Strategies to improve macroencapsulated islet graft survival

Chronic immunosuppressive therapy may have severe side-effects. In cell transplantation, the graft can be encapsulated within a membrane chamber, providing a physical barrier against the immune system. The cell graft then becomes dependent on the diffusion of nutrients and oxygen from the surrounding microcirculation. A major drawback has been the formation of avascular fibrotic tissue around the chamber. The immunoprotective device studied (TheraCyte ) has an outer membrane inducing neovascularization. However, major parts of the encapsulated graft are still lost soon after transplantation, probably because of relative hypoxia and malnutrition. The overall aim of this thesis was to assess various strategies to improve islet graft survival in the device, using rodent models. The purpose of the first paper was to improve the method for histological evaluation of the vascularization around the device. Vascular profiles within various distances from the membrane surface were counted at different times and then correlated with glucose kinetics. We found that the vascular profiles within 100 ìm had the highest correlations with glucose kinetics and concluded that vessels within this distance are important for the exchange of small molecules between the circulation and the device s lumen. Therefore, we recommend that 100 ìm should be used in histological evaluations of the membrane vascularization. In the second paper we hypothesized that preimplantation of the device should improve encapsulated islet graft survival. Previous studies have indicated that it takes up to 3 months for recovery of the microcirculation after membrane implantation. Therefore, we implanted empty devices and transplanted islets 3 months later in these chambers. This approach significantly improved the cure rates of diabetic animals, and the islet dose required for cure was reduced by about 10 times. Morphometry evaluations confirmed increased graft survival in preimplanted devices. The third paper aimed at evaluating the effects of exendin-4 treatment on the metabolic outcome after islet transplantation. Exendin-4 inhibits islet apoptosis, stimulates islet differentiation and regeneration and has beneficial effects on peripheral tissues. We found that exendin-4 treatment significantly improved the metabolic outcome after free islet transplantation to the renal subcapsular site. The benefit lasted longer than the treatment, suggesting that exendin-4 had long-standing effects on the islet graft. This substance seems to be an interesting new approach to improve the survival also of encapsulated islet grafts. In the last paper we evaluated the risk of recipient sensitization using macroencapsulated islets. A heterotopic heart graft was transplanted one month after free or encapsulated islet transplantation. The time-to-rejection was significantly shorter in the free islet group, while it did not differ between encapsulated islet graft recipients and naive animals. We therefore conclude that the device protects against sensitization, at least during the first month after transplantation. Today, side-effects of the immunosuppressive therapy are one of the main limiting factors for the use of islet transplantation. If immunoprotection could be achieved by encapsulation of the islet graft, it should be possible to widen the indications. This thesis describes promising strategies to improve the survival of macroencapsulated islet grafts, which might contribute to make macroencapsulation a clinical reality

Should we Refrain from Performing Oophorectomy in Conjunction with Radical Cystectomy for Bladder Cancer?

Radical cystectomy with neoadjuvant chemotherapy is the gold standard for treating muscle-invasive bladder cancer. Women subjected to radical cystectomy are frequently postmenopausal, and the median age for bladder cancer diagnosis in women in Sweden is currently 73 yr (Swedish National Bladder Cancer Register). Traditionally, most women treated with radical cystectomy have undergone simultaneous bilateral oophorectomy and hysterosalpingectomy to diminish the risk of later ovarian disease and ovarian bladder cancer recurrence, but also the belief that there is no impact on health or health-related quality of life associated with oophorectomy and the fact that it might be easier surgery to take the ovarian pedicles, rather than sparing the ovaries. However, pelvic organ preservation is considered in some younger women to diminish postoperative functional impairment. Based on recent literature in several areas related to oophorectomy, we question the rationale and arguments for performing oophorectomy in women in conjunction with radical cystectomy for bladder cancer. It can be questioned whether routine bilateral oophorectomy during radical cystectomy is advisable in premenopausal women, and the same might also apply to selected postmenopausal women

Port-site Metastases After Robot-assisted Radical Cystectomy: Is There a Publication Bias?

To access publisher's full text version of this article click on the hyperlink belowSwedish Cancer Society Gosta Jonsson Research Foundation Lund Medical Faculty (ALF

Complete metabolic response with [18F]fluorodeoxyglucose-positron emission tomography/computed tomography predicts survival following induction chemotherapy and radical cystectomy in clinically lymph node positive bladder cancer

Objective: To determine whether repeated [18F]fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET-CT) scans can predict increased cancer-specific survival (CSS) after induction chemotherapy followed by radical cystectomy (RC). Patients and Methods: Between 2007 and 2018, 86 patients with clinically lymph node (LN)-positive bladder cancer (T1–T4, N1–N3, M0–M1a) were included and underwent a repeated FDG-PET-CT during cisplatin-based induction chemotherapy. The 71 patients that had a response to chemotherapy underwent RC. Response to chemotherapy was evaluated in LNs through repeated FDG-PET-CT and stratified as partial response or complete response using three different methods: maximum standardised uptake value (SUVmax), adapted Deauville criteria, and total lesion glycolysis (TLG). Progression-free survival (PFS) and CSS were analysed for all three methods by Cox regression analysis. Results: After a median follow-up of 40 months, 15 of the 71 patients who underwent RC had died from bladder cancer. Using SUVmax and the adapted Deauville criteria, multivariable Cox regression analyses adjusting for age, clinical tumour stage and LN stage showed that complete response was associated with increased PFS (hazard ratio [HR] 3.42, 95% confidence interval [CI] 1.20–9.77) and CSS (HR 3.30, 95% CI 1.02–10.65). Using TLG, a complete response was also associated with increased PFS (HR 5.17, 95% CI 1.90–14.04) and CSS (HR 6.32, 95% CI 2.06–19.41). Conclusions: Complete metabolic response with FDG-PET-CT predicts survival after induction chemotherapy followed by RC in patients with LN-positive bladder cancer and comprises a novel tool in evaluating response to chemotherapy before surgery. This strategy has the potential to tailor treatment in individual patients by identifying significant response to chemotherapy, which motivates the administration of a full course of induction chemotherapy with a higher threshold for suspending treatment due to toxicity and side-effects

Anorectal dysfunction after radical cystectomy for bladder cancer

Objective: To prospectively assess anorectal dysfunction using patient-reported outcomes using validated questionnaires, manovolumetry and endoanal ultrasound before and 12 months after RC. Patients and methods: From 2014 to 2019, we prospectively included 44 patients scheduled for RC. Preoperatively and 12 months after surgery, 41 patients filled in a low anterior resection syndrome score (LARS-score) to assess fecal incontinence, increased frequency, urgency and emptying difficulties and a St Mark’s score to assess fecal incontinence in conjunction with manovolumetry and endoanal ultrasound examinations. Pre- and postoperative patient-reported anorectal dysfunction were assessed by LARS-score and St Marks’s score. At the same time-points, anorectal function was evaluated by measuring mean anal resting and maximal squeeze pressures, volumes and pressures at first desire, urgency to defecate and maximum toleration during manovolumetry. Wilcoxon's signed rank test was used to compare pre- and postoperative outcomes by questionnaires. Results: Postoperatively 6/41 (15%) patients reported flatus incontinence assessed by the LARS-questionnaire, and correspondingly the St Mark’s score increased postoperatively. The median anal resting pressure decreased from 57 mmHg preoperatively to 46 mmHg after RC, but without any postoperative anatomic defects detected by endoanal ultrasound. Volumes and pressures at first desire, urgency to defecate and maximum toleration during manovolumetry all increased after RC, indicating decreased postoperative rectal sensation, as rectal compliance was unaltered. Conclusions: Postoperative flatus incontinence is reported by one out of seven patients after RC, which corresponds to decreased anal resting pressures. The finding of decreased rectal sensation might also contribute to patient-reported symptoms and anorectal dysfunction after RC

Reducing recurrence in non-muscle-invasive bladder cancer by systematically implementing guideline-based recommendations : effect of a prospective intervention in primary bladder cancer patients

Objective: In non-muscle-invasive bladder cancer (NMIBC), local recurrence after transurethral resection of the bladder (TURB) is common. Outcomes vary between urological centres, partly due to the sub-optimal surgical technique and insufficient application of measures recommended in the guidelines. This study evaluated early recurrence rates after primary TURB for NMIBC before and after introducing a standardized treatment protocol. Methods: Medical records of all patients undergoing primary TURB for NMIBC in 2010 at Skåne University Hospital, Malmö, Sweden, were reviewed. A new treatment protocol for NMIBC was defined and introduced in 2013, and results documented during the first year thereafter were compared with those recorded in 2010 prior to the intervention. The primary endpoint was early recurrence at first control cystoscopy. Comparisons were made by Chi-square analysis and Fisher’s exact test. Recurrence-free survival (RFS) in the two cohorts was also investigated. Results: TURB was performed on 116 and 159 patients before and after the intervention, respectively. The early recurrence rate decreased from 22% to 9.6% (p = 0.005) at the first control cystoscopy after treatment. Residual/Recurrent tumour at the first control cystoscopy after the primary TURB (i.e. at second-look resection or first control cystoscopy) decreased from 31% to 20% (p = 0.038). The proportion of specimens containing muscle in T1 tumours increased from 55% to 94% (p < 0.001). RFS was improved in the intervention group (HR = 0.65, CI = 0.43–1.0; p = 0.05). Conclusions: Introduction of a standardized protocol and reducing the number of surgeons for primary treatment of NMIBC decreased the early recurrence rate from 22% to 9.6% and lowered the recurrence incidence by 35%

Reply to Amit Bansal, Ruchir Maheshwari, and Anant Kumar's Letter to the Editor re: Fredrik Liedberg, Petter Kollberg, Marie Allerbo, et al. Preventing Parastomal Hernia After Ileal Conduit by the Use of a Prophylactic Mesh: A Randomised Study. Eur Urol 2020;78:757-63.

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