Faculty Bibliography

Mutations of both nuclear and mitochondrial DNA (mtDNA)-encoded mitochondrial proteins can cause cardiomyopathy associated with mitochondrial dysfunction. Hence, the cardiac phenotype of nuclear DNA mitochondrial mutations might be modulated by mtDNA variation. We studied a 13-generation Mennonite pedigree with autosomal recessive myopathy and cardiomyopathy due to an SLC25A4 frameshift null mutation (c.523delC, p.Q175RfsX38), which codes for the heart-muscle isoform of the adenine nucleotide translocator-1. Ten homozygous null (adenine nucleotide translocator-1(-/-)) patients monitored over a median of 6 years had a phenotype of progressive myocardial thickening, hyperalaninemia, lactic acidosis, exercise intolerance, and persistent adrenergic activation. Electrocardiography and echocardiography with velocity vector imaging revealed abnormal contractile mechanics, myocardial repolarization abnormalities, and impaired left ventricular relaxation. End-stage heart disease was characterized by massive, symmetric, concentric cardiac hypertrophy; widespread cardiomyocyte degeneration; overabundant and structurally abnormal mitochondria; extensive subendocardial interstitial fibrosis; and marked hypertrophy of arteriolar smooth muscle. Substantial variability in the progression and severity of heart disease segregated with maternal lineage, and sequencing of mtDNA from five maternal lineages revealed two major European haplogroups, U and H. Patients with the haplogroup U mtDNAs had more rapid and severe cardiomyopathy than those with haplogroup H.

BACKGROUND: Full-field optical coherence tomography (FFOCT) is a real-time imaging technique that generates high-resolution three-dimensional tomographic images from unprocessed and unstained tissues. Lack of tissue processing and associated artifacts, along with the ability to generate large-field images quickly, warrants its exploration as an alternative diagnostic tool. MATERIALS AND METHODS: One section each from the tumor and from adjacent non-neoplastic tissue was collected from 13 human lobectomy specimens. They were imaged fresh with FFOCT and then submitted for routine histopathology. Two blinded pathologists independently rendered diagnoses based on FFOCT images. RESULTS: Normal lung architecture (alveoli, bronchi, pleura and blood vessels) was readily identified with FFOCT. Using FFOCT images alone, the study pathologists were able to correctly identify all tumor specimens and in many cases, the histological subtype of tumor (e.g., adenocarcinomas with various patterns). However, benign diagnosis was provided with high confidence in roughly half the tumor-free specimens (others were diagnosed as equivocal or false positive). Further analysis of these images revealed two major confounding features: (a) Extensive lung collapse and (b) presence of smoker's macrophages. On a closer inspection, however, the smoker's macrophages could often be identified as distinct from tumor cells based on their relative location in the alveoli, size and presence of anthracosis. We posit that greater pathologist experience, complemented with morphometric analysis and color-coding of image components, may help minimize the contribution of these confounders in the future. CONCLUSION: Our study provides evidence for the potential utility of FFOCT in identifying and differentiating lung tumors from non-neoplastic lung tissue. We foresee its potential as an adjunct to intra-surgical frozen section analysis for margin assessment, especially in limited lung resections.

PURPOSE/OBJECTIVE:We investigated oncological outcomes in patients who underwent robot-assisted radical prostatectomy more than 5 years previously. MATERIALS AND METHODS/METHODS:Between June 2002 and August 2006 we prospectively followed 435 consecutive patients who underwent robot-assisted radical prostatectomy. Five patients were excluded from analysis, including 4 lost to followup and 1 with prior therapy. Biochemical recurrence was denoted as 1) adjuvant therapy or 2) 2 prostate specific antigen values above 0.2 ng/ml. Biochemical recurrence-free survival, and patient and tumor characteristics were investigated. RESULTS:Mean ± SD patient age was 61.4 ± 7.1 years. A total of 289 patients (63%) had 5 or more years of followup and 4 (1%) were lost to followup. Median time to biochemical recurrence was 18 months (range 1 month to 9.1 years). Four patients (0.93%) died of prostate cancer. The 5-year biochemical recurrence-free survival rate was 84.9% (95% CI 81.4-88.4). Five-year biochemical recurrence-free survival was 94.4% (95% CI 91.7-97.1) for pT2 disease compared to 63.8% (95% CI 53.4-74.1) and 47.1% (95% CI 27.3-67.0) for pT3a and pT3b, respectively (p <0.001). Patients with a Gleason score of 3 or less + 3, 3 + 4, 4 + 3 and 4 or greater + 4 experienced a 5-year biochemical recurrence-free survival of 97%, 86%, 62% and 43%, respectively (p <0.001). Patients with positive margins had a 5-year biochemical recurrence-free survival of 60.7% (95% CI 48.7-72.7) compared to 89.6% (95% CI 86.3-92.9) in those with negative margins (p <0.001). CONCLUSIONS:This represents the third report of the oncological outcomes of robot-assisted radical prostatectomy, demonstrating a 5-year biochemical recurrence rate of approximately 14% and just below 1% prostate cancer specific mortality.

OBJECTIVE:• To evaluate associations between baseline characteristics, nerve-sparing (NS) status and return of continence, as a relationship may exist between return to continence and preservation of the neurovascular bundles for potency during radical prostatectomy (RP). PATIENTS AND METHODS/METHODS:• The study included 592 consecutive robotic RPs completed between 2002 and 2007. • All data were entered prospectively into an electronic database. • Continence data (defined as zero pads) was collected using self-administered validated questionnaires. • Baseline characteristics (age, International Index of Erectile Function [IIEF-5] score, American Urological Association symptom score, body mass index [BMI], clinical T-stage, Gleason score, and prostate-specific antigen level), NS status and learning curve were retrospectively evaluated for association with overall continence at 1, 3 and 12 months after RP using univariate and multivariable methods. • Any patient taking preoperative phosphodiesterase inhibitors was excluded from the postoperative analysis. RESULTS:• Complete data were available for 537 of 592 patients (91%). • Continence rates at 12 months after RP were 89.2%, 88.9% and 84.8% for bilateral NS, unilateral NS and non-NS respectively (P= 0.56). • In multivariable analysis age, IIEF-5 score and BMI were significant independent predictors of continence. • CavernosalNS status did not significantly affect continence after adjusting for other co-variables. CONCLUSION/CONCLUSIONS:• After careful multivariable analysis of baseline characteristics age, IIEF-5 score and BMI affected continence in a statistically significant fashion. This suggests that baseline factors and not the physical preservation of the cavernosal nerves predict overall return to continence.