Hugo Coelho

A cancer specific hypermethylation signature of the TERT promoter predicts biochemical relapse in prostate cancer: A retrospective cohort study

The identification of new biomarkers to differentiate between indolent and aggressive prostate tumors is an important unmet need. We examined the role of THOR (TERT Hypermethylated Oncological Region) as a diagnostic and prognostic biomarker in prostate cancer (PCa). We analyzed THOR in common cancers using genome-wide methylation arrays. Methylation status of the whole TERT gene in benign and malignant prostate samples was determined by MeDIP-Seq. The prognostic role of THOR in PCa was assessed by pyrosequencing on discovery and validation cohorts from patients who underwent radical prostatectomy with long-term follow-up data. Most cancers (n = 3056) including PCa (n = 300) exhibited hypermethylation of THOR. THOR was the only region within the TERT gene that is differentially methylated between normal and malignant prostate tissue (p < 0.0001). Also, THOR was significantly hypermethylated in PCa when compared to paired benign tissues (n = 164, p < 0.0001). THOR hypermethylation correlated with Gleason scores and was associated with tumor invasiveness (p = 0.0147). Five years biochemical progression free survival (BPFS) for PCa patients in the discovery cohort was 87% (95% CI 73–100) and 65% (95% CI 52–78) for THOR non-hypermethylated and hypermethylated cancers respectively (p = 0.01). Similar differences in BPFS were noted in the validation cohort (p = 0.03). Importantly, THOR was able to predict outcome in the challenging (Gleason 6 and 7 (3 + 4)) PCa (p = 0.007). For this group, THOR was an independent risk factor for BPFS with a hazard-ratio of 3.685 (p = 0.0247). Finally, THOR hypermethylation more than doubled the risk of recurrence across all PSA levels (OR 2.5, p = 0.02).

Coagulum Pyelolithotomy “Revisited” by Laparoscopy: Technique Modification

OBJECTIVE Laparoscopic ureteropyeloplasty is a widely accepted treatment option for the obstructed ureteropelvic junction (UPJ). Although it is often a straightforward surgical procedure, there may be technical difficulties in the case of concomitant stone burden, with multiple calicial, small, mobile stones. The authors describe a modification to the classic coagulum pyelolitothomy, using a mixture based on commercially available fibrin sealant, first used in the laparoscopic era. METHODS During a laparoscopic transperitoneal dismembered ureteropyeloplasty complemented with coagulum pyelolithotomy, the following steps are suggested: (1) Exposure of the UPJ; (2) ureter clamping with a vessel loop 2 cm distal to the UPJ (to allow pelvis filling); (3) transabdominal puncture of the pelvis with an 18-G, 20-cm needle (under laparoscopic vision) and urine aspiration; (4) recording the volume of urine aspirated; (5) preparing an equal volume of fibrin sealant (to avoid overdistention of the pelvis); (6) injecting the sealer protein solution through that needle + 1 mL of methylene blue (color the coagulum and facilitate its identification in the removal procedure); (7) insertion of another needle to inject the thrombin solution; (8) wait 5 minutes to allow coagulum cast formation; (9) circumferential excision of the UPJ; (10) coagulum removal; (11) pelvis plastic reduction (if needed) and ureter spatulation; (12) double-J stent placement; and (13) tension-free anastomosis completion. RESULTS The procedure results in the extraction of a tenacious coagulum containing more stones than normally anticipated from the x-ray studies. CONCLUSIONS This technique modification reduces the incidence of incomplete stone removal, when there are small, free stones lying in a large renal pelvis.

Pararenal sclerosing PEComa

Small renal or pararenal masses and retroperitoneum lesions are extremely difficult to diagnose. Imaging technology is a precious diagnostic tool; however, it places physicians in a difficult position since many lesions are not precisely diagnosed. Clinical and radiological findings can guide suspicion towards the diagnosis; however, in our current practice most diagnoses are based on histological findings. We aim to present a pararenal sclerosing perivascular epithelioid cell tumour (PEComa), a rare entity, whose diagnosis is only possible through invasive approaches and histological analysis. This rare lesion not only is difficult to diagnose but also has an uncertain behaviour, which is of major importance concerning its follow-up and prognosis. This case report is an attempt to add more data that will help establish criteria for diagnosis and follow-up of this rare disease.

Inguinal hernia containing bladder and ureteroneocystostomy: a rare cause for acute renal graft dysfunction

A 77-year-old man presented with acute graft dysfunction 25 years after a renal transplant in the left iliac fossa. He also had an asymptomatic left inguinal hernia. Renal ultrasound showed a significant pyelocalicial dilation of the kidney graft and the patient was submitted to a percutaneous nephrostomy. An antegrade nephrostogram was performed, which showed a dilated ureter and the bladder included in the left inguinal hernia that caused the obstructive uropathy. Concomitant retrograde cystography also showed a significant portion of the bladder in the hernia sac. The patient was submitted to inguinal hernia repair, which resolved the obstruction. We present a rare and potentially curable cause of obstructive uropathy in a transplant recipient; it is possible to revert graft dysfunction and prevent graft loss if the condition is recognised early.

Small-cell neuroendocrine cancer of the prostate: an atypical presentation of a common disease

A 70-year-old man with a history of prostate cancer, previously submitted to surgical castration and trans-urethral resection of the prostate, was admitted to Accident and Emergency department. He had been suffering from osteoarticular and abdominal pain, and recent weight loss. An abdominal and a pelvic CT showed multiple hepatic metastases and a pelvic mass, but his prostate-specific antigen values were low (0.26 n/mL). A biopsy of a hepatic metastasis and of the pelvic mass revealed a small-cell neuroendocrine prostate cancer, a rare and aggressive androgen-independent form of prostate cancer with a poor prognosis. Our purpose was to report a clinical case of a rare and aggressive variant of a common disease. A high index of suspicion is required to make an early diagnosis and to ensure a proper therapeutic approach.

Benign Prostate Hyperplasia and Chronic Kidney Disease

BHP is theoretically the detection of prostatic hyperplasia, which is the benign proliferation of the stroma and epithelium, by histological study. However histological studies for all men are unfeasible in clinical practice, so BHP usually refers to the palpable enlargement of the prostate, which can be detected by clinical or ultrasonographic examination, or presence of urinary symptoms loosely defined as lower urinary tract symptoms (LUTS), which are usually classified as obstructive or irritative (Levy and Samraj 2007).

Combined genetic and epigenetic alterations of the TERT promoter affect clinical and biological behaviour of bladder cancer: Combined genetic and epigenetic alterations of the TERT promoter affect clinical and biological behaviour of bladder cancer

In urothelial bladder cancer (UBC), risk stratification remains an important unmet need. Limitless self‐renewal, governed by TERT expression and telomerase activation, is crucial for cancer progression. Thus, telomerase activation through the interplay of mutations (TERTpMut) and epigenetic alterations in the TERT promoter may provide further insight into UBC behavior. Here, we investigated the combined effect of TERTpMut and the TERT Hypermethylated Oncological Region (THOR) status on telomerase activation and patient outcome in a UBC international cohort (n = 237). We verified that TERTpMut were frequent (76.8%) and present in all stages and grades of UBC. Hypermethylation of THOR was associated with higher TERT expression and higher‐risk disease in nonmuscle invasive bladder cancers (NMIBC). TERTpMut alone predicted disease recurrence (HR: 3.18, 95%CI 1.84 to 5.51, p < 0.0001) but not progression in NMIBC. Combined THORhigh/TERTpMut increased the risk of disease recurrence (HR 5.12, p < 0.0001) and progression (HR 3.92, p = 0.025). Increased THOR hypermethylation doubled the risk of stage progression of both TERTpwt and TERTpMut NMIBC. These results highlight that both mechanisms are common and coexist in bladder cancer and while TERTpMut is an early event in bladder carcinogenesis THOR hypermethylation is a dynamic process that contributes to disease progression. While the absence of alterations comprises an extremely indolent phenotype, the combined genetic and epigenetic alterations of TERT bring additional prognostic value in NMIBC and provide a novel insight into telomere biology in cancer.

Influence of secondary diagnoses in the development of urinary incontinence after radical prostatectomy

OBJECTIVE To study whether there are factors related to secondary diagnoses (SDg) present in patients with prostate cancer that influence the development of urinary incontinence after radical prostatectomy (RP). MATERIALS AND METHODS A retrospective multicenter observational study was performed reviewing the medical records of 430 men who underwent RP due to organ-confined prostate cancer in 9 different hospitals. Two study groups were distinguished: Group A (GA): Patients without urinary incontinence after RP; Group B (GB): patients with any degree of post-surgical urinary incontinence. RESULTS Average age at surgery was 63.42 years (range 45-73). 258 patients were continent after surgery and 172 patients complaint of any degree of incontinence after RP. A higher percentage of healthy patients was found in group A (continent after surgery) than in group B (p = 0.001). The most common SDg prior to surgery were hypertension, lower urinary tract symptoms, dyslipidemia, diabetes mellitus and erectile dysfunction, but none did show a greater trend towards post-surgical incontinence. CONCLUSIONS A better health status prior to surgery is associated to a lower incidence of new-onset urinary incontinence after radical prostatectomy. However, no correlation was found between the most common medical disorders and the development of post-surgical urinary incontinence.

Arterioureteral fistula: an unusual clinical case

Arterioureteral fistulas (AUFs) are abnormal communications between a major artery and the mid to distal ureter. It is a rare but potentially life-threatening condition that is seldom recognised. We present a case of a 66-year-old man who was admitted to the surgical ward owing to infection of an aortic bifemoral bypass graft. During admission, the patient developed persistent haematuria with considerable loss of haemoglobin. He was submitted to urgent surgical exploration of the graft. An ascending pyelography performed at the beginning of the surgery clearly shows a communication between the left ureter and the vascular graft. Open surgical exploration was undertaken, the fistulised section of the ureter resected and an end-to-end ureteroplasty was performed. The vascular graft was removed and the patient later submitted to left supracondylar amputation. Urinary drainage remained intact.

MP37-11 TERT PROMOTER METHYLATION IS A PAN-CANCER BIOMARKER WITH PROGNOSTIC SIGNIFICANCE IN PROSTATE CANCER PATIENTS

Ricardo Leao*, Toronto, Canada; Pedro Castelo-Branco, Faro, Portugal; Tatiana Lipman, Brittany Campbell, Aryeh Price, Cindy Zhang, Toronto, Canada; Ana Gomes, Hugo Coelho, Coimbra, Portugal; Robert G. Bristow, Toronto, Canada; Michal Schweiger, Berlin, Germany; Robert J. Hamilton, Alexandre R. Zlotta, Toronto, Canada; Arnaldo Figueiredo, Coimbra, Portugal; Helmut Klocker, Innsbruck, Austria; Holger Sulttmann, Heidelberg, Germany; Uri Tabori, Toronto, Canada