Paul L. Crispen

Natural history, growth kinetics, and outcomes of untreated clinically localized renal tumors under active surveillance

The growth kinetics of untreated solid organ malignancies are not defined. Radiographic active surveillance (AS) of renal tumors in patients unfit or unwilling to undergo intervention provides an opportunity to quantify the natural history of untreated localized tumors. The authors report the radiographic growth kinetics of renal neoplasms during a period of surveillance.

Delayed intervention of sporadic renal masses undergoing active surveillance

Prompt surgical management remains the standard of care for renal cell carcinoma (RCC). Occasionally, it is necessary to postpone or delay surgical treatment. The authors of this report assessed whether delayed intervention following a period of active surveillance altered minimally invasive or nephron‐sparing treatment plans, increased the risk of stage progression, and/or decreased recurrence‐free survival rates.

Predicting Growth of Solid Renal Masses Under Active Surveillance

OBJECTIVES The natural history and growth rates of untreated solid enhancing renal tumors is being defined through active surveillance series. Serial radiographic evaluation of patients who are not surgical candidates or refuse surgical treatment provides an opportunity to characterize the growth of untreated enhancing renal tumors. Here we evaluate factors that may help predict radiographic growth during observation. MATERIALS AND METHODS We reviewed our renal cancer database for enhancing renal masses that were radiographically observed for a period of at least 12 months. Variables examined included patient age, gender, lesion size on presentation, radiographic tumor characteristics, duration of active surveillance, linear growth rate, surgical pathology, development of new renal tumors, and stage progression. RESULTS One hundred nine patients with 124 sporadic enhancing renal tumors were identified undergoing a period of active surveillance of at least 12 months. Median patient age was 73 years (mean 69.8, range 35-87); 72% (78/109) of patients were males. Median duration of active surveillance was 26 months (mean 33.4, range 12-156). Multifocal disease was present in 9% (10/109) of patients on presentation, accounting for 20% (25/124) of all tumors. Tumor size on presentation was a median of 2.0 cm (mean 2.61, range 0.4-12.0). Overall median tumor growth rate was 0.21 cm/y (mean 0.28, range 1.4-2.47). Observed linear growth rates were independent of patient age, gender, tumor size on presentation, multifocality, and radiographic characteristics (solid versus cystic), P > 0.05. Of the patients initiating a period of active surveillance 36% (39/109) eventually underwent definitive therapy. Malignant pathology was present in 90% (35/39) of patients undergoing treatment. In patients continuing active surveillance [64% (70/109)], 2.9% (2/70) developed de novo renal lesions and 1.4% (1/70) developed metastatic disease. CONCLUSIONS Currently, no clinical predictors of tumor growth or disease progression have been identified, although, the risk of developing progressive disease over the short term appears low. Clinical and molecular markers of disease progression are needed prior to offering active surveillance to otherwise acceptable surgical candidates.

Zinc chelation induces rapid depletion of the X-linked inhibitor of apoptosis and sensitizes prostate cancer cells to TRAIL-mediated apoptosis

The X-linked inhibitor of apoptosis (XIAP), the most potent member of the inhibitor of apoptosis protein (IAP) family of endogenous caspase inhibitors, blocks the initiation and execution phases of the apoptotic cascade. As such, XIAP represents an attractive target for treating apoptosis-resistant forms of cancer. Here, we demonstrate that treatment with the membrane-permeable zinc chelator, N,N,N′,N′,-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) induces a rapid depletion of XIAP at the post-translational level in human PC-3 prostate cancer cells and several non-prostate cell lines. The depletion of XIAP is selective, as TPEN has no effect on the expression of other zinc-binding members of the IAP family, including cIAP1, cIAP2 and survivin. The downregulation of XIAP in TPEN-treated cells occurs via proteasome- and caspase-independent mechanisms and is completely prevented by the serine protease inhibitor, Pefabloc. Finally, our studies demonstrate that TPEN promotes activation of caspases-3 and -9 and sensitizes PC-3 prostate cancer cells to TRAIL-mediated apoptosis. Taken together, our findings indicate that zinc-chelating agents may be used to sensitize malignant cells to established cytotoxic agents via downregulation of XIAP.

Depletion of intracellular zinc increases expression of tumorigenic cytokines VEGF, IL-6 and IL-8 in prostate cancer cells via NF-κB-dependent pathway

Zinc accumulation diminishes early in the course of prostate malignancy and continues to decline during progression toward hormone‐independent growth. In contrast, constitutive levels of NF‐κB activity increase during progression of prostate cells toward greater tumorigenic potential. We have reported previously that physiological levels of zinc suppress NF‐κB activity in prostate cancer cells and reduce expression of pro‐angiogenic and pro‐metastatic cytokines VEGF, IL‐6, IL‐8, and MMP‐9 associated with negative prognostic features in prostate cancer.

Mechanisms of apoptosis resistance and treatment strategies to overcome them in hormone‐refractory prostate cancer

New therapeutic strategies are needed to improve treatment outcomes in men with hormone‐refractory prostate cancer. A better understanding of the molecular mechanisms of cell death in response to therapeutic strategies will help avoid ineffective treatment regimens and provide a molecular basis for new therapeutic modalities targeting apoptosis‐resistant forms of prostate cancer. In this review, the authors focused on the established aberrations of apoptosis in hormone‐refractory prostate cancer, and they have described novel treatment strategies to overcome apoptosis resistance. Cancer 2008.

Residual Prostate Cancer After Radiotherapy: A Study of Radical Cystoprostatectomy Specimens

OBJECTIVES The incidence of histologic prostate cancer (CaP) after definitive radiation therapy (RT) for localized disease is rarely quantitated. We investigated the relationship between prostate-specific antigen (PSA) and histologically residual CaP after definitive RT in patients undergoing radical cystoprostatectomy (RCP) for unrelated indications. METHODS We reviewed our prostate cancer database to identify patients undergoing RCP who previously received definitive RT for localized CaP. Pre-radiation variables examined include PSA, Gleason score, radiation modality, and dose. Post-radiation variables reviewed include PSA, time to RCP, the presence of histologically proven prostate cancer, and Gleason score. RESULTS We identified 21 patients who underwent RCP at a median of 60 months after RT for localized CaP. Pre-radiation Gleason scores were low (6 or less) to intermediate risk (3+4) in 82% (14 of 17), intermediate (4+3) to high (8 or greater) in 18% (3 of 17), and unavailable in 4 patients. Median pre-radiation PSA was 9 ng/mL. Median PSA before RCP in all patients was 0.8 ng/mL. A total of 52% (11 of 21) of patients demonstrated active CaP in the RCP specimen. Although 89% (16 of 18) of patients met the Phoenix definition of biochemical freedom from disease, 50% (8 of 16) of these patients had histologically residual CaP at the time of RCP. Median PSA was not significantly different between patients with and without active CaP. CONCLUSIONS Histologic evidence of CaP was noted in 50% of patients demonstrating biochemical freedom from disease at the time of RCP. Although the biological significance of active CaP in this select population is uncertain, our findings demonstrate the limitations of PSA in monitoring CaP disease activity after definitive RT.

Active Surveillance of Localized Renal Tumors

The incidental detection of small enhancing renal masses presumed to be renal cell carcinoma has increased due to the widespread use of cross-sectional body imaging. Active surveillance of these lesions has been pursued in elderly or infirm patients. Here we review the current data regarding the growth kinetics, pathology, stage progression, and clinical management of renal masses under active surveillance. The limitations of these data are discussed.

The Role of Angioinfarction in the Management of Renal Tumors

Hypervascularity is a radiographic and pathologic hallmark of most solid tumors of the kidney. Angioinfarction targets the end product of altered angiogenesis pathways by eliminating the tumor’s blood supply. Angioinfarction of renal tumors may be used to both the surgeon’s and patient’s advantage. Here we review the history, indications, techniques, and complications of angioinfarction in the management of primary renal tumors and their metastases.