Isolated soft tissue mass of the finger as the first presentation of oligometastatic renal cell carcinoma.

A man in his 70s was referred to plastic surgery with a suspected foreign body in the pulp of his right index finger. An excisional biopsy was performed for a presumed foreign body granuloma. Histology revealed metastatic renal cell carcinoma (mRCC). CT imaging demonstrated a 7.4 cm heterogeneous mass arising from the upper pole of the left kidney consistent with primary renal malignancy, in addition to a 9 mm lung nodule. He underwent an uncomplicated left laparoscopic cytoreductive nephrectomy and made a satisfactory recovery. To our knowledge, this is the first reported case of primary mRCC presenting with digital soft tissue metastasis. Cytoreductive nephrectomy with metastasectomy is the preferred management for mRCC where feasible. For unfavourable mRCC cases, first-line systemic therapy is indicated. Adjuvant systemic therapy in mRCC is currently limited to clinical trials, though promising data emerging on the use of pembrolizumab may herald a future shift in practice.

Current management of radiation cystitis: a review and practical guide to clinical management.

INTRODUCTION: Haemorrhage is a frequent complication of radiation cystitis leading to emergency presentations in patients with prior pelvic radiation therapy. Standard initial patient management strategies involve resuscitation, bladder washout with clot evacuation and continuous bladder irrigation. Beyond this, definitive surgical treatment is associated with significant morbidity and mortality. Alternative less invasive management options for non-emergent haemorrhagic cystitis include systemic medical therapies, hyperbaric oxygen (HBO), intravesical therapies and laser ablation. However, evidence to support and compare treatment for haemorrhagic radiation cystitis is limited. METHODS: Herein, a literature search pertaining to the current management of haemorrhagic cystitis was conducted. RESULTS: In total, 23 studies were included in this review with 2 studies reviewing systemic therapy, 7 studies evaluating HBO therapy, 10 studies investigating a variety of intravesical therapies and the remaining 4 were relating to ablative therapies. Across these studies, the patient groups were heterogenous with small numbers and variable follow up periods. CONCLUSION: With evaluation of existing literature, this narrative review also provides a stepwise clinical algorithm to aid the urologist in treating patients presenting with complications associated with radiation cystitis.

The transobturator suburethral sling: a safe and effective option for all degrees of post prostatectomy urinary incontinence.

INTRODUCTION: Male stress urinary incontinence (SUI) after radical prostatectomy (RP) is common. The surgical standard of care traditionally has been placement of an artificial urinary sphincter (AUS) but since its introduction the transobturator male sling has been shown to have particular unique advantages. Our aim was to assess outcomes of a consecutive series of suburethral sling insertions in men presenting with all degrees of post RP SUI. MATERIALS AND METHODS: A consecutive cohort of men undergoing AdVance sling insertion following RP were studied. Parameters assessed included pre and postoperative urinary function, 24 hour pad use, quality of life (QoL) outcomes, complications and further treatments. Degree of incontinence was categorized as mild (1-2), moderate (3-5) or severe (≥ 6) depending on daily pad use. Patients were reviewed at 1, 4 and 6 months. The International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) was used to assess symptom severity and QoL outcomes. RESULTS: Seventy-seven patients were included, mean age 68 and mean time to sling post RP 34 (8-113) months. Preoperative degree of incontinence: mild 22%, moderate 58%, severe 20%. Fourteen percent had undergone post RP radiation therapy (RT). In total 73% experienced complete resolution of symptoms post sling, 12% significant improvement, 15% no reduction in pad use. Sixty percent with severe incontinence were classified as cured (no pad or 1 dry pad for security reasons). When patients with preoperative RT were excluded, cure rate rose to 82%. On follow up survey at 30 months (mean), the ICIQ-SF score decreased from baseline 17.7 (9-21.0) to 8.0 (0-20) (p < 0.0001), CI 95% (8-12). CONCLUSIONS: Suburethral slings are effective and safe for all degrees of post RP incontinence, are associated with improved QoL parameters and with appropriate selection and counseling are a viable option for more severe degrees of post RP SUI.

Digital rectal examination in primary care is important for early detection of prostate cancer: a retrospective cohort analysis study.

BACKGROUND: Currently, there is no standardised screening for prostate cancer in Europe. Assessment of risk is opportunistically undertaken in consultation with the GP or urologist. Evaluation of the prostate gland consists of a prostate-specific antigen (PSA) serum level and a digital rectal examination (DRE) of the gland. DRE is an essential part of the assessment that can independently predict prostate cancer in the setting of a normal PSA level. AIM: To evaluate the clinical usefulness of the DRE in general practice and urology clinics, and to ascertain its positive predictive value and sensitivity. DESIGN AND SETTING: A retrospective analysis study of a cohort of Irish men who underwent TRUS guided biopsy of the prostate in a single Irish tertiary referral centre, despite a normal PSA level. Patients were identified from a Rapid Access Prostate Clinic patient database. Pathological biopsy results were correlated with clinical DRE findings. METHOD: Patient demographics, PSA levels, and DRE findings from a prospectively established database and hospital data systems from May 2009 to October 2013 were analysed. RESULTS: Of 103 men referred over a 53-month period with a normal age-adjusted PSA level, 67% were referred on the basis of an abnormal DRE alone. Thirty-five per cent of males with a normal PSA had prostate cancer. DRE alone had a sensitivity and specificity of 81% and 40% respectively in diagnosing prostate cancer, with a positive predictive value of 42%. Seventy-six per cent of these men had high-grade disease. CONCLUSION: DRE is a key part of the assessment for prostate cancer. It can independently identify patients at risk of prostate cancer, with a substantial proportion of these having clinically significant disease requiring treatment. This study reinforces the importance of DRE in the primary care setting in the assessment for prostate cancer. An abnormal DRE, even in the setting of a normal PSA level, necessitates referral.

Exposure to low dose ionising radiation: Molecular and clinical consequences.

This review article provides a comprehensive overview of the experimental data detailing the incidence, mechanism and significance of low dose hyper-radiosensitivity (HRS). Important discoveries gained from past and present studies are mapped and highlighted to illustrate the pathway to our current understanding of HRS and the impact of HRS on the cellular response to radiation in mammalian cells. Particular attention is paid to the balance of evidence suggesting a role for DNA repair processes in the response, evidence suggesting a role for the cell cycle checkpoint processes, and evidence investigating the clinical implications/relevance of the effect.

Long noncoding RNAs and prostate carcinogenesis: the missing 'linc'?

Long noncoding RNAs (lncRNAs) are rapidly becoming essential pieces in the cancer puzzle. Our understanding of their functional capabilities is in its infancy. One certain fact, however, is that their molecular interactions extend beyond chromatin complexes into diverse biological processes. In prostate cancer, aberrant expression of lncRNAs is associated with disease progression. Overexpression of oncogenic lncRNAs promotes tumor-cell proliferation and metastasis through chromatin looping and distal engagement with the androgen receptor, antisense gene regulation, alternative splicing, and impeding DNA repair. Several lncRNAs, such as prostate cancer antigen 3 (PCA3), prostate cancer gene expression marker 1 (PCGEM1), and prostate cancer associated ncRNA transcript 1 (PCAT1), are highly prostate-specific, posing as attractive biomarkers. Herein we review the mechanisms of action of lncRNAs in prostate carcinogenesis and their potential clinical utility for disease.

Isogenic radiation resistant cell lines: development and validation strategies.

PURPOSE: The comparison of cell lines with differing radiosensitivities and their molecular response to radiation exposure has been used in a number of human cancer models to study the molecular response to radiation. This review proposes to analyze and compare the protocols used by investigators for the development and validation of these isogenic models of radioresistance. CONCLUSION: There is large variability in the strategies used to generate and validate isogenic models of radioresistance. Further characterization of these models is required.

Exposure to low dose ionising radiation: molecular and clinical consequences.

This review article provides a comprehensive overview of the experimental data detailing the incidence, mechanism and significance of low dose hyper-radiosensitivity (HRS). Important discoveries gained from past and present studies are mapped and highlighted to illustrate the pathway to our current understanding of HRS and the impact of HRS on the cellular response to radiation in mammalian cells. Particular attention is paid to the balance of evidence suggesting a role for DNA repair processes in the response, evidence suggesting a role for the cell cycle checkpoint processes, and evidence investigating the clinical implications/relevance of the effect.

Vesicocutaneous fistula following adjuvant radiotherapy for prostate cancer.

Vesicocutaneous fistulas (VCF) are a rare complication of radical radiotherapy to the pelvis. Timely diagnosis and management are often difficult and complex. We report the unusual case of a 64-year-old gentleman who presented to the emergency department with worsening sepsis and profuse discharge from a cutaneous opening in the left groin. This presentation was 6 weeks following the completion of external beam radiotherapy for apical margin-positive prostate cancer (pT3a). A diagnosis of a VCF was confirmed after CT scanning of the abdomen and pelvis with contrast. Urinary diversion was achieved by a temporary urethral catheter insertion. Full resolution of this gentleman's symptoms was accomplished. In this article, we present a non-invasive approach to the management of VCF. This case raises intricate management issues in the atypical development of an early urinary tract fistula postradiotherapy.

Mixed collecting duct and renal cell carcinoma presenting with spinal cord compression.

Collecting duct carcinoma (CDC) is a rare renal malignancy thought to develop from the collecting duct epithelium of the kidney. CDC tends to have a more aggressive clinical course than conventional renal cell carcinoma (RCC), with early metastases. The occurrence of a mixed CDC and conventional RCC is infrequently reported in the literature. We report the first case of a metastatic mixed CDC and RCC presenting as back pain in a young adult. In addition we discuss the epidemiology of and current adjuvant therapies for CDC.

DNA mismatch repair protein MSH2 dictates cellular survival in response to low dose radiation in endometrial carcinoma cells.

DNA repair and G2-phase cell cycle checkpoint responses are involved in the manifestation of hyper-radiosensitivity (HRS). The low-dose radioresponse of MSH2 isogenic endometrial carcinoma cell lines was examined. Defects in cell cycle checkpoint activation and the DNA damage response in irradiated cells (0.2 Gy) were evaluated. HRS was expressed solely in MSH2+ cells and was associated with efficient activation of the early G2-phase cell cycle checkpoint. Maintenance of the arrest was associated with persistent MRE11, γH2AX, RAD51 foci at 2 h after irradiation. Persistent MRE11 and RAD51 foci were also evident 24 h after 0.2 Gy. MSH2 significantly enhances cell radiosensitivity to low dose IR.

Zero ischemia laparoscopic partial thulium laser nephrectomy.

BACKGROUND AND PURPOSE: Laser technology presents a promising alternative to achieve tumor excision and renal hemostasis with or without hilar occlusion, yet its use in partial nephrectomy has not been significantly evaluated. We prospectively evaluated the thulium:yttrium-aluminum-garnet laser in laparoscopic partial nephrectomy (LPN) in our institution over a 1-year period. PATIENTS AND METHODS: We used the thulium laser with a wavelength of 2013 nm in the infrared spectrum. Data were recorded prospectively. Tumor size, preoperative aspects and dimensions used for an anatomical classification (PADUA) score, operative time, warm ischemia time (WIT), and perioperative and postoperative morbidity were recorded. Blood loss, preoperative and postoperative creatinine level, and estimated glomerular filtration rate (eGFR) were also collected. RESULTS: A total of 15 patients underwent consecutive LPN. The mean tumour diameter was 2.85 (1.5-4). The mean PADUA score was 6.8 (6-9). The mean total operative time was 168 minutes (128-306 min). Mean blood loss was 341 mL (0-800 mL). Date of discharge was 3.2 days postoperatively (2-8 days). The renal vessels were not clamped, resulting in a WIT of 0 minutes in all cases. There was no statistical significant increase in serum creatinine level or decrease in eGFR postoperatively. Histologically, the majority of lesions (13/15 patients) were renal-cell carcinoma stage pT1a. In all cases, base margins had negative results for tumor. CONCLUSION: The 2013-nm thulium laser system offers excellent hemostasis and precise resection capability of the renal cortex during LPN of small partially exophytic renal tumors. Our series showed excellent perioperative functional and pathologic outcomes, including minimal blood loss, zero ischemia, negative tumor margins, and preservation of renal function.

Exposure to hypoxia following irradiation increases radioresistance in prostate cancer cells.

BACKGROUND: Tumor hypoxia is a common feature of prostate tumors associated with the stabilization of hypoxia-inducible-factor 1alpha (HIF-1α) and poor prognosis following radiation therapy. Lack of oxygen at the time of irradiation is associated with radioresistance, but recent reports suggest radioresponse is also modulated by the dynamic nature of tumor hypoxia. OBJECTIVE: We proposed to evaluate the effect of post-irradiation hypoxic exposure on the radioresponse of 2 prostate cancer (CaP) cell lines (22Rv1, DU145) and to examine whether it correlates with modified cellular responses induced by hypoxia. METHODS AND RESULTS: Aerobic and hypoxic CaP cells exposed to hypoxia (24 h) after irradiation (4 Gy) gained a survival advantage compared with cells fully oxygenated after irradiation. This survival advantage was associated with induction of a G2/M cell cycle arrest, reduced induction of apoptosis and decreased amount of senescent cells. These modified cellular responses appeared mediated by HIF-1α. CONCLUSION: Our data suggest that targeting hypoxia after irradiation may benefit patients with aggressive hypoxic prostate tumors.

Gene expression analysis in prostate cancer: the importance of the endogenous control.

BACKGROUND: Aberrant gene expression is a hallmark of cancer. Quantitative reverse-transcription PCR (qRT-PCR) is the gold-standard for quantifying gene expression, and commonly employs a house-keeping gene (HKG) as an endogenous control to normalize results; the choice of which is critical for accurate data interpretation. Many factors, including sample type, pathological state, and oxygen levels influence gene expression including putative HKGs. The aim of this study was to determine the suitability of commonly used HKGs for qRT-PCR in prostate cancer. METHODS: Prostate cancer (LNCaP, 22Rv1, PC3, and DU145) and normal (PWR1E and RWPE1) cell lines were cultured in air and hypoxia. The performance of 16 HKGs was assessed using Normfinder and coefficient of variation. In silico promoter analysis was performed to identify putative hypoxia response elements (HREs). The impact of the endogenous control on expression levels of HIF1A and GSTP1 was investigated by qRT-PCR in cell lines and tissue specimens respectively. RESULTS: Hypoxia altered expression of several HKGs: IPO8, B2M, and PGK1. The most stably expressed HKGs were ACTB, PPIA, and UBC. Both UBC and ACTB showed constitutive expression of HIF1A in air and hypoxia, while PGK1 falsely implied a sixfold hypoxia-induced down-regulation. In prostate tumors, UBC and PGK1 both revealed down-regulation of GSTP1 relative to matched benign, whereas ACTB showed variability. CONCLUSIONS: This study demonstrates that no universal endogenous control exists for gene expression studies, even within one disease type. It highlights the importance of validating expression of intended HKGs between different sample types and environmental exposures.

Standardization of assay methods reduces variability of total PSA measurements: an Irish study.

UNLABELLED: What's known on the subject? and What does the study add? Today, numerous assays for PSA detection are available from various manufacturers. However, these various assays do not detect PSA equally and several studies have demonstrated variability between them. In order to harmonise PSA results and reduce the discrepancies, reference materials are available for assay calibration. We have demonstrated significantly variability between 6 different assay methods currently in use in 9 hospitals despite assay calibration. Variability in PSA values was reduced with the standardisation of the assay method in 4 hospitals. Our results highlight the dilemma of PSA assay variability and stress the need for nationwide standardisation of PSA testing. OBJECTIVE: To determine whether standardization of total prostate-specific antigen (tPSA) assay methods reduces variability in tPSA measurements. PATIENTS AND METHODS: Blood samples from 84 patients attending a single urology department were distributed across nine hospitals selected throughout Ireland for the independent determination of tPSA under the same conditions. The selected hospitals collectively used six different assay methods for tPSA detection: Beckman Hybritech WHO Calibrated (used as reference method), Tosoh AIA 1800, Roche E170 (used in three hospitals), Abbott AxSYM, Immulite 2500 2nd Generation (used in two hospitals) and Siemens ADVIA Centaur. The method of tPSA detection was next standardized in a subset of four hospitals using the same assay method and the measurements were repeated. The difference in mean tPSA in the cohort across the hospitals tested was determined and the Bland-Altman test was used to assess the agreement between each test. Analysis was performed over both the full (0.5-30 µg/L, N = 84) and a narrow (3-7 µg/L, n = 25) tPSA range. RESULTS: The range and the mean tPSA of the full cohort were inflated across the eight test hospitals, when compared with the reference hospital. The poorest agreement between assay methods was associated with a bias of 2.2 ± 2.4 µg/L. The variability in tPSA measurements between assay methods was inconsistent across the range of tPSA values tested and increased with increasing mean tPSA. Agreement in reported tPSA was excellent after standardization of tPSA assay methods (bias <0.2 µg/L). Over the narrow 3-7 µg/L PSA range, 12/25 (48%) patients had a tPSA range of values across all hospitals in excess of 2 µg/L. Following standardization of the tPSA assay method, patient tPSA ranges were <0.5 µg/L for 13/25 (52%) patients. CONCLUSIONS: We have shown that the lack of standardization of tPSA assay methods across a panel of Irish hospitals leads to significant variability in the measured tPSA values for the same patient samples. Variability in tPSA values was reduced with the standardization of the assay method in four hospitals. Standardization of PSA testing on a nationwide scale is warranted.

MicroRNAs as putative mediators of treatment response in prostate cancer.

MicroRNAs (miRNAs) are an abundant class of noncoding RNAs that function to regulate post-transcriptional gene expression, predominantly by translational repression. In addition to their role in prostate cancer initiation and progression, recent evidence suggests that miRNAs might also participate in treatment response across a range of therapies including radiation treatment, chemotherapy and androgen suppression. The mechanism of this regulation is thought to be multifactorial and is currently poorly understood. To date, only a small number of studies have examined the functional role of miRNAs in response to prostate cancer treatment. Elucidating the role of miRNAs in treatment response following radiotherapy, chemotherapy and androgen suppression will provide new avenues of investigation for the development of novel therapies for the treatment of prostate cancer.

Discontinuation of anticoagulant or antiplatelet therapy for transrectal ultrasound-guided prostate biopsies: a single-center experience.

PURPOSE: Historically, it was thought that hemorrhagic complications were increased with transrectal ultrasound-guided prostate biopsies (TRUS biopsy) of patients receiving anticoagulation/antiplatelet therapy. However, the current literature supports the continuation of anticoagulation/antiplatelet therapy without additional morbidity. We assessed our experience regarding the continuation of anticoagulation/antiplatelet therapy during TRUS biopsy. MATERIALS AND METHODS: A total of 91 and 98 patients were included in the anticoagulation/antiplatelet (group I) and control (group II) groups, respectively. Group I subgroups consisted of patients on monotherapy or dual therapy of aspirin, warfarin, clopidogrel, or low molecular weight heparin. The TRUS biopsy technique was standardized to 12 cores from the peripheral zones. Patients completed a questionnaire over the 7 days following TRUS biopsy. The questionnaire was designed to assess the presence of hematuria, rectal bleeding, and hematospermia. Development of rectal pain, fever, and emergency hospital admissions following TRUS biopsy were also recorded. RESULTS: The patients' mean age was 65 years (range, 52 to 74 years) and 63.5 years (range, 54 to 74 years) in groups I and II, respectively. The overall incidence of hematuria was 46% in group I compared with 63% in group II (p=0.018). The incidence of hematospermia was 6% and 10% in groups I and II, respectively. The incidence of rectal bleeding was similar in group I (40%) and group II (39%). Statistical analysis was conducted by using Fisher exact test. CONCLUSIONS: There were fewer hematuria episodes in anticoagulation/antiplatelet patients. This study suggests that it is not necessary to discontinue anticoagulation/antiplatelet treatment before TRUS biopsy.

Docetaxel maintains its cytotoxic activity under hypoxic conditions in prostate cancer cells.

OBJECTIVE: The efficacy of docetaxel has recently been shown to be increased under hypoxic conditions through the down-regulation of hypoxia-inducible-factor 1α (HIF1A). Overexpression of the hypoxia-responsive gene class III ß-tubulin (TUBB3) has been associated with docetaxel resistance in a number of cancer models. We propose that administration of docetaxel to prostate patients has the potential to reduce the hypoxic response through HIF1A down-regulation and that TUBB3 down-regulation participates in sensitivity to docetaxel. METHODS: The cytotoxic effect of docetaxel was determined in both 22Rv1 and DU145 prostate cancer cell lines and correlated with HIF1A expression levels under aerobic and hypoxic conditions. Hypoxia-induced chemoresistance was investigated in a pair of isogenic docetaxel-resistant PC3 cell lines. Basal and hypoxia-induced TUBB3 gene expression levels were determined and correlated with methylation status at the HIF1A binding site. RESULTS: Prostate cancer cells were sensitive to docetaxel under both aerobic and hypoxic conditions. Hypoxic cytotoxicity of docetaxel was consistent with a reduction in detected HIF1A levels. Sensitivity correlated with reduced basal and hypoxia-induced HIF1A and TUBB3 expression levels. The TUBB3 HIF1A binding site was hypermethylated in prostate cell lines and tumor specimens, which may exclude transcription factor binding and induction of TUBB3 expression. However, acquired docetaxel resistance was not associated with TUBB3 overexpression. CONCLUSION: These data suggest that the hypoxic nature of a tumor may have relevance as regard to their response to docetaxel. Further investigation into the nature of this relationship may allow identification of novel targets to improve tumor control in prostate cancer patients.

Clinical potential of gene-directed enzyme prodrug therapy to improve radiation therapy in prostate cancer patients.

Despite the advances in prostate cancer diagnosis and treatment, current therapies are not curative in a significant proportion of patients. Gene-directed enzyme prodrug therapy (GDEPT), when combined with radiation therapy, could improve the outcome of treatment for prostate cancer, the second leading cause of cancer death in the western world. GDEPT involves the introduction of a therapeutic transgene, which can be targeted to the tumour cells. A prodrug is administered systemically and is converted to its toxic form only in those cells containing the transgene, resulting in cell kill. This review will discuss the clinical trials which have investigated the potential of GDEPT at various stages of prostate cancer progression. The advantages of using GDEPT in combination with radiotherapy will be examined, as well as some of the recent advances which enhance the potential utility of GDEPT.