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Prostate cancer screening using prostate-specific antigen (PSA) has been shown to reduce mortality but with substantial overdiagnosis, leading to unnecessary biopsies. The identification of a highly specific biomarker using liquid biopsies, represents an unmet need in the diagnostic pathway for prostate cancer. In this study, we employed a method that enriches for methylated cell-free DNA fragments coupled with a machine learning algorithm which enabled the detection of metastatic and localized cancers with AUCs of 0.96 and 0.74, respectively. The model also detected 51.8% (14/27) of localized and 88.7% (79/89) of patients with metastatic cancer in an external dataset. Furthermore, we show that the differentially methylated regions reflect epigenetic and transcriptomic changes at the tissue level. Notably, these regions are significantly enriched for biologically relevant pathways associated with the regulation of cellular proliferation and TGF-beta signaling. This demonstrates the potential of circulating tumor DNA methylation for prostate cancer detection and prognostication.
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PURPOSE: To describe and compare differences in peri-operative outcomes of robot-assisted (RA-RPLND) and open (O-RPLND) retroperitoneal lymph node dissection performed by a single surgeon where chemotherapy is the standard initial treatment for Stage 2 or greater non-seminomatous germ cell tumour. METHODS: Review of a prospective database of all RA-RPLNDs (28 patients) and O-RPLNDs (72 patients) performed by a single surgeon from 2014 to 2020. Peri-operative outcomes were compared for patients having RA-RPLND to all O-RPLNDs and a matched cohort of patients having O-RPLND (20 patients). Further comparison was performed between all patients in the RA-RPLND group (21 patients) and matched O-RPLND group (18 patients) who had previous chemotherapy. RA-RPLND was performed for patients suitable for a unilateral template dissection. O-RPLND was performed prior to the introduction of RA-RPLND and for patients not suitable for RA-RPLND after its introduction. RESULTS: RA-RPLND showed improved peri-operative outcomes compared to the matched cohort of O-RPLND-median blood loss (50 versus 400 ml, p < 0.00001), operative duration (150 versus 195 min, p = 0.023) length-of-stay (1 versus 5 days, p < 0.00001) and anejaculation (0 versus 4, p = 0.0249). There was no statistical difference in complication rates. RA-RPLND had lower median lymph node yields although not significant (9 versus 13, p = 0.070). These improved peri-operative outcomes were also seen in the post-chemotherapy RA-RPLND versus O-RPLND analysis. There were no tumour recurrences seen in either group with median follow-up of 36 months and 60 months, respectively. CONCLUSIONS: Post-chemotherapy RA-RPLND may have decreased blood loss, operative duration, hospital length-of-stay and anejaculation rates in selected cases and should, therefore, be considered in selected patients. Differences in oncological outcomes require longer term follow-up.
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Escisión del Ganglio Linfático/métodos , Neoplasias de Células Germinales y Embrionarias/cirugía , Procedimientos Quirúrgicos Robotizados , Neoplasias Testiculares/cirugía , Terapia Combinada , Humanos , Metástasis Linfática , Masculino , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias de Células Germinales y Embrionarias/secundario , Espacio Retroperitoneal , Neoplasias Testiculares/tratamiento farmacológico , Neoplasias Testiculares/patología , Neoplasias Testiculares/secundario , Resultado del TratamientoRESUMEN
BRCA1 deficiencies cause breast, ovarian, prostate and other cancers, and render tumours hypersensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. To understand the resistance mechanisms, we conducted whole-genome CRISPR-Cas9 synthetic-viability/resistance screens in BRCA1-deficient breast cancer cells treated with PARP inhibitors. We identified two previously uncharacterized proteins, C20orf196 and FAM35A, whose inactivation confers strong PARP-inhibitor resistance. Mechanistically, we show that C20orf196 and FAM35A form a complex, 'Shieldin' (SHLD1/2), with FAM35A interacting with single-stranded DNA through its C-terminal oligonucleotide/oligosaccharide-binding fold region. We establish that Shieldin acts as the downstream effector of 53BP1/RIF1/MAD2L2 to promote DNA double-strand break (DSB) end-joining by restricting DSB resection and to counteract homologous recombination by antagonizing BRCA2/RAD51 loading in BRCA1-deficient cells. Notably, Shieldin inactivation further sensitizes BRCA1-deficient cells to cisplatin, suggesting how defining the SHLD1/2 status of BRCA1-deficient tumours might aid patient stratification and yield new treatment opportunities. Highlighting this potential, we document reduced SHLD1/2 expression in human breast cancers displaying intrinsic or acquired PARP-inhibitor resistance.
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Proteína BRCA1/genética , Neoplasias Óseas/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Reparación del ADN por Unión de Extremidades , Resistencia a Antineoplásicos , Osteosarcoma/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Proteínas/metabolismo , Reparación del ADN por Recombinación , Animales , Proteína BRCA1/deficiencia , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proteínas de Ciclo Celular , Línea Celular Tumoral , Cisplatino/farmacología , Roturas del ADN de Doble Cadena , Proteínas de Unión al ADN , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos/genética , Femenino , Células HEK293 , Humanos , Proteínas Mad2/genética , Proteínas Mad2/metabolismo , Ratones , Complejos Multiproteicos , Osteosarcoma/genética , Osteosarcoma/metabolismo , Osteosarcoma/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Proteínas/genética , Proteínas de Unión a Telómeros/genética , Proteínas de Unión a Telómeros/metabolismo , Proteína 1 de Unión al Supresor Tumoral P53/genética , Proteína 1 de Unión al Supresor Tumoral P53/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Emerging data demonstrate homologous recombination (HR) defects in castration-resistant prostate cancers, rendering these tumours sensitive to PARP inhibition. Here we demonstrate a direct requirement for the androgen receptor (AR) to maintain HR gene expression and HR activity in prostate cancer. We show that PARP-mediated repair pathways are upregulated in prostate cancer following androgen-deprivation therapy (ADT). Furthermore, upregulation of PARP activity is essential for the survival of prostate cancer cells and we demonstrate a synthetic lethality between ADT and PARP inhibition in vivo. Our data suggest that ADT can functionally impair HR prior to the development of castration resistance and that, this potentially could be exploited therapeutically using PARP inhibitors in combination with androgen-deprivation therapy upfront in advanced or high-risk prostate cancer.Tumours with homologous recombination (HR) defects become sensitive to PARPi. Here, the authors show that androgen receptor (AR) regulates HR and AR inhibition activates the PARP pathway in vivo, thus inhibition of both AR and PARP is required for effective treatment of high risk prostate cancer.
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Colágeno Tipo XI/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/genética , Receptores Androgénicos/metabolismo , Mutaciones Letales Sintéticas , Colágeno Tipo XI/genética , Recombinación Homóloga , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/enzimología , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Receptores Androgénicos/genética , Transducción de SeñalRESUMEN
OBJECTIVES: Evidence of the accuracy of predictive tests in confirming the presence and grade of upper urinary tract urothelial carcinomas (UUTUC) is limited. We present the largest series evaluating the diagnostic value of pre- and intra-operative parameters in the detection of UUTUC. MATERIALS AND METHODS: We retrospectively analysed records of patients who underwent diagnostic ureteroscopy between 2005 and 2014 for suspected UUTUC. Pre-operative workup included voided urine cytology and CT imaging. Intra-operative assessments involved ureteroscopy to directly visualise suspicious lesions, and where possible selective cytology and biopsy. Primary outcomes were the visualisation of UUTUC and histopathological confirmation of tumour. RESULTS: Hundred out of 160 (63 %) patients presenting with suspected upper tract malignancy had UUTUC. Voided and selective urine cytology and CT individually predicted UUTUC with a sensitivity/specificity of 63/67, 76/73, and 95/26 %, respectively. Forty out of 48 (83 %) patients who had abnormal CT and abnormal voided urine cytology had UUTUC, while 100 % of those with normal CT and normal voided cytology (investigated for ongoing symptoms) were normal. Comparing endoscopic biopsy to nephroureterectomy specimen grade, 19 (46 %), 18 (44 %), and 4 (10 %) were identical, upgraded, and downgraded, respectively. CONCLUSION: Pre-operative investigations can predict UUTUCs. When these investigations were normal, the risk of UUTUC is negligible. In selective patients with abnormal investigations, ureteroscopy should be performed to confirm and predict the grade of UUTUC, in order to guide future management. Selective cytology is unlikely to significantly contribute to the diagnostic workup of UUTUC.
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Carcinoma de Células Transicionales/diagnóstico por imagen , Neoplasias Renales/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Neoplasias Ureterales/diagnóstico por imagen , Ureteroscopía , Orina/citología , Anciano , Anciano de 80 o más Años , Biopsia , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/orina , Citodiagnóstico , Femenino , Humanos , Neoplasias Renales/patología , Neoplasias Renales/orina , Pelvis Renal/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sensibilidad y Especificidad , Factores de Tiempo , Neoplasias Ureterales/patología , Neoplasias Ureterales/orinaRESUMEN
Positive surgical margins (PSM) after radical prostatectomy (RP) are a predictor of biochemical recurrence (BCR), and highly dependent on surgeon, experience, and skill. The length and location PSMs are important, with significant differences between open and robotic RP. The impact of PSMs on BCR remains secondary to other clinico-pathologic variables: Gleason Score, pathologic stage, and baseline PSA. However, lower PSM rates are associated with reduced use of secondary interventions and patient anxiety of cancer recurrence.
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Biomarcadores de Tumor/sangre , Recurrencia Local de Neoplasia/prevención & control , Antígeno Prostático Específico/sangre , Prostatectomía/métodos , Prostatectomía/normas , Neoplasias de la Próstata/prevención & control , Neoplasias de la Próstata/cirugía , Humanos , Masculino , Clasificación del Tumor , Recurrencia Local de Neoplasia/sangre , Estadificación de Neoplasias , Neoplasia Residual/prevención & control , Valor Predictivo de las Pruebas , Pronóstico , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patología , Factores de Riesgo , Procedimientos Quirúrgicos RobotizadosRESUMEN
PURPOSE: Enterococci are a common cause of urinary tract infection and vancomycin-resistant strains are more difficult to treat. The purpose of this surveillance program was to assess the prevalence of and determine the risk factors for vancomycin resistance in adults among urinary isolates of Enterococcus sp. and to detail the antibiotic susceptibility profile, which can be used to guide empirical treatment. MATERIALS AND METHODS: From 2005 to 2014 we retrospectively reviewed 5,528 positive Enterococcus sp. urine cultures recorded in a computerized laboratory results database at a tertiary teaching hospital in Cambridge, United Kingdom. RESULTS: Of these cultures, 542 (9.8%) were vancomycin resistant. No longitudinal trend was observed in the proportion of vancomycin-resistant strains over the course of the study. We observed emerging resistance to nitrofurantoin with rates climbing from near zero to 40%. Ampicillin resistance fluctuated between 50% and 90%. Low resistance was observed for linezolid and quinupristin/dalfopristin. Female sex and inpatient status were identified as risk factors for vancomycin resistance. CONCLUSIONS: The incidence of vancomycin resistance among urinary isolates was stable over the last decade. Although resistance to nitrofurantoin has increased, it still serves as an appropriate first choice in uncomplicated urinary tract infection caused by vancomycin-resistant Enterococcus sp.
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Infecciones por Bacterias Grampositivas/microbiología , Infecciones Urinarias/microbiología , Resistencia a la Vancomicina , Enterococos Resistentes a la Vancomicina/aislamiento & purificación , Anciano , Farmacorresistencia Bacteriana , Inglaterra , Femenino , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Centros de Atención Terciaria , Urinálisis , Infecciones Urinarias/tratamiento farmacológico , Enterococos Resistentes a la Vancomicina/efectos de los fármacosRESUMEN
PURPOSE: Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are an increasing concern regarding antibiotic resistance and their potential to cause serious infections which are difficult to treat. The purpose of this surveillance programme was to assess the incidence of ESBL in adults amongst urinary isolates, identify risk factors, and detail the antibiotic susceptibility profile in order to guide empirical treatment. METHODS: From 2006 to 2014, we reviewed 21,414 positive urine cultures for E. coli and Klebsiella sp. from a University hospital in the UK and found 1420 ESBL-positive specimens. Susceptibility testing was performed by British Society of Antimicrobial Chemotherapy disc diffusion testing. ESBL screening was performed on samples resistant to cefpodoxime and confirmed by double disc diffusion (Oxoid Ltd, Basingstoke, UK). Patient gender, age, inpatient status, and catheterisation were assessed as risk factors. RESULTS: ESBL production amongst E. coli urine cultures increased 44 %, from 4.6 to 6.6 % of all E. coli isolates. ESBL-positive organisms were associated with increases in drug resistance, particularly amongst fluoroquinolones, trimethoprim, and cephalexin. Multidrug resistance was a feature with 75 % of ESBL+ Klebsiella sp.-resistant ≥6 antibiotic classes. ESBL producers remained largely susceptible to carbapenems. Male gender, urinary catheterisation, inpatient status, and increasing age were identified as risk factors for ESBL infection or colonisation. CONCLUSION: We demonstrate that the incidence of ESBL-producing E. coli in urine cultures is increasing and that such isolates are multidrug resistant. Carbapenems and nitrofurantoin for E. coli infections remain effective, which may guide empirical antibiotic therapy.
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Antibacterianos/uso terapéutico , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/microbiología , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/microbiología , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/microbiología , Klebsiella/efectos de los fármacos , Klebsiella/enzimología , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/microbiología , beta-Lactamasas/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Infección Hospitalaria/orina , Escherichia coli/aislamiento & purificación , Infecciones por Escherichia coli/orina , Femenino , Humanos , Klebsiella/aislamiento & purificación , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Factores de Tiempo , Infecciones Urinarias/orinaRESUMEN
BACKGROUND: Robotic-assisted laparoscopic radical prostatectomy is a current standard treatment for localized prostate cancer, with treatment failure defined by biochemical recurrence (BCR). Open radical prostatectomy series have identified the presence of a positive surgical margin (PSM) as a predictor of long-term recurrence, a measure that is affected by the surgeon׳s skill. We evaluate the effect of PSM parameters on BCR rates from robotic-assisted laparoscopic radical prostatectomy, across 3 high-volume institutions. METHODS: De-identifiable clinicopathological and histopathological data were prospectively collected for 4,001 patients with at least 3 years of follow-up. Kaplan-Meier plots and 3 statistical models were used to evaluate the effect of margin parameters on BCR, via crude rates, traditional multivariable Cox regression, and a propensity-adjusted Cox regression model. RESULTS: Overall, 37% of men with a PSM developed BCR compared with 10% of men with negative margins (hazard ratio [HR] = 1.81, 95% CI: 1.47-2.22). Length ≥3 mm or a multifocal positive margin was associated with a higher risk of BCR compared with negative margin cases. On multivariable Cox regression analysis of the positive margin cohort, only apical margins significantly predicted BCR relative to basal margins (HR = 2.03, 95% CI: 1.01-4.09), whereas there was no significant difference in BCR rates for posterolateral margins relative to basal margins (HR = 1.62, 95% CI: 0.84-3.11). Propensity-adjusted modeling confirmed a greater effect of apical compared with posterolateral PSM. CONCLUSIONS: A PSM length ≥3 mm is predictive of BCR, as is to a lesser extent multiple positive margins. In contrast to open prostatectomy series, posterolateral margins carry a smaller risk of BCR compared with apical margins.
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Recurrencia Local de Neoplasia , Prostatectomía/métodos , Neoplasias de la Próstata/cirugía , Procedimientos Quirúrgicos Robotizados , Supervivencia sin Enfermedad , Humanos , Estimación de Kaplan-Meier , Masculino , Análisis Multivariante , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Próstata/patología , Antígeno Prostático Específico/metabolismo , Neoplasias de la Próstata/patología , Factores de Riesgo , Cirugía Asistida por ComputadorRESUMEN
Radical prostatectomy remains the gold-standard treatment for clinically localized prostate cancer. Although cancer control is the primary goal, secondary outcomes such as continence recovery are of great importance to patients. Thus, it is a challenge for prostate cancer surgeons to optimize continence outcomes without compromising oncologic results. Many high-volume surgeons have demonstrated excellent long-term continence rates in their patients, but early continence is variable and less than ideal even in expert hands. A plethora of individual technical maneuvers exist to optimize early recovery of continence, but as yet there is no composite technique that incorporates the relevant anatomic principles of minimizing damage to the urinary sphincters and their nerves, maximizing functional urethral length, creating a secure and watertight vesicourethral anastomosis, providing circumferential fascioligamentous support to the anastomosis and external sphincter, and ameliorating postoperative bladder descent. Our ten-step approach to collating these individual maneuvers into a unified technique could be used by surgeons to obtain the best possible early recovery of urinary control for their patients, without risking their oncologic outcomes.
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Complicaciones Posoperatorias/prevención & control , Prostatectomía/normas , Neoplasias de la Próstata/cirugía , Recuperación de la Función/fisiología , Incontinencia Urinaria/prevención & control , Animales , Humanos , Masculino , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/fisiopatología , Prostatectomía/efectos adversos , Neoplasias de la Próstata/fisiopatología , Factores de Tiempo , Incontinencia Urinaria/etiología , Incontinencia Urinaria/fisiopatología , Fenómenos Fisiológicos del Sistema UrinarioRESUMEN
OBJECTIVE: ⢠To establish its current status, this study reviews the literature, and reports developments in robotic-assisted partial nephrectomy (RPN), highlighting results from various studies that investigate the oncological and functional efficacy of RPN. Partial nephrectomy has become the standard therapy for the management of small renal masses. In an effort to overcome the perioperative morbidity associated with an open approach, and the extended warm ischaemia times associated with a laparoscopic approach, robotic platforms have been introduced. PATIENTS AND METHODS: ⢠A search of Medline, EMBASE and Cochrane library databases was completed in July 2010 and used to identify pertinent original articles, editorials, comments and reviews, using the search term 'partial nephrectomy'. Links to related references were surveyed, and all articles finally included were based on relevance and importance of content, as determined by the authors. RESULTS: ⢠The robotic platform may offer the solution to bridge the gap between open and laparoscopic approaches, achieving warm ischaemia times that consistently average 20 minutes, and providing similar oncological and functional results via a shorter learning curve. It offers cosmesis and convalescence equivalent to that from laparoscopic partial nephrectomy, but with potentially fewer postoperative complications. CONCLUSION: ⢠In terms of oncological and functional outcomes, the early experiences of RPN in selected series of patients appear at least equivalent to open and laparoscopic partial nephrectomy series. Randomized comparisons between the approaches are lacking, as are longer-term follow-up data for the robotic technique and formal cost analysis; these will be necessary before RPN can replace open partial nephrectomy as the new standard for the management of small renal masses. Trends continue to emerge that highlight the advantage of using the robotic platform to achieve a minimally invasive approach for partial nephrectomy, and with time and increasing expertise, this may become further apparent.
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Nefrectomía/métodos , Robótica , Predicción , Humanos , Laparoscopía , Procedimientos Quirúrgicos Mínimamente Invasivos , Nefrectomía/tendencias , Isquemia TibiaRESUMEN
OBJECTIVES: Structured mentor-led training programmes permit the safe introduction of novice trainees to robotic-assisted laparoscopic prostatectomy (RALP). We outline the first description of parallel learning curves for individual surgical steps and quantify the relative difficulty of each step to propose an order of training in our structured mentoring programme. PATIENTS AND METHODS: A prospective ethically approved database was used to evaluate the operating times of each individual surgical step, in the first 150 RALP cases performed independently by a robotic-naive laparoscopic surgeon. Linear regression analysis was used to quantify the effect of surgeon experience on the operating time for each individual surgical step. RESULTS: Univariate linear regression analysis revealed significant reductions in operating time over the first 150 cases for all of the RALP steps, with the exception of the Rocco stitch. Multivariate linear regression analysis compensated for confounding variables and led to the identification of five surgical steps in which the operating time of each was significantly influenced by experience of the procedure. The most substantial improvement in operating time was seen in the bladder take down step. After taking into account the multivariate regression model, standardized univariate coefficients allowed an order of training to be identified for future RALP novices, of increasing complexity rather than order of surgery, beginning with the bladder take down step and ending with the vesico-urethral anastomosis. CONCLUSIONS: We can begin the training of new robotic-naive surgeons at simpler surgical steps, in which the greatest gains in expediency are made. We anticipate that identifying the more challenging surgical steps from this study and targeting training towards them may expedite our future trainees' proficiency at RALP.
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Laparoscopía/educación , Curva de Aprendizaje , Prostatectomía/educación , Robótica/educación , Cirugía General/educación , Humanos , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
INTRODUCTION AND OBJECTIVES: There is a paucity of information in the literature about the characteristics of prostate cancer in the Asian-Indian population. We wanted to evaluate the oncological outcomes of Asian-Indians and Caucasians. We also derived a nomogram for prediction of extraprostatic extension (EPE) and presented biochemical recurrence (BCR) rates in the Asian-Indian population. MATERIALS AND METHODS: A total of 2367 D'Amico low-risk patients underwent robotic-assisted radical prostatectomy (RARP) for clinically localized prostate cancer between January 2005 and July 2010 by a single surgeon. Of these 56 (2.4%) patients were Asian-Indians and 2025 were Caucasians (85.6%). Univariate and multivariate models were created for predicting EPE. A multivariate logistic regression model was used to develop a predictive nomogram. BCR was defined as a prostate-specific antigen ≥0.2 at any postoperative time point. Kaplan-Meier survival analysis was used to investigate BCR rates. RESULTS: A significantly greater percentage of Asian-Indians compared to Caucasians had EPE (32.3 vs. 16.5; P = 0.01). In multivariate analysis adjusted for significant variables from univariate analyses, Asian-Indian race (P = 0.028), age (P = 0.050), maximum percentage cancer on biopsy (P < 0.001), and pathology prostate weight (P = 0.047) were independent predictors of EPE. Kaplan-Meier analysis demonstrated BCR free rates of 94.6% and 95.4%, for Asian-Indians and Caucasians, respectively, at a median follow-up of 16 months (range 2-70 months). There was no statistically significant difference in BCR rates across the two cohorts (log-rank P-value = 0.405). CONCLUSIONS: This study highlights that while Asian-Indians have more advanced cancer variables, their risk of BCR after surgery is similar to Caucasian patients. Further work is required to better understand the social, genetic and environmental factors that affect the biology of prostate cancer in men of Asian-Indian descent.
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BACKGROUND: RNA quality is believed to decrease with ischaemia time, and therefore open radical prostatectomy has been advantageous in allowing the retrieval of the prostate immediately after its devascularization. In contrast, robotic-assisted laparoscopic radical prostatectomies (RALP) require the completion of several operative steps before the devascularized prostate can be extirpated, casting doubt on the validity of this technique as a source for obtaining prostatic tissue. We seek to establish the integrity of our biobanking process by measuring the RNA quality of specimens derived from robotic-assisted laparoscopic radical prostatectomy. METHODS: We describe our biobanking process and report the RNA quality of prostate specimens using advanced electrophoretic techniques (RNA Integrity Numbers, RIN). Using multivariate regression analysis we consider the impact of various clinicopathological correlates on RNA integrity. RESULTS: Our biobanking process has been used to acquire 1709 prostates, and allows us to retain approximately 40% of the prostate specimen, without compromising the histopathological evaluation of patients. We collected 186 samples from 142 biobanked prostates, and demonstrated a mean RIN of 7.25 (standard deviation 1.64) in 139 non-stromal samples, 73% of which had a RIN ≥ 7. Multivariate regression analysis revealed cell type--stromal/epithelial and benign/malignant--and prostate volume to be significant predictors of RIN, with unstandardized coefficients of 0.867(p = 0.001), 1.738(p < 0.001) and -0.690(p = 0.009) respectively. A mean warm ischaemia time of 120 min (standard deviation 30 min) was recorded, but multivariate regression analysis did not demonstrate a relationship with RIN within the timeframe of the RALP procedure. CONCLUSIONS: We demonstrate the robustness of our protocol--representing the concerted efforts of dedicated urology and pathology departments--in generating RNA of sufficient concentration and quality, without compromising the histopathological evaluation and diagnosis of patients. The ischaemia time associated with our prostatectomy technique using a robotic platform does not negatively impact on biobanking for RNA studies.
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Bancos de Muestras Biológicas/normas , Próstata/metabolismo , Prostatectomía/métodos , Garantía de la Calidad de Atención de Salud/métodos , ARN/genética , ARN/normas , Robótica , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Próstata/patología , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugíaRESUMEN
Since the introduction of laparoscopic surgery, the promise of lower postoperative morbidity and improved cosmesis has been achieved. LaparoEndoscopic Single Site (LESS) surgery potentially takes this further. Following the first human urological LESS report in 2007, numerous case series have emerged, as well as comparative studies comparing LESS with standard laparoscopy. Technological developments in instrumentation, access and optics devices are overcoming some of the challenges that are raised when operating through a single site. Further advances in the technique have included the incorporation of robotics (R-LESS), which exploit the ergonomic benefits of ex vivo robotic platforms in an attempt to further improve the implementation of LESS procedures. In the future, urologists may be able to benefit from in vivo micro-robots that will allow the manipulation of tissue from internal repositionable platforms. The use of magnetic anchoring and guidance systems (MAGS) might allow the external manoeuvring of intra-corporeal instruments to reduce clashing and facilitate triangulation. However, the final promise in minimally invasive surgery is natural orifice transluminal endoscopic surgery (NOTES), with its scarless technique. It remains to be seen whether NOTES, LESS, or any of these future developments will prove their clinical utility over standard laparoscopic methods.
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Laparoscopía/tendencias , Robótica , Procedimientos Quirúrgicos Urológicos/tendencias , Métodos Epidemiológicos , Humanos , Laparoscopía/instrumentación , Laparoscopía/métodos , Procedimientos Quirúrgicos Urológicos/instrumentación , Procedimientos Quirúrgicos Urológicos/métodosAsunto(s)
Laparoscopía , Prostatectomía/métodos , Neoplasias de la Próstata/cirugía , Robótica , Cirugía Asistida por Computador , Humanos , Laparoscopía/instrumentación , Masculino , Prostatectomía/instrumentación , Robótica/instrumentación , Cirugía Asistida por Computador/instrumentación , Factores de Tiempo , Resultado del TratamientoRESUMEN
INTRODUCTION: We discuss the case of a 51 year old former mid-wife presented to the NHS Luton and Bedfordshire psychiatric services with a 2 year history of increasing forgetfulness with significant impairment to her daily function. She was diagnosed with non-familial early-onset Alzheimer's Disease (EOAD) and started on 8mg daily of the acetylcholinesterase inhibitor Galantamine. METHODS: The information for this study was gathered from patient notes, consultant, collateral and personal accounts. Periodic outpatient consultations at the NHS Luton and Bedfordshire psychiatric services were used to monitor Mrs LF's global, functional and behavioral progress. These were supplemented with the mini mental state examination (MMSE) at each outpatient appointment. RESULTS: The graph of MMSE scores illustrates severe decline in scores, followed eventually by increase in score to sustained improvement while continuing on galantamine. Functionally, this lady has successfully negotiated a divorce, moved into her own accommodation, began travelling on holidays, including abroad, with friends, and has now embarked on a new relationship. DISCUSSION: Whilst only being a single case study, this demonstrates the significant benefits which are attainable with Galantamine in EOAD. The extent of this improvement may be a result of individual variation, or perhaps a greater efficacy for this drug in the subset of 'early-onset' AD patients, which has long been thought to share the same mechanism as traditional AD. The responsiveness to Galantamine in this patient may suggest an alternative mechanism of Early Onset Alzheimer's Disease to typical Alzheimer's Disease in the over 65's. CONCLUSION: The case raises interesting questions as to whether EOAD should be considered distinct to typical (over 65's) AD, given the greater than expected response to Galantamine.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Galantamina/uso terapéutico , Nootrópicos/uso terapéutico , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Inglaterra , Femenino , Estudios de Seguimiento , Galantamina/efectos adversos , Humanos , Escala del Estado Mental , Persona de Mediana Edad , Nootrópicos/efectos adversos , Medicina EstatalRESUMEN
There has been confusion about the subunit stoichiometry of the degenerin family of ion channels. Recently, a crystal structure of acid-sensing ion channel (ASIC) 1a revealed that it assembles as a trimer. Here, we used atomic force microscopy (AFM) to image unprocessed ASIC1a bound to mica. We detected a mixture of subunit monomers, dimers and trimers. In some cases, triple-subunit clusters were clearly visible, confirming the trimeric structure of the channel, and indicating that the trimer sometimes disaggregated after adhesion to the mica surface. This AFM-based technique will now enable us to determine the subunit arrangement within heteromeric ASICs.