Efficacy of Injection of Freshly Collected Autologous Adipose Tissue Into Complex Cryptoglandular Anal Fistulas.

BACKGROUND: Treatment of cryptoglandular anal fistulas with injection of autologous or allogenic adipose tissue-derived mesenchymal stem cells has shown promising results. However, allogenic adipose tissue-derived mesenchymal stem cells are expensive and use of autologous adipose tissue-derived mesenchymal stem cells requires preceding liposuction and isolation of stem cells, time for cell culture, and laboratory facilities. Freshly collected autologous adipose tissue may be an easily available and inexpensive alternative. OBJECTIVE: This study aimed to investigate the efficacy of injection with freshly collected autologous adipose tissue into complex cryptoglandular anal fistulas. DESIGN: Prospective cohort study. SETTING: Single tertiary center for treatment of cryptoglandular fistulas in Denmark. PATIENTS: This study included 77 patients with complex cryptoglandular anal fistulas. INTERVENTIONS: The intervention included injections of freshly collected autologous adipose tissue. Patients not achieving healing after 8 to 12 weeks were offered a second injection. MAIN OUTCOME MEASURES: Primary outcome was fistula healing defined as no symptoms of discharge and no visible external and palpable internal opening by anorectal digital examination at clinical evaluation 6 months after final treatment. Secondary end points were combined clinical and MRI fistula healing, reduced fistula secretion and anal discomfort, and complications to the treatment. RESULTS: Thirty-nine patients (51%) achieved the primary outcome of fistula healing 6 months after their final treatment. Nine patients (12%) experienced reduced secretion and decreased anal discomfort. Thirty-seven patients (48%) achieved combined clinical and MRI fistula healing. Treatment was well tolerated; 5 patients (4%) experienced serious adverse events (infection or bleeding) requiring surgical intervention. LIMITATIONS: No control group was included. CONCLUSION: Injection of freshly collected autologous adipose tissue is a safe treatment of complex cryptoglandular anal fistulas and may be an easily accessible inexpensive alternative to cultured autologous and allogenic adipose tissue-derived mesenchymal stem cells. See Video Abstract at http://links.lww.com/DCR/C45 . EFICACIA DE LA INYECCIN DE TEJIDO ADIPOSO AUTLOGO RECIN RECOLECTADO EN FSTULAS ANALES CRIPTOGLANDULARES COMPLEJAS: ANTECEDENTES:El tratamiento de las fístulas anales criptoglandulares con inyección de células madre mesenquimales derivadas de tejido adiposo autólogo o alogénico ha mostrado resultados prometedores. Sin embargo, las células madre mesenquimales derivadas de tejido adiposo alogénicas son costosas y el uso de células madre mesenquimales derivadas de tejido adiposo autólogas requiere una liposucción previa y el aislamiento de las células madre, tiempo para el cultivo celular e instalaciones de laboratorio. El tejido adiposo autólogo recién recolectado puede ser una alternativa económica y de fácil acceso.OBJETIVO:Investigar la eficacia de la inyección con tejido adiposo autólogo recién recolectado en fístulas anales criptoglandulares complejas.DISEÑO:Estudio de cohorte prospectivo.ESCENARIO:Centro terciario para el tratamiento de fístulas criptoglandulares en Dinamarca.PACIENTES:Setenta y siete pacientes con fístulas anales criptoglandulares complejas.INTERVENCIONES:Inyecciones de tejido adiposo autólogo recién recolectado. A los pacientes que no lograron la curación después de 8 a 12 semanas se les ofreció una segunda inyección.MEDIDAS DE RESULTADO PRINCIPALES:El resultado primario fue la cicatrización de la fístula definida como ausencia de síntomas de secreción, apertura externa visible e interna palpable mediante examen digital anorrectal en la evaluación clínica 6 meses después del tratamiento final. Los resultados secundarios fueron la combinación clínica y de curación en la resonancia magnética, la reducción de la secreción de la fístula y las molestias anales, y las complicaciones del tratamiento.RESULTADOS:Treinta y nueve pacientes (51%) lograron el resultado primario de curación de la fístula 6 meses después de su tratamiento final. Nueve pacientes (12%) experimentaron una reducción de la secreción y una disminución de las molestias anales. Treinta y siete pacientes (48%) lograron la curación combinada de la fístula clínica y en la resonancia magnética. El tratamiento fue bien tolerado; 5 pacientes (4%) experimentaron eventos adversos graves (infección o sangrado) que requirieron intervención quirúrgica.LIMITACIONES:No se incluyó ningún grupo de control.CONCLUSIÓN:La inyección de tejido adiposo autólogo recién recolectado es un tratamiento seguro de las fístulas anales criptoglandulares complejas y puede ser una alternativa económica de fácil acceso a las células madre mesenquimales derivadas de tejido adiposo autólogo y alogénico cultivadas. Consulte Video Resumen en http://links.lww.com/DCR/Cxx . (Traducción-Dr. Felipe Bellolio ).

Anorectal function and radiation dose to pelvic floor muscles after primary treatment for anal cancer.

BACKGROUND AND PURPOSE: Chemoradiotherapy is the primary treatment for localized anal cancer (AC). This treatment offers high rates of cure and organ preservation. Radiotherapy can however, result in late persisting anorectal dysfunction, with anal incontinence, urge and clustering. Correlation of radiation doses to pelvic substructures and functional outcome is not well described in AC. We correlated patient reported anorectal function to radiation doses to sphincters and pelvic floor muscles. MATERIALS AND METHODS: Patients treated with (chemo)radiotherapy for AC were asked to fill out LARS (lower anterior resection syndrome) questionnaires at follow-up. We compared patients with no LARS (score 0-19) and patients with major LARS (30-42) as well as individual LARS questions to specific radiation doses to sphincters, levators and puborectal muscles. RESULTS: Thirty-six patients were included, 18 with no LARS and 18 with major LARS. Gender, age, TNM stage, PTV, chemotherapy, time to LARS score (mean 660 and 749 days) were comparable between the two groups. LARS symptoms, occurring at least once per week, were reported between 25-55.7%, and poorer LARS outcome was associated to worse quality of life. Dose to sphincter complex (Dmean, V50Gy and D90%) differed significantly between patients with no and major LARS (p = 0.048, 0.035 and 0.02 respectively). Further, D90% to the sphincter complex was significantly higher in patients who had accidental leakage of stool, (p = 0.044). CONCLUSION: Patients treated with (chemo)radiotherapy for AC show high frequency of patient reported anorectal dysfunction. Specific doses to the sphincters could become a useful predictor of anal incontinence and major LARS and incorporated into future radiotherapy planning studies.

Independent Validation of a Diagnostic Noninvasive 3-MicroRNA Ratio Model (uCaP) for Prostate Cancer in Cell-Free Urine.

BACKGROUND: Detection of prostate cancer (PC) based on serum prostate-specific antigen (PSA) testing leads to many unnecessary prostate biopsies, overdiagnosis, and overtreatment of clinically insignificant tumors. Thus, novel and more accurate molecular biomarkers are required. METHODS: Using reverse transcription quantitative PCR, we measured the concentrations of 45 preselected microRNAs (miRNAs) in extracellular vesicle-enriched cell-free urine samples from 4 independent patient cohorts from Spain and Denmark, including 758 patients with clinically localized PC, 289 noncancer controls with benign prostatic hyperplasia (BPH), and 233 patients undergoing initial transrectal ultrasound (TRUS)-guided prostate biopsy owing to PC suspicion (101 with benign and 132 with malignant outcome). Diagnostic potential was assessed by ROC and decision curve analysis. RESULTS: We identified and successfully validated 8 upregulated and 21 downregulated miRNAs in urine from PC patients. Furthermore, we validated a previously identified 3-miRNA diagnostic ratio model, uCaP (miR-222-3p*miR-24-3p/miR-30c-5p). High uCaP scores were distinctive of PC in urine samples from BPH vs PC patients in 3 independent cohorts [area under the curve (AUC) = 0.84, 0.71, 0.72]. Additionally, uCaP predicted TRUS biopsy results with greater accuracy than PSA (AUC uCaP = 0.644; AUC PSA = 0.527) for patients within the diagnostic gray zone (PSA ≤ 10 ng/mL). CONCLUSIONS: We successfully validated a urine-based diagnostic 3-miRNA signature for PC (uCaP) in 3 independent patient cohorts from 2 countries. In the future, the simple and noninvasive uCaP test may be used to help more accurately select patients for prostate biopsy. Prospective clinical validation is warranted.

Quantitative Tumor Perfusion Imaging with 82Rb PET/CT in Prostate Cancer: Analytic and Clinical Validation.

The aim of this work was to evaluate 82Rb PET/CT as a diagnostic tool for quantitative tumor blood flow (TBF) imaging in prostate cancer (PCa). Study 1 was performed to evaluate 82Rb as a marker of TBF, using 15O-H2O PET as a reference method. Study 2 investigated the ability of 82Rb uptake measurements to differentiate between PCa and normal prostate. Methods: Study 1: 9 PCa patients scheduled for radical prostatectomy were included. Prostate multiparametric MRI and both cardiac and pelvic 15O-H2O PET and 82Rb PET were performed. PET findings were compared with postprostatectomy Gleason grade group (GGG). Study 2: 15 primary high-risk PCa patients and 12 controls without known prostate disease were included in a clinical drug trial (EudraCT 2016-003185-26). 68Ga-prostate-specific membrane antigen PET/CT scans of PCa patients were available. Pelvic 82Rb PET was performed. Results: Study 1: both 82Rb K1 and 82Rb SUVs correlated strongly with 15O-H2O TBF (ρ = 0.95, P < 0.001, and ρ = 0.77, P = 0.015, respectively). 82Rb SUV and K1 were linearly correlated (r = 0.92, P = 0.001). 82Rb SUV correlated with postprostatectomy GGG (ρ = 0.70, P = 0.03). Study 2: 82Rb SUV in PCa (3.19 ± 0.48) was significantly higher than prostate 82Rb SUV in healthy controls (1.68 ± 0.37) (P < 0.001), with no overlap between groups. Conclusion: Study 1 shows that 82Rb PET/CT can be used for TBF quantification and that TBF can be estimated by simple SUV and suggests that 82Rb SUV is associated with postprostatectomy GGG and, hence, cancer aggressiveness. Study 2 shows that 82Rb uptake is significantly higher in PCa than in normal prostate tissue with no overlap between cohorts, confirming the primary hypothesis of the clinical trial. Consequently, 82Rb PET/CT may have potential as a noninvasive tool for evaluation of tumor aggressiveness and monitoring in nonmetastatic PCa.

Hypercortisolism in Newly Diagnosed Type 2 Diabetes: A Prospective Study of 384 Newly Diagnosed Patients.

Cross-sectional studies in small and selected populations report a high prevalence of hypercortisolism in patients with type 2 diabetes (T2D), which could have therapeutic implications, if confirmed. We therefore estimated the prevalence of hypercortisolism in a large and unselected cohort of recently diagnosed T2D patients. Consecutive patients with recently diagnosed T2D first underwent an overnight dexamethasone (1 mg) suppression test (OD). Patients not suppressing serum cortisol ≤50 nmol/l proceeded with a 48-h low dose dexamethasone suppression test (LDDST) and 24-h urinary free cortisol collection (UFC). Patients with elevated cortisol levels according to LDDST and/or UFC underwent imaging guided by plasma ACTH levels, and assessment of bone mineral density. A total of 384 T2D patients (232male/152 females) with a mean age of 60±10 years were included. Eighty-five (22%) patients suppressed incompletely to OD of whom 20 (5%) failed to suppress after LDDST and/or had elevated UFC (=hypercortisolism). Patients with hypercortisolism did not differ as regards age, BMI, HbA1c, T-score or blood pressure, but a higher proportion of them received antihypertensive treatment (100% vs. 64%, p=0.001). Imaging revealed adrenal adenoma(s) in 9 cases and a pituitary macroadenoma in 1 case. We found a 5% prevalence of hypercortisolism in unselected, recently diagnosed T2D, which was not associated with a persuasive cushingoid phenotype. The clinical implications are therefore uncertain.

Non-invasive quantification of tumor blood flow in prostate cancer using 15O-H2O PET/CT.

Tumor blood flow (TBF) measurements in prostate cancer (PCa) provide an integrative index of tumor growth, which could be important for primary diagnosis and therapy response evaluation. 15O-water PET is the non-invasive gold standard but is technically demanding. The aim of this study was to compare the accuracy of three different non-invasive strategies with an invasively measured arterial input function (BSIF): Using image-derived input functions (IDIF) from either 1) a separate heart scan or 2) the pelvic scan or 3) a populations-based input function (PBIF). Nine patients with biopsy-verified PCa scheduled for prostatectomy were included. All patients were characterized with serum levels of PSA (s-PSA), multiparametric magnetic resonance imaging (mpMRI) and post-surgical histopathology Gleason Grade. Dynamic 15O-water was performed of the heart and the pelvic area 15 minutes apart. TBF estimated from both wash-in (K1) and wash-out (k2) constants was calculated using a one-compartmental model. Results: Mean (range) s-PSA was 12 (3-27) ng/mL, Gleason Grade Group was 2.9 (1-5), k2 was 0.44 (0.007-1.2), and K1 was 0.24 (0.07-0.55) mL/mL/min. k2 (BSIF) correlated with s-PSA (r=0.86, P<0.01) and Gleason Grade Group (rho=0.78, P=0.01). BSIF, heart-IDIF and PBIF provided near-identical k2 and K1 (r>0.95, P<0.001) with slopes near unity. The correlations of BSIF and pelvic-IDIF rate constants were good (r>0.95, P<0.001), but individual errors high. In conclusion, non-invasive protocols for 15O-water PET with IDIF or PBIF accurately measures perfusion in prostate cancer and might be useful for evaluation of tumor aggressiveness and treatment response.

Noncontrast-Enhanced Magnetic Resonance Versus Computed Tomography Angiography in Preoperative Evaluation of Potential Living Renal Donors.

RATIONALE AND OBJECTIVES: Living renal donors undergo an extensive examination program. These examinations should be as safe, gentle, and patient friendly as possible. To compare computed tomography angiography (CTA) and an extensive magnetic resonance imaging (MRI) protocol without contrast agents to observations from nephrectomy in living renal donors and to evaluate whether noncontrast-enhanced MRI can replace CTA for vessel assessment in living renal donors. MATERIAL AND METHODS: CTA and MRI results were compared to observations from nephrectomy, which served as the reference standard. Fifty-one potential kidney donors underwent imaging, and 31 donated a kidney. Comparisons in sensitivity, specificity, and accuracy were made with respect to the number of arteries, early branching, and the number of veins. Agreement was assessed using Cohen's kappa. The exact McNemar's test was used to test for statistically significant differences. RESULTS: In the assessment of more than one renal artery, the sensitivity and specificity of MRI and CTA were high and in perfect agreement compared to observations from surgery. The results for both MRI and CTA were as follows: (sensitivity 100%/specificity100%/accuracy 100%/Kappa = 1/P = 1). When comparing the ability to test for early branching we found, MRI: (sensitivity 33%/specificity 100%/accuracy 87%/Kappa = 0.45/P = 1) and CTA: (sensitivity 50%/specificity 100%/accuracy 90%/Kappa = 0.62/P = 1). When used to depict supernumerary veins, we found MRI: (sensitivity60%/specifivity100%/accuracy 93%/Kappa = 0.72/P = 1), whereas CTA showed: (sensitivity 40%/specificity 96%/accuracy 87% Kappa = 0.43/P = 1). CONCLUSIONS: In conclusion, an optimized MRI protocol that includes noncontrast-enhanced magnetic resonance angiography can be substituted for CTA for preoperative assessment of the renal vessels before living donor nephrectomy.

Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up.

BACKGROUND: Progressive resistance training (PRT) is acknowledged to effectively improve muscle strength for people with multiple sclerosis (PwMS), but diverging results exist regarding whether such improvements translates to improved functional capacity, possibly relating to insufficient duration and/or intensity in some previous studies. OBJECTIVE: The purpose of this study was to evaluate potential changes in functional capacity and neuromuscular function after 24 weeks of supervised PRT, and whether improvements are maintained after an additional 24 weeks of self-guided exercise. METHODS: This study was a randomised controlled trial, with a training group and a waitlist group undergoing supervised PRT for 24 weeks initially or after 24 weeks of habitual lifestyle, respectively. Functional capacity, isometric muscle strength of knee extensors and flexors, neural drive and thigh muscle cross-sectional area was measured at baseline, after 24 and 48 weeks. RESULTS: The training group significantly improved neuromuscular function of the knee extensors and flexors, which translated to improvements in functional capacity. Furthermore, the improved functional capacity was maintained after 24 weeks of self-guided physical activity. The waitlist group produced similar patterns of changes after PRT. CONCLUSION: Compelling evidence is provided, that PRT performed over sufficiently long periods, improves functional capacity, likely due to neuromuscular adaptations.

Preoperative planning of renal transplantation: a comparison of non-contrast-enhanced ultrasonography, computed tomography, and magnetic resonance angiography with observations from surgery.

BACKGROUND: Many candidates for kidney transplantation need to undergo vessel examination before the transplantation procedure. PURPOSE: To identify the optimal preoperative modality for the examination of vessel status without the use of contrast agents in kidney transplant candidates. MATERIAL AND METHODS: Fifty-three consecutive patients were examined and 31 patients were transplanted. Ultrasonography (US), non-contrast-enhanced computed tomography (NCCT), and non-contrast-enhanced magnetic resonance angiography (NCMRA) were compared using inspection during kidney transplantation (TX) as a reference standard. The sensitivity and specificity to severe arteriosclerotic changes and the accuracy were calculated. Kappa statistics were used to assess the agreement between TX and the different examination modalities, and McNemar's test was used to test for significant differences. RESULTS: US had higher sensitivity (1.0) and better agreement with observations from surgery (k = 0.89) than both NCCT (sensitivity = 0.60; k = 0.72) and NCMRA (sensitivity = 0.20; k = 0.30). No significant difference was found between TX and US (P = 0.3173) or TX and NCCT (P = 0.1573), but there was a significant difference between TX and NCMRA (P = 0.0455). US was inconclusive in 20% of cases, and the internal iliac artery could not be visualized in 69% of cases. CONCLUSION: Either US or NCCT can be used as the preferred preoperative imaging modality to examine vessel status before kidney transplantation, but a combination of the two is preferable. NCMRA should not be used as the sole imaging modality for preoperative imaging before kidney transplantation because of its low sensitivity in detecting severe arteriosclerotic disease without the presence of stenosis.