A National Referral Service for Paediatric Brachytherapy: An Evolving Practice and Outcomes Over 13 Years.

AIMS: Most children requiring radiotherapy receive external beam treatment and few have tumours suitable for brachytherapy. No paediatric radiotherapy centre will treat enough patients from its own normal catchment population for expertise in brachytherapy to be developed and sustained. Following discussion and agreement in the national paediatric radiotherapy group, a service for paediatric brachytherapy in the UK has been developed. We report the process that has evolved over more than 10 years, with survival and functional outcome results. MATERIALS AND METHODS: Since 2009, potential patients have been referred to the central paediatric oncology multidisciplinary team meeting, where imaging, pathology and treatment options are discussed. Since 2013, the National Soft Tissue Sarcoma Advisory Panel has also reviewed most patients, with the principal aim of advising on the most suitable primary tumour management for complex patients. Clinical assessment and examination under anaesthetic with biopsies may be undertaken to confirm the appropriateness of brachytherapy, either alone or following conservative surgery. Fractionated high dose rate brachytherapy was delivered to a computed tomography planned volume after implantation of catheters under ultrasound imaging guidance. Since 2019, follow-up has been in a dedicated multidisciplinary clinic. RESULTS: From 2009 to 2021 inclusive, 35 patients (16 female, 19 male, aged 8 months to 17 years 6 months) have been treated. Histology was soft-tissue sarcoma in 33 patients and carcinoma in two. The treated site was pelvic in 31 patients and head and neck in four. With a median follow-up of 5 years, the local control and overall survival rates are 100%. Complications have been few, and functional outcome is good. CONCLUSION: Brachytherapy is effective for selected paediatric patients, resulting in excellent tumour control and good functional results. It is feasible to deliver paediatric brachytherapy at a single centre within a national referral service.

In transit metastases in children, adolescents and young adults with localized rhabdomyosarcoma of the distal extremities: Analysis of the EpSSG RMS 2005 study.

In-transit metastases (ITM) are defined as metastatic lymph nodes or deposits occurring between the primary tumor and proximal draining lymph node basin. In extremity rhabdomyosarcoma (RMS), they have rarely been reported. This study evaluates the frequency, staging and survival of patients with ITM in distal extremity RMS. METHODS: Patients with extremity RMS distal to the elbow or knee, enrolled in the EpSSG RMS 2005 trial between 2005 and 2016 were eligible for this study. RESULTS: One hundred and nine distal extremity RMS patients, with a median age of 6.2 years (range 0-21 years) were included. Thirty seven of 109 (34%) had lymph node metastases at diagnosis, 19 of them (51%) had ITM, especially in lower extremity RMS. 18F-FDG-PET/CT detected involved lymph nodes in 47% of patients. In patients not undergoing 18F-FDG-PET/CT lymph node involvement was detected in 22%. The 5-yr EFS of patients with ITM vs proximal lymph nodes vs combined proximal and ITM was 88.9% vs 21.4% vs 20%, respectively (p = 0.01) and 5-yr OS was 100% vs 25.2% vs 15%, respectively (p = 0.003). CONCLUSION: Our study showed that in-transit metastases constituted more than 50% of all lymph node metastases in distal extremity RMS. 18F-FDG-PET/CT improved nodal staging by detecting more regional and in-transit metastases. Popliteal and epitrochlear nodes should be considered as true (distal) regional nodes, instead of in-transit metastases. Biopsy of these nodes is recommended especially in distal extremity RMS of the lower limb. Patients with proximal (axillary or inguinal) lymph node involvement have a worse prognosis.

Mid- to long-term outcomes of the 'anatomical approach' to congenital megaprepuce repair.

INTRODUCTION: The understanding of the aetiopathogenesis and the long-term outcomes of correctional repair of congenital megaprepuce (CMP) remains unestablished. Different techniques have been described; however, optimum results have been difficult to achieve. OBJECTIVE: The aim of our study was to review our experience of the 'anatomical approach' to the correction of CMP. MATERIAL AND METHODS: This is a retrospective review of boys who underwent CMP repair between 2003 and 2014. All of them had the anatomical approach: A curved incision is made between the scrotal and penile skin. Circumferential dissection superficial to Buck's fascia frees the penis and allows the scrotum to assume a more caudal position. The dissection distally lifts the preputial sac that is opened ventrally. The redundant inner preputial skin is excised. After full degloving, the dorsal flap of skin is thinned. The base of the flap is anchored, and the rectangle of skin is wrapped around the shaft. The remaining diamond-shaped incision is closed in a vertical line. Postoperatively, foam dressings and urethral catheter are left in place. Symptomatology, hospital stay, postoperative complications, redosurgery, voiding and cosmesis were evaluated. RESULTS: Sixty-one patients had surgery at 5-151 months (median 17 months). Median hospital stay was 24 h (12-168 h). Foam dressings and urethral catheter were used in 47 boys and removed in outpatient clinic after 3-7 days. There were two immediate postoperative complications requiring surgery. One due to severe oedema and constriction ring, and the other had wound infection with wound breakdown, both in patients with no dressings (P < 0.05). Follow-up was available for 58 patients, with a median of 22 months (3-79 months). Two required redosurgery (3.5%), one with poor cosmetic result and one recurrence. In all patients, a normal circumcised appearance had been achieved and in 47, cosmetic result was excellent (81%). Five patients have residual suprapubic fat, and four, excess ventral skin. One with residual suprapubic fat has reached puberty and it has resolved. All declared good stream. The same technique was used for six patients with poor cosmetic result after surgery elsewhere. The outcome is excellent for all, with median follow-up of 20.5 months (5-31 months). CONCLUSION: The 'anatomical' repair provides the ability to create the appearance of a standard circumcision, which is generally accepted as normality. Apart from the penis itself, this technique facilitates correction of the penoscrotal transposition, giving the external genitalia the best appearance. It seems to provide good functional and cosmetic outcomes, and it holds true at mid- to long-term follow-up. Dressings and catheter can potentially prevent postoperative complications. However, a prospective study with standardised parameters is required to confirm these findings.

Paediatric cystolitholapaxy through the Mitrofanoff/Monti channel.

INTRODUCTION: Bladder calculi are a known complication of bladder augmentation. Open cystolithotomy remains the preferred option for treating large or multiple stones. Increasingly, however, minimal access techniques have been used. Reports of Mitrofanoff cystolitholapaxy are rare and have been limited to adults. This study presented a two centre series of children treated by cystolitholapaxy via the Mitrofanoff/Monti channel. MATERIALS AND METHODS: With institutional approval the current study retrospectively reviewed and identified 14 patients, on a prospective database, who underwent Mitrofanoff cystolitholapaxy to treat bladder calculi at two independent institutions in the UK and Chile between 2004 and 2016. It looked at patient demographics, surgical technique, stone clearance and recurrence, as well as leak or catheterisation difficulties of the Mitrofanoff/Monti channel post-procedure. RESULTS: Fourteen patients underwent Mitrofanoff cystolitholapaxy during the period 2004-2016. One patient was excluded due to lack of follow-up. The remaining 13 patients were aged 5-22 (median 14) years at the time of the procedure. Their underlying diagnoses were four neuropathic bladders, four bladder exstrophy, four cloacal exstrophy and one posterior urethral valve. Patients underwent augmentation cystoplasty at a median age of 5 (range 1-15) years, using ileum in 10 and sigmoid colon in three. The channel for clean intermittent catheterisation was an appendix Mitrofanoff in nine and a Monti channel in four. An Amplatz sheath was placed through the Mitrofanoff to allow safe access to the bladder for treating the stones (see Summary Table). Recurrent stones were treated using the same technique. Stone and channel outcomes were analysed for each procedure. There were 22 procedures in 13 patients; five (38%) patients had recurrent stones. Median time to recurrence was 6 months. There were no immediate complications. Stone clearance was confirmed by ultrasound and abdominal x-ray at 3-6 months after the procedure. Median follow-up was 15 (range 3-53) months. There were no leaks or difficulties catheterising the channel on follow-up. DISCUSSION: This was the first series of Mitrofanoff/Monti cystolitholapaxy for the treatment of calculi in augmented bladders of paediatric patients. Previous concerns about damaging the continence mechanism of the conduit appeared to be unwarranted. The use of an Amplatz sheath protected the continence system from repeated instrumentation, and permitted free backflow of irrigation and rapid clearance of stone fragments. Recurrence of stones occurred in 38%, which was in keeping with rates reported in the wider literature. CONCLUSION: Mitrofanoff cystolitholapaxy was safe, and with appropriate care did not result in leakage or difficulty catheterising.

Primary bladder exstrophy closure in neonates: challenging the traditions.

PURPOSE: We describe a novel approach to neonatal bladder exstrophy closure that challenges the role of postoperative immobilization and pelvic osteotomy. MATERIALS AND METHODS: We reviewed the primary management of bladder exstrophy at our institutions between 2007 and 2011. In particular we compared postoperative management in the surgical ward using epidural analgesia to muscle paralysis and ventilation in the intensive care unit. Clinical outcome measures were time to full feed, length of stay, postoperative complications and redo closure. Cost-effectiveness was also evaluated using hospital financial data. Data are expressed as median (range). Significance was explored by Fisher exact test and unpaired t-test. RESULTS: A total of 74 patients underwent primary closure without osteotomy. Successful closure was achieved in 70 patients (95%). A total of 48 cases (65%) were managed on the ward (group A) and 26 (35%) were transferred to the intensive care unit (group B). The 2 groups were homogeneous for gestational age (median 39 weeks, range 27 to 41) and age at closure (3 days, 1 to 152). Complications requiring surgical treatment were noted in 4 patients (8.3%) in group A and 3 (11.5%) in group B (p = 0.609). Length of stay was significantly shorter for the group managed on the ward (11 vs 18 days, p <0.0001). Median costs were $42,732 for patients admitted to the intensive care unit and $16,214 for those admitted directly to the surgical ward (p <0.0001). CONCLUSIONS: Primary closure of bladder exstrophy without lower limb immobilization and osteotomy is feasible. Postoperative care on the surgical ward using epidural analgesia results in shorter hospitalization.

Cell biology of bladder development and the role of the extracellular matrix.

The bladder is unique. It is the most distensible organ in the body. If the normal pattern of development is disturbed, the bladder can become dysfunctional and poorly compliant. Renal outcome is intimately linked to bladder function and hence bladder development. In this review we describe our current knowledge of the molecular processes that govern bladder development, with particular emphasis on the role of the extracellular matrix. Finally, we suggest a hypothetical model for bladder development.

Extracellular matrix protein expression during mouse detrusor development.

BACKGROUND/PURPOSE: Extracellular matrix proteins are implicated in regulating cell proliferation and differentiation. The authors systematically analysed the expression of elastin; collagen types I, III, IV; laminin; and fibronectin during mouse detrusor muscle development, a period during which downregulation of detrusor proliferation and increasing smooth muscle differentiation is known to occur. METHODS: Embryonic days 14 (E14) and 18 (E18), and postnatal day 1 (D1) and week 6 (6wk) were examined, a period spanning the inception of the bladder to postnatal maturity. Immunohistochemistry of whole bladders was used to immunolocalise protein expression, and Western blot of dissected detrusor layers was used to semiquantify soluble protein expression. RESULTS: All proteins were detected at all 4 stages. Statistically significant increases were documented for elastin (E14 to 6wk), collagen type I (E18 to 6wk), collagen type III (D1 to 6wk) and laminin (E14 to 6wk). Fibronectin levels were relatively high up to D1, after which levels declined significantly. Collagen type IV levels decreased significantly (E18 to 6wk). CONCLUSIONS: The authors postulate that changing levels of laminin and fibronectin have opposing effects on the transition from proliferating primitive mesenchymal cells to differentiated detrusor muscle. Furthermore, changes in collagen type III and elastin may be important for bladder compliance.

Smooth muscle differentiation and cell turnover in mouse detrusor development.

PURPOSE: We systematically analyzed detrusor muscle differentiation in normal mice with a focus on cell turnover (proliferation and apoptosis) as well as on expression of the muscle specific proteins alpha-smooth muscle actin and desmin. MATERIALS AND METHODS: The stages examined were embryonic days 14 and 18, and postnatal day 1 and week 6, representing a period spanning organ inception to postnatal maturity. Alpha-smooth muscle actin, desmin and proliferating cell nuclear antigen were assessed by immunohistochemical testing of whole bladders and Western blot analysis of dissected detrusor layers. Apoptosis was detected in tissue sections by end-labeling. RESULTS: Alpha-smooth muscle actin was expressed by the detrusor layer throughout maturation with levels significantly increasing from embryonic days 14 to 18 and cytoplasmic staining gaining in uniformity postnatally. Desmin expression in the detrusor was insignificant at embryonic day 14 but increased progressively thereafter. Proliferating cell nuclear antigen expression in the detrusor was highest at organ inception and fell stepwise at each developmental stage with low levels postnatally. Apoptosis in the detrusor was only detected at embryonic day 14. CONCLUSIONS: These results demonstrate that morphological growth of the mouse detrusor muscle is accompanied by complex serial changes in the expression of muscle specific proteins and in cell turnover. Strikingly, detrusor muscle cell differentiation and proliferation are inversely related. These detailed studies may serve as a comparison for future experiments involving aberrant mouse bladder development.

Neoplasia in adult exstrophy patients.

OBJECTIVE: To document the incidence of neoplasia in a cohort of 103 patients born with classical exstrophy. PATIENTS AND METHODS: The notes of patients born before 1964 with exstrophy were reviewed retrospectively. The patients were divided into two groups; 42 were thought to be at high risk of developing neoplasia because they had (at some time) had mixing of urine and faeces in a colorectal reservoir, whereas 61 had never been exposed to such a mixture and were thought to have a low risk of neoplasia. RESULTS: At a minimum of 35 years of follow-up, complete data were available for 61 patients; 42 were lost to follow-up, of whom 14 were at high risk and 28 at low risk of neoplasia. In the high-risk group, there were three with colonic carcinoma (two of whom presented before 1980 and died), one with carcinoma in situ of the colon, 10 with benign colonic neoplasms and three with bladder cancer (two of whom died). In the low-risk group, there was one patient with bladder cancer (who died) and one with a clear cell carcinoma of the kidney. Three of the four patients with bladder cancer had undergone cystectomy before 5 years of age. Assuming that all the lost patients are alive and free of neoplasia, the risk of neoplasia in adults born with exstrophy is 17.5%. The main risk is in those who have been exposed to mixing of urine and faeces in a colorectal reservoir (38%). Even in low-risk patients the risk of malignant neoplasia is 3.3% at a median (range) age of 42 (40-44) years, which is 27 times higher than that of the age-matched general population. CONCLUSIONS: Annual colonoscopy of patients deemed at high risk of colorectal neoplasia appears to be an effective screen for colorectal carcinoma, by identifying a premalignant stage, as there were no deaths after this was introduced. Despite bladder closure or diversion surgery within the first few years of life, patients with exstrophy have an almost 700-fold greater incidence of carcinoma of the bladder than the age-matched general population. Early cystectomy is not protective.

Lateral ligaments of the rectum: an anatomical study.

BACKGROUND: The lateral ligaments of the rectum are surrounded by confusion and misconception. Their identification before 'hooking them on the finger', clamping and ligating is considered in many surgical texts to be an essential step in mobilization of the rectum. By contrast, it is the experience of many colorectal surgeons that the mesorectum can be dissected out either by diathermy or sharp dissection alone. METHODS: Dissection in the mesorectal plane was performed on 28 cadaveric pelves. RESULTS: In ten of the pelves, no connective tissue structure crossed from the pelvic side wall to the rectum. The remaining 18 had only very insubstantial connective tissue strands crossing this space. A total of 17 middle rectal arteries were found, all of them unilateral. Fourteen of these vessels crossed the mesorectum independent of any structure, while the remainder were part of a neurovascular bundle with a connective tissue element. CONCLUSION: It is proposed that the 'lateral ligaments' of the rectum do not exist and that the term should be dropped from surgical texts. When present, the middle rectal artery is a small vessel, close to the pelvic floor. The entire rectum may be mobilized by sharp dissection without the need for clamping or ligation of any significant structure.

The role of delineation and spatial frequency in the perception of the colours of the spectrum.

The observations of the spectrum made by Newton, Young, Wollaston and Helmholtz are approximated and accounted for. Increasing the number of delineations allows progressively more bands differing in colour to be perceived, in addition to the three blocks of colour seen in the undelineated spectrum. The rate at which further delineation permits more colours to be observed decreases, however, so that up to 30 colours can be perceived in the subdivided spectrum. The wavelength discrimination measurements agree well with previous data. Enhanced colour discrimination is shown to require luminance contrast transients containing only the first few Fourier harmonics.