bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II trial of bevacizumab and lenalidomide with docetaxel and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Adesunloye Bamidele , Huang Xuan , Ning Yangmin M. , Madan Ravi A. , Gulley James L. , Beatson Melony , Kluetz Paul Gustav , Adelberg David , Arlen Philip M. , Parnes Howard L. , Mulquin Marcia , Steinberg Seth M. , Wright John Joseph , Trepel Jane B. , Dawson Nancy Ann , Chen Clara , Apolo Andrea Borghese , Figg William Douglas , Dahut William L.
Published: February 2017

207

Background: Angiogenesis may be vital to mCRPC. Previously, we had shown the potent anti−tumor activity of dual antiangiogenic therapy by combining thalidomide (T) and bevacizumab (B) with docetaxel (D) and prednisone (P) in mCRPC (Ning JCO 2010). We hypothesized that combining lenalidomide (L), an analogue of T, with B, D, and P would have a more favorable efficacy/toxicity profile.

Methods: All patients (pts) had chemotherapy−naïve mCRPC. 3 pts received R 15 mg daily, 3 pts had 20 mg daily, and the rest had 25 mg daily for 14 days of every 21−day cycle (C). All pts received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and enoxaparin daily throughout each C. Pegfilgrastim was given on day 2. PSA was assayed each C with imaging after C2 and then after every 3C.

Results: 47 of the planned 51 pts have been enrolled. Median age was 66 (51−82), Gleason score 8 (5−10), on−study PSA 91.6 ng/ml (0.15−3520), pre−study PSA doubling time 1.43 months (0.52−6.73), number of Cs 14 (1−31), and PFS was 19.3 months as of this analysis. Among 45 pts who have completed ≥2 cycles, 39 (86.7%) and 30 (66.7%) had PSA declines of ≥50% and ≥75%, respectively. Of 29 pts with measurable disease there were 2 CR, 21 PR, and 6 SD (79.3% overall RR). 10/47 pts were taken off study for radiographic disease progression and 5/47 for other reasons. Grade ≥3 toxicities included neutropenia (24/47), anemia (9/47), thrombocytopenia (5/47), weight loss (1/47), hypertension (3/47), and febrile neutropenia (4/47). Other toxicities included perianal fistula (3/47), rectal fissure (1/47), myocardial infarction (1/47), and osteonecrosis of the jaw (ONJ) (16/47, 34.0%). At the time of diagnosis of ONJ, 9/16 pts were on bisphosphonates and 3/16 had used bisphosphonates previously. Although the incidence of ONJ was higher than the 18.3% reported by Ning, a recent study of carboplatin plus weekly docetaxel reported an incidence of 29.3%.

Conclusions: Dual antiangiogenic therapy with, B and L, plus D and P was associated with high PSA (86.7%) and tumor (79.3%) responses with manageable toxicities. Further studies are underway to explore the high incidence of ONJ.
Impact of U.S. Preventive Services Task Force recommendation on screening for prostate cancer in men age 75 or older.
Authors: Drazer Michael W. , Prasad Sandip M. , Huo Dezheng , Schonberg Mara A , Eggener Scott E.
Published: February 2017

216

Background: In 2008, the U.S. Preventive Services Task Force (USPSTF) recommended against screening for prostate cancer in men age 75 years or older. We sought to determine the impact of this statement on utilization of prostate-specific antigen (PSA) testing in this patient group.

Methods: Using the 2005 and 2010 National Health Interview Survey, a cross-sectional household interview survey providing a representative sample of the U.S. population, we analyzed the use of PSA testing in men age 40 years or older prior to and following the release of the USPSTF statement on prostate cancer screening.

Results: In 2010, there were an estimated 2.0 million PSA tests ordered in men 75 years of age and older. In this group, PSA testing rates did not decline between 2005 and 2010 (40.4% vs. 40.6%). In 2010, PSA testing was more common in men aged 75 years and older than in men aged 40 to 49 (9.2%) and 50 to 59 (26.2%) (p < 0.01 between groups). In both 2005 and 2010, PSA testing rates were lowest in men aged 40-49 and highest in men aged 60-74.

Conclusions: Despite the USPSTF recommendation against prostate cancer screening in men age 75 or older, there was no decrease in PSA testing rates in these men. A significant proportion of elderly men continue to receive PSA screening despite a very low likelihood of benefit.

[Table: see text]
The influence of metabolic syndrome on prostate cancer risk detection and its aggressiveness.
Authors: Morales Rafael , Suarez Cristina , Ropero Jordi , Nunez Isaac , Planas Jacques , Placer Jose , Valverde Claudia María , Maldonado Xavier , Morote Juan , Carles Joan
Published: February 2017

226

Background: Metabolic syndrome (MS) is a frequent pathological condition that increase cardiovascular risk and mortality. MS is frequently diagnosed in adult men who are at risk of prostate cancer (PC). Some studies have postulated a relationship between MS and overall oncogenesis, however no information exist in relation to PC. The objective of this study was to analyze the impact of MS on PC detection risk and PC aggressiveness.

Methods: A group of 2408 men were consecutively subjected to prostate biopsy for cause, PSA >4 ng/mL (64.4%), abnormal DRE (9%) or both (26.6%). Median PSA was 7.0 ng/mL (0.7-1279) and median age 68 years (46–86). MS was evaluated according to the ATPIII criteria (three or more conditions: waist circumference >102 cm, triglyceride level >150 mg/dL, high density lipoprotein level <40 mg/dL, fasting glucosa level >110 ng/dL and blood pressure >130/85 mmHg. Men on lipid-lowering medications, hypoglicemiants and antihypertensives were classified as positive for the respective criterion. We took at least 10 cores in PB, plus 1 to 8 additional cores depending on age and prostate volume according to a modified Vienna’s nomogram. Overall PC detection rate was 35.2% and high grade (HG) rate (Gleason score >7) 28.3%. Binary logistic regression and contingence analysis were performed and odds ratios (OR) calculated to analyze the strength of relationships.

Results: The overall prevalence of MS was 61.5% (1480/2408). Multivariate analysis showed that MS was not an independent predictor of PC however MS was an independent predictor of HGPC. The rate of PC was 34.3% in men with MS (508 of 1480) and 36.6% in men without MS (340/928), p=0.255. OR: 0.904 (95%CI 0.762-1.073). The rate of HGPC was 33.1% among the PCs detected in men with MS and 21.2% among the PCs detected in men without MS, p <0.001, OR 1.839 (95%IC 1.337-2.531).

Conclusions: MS does not seem to increase the risk of prostate cancer detection in men subjected to PB for cause. However, we have detected an increase of the aggressiveness among PCs detected in men with MS.
Association of single-nucleotide polymorphisms in BCL2L1 and TACC3 with response to bacillus Calmette-Guérin intravesical therapy in non-muscle-invasive bladder cancer.
Authors: Alanee Shaheen , Gallagher David James , Vijai Joseph , Hamilton Robert James , Ostrovnaya Irina , Garcia-Grossman Ilana Rebecca , Riches Jamie C. , Regazzi Ashley Marie , Przybylo Jennifer A. , Gaudet Mia , Milowsky Matthew I. , Herr Harry W. , Offit Kenneth , Bajorin Dean F.
Published: February 2017

260

Background: Bacillus Calmette-Guérin intravesical therapy (BCG) has an important role in the management of high risk non-muscle-invasive bladder cancer (NMIBC). This study examines the association between germline single nucleotide polymorphisms (SNPs) and response to BCG therapy.

Methods: Saliva or blood was collected from pts with NMIBC treated at a single center and diagnosed between 1984 and 2010. SNPs were selected based on reported associations with bladder cancer and BCG response, and genotyped using the Sequenom MassARRAY iPLEX system. No response to BCG was defined as the presence at 6 months of pathologically documented tumor in the bladder. Univariate logistic regression was used to test the association between the outcome of interest (no response to BCG at 6 months) and clinical variables (stage, grade and multifocality), or individual SNPs.

Results: The cohort consisted of 158 pts with a median age of 65 years who received intravesical BCG for NMIBC (35.2% stage T1, 32.7% stage Ta and 31.4% stage Tis) with 93% having high-grade disease. At 6 months follow up, 22 (13.9%) patients showed no response to BCG. We successfully genotyped 80 of the 88 selected SNPs. Of these, 2 SNPs were associated with lack of response to BCG; rs798766 is an intronic SNP in TACC3 (OR for no response is 2.4 for each T allele relative to CC genotype, P=0.01), and rs1994251 an intronic SNP in BCL2L1 (OR for no response is 3.2 for each C allele relative to AA, p= 0.0008). Both SNPs remained significantly associated with lack of response after adjusting for predictive clinical variables.

Conclusions: Single nucleotide polymorphisms of BCL2L1 and TACC3 may be predictive of BCG refractory bladder cancer. Future validation studies on independent datasets are needed to determine the clinical utility of these findings.
The influence of variant histology on survival outcomes of radical cystectomy for bladder cancer.
Authors: Fairey Adrian Stuart , Skinner Eila C. , Schuckman Anne , Leiskovsky Gary , Cai Jie , Miranda Gus , Daneshmand Siamak
Published: February 2017

278

Background: The role of variant histology bladder cancer as an independent prognostic factor for survival after radical cystectomy is poorly defined. Our aim was to examine the impact of variant histology on survival.

Methods: A retrospective analysis of prospectively collected data from the University of Southern California Bladder Cancer Database was performed. Between 1971 and 2008, 2098 patients underwent radical cystectomy and extended pelvic lymph node dissection for primary bladder cancer. All surgical specimens underwent centralized pathologic review by dedicated genitourinary pathologists. Histologic type was categorized according to the WHO/ISUP 1998 classification as urothelial carcinoma (UC; n=1595), UC + variant (n=380), or non-urothelial carcinoma (Non-UC; n=123). The outcomes were overall survival (OS) and recurrence-free survival (RFS). The Kaplan-Meier method and Cox proportional regression models were used to analyze survival data.

Results: The median follow-up duration was 12.8 years (range, 0 to 36.6 years). The predicted 5-year OS (61%, 53%, and 47%, Log rank p=0.005) and RFS (68%, 59%, and 58%, Log rank p=0.001) rates differed between patients with UC, UC + variant, and Non-UC histology. Multivariable analysis showed that Non-UC (but not UC + variant) histology was independently associated with OS (Non-UC versus UC: HR 1.26, 95% CI 1.01 to 1.57, p=0.040; UC + variant versus UC: HR 0.97, 95% CI 0.85 to 1.12, p=0.697) but not RFS (Non-UC versus UC: HR 1.14, 95% CI 0.83 to 1.56, p=0.411; UC + variant versus UC: HR 1.06, 95% CI 0.88 to 1.28, p=0.551).

Conclusions: Non-UC histology was independently associated with poorer OS after radical cystectomy for bladder cancer. Clinical trials are needed to determine whether this high risk group will benefit from multimodal therapy.
Multi-institutional review of sequential intravesical gemcitabine and mitomycin C chemotherapy for non-muscle-invasive bladder cancer.
Authors: Lightfoot Andrew J. , Breyer Benjamin N. , Rosevear Henry M. , Konety Badrinath , O'Donnell Michael A.
Published: February 2017

294

Background: Combination chemotherapy is the standard of care for neoadjuvant, adjuvant, and metastatic bladder cancer due to increased efficacy when compared to monotherapy. We report our experience with sequential intravesical combination chemotherapy using gemcitabine and mitomycin C (MMC) for non-muscle invasive bladder cancer (NMIBC).

Methods: We performed a multi-institutional retrospective review of 47 consecutive patients who received 6 weekly treatments with sequential gemcitabine (1g) and mitomycin C (40mg) chemotherapy for NMIBC. Thirty patients received treatment at University of Iowa, 14 at UCSF and 3 at University of Minnesota.

Results: A total 47 patients (median age 70, range 32-85; 36 males, 11 females) previously failing a median of 2 intravesical treatments were reviewed. The complete response (CR), 1-year recurrence-free survival (1-RFS) and 2-year recurrence-free survival (2-RFS) for all patients was 68%, 48% and 38%, respectively. In all, 14 of 47 patients (30%) remain free of recurrence with a median time to followup of 26 months (range 6-80 months). The median time to recurrence for all patients who recurred was 4 months (range 1-33 months). Ten patients required cystectomy.

Conclusions: Sequential intravesical combination chemotherapy using gemcitabine and MMC appears to be a useful treatment for patients with a history of NMIC which has failed BCG or other intravesical therapy, in addition to patients with intermediate and high-risk disease.
Survival trends among patients with metastatic bladder cancer in the United States.
Authors: Shah Binay Kumar , Mandal Rakesh
Published: February 2017

306

Background: The chemotherapy regimens for metastatic bladder cancer (MBC) have evolved over the last two decades. Due to favorable toxicity profile, a combination of cisplatin and gemcitabine is widely used for the treatment of MBC since 2000. It is unclear if the survival trend in MBC has changed over last two decades. This study was conducted to evaluate the relative survival rates for patients with MBC in the United States during 1991-1999 and 2000-2008.

Methods: We used the Surveillance, Epidemiology, and End Results (SEER*Stat) program to analyze 6-month and 12-month relative survival rates of AJCC stage-IV bladder cancer patients included in the SEER database. We used Z-test in the SEER*Stat program to compare relative survival rates among cohorts of patients categorized by race, gender, and age groups (<60 and ≥60 years).

Results: The dataset comprised 9,819 and 986 patients with AJCC stage-IV bladder cancer among Caucasians and African Americans (AA), respectively. Among Caucasian men (<60 years), 6-month survival rates were 85.4±1.7% (n=442) and 77.9±1.3% (n=1,117) for 1991-1999 and 2000-2008, respectively. Similarly, 12-month survival rates in this group were 68.6±2.2% (n=442) and 60.4±1.5% (n=1,117) for 1991-1999 and 2000-2008, respectively. Thus, both 6-month and 12-month survival rates in 2000-2008 were lower among young Caucasians; and the differences were statistically significant when compared to 1991-1999 (6-month: Z-value = -3.205, p=0.001; 12-month: Z-value= -2.984, p=0.003). The survival rates among AA were not statistically significant.

Conclusions: In young Caucasian patients (<60 years) with MBC, 6- month and 12-month relative survival rates were lower for the period 2000-2008 compared to 1991-1999. Further studies may be required to evaluate factors responsible for decreased survival rates among this population.
Empiric antibiotics for an elevated PSA: A randomized, prospective multi-institutional trial.
Authors: Large Michael Christopher , Gerber Glenn Scott , Pettus Joseph Atkins , Smith John , Yossepowitch Ofer , Smith Norm D. , Kundu Shilajit , Raman Jay D. , Eggener Scott E.
Published: February 2017

32

Background: The impact of an empiric course of antibiotics for a newly elevated PSA in an asymptomatic male is poorly understood.

Methods: Men of any age with a PSA > 2.5 ng/ml and normal digital rectal examination undergoing their first prostate biopsy were recruited from six medical centers. Patients with previous biopsy, prostate cancer, urinary tract infection (UTI) or prostatitis within the prior year, antibiotic use within one month, 5−alpha reductase inhibitor use, allergy to fluoroquinolones or clinical suspicion of UTI were excluded. Men were randomized to two weeks of ciprofloxacin 500 mg twice daily or no antibiotic. A PSA was obtained 21−45 days following randomization and immediately prior to prostate biopsy. All patients received institution−specific prophylactic peri−procedural antibiotics. Primary endpoint was change in PSA between baseline and on the day of biopsy. The trial was closed early following an interim analysis and decision rule for futility and early stopping.

Results: Complete data was available on 77 men with a mean age of 60.6 (IQR: 53.8 – 66.7). In the control group (no antibiotic; n=39), mean baseline and pre−biopsy PSA were 6.5 and 6.9 ng/ml, respectively (p=0.8). In men receiving antibiotic (n=38), mean baseline and pre−biopsy (post−antibiotic) PSA were 7.6 and 8.5 ng/ml, respectively (p=0.7). Prostate cancer was detected in 36 (47%) men. Detection rates did not significantly differ between individuals with an increasing PSA or decreasing PSA between the two measurements.

Conclusions: Empiric use of antibiotics for an elevated PSA in an asymptomatic patient is not of clinical benefit.
Impact of renal impairment and granulocyte colony stimulating factor (GCSF) on bleomycin-induced pneumonitis (bleo lung), febrile neutropenia (FN), and survival in patients (pts) with germ cell tumor (GCT) treated with chemotherapy (chemo).
Authors: Tran Ben , Moore Malcolm J. , Amir Eitan , Jewett Michael A , Anson-Cartwright Lynn , Sturgeon Jeremy F. G. , Chung Peter W. M. , Warde Padraig Richard , Bedard Philippe
Published: February 2017

328

Background: Use of GCSF and the development of renal impairment in GCT pts receiving chemo are common, but their effect on toxicity and survival is unclear. This study examines the impact of GCSF and renal impairment on bleo lung, FN and survival, in GCT pts receiving 1st line chemo.

Methods: Clinical data from our institutional GCT database was complemented by review of radiology, pharmacy and medical records. All GCT pts receiving 1st line chemo between 1-Jan-00 and 31-Dec-10 were included. Pts receiving at least one GCSF dose were identified. Renal impairment during chemo was defined as any serum creatinine above the institutional upper limit of normal. Bleo lung was graded (G1-5) using CTCAE criteria. FN was defined as temperature ≥38C and neutrophil count <1.0.

Results: The cohort consisted of 260 GCT pts, median age 31.5 years, 171 (66%) had IGCCCG good risk disease, 42 (16%) intermediate, and 41 (16%) poor, while 6 (2%) received adjuvant chemo. 159 (61%) received GCSF and 49 (19%) developed renal impairment. 212 (82%) received BEP of which 73 (34%) developed bleo lung (56 pts G1 asymptomatic, 13 pts G2, 4 pts ≥G3). Renal impairment was associated with bleo lung in univariate (OR 2.87, p=0.008) and multivariate (OR 2.69, p=0.01) analyses. GCSF was associated with increasing severity of bleo lung (OR 1.86, p=0.045) but this was not significant in a multivariate analysis (OR 1.72, p=0.08). FN occurred in 33 (13%) of 260 pts. Renal impairment (OR 3.91, p=0.001) was associated with FN. Primary GCSF prophylaxis reduced FN (OR 0.26, p=0.001), however, 8 (7%) of 112 patients developed FN in spite of GCSF prophylaxis. Survival analyses demonstrated GCSF and renal impairment did not impact progression free or overall survival (OS), however, bleo lung was associated with poorer OS in a multivariable Cox proportional hazards analysis (HR 2.85, p=0.029).

Conclusions: Our findings demonstrate both renal impairment and GCSF are risk factors for bleo lung, while renal impairment itself is also a risk factor for FN. Additionally, we identify bleo lung as a significant poor prognostic factor for OS.
Seminoma and sarcoid: A confusing collision.
Authors: Brady Claire , Bambury Richard Martin , Teo MinYuen , El-Gammal Alamani , McCarthy Julie , O'Driscoll Martin , Kennedy Marcus , O'Connor Terry , O'Reilly Seamus , Power Derek Gerard
Published: February 2017

339

Background: In patients with active or prior malignancy, the presence of mediastinal lymphadenopathy is often assumed to indicate metastases. However, sarcoidosis can imitate malignancy on CT and PET imaging. The incidence of sarcoidosis or “sarcoid-like reaction” in cancer patients (especially testicular germ cell tumor patients) appears to be higher than in the general population.

Methods: We report a series of 4 testicular cancer patients with mediastinal adenopathy mimicking metastatic disease. Subsequent investigations and follow-up revealed sarcoid-like reaction without active malignancy.

Results: A 25 year old man presented with a neck swelling and was found to have left cervical adenopathy, mediastinal adenopathy and a right testicular mass. Biopsy of the cervical nodes revealed a mixed seminoma and non-seminomatous germ cell tumour. After 4 cycles of chemotherapy PET/CT revealed persistent hypermetabolic mediastinal adenopathy. Transbronchial needle aspirate (TBNA) revealed non-caseating granulomas (NCGs). After right orchiectomy and retroperitoneal lymph node dissection he remains in complete remission. A 26 year old man presented with scrotal swelling and investigations revealed bilateral testicular seminoma. CT revealed mediastinal adenopathy. TBNA revealed NCGs and he remains disease free after orchiectomy. A 42 year old man presented with right sided scrotal swelling. CT revealed mediastinal adenopathy. TBNA revealed NCGs. He was treated successfully with orchiectomy and chemotherapy for stage 1 seminoma. A 20 yr old man had mediastinal adenopathy on a surveillance CT 5 years after high dose chemotherapy and stem cell transplant for platinum-refractory seminoma. TBNA revealed NCGs and the adenopathy resolved with oral prednisone therapy.

Conclusions: Sarcoid-like reaction in cancer patients may be due to an immunologic hypersensitivity to tumor-associated antigens. Although the precise pathogenesis is unknown, the clinical relevance of this phenomenon is clear. There is a need for histologic confirmation of suspected metastatic mediastinal adenopathy in patients with testicular cancer. We are collecting more cases in other malignancies and will present an update.
ABO blood group and risk of renal cell cancer.
Authors: Cho Eunyoung , Joh Hee-Kyung , Choueiri Toni K.
Published: February 2017

371

Background: The genetic determinants of sporadic renal cell cancer (RCC) are largely unknown. Previous studies have suggested associations between the ABO blood group and risk of various cancers, however, its relationship to RCC remains unclear.

Methods: We prospectively evaluated the association between the ABO blood group and risk of RCC in two large independent cohorts of women (the Nurses’ Health Study) and men (the Health Professionals Follow-up Study) from 1996 to 2008. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models with adjustment for other risk factors for RCC including obesity, smoking, and hypertension. All statistical tests were two-sided.

Results: During 12 years of follow-up of 77 242 women and 29 548 men, 163 cases of incident RCC were documented in women and 84 cases in men. After multivariate adjustment, non-O blood group (combined group of A, AB, and B) was associated with a 1.5-fold elevated risk of RCC (95% CI 1.09–2.09) than O blood group in women. In contrast, no significant associations were observed between the ABO blood group and risk of RCC in men. The associations between the ABO blood group and RCC were consistent across strata of known risk factors including obesity, smoking status, and history of hypertension (Pinteraction≥ 0.58) in both cohorts.

Conclusions: We show for the first time that non-O blood group is significantly associated with a higher risk of RCC compared with blood group O in women. Further studies that elucidate the biological mechanisms underlying this association are warranted.
Tumor suppressor effects for miR-215 identified through use of miRNA profiling in metastatic renal cell carcinoma.
Authors: Bjarnason Georg A. , White Nicole MA , Khella Heba WZ , Grigull Joerg , Adzovic Sonja , Youssef Youssef M. , Honey R. John , Stewart Robert , Pace Kenneth T , Jewett Michael A , Evans Andrew , Gabril Manal , Yousef George M.
Published: February 2017

392

Background: Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney. Metastatic RCC is difficult to treat. The five-year survival rate for metastatic RCC is <10%. Recently, microRNAs (miRNAs) have been shown to have a role in cancer metastasis and potential as prognostic biomarkers in cancer.

Methods: We preformed a miRNA microarray to identify a miRNA signature characteristic of metastatic compared to primary RCC. Results were validated by quantitative real time PCR. Target prediction analysis and gene expression profiling identified many of the dysregulated miRNAs could target genes involved in tumor metastasis. The effect of miR-215 on cellular migration and invasion was shown in a RCC cell line model.

Results: We identified 65 miRNAs that were significantly altered in metastatic when compared to primary RCC. Nine (14%) miRNAs had increased expression while 56 (86%) miRNAs showed decreased expression. miR-10b, miR-196a, and miR-27b were the most downregulated while miR-638, miR-1915, and miR-149* were the most upregulated. A non-supervised 2D-cluster analysis showed that a sub-group of the primary tumors clustered under the metastatic arm with a group of miRNAs that follow the same pattern of expression suggesting they have an inherited aggressive signature. We validated our results by examining the expressions of miR-10b, miR-126, miR-196a, miR-204, and miR-215, in two independent cohorts of patients. We also showed that overexpression of miR-215 decreased cellular migration and invasion in a RCC cell line model. In addition, through gene expression profiling, we identified direct and indirect targets of miR-215 that can contribute to tumor metastasis.

Conclusions: Our analysis showed that miRNAs are altered in metastatic RCC and can contribute to kidney cancer metastasis through different biological processes. Dysregulated miRNAs represent potential prognostic biomarkers and may have therapeutic applications in kidney cancer.
Long-term toxicity and associated cost of initial treatment and subsequent toxicity-related intervention for patients treated with prostatectomy, external beam radiotherapy, or brachytherapy: A SEER/Medicare database study.
Authors: Ciezki Jay P. , Reddy Chandana A. , Angermeier Kenneth , Ulchaker James , Stephans Kevin L. , Tendulkar Rahul D. , Altman Andrew , Chehade Nabil , Klein Eric A.
Published: February 2017

4

Background: Treatment-related toxicity for prostate cancer (CaP) is rarely reported more than 5 years after therapy. We examined the SEER-Medicare linked database with the potential of having 16 years of follow-up data on toxicity requiring procedural intervention.

Methods: The SEER-Medicare database was queried for CaP patients treated with prostatectomy (RP), external beam radiotherapy (EBRT), or brachytherapy (PI) between 1991-2007. We identified procedural billing codes associated with toxicity-related treatments. We obtained information on the Medicare reimbursement rates for the initial treatment and any toxicity-related interventions. We then computed the cost per patient-year within each treatment modality over time.

Results: A total of 137,427 patients who were 65 years or older at the time of CaP diagnosis and who had CaP as their only cancer diagnosis were retrieved from the SEER/Medicare database: 59,559 (43.3%) treated with RP, 60,806 (44.2%) treated with EBRT, and 17,062 (12.4%) treated with PI. No patient received combined therapy. The median follow-up is 71 months. Overall, 10,585 (7.3%) patients experienced a toxicity requiring intervention. Within treatment modalities, the percentages receiving toxicity-related intervention were: RP 6.9%, EBRT 8.8%, and PI 3.7%. The gastrointestinal (GI) and genitourinary (GU) toxicity comparisons are listed in the table. Dilation of a urethral stricture was the most common GU toxicity (3.6% of all patients) while cauterization of rectal bleeding was the most common GI toxicity (0.8% of all patients).

Conclusions: The long-term toxicity and cost per patient-year of the major prostate cancer treatment modalities differ. EBRT is the most toxic and most costly.

[Table: see text]
Reassessment of a proposed molecular classification system for clear cell renal cell cancer (ccRCC): Results from a randomized phase II trial of pazopanib.
Authors: Mims Martha P. , Gagnon Robert C. , Liu Yuan , Heath Elisabeth I. , Lara Primo
Published: February 2017

404

Background: Understanding the molecular basis of ccRCC heterogeneity could optimize the use of targeted therapies. Using consensus clustering and logical analysis of data (LAD) of gene expression data (Agilent), Brannon et al (Genes Cancer 2010) identified two distinct subtypes of ccRCC [ccA & ccB] defined by a predictive gene set. Patients (pts) with ccA tumors had better disease-specific survival vs. ccB (8.6 vs 2.0 years, P = 0.002). We evaluated these results in an independent dataset.

Methods: Gene expression analysis of archival FFPE samples obtained from pts in a randomized phase II trial of pazopanib in ccRCC (Hutson, JCO 2009) were done using Affy U133 plus chips. Corresponding probe sets from the Agilent and Affy platform were identified using Unigene ID’s (DAVID alignment tool). LAD was applied; pts were stratified into ccA/ccB. Kaplan-Meier analysis was used to compare progression-free survival (PFS) for pts stratified by ccA/ccB.

Results: RNA was available for 46 pts. Of 110 genes, 108 were mapped to the Affy platform (probe closest to 3` was used). The 108 Affy genes were assessed for signal (present/absent calls) across the 46 samples. 74/108 genes were present in at least 20% (9/46) of pts, 96/108 genes were present in at least 1/46, and 12/108 were not present (0/46). No obvious patterns of expression were evident from heat maps of the 74 or 96 genes. LAD scoring was problematic due to loss of information imposed by using genes present. Of the total LAD patterns in the Brannon paper, 59% or 78% were available using 74 or 96 genes present. PFS based on ccA/ccB were not statistically distinct using either set of present genes.

Conclusions: FFPE samples are routinely available from pts with ccRCC and could be used for gene expression studies which could inform clinical practice. Using the Affy platform and FFPE-RNA samples, stratification of ccRCC pts into ccA/ccB subtypes did not reveal PFS differences. While the analysis was confounded by differences in cross-study platform performance, results suggest that further investigation will be necessary to identify a robust set of genes that separates ccRCC into prognostic categories.
Epigenetic inactivation of HOXA5 and MSH2 gene in clear cell renal cell carcinoma.
Authors: Choi Seung-Kwon , Lee Joong Geun , Yoo Koo Han
Published: February 2017

424

Background: The high-throughput method using microarray is easy and fast way to analyze the methylation status of hundreds of preselected genes and to screen them for signatures in methylation. The aim of our study is to detect hypermethylated genes and to analyze the association between methylation status and clinicopathological parameters of clear cell renal cell carcinoma.

Methods: The genetic substrate included 62 cancer tissues and 62 matched adjacent normal kidney tissues. We adapted the GoldenGate genotyping assay to determine the methylation state of 1505 specific CpG sites in 807 genes.

Results: We identified two genes (HOXA5 and MSH2) with β-value differences of more than 0.3 between cancer and normal tissues. High methylation group in HOXA5 had high Fuhrman’s nuclear grade (P=0.041). Other data in HOXA5 and MSH2 were not significant with methylation status (P>0.05). Survival curve of high methylation group in HOXA5 was slightly lower than that of low methylation group. However, the statistical significances of overall survival in HOXA5 and MSH2 were low (P>0.05).

Conclusions: We report the hypermethylation of two genes in clear cell renal cell carcinoma. The data we obtained could provide the basis for a diagnostic test pathological assessment, or prognosis in clear cell renal cell carcinoma.
Therapies and outcomes of non-renal cell carcinoma (non-RCC) neoplasms of the kidney: A single-institution experience.
Authors: Matrana Marc Ryan , Rao Priya , Atkinson Bradley J. , Guo Charles , Tannir Nizar M.
Published: February 2017

431

Background: Non-RCC neoplasms of the kidney include neuroendocrine tumors (small cell carcinoma and carcinoid) and Primitive Neuroectodermal Tumors (PNET). Small cell carcinoma and renal carcinoids are small blue cell tumors that rarely occur as primary renal neoplasms. PNET, known as extraskeletal Ewing sarcoma, is characterized by t(11;22), the gold standard for diagnosis. It is a small round cell tumor derived from the neural crest and treated with chemotherapy; the role of nephrectomy is unclear.

Methods: We reviewed records of patients seen at MDACC between 01/01/2001 and 01/01/2011 for PNET, small cell carcinomas, and carcinoid tumors of the kidney. Overall survival (OS) was determined from diagnosis to death.

Results: 21 pts met inclusion criteria. Disease-specific data is shown in the table. Common treatments included: carboplatin/etoposide for small cell carcinomas; vincristine/doxorubicin/ifosfamide, vincristine/doxorubicin/cyclophosphamide, and doxorubicin/ifosfamide alternating with cisplatin/etoposide for PNET. Irinotecan was a common salvage agent in PNET. Most carcinoid tumors were treated with surgery alone. Two patients with small cell received whole brain radiation for brain metastases.

Conclusions: Carcinoid tumors of the kidney had better outcomes compared to renal small cell carcinomas or PNET. Local carcinoid tumors of the kidney were generally managed with surgery alone. Renal small cell carcinomas and PNET were treated with systemic therapies.

[Table: see text]
Impact of pretreatment C-reactive protein on overall survival for patients with metastatic renal cell carcinoma treated with sunitinib.
Authors: Yasuda Yosuke , Saito Kazutaka , Sukegawa Gen , Tanaka Hajime , Ito Masaya , Kitsukawa Shinichi , Yuasa Takeshi , Urakami Shinji , Yamamoto Shinya , Takahashi Shunji , Fukui Iwao , Yonese Junji
Published: February 2017

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Background: C-reactive protein (CRP) has been shown to be a significant prognostic factor for metastatic renal cell carcinoma (mRCC) in cytokine era. We further evaluated the prognostic impact of CRP for mRCC treated with sunitinib.

Methods: Consecutive 37 patients were treated with sunitinib for mRCC from April 2008 to January 2011 at our institution. Seven patients were excluded because they received prior other tyrosine kinase inhibitors, sorafenib. Among eligible 30 patients, 9 patients (30%) had prior immunotherapy and 16 patients (55.5%) had prior nephrectomy. All clinical charts of the patients were reviewed for variables. Overall survival were estimated using the Kaplan-Meier method. Variables including hemoglobin, albumin, calcium, lactate dehydrogenase (LDH), thrombocytosis, number of the metastatic sites, ECOG performance status (PS), prior immunotherapy, prior nephrectomy, and pretreatment CRP concentration were evaluated. The cut-off point of pretreatment CRP concentration was set at 8mg/l. Multivariate analysis was carried out by Cox proportional hazard model. For all analysis the difference was considered significant when p < 0.05.

Results: Median follow up period was 9 months (range; 1 to 25 months). The 1-year overall and progression free survival rates for the entire cohort were 68.9% and 45.8%. During follow up, 6 patients (20 %) died of disease. In univariate analysis, pretreatment CRP was a significant factor for overall survival as well as thrombocytosis. Multivariate analysis showed pretreatment CRP was solely an independent prognostic factor for overall survival. The elevations of pretreatment CRP concentrations were found in 14 patients (46.7%). The median overall survival length of patients with nonelevated CRP concentrationswas not reached compared with that of patients with elevated CRP concentration of 9.9 months. The 1-year overall survival rates of the patients with preoperative CRP elevation (35.7%) were significantly worse than those of patients without CRP elevation (91.7%) (p = 0.012).

Conclusions: CRP had also prognostic impact on overall survival for patients with mRCC treated with sunitinib.
Phase I trial of the HDAC inhibitor LBH589 in combination with sorafenib in patients with renal cell carcinoma, non-small cell lung cancer and soft tissue sarcomas.
Authors: Butler Charles Mackie , Laboccetta Lydia T. , Brisendine Alan , Keane Thomas E. , Sherman Carol Arthur , Drabkin Harry A.
Published: February 2017

440

Background: LBH589 is a novel histone deacetylase inhibitor (HDACi) that induces apoptosis of tumor cells. In renal cell carcinoma (RCC) and non-small-cell lung cancer (NSCLC) cell lines, the combination of sorafenib and HDACi was found to have synergistic inhibition, which correlated with the induction of an ER stress response. In this phase I study, we evaluated the combination of LBH589 and sorafenib in previously treated patients with RCC (9pts), soft tissue sarcomas (1pt), and NSCLC (6pts). The trial was designed to determine the safety profile and maximum tolerated dose of LBH589 and sorafenib when administered concurrently.

Methods: Patients were dosed with either i.v. or oral LBH 589 (three times per week, continuously) every twenty eight days in combination with standard daily dose sorafenib (400 mg bid). The dose escalation was based on a “3+3” algorithmic design. LBH was initially administered at an i.v. dose of 5 mg/m2 with escalation to 10 mg/m2. Due to the manufacturer’s phase-out of the i.v. formulation, this was then changed to an oral formulation administered three times a week (doses 15 mg, 20 mg, and 25 mg).

Results: Sixteen patients, median age 57 years, have been treated. Dose limiting toxicities were observed with grade 4 thrombocytopenia in two patients at the oral dose of 25 mg. There were no other grade 4 events. Grade 3 events included fatigue (2 pts), hypophosphatemia (2 pts), hypertension (1 pts), anemia (1 pt), rash (1 pt) and hand-foot erythroderma (1 pt). Common toxicities for the combination were fatigue (81%), weight loss (62%), loss of appetite (56%), diarrhea (56%), rash (50%), thrombocytopenia (31%), and hand-foot erythroderma (25%). No patients had significant QT prolongation. There was 1 partial response in a patient with lung cancer (31 weeks). Stable disease was noted in seven patients with RCC (78+, 48, 47, 31, 21, 17, and 10+ weeks). Seven patients had progressive disease

Conclusions: The administration of oral LBH589 at a dose of 20 mg was found to be well tolerated and will be used in the expansion phase of the trial. Prolonged stable disease was observed in patients previously treated with sorafenib alone, sunitinib and axitinib.
What is the benfit of mTOR inhibitors (mTORi) rechallenge in metastatic renal clear cell carcinoma (mRCC) patients (pts) initially treated with TKI?
Authors: Maj-HES Agnes , Elaidi Reza-Thierry , Medioni Jacques , Scotte Florian , Kramer Gero , Hoeltl Wolfgang , Gachet Julie , Teghom Corine , Gornadha Yohan , Oudard Stephane
Published: February 2017

442

Background: question regarding the benefit of a mTORi re-challenge for pts treated with a previous line of TKI and 1 line of mTORi remains unanswered in mRCC.

Methods: this study retrospectively investigated Treatment Duration (TD), best overall response (OR) in pts treated with TKI and mTORi in a sequence temsirolimus-everolimus (T-E) or everolimus-temsirolimus (E-T). Eligibility criteria: TKIs prior to either sequence of mTORi. Pts characteristics and prognostic factors (Heng’s score) were considered prior to TKI and 1st mTORi. Response was defined with respect to TD and best OR: E: Non Responders (NR): < 4.9 months (m) + progressive disease (PD), Responders (R): >4.9m + SD/PR; T: Non Responders (NR): < 3.6 months (m) + PD; Responders (R): >3.6 m + SD/PR.

Results: 12 pts were eligible. 5 and 7 pts received 1 and 2 TKIs prior to 1st mTOR, respectively. 9 and 3 pts were in the intermediate and poor risk group respectively prior 1st mTORi (Heng’s score). 7 pts received E and 5 pts received T as first mTORi. Whatever the sequence, 7 pts out of 12 were responders to E and 2 out of 12 were responders to T (3 pts did not respond to any mTORi). In the E-T sequence, 5 pts were responders to E with no response to T, 1 pt no responder to E but responder to T (1 pt didn’t respond to both mTORi). In the T-E sequence, 2 pts were responders to E, 1 pt was responder to T and 2 pts didn’t response to both mTORi. Median TD for E-T and T-E sequences was 10.3m (95%CI: 8.8-19.2) and 5.8m (95%CI: 2.9-19.3), respectively. Response was not related to pt’s prognosis group.

Conclusions: despite the small effective of this study, results suggest that responders to everolimus as 1st mTORi could not benefit from a re-challenge with temsirolimus. Pts who were not responders to temsirolimus could still be responders to everolimus. This observation should be confirmed with larger databases and prospective studies.

[Table: see text]
A hypothesis-generating exploratory analysis of efficacy and safety of abiraterone acetate (AA) in African American (Af Am) patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Efstathiou Eleni , Assikis Vasily J. , North Scott A. , Showel John , Hutson Thomas E. , Riggs Stephen Boyd , Waxman Jonathan , Park Youn Choi , Kheoh Thian San , Haqq Christopher M. , Logothetis Christopher , Molina Arturo
Published: February 2017

55

Background: The reported increased prostate cancer lethality in Af Ams has been attributed by some to altered androgen receptor (AR) signaling. We compared toxicity, PSA response, time-to-PSA progression (TTPP), and radiographic progression-free survival (rPFS) in Af Am vs non Af Am pts with CRPC treated with AA + prednisone (P) vs placebo + P. We hypothesized that differences in response to AA may be observed if differences in AR signaling exist in Af Ams.

Methods: COU-AA-301 is a randomized double blind study of AA (1000 mg + P 5 mg po BID) vs placebo + P post-docetaxel.

Results: TTPP, rPFS, and PSA response rate were higher with AA vs placebo. In Af Am pts, treatment emergent AEs (TEAEs) for AA vs placebo occurred in 96.4% vs 100.0% of pts (50.0% and 66.7%, respectively, grade 3/4); serious TEAEs occurred in 42.9% and 33.3% of pts (28.6% and 26.7%, respectively, grade 3/4). The safety profile of AA appears comparable between the Af Am and overall study populations.

Conclusions: Although the small number of Af Am pts in this study precludes formal conclusions regarding efficacy and safety of AA in this pt population, the overall trend suggests these pts experienced clinical benefit from AA with a safety profile comparable to the overall study population. These findings do not appear to support the hypothesis that AR signaling accounts for the increased lethality of prostate cancer seen in Af Ams. Further studies of AA in Af Am pts are planned to understand the potential benefit in this population. Additional efforts are needed to increase participation of Af Am pts in clinical trials.

[Table: see text]
Impact of marital status on prostate cancer-specific mortality and overall mortality after radical prostatectomy.
Authors: Nepple Kenneth Gerard , Kibel Adam Stuart , Sandhu Gurdarshan S , Kallogjeri Dorina , Strope Seth A. , Grubb Robert L. , Wolin Kathleen Y. , Sutcliffe Siobhan
Published: February 2017

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Background: Analysis from population-based cancer registry data has suggested that being married is associated with improved survival in men with prostate cancer. However, a limitation of such analysis is the inability to control for PSA or medical comorbidity which may differ by marital status. We investigated the association between marital status and both prostate cancer specific mortality (PCSM) and overall mortality (OM) in men treated with radical prostatectomy.

Methods: The study population included 3596 men treated with radical prostatectomy at a single institution between 1994 and 2004 and followed for a median of 72 months. Disease specific factors (PSA, clinical stage, and biopsy Gleason grade), comorbidity (validated ACE-27 comorbidity index), ethnicity, age, and marital status at time of treatment were retrieved from an institutional cancer registry. Differences between marital status groups were evaluated by Chi square or ANOVA. Multivariable Cox proportional hazard regression models were used to estimate the hazard ratio (HR) of PCSM and OM by marital status.

Results: 86.9% of men were married, 5.3% divorced, 2.4% widowed, and 5.5% never married. Marital status was associated with differences in PSA (p<0.01), comorbidity (p=0.04), and age (p<0.01). Married men had the lowest mean PSA at diagnosis and never married men were younger and the most likely to have no known medical comorbidity. A total of 386(11%) men were dead at the end of follow up, but only 55 of them died of prostate cancer. In multivariable analyses (Table), never married men had a significantly increased risk of PCSM and OM compared to married men, whereas no additional risk was observed for divorced or widowed men.

Conclusions: Never married men had an increased risk of PCSM and OM. Factors associated with social isolation or unhealthy behaviors may have a detrimental effect on survival after prostatectomy.

[Table: see text]
Insomnia among elderly men and risk of prostate cancer.
Authors: Sigurdardottir Lara , Valdimarsdottir Unnur Anna , Mucci Lorelei , Fall Katja , Rider Jennifer R. , Schernhammer Eva S. , Czeisler Charles A , Launer Lenore , Harris Tamara B. , Stampfer Meir J. , Gudnason Vilmundur , Lockley Steven W.
Published: February 2017

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Background: While a large number of studies have reported a positive association between sleep disruption and breast cancer, little is known about its potential role in prostate cancer.

Methods: Within the prospective AGES-Reykjavik cohort study, we followed 2102 men from 2002-2006 until the end of 2009. The men answered questions on sleep disturbances, which were combined in various ways to reflect onset and/or maintenance insomnia. Information on the occurrence of prostate cancer was obtained through record-linkages across the Icelandic Cancer and Causes of Death Registers. We used Cox regression models with 95% confidence intervals [CIs] to estimate age- and multivariable adjusted hazard ratios [HR] of prostate cancer by symptoms of insomnia.

Results: During follow-up, 135 men (6,4%) were diagnosed with prostate cancer. Compared to men without insomnia, men with severe onset and maintenance insomnia and very severe insomnia were at increased risk of total prostate cancer with HR 1.9 (CI 1.2, 3.0) and 2.2 (CI 1.3, 3.8), respectively. For advanced prostate cancer, the corresponding HRs were 2.3 (CI 0.9-6.2) and 3.7 (CI 1.4-9.9), respectively.

Conclusions: These data suggest that insomnia may confer an increased risk of prostate cancer. Reduced melatonin levels represent a plausible biological explanation, although additional studies using biomarkers and longer follow-up times are needed to further clarify the underlying mechanisms.