Joanna Perry-Keene

Robot-assisted laparoscopic prostatectomy versus open radical retropubic prostatectomy: early outcomes from a randomised controlled phase 3 study.

BACKGROUND The absence of trial data comparing robot-assisted laparoscopic prostatectomy and open radical retropubic prostatectomy is a crucial knowledge gap in uro-oncology. We aimed to compare these two approaches in terms of functional and oncological outcomes and report the early postoperative outcomes at 12 weeks. METHOD In this randomised controlled phase 3 study, men who had newly diagnosed clinically localised prostate cancer and who had chosen surgery as their treatment approach, were able to read and speak English, had no previous history of head injury, dementia, or psychiatric illness or no other concurrent cancer, had an estimated life expectancy of 10 years or more, and were aged between 35 years and 70 years were eligible and recruited from the Royal Brisbane and Womens Hospital (Brisbane, QLD). Participants were randomly assigned (1:1) to receive either robot-assisted laparoscopic prostatectomy or radical retropubic prostatectomy. Randomisation was computer generated and occurred in blocks of ten. This was an open trial; however, study investigators involved in data analysis were masked to each patients condition. Further, a masked central pathologist reviewed the biopsy and radical prostatectomy specimens. Primary outcomes were urinary function (urinary domain of EPIC) and sexual function (sexual domain of EPIC and IIEF) at 6 weeks, 12 weeks, and 24 months and oncological outcome (positive surgical margin status and biochemical and imaging evidence of progression at 24 months). The trial was powered to assess health-related and domain-specific quality of life outcomes over 24 months. We report here the early outcomes at 6 weeks and 12 weeks. The per-protocol populations were included in the primary and safety analyses. This trial was registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), number ACTRN12611000661976. FINDINGS Between Aug 23, 2010, and Nov 25, 2014, 326 men were enrolled, of whom 163 were randomly assigned to radical retropubic prostatectomy and 163 to robot-assisted laparoscopic prostatectomy. 18 withdrew (12 assigned to radical retropubic prostatectomy and six assigned to robot-assisted laparoscopic prostatectomy); thus, 151 in the radical retropubic prostatectomy group proceeded to surgery and 157 in the robot-assisted laparoscopic prostatectomy group. 121 assigned to radical retropubic prostatectomy completed the 12 week questionnaire versus 131 assigned to robot-assisted laparoscopic prostatectomy. Urinary function scores did not differ significantly between the radical retropubic prostatectomy group and robot-assisted laparoscopic prostatectomy group at 6 weeks post-surgery (74·50 vs 71·10; p=0·09) or 12 weeks post-surgery (83·80 vs 82·50; p=0·48). Sexual function scores did not differ significantly between the radical retropubic prostatectomy group and robot-assisted laparoscopic prostatectomy group at 6 weeks post-surgery (30·70 vs 32·70; p=0·45) or 12 weeks post-surgery (35·00 vs 38·90; p=0·18). Equivalence testing on the difference between the proportion of positive surgical margins between the two groups (15 [10%] in the radical retropubic prostatectomy group vs 23 [15%] in the robot-assisted laparoscopic prostatectomy group) showed that equality between the two techniques could not be established based on a 90% CI with a Δ of 10%. However, a superiority test showed that the two proportions were not significantly different (p=0·21). 14 patients (9%) in the radical retropubic prostatectomy group versus six (4%) in the robot-assisted laparoscopic prostatectomy group had postoperative complications (p=0·052). 12 (8%) men receiving radical retropubic prostatectomy and three (2%) men receiving robot-assisted laparoscopic prostatectomy experienced intraoperative adverse events. INTERPRETATION These two techniques yield similar functional outcomes at 12 weeks. Longer term follow-up is needed. In the interim, we encourage patients to choose an experienced surgeon they trust and with whom they have rapport, rather than a specific surgical approach. FUNDING Cancer Council Queensland.

High specificity of combined narrow band imaging and autofluorescence mucosal assessment of patients with head and neck cancer

The purpose of this study was to evaluate combined autofluorescence (AF) and narrow band imaging (NBI) for detection of mucosal lesions additional to known primary head and neck cancers and to determine impact on management.

Leukaemia cutis in atypical chronic myeloid leukaemia with a t(9;22) (p24;q11.2) leading to BCR-JAK2 fusion

A 44-year-old male presented with a violaceous papular scalp rash and bilateral small volume (1 cm) cervical lymphadenopathy. A full blood count showed a mild neutrophil leucocytosis (11.9 · 10/l) and left shift. The blood film was leucoerythroblastic with toxic changes and occasional tear drop poikilocytes. A skin biopsy demonstrated a dense dermal infiltrate comprising intermediate sized blast cells with granular cytoplasm. These cells stained positively with CD117, CD34 and CD43, consistent with granulocytic sarcoma [top left; haematoxylineosin stain (HE there was an increase of cells of neutrophilic and eosinophilic lineages, and megakaryocyte clustering with morphologically abnormal forms (top right; HE22)(p24;q11.2) in 23 of 50 cells examined (bottom left). Fluorescence in situ hybridization using the BCR/ABL1 dual fusion probe (Vysis) detected no fusion signals and molecular studies for BCR-ABL1 fusion transcripts [expected in association with t(9;22)(q34;q11)] were also negative. Further molecular studies were performed and an abnormal fusion transcript between exon 1 of BCR and exon 17 of JAK2 was amplified and sequenced from the patient’s bone marrow (bottom right). The BCR exon 1 is in-frame with the tyrosine kinase domain of JAK2. This unique BCR-JAK2 fusion gene was clinically manifest as an MPD with early extramedullary transformation. A previous report of an MPD with a BCR-JAK2 fusion (Griesinger et al, 2005) with different breakpoints also showed relatively early blast crisis. Whether BCR-JAK2 positive MPD represents a distinct clinical-pathological entity requires further study.

Total submission of pelvic lymphadenectomy tissues removed during radical prostatectomy for prostate cancer increases lymph node yield and detection of micrometastases

The detection of lymph node metastases has prognostic and therapeutic implications for patients undergoing radical prostatectomy for prostate cancer. Macroscopic identification of pelvic lymph nodes in surgical lymphadenectomy specimens can be difficult, with a potential for incomplete submission of lymph nodes for microscopic examination. This study was undertaken to determine whether complete sampling of lymphadenectomy specimens would improve the detection of metastatic disease in patients undergoing radical prostatectomy.

A progress report on a prospective randomised trial of open and robotic prostatectomy

A randomised trial of robotic and open prostatectomy commenced in October 2010 and is progressing well. Clinical and quality of life outcomes together with economic costs to individuals and the health service are being examined critically to compare outcomes.

Improved surgical margin definition by narrow band imaging for resection of oral squamous cell carcinoma: A prospective gene expression profiling study

Incomplete primary tumor excision contributes to localized postsurgical recurrence of oral squamous cell carcinoma (OSCC). The purpose of this study was to provide molecular evidence that surgical margin definition using narrow band imaging (NBI) resulted in more complete OSCC excision than conventional white light (WL) panendoscopy.

Patient samples of renal cell carcinoma show reduced expression of TRAF1 compared with normal kidney and functional studies in vitro indicate TRAF1 promotes apoptosis: potential for targeted therapy

Aims: The tumour necrosis factor (TNF) receptor-associated factor (TRAF) family of proteins links the TNF receptor superfamily to cell signalling cascades. TRAF1 is involved in regulation of apoptosis, proliferation, differentiation and stress responses. It has a role in development of several malignancies, but no information for renal cell carcinoma (RCC) is available. Methods: Expression profiles for TRAF1 were investigated in 121 samples of human RCC of various subtypes plus paired normal kidney prepared in tissue microarrays, in comparison with apoptosis (morphology, ApopTag) and mitosis (morphology, proliferating cell nuclear antigen/PCNA). TRAF1 function was tested in vitro in RCC ACHN cells. TRAF1 short interfering RNA (siRNA) was used to inhibit expression of TRAF1 in ACHN cells untreated or treated with cancer therapies known to induce apoptosis (20 Gy X-irradiation and/or 500 IU/mL interferon-alpha). Results: In patient samples, TRAF1 localised to proximal tubular epithelium in normal kidney and was significantly decreased in clear cell RCC as one group (p < 0.01) and all other RCC subclassifications grouped together (p < 0.05). There was little apoptosis identified in any RCC samples. In vitro, TRAF1 siRNA caused significant reduction in TRAF1 expression and a concurrent decrease in apoptosis and increase in proliferative activity (both p < 0.05) in the ACHN RCC cells treated with radiation and interferon-alpha. Conclusion: TRAF1 may have a pro-apoptotic, anti-mitotic role in RCC. The low TRAF1 expression in untreated RCC patient samples compared with normal kidney, and the localisation of TRAF1 to the proximal tubular epithelium from which many RCC originate, may indicate a potential for targeted therapy in RCC.

Distal seminal vesicle invasion by prostate adenocarcinoma does not occur in isolation of proximal seminal vesicle invasion or lymphovascular infiltration

Aims: Seminal vesicle (SV) invasion by prostatic adenocarcinoma is a poor prognostic indicator. Despite this, there are currently no guidelines regarding SV sampling in radical prostatectomy specimens. This study examines the distribution of invasive prostatic adenocarcinoma in SVs and makes recommendations regarding sampling procedures. Method: The SVs from 773 consecutive radical prostatectomy specimens were serially sectioned and blocked entirely, with sections grouped into the proximal, mid and distal thirds of the glands. The site of invasive prostatic carcinoma within the muscular wall of the SV and its presence in the ejaculatory duct was recorded. Results: SV invasion (pT3b) was present in 56 (7.2%) cases. Patients ranged in age from 52 to 73 years (mean 64 years), with a serum prostatic specific antigen ranging from 3.7 to 46 ng/mL (mean 10.6 ng/mL). Fourteen patients (25%) had a palpable nodule or induration on digital rectal examination. Ejaculatory duct involvement was present in 49 cases. Forty‐seven of 49 (95.9%) cases with ejaculatory duct involvement also had SV invasion. The mean tumour volume was 5.53 cm3 (range 1.0–12.1 cm3). The tumours had a Gleason score of 4 + 3 in five cases, 4 + 3 with tertiary pattern 5 in 12 cases, 8 in two cases and 5 + 4/4 + 5 in 37 cases. All but one of the SV positive cases (98.2%) had involvement of the proximal third (15 right, 17 left and 23 both) of the gland, 35 of which (63.6%) had infiltration only of the proximal SV. For the remainder, 11 also had mid third and nine had mid and distal third involvement. Lymphovascular invasion within the prostate was seen in 71.4% of cases. In one of these cases involvement of the distal right SV was present in the absence of involvement of the proximal or mid SV. Conclusions: In this study, as distal SV invasion in the absence of proximal SV invasion was found in <2% of cases, we conclude that sampling of the proximal third of the SVs is sufficient to identify virtually all cases of tumour infiltration into the SVs. If lymphovascular invasion is present in the absence of proximal SV invasion, then the remaining parts of the SV must be examined. Also, in cases with involvement of the ejaculatory duct, thorough examination of the SV is warranted.

Prostate-based biofluids for the detection of prostate cancer: a comparative study of the diagnostic performance of cell-sourced RNA biomarkers

Background Prostate cancer (PCa) diagnosis requires improvement with the aid of more accurate biomarkers. Postejaculate urethral washings (PEUW) could be a physiological equivalent to urine obtained following rectal prostatic massage, the current basis for the prostate cancer antigen 3 (PCA3) test. The aim of this study was to investigate if PEUW contained prostate-based material, evidenced by the presence of prostate specific antigen (PSA), and to evaluate the diagnostic performance of PEUW-based biomarkers. Methods Male patients referred for elevated serum PSA or abnormal digital rectal examination provided ejaculate and PEUW samples. PSA, PCA3, and β2-microglobulin (β2M) were quantified in ejaculate and PEUW and compared with absolute and clinically significant (according to D’Amico criteria) PCa presence, as determined by biopsies. Diagnostic performance was determined and compared with serum PSA using receiver operating characteristic analysis. Results From 83 patients who provided PEUW samples, paired analysis with ejaculate samples was possible for 38 patients, while analysis in an unpaired, extended cohort was possible for 62 patients. PSA and PCA3 were detected in PEUW, normalized to β2M, and PCA3:PSA was calculated. In predicting absolute PCa status, PCA3:β2M in ejaculate [area under the curve (AUC) 0.717] and PEUW (AUC 0.569) were insignificantly better than PCA3:PSA (AUC 0.668 and 0.431, respectively) and comparable with serum PSA (AUC 0.617) with similar trends observed for the extended cohort. When considering clinically significant PCa presence, serum PSA in the comparison (AUC 0.640) and extended cohorts (AUC 0.665) was comparable with PCA3: β2M (AUC 0.667) and PCA3:PSA (AUC 0.605) in ejaculate, with lower estimates for PEUW in the comparison (PCA3: β2M AUC 0.496; PCA3:PSA AUC 0.342) and extended (PCA3: β2M AUC 0.497; PCA3:PSA AUC 0.469) cohorts. The statistical analysis was limited by sample size. Conclusion PEUW contains prostatic material, but has limited diagnostic accuracy when considering cell-derived DNA analysis. PCA3-based markers in ejaculate are comparable to serum PSA and digital rectal examination–urine markers.

Clinical significance of cancer in radical prostatectomy specimens: analysis from a contemporary series of 2900 men

Summary With prostate specific antigen (PSA) testing, up to 49% of detected tumours are small and in some of these cases there is a possibility that the tumour will remain clinically insignificant during the patients remaining lifetime. The current study was performed to characterise the extent of cancer in men treated by radical prostatectomy (RP) in a community without population-based PSA screening. Clinical and pathological data of 2900 patients who underwent RP between 2008 and 2012 were analysed. Specimens were entirely embedded and evaluated by routine haematoxylin and eosin staining. Tumours were graded using recent modifications to the International Society of Urological Pathology (ISUP) modified Gleason grading system, and staged according to the ISUP recommendations. Tumours were considered pathologically insignificant if organ confined, with a volume of <0.5 cc and a Gleason score (GS) of <7. The mean age of patients in the series was 63 years (range 32–79 years) and the mean pre-operative PSA was 7.16 ng/mL (range 0.4–69). In total, 2614 (90.1%) were classified as cT1; however, insignificant tumours were found in only 150 (5.2%) patients following examination of the radical prostatectomy specimen. A total of 2681 cases (92.4%) had a final GS of ≥7, 1144 (39.4%) had extraprostatic extension (EPE), of which 88.7% were classified as established; 669 (23.1%) had a tumour volume of >3 cc and 284 (9.8%) had surgical margin positivity. Seminal vesicle involvement was seen in 159 (5.5%) cases. Of 693 patients who had a lymphadenectomy, 31 (4.5%) had lymph node metastases. Aged ⩽50 years were 212 (7.3%) patients (mean age 47 years). Of these, 194 were classified as cT1 while 192 (90.6%) were found to have significant cancer on examination of the radical prostatectomy specimen. We have shown in our series that although 90.1% of tumours were cT1, an overwhelming majority of tumours were found to be pathologically significant following RP, with a high proportion of cases showing high stage disease, seminal vesicle involvement and lymph node metastasis. These results suggest that, contrary to estimates from international trials, ad hoc PSA testing is associated with low levels of over-treating.