[Show abstract][Hide abstract]ABSTRACT: Immune tolerance to self-antigens can limit robust anti-tumor immune responses in the use of tumor vaccines. Expression of novel tumor associated antigens can improve immune recognition and lysis of tumor cells. The cancer-testis antigen (CTA) family of proteins has been hypothesized to be an ideal class of antigens due to tumor-restricted expression, a subset of which have been found to induce antibody responses in patients with prostate disease. We demonstrate that CTA expression is highly inducible in five different Prostate Cancer (PC) cell lines using a hypomethylating agent 5-Aza-2'-deoxycytidine (5AZA) and/or a histone deacetylase inhibitor LBH589. These CTAs include NY-ESO1, multiple members of the MAGE and SSX families and NY-SAR35. A subset of CTAs is synergistically induced by the combination of 5AZA and LBH589. We developed an ex vivo organ culture using human PC biopsies for ex vivo drug treatments to evaluate these agents in clinical samples. These assays found significant induction of SSX2 in 9/9 distinct patient samples and NY-SAR35 in 7/9 samples. Further, we identify expression of SSX2 in circulating tumor cells (CTC) from patients with advanced PC. These results indicate that epigenetic modifying agents can induce expression of a broad range of neoantigens in human PC and may serve as a useful adjunctive therapy with novel tumor vaccines and checkpoint inhibitors.
Full-text available · Article · Oct 2016 · Oncotarget
[Show abstract][Hide abstract]ABSTRACT: IntroductionA significant proportion of patients that fail active surveillance (AS) for prostate cancer management do so because of cancer upgrading. A previously validated upgrading nomogram generates a score that predicts risk of biopsy Gleason 6 upgrading following radical prostatectomy in lower-risk populations that are candidates for Active Surveillance (Cancer, 2013). Objectives
We hypothesize that the upgrading risk (UR) score generated by this nomogram at diagnosis improves the ability to predict patients that will subsequently fail AS. Methods
To evaluate the nomogram, retrospective data from several institutional cohorts of patients who met AS criteria, group 1 (n = 75) and group 2 (n = 1230), were independently examined. A UR score was generated using the coefficients from the nomogram consisting of PSA density (PSAD), BMI, maximum % core involvement (MCI), and number of positive cores. AS failure was defined as Gleason score (GS) >6, >50 % maximum core involvement, or >2 positive cores on biopsy. Univariate and multivariate Cox proportional-hazards regression models, upgrading risk score, and other clinicopathologic features were each assessed for their ability to predict AS failure. ResultsClinicopathologic parameters were similar in both groups with the exception of mean PSAD (0.13 vs. 0.11, p < 0.01) and follow-up (2.1 vs. 3.2 years, p = 0.2). Most common cause of AS failure was GS > 6 (group 1) compared to >2 positive cores (group 2). On univariate analysis in both populations, features at diagnosis including PSAD and the UR score were significant in predicting AS failure by upgrading (Gleason > 6) and any failure. Multivariate analysis revealed the UR score predicts AS failure by GS upgrading (HR 1.8, 95 % CI 1.12–2.93; p = 0.01) and any failure criteria (HR 1.7, 95 % CI 1.06–2.65); p = 0.02) for group 1. Likewise, the UR score in group 2 predicts AS failure with GS upgrading (HR 1.3, 95 % CI 1.15–1.42; p < 0.0001) and any failure criteria (HR 1.18, 95 % CI 1.18–1.38; p < 0.0001). An ROC generated an AUC of 0.66. Decision curve analysis demonstrated a high net benefit for the UR score across a range of threshold probabilities. Based on these outcomes, at 3 years, patients in the lowest risk quartile have a 15 % risk of AS failure versus a 46 % risk in the highest quartile (p < 0.0001). Conclusions
The UR score was predictive of pathologic AS failure on multivariate analysis in several AS cohorts. It outperformed single clinicopathologic criteria and may provide a useful adjunct using clinicopathologic data to stratify patients considering AS.
[Show abstract][Hide abstract]ABSTRACT: To compare one dimensional (1D) and three dimensional (3D) volume measurements and determine whether primary tumor (PT) burden is predictive of overall survival (OS) following cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC).
[Show abstract][Hide abstract]ABSTRACT: Objective:
To evaluate if BMI≥40 is associated with risk of postoperative complications, receipt of blood transfusion (PBT), length of hospitalization (LOS), perioperative death or hospital readmission rate following renal mass surgery.
After IRB approval, comprehensive information was collected for patients treated with surgery for renal mass from 2000-2015 at one institution. Univariable and multivariable analyses were used to evaluate the association of BMI≥40 among risk factors for perioperative outcomes.
A total of 1138 patients were treated surgically, including 118 (10.4%) patients with BMI≥40. Laparoscopic/robotic or open approach was used in 534 (47%) and 604 (53%) of patients. Morbid obesity was not associated with risk of major complications, overall complications, receipt of PBT, LOS, hospital readmission rate or perioperative death. Charlson Comorbidity index was the only independent predictor of major complications following renal mass surgery, p=0.0006, per point OR 1.2 (95%C.I. 1.08-1.32). Surgical site infections were more common in patients with BMI≥40 vs. BMI<40, (10.5% vs. 4.8%, p=0.01). Following multivariable analysis, BMI≥40 was the only independent predictor of surgical site infections, p=0.006, OR 2.6 (95%C.I. 1.32-5.13).
Morbid obesity (BMI≥40) is an independent predictor of developing surgical site infections. Morbid obesity is not predictive of risk for major complications, receipt of PBT, hospital readmission, perioperative death or LOS.
[Show abstract][Hide abstract]ABSTRACT: Kaposi’s sarcoma (KS) is a mesenchymal tumor of blood and lymph vessels associated with infection of human herpesvirus type 8 (HHV-8). Four distinct clinical variants are found including (1) classic, (2) African or endemic, (3) AIDS related or epidemic, and (4) iatrogenic. Commonly affected sites include mucocutaneous surfaces, the oropharynx, genitals, lower extremities, and, in advanced stages, viscera.
For the period 1971–2014, we identified 44 reported cases of penile KS: 6 in HIV-seropositive patients, 29 in HIV-seronegative patients, and 9 patients with unspecified HIV status. Excisional biopsy and histology including intralesional HHV-8 testing were performed in all cases to establish the diagnosis. HIV-seropositive patients had more severe presentations including multiple lesions, ulceration, lesions extending to the groin, and non-discolored nodules. Treatment for these patients included maximizing highly active antiretroviral therapy (HAART). Patients with other clinical variants (HIV negative or unknown) had local treatment performed in 55.3 % (21 out of 38) of cases. Average follow-up was 14.2 months with local recurrence in two cases (2 out of 38, 5.3 %) and distant recurrence in five cases (5 out of 38, 13.2 %). In addition, six case reports of genitourinary KS in HIV-seropositive patients were reported. These cases had more severe presentations including nonpigmented nodules, multiple ulcerated lesions, lesions extending to groin area, deformity of the penis, and urethral stricture. More invasive treatment was attempted in addition to maximizing HAART.
Penile KS is a virus-induced neoplasm affecting primarily men who are HIV positive, have other forms of immunosuppression, or are of Mediterranean or African origin. These subgroups may have different patterns of presentation and require different treatment strategies.
[Show abstract][Hide abstract]ABSTRACT: Objective:
To evaluate if extreme obesity (BMI ≥ 40) is associated with perioperative outcomes, overall survival (OS), cancer-specific survival (CSS), or recurrence-free survival (RFS) after surgical treatment for RCC.
Patients and methods:
After IRB approval, an institutional database identified patients treated surgically between January 2000 and December 2014 with pathologic diagnosis of RCC. Comprehensive clinical and pathologic data were reviewed. Kaplan-Meier analyses were used to estimate OS, RFS, and CSS. Univariate and multivariate Cox proportional hazards analysis was used to evaluate for associations with OS, CSS and RFS in patients with extreme obesity among other known predictive variables.
A total 100 (11.9%) patients were identified with BMI ≥ 40 and 743 (88.1%) with BMI<40 who were treated surgically for RCC. Morbid obesity was not associated with increased risk of blood transfusion (OR 1, 95% CI 0.587-1.70; p=1.0). Median hospital LOS was 4 days (IQR 3-6). Morbid obesity was not associated with longer LOS (p=0.26) or 30 day hospital readmission rates (p=1.0). Major complications (Clavien ≥3a) were recorded in 67 (7.95%) patients. BMI ≥ 40 was not a predictor of major complications (OR 0.58, 95% (CI 0.227-1.47), p=0.251 or 90 day mortality, p=0.4067. BMI ≥ 40 was not associated with worse OS (p= 0.7) or CSS (p=0.2), or RFS (p=0.5). BMI ≥ 35 was not also not associated with worse OS, CSS or RFS (p=0.3, 0.1, 0.5). Five year OS was 68.9% for the entire cohort including 69% and 70%, for patients with BMI < 40 and BMI ≥ 40 respectively, p=0.69. The 5 year CSS was 79.5% for the entire cohort, including 78.4% and 87.9% (p=0.16) for patients with BMI < 40 and BMI ≥ 40 respectively. The 5-year RFS rates for BMI < 40 and BMI ≥ 40 were 84.1% and 90.6% respectively, p=0.48.
Extreme obesity is not associated with worse perioperative or cancer outcomes after surgery for RCC. Surgery should remain a standard treatment option in well selected morbidly obese patients. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract]ABSTRACT: Defects in immune surveillance have been correlated with tumorigenesis and poor clinical outcomes in cancer patients. Given recent advances in vaccine therapies and checkpoint inhibition, therapeutic targeting of defective antigen processing may play a critical role in improving the broad utility of immunotherapies. Epigenetic alterations have been found to alter expression of genes involved in antigen processing and presentation. We evaluated the ability of epigenetic modifying agents to increase expression of antigen presentation machinery (APM) molecules ex vivo drug culture using primary human prostate tumor tissue biopsies. Prostate tissue biopsies were collected from patients with advanced, localized prostate cancer undergoing radical prostatect-omy. These tumor biopsies sectioned into 200uM slices and cultured with the hypomethylating agent decitabine (5AZA) and/or histidine-deacetylase inhibitor panobi-nostate (LBH589). After 72 hours of treatment, tissue slices were harvested and subjected to qRT-PCR analysis. 5AZA alone or in combination with LBH589 have increased expression of MHC Class I molecules (HLA-ABC, B2M) and APM elements including TAP2, Tapasin and LMP7. Increased expression of MHC class I molecules was identified in human prostate cancer treated with 5AZA and the combination of 5AZA and LBH589. Significant inter-patient heterogeneity was also observed, suggesting other mechanisms by which pros-tate cancer downregulates MHC class I expression. We further identify increased expression of Cancer-Testis Antigens in these samples, indicating multiple mechanisms by which epigenetic modifying agents may improve immune recognition of human prostate cancer. These include NY-ESO, SSX2 and NYSAR35. These results suggest novel therapeutic strategies that can be employed with other immune based therapies for men with localized and advanced prostate cancer.