Biophysical phenotype mixtures reveal advantages for tumor muscle invasion in vivo.

Bladder, colon, gastric, prostate, and uterine cancers originate in organs surrounded by laminin-coated smooth muscle. In human prostate cancer, tumors that are organ confined, without extracapsular extension through muscle, have an overall cancer survival rate of up to 97% compared with 32% for metastatic disease. Our previous work modeling extracapsular extension reported the blocking of tumor invasion by mutation of a laminin-binding integrin called α6ß1. Expression of the α6AA mutant resulted in a biophysical switch from cell-ECM (extracellular matrix) to cell-cell adhesion with drug sensitivity properties and an inability to invade muscle. Here we used different admixtures of α6AA and α6WT cells to test the cell heterogeneity requirements for muscle invasion. Time-lapse video microscopy revealed that tumor mixtures self-assembled into invasive networks in vitro, whereas α6AA cells assembled only as cohesive clusters. Invasion of α6AA cells into and through live muscle occurred using a 1:1 mixture of α6AA and α6WT cells. Electric cell-substrate impedance sensing measurements revealed that compared with α6AA cells, invasion-competent α6WT cells were 2.5-fold faster at closing a cell-ECM or cell-cell wound, respectively. Cell-ECM rebuilding kinetics show that an increased response occurred in mixtures since the response was eightfold greater compared with populations containing only one cell type. A synthetic cell adhesion cyclic peptide called MTI-101 completely blocked electric cell-substrate impedance sensing cell-ECM wound recovery that persisted in vitro up to 20 h after the wound. Treatment of tumor-bearing animals with 10 mg/kg MTI-101 weekly resulted in a fourfold decrease of muscle invasion by tumor and a decrease of the depth of invasion into muscle comparable to the α6AA cells. Taken together, these data suggest that mixed biophysical phenotypes of tumor cells within a population can provide functional advantages for tumor invasion into and through muscle that can be potentially inhibited by a synthetic cell adhesion molecule.

Preliminary evaluation of urinary soluble Met as a biomarker for urothelial carcinoma of the bladder.

BACKGROUND: Among genitourinary malignancies, bladder cancer (BCa) ranks second in both prevalence and cause of death. Biomarkers of BCa for diagnosis, prognosis and disease surveillance could potentially help prevent progression, improve survival rates and reduce health care costs. Among several oncogenic signaling pathways implicated in BCa progression is that of hepatocyte growth factor (HGF) and its cell surface receptor, Met, now targeted by 25 experimental anti-cancer agents in human clinical trials. The involvement of this pathway in several cancers is likely to preclude the use of urinary soluble Met (sMet), which has been correlated with malignancy, for initial BCa screening. However, its potential utility as an aid to disease surveillance and to identify patients likely to benefit from HGF/Met-targeted therapies provide the rationale for this preliminary retrospective study comparing sMet levels between benign conditions and primary BCa, and in BCa cases, between different disease stages. METHODS: Normally voided urine samples were collected from patients with BCa (Total: 183; pTa: 55, pTis: 62, pT1: 24, pT2: 42) and without BCa (Total: 83) on tissue-procurement protocols at three institutions and sMet was measured and normalized to urinary creatinine. Normalized sMet values grouped by pathologic stage were compared using non-parametric tests for correlation and significant difference. ROC analyses were used to derive classification models for patients with or without BCa and patients with or without muscle-invasive BCa (MIBCa or NMIBCa). RESULTS: Urinary sMet levels accurately distinguished patients with BCa from those without (p<0.0001, area under the curve (AUC): 0.7008) with limited sensitivity (61%) and moderate specificity (76%), and patients with MIBCa (n=42) from those with NMIBCa (n=141; p<0.0001, AUC: 0.8002) with moderate sensitivity and specificity (76% and 77%, respectively) and low false negative rate (8%). CONCLUSIONS: Urinary sMet levels distinguish patients with BCa from those without, and patients with or without MIBCa, suggesting the potential utility of urinary sMet as a BCa biomarker for surveillance following initial treatment. Further studies are warranted to determine its potential value for prognosis in advanced disease, predicting treatment response, or identifying patients likely to benefit from Met-targeted therapies.

Penile Fournier's gangrene.

Fournier's gangrene is a fulminant, necrotizing soft-tissue infection of the genital, perineal, and perianal regions. Fournier's isolated to the penis is a rare occurrence due the highly vascular nature of the penis. Reported occurrences of penile Fournier's gangrene have occurred in the setting of a clear vascular or traumatic insult. Here we present a case of Fournier's gangrene isolated to the penis in an adult with calciphylaxis secondary to end-stage renal disease.

Decreasing the indications for radical nephrectomy: a study of multifocal renal cell carcinoma.

Multifocal renal cell carcinoma (RCC) has been reported in 5-25% of cases worldwide. Although management of patients with multifocal RCC has not been clearly defined, presence of multifocal renal masses in one kidney and a normal contralateral kidney has often been considered a reason for performing radical nephrectomy. This study reviews the world literature to provide an accurate estimate of the prevalence of multifocal RCC and evaluates the oncologic outcomes of multifocal RCC after exclusion of patients with known hereditary and familial renal syndromes. A PubMed search of the literature was performed for articles in the English language using the following terms for the query: "multifocal RCC," "multifocality and RCC," "multicentric RCC," or "bilateral RCC." The references of the published articles were also reviewed for additional publications. Articles that did not specifically exclude patients with familial RCC or known hereditary RCC syndromes were excluded for estimation of multifocality prevalence and oncologic outcomes. After applying our exclusion criteria, nine articles were selected and form the basis of the current analysis. Weighted averages were used to calculate the prevalence of multifocality. Multifocal RCC was found in 6.8% of cases (373 of 5433 patients). Ipsilateral multifocality was found in 6.8% of cases. Bilateral multifocality was found in 11.7% of cases. Of all cases reported in this study, only 10% underwent partial nephrectomy. The rest of the study cohort underwent radical nephrectomy. The review of the literature showed that the use of nephron-sparing techniques in patients with multifocal disease did not compromise oncologic outcomes, despite the need for reoperation in certain cases. In conclusion, multifocal RCC remains a prevalent entity. Most clinicians still prefer to perform radical nephrectomies in these patients despite proven equivalent oncologic outcomes compared to nephron-sparing techniques. Urologists should be aware of these data when proposing treatment options to patients with multifocal RCC.

Prognostic nomogram for renal insufficiency after radical or partial nephrectomy.

PURPOSE: We analyzed prognostic factors to predict renal insufficiency after partial or radical nephrectomy. We developed and performed internal validations of a postoperative nomogram for this purpose. We used a prospectively updated renal tumor database of more than 1,500 patients. MATERIALS AND METHODS: From July 1989 to October 2003, 161 partial nephrectomies and 857 radical nephrectomies performed at Memorial Sloan-Kettering Cancer Center for renal cortical tumors were analyzed. Computerized tomography images were reviewed by a single radiologist. Kidney volume was calculated using the ellipsoid formula, V = L1 x L2 x L3 x pi/6, where V represents volume and L represents length. Renal insufficiency was defined by 2 serum creatinine values greater than 2.0 mg/dl at least 1 month postoperatively. Tumor histology was not an exclusion criterion and yet we excluded cases of bilateral synchronous disease. Prognostic variables were preoperative serum creatinine, American Society of Anesthesiologists score, percent change in kidney volume after surgery, and patient age and sex. RESULTS: Renal insufficiency was noted in 105 of the 857 patients with radical nephrectomy (12.3%) and in 6 of the 161 with partial nephrectomy (3.7%) studied. Patients had a median followup of 21.2 months (maximum 157.9). The 7-year probability of freedom from renal insufficiency in the cohort was 79.1% (95% CI 74.6 to 83.6). The nomogram was designed based on a Cox proportional hazards regression model. Following internal statistical validation nomogram predictions appeared accurate and discriminating with a concordance index of 0.835. CONCLUSIONS: A nomogram was developed that can predict the 7-year probability of renal insufficiency in patients undergoing radical or partial nephrectomy.

A postoperative prognostic nomogram predicting recurrence for patients with conventional clear cell renal cell carcinoma.

PURPOSE: Few published studies have simultaneously analyzed multiple prognostic factors to predict recurrence after surgery for conventional clear cell renal cortical carcinomas. We developed and performed external validation of a postoperative nomogram for this purpose. We used a prospectively updated database of more than 1,400 patients treated at a single institution. MATERIALS AND METHODS: From January 1989 to August 2002, 833 nephrectomies (partial and radical) for renal cell carcinoma of conventional clear cell histology performed at Memorial Sloan-Kettering Cancer Center were reviewed from the center's kidney database. Patients with von Hippel-Lindau disease or familial syndromes, as well as patients presenting with synchronous bilateral renal masses, or distant metastases or metastatic regional lymph nodes before or at surgery were excluded from study. We modeled clinicopathological data and disease followup for 701 patients with conventional clear cell renal cell carcinoma. Prognostic variables for the nomogram included pathological stage, Fuhrman grade, tumor size, necrosis, vascular invasion and clinical presentation (ie incidental asymptomatic, locally symptomatic or systemically symptomatic). RESULTS: Disease recurrence was noted in 72 of 701 patients. Those patients without evidence of disease had a median and maximum followup of 32 and 120 months, respectively. The 5-year probability of freedom from recurrence for the patient cohort was 80.9% (95% confidence interval 75.7% to 85.1%). A nomogram was designed based on a Cox proportional hazards regression model. Following external validation predictions by the nomogram appeared accurate and discriminating, and the concordance index was 0.82. CONCLUSIONS: A nomogram has been developed that can be used to predict the 5-year probability of freedom from recurrence for patients with conventional clear cell renal cell carcinoma. This nomogram may be useful for patient counseling, clinical trial design and effective patient followup strategies.