occlusion of peripheral hemodialysis shunt, 3) and two grade 4 (pulmonary embolism, 1; acute heart failure, 1) surgical complications occurred. In dialysis patients, the mean BMI was lower (20.4 vs. 23.3, p<0.0001), the mean OT was shorter (170 vs. 201 minutes, p<0.0001) and the mean EBL was lower (216 vs. 311mL, p<0.0001) than non-dialysis patients. There was no Clavien grade 3 or 4 surgical complications except dialysis access occlusion in dialysis patients. The average time to oral feeding and walking were equivalent, but possible discharge were longer in dialysis patients (4.3 vs. 3.4 days, p<0.0037). Conclusions: Our data supports the safety and feasibility of gasless single port retroperitoneal radical nephrectomy for dialysis patients. No significant financial relationships to disclose.
Genomic analysis of circulating tumor cells to evaluate predictive biomarkers.
Authors: Danila D. C. , Anand A. , Yao J. , Gierszewska M. , Kramer M. , Fleisher M. , Sawyers C. L. , McCombie W. R. , Scher H. I. 
Published: February 2017

38 Background: To estimate the association between molecular biomarkers detected in circulating tumor cells (CTC) and tumor sensitivity to treatment, robust assays are needed before qualification in prospective clinical trials. Methods: To address the limitations of the current FDA cleared technology, we focused on improving our ability to isolate more purified CTC populations based on fluorescence-activated cell sorting (FACS) to capture EpCAM+, CD45−, DAPI− cells from patients with castration-resistant prostate cancer (CRPC). Androgen receptor (AR) and genes frequently mutated in CRPC have been selected from the integrative genomic profiling at MSK. We optimized the RainDance microfluidic PCR followed by targeted sequencing in low number of cancer cells, before proceeding to clinical samples. Results: On blood samples from124 patients with progressive CRPC, FACS method isolates an average 100-fold more EpCAM+ events compared to the current FDA cleared CellSearch assay. By FACS, >10 or >50 events were isolated in 88% or 58% of patients, compared to 32% or 10% of patients by CellSearch, respectively. FACS isolated cells express prostate-specific mRNAs (PSA, AR, TMPRSS2-ERG), as detected by an analytically validated multiplex RT-PCR, indicating that these EpCAM+ events are bona fide CTC. For genomic profiling, sufficient high quality DNA was obtained from as little as 50 CTC, with a recovery rate of 89% from FACS sorted samples and adequate sequencing coverage, and 1:4 detection threshold in a heterogeneous cell population. Selected missense mutations in AR, PIK3CA and TP53 found in CTC but not in WBC from same patient are further analyzed. Conclusions: Molecular alterations in CTC can potentially serve as predictive markers of sensitivity and clinical outcomes as surrogate tissue in clinical practice. We established standard operating procedures for specimen processing, and confirmed the sequencing coverage and polymorphism detection thresholds in a heterogeneous cell population. In the context of available samples collected from patients enrolled on AR-targeted therapies, we will generate data to qualify CTC as biomarkers under the Oncology Biomarker Qualification Initiative. [Table: see text]
Prognostic factors in patients with advanced renal carcinoma.
Authors: Muriel C. , Esteban E. , Astudillo A. , Martinez-Camblor P. , Corral N. , Crespo G. , Berros J. , Fonseca P. J. , Luque M. , Lacave A. J. 
Published: February 2017

391 Background: A retrospective cohort of 135 patients with advanced RCC treated with biological agents and/or cytokines (CK) was analysed between July 1996 and February 2010. Methods: The expression of several biomarkers by immunohistochemistry and 2 analytical variables: thrombocytosis and neutrophilia were analysed and were correlated with prognosis. Results: 67 patients were treated only with biological agents and 68 with CK (23 received also biological agents). The univariate statistical analysis showed that the enhanced expression of HIF-1alpha correlated with a poor prognosis in patients treated with sunitinib (PFS was 5.4 vs. 13.4 months in those with low expression, p=0.001). The overexpression of ACIX was associated to a better prognosis in patients that received biological agents (PFS was 18.3 vs. 5.2 months in those with decreased expression, p<0.001; OS was 32.1 vs. 7.8 months, p<0.001), including sunitinib (PFS was 16.8 vs. 5.5 months, p<0.001), sorafenib (PFS was 8 vs 3.5 months, p<0.001)) and CK (PFS was 6.3 vs. 2.7 months, p=0.003; OS was 32.9 vs. 5.9 months, p=0.001). Positive PTEN was related to a good prognosis in patients treated with sunitinib (PFS was 15.1 vs. 6.5 months, p=0.003) and CK (PFS was 7.5 vs. 3.8 months, p=0.037, OS was 13.7 vs 7.9 months, p=0.039). The increased expression of p21 was related to a poor prognosis in patients that received biological agents (PFS was 5.9 vs. 16.8 months with high expression, p=0.024), including sunitinib (PFS was 6.2 vs 18.9 months, p<0.001), sorafenib (PFS was 4 vs 9 months, p=0.013) and CK (PFS was 3.9 vs. 7.5 months, p<0.001). Thrombocytosis was related to a poor prognosis in patients treated with CK (PFS was 2.6 vs. 5.1 months p=0.017; OS was 5.9 vs. 14.3 months p=0.010). Neutrophilia was related to a poor prognosis in patients that received CK (PFS was 2.6 vs. 5.7 months, p=0.019; OS was 5.9 vs. 12.8 months, p=0.035). In the multivariate analysis, the overexpression of ACIX was a favorable prognostic factor independent of PFS with a HR of 0.107 (p<0.001) and OS with a HR of 0.055 (p<0.001). Conclusions: Our experience has suggested the utility of de HIF-1alpha, ACIX, PTEN, p21, thrombocytosis and neutrophilia as prognostic factors in patients with advanced RCC. ACIX has shown to be an independent prognostic factor. No significant financial relationships to disclose.
Modulation of immune cell subpopulations in renal cell carcinoma patients by sunitinib.
Authors: Seliger B. , Giersberg C. , Staehler M. D. 
Published: February 2017

395 Background: Increased numbers of immune suppressive cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC) as well as alterations in the frequency and function of activated and memory T cells in peripheral blood mononuclear cells (PBMNC) represent immune escape mechanisms of renal cell carcinoma (RCC). The tyrosine kinase inhibitor sunitinib, which is currently successfully implemented in the treatment of RCC has been shown to modulate immune suppressive cells as well as T lymphocytes thereby shifting the immune balance in these patients to a more stimulating setting. Methods: Using flow cytometry and a large panel of antibodies directed against different immunomodulatory molecules, we here analysed the effects of (i) adjuvant sunitinib treatment (50 mg for 4 weeks, on 2 weeks off) on the composition of various immune cell populations, their function and activity in RCC patients and (ii) sunitinib treatment of PBMNC from healthy donors over time Results: A time-dependent decrease in the frequency of Treg and MDSC was found in PBMNCs during in vitro and in vivo sunitinib treatment. In addition, the number of NK cells, activated and/or memory T cells was increased in PBMNC of TKI-treated patients over time. Conclusions: This observation may have important implications for (i) the monitoring of the sunitinib activity on immune cells, (ii) the treatment schedule including duration of TKI therapy, and (iii) the implementation of sunitinib in combination with immunotherapies in RCC patients. Long-term monitoring of a larger patients' group will show whether the activation of T cells and NK cells as well as the decrease of immune suppressive cells due to sunitinib treatment is associated with enhanced antitumor responses. [Table: see text]