Ignacio Pascual

Chemoradiotherapy for muscle invading bladder carcinoma. Final report of a single institutional organ-sparing program

PURPOSE Chemoradiotherapy is becoming an alternative to radical cystectomy among patients with muscle invading bladder cancer. We began a prospective study in 1988 to determine the possibilities of conservative treatment and aiming to improve the results obtained by cystectomy alone in invasive bladder cancer. A combination of methotrexate, vinblastine, adriamycin, and cisplatin (M-VAC), followed by radiotherapy and concomitant cisplatin was used. METHODS Fifty patients with good performance status and with stages T2 to T4 operable untreated invasive bladder cancer were entered in the study. Treatment protocol was as follows: (i) cytoreductive transurethral resection; (ii) two cycles of M-VAC chemotherapy; (iii) radiotherapy, 45 Gy on pelvic volume and, at the same time, 20 mg/m(2) cisplatin on days 1 to 5. Cystoscopic evaluation: if there was a complete response, radiotherapy was completed up to 65 Gy; if there was not a complete response, a cystectomy was performed. Median follow-up of the series was 73 months (18-180 m). RESULTS Tumor response was as follows: 34 complete responses (68%), 9 partial responses (18%), and 7 nonresponses (14%) were observed. The 5-year overall survival and local control were 48% and 47%, respectively. For the complete responder patient, 5-year survival and local control were 65% and 70%, respectively. Severe toxicity was uncommon. The most frequent were leucopenia and cystitis. No treatment-related deaths occurred with either treatment protocol. CONCLUSIONS Conservative combination treatment may be an acceptable alternative to immediate cystectomy in selected patients with bladder cancer, although a randomized clinical trial would be required to produce definitive results.

Promising Prospects for 44Sc-/47Sc-Based Theragnostics: Application of 47Sc for Radionuclide Tumor Therapy in Mice

In recent years, 47Sc has attracted attention because of its favorable decay characteristics (half-life, 3.35 d; average energy, 162 keV; Eγ, 159 keV) for therapeutic application and for SPECT imaging. The aim of the present study was to investigate the suitability of 47Sc for radionuclide therapy in a preclinical setting. For this purpose a novel DOTA-folate conjugate (cm10) with an albumin-binding entity was used. Methods: 47Sc was produced via the 46Ca(n,γ)47Ca→β−47Sc nuclear reaction at the high-flux reactor at the Institut Laue-Langevin. Separation of the 47Sc from the target material was performed by a semi-automated process using extraction chromatography and cation exchange chromatography. 47Sc-labeled cm10 was tested on folate receptor–positive KB tumor cells in vitro. Biodistribution and SPECT imaging experiments were performed in KB tumor–bearing mice. Radionuclide therapy was conducted with two groups of mice, which received either 47Sc-cm10 (10 MBq) or only saline. Tumor growth and survival time were compared between the two groups of mice. Results: Irradiation of 46Ca resulted in approximately 1.8 GBq of 47Ca, which subsequently decayed to 47Sc. Separation of 47Sc from 47Ca was obtained with 80% yield in only 10 min. The 47Sc was then available in a small volume (∼500 μL) of an ammonium acetate/HCl (pH 4.5) solution suitable for direct radiolabeling. 47Sc-cm10 was prepared with a radiochemical yield of more than 96% at a specific activity of up to 13 MBq/nmol. In vitro 47Sc-cm10 showed folate receptor–specific binding and uptake into KB tumor cells. In vivo SPECT/CT images allowed the visualization of accumulated radioactivity in KB tumors and in the kidneys. The therapy study showed a significantly delayed tumor growth in mice, which received 47Sc-cm10 (10 MBq, 10 Gy) resulting in a more than 50% increase in survival time, compared with untreated control mice. Conclusion: With this study, we demonstrated the suitability of using 47Sc for therapeutic purposes. On the basis of our recent results obtained with 44Sc-folate, the present work confirms the applicability of 44Sc/47Sc as an excellent matched pair of nuclides for PET imaging and radionuclide therapy.

External-beam radiation therapy and high-dose rate brachytherapy combined with long-term androgen deprivation therapy in high and very high prostate cancer: preliminary data on clinical outcome.

PURPOSE To determine the feasibility of combined long-term androgen deprivation therapy (ADT) and dose escalation with high-dose-rate (HDR) brachytherapy. METHODS AND MATERIALS Between 2001 and 2007, 200 patients with high-risk prostate cancer (32.5%) or very high-risk prostate cancer (67.5%) were prospectively enrolled in this Phase II trial. Tumor characteristics included a median pretreatment prostate-specific antigen of 15.2 ng/mL, a clinical stage of T2c, and a Gleason score of 7. Treatment consisted of 54 Gy of external irradiation (three-dimensional conformal radiotherapy [3DCRT]) followed by 19 Gy of HDR brachytherapy in four twice-daily treatments. ADT started 0-3 months before 3DCRT and continued for 2 years. RESULTS One hundred and ninety patients (95%) received 2 years of ADT. After a median follow-up of 3.7 years (range, 2-9), late Grade ≥2 urinary toxicity was observed in 18% of the patients and Grade ≥3 was observed in 5%. Prior transurethral resection of the prostate (p = 0.013) and bladder D(50) ≥1.19 Gy (p = 0.014) were associated with increased Grade ≥2 urinary complications; age ≥70 (p = 0.05) was associated with Grade ≥3 urinary complications. Late Grade ≥2 gastrointestinal toxicity was observed in 9% of the patients and Grade ≥3 in 1.5%. CTV size ≥35.8 cc (p = 0.007) and D(100) ≥3.05 Gy (p = 0.01) were significant for increased Grade ≥2 complications. The 5-year and 9-year biochemical relapse-free survival (nadir + 2) rates were 85.1% and 75.7%, respectively. Patients with Gleason score of 7-10 had a decreased biochemical relapse-free survival (p = 0.007). CONCLUSIONS Intermediate-term results at the 5-year time point indicate a favorable outcome without an increase in the rate of late complications.

Recipient and donor risk factors for surgical complications following kidney transplantation

Abstract Objective. The aim of this study was to evaluate recipient and donor risk factors that are related to surgical complications after renal transplantation. Material and methods. In total, 419 kidney transplantations were analysed with regard to the influence of recipient and donor risk factors on the main postoperative surgical complications. Results. The mean follow-up for the entire group was 72.8 months (± 54.2 SD). Vascular complications were independently associated with donor age; and urological complications with recipient age >65 years and cyclosporine rather than tacrolimus therapy. Wound complications were independently associated with recipient age, preoperative dialysis time, recipient body mass index (BMI) and cyclosporine rather than tacrolimus therapy. Collections were independently associated with retransplantation, type 2 diabetes mellitus and wound complications. Overall surgical complications were associated with donor age and delayed graft function. In terms of severity, grade I complications were independently associated with recipient age and surgical revision, grade II with recipient age >50 years, grade III with recipient BMI, and grade IV with donor age. Conclusions. Recipient characteristics are the primary determinants of wound, urological and minor (Clavien grades I, II and III) complications; however, graft or donor characteristics are the primary risk factors for vascular, overall and major (Clavien grade IV) surgical complications.

Existe un intervalo de tiempo de isquemia fría seguro para el injerto renal

OBJECTIVE It is aimed to characterize the true relationship of the cold ischemia time (CIT) with graft survival and with the principal post-transplantation events. MATERIAL AND METHODS We analyzed 378 kidney transplants, studying the relationship of the CIT with graft survival using a univariate analysis according to the COX model and seeking the optimum cutoff according to the Kaplan-Meier method and log-rank test. The relationship between CIT and the principal events of the post-transplant was studied using the binary logistic regression. RESULTS The mean follow-up of all the group was 77.8 months (± 51 SD) and the mean CIT was 14.8 hours (± 5.1 SD). The univariate analysis revealed that the CIT was not related with the graft survival as a continuous variable (OR=1.04; 95% CI: 0.9-1.08; p>0.05). On establishing the cutoff at 18 hours, we found differences in the actuarial survival. Survival at 5 years was 91% with CIT < 18 h versus 84% with CIT >18 h. Each hour of cold ischemia increased risk of delay in the graft function by 10% (OR=1.1; 95% CI: 1.05-1.15; p<0.001) and also conditioned a greater incidence of acute rejection (41.5% vs. 55.3%; p=0.02) and less time to the first rejection episode (72.6 days±137 vs. 272.2 days±614.8; p=0.023) after 18 hours. The CIT did not seem to be related (p<0.05) with the rest of the post-transplantation events, such as surgical complications or hospital admissions. CONCLUSIONS In our experience, cold ischemia under 18 hours does not seem to negatively affect graft survival.

New Immunosuppressive Therapies and Surgical Complications After Renal Transplantation

BACKGROUND To analyze the association between the principal immunosuppressive drugs (mycophenolate mofetil, calcineurin inhibitors and mammalian target of rapamycin [mTOR] inhibitors) used in the routine management of kidney transplant patients and the development of postoperative surgical complications. MATERIALS AND METHODS We analyzed 415 kidney transplants, studying the influence of various immunosuppressive regimens on the main postoperative surgical complications. RESULTS The mean follow-up for the entire group was 72.8 months (± 54.2 SD). Patients treated with myeophonolate mofetil (MMF) and cyclosporine (n = 121) experienced a higher frequency of wound eventration odds ratio [OR], 5.2; 95% confidence interval [CI], 1.2-23.5; P = .03) compared with azathioprine and cyclosporine (n = 71). Compared with transplant recipients treated with tacrolimus and MMF (n = 181), transplant recipients treated with cyclosporine and MMF (n = 121) had a significantly greater frequency of wound eventration (OR, 3.7; 95% CI, 1.5-9.5; P = .005), urologic (OR, 2; 95% CI; 1.02-3.9; P = .04), wound (OR; 2.2; 95% CI; 1.07-4.6; P = .03), late (OR, 1.7; 95% CI; 1.01-3.03; P = .04), and Clavien grade 3 surgical complications (OR; 1.9; 95% CI, 1.1-3.37; P = .01). Patients treated with mTOR inhibitors (n = 26) had higher rates of lymphocele (OR, 3.6; 95% CI, (1.1-11.4; P = .002) compared with those who received tacrolimus (n = 197). CONCLUSIONS New immunosuppressive drugs have improved short-term functional results; however, in some cases they seem to increase surgical complications rates.

Asymptomatic Schistosoma haematobium Infection in a Traveler With Negative Urine Microscopy and Late Seroconversion Presumably Linked to Artemisinin

We describe a Schistosoma haematobium infection with asymptomatic eosinophilia, persistently negative urine microscopy, and late seroconversion (7.5 months) in a traveler returning from Mali. After initial negative parasitological tests, travel history led to diagnostic cystoscopy, allowing final diagnosis with urine microscopy after the bladder biopsy. The patient was successfully treated with praziquantel. Difficulties in making the diagnosis of schistosomiasis in asymptomatic returning travelers are discussed; we propose a trial treatment in these cases.

Index lesion characterization by 11C‐Choline PET/CT and Apparent Diffusion Coefficient parameters at 3 Tesla MRI in primary prostate carcinoma

Index lesion characterization is important in the evaluation of primary prostate carcinoma (PPC). The aim of this study was to analyze the contribution of 11C‐Choline PET/CT and the Apparent Diffusion Coefficient maps (ADC) in detecting the Index Lesion and clinically significant tumors in PPC.

Survival analysis of patients with biochemical relapse after radical prostatectomy treated with androgen deprivation: Castration-resistance influential factors

INTRODUCTION We evaluate the prognosis of patients with biochemical recurrence (BCR) treated with androgen deprivation therapy (ADT) and to determine the influential factors to castration resistance (CR) and death. METHODS From a series of 1310 patients with T1-T2 prostate cancer treated with radical prostatectomy between 1989 and 2012, 371 had BCR. Patients with lymph node involvement were excluded. We analyzed only the 159 treated with salvage ADT. At the end of the study, 77 (48%) had developed CR. RESULTS The median follow-up to CR was 9.2 years. The CR-resistant free survival (RFS) was 76 ± 3%, 62 ± 3% and 43 ± 9% in 5, 10 and 15 years, respectively. The RFS median time was 14 years. In the multivariate study, the prostate-specific antigen (PSA) doubling time (PSA-DT) was <6 months (p = 0.01) (hazard ratio [HR] 3; 95% confidence interval [CI] 1.4-6.8, p = 0.007); seminal vesicle involvement (HR 3.1; 95% CI 1.5-6.2, p = 0.01) and PSA velocity in ng/mL/year (HR 1.3; 95% CI 1.1-1.5, p = 0.002) with better cut-off points of 0.84 ng/mL/year (p = 0.04) (HR 4; 95% CI 1.7-9.4, p = 0.001) were influential variables. Specific survival (SS) at 5, 10 and 15 years since surgery was 96 ± 1, 85 ± 2 and 76 ± 4, respectively. The time of CR to death was 30 ± 6% at 5 years, with the median at 3.2 years. In the multivariate only Ki 67 (HR 1.04; 95% CI 1.005-1.08, p = 0.02) had an independent influence. CONCLUSIONS In BCR patients treated with ADT, the median to CR was 14 years. PSA-DT <6 months, PSA velocity (ng/mL/year) and seminal vesicle involvement were influential variables. From the CR, the median time to death was 3.2 years. Ki-67 marker was an independent influence.

Dose escalation with external beam radiation therapy and high-dose-rate brachytherapy combined with long-term androgen deprivation therapy in high and very high risk prostate cancer: Comparison of two consecutive high-dose-rate schemes

PURPOSE To compare rectal toxicity, urinary toxicity, and nadir+2 PSA relapse-free survival (bRFS) in two consecutive Phase II protocols of high-dose-rate (HDR) brachytherapy used at the authors institution from 2001 to 2012. METHODS AND MATERIALS Patients with National Comprehensive Cancer Network high risk and very high risk prostate cancer enrolled in studies HDR4 (2001-2007, n = 183) and HDR2 (2007-2012, n = 56) were analyzed. Patients received minipelvis external beam radiation therapy/intensity-modulated external radiotherapy to 54 Gy and 2 years of androgen blockade along with HDR brachytherapy. HDR4 protocol consisted of four 4.75 Gy fractions delivered in 48 hours; the HDR2 protocol delivered two 9.5 Gy fractions in 24 hours. Average 2-Gy equivalent dose (α/β = 1.2) prostate D90 doses for the HDR4 and HDR2 groups were 89.8 Gy and 110.5 Gy, respectively (p = 0.0001). Both groups were well balanced regarding risk factors. Prior transurethral resection of the prostate was more frequent in the HDR2 group (p = 0.001). RESULTS After a median followup of 7.4 years (range, 2-11.2), there was no difference in adverse grade ≥ 2 rectal events (HDR4 = 10.4% vs. HDR2 = 12.5%; p = ns) or grade ≥3 (HDR4 = 2.2% vs. HDR2 = 3.6%; p = ns). No differences in urinary grade ≥2 adverse events (HDR4 = 23% vs. HDR2 = 26.8%; p = ns) or grade ≥3 (HDR4 = 7.7% vs. HDR2 = 8.9%; p = ns) were detected. The 7-year bRFS for HDR4 and HDR2 protocols was 88.7% and 87.8%, respectively (p = ns). CONCLUSIONS HDR4 and HDR2 protocols produce similar results in terms of toxicity and bRFS at the intermediate time point of 7 years.