Image-guided high-dose-rate brachytherapy for rectal cancer: technical note and first clinical experience on an organ-preserving approach.

PURPOSE: As the population ages, the incidence of rectal cancer among elderly patients is rising. Due to the risk of perioperative morbidity and mortality, alternative nonoperative treatment options have been explored in elderly and frail patients who are clinically inoperable or refuse surgery. METHODS: Here we present technical considerations and first clinical experience after treating a cohort of six rectal cancer patients (T1­3, N0­1, M0; UICC stage I-IIIB) with definitive external-beam radiation therapy (EBRT) followed by image-guided, endorectal high-dose-rate brachytherapy (HDR-BT). Patients were treated with 10-13â€¯× 3 Gy EBRT followed by HDR-BT delivering 12-18 Gy in two or three fractions. Tumor response was evaluated using endoscopy and magnetic resonance imaging of the pelvis. RESULTS: Median age was 84 years. All patients completed EBRT and HDR-BT without any high-grade toxicity (> grade 2). One patient experienced rectal bleeding (grade 2) after 10 weeks. Four patients (67%) demonstrated clinical complete response (cCR) or near cCR, there was one partial response, and one residual tumor and hepatic metastasis 8 weeks after HDR-BT. The median follow-up time for all six patients is 42 weeks (range 8-60 weeks). Sustained cCR without evidence of local regrowth has been achieved in all four patients with initial (n)cCR to date. CONCLUSION: Primary EBRT combined with HDR-BT is feasible and well tolerated with promising response rates in elderly and frail rectal cancer patients. The concept could be an integral part of a highly individualized and selective nonoperative treatment offered to patients who are not suitable for or refuse surgery.

International consensus recommendations on key outcome measures for organ preservation after (chemo)radiotherapy in patients with rectal cancer.

Multimodal treatment strategies for patients with rectal cancer are increasingly including the possibility of organ preservation, through nonoperative management or local excision. Organ preservation strategies can enable patients with a complete response or near-complete clinical responses after radiotherapy with or without concomitant chemotherapy to safely avoid the morbidities associated with radical surgery, and thus to maintain anorectal function and quality of life. However, standardization of the key outcome measures of organ preservation strategies is currently lacking; this includes a lack of consensus of the optimal definitions and selection of primary end points according to the trial phase and design; the optimal time points for response assessment; response-based decision-making; follow-up schedules; use of specific anorectal function tests; and quality of life and patient-reported outcomes. Thus, a consensus statement on outcome measures is necessary to ensure consistency and facilitate more accurate comparisons of data from ongoing and future trials. Here, we have convened an international group of experts with extensive experience in the management of patients with rectal cancer, including organ preservation approaches, and used a Delphi process to establish the first international consensus recommendations for key outcome measures of organ preservation, in an attempt to standardize the reporting of data from both trials and routine practice in this emerging area.

Stop the rot. Enzyme inactivation at brain harvest prevents artifacts: A guide for preservation of the in vivo concentrations of brain constituents.

Post-mortem metabolism is widely recognized to cause rapid and prolonged changes in the concentrations of multiple classes of compounds in brain, that is, they are labile. Post-mortem changes from levels in living brain include components of pathways of metabolism of glucose and energy compounds, amino acids, lipids, signaling molecules, neuropeptides, phosphoproteins, and proteins. Methods that stop enzyme activity at brain harvest were developed almost 50 years ago and have been extensively used in studies of brain functions and diseases. Unfortunately, these methods are not commonly used to harvest brain tissue for mass spectrometry-based metabolomic studies or for imaging mass spectrometry studies (IMS, also called mass spectrometry imaging, MSI, or matrix-assisted laser desorption/ionization-MSI, MALDI-MSI). Instead these studies commonly kill animals, decapitate, dissect out brain and regions of interest if needed, then 'snap' freeze the tissue to stop enzymatic activity after harvest, with post-mortem intervals typically ranging from ~0.5 to 3 min. To increase awareness of the importance of stopping metabolism at harvest and preventing the unnecessary complications of not doing so, this commentary provides examples of labile metabolites and the magnitudes of their post-mortem changes in concentrations during brain harvest. Brain harvest methods that stop metabolism at harvest eliminate post-mortem enzymatic activities and can improve characterization of normal and diseased brain. In addition, metabolomic studies would be improved by reporting absolute units of concentration along with normalized peak areas or fold changes. Then reported values can be evaluated and compared with the extensive neurochemical literature to help prevent reporting of artifactual data.

Human ex vivo lung perfusion: a novel model to study human lung diseases.

Experimental animal models to predict physiological responses to injury and stress in humans have inherent limitations. Therefore, the development of preclinical human models is of paramount importance. Ex vivo lung perfusion (EVLP) has typically been used to recondition donor lungs before transplantation. However, this technique has recently advanced into a model to emulate lung mechanics and physiology during injury. In the present study, we propose that the EVLP of diseased human lungs is a well-suited preclinical model for translational research on chronic lung diseases. Throughout this paper, we demonstrate this technique's feasibility in pulmonary arterial hypertension (PAH), idiopathic pulmonary fibrosis (IPF), emphysema, and non-disease donor lungs not suitable for transplantation. In this study, we aimed to perfuse the lungs for 6 h with the EVLP system. This facilitated a robust and continuous assessment of airway mechanics, pulmonary hemodynamics, gas exchange, and biochemical parameters. We then collected at different time points tissue biopsies of lung parenchyma to isolate RNA and DNA to identify each disease's unique gene expression. Thus, demonstrating that EVLP could successfully serve as a clinically relevant experimental model to derive essential insights into pulmonary pathophysiology and various human lung diseases.

Cardioprotection via Metabolism for Rat Heart Preservation Using the High-Pressure Gaseous Mixture of Carbon Monoxide and Oxygen.

The high-pressure gas (HPG) method with carbon monoxide (CO) and oxygen (O2) mixture maintains the preserved rat heart function. The metabolites of rat hearts preserved using the HPG method (HPG group) and cold storage (CS) method (CS group) by immersion in a stock solution for 24 h were assessed to confirm CO and O2 effects. Lactic acid was significantly lower and citric acid was significantly higher in the HPG group than in the CS group. Moreover, adenosine triphosphate (ATP) levels as well as some pentose phosphate pathway (PPP) metabolites and reduced nicotinamide adenine dinucleotide phosphate (NADPH) were significantly higher in the HPG group than in the CS group. Additionally, reduced glutathione (GSH), which protects cells from oxidative stress, was also significantly higher in the HPG group than in the CS group. These results indicated that each gas, CO and O2, induced the shift from anaerobic to aerobic metabolism, maintaining the energy of ischemic preserved organs, shifting the glucose utilization from glycolysis toward PPP, and reducing oxidative stress. Both CO and O2 in the HPG method have important effects on the ATP supply and decrease oxidative stress for preventing ischemic injury. The HPG method may be useful for clinical application.

A review of long-term corneal preservation techniques: Relevance and renewed interests in the COVID-19 era.

The growth of eye banking in India was showing positive trends until the nation was hit by unprecedented times as a result of the COVID-19 pandemic. The impact of this has led to a downward spiraling in eye banking activities globally. Several measures had to be implemented to tide over the crisis and strategies planned for future to prepare for the needs of corneal transplantation. While eye banks in India have been practicing short- term and intermediate storage preservation media, there is a definite need to evolve other methods of very long-term preservation. This review discusses various methods of long term corneal preservation, their relevance and applications in the present times. We reviewed relevant medical literature in English from PUBMED with the key words "Corneal preservation", "Cryopreservation", "Glycerol preservation", Gamma Irradiation", "Eye Banking" ,"COVID-19".

Long-term Outcomes of Laser Ablation of Fistula Tract for Fistula-in-Ano: A Considerable Option in Sphincter Preservation.

BACKGROUND: Ablation of anal fistula tract using a radial laser-emitting probe is a sphincter-preserving technique. OBJECTIVE: The purpose of this study was to assess long-term outcomes of laser ablation of fistula tract. DESIGN: This was a retrospective analysis of the long-term outcomes of 100 patients who underwent laser ablation of fistula tract. SETTINGS: This was a single-center study from a tertiary center in Turkey. PATIENTS: All of the patients with fistula-in-ano were included. Exclusion criteria were the presence of perianal abscess, underlying Crohn's disease, fistula tract <2 cm, fistulas suitable for simple fistulotomy, and intersphincteric fistulas originated from posterior located chronic anal fissure. INTERVENTIONS: A probe housing a 15-watt laser emitting at a wavelength of 1470 nm and an energy level of 100 to 120 joule/cm was used. MAIN OUTCOME MEASURES: No discharge, no symptoms, and fibrotic scar on skin where previously an external opening was present were defined as overall complete healing. All results other than overall complete healing were accepted as failure. RESULTS: A total of 100 patients underwent laser ablation of fistula tract with a median age of 42 years (range, 21-83 y). The majority of them were men. The overall success rate was 62% (95% CI, 52%-71%) in a median follow-up time of 48 months (range, 6-56 mo). None of the patients experienced permanent major or minor anal incontinence. LIMITATIONS: The retrospective nature of this study is its main limitation. Other limitations consist of phone interview for follow-up of the majority of the patients, single-institution data, and the relatively small number of patients. CONCLUSIONS: Laser ablation of the fistula tract is a sphincter-preserving procedure with an acceptable long-term success rate. See Video Abstract at http://links.lww.com/DCR/B186. RESULTADOS A LARGO PLAZO DE LA ABLACIóN CON LáSER DEL TRACTO EN LA FíSTULA ANAL: UNA CONSIDERABLE OPCIóN EN LA PRESERVACIóN DEL ESFíNTER: La ablación con una sonda radial emisora de láser del tracto de fístula anal, es una técnica de preservación del esfínter.Evaluar los resultados a largo plazo de la ablación con láser del tracto fistuloso.Análisis retrospectivo de los resultados a largo plazo de 100 pacientes que se sometieron a la ablación con láser del tracto de fístula.Este es un estudio de centro único de un centro terciario en Turquía.Fueron incluidos todos pacientes con fístula anal. Los criterios de exclusión fueron la presencia de absceso perianal, enfermedad de Crohn subyacente, tracto de fístula menor de 2 cm, fístulas adecuadas para fistulotomía simple y fístulas interesfintéricas originadas en una fisura anal crónica posterior.Se utilizó una sonda que alberga un láser de 15 vatios que emite a una longitud de onda de 1,470 nm y un nivel de energía de 100-120 julios / cm.Sin secreción, sin síntomas y la cicatriz fibrótica en la piel, donde anteriormente estaba presente la apertura externa, se definió como "curación completa general." Todos los resultados que no sean "curación completa en general" se aceptaron como fracaso.Cien pacientes fueron sometidos a ablación con láser del tracto de fístula anal, con una edad media de 42 (21-83) años. La mayoría de ellos fueron varones. La tasa de éxito general fue del 62% (intervalo de confianza del 95%, 52%-71%) en una mediana de tiempo de seguimiento de 48 (6-56) meses. Ninguno de los pacientes experimentó incontinencia anal mayor o menor permanente.La naturaleza retrospectiva de este estudio es su principal limitación. Otras limitaciones consisten en una entrevista telefónica para el seguimiento de la mayoría de los pacientes, datos de una sola institución y un número relativamente pequeño de pacientes.La ablación con láser del tracto de la fístula anal, es un procedimiento de preservación del esfínter y con una aceptable tasa de éxito a largo plazo. Consulte Video Resumen en http://links.lww.com/DCR/B186. (Traducción-Dr Fidel Ruiz Healy).

Ocular tissue distribution in the State of São Paulo: analysis on corneal discarding reasons. / Distribuição do tecido ocular no Estado de São Paulo: análise por razões de descarte de córneas.

OBJECTIVE: to identify the reasons for refusal of corneas. METHOD: this was a cross-sectional, retrospective, descriptive and correlational study composed of 5,560 optical corneas. The information was taken from the notification, organ procurement and distribution centers database as well as donor records. Descriptive statistics were used for the analysis of categorical variables and specific tests with a significance level of 5% for assessing the associations between variables. This study met the ethical aspects of scientific research. RESULTS: 60% of the donors were male and 40% died by circulatory problems. The main reason for refusal as informed by transplant teams is the donor's age and the endothelial cell count. For each year added to the donor's age, there is a 1% decrease in the chance that this cornea will be used for transplantation, and the increase of 100 cells per mm2 increases the chances that this cornea will be used by 9%. CONCLUSION: the main cause of refusal in the acceptance of corneal tissue is related to the age and the endothelial cell count.

Avoiding initial hypothermia does not improve liver graft quality in a porcine donation after circulatory death (DCD) model of normothermic perfusion.

BACKGROUND: Normothermic machine perfusion (NMP) of liver grafts donated after circulatory death (DCD) has shown promise in large animal and clinical trials. Following procurement, initial flush with a cold preservation solution is the standard of care. There is concern that initial cooling followed by warming may exacerbate liver injury, and the optimal initial flush temperature has yet to be identified. We hypothesize that avoidance of the initial cold flush will yield better quality liver grafts. METHODS: Twenty-four anaesthetized pigs were withdrawn from mechanical ventilation and allowed to arrest. After 60-minutes of warm ischemia to simulate a DCD procurement, livers were flushed with histidine-tryptophan-ketoglutarate (HTK) at 4°C, 25°C or 35°C (n = 4 per group). For comparison, an adenosine-lidocaine crystalloid solution (AD), shown to have benefit at warm temperatures in heart perfusions, was also used (n = 4 per group). During 12-hours of NMP, adenosine triphosphate (ATP), lactate, transaminase levels, and histological injury were determined. Bile production and hemodynamics were monitored continuously. RESULTS: ATP levels recovered substantially following 1-hour of NMP reaching pre-ischemic levels by the end of NMP with no difference between groups. There was no difference in peak aspartate aminotransferase (AST) or in lactate dehydrogenase (LDH). Portal vein resistance was lowest in the 4°C group reaching significance after 2 hours (0.13 CI -0.01,0.277, p = 0.025). Lactate levels recovered promptly with no difference between groups. Comparison to AD groups showed no statistical difference in the abovementioned parameters. On electron microscopy the HTK4°C group had the least edema with mean cell thickness of 2.92µm (p = 0.41) while also having the least sinusoidal dilatation with a mean diameter of 5.36µm (p = 0.04). For AD, the 25°C group had the lowest mean cell thickness at 3.14µm (p = 0.09). CONCLUSIONS: Avoidance of the initial cold flush failed to demonstrate added benefit over standard 4°C HTK in this DCD model of liver perfusion.

Use of ex vivo normothermic machine perfusion after normothermic regional perfusion to salvage a poorly perfused DCD kidney.

Normothermic regional perfusion (NRP) and normothermic machine perfusion (NMP) have both been used in the procurement and conditioning of abdominal organs from donation after circulatory death donors with reported improved outcomes for the recipients. Here, we describe an unusual case of a kidney that underwent NMP after NRP. After 2 hours of abdominal NRP, the intra-abdominal organs were cold flushed in situ. The liver and right kidney were well flushed, but the left kidney was poorly flushed. Further attempts to clear the left kidney by flushing on the backtable were unsuccessful, and the kidney was thought to be unsuitable for transplant. The left kidney then underwent a 1-hour period of NMP using a red cell-based perfusate. During NMP, the kidney met previously described quality assurance criteria for transplant with good global perfusion and adequate renal blood flow and urine production. The kidney was transplanted into a suitable recipient who had slow early graft function but did not require dialysis posttransplant. The recipient was discharged 6 days posttransplant, and the serum creatinine level was 160 µmol/L (1.8 mg/dL) at 2 months posttransplant.

Outcomes of DCD kidneys recovered for transplantation with versus without pre-mortem heparin administration.

BACKGROUND: Pre-mortem heparin administration during donation after circulatory death (DCD) organ recovery may be particularly important to improve perfusion and prevent graft thrombosis. However, pre-mortem heparin administration is not universally practiced in the US and scarce data exist regarding its efficacy. METHODS: Using a national transplant registry data, we identified DCD kidneys recovered for transplantation from January 1, 2003, to March 10, 2017, and examined discard and outcomes after transplantation using bivariate and multivariable analyses. Organs with unknown or missing donor heparin status (n = 193), seropositive HIV (n = 10), HTLV (n = 33), hepatitis B (n = 26), or hepatitis C (n = 648) were excluded. RESULTS: Of 24 861 DCD kidneys recovered with (n = 22 557) or without pre-mortem heparin administration (n = 2304), discard occurred in 19.1% and 20.8%, respectively (P = 0.05). On multivariate analysis, heparin use was not associated with discard (aOR 1.02, 95% CI 0.89-1.17, P = 0.820). Overall graft survival of no-heparin (n = 1791) vs heparin groups (n = 17 968) was similar on univariate and multivariate analysis (aHR 0.98, 95% CI 0.87-1.09, P = 0.640). CONCLUSION: DCD kidneys from donors that have not received pre-mortem heparin administration have acceptable transplant outcomes and are not associated with discard.

Modifying the Organ Matrix Pre-engraftment: A New Transplant Paradigm?

The availability of solid organs for transplantation remains low and there is a substantial need for methods to preserve the viability of grafted tissues. Suppression of solid-organ transplant rejection has traditionally focused on highly effective T cell inhibitors that block host immune lymphocyte responses. However, persistent and destructive innate and acquired immune reactions remain difficult to treat, causing late graft loss. Pretreatment of grafts to reduce organ rejection provides an alternate strategy. Approaches using antithrombotics, stem cells, genetic modifications, modulation of infrastructural components (connective tissue, CT; glycocalyx) of donor organs, and engineering of new organs are under investigation. We discuss here new approaches to modify transplanted organs prior to engraftment as a method to reduce rejection, focusing on the CT matrix.

Retrieval Practice or Overall Donor and Recipient Risk: What Impacts on Outcomes After Donation After Circulatory Death Liver Transplantation in the United Kingdom?

Parameters of retrieval surgery are meticulously documented in the United Kingdom, where up to 40% of livers are donation after circulatory death (DCD) donations. This retrospective analysis focuses on outcomes after transplantation of DCD livers, retrieved by different UK centers between 2011 and 2016. Donor and recipient risk factors and the donor retrieval technique were assessed. A total of 236 DCD livers from 9 retrieval centers with a median UK DCD risk score of 5 (low risk) to 7 points (high risk) were compared. The majority used University of Wisconsin solution for aortic flush with a median hepatectomy time of 27-44 minutes. The overall liver injury rate appeared relatively high (27.1%) with an observed tendency toward more retrieval injuries from centers performing a quicker hepatectomy. Among all included risk factors, the UK DCD risk score remained the best predictor for overall graft loss in the multivariate analysis (P < 0.001). In high-risk and futile donor-recipient combinations, the occurrence of liver retrieval injuries had negative impact on graft survival (P = 0.023). Expectedly, more ischemic cholangiopathies (P = 0.003) were found in livers transplanted with a higher cumulative donor-recipient risk. Although more biliary complications with subsequent graft loss were found in high-risk donor-recipient combinations, the impact of the standardized national retrieval practice on outcomes after DCD liver transplantation was minimal.

Management of the brain-dead donor in the ICU: general and specific therapy to improve transplantable organ quality.

PURPOSE: To provide a practical overview of the management of the potential organ donor in the intensive care unit. METHODS: Seven areas of donor management were considered for this review: hemodynamic management; fluids and electrolytes; respiratory management; endocrine management; temperature management; anaemia and coagulation; infection management. For each subchapter, a narrative review was conducted. RESULTS AND CONCLUSIONS: Most elements in the current recommendations and guidelines are based on pathophysiological reasoning, epidemiological observations, or extrapolations from general ICU management strategies, and not on evidence from randomized controlled trials. The cardiorespiratory management of brain-dead donors is very similar to the management of critically ill patients, and the same applies to the management of anaemia and coagulation. Central diabetes insipidus is of particular concern, and should be diagnosed based on clinical criteria. Depending on the degree of vasopressor dependency, it can be treated with intermittent desmopressin or continuous vasopressin, intravenously. Temperature management of the donor is an area of uncertainty, but it appears reasonable to strive for a core temperature of > 35 °C. The indications and controversies regarding endocrine therapies, in particular thyroid hormone replacement therapy, and corticosteroid therapy, are discussed. The potential donor should be assessed clinically for infections, and screening tests for specific infections are an essential part of donor management. Although the rate of infection transmission from donor to receptor is low, certain infections are still a formal contraindication to organ donation. However, new antiviral drugs and strategies now allow organ donation from certain infected donors to be done safely.

The development of a predictive model of graft function in uncontrolled donors after circulatory death: validity of a pulsatile renal preservation machine cut-off value for kidney acceptance.

BACKGROUND: The criteria for kidney suitability in uncontrolled donors after circulatory death (uDCD) procured after regional normothermic perfusion are based on macroscopic appearance and renal haemodynamic values with final renal resistance (FRR). However, these criteria have not been analysed to predict the future graft function. This study presents a model to predict the outcome in uDCD kidneys and define the predictive FRR value. METHODS: All uDCD kidney transplants performed in our hospital from 2004 to 2016 were included. Donors and recipients and pre-transplantation data are described. The endpoint was glomerular filtration rate (GFR) ≥30 mL/min at 6 months after transplantation. RESULTS: A total of 194 recipients were included. FRR in donors ≥60 years old was (mean ± SD) 0.27 ± 0.11 versus 0.22 ± 0.09 mmHg/mL/min in donors <60 years (P = 0.042). Kidney survival was 88.2% versus 84% at 12 months and 60.7% versus 30.8% at 120 months (P = 0.067). For the group of recipients from donors ≥60 years, the FRR was 0.37 ± 0.08 mmHg/mL/min in the GFR <30 mL/min group versus 0.18 ± 0.06 mmHg/mL/min in the GFR ≥30 mL/min group (P < 0.001). The value FRR ≥0.3 mmHg/mL/min predicts 59-79% of GFR <30 mL/min [odds ratio = 2.16, 95% confidence interval (CI) 1.80-6.40; P < 0.001]. The predictive accuracy of FRR for GFR by ROC curve was 0.968 (95% CI). The best cut-off for FRR was 0.3 mmHg/mL/min to predict GFR at 6 months with a sensitivity of 67%, specificity of 100%, positive predictive value of 83% and negative predictive value of 92%. CONCLUSIONS: Our results suggest that in uDCD donors the combination of donor age ≥60 years together with FRR ≥0.3 mmHg/mL/min could predict poor outcome at 6 months after transplantation in low immunological risk recipients.

The effect on early renal function of various dynamic preservation strategies in a preclinical pig ischemia-reperfusion autotransplant model.

The aims of this study were to determine the most optimal timing to start machine perfusion during kidney preservation to improve early graft function and to evaluate the impact of temperature and oxygen supply during machine perfusion in a porcine ischemia-reperfusion autotransplant model. The left kidney of an approximately 40-kg female Belgian Landrace pig was exposed to 30 minutes of warm ischemia via vascular clamping and randomized to 1 of 6 study groups: (1) 22-hour static cold storage (SCS) (n = 6), (2) 22-hour hypothermic machine perfusion (HMP) (n = 6), (3) 22-hour oxygenated HMP (n = 7), (4) 20-hour HMP plus 2-hour normothermic perfusion (NP) (n = 6), (5) 20-hour SCS plus 2-hour oxygenated HMP (n = 7), and (6) 20-hour SCS plus 2-hour NP (n = 6). Graft recovery measured by serum creatinine level was significantly faster for continuous HMP preservation strategies compared with SCS alone and for all end-ischemic strategies. The active oxygenated 22-hour HMP group demonstrated a significantly faster recovery from early graft function compared with the 22-hour nonactive oxygenated HMP group. Active oxygenation was also found to be an important modulator of a faster increase in renal flow during HMP preservation. Continuous oxygenated HMP applied from the time of kidney procurement until transplant might be the best preservation strategy to improve early graft function.