bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incidence of secondary malignancies (SM) in patients (pts) with germ cell tumors (GCT) who received high-dose chemotherapy (HDCT): A retrospective study from the European Society for Blood and Marrow Transplantation (EBMT) database.
Authors: Necchi Andrea , Rosti Giovanni , Badoglio Manuela , Giannatempo Patrizia , Secondino Simona , Lanza Francesco , Pedrazzoli Paolo ,   EBMT Solid Tumors Working Party
Published: March 2017

409 Background: Little is still known about the incidence of SM in young adult pts with GCT after HDCT, owing to the rarity of the disease, and the need for long term follow-up (FUP) data registries. In Europe, the EBMT systematically collect relevant data and may provide a suitable platform for retrospective analyses. Methods: Criteria for patient selection included diagnosis of GCT, adult male gender, ≥ 2yr of FUP after the administration of HDCT. Summary statistics were used to describe pt characteristics and outcomes. χ2 tests were used to compare groups according to the length of FUP. Kaplan-Meier estimates were used to estimate overall survival (OS) since the diagnosis of SM. Log-rank test was used to compare OS in pt subgroups. Univariable Cox regression analyses examined clinical factors potentially associated with OS following SM diagnosis. Results: From 1981 to 2014, 9,153 autografts, accounting for 5,100 pts, have been registered. Of them, 1,855 had ≥ 2yr of FUP. Among the latter, a total of 56 cases of SM were identified (3.0%). 28 (50%) had solid SM, 22 (39.3%) hematologic SM (5 had uncoded SM). Median age at first HDCT was 34 years (IQR: 30-42), median age at development of SM was 42 (37-51). 26 pts (46.4%) received single HDCT cycle, 22 (39.3%) multiple HDCT cycles (8 unknown). 31 pts had ≥ 5 yr FUP, 25 pts 2-5 yr FUP. Solid SM were developed more frequently in those with longer FUP ( ≥ 5 yrs) compared to hematologic SM (p = 0.008). Median follow-up (FUP) was 76.9 months. Univariably, the type of SM (solid vs. hematologic) was significantly associated with OS. Hematologic vs solid SM: HR: 3.49 (95%CI: 2.09-10.47, p < 0.001). Median OS of pts who developed solid SM was 32.8 months compared to 7 months of those with hematologic SM. The retrospective nature of the data is the major limitation. Conclusions: The incidence of SM in GCT pts who have received HDCT is a concern. During the FUP, there seems to be a non-overlapping risk of developing solid or hematologic SM, with a significantly different prognostic impact. These data may be important to improve patient counselling and the planning of post-HDCT FUP.
Administration of high-dose chemotherapy (HDCT) with stem-cell support in patients (pts) with advanced germ cell tumors (GCT) 40 years of age or older: A retrospective study from the European Society for Blood and Marrow Transplantation (EBMT) database.
Authors: Necchi Andrea , Rosti Giovanni , Badoglio Manuela , Giannatempo Patrizia , Raggi Daniele , Secondino Simona , Lanza Francesco , Pedrazzoli Paolo ,   EBMT Solid Tumors Working Party
Published: March 2017

415 Background: The administration of HDCT in GCT pts ≥ 40 years may raise concerns, owing to the limited data on safety outcomes. Yet HDCT strategy may be the optimal one to achieve a cure in many cases. Consequently, understanding more on the outcomes of these pts and on safety of HDCT delivery has relevant clinical impact. Methods: Criteria for patient selection consisted of: GCT diagnosis, male gender, age ≥ 40 at the time of first HDCT course. Summary statistics were used to describe patient characteristics and outcomes. Probabilities for overall survival (OS) and transplant-related mortality (TRM) were calculated using the Kaplan-Meier method. TRM was defined as mortality from any cause other than disease progression within 100 days of HDCT. Results: From 11/1981 to 12/2015, 1,179 pts aged ≥ 40 have been registered, from 236 centers, in the EBMT database after having received single (n = 578) or multiple (n = 601) HDCT courses. Age distribution was: 917 pts 40-49, 236 pts 50-59, 26 pts 60-71. 56 had extragonadal GCT. Bone marrow was used as stem cell source in 85 pts (7.2%). Median follow-up was 38.6 months. Overall 74 TR deaths were found. Significant decrease of TRM was observed during the decades: 1981-1990 (8.3%), 1991-2000 (6.8%), 2001-2015 (4,1%, p = 0.024). Focusing on 2001-2015 period, no differences were found according to age: 40-49y (n = 673): 4.7%, 50-59y (n = 174): 1.8%, 60-71y (n = 23): 4,3% (p = 0.419). TRM for HD-carboplatin-etoposide regimen only (all pts > 1990) was as follows: 40-49y (n = 289): 2.9%, 50-71y (n = 90): 1.1% (p = 0.713). 2-y OS was consistent across all age subgroups. Causes of death were: infection/sepsis (46/74, 62.2%), organ failure (11/74, 14.9%), and cardiac toxicity (8/10.8%), other (9 pts). The retrospective nature of the data is a major limitation. Conclusions: The administration of HD-carboplatin-etoposide in GCT pts ≥ 40 and ≥ 50 years is feasible and is supported by adequate safety data. Collecting additional information on non-severe long-term sequelae is needed. These results may add important information to improve patient counselling.
Nationwide disparities in testicular cancer care delivery: Racial, ethnic, and economic markers of patient vulnerability.
Authors: Macleod Liam Connor , Cannon Shannon , Ko Oliver , Wright Jonathan L. , Schade George , Lin Daniel W. , Gore John L. , Dash Atreya 
Published: March 2017

421 Background: Testis cancer is often curable, yet early presentation is a key determinant of survival and treatment morbidity. Testis cancer affects the young, who have less consistent primary care access. This may impede timely mobilization of complex healthcare resources needed for cancer care. We analyze the National Cancer Database (NCDB) for disparity in disease-specific outcomes. Methods: The NCDB identified adult males with testicular tumors (2004-2013). Four outcomes were selected as markers of care delays: higher stage presentation (defined as stage III+), large primary lesion at diagnosis, time to orchiectomy and overall mortality. Key exposures included race/ethnicity, socioeconomic factors and insurance status. Outcomes were assessed with multivariable hazards regression (survival) or logistic regression (others). Results: 31,964 men were eligible. Seventeen percent had higher stage presentation, 29% had a large primary, and 9.9% had delayed orchiectomy and 4.8% died during follow up. All outcomes were associated with multiple markers of patient vulnerability at the p < 0.001 level. The most consistent and greatest magnitude association was insurance status (e.g. for mortality Medicaid HR 1.9, 95% CI 1.6-2.3, uninsured HR 1.7, 95% CI 1.5-2.1, for large primary Medicaid OR 1.8, 95% CI 1.7-2.0, uninsured OR 2.1, 95% CI 2.0-2.3 [referent private payer]). In addition to markers of vulnerability, center case volume and travel burden were also associated with poor outcomes (p < 0.001). Conclusions: We find association between severity of disease and markers of patient vulnerability. Insurance had the greatest magnitude and most consistent association with poor outcomes and is therefore a priority for quality improvement. As access to primary care is expanded for the testis cancer population with the Affordable Care Act, it will be important to assess whether gains in coverage translate to improvements in cancer outcomes.
Impact of modern treatment strategies on second cancer incidence for patients with early stage seminoma: A population-based study in British Columbia.
Authors: Bahl Gaurav , Pathak Rima Sanjay , Ko Jenny J. , Sia Michael , Bowering Gale , Kollmannsberger Christian K. , Tyldesley Scott 
Published: March 2017

423 Background: The purpose of this study is to examine the incidence of Second Cancers (SC) in patients with Stage I or II Seminoma treated in British Columbia (BC), and compare rates between patients managed with Radiation Therapy, Chemotherapy, or Active Surveillance. Methods: Consecutive patients with Stage I or II Seminoma (n = 1549, 21167 person years) diagnosed in British Columbia between 1984 and 2013 were identified from the BC Cancer Registry and included in this study. Patients were managed with Radiation Therapy (RT; n = 663), Chemotherapy (CT; n = 259) or Active Surveillance (AS; n = 624). Data was extracted from the registry and verified by individual patient chart review. Cumulative incidence rates were computed using competing risk analysis. Age and Sex Standardized Incidence Ratios (ASIR) were calculated (compared to the Canadian population). Results: After a median follow-up of 14 years (RT group: 21.5yrs, CT group: 10yrs, AS group: 8yrs), the 15 year Overall Survival was 91.4%. Only 15 patients died from progressive Seminoma, while 46 died from second cancers. A total of 115 patients developed SCs, and the cumulative incidence (CI) of SC, at 15 years, was: 5.9% for patients who received RT, 8.6% for those who had CT, and 4.9% for patients managed with AS. The higher CI for patients treated with CT, versus RT, was not statistically significant (p = 0.08). The ASIR for RT, CT and AS groups were 1.31 (95% Confidence Intervals: 0.92- 1.86), 2.57 (1.07- 6.15; p = 0.03), and 1.38 (0.75- 2.54), respectively. Patients who underwent treatment at ages 30-44yr and 45-59yr had a significantly higher ASIRs of 4.33 (2.1- 8.9; p < 0.001) and 1.8 (1.16- 2.8; p = 0.008). ASIR was not significantly different when stratified by radiation dose, field types, or year of diagnosis. Conclusions: We found no statistically significant difference in the Cumulative Incidence of Second Cancers for patients treated with Radiation Therapy versus Chemotherapy in our patient population. Longer follow-up for the CT group is required to confirm trends evident in our analysis.
A single-arm biomarker-based phase II trial of savolitinib in patients with advanced papillary renal cell cancer (PRCC).
Authors: Choueiri Toni K. , Plimack Elizabeth R. , Arkenau Hendrik-Tobias , Jonasch Eric , Heng Daniel Yick Chin , Powles Thomas , Frigault Melanie M. , Clark Edwin , Handzel Amir , Gardner Humphrey Athelstan , Morgan Shethah , Albiges Laurence , Pal Sumanta K. 
Published: March 2017

436 Background: Savolitinib (HMPL504/Volitinib, AZD6094) is a potent, selective MET inhibitor (IC50 of 4nM). MET and its ligand, HGF, are known to play an important role in the molecular events underlying oncogenesis in PRCC, a disease without a clear standard of care and marked by alterations of chromosome 7 (containing both MET and HGF genes) in a majority of patients as well as gene amplification or MET kinase domain mutations (Albiges et al. 2014, Linehan et al., 2015). Methods: This study evaluates savolitinib in PRCC patients dosed at 600mg daily until disease progression. ORR is the primary endpoint. PFS & DoR are secondary endpoints. PRO & HRQoL questionnaires are exploratory endpoints. Eligibility includes naive and previously treated metastatic PRCC, ECOG PS 0 or 1. Archival tumor was used to centrally confirm PRCC pathology post hoc and to determine MET status using Next Generation Sequencing (Foundation Medicine Inc, USA). Results: As of 27 June 2016, 109 pts were dosed. Best response was PR n=8, SD n=43, PD n=48 and 10 patients were not evaluable for response. 44 pts are MET-driven (MET/HGF gene copy number gain or kinase domain mutations), 46 pts were MET-negative, 19 pts are status unknown. MET-driven pts included Papillary Type I & II histologies. All 8 responders were in the MET-driven group, 18% RR in this subset. Median PFS in the MET-driven group was 6.2 months (95% CI: 4.1–7.0) vs. 1.4 months (95% CI: 1.4–2.7) in the MET-negative group (p = 0.002). Overall 10/109 pts had AEs leading to discontinuation. 23/109 pts had ≥ Grade 3 toxicity related to savolitinib. The most common AEs (all grades) includes: nausea (39%), fatigue (27%), edema (18%), and abnormal LFTs (17%). One death from hepatic encephalopathy was considered related to savolitinib. PRO & HRQoL data was not statistically analysed, descriptive data support main efficacy findings. Conclusions: In the largest biomarker-profiled trial dedicated to PRCC, savolitinib was generally well tolerated with anti-tumor activity in MET-driven patients. These findings warrant further clinical investigation of savolitinib in MET-driven PRCC. Clinical trial information: NCT02127710.
Improved imaging-pathology correlation with MR imaging-derived, 3D-printed, patient-specific whole-mount molds of the prostate.
Authors: Costa Daniel N. , Chatzinoff Yonatan , Passoni Niccolo M. , Kapur Payal , Roehrborn Claus G , Xi Yin , Rofsky Neil , Torrealba Jose , Francis Franto , Futch Cecil , Hagens Phyllis , Notgrass Hollis , Otero-Muinelo Susana , Chopra Rajiv , Pedrosa Ivan 
Published: March 2017

44 Background: A critical requirement for imaging-pathology correlation is adequate image registration. Since the prostate is deformable, sectioning the gland in a plane similar to imaging is challenging. To improve the in vivo imaging and ex vivo histology image registration, 3D-printed, patient-specific, MRI-derived molds (PSMs) for whole-mount processing have been proposed. This study compared the anatomical registration of preoperative MRI and prostate whole-mounts obtained with PSMs versus conventional whole-mount sectioning (WMS). Methods: Based on an a priori power analysis, 50 men who underwent 3T prostate MRI followed by radical prostatectomy were included. Two blinded and independent readers (R1, R2) outlined the contours of the gland and of the tumor in the MRI using regions of interest (ROIs). These were compared with the ROIs from the whole-mount histology, the reference standard, using PSMs in the study group (n=25) or conventional WMS in the control group (n=25). The spatial overlap across the MRI and histology data sets was calculated using the Dice similarity coefficient (DSC) for the prostate overall and tumor. Results were compared using Wilcoxon rank sum test. Results: The MRI-histopathology anatomical registration for the prostate gland overall and the tumor were significantly superior with the use of PSMs than with the use of WMS for both readers (Table). Conclusions: The use of PSMs for prostate specimen whole-mount sectioning provides significantly superior anatomical registration of in vivo multiparametric MRI and ex vivo prostate whole-mounts than conventional WMS. The use of PSMs should facilitate the exchange of information across imaging and pathology required for research and patient care. [Table: see text]
Safety and preliminary activity of hydroxychloroquine and aldesleukin in metastatic renal cell carcinoma (mRCC): A cytokine working group study.
Authors: Appleman Leonard Joseph , Logan Theodore F. , Normolle Daniel Paul , Ernstoff Marc S. , Parikh Rahul Atul , McDermott David F. , Monk Paul , Olencki Thomas , Friedland David , Maranchie Jodi Kathleen , Lotze Michael T. 
Published: March 2017

440 Background: Aldesleukin (recombinant human interleukin-2) has been an FDA-approved treatment for mRCC since 1992, based on a 5-10% rate of durable complete remissions. Autophagy is a protective mechanism that enables cells to survive the metabolic stress of cancer therapy. Hydroxychloroquine (HCQ) inhibits cellular autophagy and has shown synergy with interleukin-2 in animal tumor models. We hypothesized that this combination would be tolerable and active in patients with mRCC. Methods: The Cytokine Working Group initiated a study of high-dose aldesleukin in combination with oral HCQ for patients with mRCC. Subjects receive up to 6 cycles of aldeskleukin, 600,000 International Units per kg, on a standard schedule. HCQ is administered orally starting 2 weeks prior to the first dose of aldesleukin and continuing up to one year. The initial HCQ dose was 600 mg daily, with a planned dose escalation to 1200 mg daily after safety was demonstrated in five subjects. Subjects were monitored for safety and tolerability as well as response per RECIST 1.1. Results: Five subjects were treated at the first dose level of 600 mg daily HCQ plus aldesleukin with no unexpected toxicity. Thirteen subjects were then treated at HCQ 1200 mg daily with aldesleukin. Of these, two experienced hypotension and tachycardia and 1 patient died from pulmonary emboli. The cardiac events were consistent with aldesleukin toxicity, but were observed earlier in the course of treatment than anticipated for aldesleukin alone. HCQ dose was therefore de-escalated to 600 mg daily, and 8 additional subjects have been enrolled with no unexpected toxicity. In 26 of 39 planned subjects, there has been 1 complete response (CR) and 1 partial response (near CR), both in the 600 mg cohort. As of Oct 24, 2016, after a median of 36.6 months of follow-up, seven out of 26 subject have died, with median overall survival not yet obtained (95% C.I. = (29.6 months,unknown)). Conclusions: HCQ in combination with aldesleukin was found to be tolerable at a dose of 600 mg daily, with expected toxicities. Clinical responses have been observed. Clinical trial information: NCT01550367.
The association between age-related macular degeneration (AMD) and renal cell carcinoma (RCC): A nested case-control study.
Authors: Keizman Daniel , Rouvinov Keren , Neumann Avivit , Yang Yu-Xiao , Gottfried Maya , Dresler Hadas , Leibovitch Ilan , Haynes Kevin , Mamtani Ronac , Boursi Shimon Ben 
Published: March 2017

443 Background: Overexpression of vascular endothelial growth factor (VEGF) is implicated in the pathogenesis of both RCC and AMD. To date, there are no data on an association between AMD and RCC. In the present nested case control study, we aimed to evaluated the association between age-related macular degeneration and RCC risk. Methods: We conducted a matched case-control study within a population-representative database from the United Kingdom. Study cases were defined as individuals with any diagnostic code of RCC. For every case, four eligible controls were matched on age, sex, practice site, time, and duration of follow-up. Exposure of interest was diagnosis of AMD prior to cancer diagnosis. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for RCC were estimated using conditional logistic regression. Adjustment was performed for confounders associated with both AMD and RCC such as smoking, obesity, hypertension, and diabetes. Furthermore, in a secondary analysis, we evaluated the association between other non-VEGF associated retinopathies and RCC, and between AMD and pancreatic cancer, a malignancy characterized by hypovascularity in contrast to the hypervascularity of RCC. Results: The study population included 1,547 patients with RCC and 6,066 matched controls. Median follow-up time was 6 years (IQR 3-9). AMD diagnosis was associated with a significantly increased RCC risk (OR 1.89, 95% CI 1.09-3.29). In contrast, there was no association between other retinopathies and RCC risk (OR 0.8, 95% CI 0.56-1.15). AMD was associated with a lower risk for pancreatic cancer (OR 0.47, 95% CI 0.35-0.64). Conclusions: Patients with AMD may be at higher risk for RCC. Providers should consider screening for RCC within this population.
A novel strategy for axitinib dosing in the treatment of metastatic renal cell carcinoma.
Authors: Doherty Gary , Lynskey Deirdre , Matakidou Athena , Fife Kate , Eisen Tim 
Published: March 2017

464 Background: The AXIS trial established axitinib as an effective second line treatment for patients with metastatic renal cell carcinoma (mRCC). The dosing schedule of axitinib in this trial begins at 5mg twice daily, with escalation of individual doses to 7mg and 10mg after consecutive 2 week intervals if tolerated. We observed significant drug-related toxicity using this dosing strategy, particularly after dose escalations, while clinical responses were often observed at the starting dose. We therefore switched to a pragmatic strategy where dose escalations were made only after disease progression or where a rapid response was deemed clinically pertinent. Methods: We performed a retrospective review of electronic health records and radiology of all patients with mRCC treated with axitinib for greater than 2 weeks at Addenbrooke’s Hospital, Cambridge, UK (a tertiary referral center), over a 40 month period to determine the clinical and radiological effects of dose escalations made according to the above strategy. Results: 42 patients fitting these criteria were identified; of these, 29 had at least one dose escalation event (DEE). A total of 58 DEEs were identified, with a median of 2 per patient, and the objective radiological consequences of 50 of these could be determined. The disease control rate (partial response or stable disease) after the first DEE instituted for disease progression was similar to that after the second DEE (68.8% versus 70%). 56% of all DEEs, and 62.5% of DEEs made as a result of disease progression, resulted in disease control. The median overall survival from the commencement of axitinib for all dose-escalated patients was 19.9 months, and 6.7 months for non-dose-escalated patients. The median survival for dose-escalated patients with a higher than median time on a prior tyrosine kinase inhibitor has not been reached at the time of data cut-off. The mean dose (for all patients) at 90 days after starting axitinib was 5.92 mg. Conclusions: These data suggest that dose escalation of axitinib after disease progression may be an effective dosing strategy for patients with mRCC, and may reduce toxicity through lower drug exposure. Our survival data compares favourably to the AXIS trial in a real practice population.
An exploratory study of radium-223 and vascular endothelial growth factor targeted therapy (VEGF TT) in patients (pts) with metastatic renal cell carcinoma (mRCC) and bone metastases (BM).
Authors: McKay Rana R. , Gray Kathryn P. , Polacek Laura , Pomerantz Mark M , Krajewski Katherine M. , Jacene Heather , Bellmunt Joaquim , Michaelson Dror , Harshman Lauren Christine , Choueiri Toni K. 
Published: March 2017

466 Background: BM frequently occur in pts with mRCC and are associated with worse survival. The primary aim was to investigate the effect of radium-223 with VEGF TT on bone turnover markers (BTMs) in mRCC pts with BM. Methods: Pts were stratified into cohort 1 (C1) if treatment (tx) naive (n=15) to receive pazopanib 800 mg daily or cohort 2 (C2) if previously treated (n=15) to receive sorafenib (SOR) 400 mg twice BID and could escalate to 600 mg BID at progression. All pts received radium-223 55 kBq/kg every 4 weeks x 6. A safety run-in was performed after 6 pts per cohort completed 2 cycles with criteria to halt enrollment if grade ≥3 tx-related adverse events (TRAEs) were observed in ≥80% of pts. Herein, we report the results of the safety run-in and early safety, biomarker, and imaging data for C2. Results: In the safety run-in, 5/12 (42%) pts experienced TRAEs including anemia, fatigue, liver test elevation, amylase elevation, rash, hand-foot-syndrome, and hypertension, and therefore enrollment continued. In C2, most pts had clear cell mRCC (n=10, 67%) and 47% (n=7) had liver metastases. 60% (n=9) received ≥3 prior txs. At the time of analysis, 8 (53%) pts discontinued tx with both agents for progression and 1 (7%) for toxicity. 5 pts (33%) received 6 doses of radium-223 and 2 (13%) remain on tx. 4 pts (27%) had SOR reductions and 4 (27%) had escalations. 5 pts (33%) had grade 3 TRAEs. Changes in BTM were assessed (Table). 33% of pts (n=5) had stable disease by RECIST, 27% (n=4) by Positron Emission Tomography Response Criteria in Solid Tumors, and 40% by MD Anderson Bone Response Criteria at first response assessment (FRA). Conclusions: Early data suggests that tx with radium-223 and SOR is safe and feasible. Tx resulted in early declines in BTM. Longer follow-up is needed to characterize the safety and effect on BTM. Clinical trial information: NCT02406521. [Table: see text]