bluuebunny/crossref_metadata_2025 huggingface dataset:
Health related quality of life analysis among testicular germ cell tumor survivors treated in a tertiary cancer hospital in India.
Authors: Raj Abhishek , Kumar Lalit , Sharma Atul , Pramanik Raja , Batra Atul , Seth Amlesh , Ray Mukurdipi , Haresh KP , Kaushal Seema , Sahoo Ranjit
Published: May 2019

e16057

Background: Testicular Germ Cell Tumor (TGCT) is a highly curable malignancy treated with surgery, radiotherapy and chemotherapy. The available literature has conflicting results on quality of life (QoL) of survivors determined using various tools. There is no Indian data on QoL among TGCT patients. Methods: The study was a prospective case-control study. EORTC QLQ-C30 questionnaire were administered to survivors (last treatment completed at least 2 years back) and healthy age matched controls attending the uro-malignancy clinic of AIIMS between 1st January 2017 to 31st December 2018. The functional, symptom and global QoL scales were scored as per EORTC manual and were compared with each other using student t-test and Mann-Whitney test. The data was analysed with stata v.13.0. Results: The mean scores of all domains of functional scales and global QoL of 114 TGCT survivors were significantly worse than 100 controls except role functioning and cognitive functioning (Table). The symptom scores of cases were significantly worse for each domain except insomnia and constipation (Table). There was no difference in QoL parameters between Seminoma or Non-Seminoma or different stages of GCT. Conclusions: The QoL among TGCT survivors was significantly inferior indicating the long term physical, emotional, social, sexual and financial effects of disease and its treatment on survivors. More robust tools and studies are needed to better define QoL among survivors. ± SD of Functional, symptom and Global QoL Scales) [Table: see text]
Improved outcomes in testicular germ cell tumor patients treated at the referral center in Slovakia in the last decade.
Authors: Chovanec Michal , Rejlekova Katarina , Sycova-Mila Zuzana , Obertova Jana , Palacka Patrik , Hapakova Nikola , De Angelis Valentina , Kalavska Katarina , Svetlovska Daniela , Pindak Daniel , Mardiak Jozef , Mego Michal
Published: May 2019

e16059

Background: Treatment at expert centers results in superior survival in patients with germ cell tumors (GCTs). This study evaluated outcomes in patients treated at National Cancer Institute in Slovakia before and after the year 2008 after refining the treatment strategies. Methods: Our institutional database was searched for GCT patients treated at National Cancer Institute in Slovakia between 1992 and 2016. A year of 2008 was selected for cutoff to compare changes in outcomes before and after this time-point due to refining treatment strategies such as centralization of post-chemotherapy surgery and incorporation of granulocyte-colony stimulating factor (G-CSF) for routine prophylaxis of febrile neutropenia. Kaplan-Meier product limit and log-rank test were used for statistical analysis. Results: This retrospective study included 485 patients treated for metastatic GCT. Two hundred and sixty-three patients (54%) were treated before 2008 (group 1) and 222 patients (46%) were treated after 2008, including (group 2). Progression-free survival (PFS) and overall survival (OS) was significantly improved in group 2 vs 1 (HR = 0.63, 95% CI 0.46-0.87; P= 0.0039 for PFS and HR = 0.44, 95% CI 0.30-0.65; P = 0.0003 for OS, respectively). In a subgroup analysis of International Germ Cell Cancer Collaborative Group criteria, favorable change in survival was observed in good-risk GCTs (HR = 0.40, 95% CI 0.24-0.67; P = 0.0009 for PFS, and HR = 0.20, 95% CI 0.10-0.38; P = 0.0002 for OS), but nor in intermediate or poor risk group. Conclusions: Treatment outcomes of GCTs have significantly improved in the last decade at our institution. We hypothesize that changes in treatment approach contributed to this improvement including centralization of post-chemotherapy retroperitoneal lymph-node dissections and routine use of granulocyte-colony stimulating factors that have been implemented in 2007. Referral bias for extremely poor risk patients in recent years may be an accounting factor for lack of improvement in this subgroup.
Efficacy and safety profile of sunitinib as a first line treatment for advanced/metastatic clear-cell renal cell carcinoma: Pooled analysis of randomized controlled trials.
Authors: Haykal Tarek , Samji Varun , Zayed Yazan , Al-Dulaimi Ragheed , Gakhal Inderdeep , Bala Areeg , Sotzen Jason , Ghamrawi Ranine , Katato Khalil , Danish Rizwan
Published: May 2019

e16067

Background: Metastatic clear-cell renal cell carcinoma (RCC) is largely incurable, and its treatment remains challenging. Sunitinib, a tyrosine kinase inhibitor, is one of the current standard-of-care options for treatment-naïve patients with metastatic RCC. Despite the proven efficacy of Sunitinib, prolonged treatment with some tyrosine kinase inhibitors (TKIs) has been associated with significant adverse events (AEs). Therefore, we aimed to calculate the exact efficacy in addition to the prevalence of all AEs of Sunitinib in a pooled analysis from all available randomized controlled trials (RCTs). Methods: A comprehensive electronic database search was conducted for all RCTs comparing the clinical outcomes and adverse events of Sunitinib versus all other available treatments for treatment-naïve advanced/metastatic clear-cell renal cell carcinoma. We then calculated the pooled outcomes and prevalence of the most common reported side effects of Sunitinib. All statistical analyses were performed using R Statistical Software v3.4.0 (R Foundation, Vienna, Austria). Results: We included 8 RCTs, with a total of 4106 patients. The mean age was62, with 66.44% males.The efficacy of Sunitinib was reported as 3 main outcomes: Median progression free survival at 10.73 [7.76, 13.7] months, median overall survival at 23.28 [16.74, 29.81] months and the estimated objective response rate at 25[13, 37] %. Any grade AEs were reported in 72% of patients with the following frequencies: fatigue 44%, diarrhea 38%, nausea 31%, hand-foot syndrome 30%, hypertension 27%, dysgeusia 25%, hypothyroidism25%, constipation 20%, stomatitis 20%, inflammation of the mucosa 18%, dyspepsia 16%, vomiting 14%, rash 12%, asthenia 11%, and epistaxis10%.Grade 3&4 (severe) AEs were reported in 52% of patients with the following frequencies: hypertension 9%, fatigue 8%, hand-foot syndrome 5%, asthenia 5%, diarrhea 4%, and inflammation of the mucosa 2%. Conclusions: Despite Sunitinib being one of the current standard treatments for patients with metastatic/advanced clear-cell RCC, with well-described efficacy, its safety profile is still concerning with a significant prevalence of reported grade 3-4 AEs of 52% of the treated patients in the included RCTs. These findings underscore the importance of the emergence of newer drugs and treatment plans for patients with metastatic RCC, not only to achieve similar or better clinical outcomes but also to decrease the percentage of grade 3-4 AEs.
Molecular profile of early-stage and advanced-stage of renal cell cancer in China.
Authors: Chen Jimin , Zhang Yanrui , Yang Tongtong , Wang Huina , Guo Jing , Liang Xiayuan , Lou Feng , Cao Shanbo , Du Chuanjun
Published: May 2019

e16071

Background: The mutation spectrum has been extensively studied in Renal Cell Cancer (RCC), a heterogeneous disease. While major investigations have focused on metastatic RCC (mRCC). This study intended to explore the molecular characteristics between early-stage (stage I/Ⅱ) and advanced-stage (Ⅲ/Ⅳ) of RCC patients (pts). Methods: 36 tumor specimens were obtained from individual pts diagnosed RCC, including 22 tissues paired with blood samples. Somatic mutations were identified via targeted next generation sequencing with Acornmed panel including 808 genes associated with tumor development. Sequencing data were analyzed to call tumor specific single nucleotide variants (SNV), small insertions and deletions (InDels), copy number alterations (CNA) and chromosomal rearrangements. Clinical data of a cohort from TCGA who had RCC was collected and analyzed. Results: Among the 36 pts enrolled, 61% were early-stage group and 39% were advanced-stage group. The most frequently mutated genes in RCC were VHL (50%), PBRM1 (14%), BAP1 (11%), TP53 (11%) and PIK3CA (6%). Truncating mutations were the most frequent alterations accounting for 66% (33/50) of genetic alterations. Mutations in VHL, BAP1, PBRM1 and TP53 were shared by both early and advanced RCC. While mutations in PIK3CA, CDKN2C, EGFR, FAMCA, GRIN2A, KDM6A, SOX17, TSC1 and APC were only detected in early stage group. KNSTRN, KRAS, MYD88, NF2, ATM, PTEN and STAT5B mutations were only detected in advanced group. Among 22 plasma samples, genomic alterations were detected in 40.9% (9/22) of pts postoperatively, such as TP53, PIK3CA, PTEN, and APC. Functional annotation clustering revealed that 4/9 in these genes were tumor suppressors, which negatively regulated apoptosis. Pts with genomic alterations in TP53 (p = 0.0034), PIK3CA (p = 0.0015) or PTEN (p = 0.00017) had worse OS significantly (TCGA). Conclusions: VHL, PBRM1, BAP1 were the most important driver genes mainly detected in all stages of RCC. The heterogeneity between early and advanced-stage may be related with clinical status. Gene alterations in plasma ctDNA postoperatively should have the potential to stratify patients with different prognostic outcome.
Association of body mass index and systemic inflammation index with survival in patients with renal cell cancer treated with nivolumab.
Authors: De Giorgi Ugo , Procopio Giuseppe , Sabbatini Roberto , Caserta Claudia , Mitterer Manfred , Ortega Cinzia , Scoppola Alessandro , Fornarini Giuseppe , Ferraú Francesco , Marchetti Paolo , Verusio Claudio , Mini Enrico , Bidoli Paolo , Buti Sebastiano , Crino Lucio , Basso Umberto , Frassoldati Antonio , Bearz Alessandra , Carteni Giacomo , Sternberg Cora N.
Published: May 2019

e16077

Background: Body mass index (BMI) and inflammation indexes are easily evaluated, predict survival in many tumors, and are potentially modifiable. The "obesity paradox" of longer survival in cancer patients with high BMI has been explained by altered fatty acid pathways, which could have an impact in immune-inflammatory function, and leptin-driven increase in T cell aging resulting in higher PD-1 expression and dysfunction, which leaves tumors notably more sensitive to checkpoint blockade. We evaluated the potential association of inflammatory indexes and BMI with the clinical outcome of metastatic renal cell carcinoma (mRCC) undergoing immune checkpoint inhibitor therapy. Methods: A prospective cohort of patients with mRCC treated with nivolumab enrolled in the Italian Expanded Access Program (EAP) from July 2015 through April 2016 was examined. Reference measures of inflammation were identified for neutrophil to lymphocyte ratio (NLR) < /≥3, systemic immune-inflammation index (SII) < /≥3 and platelet to lymphocyte ratio (PLR) < /≥232. Patients were classified as high BMI (≥25 kg/m2) versus normal BMI ( < 25 kg/m2). Results: Among 313 evaluable patients, 289 (75.1%) were male, median age was 65 years (range, 40 to 84), with 105 (24.9%) ≥70 years. In univariate analysis, age ≥70 years, performance status, BMI, SII, NLR and PLR were able to predict outcome. In multivariate analyses, SII ≥1375, BMI < 25 and age ≥70 years independently predicted OS (HR, 2.96; 95% CI, 2.05-4.27; HR, 1.59; 95% CI, 1.10-2.30 and HR, 1.65; 95% CI, 1.07-2.55, respectively). Under the model of independent effects, a patient with both SII ≥1375 and BMI < 25 was estimated to have much worse OS (HR, 3.37; 95% CI, 2.29-4.95, p < 0.0001) than a patient with neither or only one risk factor. SII changes at 3 months predicted OS (P < 0.0001). Conclusions: BMI combined with inflammation tripled the risk of death, suggesting that these biomarkers are critical prognostic factors for OS in patients with mRCC treated with nivolumab.
Efficacy of systemic therapy for metastatic renal cell carcinoma in patients over 75 years of age.
Authors: Mizuno Ryuichi , Takamatsu Kimiharu , Hayakawa Nozomi , Kosaka Takeo , Tanaka Nobuyuki , Oya Mototsugu
Published: May 2019

e16080

Background: In the last decade, approval of targeted agents and immune checkpoint inhibitors (ICI) have dramatically changed the scenario of systemic treatment of metastatic renal cell carcinoma (mRCC) with improved survival. Although elderly individuals represent a consistent proportion, clinical trials have not directly compared the efficacy and safety of targeted agents in the elderly population. Methods: A total of 195 patients were retrospectively reviewed. All patients received systemic therapy for mRCC at Keio University hospital in Japan (Institutional review board approval No 2013-0425). Patients were divided into two groups (≥75 or < 75 years) according to their age at the time of systemic therapy initiation. The disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were compared between the two cohorts. Results: The elderly cohort (≥75 years old) comprised of 42 patients (21.5%). The DCR for first line treatment in patients ≥75 years old and < 75 years old was 75.0 and 76.2 %, respectively (p = 0.8728). The median PFS for first line treatment in patients ≥75 years old and < 75 years old was 10.7 (95% CI 7.5–20.7) and 11.6 (95% CI 9.7–16.3) months, respectively (p = 0.6074). The median OS for systemic treatment in patients ≥75 years old and < 75 years old was 37.3 (95% CI 18.0–65.2) and 45.5 (95% CI 35.1–56.8) months, respectively (p = 0.0424). Conclusions: Systemic treatment for mRCC was feasible and effective in Japanese patients over 75 years of age.
Patient-reported experience of diagnosis, management, and burden of renal cell carcinomas: Results from a global patient survey in forty-three countries.
Authors: Giles Rachel H , Maskens Deb , Bick Robert , Martinez Robin , Packer Malcolm , Heng Daniel Yick Chin , Larkin James M. G. , Bex Axel , Maclennan Sara Jane , Jewett Michael A.S. , Jonasch Eric
Published: May 2019

e16091

Background: The International Kidney Cancer Coalition (IKCC) is a federation of 38 affiliated patient organizations representing 1.2 million patients worldwide that is committed to reduce the global burden of kidney cancer. A large-scale global survey of RCC patients to capture real world experiences (RWE) has never been undertaken. Methods: The 35-question survey was designed to identify geographic variations in patient education, experience and awareness, access to care, best practices, quality of life, involvement in clinical trials and to highlight unmet needs. The survey was conducted online or in paper form in Sept-Oct 2018 by kidney cancer patients and /or their caregivers identified by IKCC’s Affiliate Organizations and through social media in 14 languages. Results: 1,983 responses were recorded from 43 countries. Analysis revealed that at diagnosis, 43% of all respondents had no understanding of their RCC sub-type; patients with clear cell carcinoma (64%) had a notably poorer understanding of their RCC subtype than did patients with rarer RCC subtypes. While 96% of respondents reported psychosocial impacts, surprisingly, only 50% disclosed them to their healthcare team. Of the 70% of patients who were never asked to participate in a clinical trial, 89% responded they would have “fairly likely” done so if asked. RCC patients < 45 years old reported nearly twice as many barriers to treatment as patients > 45 at diagnosis. Females reported longer delays to diagnosis than males. Shared decision making remains aspirational across major cancer centers and community hospitals: globally 29% of all patients reported no involvement in their treatment decision, responding ‘my doctor decided for me’. Conclusions: This exploratory research sheds light on the unmet needs in the RCC patient experience and warrants further analysis. This first-ever global survey serves as a benchmark for longitudinal data collection. RWE indicates opportunities to improve communication about diagnosis, psychosocial impacts, and clinical trials. [Table: see text]
Unraveling the molecular profile underpinning pancreatic tropisms in metastatic clear cell renal cell carcinoma.
Authors: Singla Nirmish , Onabolu Oreoluwa , Woolford Layton , Stevens Christina , Tcheuyap Vanina , McKenzie Tiffani , Yousuf Qurratulain , Ma Yuanqing , Choi Jacob , Zhang Ze , Xie Zhiqun , Wang Tao , McKay Renee , Christie Alana , Pedrosa Ivan , Przybycin Christopher , Kapur Payal , Rini Brian I. , Brugarolas James
Published: May 2019

e16096

Background: The tropism of cancer metastases is poorly understood yet holds prognostic value. Clear cell renal cell carcinoma (ccRCC) exhibits a broad pattern of metastases, making it an optimal model to study organotropism. Notably, when ccRCC metastasizes to the pancreas (PM) independently of other sites, it is associated with favorable outcomes in patients for unclear reasons. Here, we comprehensively analyzed the clinical and molecular profile of patients with PM. Methods: RCC patients with PM from UTSW and Cleveland Clinic were identified. Clinicopathologic data and oncologic outcomes were analyzed. Whole exome sequencing (WES), RNAseq, and histologic assessment of primary and metastatic tumors from PM patients were conducted. Results: 31 RCC patients with PM were identified. We observed remarkably favorable outcomes in our PM cohort, with a median overall survival (OS) of 10.7 years from metastatic diagnosis and a long latency between initial diagnosis and development of metastasis (median 69 months in patients who were non-metastatic at diagnosis). OS was independent of both metastatic tumor burden and known IMDC prognostic factors. We discovered that tumors from PM patients were markedly uniform and clustered together by gene expression analysis. WES and DNA copy number analyses revealed a high frequency of VHL and PBRM1 mutations, 3p loss, and 5q amplification, along with a lower frequency of 9p, 14q and 4q losses and BAP1 mutations, characteristic of indolent ccRCC. Furthermore, the genomic and histologic features of tumors from patients with PM can be recapitulated in patient-derived xenograft models. Conclusions: To our knowledge, this is the first report to unravel molecular determinants of organotropism, and we highlight that organotropism can be an independent prognostic factor. Understanding tumor heterogeneity may help refine prognostic models for metastatic RCC and hold implications for improved personalization of therapy.
Comparison of efficacy and safety of checkpoint inhibitors in patients with genitourinary cancers aged below and above 75 years.
Authors: Schulz Gerald Bastian , Szabados Bernadett , Spek Annabel , Staehler Michael D. , Stief Christian , Casuscelli Jozefina
Published: May 2019

e16101

Background: Checkpoint-inhibitors have recently been introduced in the treatment of patients with genitourinary cancers. However, the use in elderly patients is controversial due to putative age-associated changes including the dysregulation of the immune system. We sought to investigate the safety and efficacy of immunotherapy in patients younger and older than 75 years of age. Methods: We conducted a retrospective review of patients with renal cell carcinoma and urothelial cancer treated with different immunotherapeutic agents between August 2015 and September 2018 at a high-volume single institution. Eligible patients received at least one cycle of single agent or a combination of checkpoint inhibitors as first or following treatment line. Immune-related adverse events (irAE) were graded using the NCI CTCAE v 4.0. Clinicopathological parameters including gender, cancer entity, ECOG, adverse events, comorbidities and response to treatment were stratified by age ≥ 75 vs. < 75 years and tested with a Pearson's chi-squared test. Additionally, we evaluated the impact of irAE on oncological outcome using the log-rank test. Results: 79 patients were identified, of those 27 (34.2%) were 75 years and older (15 renal cell carcinoma and 12 urothelial cancer patients) and 52 (65.8%) were younger than 75 years (39 renal cell carcinoma and 13 urothelial cancer patients). 2 complete responses were achieved in the elderly group and 6 in the younger group (p = 0.56). Disease control rate (stable disease, partial and complete response) was 48,1% in the elderly group and 53.8% in the younger group (p = 0.631). We observed a total of 30 irAEs (18 grade 1-2 and 12 grade 3-4), with an even distribution among the groups (≥75 years: 1 grade 4 AE; < 75 years: 12 grade 3-4 AEs). Except for ECOG ≥2 (p = 0.009) and ≥2 comorbidities (p < 0.001), there was no difference when groups were stratified by age. Both disease control rate and irAE did not differ between age subgroups. Occurrence of irAE showed no impact on oncological survival. Conclusions: The study demonstrates that patients over 75 years of age with renal cell and urothelial cancer treated with checkpoint-inhibitors respond with a good toxicity profile and an efficacy comparable with the younger population. irAE seem to have no impact on prognosis.
Express-diagnosing of acute kidney injury among patients with the localized kidney cancer after partial nephrectomy under warm ischemia: A role of biomarkers.
Authors: Dimitriadi Sergey N , Kit Oleg I. , Frantsiyants Elena M. , Velichko A. V. , Rozenko Dmitry A. , Faenson Aleksandr V. , Filatova Elena V. , Shvyrev Dmitry A. , Rozenko A. D. , Omelchuk Ekaterina P.
Published: May 2019

e16108

Background: The specialists consider partial nephrectomy (PN) under warm ischemia (WI) as a standard treatment option for localized renal cell carcinoma (RCC) patients. However, clinical use of the method is restricted by acute kidney injury (AKI) development among patients with high R.E.N.A.L. score, which usually demands long warm ischemia time (WIT). The purpose of the study consists in assessing of the diagnostic ability of cystatin С, IL-18, KIM-1, L-FABP and NGAL in express-diagnosing of AKI among patients with the localized kidney cancer after PN under WI. Methods: The sample of the examined patients consists data of the retrospective research of 100 cases with a localized RCC who underwent PN for elective indications using WI. The WIT was about 15-21 minutes. 24 hours prior to and 16 hours after the surgery, using the ELISA technique and standard test-systems the serum concentration of the following “early markers of AKI” was tested: cystatin С (BioVendor, Czech Republic), КIМ-1 (BCMDiagnostics, USA), NGAL (BCMDiagnostics, USA), L-FABP (Hycult Biotechnology, Netherlands), IL-18 (BenderMedsystems, USA). The WIT and diuresis rate were also registered. AKI was diagnosed based on the serum creatinine level measuring in accordance with the KDIGO guidelines. The clinical and laboratory data were processed using MS Excel software; the Wilcoxon test was used. Simultaneously the expert analysis of the data was carried out. Results: The AKI was registered in 24 patients having a preoperative serum cystatin С level higher than 1000 ng/ml. Another risk factor was WIT lasting 15-21 min. All patients with AKI had an increase of serum concentrations of all 3 following markers: cystatin С, NGAL and L-FABP by more than 10 per cent each (in relation to a preoperative level by each patient). In 5 patients (among the 24 ones) an elevation of creatinine serum concentration was registered just after 40 hours after the surgery – much later than the markers’ reaction appeared. Based on the expert analysis of the clinical and laboratory data the personified scale of early AKI diagnosing and its graphical representation in a form of three-dimensional model was developed. Conclusions: The new method allows diagnosing the AKI development after 16 hours in patients who underwent PN under WI on occasion of RCC. The method has good perspectives of clinical use as it allows identifying the AKI development before elevation of a serum creatinine concentration.
Full adaptome repertoire analysis of immunotherapy to predict responsiveness and correlation with CD8-LAG3, sLAG3, and hepatocyte growth factor levels in patients with renal cancer.
Authors: Lotze Michael T. , Appleman Leonard Joseph , Zhai Shuyan , Wang Yue Yolanda , Forte Alexa , Pan Wenjing , Byrne-Steele Miranda L. , Han Jian
Published: May 2019

e16116

Background: Aldesleukin (recombinant interleukin-2, IL-2), the first checkpoint inhibitor overcoming Tregs, was FDA-approved for mRCC with a 5-10% rate of durable CRs and 25% ORR. Hydroxychloroquine (HCQ) inhibits autophagy, promoting tumor apoptosis. In murine models, IL-2 and HCQ is associated with diminished toxicity and increased efficacy. We hypothesized that a novel deep seven chain analysis of the TCR and BCR repertoire would correlate with sLAG3, CD8 cytosolic LAG3, and HGF levels, associated with outcomes in RCC patients treated with this regimen. Methods: Patients (pts) received high dose IL-2, 600,000 IU/kg, every 8 hours up to 14 doses/cycle. HCQ was administered orally, starting 2 weeks prior to IL-2 and continued up to one year. The HCQ dose was 600 mg (17pts) or 1200 mg (13pts) daily. A newly available seven chain TCR/BCR Adaptome dimer avoidance multiplex-PCR followed by NextGen Sequencing allowed identification of CDR3’s associated with response and increasing clonal diversity. Results: Of 30 pts in the study, 29 were evaluable for response (3CR, 3PR) with serum samples and seven chain analysis of PBMC with 330x106 total reads of the TCR αβ, TCR γδ, IgH, and κλ light chains. HGF (p < .009) was a significant negative predictor of OS at Day 1 after IL-2 and OS at Day -14 (p < .005). Surprisingly this correlated with the TCRδ/γ ratio (p < .01). Similarly serum sLAG3 and CD8LAG3+ both > median predicted improved PFS (p = 0.019) correlating with total TCRδγ expression, p < .01. Diversity of the TCR αβ but not the TCR γδ nor the IgH, and κλ light chains predicted response, p = .005. Conclusions: IL-2 plus HCQ was well tolerated and clinically active with encouraging increase in the PFS of > 17 months at the 600 mg HCQ dose ( > 4x greater than historical controls). Powerful new technology identifying enhanced responsiveness correlating significantly with diversity of the TCR αβ identifies a novel method for predicting responsiveness to immunotherapy. This unbiased examination of the full repertoire ('Adaptome') measured in the same bioassay correlates with other novel biomarkers and should be widely applicable in the further evolution of immunotherapy. NCT01550367 ; approved as IRB 11-074. Clinical trial information: NCT01550367.
Docetaxel dose-intensity effect on overall survival in patients with metastatic castrate-sensitive prostate cancer.
Authors: Kushnir Igal , Mallick Ranjeeta , Ong Michael , Canil Christina , Bossé Dominick , Koczka Kim , Reaume M. Neil
Published: May 2019

e16501

Background: Several studies assessed the association of docetaxel dose intensity (DI) and efficacy in metastatic castrate-resistant prostate cancer (mCRPC) patients with contradicting conclusions. In this retrospective analysis we will assess whether the docetaxel DI used in patients with metastatic castrate-sensitive prostate cancer (mCSPC) is associated with overall survival (OS). Methods: We have identified all the patients with mCSPC treated at The Ottawa Hospital Cancer Centre that received docetaxel chemotherapy between June 2014 - September 2017. For each patient we calculated the relative dose intensity (RDI) and assessed whether it’s associated with OS using univariate and multivariate cox-proportional hazards analysis. Results: Eighty-0ne patients were included in the analysis. Nineteen patients (23.5%) had their body surface area capped at 2 which resulted with de facto median dose reduction of 7% (IQR 6% - 9%). Ten patients had upfront dose reduction (usually due to significant co-morbidities) with a median dose reduction of 20% (IQR 19.25 – 20.75). Only 35 patients (43.2%) were able to complete the planned treatment with a RDI of at least 90%. After a median follow-up of 29.4 months, 32 patients (39.5%) died. The median OS was 43.9 months. On a univariate analysis RDI and number of cycles of docetaxel received were found to be statistically significant associated with OS. For every 10% decrease in RDI the risk of death increased by 23% (HR 1.23, 95% CI 1.09 – 1.4, P = 0.0011). For every incremental cycle (up to a total of 6) the risk of death decreased by 27% (HR 0.73, 95% CI 0.61- 0.88, P = 0.001). On multivariate analysis we included age, Gleason score, burden of disease, visceral involvement and baseline PSA. Reduced RDI remained the only significant variable associated with OS (HR 1.2, 95% CI 1.04 – 1.39, P = 0.0117). Conclusions: Reduced docetaxel DI administrated to mCSPC patients is associated with worse survival. Therefore unnecessary docetaxel dose reductions, treatments delays and early discontinuation should be avoided. Granulocyte-colony stimulating factor should be considered in order help maintain standard DI.
Oncolytic HSV and PI3K inhibitor BKM120 synergize to promote killing of prostate cancer stem-like cells.
Authors: Wang Lei
Published: May 2019

e16503

Background: Novel therapies to override chemo-radiation resistance in prostate cancer (PCa) are needed. Prostate cancer sphere-forming cells (PCSCs) (also termed prostate cancer stem-like cells) likely participate in tumor progression and recurrence and are important therapeutic targets. Methods: We established PCSC-enriched spheres by culturing human (DU145) and murine (TRAMP-C2) PCa cells in growth factor-defined serum-free medium, and characterized stem-like properties of clonogenicity and tumorigenicity in vivo. The efficacy of two different oHSVs (G47∆ and MG18L) in PCSCs was tested alone and in combination with radiation, chemotherapy, and inhibitors of PI3K, Wnt, and NOTCH in vitro, and G47∆ with BKM120 in a PCSC-derived tumor model in vivo. Results: PCSCs were more tumorigenic than serum-cultured parental cells. Human and murine PCSCs were sensitive to oHSV and BKM120 killing in vitro, while the combination was synergistic. In contrast, oHSV combined with radiation, docetaxel, Wnt, or NOTCH inhibitors was not. In athymic mice bearing DU145 PCSC-derived tumors, combination intra-tumoral G47∆ and systemic BKM120 induced complete regression of tumors in 2 of 7 animals, and exhibited superior anti-tumor activity compared to either monotherapy alone, with no detectable toxicity. Conclusions: oHSV synergizes with BKM120 in killing PCSCs in vitro and the combination markedly inhibits tumor growth even inducing regression in vivo.
Association between circulating miRNA-141 and miRNA-375 and treatment outcome in metastatic castration-resistant prostate cancer.
Authors: Zedan Ahmed Hussien , Osther Palle Jörn Sloth , Assenholt Jannie , Madsen Jonna Skov , Hansen Torben
Published: May 2019

e16507

Background: Metastatic castration resistant prostate cancer (mCRPC) is associated with high mortality. Monitoring of disease activity at this stage, with lack of validated prognostic models, is still a major clinical challenge. The role of microRNAs (miRNAs) has been widely investigated in prostate cancer with both diagnostic and prognostic potential. The aim of this study was to investigate the relationship between circulating miRNAs and treatment outcome in mCRPC patients. Methods: The relative expression of four miRNAs was investigated in plasma samples from 84 mCRPC patients; 40 patients were treated with docetaxel and 44 patients with abiraterone. Real-time polymerase chain reaction was used for analysis. Blood was sampled at baseline, before the second treatment cycle, and at radiological progression (RP). Associations to prognoses were analyzed using the Cox Regression analyses. Results: The plasma levels of all four miRNAs decreased significantly after treatment initiation in patients receiving docetaxel, and for miRNA-141 and miRNA-375 the level increased again at the time of RP. High baseline levels of miRNA-141 were significantly associated with a shorter time to RP in patients receiving both abiraterone, hazard ratio (HR) 3.18 (95% confidence interval (CI) 1.31-7.32), p < 0.01, and docetaxel HR 2.56 (95% CI 1.45-4.50), p < 0.01, and a shorter overall survival (OS), HR 3.20 (95% CI 1.25-9.37), p = 0.02, and HR 1.77 (95% CI 1.07-2.83), p = 0.02, respectively. Likewise, high baseline levels of miRNA-375 were also significantly associated with a shorter time to RP in both cohorts and OS in patients receiving docetaxel. Conclusions: Plasma levels of miRNA-141 and miRNA-375 were of prognostic importance in patients with mCRPC receiving both abiraterone and docetaxel and may be used in treatment monitoring irrespective of treatment modality.
Real-world cardiovascular outcomes with novel anti-androgen agents in prostate cancer patients.
Authors: Kulkarni Amit , Rubin Nathan , Tholkes Tony , Prizment Anna , Ryan Charles J. , Rao Arpit
Published: May 2019

e16510

Background: Abiraterone use is associated with significant cardiovascular (CV) morbidity in clinical trials, but the magnitude of this morbidity in contemporary US prostate cancer (PC) population remains unknown. We examined a large medical claims database to answer this important question. Methods: We retrospectively reviewed Marketscan claims database (1/1/2013 to 9/30/2015) to identify adults with diagnosis of localized PC, recurrent localized PC, biochemically recurrent non-metastatic PC and metastatic PC who received treatment with androgen deprivation therapy (ADT) alone or ADT with novel antiandrogen agents (abiraterone or enzalutamide). The primary outcome measure was composite severe CV outcome of acute myocardial infarction (MI), stroke or heart failure (HF). We used Cox regression model with time dependent covariates to estimate the CV risk of various therapies. Results: A total of 7030 patients of PC were identified- 1285 received ADT for localized PC, 424 received ADT for recurrent localized PC, 554 received ADT for biochemically recurrent non-metastatic PC, 256 received ADT alone for metastatic PC and 1366 received abiraterone or enzalutamide with ADT for metastatic PC. During the study period, 143 severe CV events occurred, resulting in an incidence rate of 0.74 per 100 patient-years. In multivariate analysis, abiraterone use was associated with a trend towards increased risk of severe CV compared to non-abiraterone users (HR = 1.58; 95% CI: 0.98-2.59, p= 0.06). No such increased risk was detected for ADT (HR = 1.35; 95% CI: 0.92-2.00, p= 0.12) or enzalutamide (HR = 0.84 95% CI: 0.34-2.11, p= 0.71). Conclusions: To our knowledge, this is the first study to present real-world data on CV outcomes of PC patients receiving novel anti-androgens. Our findings support the trend towards increased severe CV risk seen in abiraterone trials. No such association was seen for enzalutamide. Additional analyses with a longer follow-up duration are planned.
Intratumoral and subcutaneous injection of HVJ-E (GEN0101) for metastatic castration-resistant prostate cancer: Open-label, phase I, dose escalation study.
Authors: Fujita Kazutoshi , Nakai Yasutomo , Kato Taigo , Kawashima Atsunari , Ujike Takeshi , Nagahara Akira , Uemura Motohide , Imamura Ryoichi , Okihara Koji , Ukimura Osamu , Miki Tsuneharu , Kaneda Yasufumi , Nonomura Norio
Published: May 2019

e16511

Background: Inactivated Sendai virus particles (hemagglutinating virus of Japan envelope (HVJ-E)) have a novel antitumor effect: HVJ-E fused to prostate cancer cells via cell surface receptor causes apoptosis of prostate cancer cells in vitro and in vivo. HVJ-E also induces antitumor immunity by activating natural killer (NK) cells and cytotoxic T cells and suppressing regulatory T cells in vivo. We conducted an open-label, phase I, dose-escalation study in patients with castration-resistant prostate cancer (CRPC) to determine the safety and efficacy of intratumoral and subcutaneous injection of HVJ-E (GEN0101). Methods: Patients with CRPC who were resistant to standard of care or could not receive standard of care were eligible. GEN0101 was injected directly into the prostate on day 1 and subcutaneously on days 5, 8 and 12 in two 28-day treatment cycles using a modified 3+3 dose-escalation design to determine the recommended dose of GEN0101. The primary end points were to evaluate safety and tolerability of GEN0101 and determine the recommended dose. The secondary end points were to analyze antitumor effect and tumor immunity. The study is registered at UMIN Clinical Trials Registry, number UMIN000017092. Results: Of the 9 patients treated, 3 received 30,000mNAU of GEN0101 and 6 received 60,000mNAU. There were no dose-limiting toxicities, and the recommended dose of GEN0101 was defined as 60,000mNAU. Radiographically, one patient had stable disease and 2 had progressive disease in the low-dose group, and 5 patients had stable disease and one had progressive disease in the high-dose group. Four patients in high dose group had reductions in lymph node metastasis after 2 treatment cycles. Final PSA increase rates in high-dose group were more suppressed than those in low-dose group. NK cell activity was enhanced in 2 patients (66%) in low-dose group and 5 patients (83%) in high-dose group, Serum interleukin-6, and IFN-γ levels were not affected by GEN0101 treatment. Conclusions: Intratumoral and subcutaneous injections of GEN0101 were well tolerated and feasible. Antitumor effect in lymph node metastasis were observed in CRPC patients. It is necessary to test whether the treatment with GEN0101 improves the survival of CRPC patients. Clinical trial information: UMIN000017092.
Addition of docetaxel or abiraterone to androgen deprivation therapy in metastatic castration-naive prostate cancer in South Asian population.
Authors: Sonthwal Neha , Hussain Shaik Maheboob , Arya Devavrat , Batra Sandeep , Chaturvedi Harit Kumar , Gupta Alok
Published: May 2019

e16514

Background: Clinical trials have shown that addition of Docetaxel or Abiraterone to androgen deprivation therapy (ADT) achieves superior survival outcome in metastatic castration naive prostate cancer (mCNPC) in predominantly western population. We sought to evaluate treatment outcomes of adding Docetaxel or Abiraterone to ADT in South Asian population. Methods: 90 mCNPC patients who received treatment between January 2015 and June 2018 were prospectively followed. Diagnosis was established by TRUS guided prostate biopsy and staging was done by Ga68 PSMA PET CT scan in all patients. Patients who were unfit for combination therapy received ADT alone. Patients diagnosed before June 2017 & fit to receive chemo-hormonal therapy, received ADT+Docetaxel. Patients diagnosed after June 2017 and fit to receive combination were offered ADT+Docetaxel or ADT+Abiraterone and therapy selected based on patient’s choice. Monthly clinical evaluation and PSA measurement was done. Outcome measures analyzed included PSA decline > 90%, serological complete response (PSA < 0.2 ng/ml) and progression to CRPC. 76 patients with atleast 6 months follow-up were included in outcome analysis. Results: Patients received ADT alone (N = 37) or ADT+Docetaxel (N = 31) or ADT+Abiraterone (N = 22). Median age was 72, 64 & 70 years, median PSA was 88, 95 & 38 ng/ml, Gleason score was ≥8 in 57%, 71% & 77% patients in ADT alone, ADT+Docetaxel & ADT+Abiraterone group, respectively. Bone & visceral metastasis were present in 62% & 24%, 74% & 26%, 68% & 23% patients in ADT alone, ADT+Docetaxel & ADT+Abiraterone group, respectively. Outcome analysis in 76 evaluable patients is shown in Table. Conclusions: ADT+Docetaxel & ADT+Abiraterone achieve deeper serological response and reduced progression to CRPC compared to ADT alone in metastatic castration naive prostate cancer patients with South Asian ethnicity. Longer follow up is required to comment on overall survival and also to determine which combination (ADT+Docetaxel or ADT+Abiraterone) is superior to other, if at all.[Table: see text]
Early PSA progression in abiraterone/enzalutamide-treated patients with metastatic castration-resistant prostate cancer.
Authors: López-Campos Fernando , Gomez-Iturriaga Alfonso , Llacer Perez Casilda , Henriquez Ivan , Peleteiro Paula , Lozano Rebeca , Castaño Ana , Romero-Laorden Nuria , Molina-Cerrillo Javier , Alvarez-Rodríguez Sara , Piquer Teresa , Navarro-Castellón Joaquin , Conde-Moreno Antonio José , Ramirez-Backhaus Miguel , Barrionuevo Patricia , García Raquel , Pérez-Haro María de los Llanos , Castro Elena , Olmos David , Lorente David
Published: May 2019

e16530

Background: Changes in PSA are widely used as a biomarker for the monitoring of treatment outcome in Metastatic Castration-Resistant Prostate Cancer (mCRPC) in the clinical real-world setting. Early PSA changes (before 12 weeks) are not considered in the definition of PSA Progression (PSAProg) due to the potential for spurious “flare” reactions. We aimed to evaluate the significance of an early PSA increase in Abiraterone/Enzalutamide (Abi/Enz)-treated mCRPC patients (pts). Methods: We retrospectively evaluated Abi/Enz-treated mCRPC pts from 11 hospitals between 2011-2018. Early PSAProg was defined as a 25% increase in PSA from baseline at 4 (PSAProg4) or 8 (PSAProg8) weeks after treatment initiation. PSA progression at 12 weeks (PSAProg12) was confirmed by a second reading. Uni- and multivariable (MV) Cox regression models were conducted to explore the association of PSAProg and overall (OS) and radiographic progression-free (rPFS) survival. Sensitivity (Se), specificity (Sp) and predictive values (PPV, NPV) for the association of early PSAProg with PSAProg12 were calculated. Results: We analyzed 581 mCRPC pts; median follow-up: 19.1 months. 96 (17.1%); 105 (21.6%) and 85 (16.9%) pts had PSAprog at 4, 8 and 12 wks. PSAProg4 and PSAProg8 were significantly associated with confirmed PSAProg12. 55.3% of pts with PSAProg4 and 66.7% of pts with PSAProg8 had a confirmed PSAProg12. Only 9% of pts with no PSA prog at 4 wks and 4.1% of pts with no PSAProg8 had a confirmed PSAProg12. PSAProg4 had Se: 56.6%, Sp: 90.5%, PPV: 55.2%, NPV: 91% for the detection of PSAProg12. PSAProg8 had Se: 81.9%, Sp: 91.2%, PPV: 66.7%, NPV: 95.9% for the detection of PSAProg12. PSAprog at 4, 8 and 12 wks was significantly associated with OS and rPFS in uni- and MV Cox models (Table). Conclusions: Early PSAProg after Abi/Enz is significantly associated with both confirmed PSA Prog at 12 wks and outcome, and may help identify pts not benefitting from Abi/Enz before clinical or radiographic progression. Prospective validation studies are needed. [Table: see text]
Association between nutritional status (NS) and health-related quality of life (HRQoL) in men with early metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Cavka Luka , Perme Maja Pohar , Kozjek Nada Rotovnik , Seruga Bostjan
Published: May 2019

e16539

Background: HRQoL is of paramount importance in men with mCRPC. It is not known how NS affects HRQoL in this population of patients. We hypothesized that NS is associated with HRQoL in men with early mCRPC and that NS outperforms body mass index (BMI) in this association. Methods: We prospectively enrolled men with early mCRPC into this study. Patients were assessed, and on the basis of established criteria, four NS categories were defined: normal NS (nNS), nutritional risk without cachexia/sarcopenia (NR), sarcopenia (S) (handgrip strength < 30 kg) and cachexia (C) (Evans`s criteria). HRQoL was assessed by the validated questionnaire Functional Assessment of Cancer Treatment (FACT-P); higher score reflects better HRQoL. After checking for normal distribution, we performed a linear regression model for HRQoL with NS as a dummy variable (with nNS as the reference group). Age, duration of previous androgen deprivation therapy (ADT), hemoglobin level (Hb), prostate-specific antigen (PSA) and BMI were included as covariates into the multivariate model. Results: One hundred forty-one patients were enrolled in our study. At presentation, their mean age was 74.2 years (SD 7.1), and 18 (12.4 %) had visceral metastases. Fifty-eight (41.3%) had nNS, 43 (30.8 %) had sarcopenia, 24 (16.8 %) NR and 16 (11.2 %) C. Mean FACT-P score [SD] in nNS was 115.3 points [22.2], following by 97 [24.6], 98.3 [22.4] and 78.8 [25] points in NR, S and C groups, respectively. We found a significant and consistent association between better NS and worse HRQoL (β [NR:nNS] = -18.2 points; β [S:nNS] = -17 points; β [C:nNS] = -36.5 points; p < 0.001; R² = 0.2). The association remained significant after adjustments (R² = 0.27). Conclusions: Suboptimal NS but not BMI is significantly associated with worse HRQoL in men with early mCRPC. Interventional trials focused on the optimization of NS in men with mCRPC are warranted.[Table: see text]
Prognostic value of PSA progression in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated in the COU-AA-302 trial.
Authors: Lorente David , Lozano Rebeca , de Velasco Guillermo , De Julian Maria , Rodrigo Miguel , Sanchez Angel L , Di Capua Carlos , Castro Elena , Sanchez Hernandez Alfredo , Olmos David
Published: May 2019

e16541

Background: PSA is a widely used biomarker for monitoring outcome in mCRPC. Current treatment guidelines do not consider PSA progression before at least 12 weeks of treatment, and recommend treatment continuation in pts experiencing progression by PSA only, without radiographic or clinicall progression. We aimed to evaluate the prognostic value of a PSA progression in mCRPC pts treated with first-line therapy. Methods: We analyzed the value of a PSA progression (PSAProg) at cycle 5 in pts treated in the COU-AA-302 trial. PSAProg was defined as an increase ≥ 25% and ≥ 2 ng/mL from baseline, confirmed by a second reading. Radiographic progression (RadProg) was defined as per PCWG2 criteria for bone scan or RECIST progression. Survival and radiographic progression-free survival (rPFS) from the time of PSAProg was calculated using Kaplan-Meier estimates. Cox-regression models were used to evaluate the impact of PSAProg and treatment arm on survival. Results: 1088 pts were randomized in the COU-AA-302 trial. 908 pts (83.5%) had valid baseline and cycle 5 PSA values. Of these, 222 (24.4%) pts experienced PSAProg, which was confirmed in 195 (21.5%) pts; 45/479 (9.4%) of abiraterone and 150/429 (35%) of placebo-treated pts. A confirmed PSAProg was associated with shorter survival (37.8 vs 26m; HR: 1.8; p < 0.001) and rPFS (13.9 vs 5.6m; HR:2.1; p < 0.001). Median survival from the time of PSAProg was 22.2m (95%CI:18.9-25.4). Abiraterone-treated pts had a significantly longer survival from the time of PSAProg (23.1 vs 17.4m; HR: 0.64; p = 0.018). 111 pts (56,9%) experienced PSAprog without RadProg; in pts with PSAprog only, median time to RadProg was 7.4m (95%CI:7.1-12.9). No differences in rPFS from the time of PSAprog were observed in abiraterone vs placebo-treated pts (HR: 0.99; p = 0.963). Conclusions: 9.4% of abiraterone-treated pts in the COU-AA-302 trial experienced PSAProg at 12 weeks (cycle 5 day 1). PSAProg was associated with significantly worse survival. Abiraterone increased survival from the time of PSAProg, which supports its continued use in pts with PSA progression only at 12 weeks. This study was carried out under YODA Project #2018-3011.