bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pan-HER tyrosine-kinase inhibitors (TKI) dacomitinib and afatinib in penile squamous cell carcinoma (PSCC): Results from an ongoing open-label, single-group, phase 2 trial of dacomitinib in chemonaive patients (pts).
Authors: Raggi Daniele , Necchi Andrea , Giannatempo Patrizia , Nicolai Nicola , Colecchia Maurizio , Calareso Giuseppina , Togliardi Elena , Crippa Flavio , Mariani Luigi , Perrone Federica , Pelosi Giuseppe , Salvioni Roberto , Sonpavde Guru 
Published: February 2017

483 Background: Prognosis of pts with advanced/metastatic PSCC is poor and chemotherapy exerts a low efficacy. Targeting HER pathway is rational and promising in PSCC. Two companion trials are enrolling in the 1st-line/neoadjuvant setting (Dacomitinib, NCT01728233) and salvage setting (Afatinib, NCT02541903). Here we present the ongoing results of the former study. Dacomitinib is a potent, irreversible TKI of human EGFR/HER1, HER2 and HER4. Methods: 37 pts with clinical N2-3 or M1 disease receive oral Dacomitinib 45 mg daily until surgery or disease progression (PD)/unacceptable toxicity. No prior systemic therapy is allowed. Computed tomography and PET scan are repeated q2 months. Simon’s Optimal 2-stage design is applied. The primary endpoint is the objective response-rate (ORR = CR/PR according to RECIST v1.1: H0 ≤ 5%, H1 ≥ 20%, α and β = 10%). Next generation sequencing (NGS) with “Hot-spot cancer panel” (Ion Torrent, Life Technologies) is being performed for all enrolled pts. Results: From 06/13 to 05/15, 14 pts were treated. Median age was 57 yrs (IQR: 54-72). 4 had received inguinal/pelvic lymphadenectomy, 4 had inguinal+pelvic nodes, 10 bilateral disease, and 4 distant mets. Two pts achieved a PR (ORR: 14.3%), 8 a SD, 4 a PD. 8 pts (57.1%) had a metabolic PR. 9 pts underwent post-Dacomitinib lymphadenectomy: > 90% necrosis was seen in one patient. After a median follow-up of 6.97 months, 6 pts (42.8%) were progression-free (median PFS was 4.47 months). Median OS was 11.9 months, 1-year OS was 50% (95%CI: 8.05-82.63). Skin toxicity was observed in 7 pts (6 G1, 1 G3), G2 diarrhea in two, and bleeding of cutaneous mets in one. Tissue from one PR pt harbored missense mutations in FBXW7 (R505S), PTEN (A3T), and TP53 (R273H, loss of function mutation) genes. Conclusions: Dacomitinib is endowed with antitumor activity in PSCC. Results are pending confirmation in the whole sample size. Dacomitinib and Afatinib trials will provide insights into the targeting of HER pathway in PSCC based on prior chemotherapy administration. Preliminary data on molecular alterations linked to clinical benefit are being observed. Clinical trial information: NCT01728233.
Programmed death-ligand 1 (PD-L1) expression in cured and not cured testicular and other germ cell tumors (GCT).
Authors: Bernard Brandon David , Albiges Laurence , Signoretti Sabina , Novak Jesse , Hirsch Michelle S. , Massard Christophe , Loriot Yohann , Fadel Elie , Chartier Suzanne , de Montpreville Vincent , Fizazi Karim , Sweeney Christopher , Adam Julien 
Published: February 2017

485 Background: PD-L1 is involved in immune regulation and is prognostic in many tumor types. The aim of this study was to assess PD-L1 expression in orchiectomy and metastases (mets) from GCT and to assess for an association with outcome. Methods: Immunohistochemistry (IHC) on whole sections from archival formalin-fixed paraffin-embedded tissue from Dana-Farber Cancer Institute (DFCI) and Gustave Roussy (IGR) was performed using anti-PD-L1 antibody E1L3N. Stained slides were scored semi-quantitatively and assessed independently. At DFCI, PD-L1 was scored as percent of positive tumor cells (TC) and extent of positive immune cell (IC) infiltrate; at IGR, a cut-off of 5% defined positive TC and IC. PD-L1 status was assessed by site, histology and chemotherapy (CT) status. PD-L1 status was correlated with clinical outcome. Most samples at DFCI were pre-CT (74.2%) whereas most at IGR were post-CT (85.4%). Results: IHC from 171 patients with GCT (89 DFCI, 82 IGR) from 1987-2014 was reviewed. The DFCI cohort included 69 orchiectomy, 15 mets and 5 unknown origin with 28 total deaths; the IGR cohort included 26 lung mets, 36 mediastinal or retroperitoneal lymph node mets and 20 primary mediastinal tumors. DFCI had 38 seminoma (S), 50 nonseminoma (NS) and 1 unknown; at IGR, 13 S and 69 NS. In both cohorts, PD-L1 staining in IC was higher in S (DFCI 33/38 moderate (mod)-high (86.8%); IGR 12/13 positive (92.3%)) vs. NS (DFCI 26/50 mod-high (52.0%); IGR 35/68 positive (51.5%)) (DFCI p = 0.003; IGR p = 0.006). At DFCI, 5 samples had PD-L1 positive TC (2 mixed GCT, 2 pure choriocarcinomas (CC) and 1 S); at IGR, 14 had positive TC (all NS, including 11 pure CC). More PD-L1 positive TC were CC than other GCT types (DFCI p = 0.003; IGR p < 0.001). In 36 S orchiectomy samples at DFCI, 0/4 that scored none-mild died and 2/31 (6.5%) that scored mod-high died (p = 1.00); in 30 NS orchiectomy samples, 4/9 (44.4%) that scored none-mild died and 2/16 (12.5%) that scored mod-high died (p = 0.14). Conclusions: Higher PD-L1 status in orchiectomy is not associated with GCT survival. PD-L1 positive TC may serve as a histological marker for CC among NS. Higher PD-L1 expression on IC in S and on TC in CC may point to immunotherapy as a therapeutic option in these tumors.
Role of cytoreductive nephrectomy in renal cell cancer (RCC) with venous tumor thrombus.
Authors: Abel Edwin Jason , Zargar Kamran , Margulis Vitaly , Mann Michael , Spiess Philippe E. , Ashouri Kenan , Borregales Leonardo Daniel , Haddad Ahmed , Rew Charles , Chen Gong , Shi Fangfang , Matin Surena F. , Wood Christopher G. , Karam Jose A. 
Published: February 2017

496 Background: RCC with tumor thrombus may require complex surgery to remove the primary tumor. Some patients with tumor venous thrombus and metastatic RCC are unlikely to benefit from cytoreductive nephrectomy. The purpose of this study was to identify risk factors for poor overall survival in metastatic RCC patients with tumor thrombus. Methods: Patient data was collected from 4 centers for patients with mRCC and venous thrombus at presentation treated surgically from 2000-2014. Kaplan Meier analysis was used to estimate OS using two prognostic classification systems (MSKCC, IMDC) assessed at time of surgery. MDACC criteria (Cancer 2010) were calculated to estimate potential benefit from cytoreductive nephrectomy. Univariate and multivariate Cox proportional hazard models were used to evaluate the association of individual variables with OS. Results: A total of 293 patients were evaluated and median OS (IQR) was 17.2 (6.4-41.0) months for the entire cohort. Venous thrombus level (Neves classification) was 0,1,2,3, and 4 for 77, 38, 104, 45, and 29 patients respectively. Median OS (IQR) was worse (p = 0.03) for patients with IVC thrombus above the diaphragm 6.8 (2.2-19.1) months compared to renal vein only thrombus 18.8(8.1-37.8) months or IVC thrombus below the diaphragm 18.9 (6.7-44.5) months. Using MSKCC criteria, patients were classified as favorable (21), intermediate (213) or poor risk (59). MSKCC risk grouping was not predictive of OS (p = 0.14). Using IMDC criteria, patients were classified as favorable (24), intermediate (176) or poor risk (93). IMDC risk grouping was not predictive of OS (p = 0.99). Using MDACC criteria, patients were divided into favorable (258) and unfavorable (35) groups. Median OS was higher (p = 0.008) in favorable risk patients, 18.8 (7.2-43.7) vs. 8.2 (2.3-28.2) months. Preoperative variables that were independent predictors of OS included: body mass index, IVC thrombus above diaphragm, lactate dehydrogenase > ULN, and retroperitoneal lymphadenopathy. Conclusions: Metastatic RCC patients with IVC thrombus above the diaphragm or patients classified as unfavorable using MDACC criteria have poor OS and may not benefit from cytoreductive nephrectomy in the presence of venous tumor thrombus.
Predicting adherent perinephric fat with preoperative clinical and radiological factors in partial nephrectomy: Development and validation of a risk score.
Authors: Borregales Leonardo Daniel , Adibi Mehrad , Thomas Arun Z. , Reis Rodolfo B. , Chery Lisly J , Devine Catherine E , Wang Xuemei , Potretzke Aaron M. , Potretzke Theodora , Figenshau Robert S. , Bauman Tyler M. , Matin Surena F. , Karam Jose A. , Wood Christopher G. 
Published: February 2017

497 Background: The decision to perform a partial nephrectomy (PN) relies largely upon the complexity of the renal mass and its surrounding anatomy. An often encountered intraoperative challenge in PN is the adherent perinephric fat (APF). The anticipation of this feature may improve preoperative risk assessment and aid in decision-making for the surgical approach. We sought to develop and externally validate a score that predicts for APF based on preoperative clinical and radiological prognostic factors. Methods: We retrospectively analyzed 495 consecutive patients that underwent open or minimally invasive PN. APF was defined as the presence of “dense”, “adherent”, or “sticky” perinephric fat at time of dissection by the surgeon and this did not required subcapsular dissection for tumor isolation. A score model was developed using multivariate logistic regression analysis. This score was further validated using an external data set with 285 patients. Discrimination and calibration were assessed by calculating the area under the receiver operating characteristic curve (AUC) and the Hosmer–Lemeshow statistic, respectively. Results: Among the 495 patients, 95 (19%) patients presented with APF. On multivariate analyses, diabetes mellitus (p = 0.009), perinephric fat thickness (p < 0.001) and perinephric stranding (p < 0.001) were predictors of encountering APF in PN. A risk score ranging from 0 to 4, was developed based on these three variables to predict for APF. Among the 285 patients in the validation cohort, 41(14.3%) presented with APF. The score demonstrated good discrimination of 0.82 and 0.84 for the development and validation cohort, respectively. The model did not show a statistically significant lack of calibration (p-values = 0.98, 0.35). Moreover, predicted probabilities of APF based on a 0.5 threshold yielded a specificity of 92.3 and 92.2 in the development and validation cohorts, respectively. Conclusions: The score can accurately predict the presence of APF in patients with small renal mass planning to undergo PN. This score could aid current algorithms of preoperative risk assessment and impact surgical approach.
Trough blood levels of sunitinib for Asian (Japanese) patients with metastatic renal cell carcinoma and therapeutic drug monitoring.
Authors: Kawasaki Yoshihide , Takasaki Shinnya , Ito Akihiro , Mitsuzuka Koji , Yamashita Shinichi , Kawamorita Naoki , Izumi Hideaki , Adachi Hisanobu , Kaiho Yasuhiro , Tanaka Masaki , Kikuchi Masafumi , Yamaguchi Hiroaki , Mano Nariyasu , Arai Yoichi 
Published: February 2017

508 Background: The optimal blood concentration of total Sunitinib (SU) (SU + its active metabolite) is reportedly 50-100 ng/ml at trough levels according to the product literature. This is, however, based on models optimally calculated for Caucasians; hence, the desirable blood concentration for Asian patients, including Japanese, is unclear. We examined trough SU levels in Japanese patients with metastatic renal cell carcinomas (mRCC), to determine the preferred concentration of total SU and its doses. We also evaluated the efficacy and dependability of therapeutic drug monitoring (TDM) through the duration of therapy. Methods: Patients with mRCC scheduled for targeted therapy were prospectively recruited between November 2011 and August 2015. TDM of trough levels for patients treated with SU was performed on a regular basis. For this, blood samples were obtained immediately before administering SU on day 8 and day 15 after the initial administration day. Pre-therapeutic characteristics and post-therapeutic outcomes were evaluated. Relationships between pre-therapeutic characteristics, the dose of SU administered, adverse events (AEs) and total SU concentration at trough levels were determined. Results: Twenty of a total of 31 eligible patients were analyzed. Median patient age was 64 years (52-82), median BMI was 23.58 kg/m2 (17.7-32.78), and the average duration of SU therapy was 5 months (1-40). Seventeen patients were treated with SU as first-line therapy and 3 patients as second-line therapy after interferons. Patients with trough SU levels of over 80 ng/ml following the first course needed to discontinue SU due to AEs. All of the patients who obtained long-term stable disease (SD) or partial response (PR) without any AE > grade 2 were those with trough SU levels of 40-60 ng/ml. Conclusions: Our study suggests that trough total SU levels of 50-100 ng/ml are too high for Japanese people. And 40-80 ng/ml seems to be the preferable trough blood concentration of total SU after the first course of SU therapy in Japanese patients. TDM appears to be effective for the management of patients, to obtain optimal benefits of SU without AEs during therapy.
Epidemiological trends in metastatic renal cell carcinoma in the era of targeted therapies: An analysis of the SEER registry.
Authors: Rao Arpit , Wiggins Charles , Lauer Richard C. 
Published: February 2017

516 Background: Clear cell RCC (ccRCC) accounts for 70-75% of all kidney and renal pelvis cancers with approximately 16% of patients presenting with distant (metastatic) disease. Five year overall survival (OS) remains dismal at 11.2% for patients with distant disease. Several tyrosine kinase inhibitors (TKI) were approved by US Food and Drug Administration for use in metastatic RCC between 2005 and 2012. While these therapies have been shown to improve outcomes in metastatic ccRCC, the long term impact remains unknown. Methods: The Surveillance, Epidemiology and End-Results (SEER) database was queried for patients aged 18 years and older diagnosed with distant stage (metastatic) ccRCC between 2001 and 2012 in the nine core SEER registries. Analyses were restricted to histologically confirmed cases. Study period was divided into 3-year intervals: 2001-03 (pre-TKI era); 2004-06 (TKI trials era); 2007-09 (early TKI era); and 2010-12 (sequential TKI era). Patients were stratified by age at diagnosis: 18-60 years, 60-69 years, and 70+ years. One, two, and three year, and median cause-specific survival were calculated by Kaplan-Meier method. Differences in cause-specific survival by time period were assessed with the Log-Rank test. Results: A total of 3,747 eligible patients were included in the analysis. For all ages combined, cause-specific survival at three years post-diagnosis was 18.8% for those diagnosed during the period 2001-03 (median 8 months), 22.7% in 2004-06 (median 10 months), 23.2% in 2007-09 (median 9 months), and 28.9% in 2010-12 (median 11.0 months) (p= 0.0004). No statistically significant improvement in survival was observed in patients aged 70 years and above (p= 0.1302). Conclusions: Our analysis quantifies the improvement in survival outcomes in metastatic ccRCC that correlate with TKI use in this setting. While there is evidence that all age groups may have benefitted from these therapies, the impact is least pronounced in patients aged 70 years and above. A SEER-Medicare analysis is planned to evaluate disparities in TKI use in this age group.
Comparing surgical tissue versus biopsy tissue in the development of a clear cell renal cell carcinoma xenograft model.
Authors: Dong Yiyu , Manley Brandon , Hakimi A. Ari , Coleman Jonathan A. , Russo Paul , Hsieh James 
Published: February 2017

519 Background: The use of xenograft tumor models is considered the ideal platform to investigate the effects and toxicities of novel drugs in primary human tumors. The establishment of a personalized xenograft model using preoperative or pretherapy biopsy for patients with metastatic or high risk disease could improve selection of targeted therapy. We report on our xenograft model using various tissue sources including biopsies and correlation with patient’s clinical features. Methods: 56 specimens from primary and metastatic ccRCC from 48 patients were collected. After surgery (n=35) or biopsy (n=21) the specimen was transplanted either subcutaneously or after cell culture to immunodeficient mice. Tumor engraftment was followed for up to 4 months. Successfully engrafted patient-derived tumors were passaged to further mice. Conformation of xenograft tumors with formalin-fixed, paraffin-embedded and Hematoxylin and eosin stained tumor sections was done to assure morphological concordance with the patients tumor. We used a two-tailed two proportion z-test to compare the number of successful xenografts harvested from surgical tissue or biopsy tissue. Results: Overall 25 of the 56 specimens were successful in growing tumor in our immunodeficient mice. The frequency of success based on the type and site of tissue harvest may be seen in Table 1. We found biopsy tissue to be significantly more successful compared to surgical tissue, 61.9% compared to 34.2% (p-value=0.044). Conclusions: We believe our xenograft model, using biopsy tissue, demonstrates the feasibility of a real time personalized in vivo model to aid in the selection of targeted treatments for systemic therapy in ccRCC patients. [Table: see text]
Brachytherapy boost and cancer-specific mortality in favorable high-risk and other high-risk prostate cancer.
Authors: Muralidhar Vinayak , Xiang MIchael H. , Orio Peter F. , Martin Neil E. , Beard Clair , Feng Felix Yi-Chung , Hoffman Karen E. , Nguyen Paul L. 
Published: February 2017

52 Background: A randomized trial has recently reported improved 5-year biochemical recurrence-free survival with brachytherapy (BT) boost compared with external beam radiation therapy (EBRT) boost in intermediate- to high-risk prostate cancer. Recent retrospective data suggest that BT boost may also confer a cancer-specific survival benefit in the high-risk subgroup. We sought to determine whether this survival benefit would extend to the recently defined favorable high-risk subgroup of prostate cancer patients (T1c, Gleason 4+4 = 8, PSA < 10 ng/mL or T1c, Gleason 6, PSA > 20 ng/mL). Methods: We identified 45,078 patients in the Surveillance, Epidemiology, and End Results database with cT1c-T3aN0M0 intermediate- to high-risk prostate cancer diagnosed 2004-2011 treated with EBRT or EBRT plus BT. We used multivariable competing risks regression to determine differences in the rate of prostate cancer-specific mortality (PCSM) after EBRT+BT or EBRT alone in patients with intermediate-risk, favorable high-risk, or other high-risk disease after adjusting for demographic and clinical factors. Results: BT boost was not associated with an improvement in 5-year PCSM compared with EBRT alone among patients with favorable high-risk disease (1.6% vs 1.9%; adjusted hazard ratio [AHR] 0.56; 95% confidence interval [CI], 0.21 to 1.52, P = 0.258) and intermediate-risk disease (0.7% vs 0.9%; AHR 0.83; 95% CI, 0.59 to 1.16; P = 0.270). Others with high-risk disease had significantly lower 5-year PCSM when treated with BT boost compared with EBRT alone (3.9% vs 5.0%; AHR 0.73; 95% CI, 0.55 to 0.95; P = 0.022). Conclusions: Brachytherapy boost is associated with a decreased rate of PCSM in men with high-risk prostate cancer, but this benefit was not seen among patients with favorable high-risk disease. This suggests that the recently-defined “favorable high-risk” category may be used to personalize therapy for men with high risk disease.
Gonadal function in male patients with metastatic renal cell cancer treated with sunitinib: Effects of testosterone replacement on quality of life.
Authors: Dalla Volta Alberto , Valcamonico Francesca , Cappelli Carlo , Delbarba Andrea , Ferrari Vittorio D. , Arcangeli Giuseppina , Rangoni Giovanni , Castellano Maurizio , Berruti Alfredo 
Published: February 2017

525 Background: Sunitinib (S) is a standard first line treatment of metastatic renal cell carcinoma (mRCC). Asthenia and fatigue are the most prevalent toxicities but the relevant causes are not fully elucidated. Since endocrine glands are highly vascularized, the potent antiangiogenic effect of S can potentially impair their function. With the exception of hypothyroidism, the endocrine-related side-effects of S have not been extensively explored. Methods: We performed a cross-sectional study in which pituitary, thyroid, parathyroid, adrenal and gonadal functions were assessed in 25 mRCC patients who received 9 months of S therapy. Since a high prevalence of hypogonadism was observed, we subsequently enrolled 16 mRCC male patients in a prospective cohort study in which serum testosterone (T) serum free T, serum FSH and LH were evaluated at baseline and after 6 weeks (1 cycle) of S therapy. In patients eligible for testosterone replacement after andrologic evaluation, a FACT-G questionnaire for quality of life (QoL) assessment was prospectively administered at baseline and after 3 months. Results: In the cross sectional study 15/22 S treated male patients (68%) had serum T below the normal range and 13 of them (87%) presented with low/normal levels of LH. In the prospective study mean T levels (95% CI) were 5.04 ng/ml (3.4 - 6.7) at baseline and 4.1 ng/ml (3 - 5.3) after 6 weeks (p 0.05). The corresponding free T were 91.4 pg/ml (66 – 116.8) and 80.2 pg/ml (65 – 95.3) (p 0.24), respectively. Hypogonadism was observed in 5 (31%) patients at baseline and 10 (63%) patients after 6 weeks of S therapy. In the 5 patients becoming hypogonadic after S therapy, LH was 11.4 mU/ml (3.2 - 19.5) at baseline and 11.5 mUI/ml (0 – 23.5) after 6 weeks. Four patients were addressed to testosterone replacement. QoL significantly improved in 3 of them, with the strongest advantage in the physical comfort area. Conclusions: S therapy induces hypogonadism in a high proportion of male patients with mRCC. Low or inappropriately normal LH levels are consistent with a pituitary origin of the endocrine disorder. Testosterone replacement may improve the QoL and treatment tolerance.