Effect of Immunosuppressive or Immunomodulatory Agents on Severe COVID-19 Outcomes: A Population-Based Cohort Study.

OBJECTIVE: We estimated the association between immunosuppressive and immunomodulatory agent (IIA) exposure and severe COVID-19 outcomes in a population-based cohort study. METHODS: Participants were 18 years or older, tested positive for SARS-CoV-2 between February 6, 2020, and August 15, 2021, and were from administrative health data for the entire province of British Columbia, Canada. IIA use within 3 months prior to positive SARS-CoV-2 test included conventional disease-modifying antirheumatic drugs (antimalarials, methotrexate, leflunomide, sulfasalazine, individually), immunosuppressants (azathioprine, mycophenolate mofetil/mycophenolate sodium [MMF], cyclophosphamide, cyclosporine, individually and collectively), tumor necrosis factor inhibitor (TNFi) biologics (adalimumab, certolizumab, etanercept, golimumab, infliximab, collectively), non-TNFi biologics or targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) (rituximab separately from abatacept, anakinra, secukinumab, tocilizumab, tofacitinib and ustekinumab collectively), and glucocorticoids. Severe COVID-19 outcomes were hospitalizations for COVID-19, ICU admissions, and deaths within 60 days of a positive test. Exposure score-overlap weighting was used to balance baseline characteristics of participants with IIA use compared with nonuse of that IIA. Logistic regression measured the association between IIA use and severe COVID-19 outcomes. RESULTS: From 147,301 participants, we identified 515 antimalarial, 573 methotrexate, 72 leflunomide, 180 sulfasalazine, 468 immunosuppressant, 378 TNFi biologic, 49 rituximab, 144 other non-TNFi biologic or tsDMARD, and 1348 glucocorticoid prescriptions. Risk of hospitalizations for COVID-19 was significantly greater for MMF (odds ratio [95% CI]): 2.82 [1.81-4.40], all immunosuppressants: 2.08 [1.51-2.87], and glucocorticoids: 1.63 [1.36-1.96], relative to nonuse. Similar outcomes were seen for ICU admission and MMF: 2.52 [1.34-4.74], immunosuppressants: 2.88 [1.73-4.78], and glucocorticoids: 1.86 [1.37-2.54]. Only glucocorticoids use was associated with a significant increase in 60-day mortality: 1.58 [1.21-2.06]. No other IIAs displayed statistically significant associations with severe COVID-19 outcomes. CONCLUSION: Current use of MMF and glucocorticoids were associated with an increased risk of severe COVID-19 outcomes compared with nonuse. These results emphasize the variety of circumstances of patients taking IIAs.

Primary Squamous Cell Carcinoma of the Male Proximal Urethra: Outcomes from a Single Centre.

BACKGROUND: Primary squamous cell carcinoma (SCC) of the male proximal urethra is an aggressive and rare urogenital malignancy. OBJECTIVE: To review the surgical management and outcomes for male proximal urethral SCCs within a single centre and to suggest an algorithm for the surgical management of these rare tumours. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective study of patients undergoing surgery for male proximal urethral SCC within a single tertiary academic centre managing rare genital tumours. Ten patients with a histological diagnosis of proximal urethral SCC were identified from an institutional database over a period of 10 yr with a median follow-up of 22.5 mo (standard deviation±25.77 mo). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Pathological staging, surgical treatment, and neoadjuvant and adjuvant treatment were recorded. Complications according to the Clavien-Dindo classification and overall survival rates were recorded. Kaplan-Meier curves were used for overall survival. RESULTS AND LIMITATIONS: A total of 10 patients were identified of whom eight underwent panurethrectomy and radical prostatectomy. Radical inguinal lymphadenectomy was performed in five patients, which confirmed bilateral metastatic disease. Perioperative complications were reported in six patients (Clavien I and II). Within 6 mo of surgery, 90% of patients developed distant metastatic disease. Nine patients died of urethra cancer during the follow-up. One patient is still on follow-up. The median overall follow-up was 13.92 mo (range: 5-91 mo). At 5 yr, cancer-specific/overall survival was 10%. A limitation of this study is the retrospective design, which is unavoidable for such a rare disease. CONCLUSIONS: Radical surgery allows local disease control, but despite neo/adjuvant treatment, proximal urethral SCC is associated with poor survival outcomes and progression to distant metastatic disease within 6 mo. PATIENT SUMMARY: Proximal urethral squamous cell carcinoma is a rare cancer in men which is often detected late. Patients often present with problems such as voiding, urethral bleeding, or a palpable mass. Aggressive surgery allows local control, but despite this the overall survival is poor. Adjuvant and neoadjuvant radiochemotherapy can improve survival. Multicentric randomised trials are needed to identify the correct treatment modality.

Restoration of the Lost Obscured Coronal Sulcus: A Novel Surgical Technique for Penile Lichen Sclerosus with Severe Preputial Adhesions.

BACKGROUND: Lichen sclerosus (LS) may cause the glans and prepuce to become fused, making a standard circumcision impossible. Most authorities recommend excision of the fused area with glans resurfacing, although partial circumcision is often performed. OBJECTIVE: To evaluate an alternative technique that preserves the fused area and allows a complete circumcision without grafting. DESIGN, SETTING, AND PARTICIPANTS: Over 3 yr (January 2016-March 2018), 28 men (age 28-93 yr; mean 62 yr) underwent the restoration of lost obscured coronal sulcus (ROLOCS) procedure with over 1 yr of follow-up. Complications were reviewed retrospectively with an additional survey. SURGICAL PROCEDURE: The shaft skin is incised at the corona. Dartos is divided, which allows antegrade dissection just outside the fused glans membrane. The foreskin is removed and shaft skin sutured to dartos below the corona. MEASUREMENTS: Postoperative pain, aesthetic satisfaction, sexual enjoyment, glans sensation, and urinary symptoms were measured. RESULTS AND LIMITATIONS: There were no major complications. In all cases, the coronal sulcus was restored and the glans skin became soft without skin grafting. All were satisfied with the aesthetics. Of the patients, <70% experienced mild to low-moderate pain; 55% and 25% had, respectively, improved or reduced glans sensation; and 40% reported improved enjoyment of sex. Histology showed LS in all cases with squamous cell carcinoma in four, including three out of five patients who had previously undergone partial circumcision. Although this is the largest series reported yet, the numbers were too small for a meaningful statistical analysis. CONCLUSIONS: The ROLOCS operation offers an aesthetically superior alternative to partial circumcision and is easier to perform with less morbidity than skin grafting. PATIENT SUMMARY: The restoration of lost obscured coronal sulcus (ROLOCS) procedure provides an alternative to partial circumcision or circumcision with skin grafting when the foreskin is welded to the head of the penis (glans) due to lichen sclerosus. It produces a good cosmetic result, but the glans can be sore until it heals.

Long-term outcomes for penile cancer patients presenting with advanced N3 disease requiring a myocutaneous flap reconstruction or primary closure-a retrospective single centre study.

BACKGROUND: Penile cancer patients with advanced metastatic disease in the inguinal region present a therapeutic challenge. We compared the outcomes for patients with advanced inguinal node disease requiring myocutaneous flap reconstruction (MFR) against primary closure for N3 disease. METHODS: A retrospective comparative study of a consecutive cohort of advanced penile cancer patients with N3 disease was performed. Patient demographics, presenting symptoms, primary tumour site, stage and grade were recorded. The type of MFR used, patient outcomes and post-operative complications were recorded from an institutional database. Kaplan-Meier (KM) curves were calculated to analyse the cancer-specific survival (CSS) rates for the MFR group and compared with the no-MFR group. P values were calculated by log-rank and Chi square tests for CSS rates and complications respectively. RESULTS: Eighteen patients requiring MFR were identified; mean age 62 years. Ten (55.6%) patients had a first presentation with penile cancer and advanced nodal disease with the remaining 8 (44.4%) presenting with an inguinal recurrence having already undergone surgery. The majority (n=15) underwent a vertical rectus abdominis myocutaneous (VRAM) flap. The average length of stay was 23 days for the MFR group versus 8.5 days for the no-MFR group. The 5-year CSS was 20.9% for the MFR group and 39.8% for the no-MFR group (P<0.01). CONCLUSIONS: Aggressive surgical management for patients with extensive nodal disease and flap reconstruction is feasible and aids wound management although the long-term prognosis is still poor.

Zonal mapping of sentinel lymph nodes in penile cancer patients using fused SPECT/CT imaging and lymphoscintigraphy.

PURPOSE: To define the anatomical location of sentinel lymph nodes (SLN) in penile cancer patients based on Daseler's original zonal description using a combination of single photon emission computed tomography-computed tomography (SPECT-CT), cross sectional imaging and lymphoscintigraphy and characterise the limits of Zone V. MATERIALS AND METHODS: Patients with primary penile cancer ≥T1G2 were included in the study. A total of 113 groins with impalpable inguinal lymph nodes (cN0) underwent planar lymphoscintigraphy and SPECT-CT. The sentinel lymph nodes were mapped on cross sectional imaging according to Daseler's anatomical description. Using measurements from fixed anatomical landmarks, a custom-made software program mapped the SLNs. SLNs were mapped to the previously undefined Zone V using 3 approaches to avoid observational bias: (a) as perceived by the uroradiologist, (b) limiting Zone V to a 5 mm radius from the sapheno-femoral junction or (c) using a 10 mm radius from the sapheno-femoral junction. RESULTS: Using SPECT-CT, drainage to the groins was seen in 109 of the 113 cN0 groins (96.5%). The majority of the SLNs were located in the central and superior quadrants with 38.2% lying within Zone I, 45% in Zone II and 13% in Zone V. More importantly, sentinel lymph nodes were still localised to the inferior zones with 3% located in Zone III and 0.8% in Zone IV. CONCLUSIONS: Using a hybrid of SPECT-CT, cross sectional imaging and lymphoscintigraphy we have demonstrated that SLNs may be located in the inferior zones. We also define the limits of Zone V as an area of 5 mm radius from the sapheno-femoral junction.

Glansectomy and Split-thickness Skin Graft for Penile Cancer.

BACKGROUND: Penile cancer is a rare malignancy that is confined to the glans in up to four out of five cases. Although descriptions of glansectomy exist, there are no contemporary video explanations or large published single centre series. OBJECTIVE: To show the efficacy and safety of glansectomy and split-thickness skin graft (STSG) reconstruction. DESIGN, SETTING, AND PARTICIPANTS: Data were collected retrospectively for patients identified from surgical theatre diaries between February 2005 and January 2016. 177 patients with histologically proven squamous-cell carcinoma on the glans underwent glansectomy and STSG at a tertiary referral centre in the UK. The median follow-up was 41.4 mo. SURGICAL PROCEDURE: The skin is incised at the subcoronal level and deepened onto Buck's fascia. Dissection is performed over or under Buck's fascia, depending on suspicion of invasion or risk of disease. The glans is excised and a neoglans is created using a STSG. MEASUREMENTS: Local recurrence, cancer-specific survival, overall survival, and complications. RESULTS AND LIMITATIONS: Sixteen out of 172 patients (9.3%) experienced local recurrence during the follow-up period. Eighteen out of 174 (10.7%) patients died of penile cancer, while 29 patients in total died during the follow-up period. Of 145 patients, 9% required operative intervention for complications, including graft loss and meatal stenosis. Limitations include the retrospective data collection and the lack of functional and sexual outcomes. CONCLUSIONS: Glansectomy and STSG comprise a safe procedure in terms of oncologic control and complications for patients with penile cancer confined to the glans penis. Further studies are required to assess functional and sexual outcomes in these patients. PATIENT SUMMARY: We report on the management of penile cancers confined to the head of the penis using glansectomy and a split-thickness skin graft to recreate the appearance of a glans. This technique is safe and effective, with limited complications.

Predictive factors for local recurrence after glansectomy and neoglans reconstruction for penile squamous cell carcinoma.

OBJECTIVES: To investigate predictive pathological factors for local recurrence (LR) after glansectomy for penile squamous cell carcinoma (SCC) and to develop a risk score for prediction of LR after glansectomy. PATIENTS AND METHODS: In this retrospective study, we analyzed 117 patients operated between February 2005 and January 2016 in a supraregional penile cancer center in the UK for LR after glansectomy and glans reconstruction. Univariate and multivariate Cox proportional hazards regression was used to identify 4 prognostic indicators for LR. The hazard ratio (HR) of LR was estimated in Kaplan-Meier analysis, and based on these data, we designed a postoperative model for prediction of LR based on 3 risk groups. RESULTS: Median follow-up period was 33.7 (95% CI: 26.8-40.3) months; 12.8% of the patients experienced LR. Univariate Cox proportional hazards regression revealed that the risk factors for recurrence were the presence of perineural invasion, carcinoma in situ, positive margin on definitive pathology, and high-grade disease. Based on Kaplan-Meier analysis stratified by number of factors present, we defined 3 risk groups for LR: low (0,1 risk factors) as reference, intermediate (2,3 risk factors) with HR of 13.9 (95% CI: 1.81-107.04, P = 0.0115), or high risk (all 4 risk factors present) with a HR of 34.2 (95% CI: 3.07-381.81, P = 0,0041). Limitations include the retrospective design and low number of events inherent to the rare nature of penile SCC. CONCLUSIONS: Perineural invasion, carcinoma in situ, positive definitive margins, and the presence of high-grade SCC predict LR following glansectomy. These factors can be used to stratify patients into low-, intermediate-, and high-risk groups for recurrence which may be used to tailor follow-up.

Investigating the role of SPECT/CT in dynamic sentinel lymph node biopsy for penile cancers.

PURPOSE: Currently, most centres use 2-D planar lymphoscintigraphy when performing dynamic sentinel lymph node biopsy in penile cancer patients with clinically impalpable inguinal nodes. This study aimed to investigate the role of SPECT/CT following 2-D planar lymphoscintigraphy (dynamic and static) in the detection and localization of sentinel lymph nodes in the groin. METHODS: A qualitative (visual) review was performed on planar followed by SPECT/CT lymphoscintigraphy in 115 consecutive patients (age 28-86 years) who underwent injection of 99mTc-nanocolloid followed by immediate acquisition of dynamic (20 min) and early static scans (5 min) initially and further delayed static (5 min) images at 120 min followed by SPECT/CT imaging. The lymph nodes detected in each groin on planar lymphoscintigraphy and SPECT/CT were compared. RESULTS: A total of 440 and 467 nodes were identified on planar scintigraphy and SPECT/CT, respectively. Overall, SPECT/CT confirmed the findings of planar imaging in 28/115 cases (24%). In the remaining 87 cases (76%), gross discrepancies were observed between planar and SPECT/CT images. SPECT/CT identified 17 instances of skin contamination (16 patients, 13%) and 36 instances of in-transit lymphatic tract activity (24 patients, 20%) that had been interpreted as tracer-avid lymph nodes on planar imaging. In addition, SPECT/CT identified 53 tracer-avid nodes in 48 patients (42%) that were not visualized on planar imaging and led to reclassification of the drainage basins (pelvic/inguinal) of 27 tracer-avid nodes. CONCLUSIONS: The addition of SPECT/CT improved the rate of detection of true tracer-avid lymph nodes and delineated their precise (3-D) anatomic localization in drainage basins.

Management of non-visualization following dynamic sentinel lymph node biopsy for squamous cell carcinoma of the penis.

OBJECTIVES: To review the management and clinical outcomes of uni- or bilateral non-visualization of inguinal lymph nodes during dynamic sentinel lymph node biopsy (DSNB) in patients diagnosed with penile cancer and clinically impalpable inguinal lymph nodes (cN0), and to develop an algorithm for the management of patients in which non-visualization occurs. PATIENTS AND METHODS: This is a retrospective observational study over a period of 4 years, comprising 166 patients with penile squamous cell carcinoma undergoing DSNB and followed up for a minimum of 6 months. All cases diagnosed with uni- or bilateral non-visualization of sentinel nodes in this cohort were identified from a penile cancer database. The management of the inguinal lymph nodes after non-visualization and the oncological outcomes including local and regional recurrence rates were documented. RESULTS: Out of 166 consecutive patients undergoing DSNB, 20 patients (12%) had unilateral non-visualization after injection of intradermal 99m Tc. Of these 20 patients, seven underwent repeat DSNB at a later date, with six having successful visualization. One patient had persistent non-visualization and proceeded to a superficial modified inguinal lymphadenectomy (SML). None of these patients experienced recurrence at follow-up. A further seven patients underwent modified SML with on-table frozen-section analysis of the lymph node packet; none of these patients were found to have micrometastatic disease in the inguinal lymph nodes, although one patient developed metastatic inguinal node disease at a later date. Six patients elected to undergo clinical surveillance and have remained disease-free. CONCLUSION: Patients with impalpable inguinal lymph nodes undergoing DSNB with ≥G2 T1 disease should ideally have bilateral visualization of the sentinel lymph nodes, reflecting the drainage pattern from the primary tumour. In the present series, 12% of patients were found to have unilateral non-visualization after DSNB. Among patients offered a repeat DSNB at a later date, localizing the sentinel node was successful in 86% of cases. Patients with favourable histological characteristics can be placed on clinical surveillance. Those with high-risk disease can be offered a repeat DSNB procedure on the proviso that SML may be carried out if there is repeated non-visualization. Larger cohorts are required to validate this proposed algorithm.

CSN1 Somatic Mutations in Penile Squamous Cell Carcinoma.

Other than an association with HPV infection, little is known about the genetic alterations determining the development of penile cancer. Although penile cancer is rare in the developed world, it presents a significant burden in developing countries. Here, we report the findings of whole-exome sequencing (WES) to determine the somatic mutational landscape of penile cancer. WES was performed on penile cancer and matched germline DNA from 27 patients undergoing surgical resection. Targeted resequencing of candidate genes was performed in an independent 70 patient cohort. Mutation data were also integrated with DNA methylation and copy-number information from the same patients. We identified an HPV-associated APOBEC mutation signature and an NpCpG signature in HPV-negative disease. We also identified recurrent mutations in the novel penile cancer tumor suppressor genes CSN1(GPS1) and FAT1 Expression of CSN1 mutants in cells resulted in colocalization with AGO2 in cytoplasmic P-bodies, ultimately leading to the loss of miRNA-mediated gene silencing, which may contribute to disease etiology. Our findings represent the first comprehensive analysis of somatic alterations in penile cancer, highlighting the complex landscape of alterations in this malignancy. Cancer Res; 76(16); 4720-7. ©2016 AACR.

Feasibility of performing dynamic sentinel lymph node biopsy as a delayed procedure in penile cancer.

INTRODUCTION: Patients diagnosed with penile cancer and clinically impalpable inguinal lymph nodes (cN0), normally undergo dynamic sentinel lymph node biopsy (DSNB) at the same time as the primary penile surgery. The aim of this study is to investigate the diagnostic accuracy and clinical outcomes of performing DSNB in patients who have already undergone surgery for the primary penile cancer. METHODS: Ninety-two patients with unilateral or bilateral impalpable inguinal lymph nodes (LNs) who had already undergone primary resection of the penile tumour (stage ≥ T1G2) were included in this study. All patients underwent a preoperative USS of the groin(s) with fine needle aspiration cytology (FNAC). Provided that the FNAC was clear, DSNB was performed. Radical inguinal lymphadenectomy was performed if the histological analysis of the SLN confirmed the presence of micrometastatic disease. RESULTS: DSNB was undertaken in 165 groins with a nonvisualisation rate of 4.8 % (8/165 groins). The SLN was positive for micrometastatic disease in nine groins (5.5 %) from a total of eight patients (8.7 %). One patient developed regional recurrence in a prepubic LN after excision of bilateral negative SLN (1.1 %). The three-year disease-specific survival for patients with negative and positive SLN was 98.8 and 87.5 %, respectively (p = 0.042). Using DSNB, occult LN metastases in penile cancer can be detected with a sensitivity of 88.9 % and specificity of 100 %. CONCLUSIONS: We have demonstrated that DSNB is feasible as a delayed procedure to localise the SLN. Surgical resection of the primary penile lesion does not appear to change the lymphatic drainage.

Epigenetics markers of metastasis and HPV-induced tumorigenesis in penile cancer.

PURPOSE: Penile cancer is a rare malignancy in the developed world with just more than 1,600 new cases diagnosed in the United States per year; however, the incidence is much higher in developing countries. Although HPV is known to contribute to tumorigenesis, little is known about the genetic or epigenetic alterations defining penile cancer. EXPERIMENTAL DESIGN: Using high-density genome-wide methylation arrays, we have identified epigenetic alterations associated with penile cancer. Q-MSP was used to validate lymph node metastasis markers in 50 cases. A total of 446 head and neck squamous cell carcinoma (HNSCC) and cervical squamous cell carcinoma (CESCC) samples were used to validate HPV-associated epigenetic alterations. RESULTS: We defined 6,933 methylation variable positions (MVP) between normal and tumor tissue, which includes 997 hypermethylated differentially methylated regions associated with tumor supressor genes, including CDO1, AR1, and WT1. Analysis of penile cancer tumors identified a 4 gene epi-signature which accurately predicted lymph node metastasis in an independent cohort (AUC of 89%). Finally, we explored the epigenetic alterations associated with penile cancer HPV infection and defined a 30 loci lineage-independent HPV specific epi-signature which predicts HPV status and survival in independent HNSCC, CESC cohorts. Epi-signature-negative patients have a significantly worse overall survival [HNSCC P = 0.00073; 95% confidence interval (CI), 0.021-0.78; CESC P = 0.0094; HR = 3.91, 95% CI = 0.13-0.78], HPV epi-signature is a better predictor of survival than HPV status alone. CONCLUSIONS: These data demonstrate for the first time genome-wide epigenetic events involved in an aggressive penile cancer phenotype and define the epigenetic alterations common across multiple HPV-driven malignancies.

MALDI mass spectrometry in prostate cancer biomarker discovery.

Matrix-assisted laser desorption/ionisation (MALDI) mass spectrometry (MS) is a highly versatile and sensitive analytical technique, which is known for its soft ionisation of biomolecules such as peptides and proteins. Generally, MALDI MS analysis requires little sample preparation, and in some cases like MS profiling it can be automated through the use of robotic liquid-handling systems. For more than a decade now, MALDI MS has been extensively utilised in the search for biomarkers that could aid clinicians in diagnosis, prognosis, and treatment decision making. This review examines the various MALDI-based MS techniques like MS imaging, MS profiling and proteomics in-depth analysis where MALDI MS follows fractionation and separation methods such as gel electrophoresis, and how these have contributed to prostate cancer biomarker research. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge.

MALDI MS profiling of post-DRE urine samples highlights the potential of ß-microseminoprotein as a marker for prostatic diseases.

BACKGROUND: To use spectra acquired by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) from pre- and post-digital rectal examination (DRE) urine samples to search for discriminating peaks that can adequately distinguish between benign and malignant prostate conditions, and identify the peaks' underlying biomolecules. METHODS: Twenty-five participants with prostate cancer (PCa) and 27 participants with a variety of benign prostatic conditions as confirmed by a 10-core tissue biopsy were included. Pre- and post-DRE urine samples were prepared for MALDI MS profiling using an automated clean-up procedure. Following mass spectra collection and processing, peak mass and intensity were extracted and subjected to statistical analysis to identify peaks capable of distinguishing between benign and cancer. Logistic regression was used to combine markers to create a sensitive and specific test. RESULTS: A peak at m/z 10,760 was identified as ß-microseminoprotein (ß-MSMB) and found to be statistically lower in urine from PCa participants using the peak's average areas. By combining serum prostate-specific antigen (PSA) levels with MALDI MS-measured ß-MSMB levels, optimum threshold values obtained from Receiver Operator characteristics curves gave an increased sensitivity of 96% at a specificity of 26%. CONCLUSIONS: These results demonstrate that with a simple sample clean-up followed by MALDI MS profiling, significant differences of MSMB abundance were found in post-DRE urine samples. In combination with PSA serum levels, obtained from a classic clinical assay led to high classification accuracy for PCa in the studied sample set. Our results need to be validated in a larger multicenter prospective randomized clinical trial.

Genital lichen sclerosus/balanitis xerotica obliterans in men with penile carcinoma: a critical analysis.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The European Association of Urology guidelines identify lichen sclerosus (LS) as a strong risk factor for penile squamous cell carcinoma (pSCC). However, this statement is based on the findings of case-control studies (Level of Evidence 2a) and a direct causal relationship between LS/balanitis xerotica obliterans (BXO) and pSCC remains to be established. Firm guidelines with respect to the appropriate follow-up policy for LS/BXO are lacking, whereas the impact of synchronous LS/BXO on the prognosis of pSCC remains to be determined. The presence of histologically-confirmed synchronous LS/BXO in patients diagnosed with pSCC is relatively high, although it is not associated with an increased risk of adverse histopathological features. LS/BXO can develop in extragenital skin grafts used for reconstruction after organ-sparing surgery for pSCC. OBJECTIVES: To determine the rate of lichen sclerosus/balanitis xerotica obliterans (LS/BXO) in patients with penile squamous cell carcinoma (pSCC) and establish whether the presence of LS/BXO is associated with adverse histopathological features of pSCC. To report the phenomenon of LS involving non-genital skin grafts in patients who underwent organ-sparing surgery and split-skin graft (SSG) reconstruction PATIENTS AND METHODS: Between January 2002 and January 2010, 223 men underwent surgical treatment for pSCC. A group of 52 patients with histologically-confirmed synchronous LS was identified (group A; overall rate of LS/BXO = 23.3%) and compared with a group of patients without synchronous LS (group B; n = 171; 76.7%). A subgroup of patients who underwent surgical excision and SSG reconstruction was also identified The histology reports of graft biopsies obtained during follow-up were reviewed and the rate of LS involving the graft was also recorded. RESULTS: Mean (range) age at diagnosis was 60.9 (34-81) years and 60.7 (28-89) years for groups A and B, respectively (P = 0.958). The mean (range) duration of follow-up was 38.3 (4-92) months for group A and 45.5 (4-107) months for group B (P = 0.162) No statistically significant differences were noted between groups A and B in terms of tumour grade (P = 0.091), stage (P = 0.697), presence of lymphovascular invasion (P = 0.333), histological subtype (P = 0.107), associated carcinoma in situ (P = 0.246) or nodal status at initial diagnosis (P = 0.555). In the subgroup of 188 patients who underwent SSG reconstruction, 41 (21.8%) patients had histologically-confirmed synchronous LS; in this subgroup, 26 (13.8%) patients underwent graft biopsy during follow-up. Genital LS involving the graft was identified in seven specimens, although none of these seven cases had associated recurrent pSCC. CONCLUSIONS: The presence of histologically-confirmed synchronous LS in patients with pSCC is relatively high but is not associated with increased rates of adverse histopathological features, including carcinoma in situ. LS can develop in extragenital skin grafts, although its association with the long-term risk for recurrent pSCC is not apparent in the present study.

Conservative surgery for squamous cell carcinoma of the penis: resection margins and long-term oncological control.

PURPOSE: We assessed the oncological outcome of penile conserving surgery and identified parameters predicting local recurrence, including resection margins. MATERIALS AND METHODS: A total of 179 patients with invasive penile cancer treated with organ sparing surgery at a tertiary center between 2002 and 2010 fulfilled our study criteria. Demographic, histopathological, management and followup data were recorded in a prospective database. Local, regional and distant recurrence rates, time to recurrence and survival rates were calculated. Survival analysis was performed by the Kaplan-Meier method. Multivariate analysis was used to identify predictors of local recurrence. RESULTS: Mean followup was 42.8 months (range 4 to 107). Local, regional and distant metastatic recurrence developed in 16 (8.9%), 19 (10.6%) and 9 patients (5.0%) at a mean of 26.1, 26.8 and 11.7 months, respectively. The 5-year disease specific survival rate after recurrence was 54.7% (95% CI 46.1-63.3). For patients with isolated local recurrence the 5-year disease specific survival rate was 91.7% compared to 38.4% for those with regional recurrence. The overall 5-year local recurrence-free rate was 86.3% (95% CI 82.6-90.4). Tumor grade (p = 0.003), stage (p = 0.021) and lymphovascular invasion (p = 0.014) were identified as predictors of local recurrence on multivariate analysis. CONCLUSIONS: Penile conserving surgery is oncologically safe and a surgical excision margin of less than 5 mm is adequate. Higher local recurrence rates are associated with lymphovascular invasion, and higher tumor stage and grade. Local recurrence has no negative impact on long-term survival.

The results of real-time brachytherapy for the management of low- and intermediate-risk prostate cancer in patients with prostate volumes up to 100 mL.

OBJECTIVES: • To report the results of real-time brachytherapy in the management of low-risk and intermediate-risk prostate cancer in patients with prostate volumes up to 100 mL, over a 6-year period. • To prospectively determine whether prostate volume influences the ability to achieve a quality implant and therefore impact upon prostate-specific antigen (PSA) relapse-free survival, and urinary and rectal toxicity. SUBJECTS AND METHODS: • In all, 216 men with localized prostate cancer were treated with real-time prostate brachytherapy using (125) I implants between November 2003 and December 2009. • Patient selection was based upon functional parameters; International Prostate Symptom Score (IPSS) and flowmetry. • Patients had computed tomography imaging at 1 month to assess post-implant dosimetry. PSA, IPSS and Radiation Therapy Oncology Group rectal toxicity scores were recorded prospectively over the follow-up period. • Patients with prostate volumes ≤50 mL and those with volumes >50 mL were compared. RESULTS: • Overall PSA relapse-free survival was 98.8%; 97.0% for intermediate-risk patients and 100.0% for low-risk patients. By volume, 98.5% of men with standard prostates were free from PSA relapse compared with 100.0% of men with large prostates. • The mean post-implant D90 was 177.0 Gy; 175.5 Gy in standard prostates and 183.5 Gy in large prostates. • The overall acute urinary retention rate was 1.9%; 1.7% in standard prostates and 2.4% in large prostates. There were three urethral strictures, all in the standard prostate group. The mean IPSS increased to 11 and 14 at 3 months for the standard and large prostate groups, respectively, before settling to 2 above baseline for both groups at 12 months. • There were no rectovesical fistulae. Persistent rectal bleeding was reported by one (0.5%) patient in the standard prostate group. CONCLUSIONS: • Prostate brachytherapy is effective in the treatment of low-risk and intermediate-risk prostate cancer. • It is technically possible to deliver a quality implant in a large prostate using real-time brachytherapy. • The treatment itself is well tolerated. Prostate volumes up to 100 mL should not exclude patients from brachytherapy providing either flow rate ≥14 mL/s or symptom score (IPSS) ≤ 10.

Nuclear localization of factor inhibitor hypoxia-inducible factor in prostate cancer is associated with poor prognosis.

PURPOSE: We determined the role of factor inhibiting hypoxia-inducible factor-1 in prostate cancer specimens. MATERIALS AND METHODS: A tissue microarray of 152 prostate cancers was constructed and stained for factor inhibiting hypoxia-inducible factor-1, hypoxia-inducible factor-1α and 2α, and glucose transporter 1 as a prototypical downstream target of hypoxia-inducible factor-1α. Correlation analysis was done between these variables, and between factor inhibiting hypoxia-inducible factor-1, and clinical and pathological variables, including prostate specific antigen as a surrogate of recurrence. RESULTS: Factor inhibiting hypoxia-inducible factor-1 was expressed in the cytoplasm and/or the nucleus in 86.5% of tumors, including exclusive cytoplasmic expression in 51.3% and exclusive nuclear expression in 5.3%. Any nuclear and exclusive expression of factor inhibiting hypoxia-inducible factor was associated with poor prognosis on univariate analysis (p = 0.007 and 0.042, respectively). On multivariate analysis men with nuclear expression in tumors were twice as likely to experience recurrence (p = 0.034). CONCLUSIONS: Factor inhibiting hypoxia-inducible factor-1 is widely expressed in prostate tumors. Its differential subcellular expression suggests that regulation of its expression is an important factor in the activity of the hypoxia-inducible factor pathway. Its modulation may help treat hypoxia-inducible factor driven aggressive prostate cancer.

A tie-over dressing for graft application in distal penectomy and glans resurfacing: the TODGA technique.

OBJECTIVES: • To describe a novel method of split-skin graft (SSG) fixation for neo-glans formation after distal penectomy for penile cancer and glans resurfacing for carcinoma in situ or lichen sclerosus (LS); the TODGA technique. • Rather than 'quilting' the graft onto the neo-glans, which requires up to 5 days bed rest, the tie-over method fixes the graft adequately enough to allow immediate patient mobilization. PATIENTS AND METHODS: • In all, 41 consecutive operations, with a follow-up of ≥ 12 months, were performed on 40 patients (mean age 62 years, range 32-83) from December 2000 to October 2008, where a SSG was applied to the raw glans or penile stump. • The protocol varied for the first 12 operations on 11 patients. The tie-over dressing was left in place for 6 (one patient) or 7 days (11) and various materials were used; paraffin gauze (one), expanded foam (five) and proflavine-soaked gauze (six). The first two patients had their dressing removed under general anaesthetic but all subsequent patients had their dressing removed on the ward. • The subsequent 29 operations used the same protocol where a proflavine-soaked gauze dressing was left undisturbed for 10 days. RESULTS: • In the original 11 patients, two required re-grafting. After this initial development period, we amended the technique to use stronger sutures and left the dressing undisturbed for 10 days. • In addition, we standardized the use of proflavin-soaked gauze, as we found it easy to apply and remove. Since we adopted this protocol, we have performed 29 operations over a 3-year period. • The cosmetic results were excellent with only one patient requiring re-grafting. The mean and median postoperative length of stay was 2 days. • One patient with a urethral squamous cell carcinoma associated with urethral and glans LS required a urethral dilatation to allow a check cystoscopy, and a further asymptomatic patient had a meatal dilatation in the clinic but meatal stenosis was otherwise not seen, with no patients requiring regular meatal dilatation. CONCLUSION: • The TODGA technique of SSG application and fixation allows immediate mobilization and reduces hospital stay whilst providing excellent cosmetic results with a high percentage of graft uptake.