Integrated analysis of the genomic instability of PTEN in clinically insignificant and significant prostate cancer.

Patients with clinically insignificant prostate cancer remain a major over-treated population. PTEN loss is one of the most recurrent alterations in prostate cancer associated with an aggressive phenotype, however, the occurrence of PTEN loss in insignificant prostate cancer has not been reported and its role in the separation of insignificant from significant prostate cancer is unclear. An integrated analysis of PTEN loss was, therefore, performed for structural variations, point mutations and protein expression in clinically insignificant (48 cases) and significant (76 cases) prostate cancers treated by radical prostatectomy. Whole-genome mate pair sequencing was performed on tumor cells isolated by laser capture microdissection to characterize PTEN structural alterations. Fluorescence in situ hybridization probes were constructed from the sequencing data to detect the spectrum of these PTEN alterations. PTEN loss by mate pair sequencing and fluorescence in situ hybridization occurred in 2% of insignificant, 13% of large volume Gleason score 6, and 46% of Gleason score 7 and higher cancers. In Gleason score 7 cancers with PTEN loss, PTEN alterations were detected in both Gleason pattern 3 and 4 in 57% of cases by mate pair sequencing, 75% by in situ hybridization and 86% by immunohistochemistry. PTEN loss by sequencing was strongly associated with TMPRSS2-ERG fusion, biochemical recurrence, PTEN loss by in situ hybridization and protein loss by immunohistochemistry. The complex nature of PTEN rearrangements was unveiled by sequencing, detailing the heterogeneous events leading to homozygous loss of PTEN. PTEN point mutation was present in 5% of clinically significant tumors and not in insignificant cancer or high-grade prostatic intraepithelial neoplasia. PTEN loss is infrequent in clinically insignificant prostate cancer, and is associated with higher grade tumors. Detection of PTEN loss in Gleason score 6 cancer in a needle biopsy specimen indicates a higher likelihood of clinically significant prostate cancer.

Evaluation of current surveillance guidelines following radical cystectomy and proposal of a novel risk-based approach.

BACKGROUND: Evidence supporting surveillance guidelines after radical cystectomy (RC) are lacking. Herein, we evaluate the ability of the National Comprehensive Cancer Network (NCCN) guidelines and the European Association of Urology (EAU) guidelines to capture recurrences and provide an alternative approach that balances risks of recurrence with non-bladder cancer death. METHODS: We identified 1,797 patients who had M0 urothelial carcinoma who underwent RC at our institution between 1980 and 2007. The success of current guidelines to capture recurrences was assessed by calculating the percentage of recurrences detected during the recommended follow-up time: the NCCN--2 years and the EAU--5 years. An alternative protocol was created using Weibull distributions, which estimate when a patient׳s risk of non-bladder cancer death exceeds their risk of recurrence. RESULTS: At a median follow-up of 10.6 years (interquartile range : 6.8-15.2), a total of 714 patients recurred. Of these, 491 (68.7%) would have been detected by the NCCN guidelines and 642 (89.8%) by the EAU guidelines. Using a risk-adapted approach, vastly different surveillance durations were appreciated. For example, for patients older than 80 years with pT0Nx-0 or pTa/CIS/1Nx-0 disease, recurrence risk to any location never exceeded their risk of non-bladder cancer death, whereas for patients aged 60 years and younger with pT3/4Nx-0 or pTanyN+disease, risk of abdominal/pelvis recurrence remained greater than their risk of non-bladder cancer death for>20 years. CONCLUSIONS: The duration of post-RC follow-up recommended by the NCCN and the EAU does not comprehensively capture recurrences. A surveillance algorithm based on the interaction between recurrence risk and competing health factors individualizes recommendations and may improve capture of recurrences and resource allocation.

Risk factors for excessive anticoagulation among hospitalized adults receiving warfarin therapy using a pharmacist-managed dosing protocol.

STUDY OBJECTIVE: To identify specific risk factors for excessive anticoagulation, defined as an international normalized ratio (INR) higher than 5, in hospitalized adults receiving warfarin therapy using a pharmacist-managed dosing protocol. DESIGN: Retrospective nested case-control study. SETTING: Large academic tertiary care medical center. PATIENTS: Hospitalized nonsurgical patients 18 years or older who received at least one dose of warfarin according to the pharmacist-managed protocol from January 1, 2009, to January 31, 2012, were included. Patients who experienced an INR higher than 5 were designated as case patients; those who received warfarin for at least as many days as the case patients but who did not experience an INR more than 5 were deemed control patients. Controls were matched to cases in a 2:1 ratio by age, sex, INR goal, and type of warfarin therapy (new start or continuation). MEASUREMENTS AND MAIN RESULTS: A total of 87 case patients were matched to 174 controls. Ten different hypothesized risk factors were examined. Two variables, severity of illness score (odds ratio [OR] 4.89, p<0.001) and poor nutritional status (OR 4.27, p<0.001), demonstrated strong independent associations with risk of excessive anticoagulation. Administration of interacting drugs that highly potentiate warfarin's effect (OR 2.26, p=0.011) and concurrent diarrheal illness (OR 4.75, p<0.001) also displayed a statistically significant risk for excessive anticoagulation. CONCLUSION: Even in a highly standardized system for warfarin dosing by a pharmacist-managed protocol, higher disease severity and poor nutritional status placed hospitalized patients at greater risk of experiencing excessive anticoagulation. In addition, administration of interacting drugs that highly potentiate warfarin's effect or the occurrence of diarrheal illness may predict increased risk.

Primary hyperoxaluria type III gene HOGA1 (formerly DHDPSL) as a possible risk factor for idiopathic calcium oxalate urolithiasis.

BACKGROUND AND OBJECTIVES: Primary hyperoxaluria types I and II (PHI and PHII) are rare monogenic causes of hyperoxaluria and calcium oxalate urolithiasis. Recently, we described type III, due to mutations in HOGA1 (formerly DHDPSL), hypothesized to cause a gain of mitochondrial 4-hydroxy-2-oxoglutarate aldolase activity, resulting in excess oxalate. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: To further explore the pathophysiology of HOGA1, we screened additional non-PHI-PHII patients and performed reverse transcription PCR analysis. Postulating that HOGA1 may influence urine oxalate, we also screened 100 idiopathic calcium oxalate stone formers. RESULTS: Of 28 unrelated hyperoxaluric patients with marked hyperoxaluria not due to PHI, PHII, or any identifiable secondary cause, we identified 10 (36%) with two HOGA1 mutations (four novel, including a nonsense variant). Reverse transcription PCR of the stop codon and two common mutations showed stable expression. From the new and our previously described PHIII cohort, 25 patients were identified for study. Urine oxalate was lower and urine calcium and uric acid were higher when compared with PHI and PHII. After 7.2 years median follow-up, mean eGFR was 116 ml/min per 1.73 m(2). HOGA1 heterozygosity was found in two patients with mild hyperoxaluria and in three of 100 idiopathic calcium oxalate stone formers. No HOGA1 variants were detected in 166 controls. CONCLUSIONS: These findings, in the context of autosomal recessive inheritance for PHIII, support a loss-of-function mechanism for HOGA1, with potential for a dominant-negative effect. Detection of HOGA1 variants in idiopathic calcium oxalate urolithiasis also suggests HOGA1 may be a predisposing factor for this condition.