Objectives
To report clinical and functional outcomes for patients who have undergone salvage robot‐assisted seminal vesicle excision (RA‐SVE) for the focal treatment of isolated seminal vesical (SV) ...recurrence after treatment for prostate cancer by low‐dose‐rate brachytherapy.
Patients and Methods
Patients with rising prostate‐specific antigen (PSA) after low‐dose‐rate prostate brachytherapy (LDR‐PB) underwent multi‐parametric magnetic resonance imaging (mp‐MRI) of the prostate and 11C‐Choline or 68Ga‐prostate‐specific membrane antigen (68Ga‐PSMA) positron emission tomography/computed tomography (PET/CT) scan, followed by targeted transperineal biopsy of the prostate and SVs. Isolated SV recurrence were identified in 17 (0.38%) LDR‐PB patients. These 17 patients were offered RA‐SVE.
Results
The median total operative time was 90 min and blood loss 50 mL with no postoperative transfusions required. The median hospital stay was 1 day. No intra‐ or postoperative complications were documented. Continence status was unaffected, no patient required urinary pads. Postoperative pathology confirmed SV invasion in all specimens. Surgical margins were positive in seven (41%) patients. All patients had at least one positive imaging study, although three (18%) mp‐MRI and five (29%) PET/CT assessments were negative. One (6%) pre‐SVE biopsy was also negative but with positive imaging. Salvage SVE failure, defined as three consecutive PSA rises or the need for further treatment, occurred in six patients of whom three had a positive margin. Overall failure‐free survival rates were 86%, 67%, and 53% at 1, 2, and 3 years after SVE, respectively.
Conclusions
Salvage RA‐SVE appears to be a safe focal treatment, with very low morbidity, for patients with localised SV recurrence after LDR‐PB. It permits deferral of androgen deprivation therapy in selected patients. Bilateral SVE is mandatory. This surgical option should be considered in patients with isolated prostate cancer recurrence to the SV.
Objectives
To assess the long‐term treatment efficacy of low‐dose‐rate (LDR) brachytherapy for the treatment of localized prostate cancer.
Patients and Methods
Cause‐of‐death annotation in our ...prospective database was supplemented with death certificate information obtained via an internal audit of patients treated from 1999 to 2017 with LDR prostate brachytherapy as monotherapy or as combination with androgen deprivation therapy and/or external beam radiotherapy. Overall and disease‐specific survival were the primary outcomes, estimated with Kaplan–Meier and competing risks multi‐state models. Clinical variables influencing mortality were assessed with Cox proportional hazards regression in a sub‐analysis of men to assess the predictive value of prostate‐specific antigen (PSA) level at 48 months post implant.
Results
The audit process began in October 2017 and culminated in June 2020 with a curated series of 2936 patients. All‐cause and prostate cancer‐specific death prevalence were 11% and 2.9%, respectively. The median (range) follow‐up time was 10 (3–21) years and the median (range) time to death from any cause was 9 (3–21) years. At 15 years post implant the overall and prostate cancer‐specific survival probability were 81% and 95%, respectively. The 15‐year cumulative incidence rates of death not due and due to prostate cancer were 14% and 5%, respectively. A greater risk of death due to prostate cancer was conferred by increasing age at therapy (hazard ratio HR 1.1, P < 0.001), advanced clinical stages relative to T1a‐T2a (HR 1.9, P = 0.048 for T2b; HR 2.7, P = 0.023 for T2c‐T3b) and a 48‐month PSA level >1.0 ng/mL (HR 6.8, P < 0.001).
Conclusion
This study constitutes the largest retrospective analyses of long‐term mortality outcomes from prospectively collected prostate brachytherapy data and confirms the excellent treatment efficacy of LDR prostate brachytherapy for localized prostate cancer. T2 clinical stage subdivisions and 48‐month PSA level >1.0 ng/mL appear to be strong indicators of prostate cancer‐related survival.
5-Hydroxymethylcytosine (hmC) is an oxidation product of 5-methylcytosine which is present in the deoxyribonucleic acid (DNA) of most mammalian cells. Reduction of hmC levels in DNA is a hallmark of ...cancers. Elucidating the dynamics of this oxidation reaction and the lifetime of hmC in DNA is fundamental to understanding hmC function. Using stable isotope labelling of cytosine derivatives in the DNA of mammalian cells and ultrasensitive tandem liquid-chromatography mass spectrometry, we show that the majority of hmC is a stable modification, as opposed to a transient intermediate. In contrast with DNA methylation, which occurs immediately during replication, hmC forms slowly during the first 30 hours following DNA synthesis. Isotopic labelling of DNA in mouse tissues confirmed the stability of hmC in vivo and demonstrated a relationship between global levels of hmC and cell proliferation. These insights have important implications for understanding the states of chemically modified DNA bases in health and disease.
Objectives
To report clinical outcomes of the Hemi‐Ablative Prostate Brachytherapy (HAPpy) trial evaluating treatment‐related toxicity and effectiveness of hemi‐gland (HG) low‐dose‐rate (LDR) ...prostate brachytherapy as a focal approach to control unilateral localised prostate cancer.
Patients and Methods
Single institution phase IIS pilot study of patients treated with focal 4D Brachytherapy™ (BXTAccelyon, Burnham, Buckinghamshire, UK). The primary outcome was patient‐reported toxicity 24 months after implant. The secondary outcome was assessment of disease control. Outcomes in HG patients were compared to whole‐gland (WG) controls obtained from our prospective cohort registry by negative binomial and linear regression models.
Results
Pre‐treatment demography was similar between the 30 HG patients and 362 WG controls. Post‐implant dosimetry was similar for the prostate gland target volumes and significantly reduced for the urethra and bowel in HG patients relative to WG controls, but this did not translate into a difference in post‐implant mean symptom scores between the two groups. Nevertheless, the change in score from baseline indicated that the impact on pre‐treatment symptom status was less after HG implants. Only HG patients showed a return to baseline urinary scores as early as 12 months. Sexual potency was conserved in 73% and 67% of HG and WG patients, respectively (P = 0.84). Post‐implant prostate‐specific antigen (PSA) kinetics revealed that baseline PSA was reduced at 24 months by 78% and 88% in HG and WG patients, respectively (P < 0.05). Treatment relapse occurred in one (3%) HG patient 55 months after implant and in nine (3%) WG patients at 32–67 months after implant.
Conclusion
This pilot study suggests that treatment‐related toxicity and biochemical outcomes after HG implants are broadly similar to those observed with WG treatment despite the lower dose delivered by HG implants.
Objective
To report the incidence of malignancy in gynaecological organs removed during radical cystectomy (RC).
Patients and Methods
A retrospective multicentre study of 1600 RCs at three ...high‐volume institutions between January 2009 and March 2022 was performed. Pathological findings in gynaecological organs in female RC specimens were reviewed. Multivariable logistic regression analyses were used to identify predictors of malignant gynaecological organ involvement (GOI) at time of RC.
Results
Overall, 302 females with a median (interquartile range) age of 68 (61–75) years underwent RC for clinical (c)Ta–T4 bladder cancer. In all, 56 patients (18.5%) received neoadjuvant chemotherapy. Malignant GOI was seen in 20 patients (6.6%); the most common single sites of GOI were the uterus (five patients) and vaginal wall (four), followed by cervix (one), and ovaries (one). Nine patients had involvement of more than one gynaecological organ. No females had a primary gynaecological malignancy detected incidentally at RC. Patients with GOI were more likely to have cT3/T4 stage (P < 0.001), preoperative hydronephrosis (P = 0.004), lymphovascular invasion (P = 0.002), and squamous cell carcinoma (P = 0.005) than those without GOI. On multivariable analysis, cT4 stage was an independent predictor of malignant GOI (odds ratio 88.3, 95% confidence interval 10.1–1214; P < 0.001).
Conclusion
To our knowledge, we present the largest multi‐institutional study examining malignant GOI in females with bladder cancer undergoing RC. The rate of GOI at the time of RC is low and associated with higher clinical stage. In the absence of clinical or radiological evidence of sexual organ involvement, our results do not support their routine removal at the time of RC.
Objectives
To report clinical outcomes of 125I low‐dose‐rate prostate brachytherapy (LDR‐PB) as monotherapy or combined with androgen‐deprivation therapy (ADT) and/or external beam radiotherapy ...(EBRT) in high‐risk localised prostate cancer.
Patients and Methods
Analysis of clinical outcomes from a prospective cohort of patients treated with LDR‐PB alone or combined treatment in a single institution. Men with a high risk of disease relapse were identified by the National Institute for Health and Care Excellence (NICE) criteria or by the National Comprehensive Cancer Network (NCCN) criteria. Relapse‐free survival (RFS), overall survival (OS), prostate cancer‐specific survival (PCSS), and metastases‐free survival (MFS), were analysed together with patient‐reported symptom scores and physician‐reported adverse events.
Results
The NICE and NCCN criteria identified 267 and 202 high‐risk patients, respectively. NICE‐defined patients had significantly lower pre‐treatment PSA levels, Gleason scores <7, and a greater proportion of patients who received LDR‐PB monotherapy. At 9 years after implantation RFS was 89% and 87% in the NICE and NCCN groups, respectively (log‐rank P = 0.637), and OS 93% and 94%, respectively (log‐rank P = 0.481). All of the survival estimates were similar between LDR‐PB monotherapy and combined therapies. Cox proportional hazards regression confirmed RFS was similar between the treatment types. Treatment‐related toxicity was also similar between the treatment methods.
Conclusion
LDR‐PB is effective at controlling localised prostate cancer in patients with a high risk of disease relapse. As the present study was not randomised, it is not possible to define those patients who need the addition of ADT and/or EBRT. However, the NICE criteria appear suitable to define treatment options where patients could benefit from LDR‐PB as monotherapy or combined treatment. This choice should be discussed with the patient taking into account comorbidities and presence of multiple high‐risk factors.
Objectives
To report oncological and functional outcomes of men treated with low‐dose‐rate (LDR) prostate brachytherapy aged ≤60 years at time of treatment.
Patients and Methods
Of 3262 patients ...treated with LDR brachytherapy at our centre up to June 2016, we retrospectively identified 597 patients aged ≤60 years at treatment with ≥3‐years post‐implantation follow‐up and four prostate‐specific antigen (PSA) measurements, of which one was at baseline. Overall survival (OS), prostate cancer‐specific survival (PCSS) and relapse free survival (RFS) were analysed together with prospectively collected physician‐reported adverse events and patient‐reported symptom scores.
Results
The median (range) age was 57 (44‐60) years, follow‐up was 8.9 (1.5‐17.2) years, and PSA follow‐up 5.9 (0.8‐15) years. Low‐, intermediate‐ and high‐risk disease represented 53%, 37% and 10% of the patients, respectively. At 10 years after implantation OS and PCSS were 98% and 99% for low‐risk, 99% and 100% for intermediate‐risk, and 93% and 95% for high‐risk disease, respectively. At 10 years after implantation RFS, using the PSA level nadir plus 2 ng/mL definition, was 95%, 90% and 87% for low‐, intermediate‐, and high‐risk disease, respectively. Urinary stricture was the most common genitourinary adverse event occurring in 19 patients (3.2%). At 5 years after implantation erectile function was preserved in 75% of the patients who were potent before treatment.
Conclusion
LDR brachytherapy is an effective treatment with long‐term control of prostate cancer in men aged ≤60 years at time of treatment. It was associated with low rates of treatment‐related toxicity and can be considered a first‐line treatment for prostate cancer in this patient group.
Environmental factors interact with the genome throughout life to determine gene expression and, consequently, tissue function and disease risk. One such factor that is known to play an important ...role in determining long-term metabolic health is diet during critical periods of development. Epigenetic regulation of gene expression has been implicated in mediating'these programming effects of early diet. The precise epigenetic mechanisms that underlie these effects remain largely unknown. Here, we show that the transcription factor Hnf4a, which has been implicated in the etiology of type 2 diabetes (T2D), is epigenetically regulated by maternal diet and aging in rat islets. Transcriptional activity of Hnf4a in islets is restricted to the distal P2 promoter through its open chromatin configuration and an islet-specific interaction between the P2 promoter and a downstream enhancer. Exposure to suboptimal nutrition during early development leads to epigenetic silencing at the enhancer region, which weakens the P2 promoter-enhancer interaction and results in a permanent reduction in Hnf4a expression. Aging leads to progressive epigenetic silencing of the entire Hnf4a locus in islets, an effect that is more pronounced in rats exposed to a poor maternal diet. Our findings provide evidence for environmentally induced epigenetic changes at the Hnf4a enhancer that alter its interaction with the P2 promoter, and consequently determine T2D risk. We therefore propose that environmentally induced changes in promoter-enhancer interactions represent a fundamental epigenetic mechanism by which nutrition and aging can influence long-term health.
Long-term remission, and likely cure, of clinically localized prostate cancer is considered when there is no evidence of prostate-specific antigen (PSA) or radiographic progression 10 years after ...initial localized therapy. 1 The PSA level thresholds to define the posttreatment (biochemical) progression differ based on the mechanism of action of a surgical or radiotherapeutic approach, making cross-modality comparisons cumbersome. Kaplan-Meier analyses showed overall 10- and 15-year FFR rates of 98% and 95% in patients with a 48-month PSA ≤ 0.2 ng/mL (Figure 1); multivariable Cox proportional hazards regression, 5 adjusted for age at treatment, risk classification, and treatment modalities (including the use of ADT), indicated survival rates were not dependent on these predictor variables in patients with a 48-month PSA ≤ 0.2 ng/mL. Kaplan-Meier relapse-free survival analysis of patients who received LDR-PB (alone or as combination with ADT and/or EBRT) stratified by their PSA value (ng/mL) 48 months post-implant Previously we reported that 92% of relapse-free high-risk patients with an available PSA 10 years after implantation had a PSA level ≤ 0.2 ng/mL. 6 Therefore, from our own long-term experience and that of others, adoption of a PSA value of ≤ 0.2 ng/mL at 48 months posttreatment as a biochemical definition of cure for patients treated with LDR-PB is reasonable and evidence based.
Cohesin is a chromatin-associated protein complex that mediates sister chromatid cohesion by connecting replicated DNA molecules. Cohesin also has important roles in gene regulation, but the ...mechanistic basis of this function is poorly understood. In mammalian genomes, cohesin co-localizes with CCCTC binding factor (CTCF), a zinc finger protein implicated in multiple gene regulatory events. At the imprinted IGF2-H19 locus, CTCF plays an important role in organizing allele-specific higher-order chromatin conformation and functions as an enhancer blocking transcriptional insulator. Here we have used chromosome conformation capture (3C) assays and RNAi-mediated depletion of cohesin to address whether cohesin affects higher order chromatin conformation at the IGF2-H19 locus in human cells. Our data show that cohesin has a critical role in maintaining CTCF-mediated chromatin conformation at the locus and that disruption of this conformation coincides with changes in IGF2 expression. We show that the cohesin-dependent, higher-order chromatin conformation of the locus exists in both G1 and G2 phases of the cell cycle and is therefore independent of cohesin's function in sister chromatid cohesion. We propose that cohesin can mediate interactions between DNA molecules in cis to insulate genes through the formation of chromatin loops, analogous to the cohesin mediated interaction with sister chromatids in trans to establish cohesion.
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