Mathematical modelling of drug delivery from pH-responsive nanocontainers.

Targeted drug delivery systems represent a promising strategy to treat localised disease with minimum impact on the surrounding tissue. In particular, polymeric nanocontainers have attracted major interest because of their structural and morphological advantages and the variety of polymers that can be used, allowing the synthesis of materials capable of responding to the biochemical alterations of the environment. While experimental methodologies can provide much insight, the generation of experimental data across a wide parameter space is usually prohibitively time consuming and/or expensive. To better understand the influence of varying design parameters on the release profile and drug kinetics involved, appropriately-designed mathematical models are of great benefit. Here, we developed a continuum-scale mathematical model to describe drug transport within, and release from, a hollow nanocontainer consisting of a core and a pH-responsive polymeric shell. Our two-layer mathematical model accounts for drug dissolution and diffusion and includes a mechanism to account for trapping of drug molecules within the shell. We conduct a sensitivity analysis to assess the effect of varying the model parameters on the overall behaviour of the system. To demonstrate the usefulness of our model, we focus on the particular case of cancer treatment and calibrate the model against release profile data for two anti-cancer therapeutical agents. We show that the model is capable of capturing the experimentally observed pH-dependent release.

Treatment of obstructed defecation syndrome due to rectocele and rectal intussusception with a high volume stapler (TST STARR-plus).

BACKGROUND: In recent years, stapled transanal resection (STARR) has been adopted worldwide with convincing short-term results. However, due to the high recurrence rate and some major complications after STARR, there is still controversy about when the procedure is indicated. The aim of this study was to assess the safety, efficacy and feasibility of STARR performed with a new dedicated device for tailored transanal stapled surgery. METHODS: All the consecutive patients affected by obstructed defecation syndrome (ODS) due to rectocele or/and rectal intussusception, who underwent STARR with the TST STARR-Plus stapler, were included in a prospective study. Pain, Cleveland Clinic Score for Constipation (CCCS) and incontinence, patient satisfaction, number of hemostatic stitches, operative time, hospital stay and perioperative complications were recorded. Postoperative complications and recurrence were also reported. RESULTS: Forty-five consecutive patients (median age 50; range 24-79) were included in the study. Median resected volume was 15 cm3 (range 12-19 cm3) with a median height of surgical specimen of 5.6 cm (range 4.5-10 cm). The mean CCCS decreased from 17.26 (± 3.77) to 5.42 (± 2.78) postoperatively (p < 0.001). Patient satisfaction grade was excellent in 14 patients (31.1%), good in 25 (55.5%), sufficient in three (6.7%) and poor in three patients (6.7%). No major complications occurred. Five patients (11%) reported urgency after 30 days and two patients (4%) after 12 months. The Cleveland Clinic Incontinence score did not significantly change. At a median follow-up of 23 months (range 12-30 months), only three patients (6.7%) reported recurrent symptoms of obstructed defecation comparable to those reported at baseline. CONCLUSIONS: TST STARR-Plus seems to be safe and effective for the treatment of ODS due to rectocele and rectal intussusception, and technical improvement could reduce the risk of some complications. However, careful patient selection is still the best means of preventing complications.

Permacol™ collagen paste injection for the treatment of complex anal fistula: 1-year follow-up.

BACKGROUND: Optimal surgical treatment for anal fistula should result in healing of the fistula track and preserve anal continence. The aim of this study was to evaluate Permacol™ collagen paste (Covidien plc, Gosport, Hampshire, UK) injection for the treatment of complex anal fistulas, reporting feasibility, safety, outcome and functional results. METHODS: Between May 2013 and December 2014, 21 consecutive patients underwent Permacol paste injection for complex anal fistula at our institutions. All patients underwent fistulectomy and seton placement 6-8 weeks before Permacol™ paste injection. Follow-up duration was 12 months. RESULTS: Eighteen patients (85.7%) had a high transsphincteric anal fistula, and three female patients (14.3%) had an anterior transsphincteric fistula. Fistulas were recurrent in three patients (14.3%). Seven patients (33%) had a fistula with multiple tracts. After a follow-up of 12 months, ten patients were considered healed (overall success rate 47.6%). The mean preoperative FISI score was 0.33 ± 0.57 and 0.61 ± 1.02 after 12 months. CONCLUSIONS: Permacol™ paste injection was safe and effective in some patients with complex anal fistula without compromising continence.

Tailored prolapse surgery for the treatment of hemorrhoids with a new dedicated device: TST Starr plus.

PURPOSE: The aim of the study was to assess the results of the stapled transanal procedure in the treatment of hemorrhoidal prolapse in terms of postoperative complications and recurrence rate using a new dedicated device, TST Starr plus. METHODS: Patients affected by III-IV degree hemorrhoidal prolapsed that underwent stapled transanal resection with the TST Starr plus were included in the present study. Results of the procedure with perioperative complications, postoperative complications, and recurrence rate were reported. RESULTS: From November 2012 to October 2014, 52 patients (19 females) were enrolled in the study. The main symptoms were prolapse (100 %) and bleeding (28.8 %). Transanal rectal resection was performed with parachute technique in 24 patients (46.2 %) and purse string technique in 23 patients (53.8 %). A mild hematoma at the suture line occurred in one patient (1.9 %). Postoperative bleeding was reported in three patients (5.7 %), in one of which, reoperation was necessary (1.9 %). Tenesmus occurred in one patient (1.9 %), and it was resolved with medical therapy. Urgency was reported in nine patients (17.1 %) at 7 days after surgery. Of these, three patients (5.7 %) complained urgency at the median follow-up of 14.5 months. Reoperation was performed in one patient (1.9 %) for chronic anal pain for rigid suture fixed on the deep plans. Occasional bleeding was reported in four patients (7.7 %). No recurrence of prolapse was reported at a median of 14.5 months after surgery, even if one patient (1.9 %) had a partial recurrent prolapse of a downstaged single pile. CONCLUSIONS: TST Starr plus seems to be safe and effective for a tailored transanal stapled surgery for the treatment of III-IV degree hemorrhoidal prolapse. The new conformation and innovative technology of the stapler seems to reduce some postoperative complications and recurrence rate.

Short-term results after STARR versus internal Delorme for obstructed defecation: a non-randomized prospective study.

Obstructed defecation syndrome due to internal intussusception and rectocele is a common disease, and various transanal surgical techniques have been proposed. Aim of the present study was to compare the internal Delorme (ID) and the stapled transanal rectal resection (STARR) results in the treatment of patients with obstructed defecation syndrome. From September 2011 to May 2012, 23 patients were operated with STARR procedure and 12 patients with Delorme's procedure for obstructed defecation syndrome. All patients underwent preoperative assessment: clinical evaluation (Altomare ODS score, Wexner constipation scoring system), proctoscopy, defecography, anorectal manometry and endoanal ultrasonography. Surgery was proposed with: failure of medical therapy, incomplete defecation, and unsuccessful attempts with long periods spent in bathroom, defecation with digital assistance, use of enemas and defecography findings of rectoanal intussusception and rectocele. The average operative time was 28 min (range 15-65) for the STARR group and 56 min (range 28-96) for the ID group with a mean hospital stay of 2 days for both the procedures. The Wexner score significantly fell postoperatively from 17 to 4, 7 in STARR group and from 15.3 to 3.3 in the ID group. The Altomare score postoperatively fell from 18.2 to 5.5 for STARR group and from 16.5 to 5.3 for ID group. No statistically significant differences were observed between the two procedures considering the outcomes parameters and the complications. Both ID and STARR procedure seem to be effective in the treatment of ODS.

[Is it necessary to always treat the relapses of superficial bladder tumour at the moment of diagnosis? Preliminary communication]. / Es necesario resecar siempre las recidivas de los tumores vesicales superficiales en el momento del diagnostico? Comunicación preliminar.

OBJECTIVE: To assess the expectant management superficial recurrent bladder tumours. MATERIAL AND METHODS: Between Jan 1998 and Dec 2003, 112 patients were diagnosed of superficial bladder tumour. 13 patients were observed after the diagnosis of tumour relapse until the decision to perform a transurethral resection. We analysed the clinical and pathological features. The patients were controlled with flexible cystoscopy every 3 months approximately. Of the 13 patients we count 15 observation events, (2 times in 2 patients). The decision between to treat or continue with observation was based in changes of appearance, size or number of tumours and presence of hematuria. RESULTS: With a mean age of 74.6 years (47-91). The mean observation time was 5.76 months (3-71). In the group of tumours previous to the observation period, in 12 events (10 patients) that means 80% any progression in grade or stage was observed. In the other 3 events we observed progression in grade and stage in 2 and only stage in 1. In any case we observed progression to invasive bladder tumour neither upper urinary tract tumour. CONCLUSIONS: Due to the low risk of progression, we believe that immediate eradication is not always necessary, thus reducing the adverse impact of repeat resections.

[Initial superficial bladder tumors: our experience. Our criteria. Study Group of Bladder Tumors]. / Tumores vesicales superficiales iniciales: nuestra experiencia. Nuestro criterio. Grupo de Estudio de Tumores Vesicales.

OBJECTIVES: Evaluation of a homogeneous series of Superficial Primary TCC of the Bladder. Utility of randomized biopsies (BMN). Study of risk factors and risk groups as a basis for determining treatment and followup patterns. MATERIALS AND METHODS: Survey of 1,529 PSBT cases that underwent TURB and BMN, with a mean followup of 4.2 years. Strict statistical treatment: multivariate analysis using Cox logistic regression according to Kaplan-Meier curves. RESULTS: Tumor features of note: single tumor (65%), smaller than 1.5 cm (45%), high grade (G3: 26%), and high stage (T1: 64%). BMN showed associated CIS in 284 cases (19%). Main risk factors for recurrence were multiplicity, size > 3 cm and association with CIS. The main risk factor for progression was grade 3 (OR 19.9). Grade 3 and association with CIS were found to increase mortality risk. On the basis of this data, we grouped tumors according to low-, middle-, and high-risk, and established our proposed treatment and followup for each group. CONCLUSIONS: This multivariate analysis of a homogeneous cohort of 1,529 primary superficial bladder tumor cases allowed vs to determine risk groups for treatment and followup.

Upper urinary tract tumors after primary superficial bladder tumors: prognostic factors and risk groups.

PURPOSE: We evaluated the prognostic factors of primary superficial bladder cancer that may predict a metachronous upper urinary tract tumor. We also determined whether the incidence of upper urinary tract disease varies according to risk group based on primary superficial bladder tumor classification. MATERIALS AND METHODS: We studied disease evolution in a cohort of 1,529 patients with a primary superficial bladder tumor. To determine the prognostic factors of upper urinary tract cancer we performed multivariate analysis using Cox regression. Independent variables were grade, T stage, multiplicity, tumor size, carcinoma in situ association, previous or synchronous upper urinary tract tumor and intravesical instillation. We also performed the chi-square test and Kaplan-Meier survival analysis to assess the variable incidence of upper urinary tract tumors according to primary superficial bladder tumor risk group classification. RESULTS: The incidence of upper urinary tract cancer was 2.6%. The only factor prognostic for an upper urinary tract tumor was multiplicity (relative risk 2.7, 95% confidence interval [CI] 1.06 to 6.84). All patients with an upper urinary tract tumor had a previously recurrent primary superficial bladder tumor. In the low, intermediate and high risk groups the incidence of upper urinary tract cancer was 0.6% (relative risk 1), 1.8% (relative risk 3.1, 95% CI 0.4 to 23.9) and 4.1% (relative risk 8.3, 95% CI 1.1 to 61.6), respectively (chi-square and log rank tests p = 0.007 and p <0.05, respectively). CONCLUSIONS: A higher risk of upper urinary tract cancer must be expected in cases of multiple primary superficial bladder tumors. This finding supports the multicentricity theory of transitional cell carcinoma. Primary superficial bladder tumor classification by risk group is also useful for predicting the various risks of metachronous upper urinary tract cancer.

Primary superficial bladder cancer risk groups according to progression, mortality and recurrence.

PURPOSE: We identified risk groups in primary superficial bladder cancer according to progression, mortality and recurrence rates. MATERIALS AND METHODS: The prognostic factors of progression, mortality and recurrence were identified by multivariate analysis in a cohort of 1,529 patients with primary superficial bladder cancer. Risk groups were designed by combining the relative risk of these prognostic factors. We performed survival analysis of progression, tumor mortality and recurrence by risk group using the Kaplan-Meier method. Relative risk in each group was calculated by Cox regression. We present timetables of progression, mortality and recurrence by risk group. RESULTS: Risk groups were classified as low-grade 1 stage Ta disease and a single grade 1 stage T1 tumor, intermediate-multiple grade 1 stage T1 tumors, grade 2 stage Ta disease and a single grade 2 stage T1 tumor, and high-multiple grade 2 stage T1 tumors, grade 3 stages Ta and T1 disease, and any stage disease associated with carcinoma in situ. Survival analysis of progression, mortality and recurrence revealed a statistically significant difference among the 3 risk groups. The rates of recurrence, progression and mortality were 37%, 0% and 0% in the low, 45%, 1.8% and 0.73% in the intermediate, and 54%, 15% and 9.5% in the high risk group, respectively. The relative risks of recurrence, progression and mortality in the low versus the intermediate and high risk groups were 1.37, 2.84 and 1, and 1.87, 24.76 and 14.69, respectively. CONCLUSIONS: Risk group classification based on prognostic factors defines progression, mortality and recurrence rates in primary superficial bladder cancer. It may be useful for designing treatment and followup strategies.

Tumores vesicales superficiales iniciales: nuestra experiencia. Nuestro criterio / Superficial bladder tuomrs. Our experience, our approach

OBJETIVOS: Evaluación de una serie homogénea de tumores vesicales superficiales iniciales (T.V.S.I.).Utilidad de las biopsias randomizadas (BMN). Estudio de factores y grupos de riesgo y basado en ello establecer propuestas terapéuticas y de seguimiento. MATERIAL Y MÉTODOS: Estudio de 1.529 T.V.S.I. sometidos a RTU y BMN, seguidos una media de 4,2 años. Tratamiento estadístico: análisis multivariante mediante la regresión de Cox y según curvas da Kaplan-Meier. RESULTADOS: Entre las características tumorales, destacan el alto porcentaje de tumores únicos (65 por ciento), menores de 1,5 cm (45 por ciento), de alto grado (G3: 26 por ciento) y estadio (T1: 64 por ciento). La BMN permitió demostrar Cis asociado en 284 c. (19 por ciento). Los principales factores de riesgo para recurrencia fueron la multiplicidad, el tamaño > 3 cm y asociación a Cis. El principal riesgo de progresión fue el grado 3 (OR 19,9). Este y la asociación a Cis aumentan el riesgo de mortalidad. Basándonos en estos datos hemos agrupado los tumores en tres grupos de bajo, medio y alto riesgo y según ellos hemos establecido una propuesta de tratamiento y seguimiento. CONCLUSIONES: El estudio multivariante de una cohorte homogénea de 1.529 tumores vesicales superficiales iniciales, nos ha permitido agrupar los tumores según riesgo y establecer propuestas terapéuticas y de seguimiento (AU)

Multivariate analysis of the prognostic factors of primary superficial bladder cancer.

PURPOSE: We evaluate the prognostic factors of recurrence, progression and disease specific mortality in patients with primary superficial Ta and T1 transitional cell carcinoma of the bladder. MATERIALS AND METHODS: We studied a cohort of 1,529 patients with primary superficial transitional cell carcinoma of the bladder treated with transurethral resection and random bladder biopsies. Mean followup was 4.2 years. Statistical analysis was performed using the Kaplan-Meier method and multivariate analysis was done with the Cox proportional hazards model with stepwise forward selection. All p values were 2-sided, with odds ratios and 95% confidence intervals. RESULTS: Multiple tumors (odds ratio 2), tumor greater than 3 cm. (1.65) and carcinoma in situ (1.6) increased, whereas intravesical bacillus Calmette-Guerin (BCG) instillations (0.39) decreased the risk of recurrence. Grade 3 disease (odds ratio 19.9), multiple tumors (1.9), tumor greater than 3 cm. (1.7) and carcinoma in situ (2.1) increased, whereas BCG (0.3) decreased the risk of progression. Grade 3 disease (odds ratio 14) and carcinoma in situ (odds ratio 3) increased the risk of disease specific mortality. CONCLUSIONS: Neither tumor stage nor dysplasia influenced tumor evolution. Multiple tumors, tumor greater than 3 cm. and intravesical BCG instillations were risk factors of recurrence and progression. Carcinoma in situ influenced recurrence, progression and disease specific mortality. Finally, the main predictor of progression and mortality was grade 3 disease.

[Prognostic factors and predictive tables of non-localized prostate cancer that exclude therapy by radical prostatectomy]. / Factores pronosticos y tablas predictivas del cáncer de prostata no localizado que excluirían la realización de la prostatectomía radical.

OBJECTIVE: To know the predictive factors of the no localized prostatic cancer (NLPC) with the intention of improving the indications of the radical prostatectomy. METHODS: A longitudinal, observational, analytic and retrospective study is made with our first 216 radical prostatectomies. A multivariate analysis by logistic regression has been made. A predictive evacuation with the odds ratio of the risc factors, a ROC curve and predictive tables of the NLPC are obtained. RESULTS: Clinical stage, PSA and Gleason are predictive factors of the NLPC. The predictive evacuation with a cut point of probability p = 0.5 has a specificity of 81%, a sensibility of 70% and global diagnostic capacity of 75%. NLCP odds ratio are: Gleason 5,6,7/Gleason 2,3,4 = 2.6, Gleason 8,9,10/Gleason 5,6,7 = 3, Gleason 8,9,10/Gleason 2,3,4 = 7.6, T2/T1 = 2, T3/T2 = 5, T3/T1 = 10 and PSA = 1. After the study of the predictive tables it can be concluded that T3, Gleason > = 8 and PSA > = 30 have a very high NLPC probability. CONCLUSIONS: PSA, Gleason and clinical stage are NLPC predictive factors. Predictive tables to know the NLPC probability by these 3 factors are available.

Incidence of tumoural pathology in horseshoe kidneys.

OBJECTIVES: To know the incidence of tumoural pathology among our cases of horseshoe kidney (HK), a congenital anomaly occurring in 0.25% of the population, as well as their prognostic factors and follow-up. METHODS: A total of 82 patients admitted at our Centre between 1967 and 1996 with an HK diagnosis were retrospectively reviewed. We have collected a total of 10 cases of HK tumours. We analyse the clinical, diagnostic, surgical and evolutionary peculiarities of the different HK tumour aetiologies, as compared with those described in literature. RESULTS: Our experience is based on 10 patients-5 adenocarcinomas, 4 transitional cell carcinomas and a Wilms' tumour. CONCLUSIONS: We have observed that in the case of transitional cell carcinomas, the diagnosis is generally made at an advanced stage. The prognosis of the tumorous disease depends upon the same prognostic factors as in the case of normal kidneys. Renal adenocarcinoma is the kind of tumour most frequently associated with HKs. Its incidence among the HK cases is not greater than among the normal population. Conservative local treatment criteria for adenocarcinoma should be valid for HKs as well.

[Orthotopic bladder substitution: II. Types and complications]. / Sustitución vesical ortotópica: II. Tipos y complicaciones.

OBJECTIVE: In the last two decades, attention has been focused on the design of continent urinary diversion and orthotopic neobladder in an attempt to find the ideal bladder substitute. The more commonly utilized techniques of orthotopic bladder replacement are described and the urodynamic aspects and complications are analyzed. METHODS: The series of Studer, Hautmann, Kock, Pagano, Thuroff (Mainz Pouch) and Goldwasser and the relevant literature on this subject were reviewed. RESULTS/CONCLUSION: To date, similar functional results have been achieved by the different techniques of bladder substitution, although different intestinal segments are utilized. A longer follow-up is warranted to determine which is the ideal technique of bladder substitution.

[Orthotopic bladder replacement: II. Functional results and complications in patients with Studer-type ileal neobladder]. / Sustitución vesical ortotópica: III. Resultados funcionales y complicaciones en los pacientes con neovejiga ileal tipo Studer.

OBJECTIVE: Since 1988, 100 Studer ileal low pressure urinary reservoirs have been performed at our institution. The functional results and the complications observed in these patients are presented. METHODS: Patients submitted to radical cystectomy and lower urinary tract reconstruction with the Studer technique from 1988 to 1994 were retrospectively studied. All patients were males, their mean age was 60 years (37-75) and the mean follow-up was 18 months (6-72). The isoperistaltic ileal segment as antireflux mechanism was utilized in 97 cases and intussusception of the ileal segment to which the ureters were anastomosed in 3 cases. Reinsertion of the ureter was done using the Wallace technique in 90 cases and by direct fixation according to a personal technique (H.V.) in 10 cases. Anastomosis of the neobladder and the urethra was done with the end of the second suture of the orthotopic reservoir. The neurovascular bands were preserved in 21 patients less than 60 years old with tumor stage T2-T3a, according to the technique described by Walsh and Mostwin (1984). RESULTS: One patient died early postoperatively from sepsis. The early complications included urinoma (4%), urinary fistula (3%), intestinal fistula (2%), pulmonary complications (4%), pelvic hematoma (1%) and intestinal obstruction (3%). Only 4 of these patients required surgical resolution of the complication. The late complications included stricture of neobladder-urethra anastomosis (6%), lithiasis in neobladder (4%), ureteroileal stricture (8%), 5 renal units were lost, chronic urinary retention (5%), symptomatic metabolic acidosis (1%) and urinary infection (14%). Thirteen of these patients with late complications required surgery. At 6 months' minimum follow-up, 90% of the patients were continent during the day and 60% during the night. Overall, 36% of the patients recovered erection postoperatively; 76% of the patients with preserved neurovascular bands recovered erection. Forty-four percent of the patients claimed they had a satisfactory sexual activity postoperatively. CONCLUSION: The Studer neobladder permits voiding through the urethra, preservation of the upper urinary tract, the urinary infection rate is acceptable, the complication rate is low and it offers patients continence rates that allow them to have a good quality of life.

[Orthotopic bladder replacement: I. Physiopathology of orthotopic bladder replacement with intestine]. / Sustitución vesical ortotópica: I. Fisiopatología de la sustitución vesical ortotópica con intestino.

OBJECTIVE: To analyze the physiopathological principles of utilizing the bowel for orthotopic bladder substitution and their effects on metabolism, function and continence. METHODS: The world literature is reviewed and our experience of 100 cases is described in the third part of this study. RESULTS/CONCLUSION: To reduce the metabolic changes, utilization of colonic or ileal segments with a maximum length of about 40 cm is advocated. This length of detubulized intestinal segment permits creating an ample, low pressure reservoir with an antireflux mechanism. The precise incidence of neoplastic degeneration of the ileal and colonic reservoirs is not known, but appears to be lower for the ileal neobladder.