bluuebunny/crossref_metadata_2025 huggingface dataset:
Patients perspectives on adjuvant therapy in renal cell carcinoma.
Authors: Battle Dena , Jonasch Eric , Hammers Hans J. , Derweesh Ithaar , George Daniel J. , Bex Axel , Ljungberg Borje , Staehler Michael D.
Published: February 2018

644

Background: At this point in time, there is no approved adjuvant therapy (AT) for renal cell carcinoma (RCC) . The discussion on AT is driven by the pending maturation of overall survival (OS) data for sunitinib in patients at high risk for recurrence. Data on patient´s perception of AT are missing. The purpose of this study was to assess the value of specific adjuvant outcome measures to patients with RCC. Methods: We conducted a survey-monkey survey in n=450 patients with RCC on the perspective on AT. The survey was promoted via kccure.org, facebook and smartpatients.com. Question were not related to specific results of adjuvant trials but asking only about the attitude towards AT as an intervention. Results: Median age was 55.6 years (17-82 years) and 56.4% of the patients were female. 73.6% of the patients underwent nephrectomy as primary therapy, while 22.0% had a partial nephrectomy. 76.4% of the patients had clear cell RCC. 39.1% had recurrence of RCC and 35.3% were receiving systemic therapy for metastatic RCC. 63.1% of patients would use AT if it prolonged OS, followed by 60.1% if AT prolonged disease free survival (DFS), 42.7% if AT demonstrated acceptable toxicity, and 36.7% if guaranteed insurance coverage and efficacy. Experience with systemic therapy was correlated with a wish for a prolonged OS (p<0.0001). Patients with a history of systemic therapy rely on the physician’s recommendation in contrast to patients without a history of systemic therapy (p<0.0001). The recurrence status, age, initial stage and type of surgery had no influence on the patients´ decisions. 28.0% of the patients would need more information prior to their decision, 24.2% would only take AT with a proven OS benefit, 16.9% would use AT if there was moderate toxicity, 13.6% would use AT independent of the associated toxicity level, 8.2% would only use AT without any toxicity. 3.8% of the patients would not use AT. Patients on systemic therapy had a significant higher acceptance of toxicity (p<0.0001). Conclusions: Patients are willing to use AT to achieve OS and DFS benefits, and place lower emphasis on toxicity. These data provide an important perspective on patient perceptions of AT, and emphasize the need for patient education on harms and benefits of AT.
Evaluating neutrophil/lymphocyte ratio as a predictor of 30-day high-grade complications following renal surgery.
Authors: Nasseri Ryan , Bindayi Ahmet , Yim Kendrick , Ryan Stephen , Reddy Madhumitha , Ballon-Landa Eric , Yee Addison , Wan Fang , Proudfoot James , Derweesh Ithaar
Published: February 2018

659

Background: Radical nephrectomy (RN) and partial nephrectomy (PN) for patients with renal cortical masses may carry significant risk for postoperative complications. We analyzed patient demographics and serum laboratories and morphometric measures to determine predictors of 30-day complications following RN and PN. Methods: Single institution retrospective analysis of RNs and PNs between 7/2008-4/2017. Demographic and clinical characteristics, serum laboratories, and RENAL nephrometry score were recorded. 30-day complications were graded according to the modified Clavien classification system. Primary purpose was to identify predictive factors associated with 30-day complications overall. Secondary purposes included identification of predictive factors high-grade complications (HGC; Clavien ≥3) overall and in the PN group. Factors were screened with logistic regression analysis. Results: 814 patients were analyzed (460 PN, 354 RN). 190 (23%) patients experienced 30-day complications, 107/460 (23%) PN and 83/354 (24%) RN (p = 0.951). Albumin level ≤3.5 mg/dL was predictive of overall complications (OR = 4.803, p = .008), while minimally invasive surgery (MIS) was negatively associated (OR 0.444, p < .001). Overall, 76 (9.3%) HGCs occurred, 52/460 (11%) in PN and 24/354 (6.8%) in RN (p = .028). Preoperative Neutrophil-Lymphocyte Ratio (NLR) of ≥2.78 (OR 3.216, p = .016) was a predictor of HGCs overall. MIS was negatively associated with HGCs (OR 0.444, p > .001). In the PN group only MIS was negatively associated with overall complications (OR 0.323, p < .001) and HGCs (OR 0.259, p < .001). Conclusions: While decreased serum albumin was predictive of overall complications in patients undergoing PN and RN, elevated preoperative NLR is a novel predictor for HGC. Use of serum markers may be incorporated in preoperative risk stratification counseling and nomograms.
A FavorAx study of axitinib in favorable risk patients with metastatic renal cell carcinoma.
Authors: Tsimafeyeu Ilya , Borisov Pavel , Abdelgafur Ahmed , Leonenkov Roman , Novikova Olga , Guseva Irina , Demchenkova Marina , Mikhailova Nadezhda , Semenov Andrey , Yurmazov Zakhar , Sivunova Irina , Ramazanova Madina , Gamayunov Sergey , Kosov Dmitry
Published: February 2018

666

Background: Targeted therapy with axitinib resulted in a greater objective response rate and prolonged progression-free survival (PFS) compared to sorafenib in patients with previously treated metastatic renal cell carcinoma (mRCC) in AXIS study. 75% of patients had intermediate and poor IMDC prognosis. In this phase 2 study, we assessed the activity of axitinib in mRCC patients with favourable risk and a history of prior VEGFR-directed therapy. Methods: Patients were required to have clear cell mRCC, favourable risk according to IMDC criteria, and to have received first-line treatment with sunitinib or pazopanib. Prior treatment with other agents was not permitted. The primary endpoint of the study was PFS. Additional endpoints included response rate, safety, and overall survival (OS). Results: A total of 21 patients were enrolled, 62% of whom were male. Median age was 59 years. 11 (52%) patients had 2 and more metastatic sites. 67% and 33% of patients received first-line sunitinib or pazopanib with a median PFS of 17 months (95% CI 14-20). After a median follow-up of 16 months, the median PFS and OS was not yet reached. The current study did achieve its primary endpoint based on the 10-month PFS of 71.4%. 3 (14.3%) patients had confirmed partial responses and 14 (66.7%) had stable disease. No grade 3/4 treatment-related adverse events were observed; the most frequent grade 1/2 treatment-related adverse events were hypertension (57.1%), fatigue (57.1%), GI (33%) and skin (19%) toxicity. 7 patients had dose-escalation of axitinib and 1 patient had dose reduction. Conclusions: The encouraging PFS and favorable safety profile observed in FavorAx study support the administration of axitinib in mRCC patients with favourable IMDC risk and a history of prior sunitinib or pazopanib. Clinical trial information: NCT02700568.
Assessing the quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) in immuno-oncology (I/O): An application to nivolumab vs. everolimus in previously treated advanced renal cell carcinoma (aRCC).
Authors: Shah Ruchit , Botteman Marc , Solem Caitlyn , Luo Linlin , Doan Justin , Cella David , Motzer Robert J.
Published: February 2018

669

Background: Traditional progression definitions based on the RECIST 1.1 criteria may lead to a premature declaration of progression due to tumor flare or pseudo-progression effects associated with I/O drugs, especially among patients with solid tumors (such as RCC). This analysis compared the Q-TWiST between nivolumab and everolimus, using both traditional and novel I/O-relevant definitions of progression. Methods: Using Checkmate 025 data at ≤45 months (m) of follow up, overall survival (OS) was partitioned into 3 health states: TWiST (time without symptoms of disease progression or toxicity), TOX (time with grade ≥3 toxicity after randomization but before progression), and REL (time after progression). The following REL definitions were considered to declare progression: 1) RECIST 1.1 criteria (i.e., traditional Q-TWiST); 2) increase in tumor burden of ≥25% from nadir; 3) treatment discontinuation; 4) ≥2-point reduction from baseline in Functional Assessment of Cancer Therapy-Kidney Cancer Index-Diseases related Symptoms (FKSI-DRS) score; and 5) any combination of ≥2 out of 3 criteria (traditional progression, treatment discontinuation, FKSI-DRS reduction of ≥2-points from baseline). Mean Q-TWiST was calculated by weighting the restricted mean time spent in each health state by a utility of 1.0 for TWiST and 0.5 for TOX and REL. Relative Q-TWiST gain (Q-TWIST difference divided by mean everolimus OS) was calculated. Results: Compared to everolimus, nivolumab patients had statistically significant improvements in Q-TWiST based on all definitions: 1) traditional Q-TWiST: 3.3 m (relative gain:14.4%); 2) 3.5 m (relative gain: 15.3%); 3) 4.3 m (relative gain: 18.7%), 4) 4.8 m (relative gain: 20.9%); and 5) 4.8 m (relative gain: 20.9%). Conclusions: Regardless of progression definition, nivolumab resulted in a statistically significant and clinically important gain in quality adjusted OS vs. everolimus. These gains were greater when using progression definitions that incorporate more I/O-relevant response definitions and/or treatment discontinuation information. Clinical trial information: NCT01668784.
The impact of prostate cancer diagnosis on the quality of life at 3 years: A case control study.
Authors: Menegaux Florence , Rebillard Xavier , Bouvet Sophie , Castelli Christel , Houede Nadine
Published: February 2018

67

Background: Prostate cancer (PCa) is the most common cancer in men. Former studies showed a time-dependent worsening of sexual or urinary long term side effects following surgery or radiotherapy that affected patients’ quality of life (QoL). These studies could not discriminate between age-related and treatment-related symptoms, as patients were their own controls. We conducted a case-control study evaluating at 3 years QoL and physical/psychological dysfunctions, whereas patients were on watchful waiting or received a treatment. Methods: We used data from the EPICAP population-based case-control carried out by INSERM and including 1700 participants. Eligible cases were men < 75 years old newly diagnosed with PCa in 2012-2014 living in the Hérault geographic area. Controls were men of the same age recruited in the general population of the same area. Participants answered a QoL questionnaire 3 years after intervention. Primary objective was to compare the impact of diagnosis or/and treatments on QoL as measured by the EORTC QLQ-C30 score. Secondary objective was to compare the impact of diagnosis or/and treatments on urinary dysfunctions (IPSS, ICS), sexual dysfunctions (IEEF-5), anxiety (HADS), and occupational integration. We also assessed these QoL parameters depending on the treatment that was received. Results: Median age was 67.9 years old in the cases and 68.4 years old in the control. At 3 years, 376 cases and 352 controls had sent back their questionnaires. Treatments were: RP (258), RT (90), focal therapy (52), hormone therapy (26) and watchful waiting (61) at the time of the study. The results show no difference between cases and controls for the global QoL score. Other parameters are being assessed and will be presented at the meeting. Conclusions: Though prostate cancer cases and population-based controls showed similar global QoL at 3 years after diagnosis, the large EPICAP study will provide a comprehensive framework to go further in the understanding of PCa sequelae and give some hints on the balance between benefit and risk of PSA testing. This study will be the first to evaluate the different types of sequelae as a function of treatments and the occupational integration for patients < 65 years old.
The role of the blood platelet-lymphocyte ratio, neutrophil–lymphocyte ratio and platelets in prognosis of metastatic renal cell carcinoma (mRCC).
Authors: Huszno Joanna , Kolosza Zofia
Published: February 2018

670

Background: Renal cell carcinoma (RCC) accounts for 2–3% of all malignant diseases in adults. In some studies, neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR) and PLT have been demonstrated to be closely related to poor prognosis of patients with RCC. The objective of this study was to evaluate the blood platelet-lymphocyte ratio (PLR), neutrophil–lymphocyte ratio (NLR) and platelets (PLT) for its prognostic value in patients with metastatic renal cell cancer (mRCC). Methods: We retrospectively reviewed 141 (49 women and 92 men) patients diagnosed with mRCC previously treated with tyrosine kinase inhibitors from MSC Memorial Cancer and Institute of Oncology, Gliwice Branch in years 2006 - 2016. We assessed the prognostic value (overall survival and progression free survival) of pretreatment PLR, NLR and PLT based on univariate analysis. The cut-off value of NLR was ‘elevated’ as > 3.68 and PLR cut-off value was ‘elevated’ as > 144.4. Results: Median time of overall survival (OS) and progression free survival (PFS) were 34.1 months (from 1 to 109 months) and 8.3 months (from 0.4 to 109 months), respectively. The median PFS was shorter in NLR > 3.68 in comparison to NLR < = 3.68 (11.5 vs. 3.6 months, HR = 2.69; 95%CI, 1.76 to 4.12). Similarly, the median OS was lower in NLR > 3.68 (7.8 vs. 36.1 months, p = 0.00003; HR = 3.39; 95%CI, 2.09 to 5.50). The median PFS was shorter in PLR > 144.4 in comparison to PLR < = 144.4 (5.7 vs. 17.6 months; p = 0.00001; HR = 2.62; 95%CI, 1.76 to 3.90). Similarly, OS was worse for PLR > 144.4 (16.6 vs. 71.2 months; p = 0.00001; HR = 3.31; 95%CI, 1.98 to 5.52). Higher value of PLT ( > 400 G/l) was associated with shorter OS median (7.2 vs. 35.3 months; p = 0.001) than standard level of PLT (150-400G/l). Similarly, patients with higher neutrophil level had shorter OS (8.0 vs. 36.1 months, p = 0.0001) and PFS (3.6 vs. 11.5 months, p = 0.0001). Conclusions: Elevated pre-treatment NLR ( > 3.68) and PLR ( > 144.4) are associated with shorter OS and PFS in patients with mRCC treated with kinase inhibitors independently of other prognostic factors. Higher level of PLT ( > 400 G/l) and higher level of neutrophil ( > 6.0 x 103/ul) were also negative prognostic factors.
Survival following upfront cytoreductive nephrectomy versus targeted therapy for metastatic renal cell carcinoma.
Authors: Bhindi Bimal , Habermann Elizabeth Butzer , Mason Ross , Costello Brian Addis , Pagliaro Lance C. , Thompson Robert Houston , Leibovich Bradley C. , Boorjian Stephen A.
Published: February 2018

672

Background: The optimal sequence of cytoreductive nephrectomy (CN) and targeted therapy (TT) for patients with metastatic renal cell carcinoma (mRCC) remains to be established. Herein, we compared overall survival (OS) between patients with mRCC receiving initial CN with or without subsequent TT versus initial TT with or without subsequent CN. Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed between 2006-2013 with RCC that was metastatic at diagnosis who received CN, TT, or both. Those with other prior cancer history were excluded. The cumulative incidence of receiving TT after CN and CN after TT were evaluated, with death prior to second treatment as a competing risk. To account for treatment selection bias, inverse probability of treatment weighting (IPTW) was performed based on the propensity to receive initial CN or TT. OS from diagnosis was compared using Cox regression. Sensitivity analyses were performed. Results: The cohort included 15,068 patients, of whom 6,731 underwent initial CN and 8,337 underwent initial TT. At 6 months from diagnosis, the probability of receiving TT after CN was 46.2%, with 13.6% of patients having died after initial CN prior to receiving TT. Meanwhile, the probability at 6 months of undergoing CN after initial TT was 4.4%, with 38.3% of this group having died prior to undergoing CN. In the IPTW analysis, baseline characteristics were balanced (standardized difference < 0.1). Initial CN was associated with improved OS compared to initial TT (median 16.5 vs 9.2 months; HR 0.62; 95%CI 0.61-0.64; p < 0.001). Findings were similar in all sensitivity analyses (propensity score matching and adjustment; regression adjustment; 6-month landmark analysis; clear cell mRCC subset; exclusion of patients who had metastasectomy). Conclusions: Although initial CN was associated improved OS versus initial TT in this national dataset, initial CN was associated with delays in, and even death prior to, receipt of TT. As such, while the survival data here support initial CN in appropriate surgical candidates, continued efforts to develop the optimal multimodal approach to these patients are warranted.
Dietary acrylamide intake and risk of renal cell carcinoma in two large prospective cohorts.
Authors: Graff Rebecca E. , Cho Eunyoung , Preston Mark A , Sanchez Alejandro , Mucci Lorelei A. , Wilson Kathryn M.
Published: February 2018

677

Background: Acrylamide, which has been classified as a probable human carcinogen, is formed during the processing and cooking of many commonly consumed, carbohydrate-rich foods. Accumulating evidence suggests that dietary intake of acrylamide intake is not associated with the risk of most cancers in humans. A meta-analysis of five epidemiological studies, however, found a suggestion of an increased risk of kidney cancer with higher acrylamide intakes. We investigated this association in two large, prospective cohorts. Methods: Acrylamide intake was calculated from food frequency questionnaires completed every four years in the Nurses’ Health Study (NHS; 1980-2014; n = 88,770) and the Health Professionals Follow-up Study (HPFS; 1986-2014; n = 47,802). Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association with renal cell carcinoma (RCC), adjusting for known and suspected risk factors. Results: We documented 569 incident cases of RCC during follow-up, 337 in women and 232 in men. There was no association between cumulative average acrylamide intake and risk of RCC risk in women (HR for top versus bottom quartile of intake: 0.85; 95% CI: 0.62-1.18; p-value for linear trend across quartiles: 0.42) or men (HR: 1.09; 95% CI: 0.77-1.55; p-trend: 0.96). Baseline acrylamide intake was also unassociated with RCC risk. Acrylamide intake was not associated with risk of fatal RCC, risk among never-smokers, or risk of clear cell RCC. Intake of foods and food groups that are the major contributors to acrylamide intake – breads, baked goods, breakfast cereal, potatoes, and coffee – were likewise not associated with risk of total or fatal RCC in women or in men. Conclusions: Dietary acrylamide was not associated with the risk of RCC in two long-term, prospective cohorts of women and men with updated measures of dietary intakes. This analysis of renal cell carcinoma adds to the body of evidence that dietary acrylamide is not an important risk factor for cancer in humans.
Sarcomatoid renal cell carcinoma: Does stage impact survival?
Authors: Blum Kyle A , DiNatale Renzo , Sanchez Alejandro , John Nirmal T , Axler Eden , Ghanaat Mazyar , Kashan Mahyar , Becerra Maria , Russo Paul , Coleman Jonathan , Tickoo Satish , Hakimi A. Ari
Published: February 2018

693

Background: Sarcomatoid differentiation is associated with poor clinical outcomes and is present in approximately 4% of patients with renal cell carcinoma (sRCC). However, limited studies have evaluated the impact of sarcomatoid differentiation among patients, especially with lower stage pT1−2 disease. Methods: This study evaluated 3,850 patients with RCC who underwent partial or radical nephrectomy between 2000−2017. Patients were divided into four groups for analysis: pT1−2NxMx RCC without sarcomatoid features, pT1−2NxMx sRCC, pT3−4 RCC without sarcomatoid features and pT3−4 sRCC. Clinicopathological outcomes including sex, race, age, primary histology, lymph node involvement and margin status were compared between groups using Chi−squared and T-tests. Overall survival rates were analyzed by constructing Kaplan−Meier curves, p−values were calculated using log−rank tests and fitting Cox proportional hazards models for adjusted analyses. Results: Among 3,850 cases, 168 (4.4%) sRCC patients were identified. Of these, 33 (19.6%) were pT1−2. The mean overall follow up time was 59.9 months. When comparing CSS between groups, survival was poorer in patients with sarcomatoid features regardless of pT stage (p < 0.0001). Of note, CSS was worse in sRCC pT1−2 patients compared to non−sarcomatoid pT3−4 patients. Overall survival (OS) results were similar, with sarcomatoid tumors having worse estimates on survival analysis (p < 0.0001). Conclusions: Patients with pT1−2 sRCC demonstrated worse CSS when compared to pT1-2 and pT3−T4 RCC without sarcomatoid features, regardless of primary histology. Sarcomatoid differentiation in low−stage disease may be a marker of poor oncologic outcomes requiring more vigilant surveillance and possible inclusion in adjuvant therapy trials. Our next step, which is currently ongoing, is to pursue a multi−institutional collaborative effort and establish a larger cohort of sRCC for analysis.
The prognostic impact of a negative confirmatory biopsy in men on active surveillance for prostate cancer.
Authors: Salari Keyan , Zlatev Dimitar V. , Kuppermann David , Preston Mark A. , Dahl Douglas M. , Efstathiou Jason A. , Blute Michael L. , Zietman Anthony L. , Feldman Adam S.
Published: February 2018

76

Background: Active surveillance (AS) is increasingly used in managing low-risk and favorable intermediate-risk prostate cancer. To mitigate the risk of unsampled higher risk disease, most institutional AS protocols call for a confirmatory prostate biopsy within 12-18 months following initial diagnostic biopsy. Here, we investigate whether the results of confirmatory biopsy impact the outcomes of men on AS. Methods: We retrospectively reviewed our institutional database of men enrolled in AS between 1997-2014 with a minimum follow-up of 6 months (n = 974). Biopsies with any prostate cancer were considered positive. Biopsies containing only benign prostatic tissue, prostatic intraepithelial neoplasia (PIN), or atypical small acinar proliferation (ASAP) were considered negative. Statistical analysis was conducted using the Kaplan-Meier method and Cox proportional hazards regression. Results: At diagnosis, median age was 67 years (IQR 62-72) and median PSA was 5.1 ng/mL (IQR 3.9-6.8). The vast majority of patients had Gleason ≤6 (97%) and clinical stage T1 (92%) disease. With a median follow-up of 4.8 years, 702 (72%) patients underwent a confirmatory biopsy. 67% of confirmatory biopsies were positive for prostate cancer; 33% were negative (167 benign, 40 PIN, and 22 ASAP). Of the 702 patients, 33% progressed to treatment, with pathologic progression the most common reason (77%). Univariate predictors of progression to treatment included initial clinical stage ( P= 0.04), involvement of > 20% of any core on diagnostic biopsy ( P < 0.01), PSA density ≥0.15 ( P < 0.001), and confirmatory biopsy status ( P < 10-14). In multivariate analysis, a negative confirmatory biopsy remained the strongest predictor of progression to treatment (HR 0.12 [95%CI 0.06-0.24], P < 10-8). Confirmatory biopsy status was not associated with risk of adverse pathology on RP, metastasis-free survival, disease-specific survival, or overall survival. Conclusions: A negative confirmatory biopsy is associated with a significantly lower rate of progression to treatment among men on AS. This may serve as a useful tool for prognostication and help determine the need for further repeat biopsies for men on AS.
Perspectives of prostate cancer patients about active surveillance.
Authors: Saad Fred , Fitch Margaret , Pang Kittie , Ouellet Veronique , Loiselle Carmen , Chevalier Simone , Drachenberg Darrel , Finelli Antonio , Sutcliffe Simon , So Alan I. , Tanguay Simon , Mes-Masson Anne-Marie
Published: February 2018

82

Background: In prostate cancer (PC), men diagnosed with low risk disease may be monitored through an active surveillance (AS) approach that runs counter to the traditional message of undergoing treatment as soon as possible following a cancer diagnosis. This research explored the perspectives of men with PC regarding their decision-making process for AS to identify the factors that influenced their decision and assisted health care professionals in discussing AS as an option. Methods: Focus group interviews (n = 7) were held in several Canadian cities with men (n = 52) diagnosed with PC and eligible for AS. The men’s viewpoints were captured regarding their understanding of AS, the factors that influenced their decision to engage in AS, and their experience with the approach. A content and theme analysis was performed on the verbatim transcripts from the interviews. Results: All patients described the perception that their disease was not “large enough” to require treatment. They understood that the waiting process avoided the side effects associated with treatments, and they were comfortable about postponing treatment while undergoing close monitoring. Conversations with their doctor and how AS was described were cited as key influences in their decision. Other influences included availability of information on treatment options, distrust in the health system, personality, experiences and opinions of others, and personal perspectives on quality of life. Conclusions: AS is a relatively new approach for the care of men with low risk PC. Men require a thorough explanation on AS as a safe and valid option, as well as guidance towards supportive resources in their decision-making.
Active surveillance in prostate cancer patients: Modeling upgrading and upsizing at 1 year rebiopsy.
Authors: Nicolai Nicola , Alvisi MariaFrancesca , Rancati Tiziana , Avuzzi Barbara , Badenchini Fabio , Catanzaro Mario , Colecchia Maurizio , Di Florio Teresa , Magnani Tiziana , Marenghi Cristina , Morlino Sara , Noris Chiorda Barbara , Paolini Biagio , Stagni Silvia , Tesone Antonio , Torelli Tullio , Villa Sergio , Zaffaroni Nadia , Salvioni Roberto , Valdagni Riccardo
Published: February 2018

90

Background: Prostate biopsy findings at diagnosis and follow-up are essential criteria in Active Surveillance (AS). In a previous work (Nicolai Eur Urol Suppl 2013) upgrading (UPG) and upsizing (UPS) at 1-yr rebiopsy resulted to be independent outcomes with different predictors. Aim of the present work is to validate these models on an independent population and to evaluate the probability of not-developing UPG, thus the chance of continuing AS Methods: Pts enrolled in 2011-2017 were considered for validation, while 318 AS pts enrolled in 2005-2011 were considered for model development. UPG model included: age (risk), PSA density (risk), prostate volume (>60 cc, protective); UPS model: age (protective), % core length containing cancer (>5%, risk), number of positive cores (>1, risk) Performance on the independent population was evaluated through AUC and calibration. Logistic model for not-developing UPG at 1 yr was fitted using all available AS pts Results: 433 pts were included in the validation set. UPG and UPS were registered in 43 and 29 pts, respectively; 38 pts had UPG+UPS. Predictors for UPG and UPS were mainly confirmed in the validation cohort (Table), with Odds Ratios (OR) very similar to the development model. Discrimination was confirmed (AUCs) and calibration was excellent (slope~1, R2>0.90). Probability of not-developing UPG (evaluated on 751 pts) was associated to age, prostate volume and PSA density (Table). Conclusions: UPG and UPS in AS pts should be considered as independent events and their management implying different strategies. Specifically, age, volume and PSA density play a key role in the chance to continue AS, i.e. in not developing UPG. A nomogram estimating the likelihood of continuing AS has been developed and will be presented. [Table: see text]
The validity of repeat prostate biopsy in prior biopsy negative patients: MRI-TRUS fusion guided biopsy.
Authors: Hwang Jinho , Kim Jung Jun , Oh Jong Jin , Jeong Chang Wook , Lee Sangchul , Hong Sung Kyu
Published: February 2018

95

Background: To investigate validity of magnetic resonance imaging (MRI)-transrectal ultrasound fusion target biopsy (Fusion-Bx) compared with transrectal ultrasound-guided biopsy (TRUS-Bx) by evaluating detection rate of prostate cancer (PCa). Methods: Medical records of 376 patients with prior negative TRUS-Bx who underwent repeat prostate biopsy between Aug. 2015 and Apr. 2017 were retrospectively reviewed. The cohort was stratified into two groups (TRUS-Bx and Fusion-Bx) and clinical and biopsy characteristics patterns were analyzed. Conventional systemic randomized 12-core biopsy was performed in TRUS-Bx group whereas Fusion-Bx group applied additional 2-croes of target biopsy against suspicious lesions in MRI. Results: There were total 195 and 181 patients in TRUS-Bx and Fusion-Bx group, respectively. The overall cancer detection rate was slightly higher in Fusion-Bx group, but no statistical significance was observed (24.6% vs 28.7%, p = 0.367). Fusion-Bx group showed a significantly greater detection rate in target core analysis (5.0% vs 17.7%, p = 0.044). In confirmed positive biopsy patients, Fusion-Bx group had a higher rate of clinically significant prostate cancer (CsPCa) cases, but failed to achieve statistical significance (85.4% vs 92.3%, p = 0.271). When the patients with highly or very highly suspicious MRI (maximum image grade 4-5) findings in Fusion-Bx group was compared to the whole cohort of TRUS-Bx group, Fusion-Bx group was significantly greater in terms of overall detection rate (24.6% vs 38.0%, p = 0.017) and CsPCa detection rate (85.4% vs 97.0%, p = 0.009). Higher the target image grade, greater biopsy yield was achieved. Conclusions: For the patients who underwent repeat biopsy due to prior negative results, fusion-Bx showed better clinical significance including detection rate. A further study with a larger cohort size and prospective design is still needed to confirm the validity of Fusion-Bx.
The role of proton beam therapy for patients with intermediate- and high-risk prostate cancer.
Authors: Arimura Takeshi , Kondo Naoaki , Matsukawa Kyoko , Wada Kiyotaka , Kitano Ikumi , Chuman Ikuko , Nagata Ichiro , Ogino Takashi
Published: February 2018

97

Background: Although there are many patterns of treatment in localized prostate caner, proton beam therapy has no definite role in them. We aimed to assess the outcomes of proton beam therapy (PBT) alone for patients with intermediate- and high-risk prostate cancer, and to clarify the role of PBT in the treatments. Methods: Between Jan. 2011 and Sep. 2014, 204 patients with intermediate- and high-risk prostate cancer who declined to receive hormonal treatments until biochemical or clinical recurrence were enrolled in the study. All patients were irradiated a 70-78 GyE in 28-39 fractions, and pre-treatment risk groups were classified in accordance with the D’Amico criteria. The 5-year (biochemical or clinical) recurrence-free survival (RFS), late gastrointestinal (GI) and genitourinary (GU) toxicity (NCI-CTCAE ver.4.0) were evaluated. We conducted a survey on sexual quality of life (QOL) every six months to evaluate any long-term damage to the sexual function using the Expanded Prostate Cancer Index Composite (EPIC). Results: The mean age and the follow-up period were 66 (range: 39-86) and 52 months (range: 24-76 months), respectively. The 5-year RFS rates in intermediate- (n = 112) and high- (n = 92) risk groups were 96.9% and 83.4%, respectively. There was a significant difference between the two groups (p = 0.002). The incidence of grade 2+ GI and GU toxicity were 4% and 3%, respectively. We found a significant difference in the GI toxicity between the two radiation protocols of 78GyE/39fractions (n = 6, 11%) and 70GyE/28fractions (n = 0, 0%) (p < 0.01). A 5.8% decrease in average after adjusting for aging was found in sexual summary score in six years after treatment, which was equivalent to aging of three years. Conclusions: Proton beam therapy alone demonstrated favorable results in patients with intermediate- and high-risk prostate cancer. Although more patients and longer follow-up are necessary to confirm the outcomes, these results suggested a hypothesis that proton beam therapy might not require androgen deprivation therapy in the treatment of localized prostate cancer, which could lead to a possibility of preserving of sexual function. Clinical trial information: MPTRC-N2 and N3.
The association between HSD3B1 genotype and steroid metabolism in normal and prostate cancer (PCa) tissue.
Authors: Emamekhoo Hamid , Barata Pedro C. , Magi-Galluzzi Cristina , Berk Mike , Taylor Jennifer , Tyler Allison Janine , Rini Brian I. , Grivas Petros , Gilligan Timothy D. , Ornstein Moshe Chaim , Stephenson Andrew J. , Klein Eric A. , Kaouk Jihad , Haber Georges-Pascal , Sharifi Nima , Garcia Jorge A.
Published: February 2018

TPS155

Background: The common germline variant HSD3B1(1245C) encodes for a gain-of-function in 3βHSD1 which is associated with a shorter duration of response to androgen deprivation therapy (ADT) and more rapid disease progression to castration resistant PCa (CRPC) as shown previously in 5 independent cohorts. Therefore, evaluating the effect of such genotype variation on the level of steroid metabolites and the intratumoral dihydrotestosterone (DHT) concentration in benign and tumor tissue of men on ADT is of significant importance. We hypothesize that patients with homozygous HSD3B1 (1245C) genotype (HZ) will have a sustained androgen synthesis from extragonadal precursor steroids and higher concentrations of DHT compared to patients with wild-type HSD3B1 (1245A) (WT) inheritance in the context of testosterone suppression. In addition, it is expected that heterozygous HSD3B1 (1245C) patients (HTZ) will have intermediate levels of DHT. We also hypothesize that treatment with androgen receptor (AR) antagonist (apalutamide) will reverse the effects of elevated DHT on AR signaling in benign and malignant prostate tissue. Methods: In this Phase II trial (NCT02770391), men with newly diagnosed intermediate or high-risk PCa (GS ≥ 4+3, ≥cT2b, or PSA ≥ 10) who are scheduled to undergo radical prostatectomy (RP) will be enrolled into 3 groups based on their HSD3B1 genotype. All pts will receive one dose of 7.5 mg leuprolide injection and apalutamide 240 mg/day orally for 28 ± 3 days prior to RP. DHT and 7 other androgens (including testosterone, Dehydroepiandrosterone, Androstenedione) will be evaluated in the normal and malignant prostate tissue as well as serum samples obtained at the time of RP. AR regulated genes expression (including PSA, FKBP5, TMPRSS2) will be compared across 3 genotypes. A sample size of 57 pts (WT = 30, HTZ = 15, HZ = 12) will allow a statistical power of > 80% (with two-sided α = 0.05) to detect a 4-fold trend in DHT concentrations in the resected prostate tissue (primary endpoint) as well as similar trend in other androgens (secondary endpoint). As of Oct 2017, 16 of planned 57 pts have been enrolled. Clinical trial information: NCT02770391.
ProBio II: An adaptive and randomized multi-arm biomarker driven phase 2 study in men with castrate resistant prostate cancer (CRPC).
Authors: Gronberg Henrik , Eklund Martin , Lindberg Johan , Ullén Anders , Bjartell Anders , Andren Ove , Robinson David , Franck Lissbrant Ingela , Enblad Gunilla , Stahl Olof , Thellenberg Camilla
Published: February 2018

TPS397

Background: Castrate-resistant prostate cancer (CRPC) affects around 3,000 men in Sweden every year. New drugs are available but they have moderate effect, low response rates, are expensive, and lack predictive treatment markers. This will lead to an unsustainable situation for prostate cancer care. Our hypothesis is that treatment decisions based on molecular profiling will significantly increase the response rate at 3 months compared to current clinical care, translating into improved progression free and overall survival. The vast majority of CRPC metastasize to the bone, with low success rate in obtaining sufficient material. Therefore, we will sequence circulating tumor DNA (ctDNA) being present at high levels in plasma. Methods: ProBio-II is an adaptive, multi-arm, open-label, multiple assignment randomized biomarker driven phase 2 trial in men with CRPC . Men (n=750) will be randomized to receive either standard of care (following Swedish national guidelines) or treatment with Enzalutamide, Abiraterone, PARP inhibitors, RA-223, Cabazitaxel, or immune modulators based on molecular subtypes. The molecular subtypes are defined as tumor properties or mutations in certain genes/pathways including: Microsatellite instability; Androgen receptor alterations; DNA-repair deficiency; TP53 inactivation; PTEN inactivation etc. The molecular subtypes will be identified by ctDNA profiling. A specially designed ctDNA profile for CRPC has been developed by our group to detect: mutations, amplifications and genomic rearrangements in the androgen receptor (AR); mutations, genomic rearrangements and amplifications/deletions in 300 key genes involved in prostate cancer; and microsatellite instable and hypermutated cancers. ProBio-II’s design is novel and inspired by successful studies as I-SPY (breast cancer) and the NCI-MATCH trial (metastatic cancer). Novel aspects of the study design includes using prior probability of treatment response; re-randomization of non-responders; and adaptive design. The ProBio II study will start recruiting patients in Sweden in Q1 2018 and recruit patients during a 18 month period. All major oncology departments in Sweden will participate.
Intergroup study EORTC-1532-gucg: A phase 2 randomized open-label study of oral darolutamide (ODM-201) vs. androgen deprivation therapy (ADT) with LHRH agonists or antagonist in men with hormone naive prostate cancer (PCa).
Authors: Tombal Bertrand F. , Gillessen Silke , Loriot Yohann , Marreaud Sandrine , Collette Laurence , Saad Fred
Published: February 2018

TPS406

Background: Androgen deprivation therapy (ADT) by LHRH analogues aims to lower serum testosterone. ADT is associated with several side effects that include hot flushes, depression, loss of libido, metabolic disturbances leading to an increase risk of cardiovascular disease, increased bone resorption leading to increased risk of osteoporosis and skeletal fracture. AR antagonists may circumvent these side effects by suppressing AR transcription by competitive inhibition of AR, without lowering systemic testosterone. In Europe, first generation AR antagonists bicalutamide 150 mg is registered for the treatment of non-metastatic hormone-naïve PCa. is a novel AR antagonist that is structurally distinct with higher AR-binding affinity compared to bicalutamide, enzalutamide, and apalutamide. The aim of this trial is to investigate the activity, safety and tolerability of darolutamide as single agent, as an alternative to LHRH analogues in men requiring ADT. Methods: EORTC-1532-GUCG (NCT02972060) will randomize 250 men with hormone-naïve PCa 1:1 to 600 mg (2× 300-mg tablets) bid of darolutamide1 or LHRH agonist or antagonist, stratified for type of ADT (agonist vs. antagonist), disease extent (measurable, non-measurable, vs. no metastasis) and age (≥70 vs < 70 years). Key inclusion criteria include histologically confirmed asymptomatic PCa (all stages) for whom continuous ADT is indicated for a minimum period of 24 weeks. Patients with up to 4 confirmed not visceral metastases, are allowed. Baseline total testosterone should be ≥ 8 nmol/L or 230 ng/dL. Primary endpoint is PSA response assessed at 24 weeks, defined as a ≥ 80% decline in PSA at week 24 in the darolutamide study arm. The ADT arm is used as an internal non comparative control. Key secondary endpoints include: Change in hormone-treatment related symptoms scale of the EORTC QLQ-PR25 at 24 weeks (comparison between arms); objective response rate at 24 weeks in patients with measurable disease at baseline, safety according to NCI-CTC version 4.0. Clinical trial information: NCT02972060.
EV-201 study: A single-arm, open-label, multicenter study of enfortumab vedotin for treatment of patients with locally advanced or metastatic urothelial cancer who previously received immune checkpoint inhibitor therapy.
Authors: Rosenberg Jonathan E. , Heath Elisabeth I. , O'Donnell Peter H. , Hahn Noah M. , Balar Arjun Vasant , Gartner Elaina M. , Melhem-Bertrandt Amal , Petrylak Daniel Peter
Published: February 2018

TPS542

Background: The majority of patients with locally advanced or metastatic urothelial cancer (la/mUC) will not respond to immune checkpoint inhibitors (CPIs) given in the post-platinum or cisplatin ineligible setting, and there are currently no approved standard therapies after disease progression. Enfortumab vedotin (EV), an antibody-drug conjugate, delivers the microtubule-disrupting agent monomethyl auristatin E to tumors expressing Nectin-4, which is overexpressed in mUC. Preliminary results from an ongoing phase 1 study of EV monotherapy in pts with mUC (Petrylak ASCO 2017) showed that EV was well tolerated in pts with mUC. Nausea (36%), pruritus (31%), and fatigue (30%) were the most commonly reported treatment-related AEs. The most common grade ≥3 AEs (regardless of attribution) were urinary tract infection (11%) and hypophosphatemia (9%). EV showed an objective response rate (ORR) of 41% (29 out of 71 pts) across all dose levels and 53% (16 out of 30 pts) ORR at the recommended phase 2 dose of 1.25 mg/kg. The ORR was not diminished in pts with prior CPI use (44%), prior taxane use (41%) or in pts with liver metastases (47%). These encouraging results along with a favorable safety and tolerability profile warrant further investigation of EV as a monotherapy. Methods: This single-arm, open label, multicenter phase 2 study (NCT03219333) evaluates the antitumor activity and safety of EV monotherapy in ~120 pts with la/mUC. Pts must have previously received a CPI and either have received prior platinum or be ineligible for cisplatin. Pts must have histologically or cytologically documented transitional cell carcinoma of the urothelium that progressed during or following receipt of most recent therapy. The primary objective is to determine antitumor activity of EV as measured by ORR. Secondary objectives include assessment of duration of response, disease control rate, PFS, OS, and safety/tolerability of EV. Pts must have tumor tissue available for exploratory analyses. Response is assessed per RECIST v1.1. Study enrollment began in Sept 2017. Clinical trial information: NCT03219333.
Forced lipophagy reveals that lipid droplets are required for early embryonic development in mouse
Authors: Tatsumi Takayuki , Takayama Kaori , Ishii Shunsuke , Yamamoto Atsushi , Hara Taichi , Minami Naojiro , Miyasaka Naoyuki , Kubota Toshiro , Matsuura Akira , Itakura Eisuke , Tsukamoto Satoshi
Published: February 2018

Although autophagy is classically viewed as a non-selective degradation system, recent studies have revealed that various forms of selective autophagy also play crucial physiological roles. However, the induction of selective autophagy is not well understood. In this study, we established a forced selective autophagy system using a fusion of an autophagy adaptor and a substrate-binding protein. In both mammalian cells and fertilized mouse embryos, efficient forced lipophagy was induced by expression of a fusion of p62 (Sqstm1) and a lipid droplet (LD)-binding domain. In mouse embryos, induction of forced lipophagy caused a reduction in LD size and number, and decreased the triglyceride level throughout embryonic development, resulting in developmental retardation. Furthermore, lipophagy-induced embryos could eliminate excess LDs and were tolerant of lipotoxicity. Thus, by inducing forced lipophagy, expression of the p62 fusion protein generated LD-depleted cells, revealing an unexpected role of LD during preimplantation development.
Case Report: “Incognito” proteus syndrome
Authors: Vestita Michelangelo , Filoni Angela , Arpaia Nicola , Ettorre Grazia , Bonamonte Domenico
Published: February 2018

Proteus syndrome (PS) is a postnatal mosaic overgrowth disorder, progressive and disfiguring. It is clinically diagnosed according to the criteria reported by Biesecker et al.

We describe the case of a 49-year-old woman who presented with a 10-year history of pauci-symptomatic infiltrating plaque lesions on the sole and lateral margin of the left foot, which had been diagnosed as a keloid. The patient had a positive history for advanced melanoma and a series of subtle clinical signs, such as asymmetric face, scoliosis, multiple lipomas on the trunk, linear verrucous epidermal nevi, and hyperpigmented macules with a mosaic distribution. Even if the clinical presentation was elusive, she had enough criteria to be diagnosed with PS.

This case describes the first evidence, to the best of our knowledge, of pauci-symptomatic PS in adulthood, reports its rare association with advanced melanoma, and illustrates the importance of even minor cutaneous clinical signs, especially when atypical, in formulating the diagnosis of a complex cutaneous condition such as this.
Birds of primary and secondary forest and shrub habitats in the peat swamp of Berbak National Park, Sumatra
Authors: Darras Kevin , Rahman Dedi , Sugito Waluyo , Mulyani Yeni , Prawiradilaga Dewi , Rozali Agus , Fitriawan Irfan , Tscharntke Teja
Published: February 2018

Background: Tropical lowland rainforests are threatened by deforestation and degradation worldwide. Relatively little research has investigated the degradation of the forests of South-east Asia and its impact on biodiversity, and even less research has focused on the important peat swamp forests of Indonesia, which experienced major losses through severe fires in 2015.

Methods: We acoustically sampled the avifauna of the Berbak National Park in 2013 in 12 sites split in three habitats: primary swamp forest, secondary swamp forest, and shrub swamp, respectively representing non-degraded, previously selectively logged, and burned habitats. We analysed the species richness, abundance, vocalisation activity, and community composition across acoustic counts, sites, feeding guilds and IUCN Red List categories. We also analysed community-weighted means of body mass, wing length, and distribution area.

Results: The avifauna in the three habitats was remarkably similar in richness, abundance and vocalisation activity, and communities mainly differed due to a lower prevalence of understory insectivores (Old-World Babblers, Timaliidae) in shrub swamp. However primary forest retained twice as many conservation-worthy species as shrub swamp, which harboured heavier, probably more mobile species, with larger distributions than those of forest habitats.

Conclusions: The National Park overall harboured higher bird abundances than nearby lowland rainforests. Protecting the remaining peat swamp forest in this little-known National Park should be a high conservation priority in the light of the current threats coming from wildlife trade, illegal logging, land use conversion, and man-made fires.
Regional Approach in the New Economic History: Contemporary Foreign Researches
Authors: Краюшкина Елена , Krayushkina Elena , Секенова О. , Sekenova O.
Published: February 2018

New economic history is a scientific school that appeared as the alternative for the classical political economy. Nowadays it goes through the serious changes. This paper focuses on the key subjects of new economic history and evaluates the historical potential of this school in regional studies. The paper is based on the analyses of contemporary foreign researches that have united the regional approach and the methodology of new economic history.