Electrochemotherapy for the treatment of primary basal cell carcinoma; A randomised control trial comparing electrochemotherapy and surgery with five year follow up.

Basal cell carcinoma (BCC) are the commonest cutaneous malignancy and incidence continues to increase. There is a need to expand the therapeutic toolbox to increase options for patients that are unsuitable for or unwilling to undergo the current therapies. Electrochemotherapy (ECT) is a technique where cells are temporarily permeabilized after exposure to a brief pulsed electrical field and combined with low dose chemotherapeutics to ablate malignancies. It is a simple technique causing minimal damage to the surrounding healthy tissue and has the potential to avoid the need for complex reconstruction. ECT is an established treatment for skin metastases but its role as a primary treatment modality is not demonstrated. A prospective randomised control trial evaluating ECT against the gold standard of treatment, Surgery, was performed for patients with primary BCC and patients followed for 5 years. All lesions treated with ECT (n = 69) responded although 8/69 (12%) needed a second treatment to ensure a complete response. All surgical lesions (n = 48) showed histological evidence of complete excision with 2/48 (4%) undergoing a second excision. At 5 years, in the surgical arm there was no evidence of recurrence in 39/40 (97.5%) lesions with 1/40 (2.5%) confirmed recurrence. In the ECT arm there was no evidence of recurrence in 42/48 lesions (87.5%). There was 5 confirmed recurrences. These groups show statistical equivalence in this non inferiority study design (p = 0.33). ECT is an effective and durable treatment option for primary BCC and should be considered as part of the armamentarium of options available.

Active surveillance is superior to radical nephrectomy and equivalent to partial nephrectomy for preserving renal function in patients with small renal masses: Results from the DISSRM registry.

PURPOSE: We compared renal function outcomes among patients in the surveillance and intervention arms of the DISSRM registry. MATERIALS AND METHODS: Patients were grouped into chronic kidney disease stages by estimated glomerular filtration rate range. Cases were considered up staged if a more advanced chronic kidney disease stage was entered during followup. Chronic kidney disease up staging-free survival was compared among groups using Kaplan-Meier analysis and paired comparisons log rank tests. Multivariate Cox regression identified independent predictors of chronic kidney disease up staging-free survival. RESULTS: A total of 162 patients met the study inclusion criteria, with 68 in the surveillance arm, 65 undergoing partial nephrectomy, 15 undergoing radical nephrectomy, and 14 undergoing cryoablation. Median tumor size was 2.2cm. Mean estimated glomerular filtration rate change was significantly larger for radical nephrectomy vs. surveillance (-9.2 vs. -0.5ml/min/1.73m2) and for radical vs. partial nephrectomy (-9.2 vs. -1.9ml/min/1.73m2) (P = 0.001). No other groups differed significantly. On Kaplan-Meier analysis, patients undergoing radical nephrectomy had significantly worse chronic kidney disease up staging-free survival vs. those treated with partial nephrectomy (P = 0.029), surveillance (P = 0.007), and cryoablation (P = 0.019). No other groups differed significantly. On multivariate analysis, radical nephrectomy independently predicted poor chronic kidney disease up staging-free survival (odds ratio vs. surveillance 30.6, P = 0.001). Neither partial nephrectomy (P = 0.985) nor cryoablation (P = 0.976) predicted poor chronic kidney disease up staging-free survival relative to surveillance. CONCLUSIONS: Patients in the surveillance arm had superior estimated glomerular filtration rate preservation compared to those in the radical nephrectomy but not the partial nephrectomy arm. In certain patients with small renal masses, surveillance and partial nephrectomy may offer comparable renal functional outcomes. This could be partly attributable to a modest estimated glomerular filtration rate decrease associated with surveillance itself. A thorough understanding of the renal functional impacts of treatment modalities is critical in the management of small renal masses.

Synergism between metformin and statins in modifying the risk of biochemical recurrence following radical prostatectomy in men with diabetes.

BACKGROUND: To determine the effect of statins and metformin in combination on biochemical recurrence (BCR) among diabetic men undergoing radical prostatectomy (RP). METHODS: Diabetic men undergoing RP at our institution from January 1995 to March 2012 were retrospectively reviewed. Recipients of adjuvant radiation or hormonal therapy were excluded. Statin and/or metformin use was determined through review of electronic records. BCR-free survival was plotted using Kaplan-Meier analysis, and the effect of statins and metformin on BCR was assessed via a multivariate Cox proportional hazards model. RESULTS: Seven hundred and sixty-seven men met the inclusion criteria. Seventy-six (9.9%) were users of statins only, 56 (7.3%) were users of metformin only and 42 (5.5%) were dual users. Median follow-up time was 27 months. Dual users were less likely than nonusers or users of either medication alone to have a biopsy Gleason sum of 8-10 (P=0.033), and tended towards a lower rate of pathological T stage of pT3 or higher (P=0.064). Dual users had the highest 2-year and 5-year BCR-free survival, although this was not statistically significant (P=0.205). On multivariate regression, neither statin nor metformin use alone was significantly associated with BCR-free survival. However, their interaction led to a significantly lower BCR risk than would be expected from each medication's independent effects (hazard ratio=0.2; P=0.037). CONCLUSIONS: The combination of statins and metformin in men undergoing RP for prostate cancer (PCa) may be associated with a lower BCR risk than would be predicted based on the independent effects of both medications. A synergism between these two agents is biologically plausible based on our current understanding of their diverse molecular pathways of action. The results of future clinical trials involving the use of either medication in men with PCa should be carefully assessed for confirmatory evidence of such a relationship.

Hyperinsulinaemic hypoglycaemia and diabetes mellitus due to dominant ABCC8/KCNJ11 mutations.

AIMS/HYPOTHESIS: Dominantly acting loss-of-function mutations in the ABCC8/KCNJ11 genes can cause mild medically responsive hyperinsulinaemic hypoglycaemia (HH). As controversy exists over whether these mutations predispose to diabetes in adulthood we investigated the prevalence of diabetes in families with dominantly inherited ATP-sensitive potassium (K(ATP)) channel mutations causing HH in the proband. METHODS: We studied the phenotype of 30 mutation carriers (14 children and 16 adults) from nine families with dominant ABCC8/KCNJ11 mutations. Functional consequences of six novel missense mutations were examined by reconstituting the K(ATP) channel in human embryonic kidney 293 (HEK293) cells and evaluating the effect of drugs and metabolic poisoning on the channels using the (86)Rb flux assay. RESULTS: The mutant channels all showed a lack of (86)Rb efflux on exposure to the channel agonist diazoxide or metabolic inhibition. In the families, dominant ABCC8/KCNJ11 mutations were associated with increased birthweight (median + 1.56 SD score [SDS]). Fourteen children had HH and five adults were reported with HH or hypoglycaemic episodes (63%). Progression from hypoglycaemia to diabetes mellitus occurred in two individuals. Eight adults had a history of gestational diabetes in multiple pregnancies or were diabetic (diagnosed at a median age of 31 years). Within these families, none of the 19 adults who were not carriers of the ABCC8/KCNJ11 mutation was known to be diabetic. CONCLUSIONS/INTERPRETATION: The phenotype associated with dominant ABCC8/KCNJ11 mutations ranges from asymptomatic macrosomia to persistent HH in childhood. In adults, it may also be an important cause of dominantly inherited early-onset diabetes mellitus.

Bladder cancer: a review of clinical management and prognostic factors.

Bladder cancer is a heterogeneous disease that offers a unique challenge for the patient and the physician as treatment paradigms are continually evolving. There are multiple factors that can influence how each individual is treated, including lymphovascular invasion, micropapillary histology, and p53 nuclear accumulation which have demonstrated a worse prognosis in patients with bladder cancer. They can influence the use of neoadjuvant and adjuvant chemotherapy, which in itself can affect the timing of extirpative surgery. This review will focus on the contemporary management and treatment of bladder cancer focusing on areas of clinical decision making.

Predictive significance of surgical margin status after prostatectomy for prostate cancer during PSA era.

OBJECTIVES: The presence of positive surgical margins (PSMs) after prostatectomy for prostate cancer has long been an indicator of poor survival outcomes. However, with the downstaging of cancer occurring in the prostate-specific antigen testing era, we sought to determine whether the risk associated with PSMs retains the same effect on prognosis as before the prostate-specific antigen testing era. METHODS: Of the 3460 patients in the Columbia University Urologic Oncology database, 2215 (64%) were identified who had undergone radical prostatectomy from 1991 to 2005 and had sufficient pathologic data to be analyzed and >or=1 year of follow-up. Three epochs were chosen: 1991-1995, 1996-2000, and 2001-2005. RESULTS: The median age, preoperative prostate-specific antigen, and Gleason score was 61.6 years, 6 ng/mL, and 7, respectively, and >50% of patients had pathologic Stage T2 disease. On multivariate analysis, PSMs were a risk factor for biochemical failure for each epoch (P < .01). The Wald's test indicated that the significance of PSMs had not changed over time (P = .8). The contribution of PSMs to the accuracy of predicting biochemical failure in a multivariate model was found only for the earliest epoch, because it improved the model by 0.15 (95% confidence interval 0.03-0.27). In the second epoch, it was 0.13 (95% confidence interval -0.01 to 0.27), and it was 0.13 for the third (95% confidence interval -0.06 to 0.32). CONCLUSIONS: The results of this study suggest that the predictive contribution of PSMs to the accuracy of a multivariate model or nomogram used to predict the outcomes after prostatectomy has decreased during the past 15 years.

Cavernous nerve graft reconstruction during radical prostatectomy or radical cystectomy: safe and technically feasible.

High local stage prostate and bladder cancers frequently require wide local resection and sacrifice of one or both cavernous nerves to achieve a negative surgical margin, thus resulting in erectile dysfunction. This is a report on preliminary experience with cavernous nerve graft reconstruction using sural nerve grafts with radical prostatectomy or radical cystectomy.Pre-operative evaluation was performed and consent was obtained in 14 potent men with prostate (11) or bladder (three) cancer. Sural nerve grafts of resected cavernous nerves were performed using a microsurgical technique. Post-operative treatment (Sildenafil or Alprostadil) was pursued until return of spontaneous function, documented by interview and adequate scores (>20) in the erectile function (EF) domain of the International Index of Erectile Function (IIEF).Twelve unilateral nerve grafts were performed, 10 during radical prostatectomy and two during radical cystoprostatectomy. Two procedures were technically not possible because of locally advanced disease. Mean age was 57.5 y (36-68 y). Mean follow up was 16.1 months (7-28 months). Pathological stage of prostate cancer was pT2 in 2, pT3 in 7 and pT4 in one. Surgical margins were positive in five out of 10 (50%), and two (20%%) had positive lymph nodes. Four patients (three post prostatectomy and one post cystectomy) were fully potent. Additionally, one patient post prostatectomy had improving partial erections. Six patients post prostatectomy and one patient post cystectomy had no erections. The only complication was one superficial wound infection in the sural nerve donor site. Preliminary experience shows that sural nerve grafts are feasible and safe after radical prostatectomy and cystectomy. However, candidates usually present with high stage disease, high risk for recurrence and frequent requirement for adjuvant therapy that further compromises erectile function. Randomized studies with more patients and long follow-up periods are necessary in order to define the ideal candidate for nerve graft procedures.

A comparison of hospital-based charges following partial and radical nephrectomy.

OBJECTIVE: Recent studies demonstrate similar survival rates in patients treated with either partial or radical nephrectomy for renal tumors less than 4 cm. We retrospectively compared the hospital based charges for these two procedures in a similar cohort of patients treated at Memorial Sloan-Kettering Cancer Center. PATIENTS AND METHODS: A retrospective review of 103 consecutive cases of renal tumors less than 4 cm treated by either radical or partial nephrectomy from 1996 to 1999 was conducted. Overall hospital charges were calculated by analyzing 18 separate departmental charge categories including room and board, pharmacy, radiologic tests, operating room charges, and laboratory services. RESULTS: A total of 66 partial and 37 radical nephrectomies were analyzed. No difference was found in the mean charge per procedure ($16,660, partial and $16,545, radical); (p > .05). The major cost drivers for partial and radical nephrectomy respectively were: 1) room and board, 42% and 44%; 2) operating room charges, 28% and 25%; 3) pathology, 6% and 6%; 4) recovery room, 6% and 7%; and 5) biochemistry, 5% and 5%. Significant increases in charges for partial nephrectomy were noted from the blood bank services and intraoperative surgical supplies. The median length of stay (5 days) was identical for partial and radical nephrectomy. No difference was found in the complication rate for these procedures (p > .05). CONCLUSION: Hospital-based charges for radical and partial nephrectomy are similar at when performed at a tertiary care referral center.

Neonatal alloimmune thrombocytopenia due to HPA-3a antibodies: a case report.

A healthy infant was born at term by elective cesarean section to a 32-year-old para 4, gravida 4, mother. Within 24 hours, the infant was noted to have fairly extensive bruising on the back and shoulders. A full blood count evaluation was remarkable for severe thrombocytopenia (platelet count of 29 x 10(9)/L). Other hematologic parameters were normal. Human leukocyte antigen (HLA) class-1 antibodies but not platelet-specific antibodies were detectable in the maternal serum using a commercial antigen-capture ELISA (GTI-PakPlus kit). Anti-HPA-3a antibodies, while weakly reactive in the monoclonal antibody immobilization of platelet antigens (MAIPA) assay in the immediate postpartum serum, were readily detectable using this assay in a sample taken 4 weeks later. Genotyping for human platelet antigens (HPA) 1-5 by the polymerase chain reaction technique with sequence-specific primers (PCR-SSP) revealed the infant's platelet genotype to be HPA-1a/1a, 3a/3b, while that of the mother was HPA-1a/1a, 3b/ 3b, consistent with a diagnosis of anti-HPA-3a neonatal alloimmune thrombocytopenia (NAIT). This case illustrates the increased sensitivity of the MAIPA technique for the detection of platelet-specific antibodies. We believe this to be the first serologically confirmed case of NAIT due to anti-HPA-3a to be reported in the republic of Ireland.

Blood-based RT-PCR assays of MN/CA9 or PSMA: clinical application in renal cancer patients.

OBJECTIVES: To report a survey of blood-based RNAs obtained from common groups of control and renal cancer patients for expression of both MN/CA9 and prostate-specific membrane antigen (PSMA) messenger RNAs. METHODS: Reverse transcription polymerase chain reaction (RT-PCR) assays for MN/CA9 and PSMA were performed on RNAs extracted from 81 blood samples (59 patients with renal cancer, 7 with benign tumors, and 15 control volunteers). The results of these assays were statistically analyzed to determine whether a positive result (individually or combined) correlates with any tumor characteristics. RESULTS: Neither MN/CA9 nor PSMA amplification products were detected in the RNAs from peripheral blood samples of the 15 control volunteers and from the 7 patients with benign renal tumor (sensitivity 100%). MN/CA9 alone was detected in 11 (19%) of 59 samples and PSMA alone in 12 (20%) of 59 samples from patients with renal cancer. PSMA positivity was significantly correlated with vascular invasion of the primary tumor. Expression of one or both of these molecular tumor markers was detected in 21 (36%) of 59 renal cancer patients. When combined, the results of the MN/CA9 and PSMA RT-PCR tests were found to be highly associated with vascular invasion in nephrectomy specimens (sensitivity 67%, specificity 77%, odds ratio = 6.89, P = 0.002). CONCLUSIONS: Combination of RT-PCR assays for MN/CA9 and PSMA provides a sensitive blood test for molecular detection of clear cell carcinoma of the kidney and its potential for vascular invasion. Further testing of this assay will be required to evaluate its efficacy in the diagnosis, screening, and follow-up of patients with kidney cancer.

Biomarkers of renal cell carcinoma. Past and future considerations.

Renal cancer includes several distinct entities with a range of biologic and clinical behaviors from relatively indolent to extremely aggressive tumors. Although conventional prognostic factors such as stage and grade are quite useful, other clinical, laboratory, and pathologic findings are now believed to have additional predictive values. This article reviews the literature on the potential utility of biomarkers in renal cell carcinoma. To date, only a few biomarkers, such as Ki-67, appeared to be potentially useful for monitoring renal cancer patients. New biomarkers including MN/CA9 and circulating cell detection require further and extensive studies to assess their potential clinical utility.

Detection of prostate-specific membrane antigen expressing cells in blood obtained from renal cancer patients: a potential biomarker of vascular invasion.

Originally, prostate-specific membrane antigen (PSMA) was described in benign and malignant prostate cells. On the basis of recent reports that this antigen also is expressed in normal renal proximal tubular cells and in the neovascular endothelium associated with renal carcinoma, we used a nested reverse transcriptase-polymerase chain reaction assay to evaluate whether PSMA-expressing cells might be present in specimens of peripheral blood obtained from renal cancer patients, benign renal tumor patients, and healthy volunteers. Our reverse transcriptase-polymerase chain reaction PSMA assay had a sensitivity of detecting 1 lymph node prostate cancer (LNCaP) per 10(7) lymphocytes. None of the 20 non-renal cancer controls were positive for PSMA mRNA, whereas 11 of 50 patients (22%) with diagnosed renal cancer were positive. Despite a comparative increase of PSMA positivity with stage, no statistical correlation was found. However, 44% of PSMA-positive patients had tumor size greater than 12 cm, versus only 9% in patients negative for PSMA (P = .03), and 67% of positive PSMA patients were found to have vascular invasion versus only 16% of patients negative for PSMA (P = .006; odds ratio, 10.8). This preliminary study suggests the possibility that PSMA expression in peripheral blood might be a useful biomarker for detecting or monitoring the progression of renal cancer in patients.

The detection of renal carcinoma cells in the peripheral blood with an enhanced reverse transcriptase-polymerase chain reaction assay for MN/CA9.

BACKGROUND: Using a reverse transcriptase-polymerase chain reaction (RT-PCR) assay, the authors previously determined the expression of MN/CA9 mRNA in renal cell carcinoma (RCC) and its absence in benign renal tissue. In the current study, the utility of an enhanced RT-PCR assay in the detection of renal carcinoma cells in the peripheral blood was assessed. METHODS: An enhanced MN/CA9 RT-PCR assay was applied to peripheral blood samples from a total of 96 patients. Forty-two patients had renal tumors, including 5 with benign renal lesions, 28 with localized RCC, and 9 with metastatic RCC. Fifty-four control patients without renal tumors were similarly tested. Pathologic staging for patients with localized cancer was T1N0M0 for 5, T2N0M0 for 9, and T3N0M0 for 14 patients. RESULTS: Cells expressing MN/CA9 were detected in 1 of 54 controls (1.8%) and in 18 of 37 cancer patients (49%). Thirteen of twenty eight patients (46%) with localized RCC and 5 of 9 (56%) with metastatic disease tested positive with the assay. No patient with a benign renal tumor exhibited MN/CA9 expression. All blood test results for patients with clear cell RCC were noted to be positive. No correlation was noted between MN/CA9 results and age, gender, or tumor grade. The differences in MN/CA9 results according to T classification were not statistically significant. CONCLUSIONS: The enhanced RT-PCR assay for MN/CA9 is a highly specific technique for detecting circulating renal carcinoma cells in the peripheral blood, and it may prove useful in the diagnosis and monitoring of RCC.

Rising risk of testicular cancer by birth cohort in the United States from 1973 to 1995.

PURPOSE: Recent epidemiological studies have demonstrated an increasing incidence of testicular cancer in white men which appears to be correlated with the period of birth. Because this birth cohort phenomenon can explain etiological factors in testicular cancer, we determine whether this trend is present throughout the United States based on an analysis of testicular cancer incidence by birth cohort. MATERIALS AND METHODS: Testicular cancer incidence was obtained from the National Cancer Institute Surveillance, Epidemiology and End Results database from 1973 to 1995. Numbers of cases were extracted and grouped by 5-year birth cohorts for all testicular germ cell neoplasms. Poisson regression analysis with variables of age, time of diagnosis and birth cohort were used to determine relative risk. Poisson models were compared using computer log linear model software. RESULTS: Between 1973 and 1995 the incidence of testicular cancer in the United States increased 51% (3.61 to 5.44/100,000). Analysis of Poisson models revealed that birth cohort was strongly associated with relative risk of testicular cancer (p = 0.001). In addition, peak age at diagnosis decreased for each successive birth cohort. CONCLUSIONS: The overall incidence of testicular cancer in white men and the relative risk of testicular cancer have been increasing in the United States. This trend is strongly associated with birth cohort in concordance with previously reported European data. Moreover, testicular cancer is being diagnosed at a younger age as evidenced by a shift to the left in the age of peak incidence. These unique epidemiological patterns offer a basis for analysis of potential etiological factors.

Alpha-adrenoceptor antagonists in the treatment of benign prostatic hyperplasia.

Lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH) have a significant impact on the lifestyle of older men. Transurethral resection of the prostate (TURP) is the most effective surgical therapy for this condition but an increasing number of patients are electing conservative medical therapy. Alpha-Adrenoceptor antagonists and 5alpha-reductase inhibitors are the 2 categories of drug therapy currently available for BPH. Use of alpha-adrenoceptor antagonists in the treatment of BPH is based on their ability to prevent the neural stimulation which induces prostate smooth muscle contraction, producing lower urinary tract symptoms. Several studies have demonstrated that alpha-receptors predominate in the prostatic stroma, capsule and bladder neck. Initial work focused on the use of phenoxybenzamine, a nonspecific alpha-blocker, in the treatment of BPH. While results were promising, significant adverse effects and concern over potential mutagenicity have resulted in a lack of use of this medication for this indication. Subsequent attention was directed towards the short-acting alpha-specific antagonist prazosin. Results conflicted regarding whether an actual sustained improvement in lower urinary tract symptoms could be achieved with this medication, and because of twice daily dosing compliance issues were a drawback. Thus, the mainstay in pharmacological treatment of BPH over the past decade has been 2 once-a-day alpha-specific antagonists, doxazosin and terazosin. Over 75% of all prescriptions written for BPH are for one of these 2 medications. Despite their tremendous success in both decreasing urinary symptoms and increasing urinary flow rates, systemic adverse effects can be bothersome. Recently, efforts have focused on use of alpha1A-urospecific antagonists such as tamsulosin and alfuzosin in an attempt to achieve similar clinical results as doxazosin and terazosin without systemic adverse effects. Thus far, results are promising, but long term studies must be done to determine whether pharmacological uroselectivity is actually clinically relevant.