bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive profiling of renal medullary and collecting duct carcinomas.
Authors: Ho Thai Huu , Swensen Jeffrey , Ghazalpour Anatole , Hes Ondrej , Stanton Melissa L. , Joshi Monika , Sanati Souzan , Purnanada Priyanka , Arguello David , Reddy Sandeep K. , Gatalica Zoran
Published: February 2017

572

Background: Renal medullary carcinoma (RMC) is an aggressive malignancy affecting predominantly young African Americans with sickle cell trait (SCT) or disease (SCD), while a pathologically similar collecting duct carcinoma (CDC) affects patients without sickle cell trait. Clinical responses to chemotherapy and IL-2 in RMC/CDC are poor and novel therapies are needed. Methods: 9 patients with RMC (ages 13-58 y. o., all male) and 15 patients (ages 26-74 y. o., M:F = 13:2) with collecting duct carcinoma (CDC) were studied. Expression of PD-L1 was evaluated with 2 monoclonal antibodies (SP142 and SP263) and tumor infiltrating lymphocytes (TIL) were evaluated for PD1 expression (MRQ-22 antibody) using immunohistochemistry (IHC). Additional studies included ALK protein expression (D5F3 antibody), gene translocation (break apart FISH), next generation sequencing (NGS), and microsatellite instability (MSI). Results: Cancer cell PD-L1 expression above the threshold ( ≥ 2+, ≥ 5%) was seen in 7/9 RMC and 5/13 CDC cases. Concordance between 2 PD-L1 antibodies was 94.4%. PD-1+ TIL were absent in 6/18 cases and variably present in 12/18 cases (from 1 to > 15 TIL/40x power field). No MSI was detected in any of the cases tested (0/6). No case expressed ALK protein, but one case of CDC showed ALK gene re-arrangement. Mutations were identified in SMARCB1, FH, TP53 (3x), ATM, BRCA2, CHEK2 (2x), NF2 (3x), SETD2, and CDKN2A. No mutations in VHL or KDR were detected. One patient with RMC (and SCT) achieved complete clinical remission after treatment with bevacizumab plus paclitaxel. Conclusions: RMC and CDC strongly express PD-L1 in the majority of cases (12/22), suggesting that these patients may benefit from targeting the PD-L1/PD1 interaction. The absence of MSI in these cancers indicates a different mechanism of PD-L1 upregulation from colorectal carcinomas. Consistent with our previous study that showed frequent activation of (pseudo)hypoxia-induced pathways in RMCs (Human Pathology 2011;42:1979), we describe a case of RMC successfully treated with anti-VEGF therapy.
Pazopanib for treatment of metastatic renal cell carcinoma with non-clear cell histology: Single-arm, open label, multicenter, phase II study.
Authors: Jung Ki Sun , Cho Jinhyun , Yoo Kwai Han , Park Se Hoon , Lee Jae-Lyun , Lee Se-Hoon , Lim Jae Yun , Kang Jung Hun , Lee Suee , Rha Sun Young , Lee Kyung Hee , Kim Ho Young , Lim Ho Yeong
Published: February 2017

577

Background: Targeted therapy has shown remarkable treatment efficacy on the outcomes of patients with advanced renal cell carcinoma. However, this advance for treatment outcomes with targeted agents has been limited to patents with clear cell histology. The optimal treatment strategy for metastatic non-clear cell renal cell carcinoma (nccRCC) remains uncertained. Recently, several vascular endothelial growth factor inhibitors have shown efficacies for nccRCC. Thus, we designed a single-arm, open label phase II study to determine the efficacy and toxicity of pazopanib in patients with nccRCC. Methods: Patients with metastatic nccRCC except for collecting duct or sarcomatoid type received 800mg/day of pazopanib daily until progression of the disease or intolerable toxicity was observed. The primary objectives were progression free survival (PFS) and second objectives were overall survival (OS), treatment response and safety profiles. Results: A total of 29 eligible patients were enrolled from September 2012 to August 2014. The median age of the patients was 59 years (range, 30-77 years) and 21 patients were male. The median PFS was 8.3 months (95% CI, 4.0-12.6 months) and median OS was not reached (range, 1.5-34.7 months). Among all 29 patients, five patients (17.2%) are ongoing treatment without disease progression. Disease progression was observed in 16 patients (55.2%) during follow up period. Five patients (17.2%) experienced a treatment-related toxicity of grade 3 or more during the study and they stopped treatment in the end. Eight patients (27%) expired during follow up period but, there were no treatment-related deaths. Conclusions: This prospective phase II study showed that pazopanib demonstrated promising activity and tolerable safety in patients with nccRCC (ClinicalTrials.gov NCT01538238). Clinical trial information: NCT01538238.
Modeling patient variability in pazopanib-induced hepatotoxicity with iPSC-derived hepatocyte-like cells.
Authors: Choudhury Yukti , Toh Yi-Chin , Qu Yinghua , Xing Jiangwa , Poh Jonathan , Tan Hui Shan , Kanesvaran Ravindran , Yu Hanry , Tan Min-Han
Published: February 2017

578

Background: The tyrosine kinase inhibitor drug, pazopanib, is commonly prescribed as a first-line treatment option for metastatic renal cell carcinoma (mRCC). Administration of pazopanib can produce severe hepatotoxicity with elevated transaminases and bilirubin levels. The idiosyncrasy of hepatotoxicity suggests individual patient-factors as the key predisposition. Patient-derived induced pluripotent stem cells (iPSCs) bearing individual genetic and other signatures, were interrogated as a novel cell-based approach to model inter-patient drug response variability. Methods: iPSC lines were generated from five mRCC patients who exhibited positive (n = 3) or negative (n = 2) clinical hepatotoxicity to pazopanib. The iPSC lines were differentiated into functional hepatocyte-like cells (HLCs), which were then dosed with pazopanib. Differential cellular viability changes among hepatotoxicity-positive and -negative lines were assessed. To gain insight into the mechanism of idiosyncratic hepatotoxicity, a comparison of transcriptomic changes in HLCs after pazopanib treatment was also done, with accompanying functional assays to investigate mechanisms of toxicity. Results: iPSCs were successfully generated from five patients and could be robustly differentiated into HLCs with uniformly high degrees of hepatocyte function. HLCs from patients with clinical hepatotoxicity exhibited higher in vitro toxicity to pazopanib compared to HLCs from patients without hepatotoxicity (p < 0.01). However, all HLCs showed similar toxicity to known hepatotoxicants. Analysis of transcriptomic changes showed differential early-stress response among pazopanib-sensitive HLCs and suggested oxidative stress as a mechanism of pazopanib toxicity, which was verified by the observed depletion of intracellular glutathione levels in HLCs. Conclusions: We have a developed a novel cellular platform using iPSC-derived HLCs that can recapitulate phenotypes corresponding to clinical variation in pazopanib-induced hepatotoxicity. Furthermore, the patient-derived HLCs are ideal tools for the investigation of specific mechanism of hepatotoxicity.
Efficacy and safety of sequential use of everolimus in patients with metastatic renal cell carcinoma previously treated by bevacizumab with or without interferon therapy: Results from pooled analysis of AVATOR, CHANGE, and TRAIN studies.
Authors: Thiery- Vuillemin Antoine , Guillot Aline , Steiner Thomas , Herrmann Edwin , Syrigos Konstantinos N. , Kelkouli Nadia , Cattaneo Agnese , Nguyen Thierry
Published: February 2017

585

Background: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor. It gained approval based on the results of the RECORD-1 trial, which included patients with metastatic renal cell carcinoma (mRCC) whose disease progressed after receiving vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). Bevacizumab is a monoclonal antibody targeting angiogenesis that is approved in patients (pts) with mRCC. AVATOR was the 1st study to explore the sequential use of bevacizumab followed by everolimus but with limited number of pts. Methods: In order to further explore this sequence pooled data from the AVATOR, CHANGE and TRAIN studies were analysed retrospectively. All pts had mRCC and were previously or currently treated with everolimus after failure of bevacizumab ± IFN. The primary end point was everolimus time to progression (TTP). Secondary end points were related to the overall survival (OS) of patients receiving the drug sequence, everolimus treatment and safety. Results: 89 pts were included in the analysis. Median age was 68 years [18-90]. At everolimus initiation ECOG was 0-1 for 72% pts and 16% were classified as poor prognosis from Heng classification. Exploring the duration of second-line everolimus treatment, 32% of patients received less than 3 months of everolimus and 35% received at least 6 months of treatment. At the time of data analysis, 20 pts (24%) were still receiving everolimus. Pts receiving everolimus after bevacizumab experienced a median TTP of 6 months [95%CI 4 - 14]. Median OS was not reached for everolimus second-line therapy. At 36 months after the start of first-line therapy, 60.4% of pts were still alive. All grades of common adverse events were consistent with the known safety profile of everolimus. Conclusions: The larger size of this cohort confirms the signal previously seen with AVATOR that the sequence of bevacizumab followed by everolimus displays interesting efficacy with not unexpected toxicity from everolimus and compares favourably with RECORD-1.
Single-fraction radiosurgery for the treatment of renal cell carcinoma.
Authors: Staehler Michael D. , Schlenker Boris , Karl Alexander , Spek Annabel , Muacevic Alexander
Published: February 2017

590

Background: We report on patients with renal cell carcinoma (RCC) who were treated with single fraction high-dose local stereotactic radiosurgery (SRS) using the robotic Cyberknife system to avoid nephrectomy and consecutive hemodialysis. Methods: Fifty-two patients with histologically confirmed RCC and median age of 63.6 years (43.6-86.5) with the indication for renal surgery and highest risk for consecutive hemodialysis were entered into a prospective case control study of single fraction SRS with 25Gy. Tumor response, renal function, survival, and adverse events were estimated every three months with a follow-up of at least six months. Results: R.E.N.A.L. score was low in 1, moderate in 30 and high in 21 patients. 28 patients had singular renal units. Median follow-up was 26.9 months (1.8 - 52.6). Local tumor control nine months after SRS was 98% (95% CI: 89-99%). 43 lesions showed a measurable tumor size reduction including six complete remissions and 33 partial remissions. Renal function remained stable with a median serum creatinine at baseline of 1.10 mg/dl (0.4 -2.0) and 1.11 mg/dl (0.8-2.2) at follow-up. In one patient grade I erythrodermia, in three patients grade I fatigue and in two patients grade I nausea occurred. In all patients nephrectomy was avoided. Conclusions: Single-fraction SRS as an outpatient procedure is a treatment modality with short-term safety and efficacy to avoid treatment-related loss of renal function and hemodialysis in selected patients with RCC. Short term follow up of oncological and functional results so far is excellent. Further studies are needed to determine the limits of SRS in this setting and long term results.
Sunitinib's effect on tumor infiltration of CD8 T cells in renal cell carcinoma (RCC) and modulation of their function by altering VEGF-induced upregulation of PD1 expression.
Authors: Haywood Samuel , Chen Roy , Pavicic Paul , Lin Lin , Diaz-Montero C. Marcela , Rayman Pat A. , Przybycin Christopher , Finke James , Rini Brian I.
Published: February 2017

591

Background: The effect of VEGF inhibitors such as sunitinib to modulate RCC tumor microenvironment and the effect on immunotherapy using checkpoint inhibitors is unknown and of clinical interest. Methods: Immune infiltrate in tissue sections from clear cell renal cell carcinomas (ccRCC) (n = 13) treated with sunitinib in the neoadjuvant setting were compared to that of untreated RCC patients with localized disease (n = 15). Immune infiltrate was scored in H&E stained tissue sections. Infiltrates were further characterized by IHC using antibodies against CD4 (Novocastra NCL-CD4-1F6 clone 1F6), CD8 (BiogeneX MU422-UC clone 1A5) or PD1 (Abcam ab52587 clone EPR4877). Intensity of staining was quantified using a Leica microscope equipped with a Retiga SRV camera. Scanned images of multiple tumor fields were analyzed using ImagePro Plus software. For pre-clinical studies, Balb/c mice bearing Renca tumors (RCC) were treated with sunitinib (40mg/kg) daily for 14 days, and tumors were dissociated and analyzed for CD8 and CD4 infiltrate by FACS analysis. Results: Qualitative analysis showed a more prominent accumulation of lymphocytes in tumor sections of patients receiving sunitinib. Quantitative analysis of these infiltrates revealed higher levels of CD8+ T cells in sunitinib treated patients (p = 0.04). By contrast, sunitinib treatment was associated with a reduction of intratumoral expression of PD1. Preclinical studies in the Renca model also showed an increase in the frequency of tumor infiltrating CD8+ T cells following sunitinib treatment. Remarkably, a higher fraction of these tumor infiltrating CD8 T cells were found to co-express the activation marker of cytotoxic effector cells (CD107a) when compared to untreated mice. Conclusions: These findings suggest that sunitinib not only promotes the accumulation of CD8+ T cells within the tumors, but also affects their activity by modulating PD1 expression and enhancing cytotoxic function.
A personalized sunitinib (S) first-line approach in elderly patients with metastatic renal cell carcinoma (mRCC).
Authors: Cossu Rocca Maria , Iacovelli Roberto , Verri Elena , Crescio Claudia , Aurilio Gaetano , Detti Serena , Cullura Daniela , Nole Franco
Published: February 2017

602

Background: About 24% of mRCC are older than 74 yo. S is a well-established first-line therapy for mRCC with a specific toxicity profile requiring a dose reduction in 30% of pts. Actually few data are available in the Literature about its use in patients > 75 yo especially as regards efficacy and cost effectiveness of tailored approaches. Methods: The primary end-point of this prospective single arm study, is to assess if a personalized approach is able to decrease the rate of dose reduction to 8% after the first cycle of S.. 19 pts have been estimated to be necessary to explore this hypothesis. Secondary objectives were the safety, treatment duration (TD) and overall survival (OS). Personalized approach was defined as the starting dose of S choose by the medical oncologist based on performance status (PS ECOG) and number of comorbidities. Results: From 2007 to 201421 pts were enrolled. The median age was 77.9 yrs (IQR 74.1-82.1). Seventy-five % had a clear cell carcinoma, 20% had a metastatic disease at diagnosis and 60% had > 2 sites of metastasis. All pts had PS ECOG ≥ 1 and 50% suffered from > 2 comorbidities. 43% were good, 52% intermediate and 5% poor prognosis by IMDC criteria. 3 pts (14%) started S at 50 mg/d, 9 pts (42%) at 37.5 mg/d and 9 pts (42%) started with 25 mg/d. All pts received S with the 4/2 schedule. The dose reduction after the first cycle was 28%. The reason was always toxicity, but no treatment interruption occurred. No pts starting at 25 mg had dose modification. The main toxicity requiring dose reduction was G3 anemia in 1pt, G3-4 thrombocytopenia in 3 pts and G3 leuconeutropenia in 3 pts . The median TD was 11.9 mos (95%CI, 6.5-17.3). The median OS was 33.3 mos (95%CI, 26.1-40.6). Conclusions: This study shows that a personalized starting dose is not able to decrease the rate of dose reduction at first cycle. Nonetheless a personalized strategy does not affect negatively the OS of elderly pts. Actually in elderly pts a disease stabilization without acute adverse events, could be considered an adequate goal. A well tolerated therapy could also be cost effective because part of health cost, especially for elderly pts, derives from their hospitalization for adverse events. Further data are required.
Time to targeted therapy after cytoreductive nephrectomy (CN) and surveillance in patients with synchronous unresectable metastases of renal cell carcinoma (RCC).
Authors: Bex Axel , de Bruijn Roderick , Noe Allard , Blank Christian U. , Horenblas Simon , Haanen John B. A. G.
Published: February 2017

604

Background: VEGF-targeted therapy does not cure metastatic RCC. Guidelines recommend cytoreductive nephrectomy and complete resection of solitary-/oligometastases when feasible to potentially cure patients. However, in patients with low-volume but unresectable multiple metastases at single or more sites surveillance with or without local therapy after debulking CN may be an option to delay non-curative systemic therapy and associated toxicity. Methods: From an IRB approved institutional database of patients with primary metastatic RCC we identified patients with low-volume but unresectable oligometastatic disease in whom surveillance after debulking CN was a local multidisciplinary tumour board recommendation. Patient data, IMDC risk, site and number of sites, time-to-progression (TTP), time-to-targeted therapy (TTT) and overall survival (OS) were retrospectively analyzed. Results: From 203 primary mRCC patients treated since 2006, 28 (13.8 %) were identified who had low-volume multiple metastasis at a single site (13 with 7 lung, 5 bone) or multiple sites (15 with ≥ 2 sites). IMDC risk was favorable in 1, intermediate in 18 and poor in 6. Median TTP was 12 (range 3-36) months and TTT was 14 (range 3-43) months. Of 8 (28.7 %) progressing within 6 months, 2 had sarcomatoid tumours, 4 grade 4, 3 IMDC poor risk and 7 had ≥ 2 sites . In 15 patients TTT was further delayed by surveillance beyond RECIST progression (median time 5 (range 1-15) months) or additional local therapy of the most rapidly progressing lesion (5 radiation, 1 ablation). Median OS was 21.5 (range 4-75) months. Conclusions: Debulking CN followed by surveillance may substantially delay VEGF-targeted therapy and associated adverse events in a subset of patients with primary mRCC and unresectable low-volume metastasis. Local therapy to control the most rapidly progressing lesion or surveillance beyond progression were additional means to delay systemic therapy.
An optimized microRNA signature algorithm to predict clear cell renal cell carcinoma metastasis: A 265-case validation study using paraffin specimens.
Authors: Wu Huiqing , Wu Xiwei , Jin Jennifer M , Li Arthur X , Tong Tommy , Ma Dongling , Nelson Rebecca A. , Li Yuping , Pal Sumanta K. , Kim Young S , Haberman Ken , Zhai Jing , Lau Clayton S. , Guo Chao , Wu Jeffrey J , Chen Wengang , Yuh Bertram E. , D'Apuzzo Massimo , Li Wenzhe , Wilczynski Sharon
Published: February 2017

612

Background: Clear cell renal cell carcinoma (ccRCC) metastasis is associated with a dismal prognosis. Early identification of patients at high or low risk of metastasis may help to guide appropriate treatment. There are currently no reliable clinico-pathologic and laboratory modalities for this purpose in a routine clinical setting. We previously performed a microarray study using frozen ccRCC specimens and identified dysregulation of 4 microRNAs (miRNAs), miR-10b, miR-139-5p, miR-130b and miR-199b-5p, to be highly associated ccRCC metastasis and prognosis. Methods: We established a training cohort including formalin-fixed paraffin-embedded (FFPE) specimens of localized (n = 13; pT1) and metastatic (n = 15; M1) ccRCCs. We measured the expression of the 4 miRNAs of the training cohort samples by quantitative RT-PCR, normalized with miR-24, one of the most stably expressed miRNAs in human renal tissue as we previously reported. Using the risk score method, we rebuilt a mathematical formula with cutoff points to predict a patient to be at high, low or equivocal risk of metastasis. We validated the signature in an FFPE test cohort of 265-case primary ccRCCs. We examined the signature performance and its correlation with the cancer-specific survival. Results: Multivariate logistic regression analysis showed the signature to be highly associated with ccRCC metastasis (OR 7.67, 95%Cl 2.80-21.09, p < 0.0001), with the overall sensitivity and specificity of 80% and 76%. The sensitivities and specificities were 72% and 78%, 70% and 67%, and 78% and 75% for stage I, II or III patients, respectively. The signature predicted metastasis of small ccRCCs ( ≤ 4.0 cm), with the sensitivity of 60% and specificity of 77%. The overall positive and negative predictive values (PPV and NPV) were 61% and 89%. The area under the curve of ROC was 0.8. The signature was also found to be well correlated with worse cancer-specific survival (HR 3.06, 95%Cl 1.49-6.93, p < 0.01). Conclusions: This optimized miRNA signature can reliably predict ccRCC metastasis and prognosis and may help to stratify patients for more appropriate therapies and suitable clinical trials.
Utilization and sequencing of targeted therapy and cytoreductive nephrectomy in non–clear cell metastatic kidney cancer.
Authors: Macleod Liam Connor , Tykodi Scott S. , Holt Sarah , Gore John L.
Published: February 2017

615

Background: Many patients with metastatic kidney cancer (mRCC) are ineligible for trials due to non-clear cell histology. Efficacy of targeted therapy agents in non-clear cell mRCC is still being investigated. We hypothesized that sequencing CN upfront is associated with improved overall survival. We analyze a population-based cohort of non-clear cell mRCC patients in the targeted therapy era. Methods: Patients from the SEER-Medicare files (2005-2011) with non-clear cell mRCC were categorized as having received upfront targeted therapy or upfront CN. Additional exclusions were age < 66 to avoid confounding by uncaptured non-Medicare coverage, and competing stage IV cancer. Targeted therapy was identified through Medicare Part D files. Cox proportional hazards regression determined association between treatment groups, clinical and cancer-related characteristics, and the main outcome, median overall survival (OS). Propensity matching controlled for measurable confounding in treatment selection. Results: Of 1,326 mRCC cases, 528 met inclusion criteria of whom 433 (82%) received targeted agents and 172 (33%) underwent CN. Of those not having CN, 74% were diagnosed by biopsy, 10% by cytology, and 16% radiographically (confirmed at autopsy). Thirteen percent received CN then targeted therapy (OS 14 mos, IQR 9-25), 2.5% received targeted therapy then CN (OS 14 mos, IQR 9-26), 18% received CN only (OS 14 mos, IQR5-40), 67% received targeted therapy only (OS 9 mos, IQR 4-19). On multivariable Cox proportional hazards regression upfront CN (regardless of post-CN therapy) was associated with improved OS (HR 0.54,95% CI 0.41,0.72). Using propensity scores, upfront CN patients (N = 161) were matched to upfront targeted therapy patient (N = 111) and the average treatment effect of CN was 8.3 months survival improvement (95% CI 4.0, 13.2). Conclusions: Although utilization of targeted agents in non-clear cell mRCC exceeds 80%, those with greatest OS received CN either upfront or after targeted therapy, though the latter was rare (2.5%). The variety of sequencing strategies observed is evidence of uncertainty regarding the best care for non-clear cell mRCC patients given limited options.
Among men with low-grade prostate cancer on prostate biopsy, the 4Kscore to predict prostate cancer aggressiveness at prostatectomy.
Authors: Nahar Bruno , Punnen Sanoj , Zappala Stephen M , Sjoberg Daniel , Parekh Dipen
Published: February 2017

65

Background: Most men diagnosed with prostate cancer in the United States have low-grade tumors. While many of these men are good candidates for active surveillance, a proportion will have a bad outcome due to the presence of a more aggressive prostate cancer that was missed on initial biopsy. A recent study confirmed the 4Kscore accurately predicts the likelihood of aggressive cancer on prostate biopsy. We analyzed if the 4Kscore could predict the presence of more significant cancer in men with low-grade tumors on the diagnostic biopsy. Methods: A recent prospective validation of the 4Kscore was conducted at 26 sites throughout the United States. We selected men who were found to have low-grade (Gleason 6) cancer on biopsy for this analysis. The 4Kscore calculates the risk of aggressive prostate cancer on prostate biopsy by a blood test that measures levels of four kallikrein biomarkers (total PSA, free PSA, intact PSA, and human kallikrein-2) plus age, DRE findings, and prior biopsy status. We investigated whether the 4Kscore was associated with more significant cancer among men found to have Gleason 6 cancer on prostate biopsy. We also looked at a subset of these men who underwent radical prostatectomy to see if the 4Kscore was associated with prostate cancer being upgraded in the surgical specimen. Results: Among the 1,312 men enrolled in this trial, 306 men were found to have Gleason 6 cancer on prostate biopsy. The 4Kscore was significantly associated with the number of positive cores (p=0.001) and the millimeters of cancer seen (p=0.0002), with higher 4Kscores relating to more extensive cancer present on biopsy. In the subpopulation of 51 men who underwent radical prostatectomy, the median 4Kscore was significantly higher among men who had an upgrade to Gleason 7 or higher [15% (8,25)] compared to men who did not experience an upgrade [7% (4,14)] (p=0.032) in their final pathology. Conclusions: Among men with Gleason 6 prostate cancer on biopsy, the 4Kscore was associated with the prostate cancer being upgraded in the surgical specimen at radical prostatectomy. The 4Kscore test may facilitate the selection of men who can be observed versus those who should undergo immediate treatment.
Effects of PSA screening guidelines on trends of diagnosis and treatment for prostate cancer: Analysis from the National Cancer Data Base (NCDB).
Authors: Aragon-Ching Jeanny B. , Hussey Heather M. , Chen Dechang , Nguyen Hong , Henson Donald , Simmens Samuel
Published: February 2017

74

Background: The initial iteration of the USPSTF ‘Screening for Prostate Cancer’ guideline published in 2008 made recommendations against PSA screening for men > 75 years followed by an updated recommendation published in 2012 against PSA screening altogether. However, two large studies that formed the basis of these recommendations, the European ERSPC and the US-led PLCO trials, have published conflicting results. Currently, active surveillance is often offered as an approach to manage early stage prostate cancer. The NCDB was used to determine the uptake and efficacy of the USPSTF screening recommendations as well as their impact on the treatment of clinical T1c disease, which by definition, is cancer identified via screening to inform clinical practice. Methods: A de-identified dataset was acquired from NCDB. Frequencies were calculated for demographic variables; correlation coefficients and chi-square statistics were generated to assess any significant correlations between potential predictors (e.g. age, race, year of diagnosis, and tumor size) and time to treatment to determine whether treatment decisions, including active surveillance increased following the guideline recommendations. Results: The NCDB included 1,802,596 patients diagnosed with prostate cancer between 1998 and 2012; the majority of whom were white (82%) followed by black (13%), and other (5%). The highest number of patients was diagnosed in 2007 and the lowest number of patients was diagnosed in 2012, although no clear decline in the diagnosis across time periods was observed. A negative correlation was identified between age and year of diagnosis (r = -0.09, p < 0.0001), indicating a potential decline in diagnosis among older men. Alternatively, a positive correlation was found between year of diagnosis and days until treatment began (r = 0.09 p < 0.0001) indicating a potential increase in alternatives to treatment such as active surveillance. Conclusions: Preliminary results suggest no major changes in the patterns of diagnosis. However, active surveillance as an alternative to treatment may be increasing perhaps as an early indication of adherence to the guideline.
Comparative effectiveness of intensity-modulated radiation therapy versus three-dimensional conformal radiation for localized prostate cancer.
Authors: Shaikh Talha , Ruth Karen , Zaorsky Nicholas George , Hallman Mark , Geynisman Daniel M. , Kutikov Alexander , Smaldone Marc C. , Chen David Y. T. , Sobczak Mark L. , Horwitz Eric M.
Published: February 2017

89

Background: Intensity-modulated radiation therapy (IMRT) has become the standard radiation delivery option for patients (pts) with localized (PCa) prostate cancer despite limited prospective data and increased cost relative to three-dimensional conformal radiation therapy (3D-CRT). The purpose of this study was to compare the treatment outcomes and toxicities of pts undergoing definitive dose-escalated radiation therapy using either 3D-CRT or IMRT for localized PCa. Methods: We identified men with clinically localized PCa treated with definitive external beam radiation at a single institution using >74 Gy between 1997-2013. Within each NCCN risk group, propensity score matching of 3D-CRT pts with one or two IMRT pts was performed accounting for age, race, diabetes, hypertension, Gleason score, T-stage, PSA, and hormone use. Conditional logistic and conditional Cox proportional hazards models were used to adjust for matched groups, with dose included as a separate covariate. Results: After matching,1,253 men (474 3D-CRT, 779 IMRT) were included. There were no significant differences between the IMRT and 3D-CRT pts according to clinical or treatment factors. There was no difference in biochemical failure (BCF), distant metastasis (DM), cancer specific survival (CSS), or overall survival (OS) amongst the low or intermediate risk subgroups. When examining the high-risk subgroup, pts receiving IMRT had higher rates of DM (HR 2.21 95% CI 1.04-4.74 p=0.040). There was a trend towards increased rates of BCF in pts receiving IMRT for high-risk disease (HR 1.60 95% CI 0.96-2.66 p=0.072). There was no difference in CSS or OS in the high-risk subset. In the intermediate risk group, patients receiving IMRT had increased rates of acute grade 3+ genitourinary toxicity versus 3D-CRT patients (OR 8.30 95% CI 2.13-2.15 p=0.002). There were otherwise no differences in acute or late grade 3+ genitourinary or gastrointestinal toxicity amongst IMRT versus 3D-CRT pts. Conclusions: Despite the widespread adoption of IMRT for localized PCa, our results do not demonstrate an improvement in outcomes or toxicity versus 3D-CRT. Further research is warranted to explain these findings.
The change in prostate cancer presentation and diagnosis coinciding with screening recommendations.
Authors: Gaylis Franklin , Choi Jae , Dato Paul , Cohen Edward , Calabrese Renee , Prime Hillary , Kader A. Karim
Published: February 2017

95

Background: The controversy surrounding prostate cancer (PCa) screening resulted in the United States Preventative Services Task Force (USPSTF) and several primary care societies to recommend against this practice. We examined the characteristics of men evaluated in a large urology practice for an elevated prostate specific antigen (PSA) and the subsequent PCa diagnoses since the USPTF recommendation. Methods: Characteristics of all men presenting for an elevated PSA from August 2011 to August 2014 were prospectively collected in a database. Age at the time of biopsy, self-declared race, insurance status, family history, digital rectal examination findings, PSA within 6 months of biopsy, biopsy history, prostate volume, number of cores sampled, pathologic read (number and percent cores positive, Gleason grading) were all recorded. Kruskall-Wallis rank sum tests were used to compare across all years with post-hoc Dunn’s tests for pairwise multiple comparisons using Bonferroni adjustment. Results: The number of men referred for elevated PSA dropped from 933 in year 1 to 754 by year 3 (19%) with a concomitant drop in the number of biopsies performed in newly referred men from 461 to 370 (20%). The group’s prostate biopsy volume decreased by 15% (1,133 biopsies in year 1 compared to 958 in year 3). Median pre-biopsy PSA increased across all years from 7.0 ng/ml to 8.1 ng/ml (p = 0.0006) with a rise in the proportion of men having PSAs > 10 from 28% to 38%. In the post-hoc analysis, median pre-biopsy PSA was significantly different between years 1 and 3 (p = 0.0002) and years 2 and 3 (p = 0.017) but not years 1 and 2 (p = 0.33). The biopsy positivity rate increased slightly from 46% to 50% across all years with a rise in the proportion of men having Gleason scores (GS) ≥ 8 from 21% to 30% (p = 0.0001). In the post-hoc analysis, median GS was significantly different between year 1 and year 3 (p < 0.0001) and year 2 to year 3 (p = 0.0004) but not year 1 to year 2 (p = 0.12). Conclusions: Our findings suggest a significant grade migration coincident with recommendations against PSA screening. While possibly desirable in the short term, should this trend continue we may miss the window of curability for many men.
Modified Kegel exercise regimen following definitive and adjuvant prostate cancer radiotherapy.
Authors: Eapen Libni , Ionescu John , Eapen Amira
Published: February 2017

e629

Background: 5-15% of patients treated with curative radiotherapy for prostate cancer experience some degree of urinary or fecal leakage. We hypothesized that a regimen of postradiotherapy perineal exercises would reduce this problem of sphincter dysfunction Methods: Upon completion of either conformal- or intensity-modulated radiotherapy to 76 Gy in 38 fractions (definitive) or 66 Gy in 33 fractions (postprostatectomy) patients were advised to commence a life-long program of daily perineal strengthening exercises. This consisted of a modified Kegel regimen for 5 minutes at a time, four times daily, and continued indefinitely. Patients have been monitored in regard to compliance and sphincter dysfunction at scheduled cancer clinic followup visits as well as by telephone survey. Results: 530 patients have been engaged in this postradiotherapy sphincter conditioning program. Parameters being analyzed are compliance with the regimen, frequency of exercise performance, urinary and fecal incontinence rates Conclusions: Pending the final tabulation of results the practical feasibility of such a prophylactic perineal exercise regimen as well as its impact on post radiotherapy sphincter integrity will be ascertained.
Integrating the primary care physician into cancer follow-up.
Authors: Salner Andrew L. , Walker Deborah , Seltzer Amanda , Panzer SarahLena , Stricker Carrie , Dornelas Ellen A
Published: February 2017

102

Background: After a diagnosis of breast cancer, it can be difficult for patients to understand the role their primary care physician (PCP) should play in their follow up care. Methods: 65 women (mean age 60 years, SD = 10) with breast cancer (stage 0-III) were seen by a nurse practitioner for a 60-90 minute consultative survivorship visit and received a treatment summary and personalized survivorship care plan (SCP) utilizing Carevive Care Planning Systems software. The Carevive system incorporates patient-reported and clinical data to create tailored care plans with personalized recommendations for follow up care and supportive referrals, including direction to follow up with primary care for specific care and health maintenance activities. Approximately 6 weeks following their survivorship care visit, patients completed a survey assessing their use of and satisfaction with the SCP. Patients were advised that the SCP would be mailed to their referring oncologist and primary care physician. Results: Out of 65 sent, 35 surveys have been completed to date. Survivors were diagnosed approximately 10 months prior, and all were within 6 months following completion of treatment. All patients (100%) reported that they read, or planned to read, their survivorship care plan packet carefully. While all care plans included a recommendation to follow up with their PCP, only (71%) of survivors remembered receiving this recommendation. Of those who did, most (74%) had either seen or scheduled an appointment with their PCP. Patients who reported higher anxiety at the time of the survivorship visit were more likely to report that the follow up care plan helped them take action about seeing their PCP (p = .03). Conclusions: Coordination between primary and oncology care providers has previously been shown to improve the quality of care for cancer survivors. SCPs that emphasize the importance of and activities to be undertaken in primary care may help to improve this coordination. Continuation of this research will help to better understand how to integrate the primary care physician into cancer follow up care. Updated data will be shared at time of presentation.
Insulin and glucose homeostasis in childhood cancer survivors treated with abdominal radiation: A pilot study.
Authors: Friedman Danielle Novetsky , Wolden Suzanne L. , Antal Zoltan , Moskowitz Chaya S. , Hilden Patrick , Cheung Nai-Kong V. , Kushner Brian H. , Tonorezos Emily S. , Carlow Dean , Oeffinger Kevin C. , Sklar Charles A.
Published: February 2017

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Background: Previous reports have suggested an increased risk of Type I and Type II diabetes mellitus (DM) in childhood cancer survivors exposed to abdominal radiotherapy (RT). The mechanisms leading to DM in this population, however, remain unknown. We sought to clarify the pathophysiology leading to these derangements by performing dynamic testing of glucose and insulin in survivors previously treated with abdominal RT. Methods: Cross-sectional pilot study of 2-year survivors of childhood cancer treated with abdominal RT at Memorial Sloan Kettering between 1975 – 2009. Eligible participants were < 21 years of age at exposure to abdominal RT; those with a known diagnosis of DM or prior exposure to brain or total body RT were excluded. Survivors underwent formal 2-hour glucose tolerance testing; auto-antibodies (insulin auto-antibodies, islet cell autoantibody, glutamic acid decarboxylase) typically present in patients with Type I DM and hemoglobin A1c levels were assessed. Insulin resistance was calculated by the homeostasis model assessment of insulin resistance (HOMA-IR) and Matsuda index. Results: 21 survivors were enrolled (male: 47.6%; median age at RT: 3.3 years; median age at study: 14.4 years [range: 8.3 – 46.9]; median time from abdominal RT: 10.7 years). Primary diagnoses included neuroblastoma (n = 15), rhabdomyosarcoma (n = 3), Wilms (n = 1), Hodgkin lymphoma (n = 1), rhabdoid tumor (n = 1). None of the participants were obese (body mass index [BMI] range: 14.7 – 23.2 kg/m2). Five participants (23.8%, 95% confidence interval: 8% – 47%) had glucose derangements at a median of 8.4 years after RT (one with impaired fasting glucose [fasting glucose ≥ 100 mg/dl) and four with impaired glucose tolerance [2-hour glucose 140-199 mg/dl]). Two additional participants with normal glucose tolerance had impaired insulin sensitivity based on an abnormal Matsuda Index and HOMA-IR. None of the participants had abnormal autoantibodies, insulinopenia, or hemoglobin A1c levels. Conclusions: These findings suggest that nonobese childhood cancer survivors treated with abdominal RT may be at high-risk for subclinical derangements of glucose and insulin. Further study is warranted in larger survivor cohorts. Clinical trial information: NCT02248779.
Fertility preservation for cancer patients: Role of nursing attitudes.
Authors: Grabowski Maria C. , Spitzer Deborah , Rezale Shaghayegh , Close Catherine , Stutzman Sonja , Olson Daiwai
Published: February 2017

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Background: Nurses play a pivotal role in ensuring adherence to quality guidelines. The 2006 American Society of Clinical Oncology - Quality Oncology Practice Initiative guidelines state that infertility risks should be discussed prior to initiation of fertility-reducing therapies for patients in their reproductive years. Despite this guideline on fertility preservation (FP), national compliance is only 6% (Tallent, 2013). Research is lacking in the understanding of nurses’ attitudes and behaviors towards FP and no tools exist from which to examine this problem. The purpose of this study is to gain increased understanding of potential barriers for nurses to recommend FP as an option for newly diagnosed patients. Methods: This instrument development study was developed by content experts and field tested with staff nurses. Next, an online survey method was used to examine factors associated with nursing recommendation for FP of newly diagnosed cancer patients. An anonymous online survey was sent to oncology nurses at UT Southwestern and members of the Oncology Nursing Society (Dallas Fort Worth Chapter). The endpoint of the study is a sound survey to assess nursing behaviors toward FP in diagnosed cancer patients. Standardized descriptive measures of central tendency were used to describe baseline characteristics for the sample. Factor analysis was completed using SAS v9.3 with orthogonal rotation. Scree plot was examined for factors and loading > 0.30 were retained. Results: Analysis of the first 67 returned surveys (Phase 1) supports a 15-item (5-factor) survey tool. Preliminary results suggested the need for education, referral availability, and system refinement. Phase 2 surveys of additional 200 was initiated in August 2015, with an expected close of enrollment date of December 2015. Conclusions: Cancer patients of childbearing age worry how treatment will affect their ability to have a child. This survey may be beneficial in identifying nursing attitudes regarding FP. All members of the care team should be sensitive to this concern and should recommend appropriate action. This study will identify nursing barriers to patient education, and will support system-wide implementation of a comprehensive FP program.
Predictors of positive test results in patients with cancer undergoing hepatitis B screening before chemotherapy.
Authors: Hwang Jessica , Lok Anna S. F. , Cantor Scott B. , Fisch Michael , Barbo Andrea G. , Lin Heather Y. , Suarez-Almazor Maria E.
Published: February 2017

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Background: Optimal hepatitis B virus (HBV) screening strategies for patients with cancer awaiting chemotherapy are unknown. We aimed to identify predictors of HBV infection in a large cohort of patients with cancer who were systematically screened for HBV before chemotherapy. Methods: In this prospective observational study, patients with cancer at MD Anderson Cancer Center awaiting first administration of chemotherapy in an outpatient chemotherapy unit were identified and approached for HBV screening. Enrolled patients completed a CDC risk survey and had blood tests to screen for HBV (HBsAg, anti-HBc) and hepatitis C virus (anti-HCV) infection. We developed a logistic regression model to identify clinical predictors of either chronic (HBsAg+/anti-HBc+) or resolved (HBsAg-/anti-HBc+) HBV infection. Model fit was assessed using the Hosmer-Lemeshow goodness-of-fit test. Results: From July 2013 to December 2014, 2124 patients (mean [SD] age, 58 [13] years) completed the risk survey and had HBV screening. Of these, 54% were women, 11% Hispanic, 77% non-Hispanic white, 8% black, and 4% Asian. Nearly 20% had a hematologic malignancy, 1% liver cancer, and 79% had a solid tumor other than liver cancer. Almost 12% of patients were born outside of the US. Seven patients (0.3%) had chronic and 128 (6%) had resolved HBV infection. Among the latter, 13 patients were also anti-HCV+. Predictors (odds ratio [OR]; 95% CI) of having either HBsAg+ or anti-HBc+ result included black race (4; 3-7), Asian race (4; 2-7), birthplace outside the US (5; 3-9), and having lived with someone with HBV (2; 1-4). Older age and lower education level were also predictive of positive HBV test results. Patients who reported ever injecting drugs (OR 10; 5-22) or being a man currently having sex with another man (OR 28; 6-135) had a high risk of HBsAg+ or anti-HBc+ result. The area under the curve for the model predicting positive HBV tests was 0.80. Conclusions: Known HBV risk factors are predictive of chronic or resolved HBV infection in patients with cancer. Future model validation using bootstrapping will allow varying levels of sensitivity in order to develop best HBV screening strategies.
Cardio-oncology interventions in outpatients referred for autologous bone marrow transplantation.
Authors: Pituskin Edith , Cox-Kennett Nanette , Becher Harald , Sandhu Irwindeep , Venner Chris , Paterson Ian
Published: February 2017

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Background: Cancer patients (PTS) referred for autologous bone marrow transplantation (autoBMT) are frequently pre-treated with established cardiotoxins and as a result may not have adequate cardiac function to meet eligibility criteria for autoBMT. Furthermore, mobilizing and consolidation chemotherapy result in additional serial exposures with acute and long-term negative cardiac sequelae. Accordingly, these PTS represent a population with a major unmet need for appropriate cardiovascular screening and interventions. Aim: to evaluate the need and effectiveness of prospective multidisciplinary cardio-oncology assessment and intervention in an unselected outpatient population referred for autoBMT. Methods: From January 1, 2013 – December 31, 2013, PTS referred for autoBMT were systematically screened for comorbid conditions, cardiovascular risk factors and eligibility for transplant. Physical exam, laboratory (ECG, complete profile) and transthoracic echocardiogram with contrast were performed. Those with EF < 50%, increased IVsd/LVpWd, ECG abnormalities +/- significant cardiac history underwent proBNP and high sensitivity troponin testing. PTS with abnormal findings or decreased left ventricular (LV) function were referred to the Edmonton Cardio-Oncology REsearch (ENCORE) program. Results: 73 unique PTS were screened by the Edmonton autoBMT program. Of these, 16 (20%) were reviewed by ENCORE. Reasons for referral included: decreased LV function (n = 6, 38%); increased IVsd (n = 5, 31%); arrhythmia (n = 4, 25%); angina (n = 1, 5%). Pharmacotherapy was initiated for 6 PTS; additional modality or serial cardiac imaging for 12 PTS; urgent stent for 1 PT. 100% proceeded to autoBMT without adverse cardiovascular outcomes or mortality. Conclusions: With systematic screening, a high proportion of PTS referred for autoBMT required cardio-oncology assessment and interventions, with 100% proceeding safely as a result. ENCORE represents a novel approach in the provision of cardio-oncology expertise for autoBMT PTS acutely during the mobilizing and transplantation period. Future examination of our prospective dataset will elucidate the longer term effects of our interventions.