DNA methylation screening of primary prostate tumors identifies SRD5A2 and CYP11A1 as candidate markers for assessing risk of biochemical recurrence.

BACKGROUND: Altered DNA methylation in CpG islands of gene promoters has been implicated in prostate cancer (PCa) progression and can be used to predict disease outcome. In this study, we determine whether methylation changes of androgen biosynthesis pathway (ABP)-related genes in patients' plasma cell-free DNA (cfDNA) can serve as prognostic markers for biochemical recurrence (BCR). METHODS: Methyl-binding domain capture sequencing (MBDCap-seq) was used to identify differentially methylated regions (DMRs) in primary tumors of patients who subsequently developed BCR or not, respectively. Methylation pyrosequencing of candidate loci was validated in cfDNA samples of 86 PCa patients taken at and/or post-radical prostatectomy (RP) using univariate and multivariate prediction analyses. RESULTS: Putative DMRs in 13 of 30 ABP-related genes were found between tumors of BCR (n = 12) versus no evidence of disease (NED) (n = 15). In silico analysis of The Cancer Genome Atlas data confirmed increased DNA methylation of two loci-SRD5A2 and CYP11A1, which also correlated with their decreased expression, in tumors with subsequent BCR development. Their aberrant cfDNA methylation was also associated with detectable levels of PSA taken after patients' post-RP. Multivariate analysis of the change in cfDNA methylation at all of CpG sites measured along with patient's treatment history predicted if a patient will develop BCR with 77.5% overall accuracy. CONCLUSIONS: Overall, increased DNA methylation of SRD5A2 and CYP11A1 related to androgen biosynthesis functions may play a role in BCR after patients' RP. The correlation between aberrant cfDNA methylation and detectable PSA in post-RP further suggests their utility as predictive markers for PCa recurrence. .

Advancing Risk Assessment of Intermediate Risk Prostate Cancer Patients.

The individual risk to progression is unclear for intermediate risk prostate cancer patients. To assess their risk to progression, we examined the level of genomic instability in circulating tumor cells (CTCs) using quantitative three-dimensional (3D) telomere analysis. Data of CTCs from 65 treatment-naïve patients with biopsy-confirmed D'Amico-defined intermediate risk prostate cancer were compared to radical prostatectomy pathology results, which provided a clinical endpoint to the study and confirmed pre-operative pathology or demonstrated upgrading. Hierarchical centroid cluster analysis of 3D pre-operative CTC telomere profiling placed the patients into three subgroups with different potential risk of aggressive disease. Logistic regression modeling of the risk of progression estimated odds ratios with 95% confidence interval (CI) and separated patients into "stable" vs. "risk of aggressive" disease. The receiver operating characteristic (ROC) curve showed an area under the curve (AUC) of 0.77, while prostate specific antigen (PSA) (AUC of 0.59) and Gleason 3 + 4 = 7 vs. 4 + 3 = 7 (p > 0.6) were unable to predict progressive or stable disease. The data suggest that quantitative 3D telomere profiling of CTCs may be a potential tool for assessing a patient's prostate cancer pre-treatment risk.

Appendico-cutaneous fistula presenting clinically as right loin necrotizing fasciitis: a case report.

Acute appendicitis and its subsequent complications continue to pose a surgical challenge. One such complication, the appendico-cutaneous fistula, represents a very rare form of enterocutaneous fistula. Very few cases have been reported thus far in the literature. The clinical presentation of this case before the final diagnosis was made makes interesting reading. The report describes a unique case that presented with the onset of cellulitis around the right lumbar/loin region, spreading down the right posterior back to the posterior gluteal area, and appearing as necrotizing fasciitis. There were no abdominal signs at all. The patient was then taken to the operating room (OR) for incision and drainage through a right flank incision, which could be extended. At drainage, there was a feculent smell with discharge that immediately raised the possibility of colonic connection with the abscess cavity. Swab sent for culture and sensitivity grew E. coli and Bacteroides. The final diagnosis proved to be a perforated appendix. Therefore, perforated appendix should always be considered in the differential diagnosis of any spreading cellulitis in the right lumbar area or right lower abdominal quadrant in the presence of limited urinary symptoms and little or no abdominal signs.

Abdominal cocoon syndrome (idiopathic sclerosing encapsulating peritonitis): how easy is its diagnosis preoperatively? A case report.

The abdominal cocoon syndrome (or idiopathic encapsulating peritonitis) is a rare cause of intestinal obstruction. It has been reported predominantly in adolescent girls living in tropical/subtropical region in which diagnosis is only made at laparotomy in most cases. The cause and pathogenesis of the condition have not been elucidated. Prolonged administration of practalol, meconium peritonitis, and tuberculous infection of the female genital tract have been incriminated as possible causes. The author reports a case of a female patient with recurrent intestinal obstruction treated for years but failed to settle down on conservative treatment during her last hospital admission and had to undergo surgery. Preoperative diagnosis of this syndrome as the cause of her intestinal obstruction was not made until at laparotomy, when a thick fibrotic peritoneal wrapping of the bowel in a concertina-like fashion with some adhesions was found. Excision of this membrane and adhesiolysis were carried out without any need for bowel resection, and this led to relief of the obstruction and patient's complete recovery. Awareness of this benign condition in the differential diagnosis of intestinal obstruction will result in early diagnosis and correct management and prevent unnecessary bowel resections and bad outcomes.

Three-dimensional Nuclear Telomere Organization in Multiple Myeloma.

Multiple myeloma (MM) is preceded by monoclonal gammopathy of undetermined significance (MGUS). Up to date, it is difficult to predict an individual's time to disease progression and the treatment response. To examine whether the nuclear telomeric architecture will unravel some of these questions, we carried out. Three-dimensional (3D) telomere analysis on samples from patients diagnosed with MGUS and MM, as well as from patients who went into relapse. Telomere signal intensity, number of telomere aggregates, nuclear volume, and the overall nuclear telomere distribution (a/c ratio) were analyzed. The telomeric profiles allowed for the differentiation of the disease stages. The telomeric profiles of myeloma cells obtained from blood and bone marrow aspirates were identical. Based on this study, we discuss the use of 3D telomere profiling as a potential future tool for risk stratification and personalized treatment decisions.