Eric Kauffman

The Basic Biology of Metastasis

It is the ability to metastasize that makes cancer a fatal disease. Of the 555,500 cancer-related deaths expected this year in the United States, the vast majority are due to the development of metastatic disease rather than the primary tumor (Jemal et al., 2002). Although treatment is available for patients with metastatic cancer, options are limited and responses can be quite variable. Furthermore, complete remissions tend to be limited in both scope and duration.

Learning curves for robot-assisted and laparoscopic partial nephrectomy.

OBJECTIVES To evaluate the learning curve of robot-assisted partial nephrectomy (RAPN) and laparoscopic partial nephrectomy (LPN) between two surgeons at a single institution. METHODS A prospectively maintained, Institutional Review Board (IRB)-approved kidney surgery database was reviewed retrospectively and the first 116 consecutive LPNs performed by one surgeon (Hyung Kim) and 116 consecutive RPNs performed by a second surgeon (Thomas Schwaab) were identified. The learning curve was evaluated by examining the operative times, warm ischemia times (WITs), estimated blood loss, the postoperative estimated glomerular filtration rate (eGFR), and intra- and postoperative complications in the quartiles of 29 patients. The LPNs performed by Hyung Kim were done following completion of a minimally invasive fellowship. Thomas Schwaab had minimal experience with LPN and no fellowship training before starting RAPN. RESULTS The RAPN and LPN groups had similar patient and tumor characteristics. The RAPN group had a higher preoperative eGFR (74.1±22.04 vs. 80.95±21.25 mL/minutes, p=0.015) and a worse Eastern Cooperative Oncology Group (ECOG) performance status (ECOG 1+ in 12% vs. 2.6%, p<0.001) compared with the LPN group. Rates of intraoperative (p=0.203) and postoperative (p=0.193) complications were similar. In the RAPN group, operating room (OR) time (161±51 vs. 203±55 minutes, p<0.001) and WIT (17.7±14.8 vs. 21.8±9.1 minutes, p<0.001) were shorter. Postoperative stay was longer in the RAPN group (2.4±2.2 vs. 1.67±1.1 days, p<0.001). The percentage decrease in postoperative eGFR was lower in the RAPN group versus the LPN (9.6% vs. 10%). The learning curves differed for log tumor size, log WIT, and postoperative complications. CONCLUSIONS The variables of the learning curve for RAPN can be obtained earlier than the same variables for LPN. RAPN had a shorter OR time and WITs. The shorter WITs, earlier in the series, led to consistently lower fluctuations in GFR and preservation of the renal function. The learning curves for each procedure need to be re-evaluated at longer intervals to ensure their accuracy.

Toll-like receptor 7 agonist therapy with imidazoquinoline enhances cancer cell death and increases lymphocytic infiltration and proinflammatory cytokine production in established tumors of a renal cell carcinoma mouse model.

Imidazoquinolines are synthetic toll-like receptor 7 and 8 agonists and potent dendritic cell activators with established anticancer activity. Here we test the hypothesis that imidazoquinoline has in vivo efficacy within established renal cell carcinoma (RCC) tumors. Immunocompetent mice bearing syngeneic RCC xenografts were treated with imidazoquinoline or placebo at two separate time points. Harvested tumors were assayed by TUNEL/caspase-3/Ki67 immunostains to evaluate cell death/apoptosis/proliferation, and CD3/B220/CD45 immunostains to evaluate T-cell lymphocyte/B-cell lymphocyte/pan-leukocyte tumor infiltration. ELISA measurement of tumor and serum levels of proinflammatory cytokines, IL-6 and MCP-1, was performed. A single imidazoquinoline dose significantly decreased RCC tumor growth by 50% and repeat dosing compounded the effect, without observed weight loss or other toxicity. Tumor immunostaining revealed significant increases in cell death and apoptosis without changes in cell proliferation, supporting induction of apoptosis as the primary mechanism of tumor growth suppression. Imidazoquinoline treatment also significantly enhanced peritumoral aggregation and intratumoral infiltration by T-cell lymphocytes, while increasing intratumoral (but not serum) levels of proinflammatory cytokines. In conclusion, imidazoquinoline treatment enhances T-cell lymphocyte infiltration and proinflammatory cytokine production within established mouse RCC tumors, while suppressing tumor growth via induction of cancer cell apoptosis. These findings support a therapeutic role for imidazoquinoline in RCC.

MP39-14 IRON ACCUMULATION DURING RENAL CELL CARCINOGENESIS AND REVERSAL WITH TUMOR PROGRESSION

microenvironment including invasions of Treg and M2 macrophages and CRP in RCC patients to explore the mechanisms underlying the association between CRP level and prognosis. METHODS: Immunohistochemical (IHC) measurement of CD4, CD8, CD163 (M2 macrophages), and FOXP3 (Treg) was performed in clear-cell RCC (ccRCC) patients (n 1⁄4111) treated with radical or partial nephrectomy. CD4+, CD8+, and CD163+ cells were counted and the optimal cut-off scores for CD4, CD8 and CD163 were determined through receiver-operating characteristic (ROC) analysis. Patients were classified into groups according to FOXP3 positive or negative status. The association between IHC status and preoperative serum CRP level and cancer-specific survival (CSS) was analyzed. RESULTS: Median follow-up period was 8.5 years. pT stage was pT1 in 58%, pT2 in 5%, pT3 in 35% and pT4 in 2% of patients. Lymph node involvement and distant metastasis were seen in 4% and 20% of patients, respectively. Thirty-three patients (30%) had a high CRP level ( 5.0 mg/L), and the CSS rate was significantly worse among these patients than among the remaining patients (p <0.0001). In patients with strong invasion of CD8+, CD163+ or FOXP3+ cells, CRP levels were significantly higher (Figure 1) and CSS was significantly worse (Figure 2) compared to patients with weak invasion. CONCLUSIONS: Invasion of the immunosuppressive cells known as Tregs and M2 macrophages in the tumor microenvironment is associated with higher CRP and poor prognosis in ccRCC patients. CRP indicates an immunosuppressive microenvironment.

Transferrin receptor 1 upregulation in primary tumor and downregulation in benign kidney is associated with progression and mortality in renal cell carcinoma patients

The central dysregulated pathway of clear cell (cc) renal cell carcinoma (RCC), the von Hippel Lindau/hypoxia inducible factor-α axis, is a key regulator of intracellular iron levels, however the role of iron uptake in human RCC tumorigenesis and progression remains unknown. We conducted a thorough, large-scale investigation of the expression and prognostic significance of the primary iron uptake protein, transferrin receptor 1 (TfR1/CD71/TFRC), in RCC patients. TfR1 immunohistochemistry was performed in over 1500 cores from 574 renal cell tumor patient tissues (primary tumors, matched benign kidneys, metastases) and non-neoplastic tissues from 36 different body sites. TfR1 levels in RCC tumors, particularly ccRCC, were significantly associated with adverse clinical prognostic features (anemia, lower body mass index, smoking), worse tumor pathology (size, stage, grade, multifocality, sarcomatoid dedifferentiation) and worse survival outcomes, including after adjustments for tumor pathology. Highest TfR1 tissue levels in the non-gravid body were detected in benign renal tubule epithelium. Opposite to TfR1 changes in the primary tumor, TfR1 levels in benign kidney dropped during tumor progression and were inversely associated with worse survival outcomes, independent of tumor pathology. Quantitative measurement of TfR1 subcellular localization in cell lines demonstrated mixed cytoplasmic and membranous expression with increased TfR1 in clusters in ccRCC versus benign renal cell lines. Results of this study support an important role for TfR1 in RCC progression and identify TfR1 as a novel RCC biomarker and therapeutic target.

Efficacy of robot-assisted radical cystectomy (RARC) in advanced bladder cancer: results from the International Radical Cystectomy Consortium (IRCC): Efficacy of RARC in advanced bladder cancer

To characterise the surgical feasibility and outcomes of robot‐assisted radical cystectomy (RARC) for pathological T4 bladder cancer.