Antoni Vilaseca

Histological subtype of renal cell carcinoma significantly affects survival in the era of partial nephrectomy

OBJECTIVES To analyze whether the histological subtype of renal cell carcinoma (RCC) affects survival after surgical resection in contemporary patients, and if so, whether prognostic significance differs according to the type of surgical resection or tumor stage. MATERIALS AND METHODS From 2006 to 2014, 2,237 patients underwent surgical resection (25% radical nephrectomy and 75% partial nephrectomy [PN]) for nonmetastatic RCC at a tertiary referral center. Estimated survival function curves and Cox regression models evaluated the effect of histological subtype on recurrence-free survival (RFS) and overall survival (OS). Interaction analyses tested whether the effect of histological subtype depends on the type of surgical resection or tumor stage. RESULTS Patients with RCC stage T2 or lower and those with low-grade conventional clear cell, papillary or chromophobe RCC of any stage had 5-year RFS probabilities>90%. Patients with clear cell papillary RCC stage T3 or greater had predicted 5-year RFS of 81%. However, 5-year OS probabilities were>94% for clear cell papillary RCC of any stage. High-grade conventional clear cell and papillary RCC stage T2 or lower, low-grade conventional clear cell and chromophobe RCC of any stage conferred 5-year OS probabilities of >93%. Unclassified RCC demonstrated the lowest OS probabilities at any stage. In multivariable analyses, histological subtype affected RFS (P<0.0001) and OS (P = 0.026) following surgical resection, with no differences in this association for radical nephrectomy vs. PN (RFS, P = 0.2; OS, P = 0.4), and across pathologic stages (RFS, P = 0.1; OS, P = 0.3). Compared with low-grade conventional clear cell RCC, chromophobe (hazard ratio [HR] = 0.72, 95% CI: 0.30-1.75) and papillary RCC (HR = 0.30, 95% CI: 0.09-0.97) conferred lower risk of recurrence. Chromophobe (HR = 0.67, 95% CI: 0.30-1.52) and clear cell papillary RCC (HR = 0.91, 95% CI: 0.12-6.78) conferred the lowest risk of all-cause mortality. CONCLUSIONS In the era of PN for RCC, histological subtype remained a significant predictor of survival, regardless of type of surgical resection or tumor stage.

Role of Cyclooxygenase-2 on Intermittent Hypoxia-Induced Lung Tumor Malignancy in a Mouse Model of Sleep Apnea

An adverse role for obstructive sleep apnea (OSA) in cancer epidemiology and outcomes has recently emerged from clinical and animal studies. In animals, intermittent hypoxia (IH) mimicking OSA promotes tumor malignancy both directly and via host immune alterations. We hypothesized that IH could potentiate cancer aggressiveness through activation of the cyclooxygenase-2 (COX-2) pathway and the concomitant increases in prostaglandin E2 (PGE2). The contribution of the COX-2 in IH-induced enhanced tumor malignancy was assessed using celecoxib as a COX-2 specific inhibitor in a murine model of OSA bearing Lewis lung carcinoma (LLC1) tumors. Exposures to IH accelerated tumor progression with a tumor associated macrophages (TAMs) shift towards a pro-tumoral M2 phenotype. Treatment with celecoxib prevented IH-induced adverse tumor outcomes by inhibiting IH-induced M2 polarization of TAMs. Furthermore, TAMs isolated from IH-exposed mice treated with celecoxib reduced the proliferation of LLC1 naïve cells, while the opposite occurred with placebo-treated IH-exposed mice. Finally, in vitro IH exposures of murine macrophages and LLC1 cells showed that both cell types increased PGE2 release in response to IH. These results suggest a crucial role for the COX-2 signaling pathway in the IH-exacerbated malignant processes, and designate macrophages and lung adenocarcinoma cells, as potential sources of PGE2.

Intermittent hypoxia increases kidney tumor vascularization in a murine model of sleep apnea

We investigate the effects of intermittent hypoxia (IH), a characteristic feature of obstructive sleep apnea (OSA), on renal cancer progression in an animal and cell model. An in vivo mouse model (Balb/c, n = 50) of kidney cancer was used to assess the effect of IH on tumor growth, metastatic capacity, angiogenesis and tumor immune response. An in vitro model tested the effect of IH on RENCA cells, macrophages and endothelial cells. Tumor growth, metastatic capacity, circulating vascular endothelial growth factor (VEGF) and content of endothelial cells, tumor associated macrophages and their phenotype were assessed in the tumor. In vitro, VEGF cell expression was quantified.Although IH did not boost tumor growth, it significantly increased endothelial cells (p = 0.001) and circulating VEGF (p<0.001) in the in vivo model. Macrophages exposed to IH in vitro increased VEGF expression, whereas RENCA cells and endothelial cells did not. These findings are in keeping with previous clinical data suggesting that OSA has no effect on kidney cancer size and that the association observed between OSA and higher Fuhrman grade of renal cell carcinoma may be mediated though a proangiogenic process, with a key role of macrophages.

The Role of Surgery in Local Recurrences after Radical Cystectomy for Bladder Cancer

Introduction: Local recurrence (LR) after radical cystectomy (RC) for bladder cancer has a bad prognosis. Treatment options include chemotherapy, radiation therapy and surgical excision, but few data is available on the advantages of surgery for these patients. Patients and Methods: We evaluated our series of 8 selected patients who underwent surgery for locally recurrent bladder cancer after RC. Results: The median time to recurrence after cystectomy was 20.8 months. The complications rate and severity were not negligible. Pathology report confirmed urothelial carcinoma with negative margins in all patients. After LR treatment, 4 patients recurred locally for a second time and 3 developed distant metastasis. They all died after a median follow-up of 10.4 months. One patient remained disease free after 14 months. Conclusions: The prognosis of patients with LR is poor regardless of surgical treatment and reflects the aggressive biological nature of urothelial tumors.

Repeat prostate biopsies prior to radical prostatectomy do not impact erectile function recovery and mid- to long-term continence

A growing number of men undergo repeat biopsies prior to radical prostatectomy for prostate cancer. However, the long‐term impact of repeat biopsies on functional outcomes in this patient population remains unelucidated. Thus, we compared functional outcomes between patients who underwent single biopsy versus repeat biopsies before radical prostatectomy.

Dynamic 18F-FDG PET- Lymphography for in Vivo Identification of Lymph Node Metastases in Murine Melanoma

Positron lymphography using 18F-FDG followed by Cerenkov-guided resection of lymph nodes in healthy mice has previously been introduced by our group. Our aim in this study was to further assess the technique’s potential beyond merely localizing sentinel lymph nodes. We now aimed to evaluate the potential of positron lymphography to characterize the nodes with respect to their tumor status in order to identify metastatic lymph nodes. We explored whether metastatic nodes could be distinguished from normal nodes via dynamic 18F-FDG lymphography, to then be resected under Cerenkov imaging guidance. Methods: A murine melanoma cell line highly metastatic to lymph nodes (B16F10) was implanted subcutaneously on the dorsal hind paw of C57 mice while the tumor-free contralateral leg served as an intraindividual control. A model of reactive lymph nodes after concanavalin A challenge served as an additional control to provide nonmalignant inflammatory lymphadenopathy. Dynamic PET/CT imaging was performed immediately after injection of 18F-FDG around the tumor or intracutaneously in the contralateral footpad. Furthermore, PET/CT and Cerenkov studies were performed repeatedly over time to follow the course of metastatic spread. In selected mice, popliteal lymph nodes underwent Cerenkov luminescence imaging. Hematoxylin and eosin staining was done to verify the presence of lymphatic melanoma infiltration. Results: Positron lymphography using 18F-FDG was successfully performed on tumor-bearing and non–tumor-bearing mice, as well as on controls bearing sites of inflammation; the results clearly identified the sentinel lymph node basin and delineated the lymphatic drainage. Significantly prolonged retention of activity was evident in metastatic nodes as compared with controls without tumor. On the basis of these results, the contrast in detection and identification of metastatic lymph nodes was distinct and could be used for guided lymph node resection, such as by using Cerenkov luminescence imaging. However, retention after 18F-FDG lymphography was also seen in acute inflammatory lymphadenopathy. Conclusion: In a tumor model, significantly longer retention of the radiotracer during 18F-FDG lymphography was seen in metastatic than nonmetastatic lymph nodes, allowing for differentiation between the two and for selective resection of tumor-bearing nodes using Cerenkov imaging. Inflammation can be better differentiated in a subacute state.

Should Fluorescence Mapping be Used to Guide Pelvic Lymph Node Dissection

THE long-term risk of death from prostate cancer is and logistics impeded its acceptance. For instance, substantially increased in patients with lymph node metastasis (LNM) and is estimated to range from 23% to 42%. Based on published surgical series 25% to 30% of patients with high risk features (prostate specific antigen greater than 20 ng/ml, Gleason score 8 or greater, or cT3a) will have LNM at presentation. This high incidence rate represents a strong rationale for the concomitant treatment of the pelvic lymph nodes at radical prostatectomy. While most clinicians would agree with this rationale, consensus has not been reached with regard to the appropriate anatomical template (limited vs extended) for pelvic lymph node dissection (PLND) and the validity of the sentinel lymph node concept in prostate cancer. In patients with intermediate or high risk cancer features extended PLND has been shown to improve staging and detect 3 times more LNM than the limited template. Extended PLND also provides valuable information to help guide further therapies without a prohibitive increase in morbidity. The risk-to-benefit ratio of extended vs limited PLND would be 1 additional grade 3 complication for the benefit of detecting 20 additional patients with nodal metastases. However, extended PLND that includes the external iliac, hypogastric and obturator fossa nodal packets does not encompass all prostate lymphatic drainage sites. Mattei et al have shown that up to 35% of prostate lymphatic drainage sites remain outside of the extended anatomical template. To circumvent this limitation and potentially reduce morbidity, several investigators have explored the sentinel lymph node concept. Early trials involved injecting a radiotracer such as colloid bound technetium directly into the prostate to detect the lymphatic drainage of the prostate on single photon emission computerized tomography/computerized tomography/ magnetic resonance imaging. Sensitivities in the range of 93% to 96% were reported. Despite promising initial findings, limitations such as variability of results and difficulties with reproducibility

Does Subclassification of Pathologically Organ Confined (pT2) Prostate Cancer Provide Prognostic Discrimination of Outcomes after Radical Prostatectomy

Purpose: We tested the latest update in the prostate cancer staging system by assessing the prognostic association of pT2 subclassification with the probability of survival related outcomes in patients who underwent radical prostatectomy. Materials and Methods: We retrospectively analyzed the records of a total of 15,305 patients who underwent radical prostatectomy at 2 referral centers between 1985 and 2016, and had pT2 disease at the final pathological evaluation. Descriptive statistics were used to compare baseline data stratified by pT2 substages (pT2a/b vs pT2c). Cox regression models were adjusted for institution analyzed differences in the rate of biochemical recurrence, metastasis, cancer specific death and overall mortality. Multivariable Cox regression models were used to evaluate the predictive value of pT2 subclassification for survival, including the linear predictor from the Stephenson nomogram. Results: Prostate specific antigen levels and Gleason score differed significantly between the pT2 substages (each p <0.0001). At a median followup of 6.0 years (IQR 3.3–10.1) 2,083 patients had biochemical recurrence, 161 had metastases, 43 had died of prostate cancer and 1,032 had died of another cause. On univariate analysis the pT2 subclassification was significantly associated with biochemical recurrence (p = 0.001) and distant metastasis (p = 0.033) but not with cancer specific death (p = 0.6) or overall mortality (p = 0.3). Multivariable analysis showed no evidence of a significant association between the pT2 subclassification and biochemical recurrence (p = 0.4) or distant metastasis (p = 0.6). Multivariable analysis of cancer specific death and overall mortality was omitted due to lack of significance on univariate analysis. Conclusions: Subclassification of pT2 prostate cancer is not a prognostic indicator of survival related outcomes after radical prostatectomy. Our results validate the elimination of pT2 substages in the updated staging system.