Quality of life following two different techniques of an open ventral hernia repair for large hernias: a prospective randomized study.

BACKGROUND: We compare the health-related quality of life (QoL) of patients with incision hernias before and after surgery with two different techniques. METHODS: In this prospective randomized study, the study population consisted of all patients who underwent the first surgical incisional hernias repair during the 1-year study period. Patients who met the criteria for inclusion in the study were randomized into two groups: the first group consisted of patients operated by an open Rives sublay technique, and the second group included patients operated by a segregation component technique. The change in the quality of life before and 6 months after surgery was assessed using two general (Short form of SF-36 questionnaires and European Quality of Life Questionnaire-EQ-5D-3L), and three specific hernia questionnaires (Hernia Related Quality of Life Survey-HerQles, Eura HS Quality of Life Scale-EuraHS QoL, and Carolinas Comfort Scale-CCS). RESULTS: A total of 93 patients were included in the study. Patients operated on by the Rives technique had a better role physical score before surgery, according to the SF-36 tool, although this was not found after surgery. The postoperative QoL measured with each scale of all questionnaires was significantly better after surgery. Comparing two groups of patients after surgery, only the pain domain of the EuraHS Qol questionnaire was worse in patients operated by a segregation component technique. CONCLUSION: Both techniques improve the quality of life after surgery. Generic QoL questionnaires showed no difference in the quality of life compared to repair technique but specific hernia-related questionnaires showed differences.

Outcomes of Open Surgery for Retroperitoneal Hematoma in Covid-19 Patients: Experience from a Single Centre.

Background: Spontaneous retroperitoneal hematoma is a severe and potentially fatal complication that appears in the course of anticoagulation therapy. Therapeutic doses of low molecular weight heparin (LMWH) are used for the prevention of thrombosis in patients seriously ill with Covid-19. Methods: We describe 27 (0.14%) patients with retroperitoneal hematomas who required emergency surgery out of 19108 patients with Covid-19 who were hospitalized in Batajnica COVID Hospital between March 2021 and March 2022. All the patients were on therapeutic doses of LMWH. The existence of retroperitoneal hematoma was confirmed by abdominal ultrasound and computed tomography scans. Results: Open surgery was performed on 27 patients with spontaneous retroperitoneal hematomas (12 female and 15 male). The mean age of the study population was 71.6+-11.9 years. D-dimer was significantly elevated two days before the surgery in comparison with the values on the day of surgery (p=0.011). Six patients (22.23%) survived, while 21 (77.77%) patients died. Conclusion: Bleeding in Covid-19 patients treated by LMWH is associated with an increased risk of developing retroperitoneal hematoma. Open surgery for retroperitoneal hematoma in Covid-19 patients on anticoagulation therapy is a procedure associated with a high rate of mortality.

Seat-Belt Abdominal Aortic Injury-Treatment Modalities.

Blunt abdominal aortic injuries are extremely rare, diagnosed in less than 0.05% of all trauma admissions. Aortic injury caused by a seat belt during a car accident is often referred as "seat-belt aorta". We present a case of an 18-year-old woman, restrained back passenger involved in a vehicular collision, sustaining vertebral column and multiple rib fractures, mesenterium and colonic injury, and infrarenal aortic contusion with localized dissection and partial thrombosis.

Survival and prognostic factors for survival, cancer specific survival and disease free interval in 239 patients with Hurthle cell carcinoma: a single center experience.

BACKGROUND: Hurthle cell carcinoma makes up 3 to 5% of all thyroid cancers and is considered to be a true rarity. The aim of our study was to analyze clinical characteristics and survival rates of patients with Hurthle cell carcinoma. METHODS: Clinical data regarding basic demographic characteristics, tumor grade, type of surgical treatment and vital status were collected. Methods of descriptive statistics and Kaplan-Meier survival curves were used for statistical analysis. Cox proportional hazards regression was used to identify independent predictors. RESULTS: During the period from 1995 to 2014, 239 patients with Hurthle cell carcinoma were treated at our Institution. The average age of the patients was 54.3, with female to male ratio of 3.6:1 and average tumor size was 41.8 mm. The overall recurrence rate was 12.1%, with average time for relapse of 90.74 months and average time without any signs of the disease of 222.4 months. Overall 5-year, 10-year and 20-year survival rates were 89.4%, 77.2%, 61.9% respectively. The 5-year, 10-year and 20-year cancer specific survival rates were 94.6%, 92.5%, 87.4%, respectively. When disease free interval was observed, 5-year, 10-year and 20-year rates were 91.1%, 86.2%, 68.5%, respectively. The affection of both thyroid lobes and the need for reoperation due to local relapse were unfavorable independent prognostic factors, while total thyroidectomy as primary procedure was favorable predictive factor for cancer specific survival. CONCLUSION: Hurthle cell carcinoma is a rare tumor with an encouraging prognosis and after adequate surgical treatment recurrences are rare.

Rationale and design of the Aortic Valve replAcemenT versus conservative treatment in Asymptomatic seveRe aortic stenosis (AVATAR trial): A randomized multicenter controlled event-driven trial.

Aortic valve replacement (AVR) therapy is an obvious choice for symptomatic severe aortic stenosis (AS) patients as it improves symptoms, left ventricular function, and survival. The treatment decisions and indication for AVR in asymptomatic patients with severe AS and normal left ventricular ejection fraction are less well established and the subject of ongoing debate. Many efforts have been made to define the best treatment option in asymptomatic AS patients with normal left ventricular ejection fraction. Retrospective and observational data imply that elective AVR for asymptomatic severe AS may lead to improvement in outcomes in comparison to surgery performed after onset of symptoms. The AVATAR trial will aim to assess outcomes among asymptomatic AS patients randomized to either elective early AVR or medical management with vigilant follow-up. In the latter group, AVR would be delayed until either the onset of symptoms or changes in predefined echocardiographic parameters. To the best of the authors' knowledge, it will be the first large prospective, randomized, controlled, multicenter clinical trial that will evaluate the safety and efficacy of elective AVR in this specific group of patients.

Survival and prognostic factors for adrenocortical carcinoma: a single institution experience.

BACKGROUND: Adrenocortical carcinoma (ACC) is aggressive, but rare tumours that have not been sufficiently studied. The aim of our study was to present the demographic and clinical characteristics of patients with ACC, to determine the overall survival rates, analyse the effect of prognostic factors on survival, as well as to identify favorable and unfavourable predictors of survival. METHOD: The study included 72 patients (42 women and 30 men) with ACC. We analysed the prognostic value of the demographic and clinical characteristics of the patients, tumour characteristics, therapy administered and survival rates. Kaplan-Meier survival curves and the log-rank test were used to estimate the overall and specific survival probabilities and the Cox regression model was used to identify independent prognostic factors for survival. RESULTS: The patients had mean age of 50 years. The 1-, 5-, and 10-year probabilities of survival in patients with ACC were 52.5 %, 41.1 %, and 16.4 %, respectively. The median survival time was 36 months. The results of multivariate Cox regression analysis showed that the presence of lymphatic metastases (HR = 7.37, 95 % CI = 2.31-23.48, p = 0.001) and therapy with mitotane (HR = 0.11, 95 % CI = 0.04-0.27, p = 0.001) were independent prognostic factors for survival. CONCLUSION: The presence of lymphatic metastasis is an unfavourable prognostic factor, while postoperative therapy with mitotane is a favorable prognostic factor for survival in patients with ACC.

Validity of the Health Personality Assessment among rectal cancer survivors in Serbia.

Understanding health personality traits in rectal cancer survivors could help to optimize recovery and coping mechanisms. The objective of this study was to evaluate psychometric properties of the Health Personality Assessment in Serbian language among rectal cancer survivors. A cross-sectional study was carried out from June to December 2022. The study sample consisted of 76 people who underwent the open lower anterior resection for rectal carcinoma at the Clinic for Digestive Surgery and the Clinic for Emergency Surgery, University of Clinical Center of Serbia (Belgrade, Serbia) and whose ileostomy was closed. Study participants were interviewed over the telephone using the Serbian version of the HPA which was translated according to the internationally accepted methodology for translation and adaptation of questionnaires. The confirmatory factor analysis suggested that the fit indices for 5-factor structure of the HPA were acceptable-to-good: Goodness of fit index = 0.939; Tucker Lewis fit index = 0.989; Comparative fit index = 0.992; Root Mean Square Error of Approximation = 0.019. Cronbach's alpha coefficients for Health Neuroticism, Health Extraversion and Health Agreeableness were>0.7 and for Health Openness and Health Conscientiousness were >0.4. Predictive validity testing suggested that not having complications with the ileostomy and a longer time since ileostomy closure were associated with stronger Health Agreeableness. Also, a longer time since ileostomy closure was associated with stronger Health Conscientiousness. The Serbian version of the HPA showed good construct validity and acceptable internal consistency. This is an important tool in further research of personality and health outcomes among rectal cancer survivors.

Clinical value of immunoscintigraphy in the rectal carcinomas: immunoscintigraphy of rectal carcinomas.

BACKGROUND/AIM: The aim of this study was to evaluate the clinical reliability of the immunoscintigraphy with radiolabeled monoclonal antibodies for the detection of metastases and recurrences of rectal carcinomas. METHODOLOGY: A total of 65 patients underwent immunoscintigraphy with radiolabeled monoclonal antibodies. Indication for that examination was suspicious rectal cancer or suspicious rectal cancer recurrence and/or metastases. RESULTS: The method proved to have 92.7% sensitivity, specificity 83.3%, positive predictive value 90.5%, negative predictive value 87.0% and accuracy 89.2%. There was a statistically significant relationship between immunoscintigraphy findings and rectoscopy findings (rs=0.415, p=0.013), as well as significant relationship between immunoscintigraphy findings and US findings (rs=0.332, p=0.001). Tumor marker levels were in positive correlation with findings of immunoscintigraphy (rs=0.845, p=0.001), especially raised CEA level (rs=0.816, p=0.004). Patients with higher CA19-9 level had higher Duke's stage (p=0.025). CONCLUSIONS: We can conclude that immunoscintigraphy can be helpful in the detection of metastases and recurrences of colon carcinomas.

West Nile Virus Infection in Liver Transplant Recipient With Neither De Novo Infection nor Donor-Derived Infection: A Case Report.

West Nile virus was first described in 1937 and has sinceperiodically appearedin variousparts oftheworld by infecting people and horses. Reported infection symptoms and signs may be highly variable, ranging from fever and myalgias to meningoencephalitis. A 59-year-old patient was admitted to the University Clinical Centre of Serbia, Belgrade, in September 2018, where livertransplantwasperformedtotreat cirrhosisof ethyl etiology. Immunosuppressive therapy was started immediately after successful transplant, with the patientreceiving methylprednisolone, tacrolimus, and mycophenolate mofetil. Mycophenolate mofetil was excluded from therapy on postoperative day 3 because of progressively worse white blood cell count. The patient became febrile on postoperative day 11 (39.6 °C), and arm tremor, nausea, vomiting, and frequent fluid stools occurred. He complained of pain in the muscles and joints of the lower extremities. The next day he experienced occasional disorientation. Neurological findings revealed no signs of acute focal neurological deficit. We performed culture tests to isolate pathological microorganisms, and results were negative in cultures of the blood, urine, feces, ascites, and a smear of the wound and tip of the central venous catheter. Lumbar puncture resulted in a clear cerebrospinal fluid that was sent for analysis that showed significant increases in white blood cell count (94 × 106 cells/L), total proteins (1.61 g/L), and microalbumin (504.5 mg/L), with a reduction of immunoglobulin G. On postoperative day 15, positive serology of West Nile virus immunoglobulin M in cerebrospinal fluid was verified. Intensive monitoring and symptomatic and supportive therapy resulted in clinical and laboratory improvement, and the patient was discharged in good general condition on postoperative day 22. Considering the high risk of posttransplant complications, there remains the question of whether all donors and recipients should be tested forWest Nile virus atthe onset oftransplant.

"Zooming" in strategies and outcomes for trauma cases with Injury Severity Score (ISS) ≥16: promise or passé?

OBJECTIVE: Rescuing severe trauma cases is extremely demanding. The present study purposed to analyze the efficiency of trauma management at Emergency Centre, University Clinical Centre of Serbia, Belgrade, included outcome within 28 days. METHODS: This retrospective study involved 131 intensive care unit trauma cases with total Injury Severity Score ≥16, in terms of administrating the two strategies: (i) definitive surgical repair and (ii) damage control laparotomy. RESULTS: The damage control laparotomy cases revealed statistically higher Injury Severity Score and APACHE II scores, significant brain dysfunction, and hemorrhagic shock on arrival (p<0.001). In addition, the damage control laparotomy had a higher rate of respiratory complications, multiple organ deficiency syndrome, and surgical wound complications (p=0.017, <0.001, and 0.004, respectively), with more days on mechanical ventilation (p=0.003). Overall mortality was 29.8%. Although higher early mortality within ≤24 h in the damage control laparotomy (p=0.021) had been observed, no difference between groups (p=0.172) after the 4th day of hospitalization was detected. CONCLUSIONS: Trauma patients have a high mortality rate in the 1st hours after the incident. Compelling evidence linking host and pathogen factors, such as mitochondrial apoptosis pathways, appears to correlate with loss of organ dysfunction, both cytopathologically and histopathologically. Adequate selection of patients necessitating damage control laparotomy, allowed by the World Society of Emergency Surgery, abdominopelvic trauma classifications, and improvements in resuscitation, may improve the results of severe trauma treatment.

Cyclin D1 and p57 expression in relation to clinicopathological characteristics and overall survival in patients with renal cell carcinoma.

PURPOSE: There is a need for identifying molecular prognostic biomarkers to better predict clinical outcomes in patients with renal cell carcinoma (RCC). This study investigated the pattern of cyclin D1 and p57 expression in RCC patients and evaluated their relation with clinicopathological characteristics and overall survival (OS). METHODS: Immunohistochemistry was applied to paraffin-embedded tissue sections of 74 RCC patients. Two cut-off groups were defined by the fraction of positive cells as follows: ≤10% and >10% positive cells for cyclin D1, and ≤5% and >5% positive cells for p57. RESULTS: Cyclin D1 expression in >10% of positive cells was observed mostly in the clear cell RCC, while p57 expression in ≤5% of positive cells was found in 86% of chromophobe RCC specimens. The higher expression of cyclin D1 and lower expression of p57 were more frequent in grade I-II tumors. OS was associated with unfavorable clinicopathological characteristics. However, cyclin D1/p57 expression did not influence the survival rates. CONCLUSION: Although cyclin D1 and p57 expression did not affect survival rates in RCC patients, proper validation and establishment of the qualitative cut-off point are needed for these tumors.

Immunohistochemical analysis of cyclin A expression in Wilms tumor.

BACKGROUND: Cyclin A overexpression is found in a variety of human tumors and correlates with unfavorable outcome. We analyzed immunohistochemical expression of cyclin A in Wilms tumor (WT) in relation to clinicopathological characteristics, preoperative chemotherapy (PrOpChTh), and overall survival (OS). METHODS: This retrospective study involved 43 patients who underwent nephrectomy from January 1996 to October 2010. Tumor stage and histological subtype were determined by revised Societé International d'Oncologie Pediatrique protocol, based on histological components/alterations caused by PrOpChTh, within the prognostic group of low, intermediate and high risk, and with criteria for anaplasia. The regressive/necrotic changes in total tumor mass of primary tumor and the proportion of epithelial, blastemal, and stromal components in the remaining viable tumor tissue were also determined. Cyclin A expression was evaluated by immunohistochemistry using a polyclonal rabbit, antihuman antibody (H-432). RESULTS: Cyclin A overexpression was found in 34.3% of WTs, with higher frequency in tumors with epithelial (31.3%) and blastemal (37.1%) components than those with stromal component (17.7%). Regarding histological type, cyclin A overexpression was found most often in focal anaplasia (100%), stromal (60%), and diffuse anaplastic (66.7) WTs. The overexpression was also more frequent in stages 3 and 4 (77.8% and 66.7%, respectively) compared to tumors in stages 1 and 2 (13.3% and 12.5%, respectively; p = 0.004) in all components, as well as in blastemal component in stages 3 and 4 (77.8% and 66.7%, respectively) vs. stages 1 and 2 (13.3% and 25%, respectively, p = 0.009). Cyclin A overexpression in all components was 66.7% in WTs with metastasis and 31.3% in WTs without metastasis (p = 0.265, Fisher test). Log-rank testing revealed differences of OS regarding stage (p = 0.000), prognostic groups (p = 0.001), and cyclin A expression in blastemal component (p = 0.025). After univariate analysis, tumor stage (p = 0.001), prognostic group (p = 0.004), and cyclin A expression in blastemal component (p = 0.042) were significant prognostic factors for OS; however, after multivariate analysis, none of these factors were confirmed as independent predictors of survival. DISCUSSION: This study showed that cyclin A overexpression might be associated with the development and progression of WT with anaplasia. Also, cyclin A overexpression was more often observed in advanced stages (3 and 4) of WT, in the group of high-risk WTs, and in focal and diffuse anaplasia WTs. There was no relation of cyclin A overexpression and metastatic ability of WT. Although this study has not confirmed the prognostic value of cyclin A overexpression, its association with unfavorable prognosis should be further evaluated.

Preoperative neutrophil-to-lymphocyte ratio as a prognostic predictor after curative-intent surgery for hepatocellular carcinoma: experience from a developing country.

PURPOSE: The aim of the study was to evaluate a prognostic value of preoperative neutrophil-to-lymphocyte ratio (NLR) on long-term survival of cirrhotic and noncirrhotic hepatocellular cancer (HCC) patients managed by a curative-intent liver surgery in a developing country. PATIENTS AND METHODS: During the study period between November 1, 2001, and December 31, 2012, 109 patients underwent potentially curative hepatectomy for HCC. Data were retrospectively reviewed from the prospectively collected database. The median follow-up was 25 months. NLR was estimated by dividing an absolute neutrophil count by an absolute lymphocyte count from the differential blood count. Receiver operating characteristic curve was constructed to assess the ability of NLR to predict long-term outcomes and to determine an optimal cutoff value for all patients group, the subgroup with cirrhosis, and the subgroup without cirrhosis. The optimal cutoff values were 1.28, 1.28, and 2.09, respectively. RESULTS: The overall 3- and 5-year survival rates were 49% and 45%, respectively, for low NLR group and 38% and 26%, respectively, for high NLR group. The difference was statistically significant (p=0.015). Overall survival was similar between low and high NLR groups in patients with cirrhosis; no difference was found between the groups (p=0.124). In patients without cirrhosis, low NLR group had longer overall survival compared with high NLR group (p=0.015). Univariate analysis identified four factors as significant predictors of long-term survival: cirrhosis, Child-Pugh score, platelet count, and NLR. On multivariate analysis, only platelet count and NLR were independent prognostic factors of long-term survival. CONCLUSION: Prognostic value of NLR was confirmed in noncirrhotic HCC patients who underwent curative-intent liver surgery. In HCC patients with cirrhosis, the prognostic role of NLR was not confirmed.

Targeted therapy and personalized medicine in hepatocellular carcinoma: drug resistance, mechanisms, and treatment strategies.

Hepatocellular carcinoma (HCC) is characterized by a growing number of new cases diagnosed each year that is nearly equal to the number of deaths from this cancer. In a majority of the cases, HCC is associated with the underlying chronic liver disease, and it is diagnosed in advanced stage of disease when curative treatment options are not applicable. Sorafenib is a treatment of choice for patients with performance status 1 or 2 and/or macrovascular invasion or extrahepatic spread, and regorafenib is the only systemic treatment found to provide survival benefit in HCC patients progressing on sorafenib treatment. Other drugs tested in different trials failed to demonstrate any benefit. Disappointing results of numerous trials testing the efficacy of various drugs indicate that HCC has low sensitivity to chemotherapy that is in great part caused by multidrug resistance. Immunotherapy for HCC is a new challenging treatment option and involves immune checkpoint inhibitors/antibody-based therapy and peptide-based vaccines. Another challenging approach is microRNA-based therapy that involves two strategies. The first aims to inhibit oncogenic miRNAs by using miRNA antagonists and the second strategy is miRNA replacement, which involves the reintroduction of a tumor-suppressor miRNA mimetic to restore a loss of function.

Burnout of Formal Caregivers of Children with Cerebral Palsy.

BACKGROUND: Burnout syndrome is under-researched within caregivers (CGs) of children with cerebral palsy. The primary aim was to determine the burnout level of formal CGs of children with cerebral palsy (G1) and to compare it with a control group (G2) of professional pediatric nurses, and second, to correlate the level of depression and anxiety with the burnout level. METHOD: In a total sample of 60 CGs, the Maslach Burnout Inventory Human Services Survey (MBI-HSS), consisting of three structural units - emotional exhaustion (MBIEE) subscale, depersonalization (MBI-DP) subscale and personal accomplishment (MBI-PA) subscale - was used to measure burnout. The Beck Anxiety Inventory (BAI) was used for the assessment of anxiety, and the Beck Depression Inventory (BDI) for depression. RESULTS: A significant difference was shown on the MBI-EE subscale and on the BDI test (p<0.05), in both cases higher scores were obtained by G1. High burnout was observed in all subscales, on the MBI-EE subscale registered 50% of CGs in G1, and 17% in control G2. Correlation of the MBI-EE subscale with BDI and BAI tests was highly significant (p<0.01). CONCLUSIONS: These findings indicate the need for future research aimed at formulating preventive strategies for caregivers' mental health. Better care for caregivers would provide them with better professional satisfaction, and consequently would lead to better care for patients.

Severe Blunt Hepatic Trauma in Polytrauma Patient - Management and Outcome.

INTRODUCTION: Despite the fact that treatment of liver injuries has dramatically evolved, severe liver traumas in polytraumatic patients still have a significant morbidity and mortality. OBJECTIVE: The purpose of this study was to determine the options for surgical management of severe liver trauma as well as the outcome. METHODS: In this retrospective study 70 polytraumatic patients with severe (American Association for the Surgery of Trauma [AAST] grade III-V) blunt liver injuries were operated on at the Clinic for Emergency Surgery. RESULTS: Mean age of patients was 48.26±16.80 years; 82.8% of patients were male. Road traffic accident was the leading cause of trauma, seen in 63 patients (90.0%). Primary repair was performed in 36 patients (51.4%), while damage control with perihepatic packing was done in 34 (48.6%). Complications related to the liver occurred in 14 patients (20.0%). Liver related mortality was 17.1%. Non-survivors had a significantly higher AAST grade (p=0.0001), higher aspartate aminotransferase level (p=0.01), lower hemoglobin level (p=0.0001), associated brain injury (p=0.0001), perioperative complications (p=0.001) and higher transfusion score (p=0.0001). The most common cause of mortality in the "early period" was uncontrolled bleeding, in the "late period" mortality was caused by sepsis and acute respiratory distress syndrome. CONCLUSION: Patients with high-grade liver trauma who present with hemorrhagic shock and associated severe injury should be managed operatively. Mortality from liver trauma is high for patients with higher AAST grade of injury, associated brain injury and massive transfusion score.

Surgical management of AAST grades III-V hepatic trauma by Damage control surgery with perihepatic packing and Definitive hepatic repair-single centre experience.

BACKGROUND: Severe liver injury in trauma patients still accounts for significant morbidity and mortality. Operative techniques in liver trauma are some of the most challenging. They include the broad and complex area, from damage control to liver resection. MATERIAL AND METHOD: This is a retrospective study of 121 trauma patients with hepatic trauma American Association for Surgery of Trauma (AAST) grade III-V who have undergone surgery. Indications for surgery include refractory hypotension not responding to resuscitation due to uncontrolled hemorrhage from liver trauma; massive hemoperitonem on Focused assessment by ultrasound for trauma (FAST) and/or Diagnostic peritoneal lavage (DPL) as well as Multislice Computed Tomography (MSCT) findings of the severe liver injury and major vascular injuries with active bleeding. RESULTS: Non-survivors have significantly higher AAST grade of liver injury and higher Injury Severity Score (ISS) (p = 0.000; p = 0.0001). Non-survivors have significant hypotension on arrival and lower Glasgow Coma Scale (GCS) on admission (p = 0.000; p = 0.0001). Definitive hepatic repair was performed in 62(51.2 %) patient. Damage Control, liver packing and planned re-laparotomy after 48 h were used in 59(48.8 %). There was no statistically significant difference in terms of the surgical approach. There was significant difference in the amount of red blood cells (RBC) transfusion in the first 24 h between survivors and non-survivors (p = 0.001). Overall mortality rate was 33.1 %. Regarding complications non-survivors had significantly prolonged bleeding and higher rate of Acute respiratory distress syndrome (ARDS) (p = 0.0001; p = 0.0001), while survivors had significantly higher rate of pleural effusion (p = 0.0001). CONCLUSION: All efforts in the treatment of severe liver injuries should be directed to the rapid and effective control of bleeding, because uncontrollable hemorrhage is the cause of early death and it requires massive blood transfusion, all of which contributes to the late fatal complication.

Endpoints in stem cell trials in ischemic heart failure.

Despite multimodal regimens and diverse treatment options alleviating disease symptoms, morbidity and mortality associated with advanced ischemic heart failure remain high. Recently, technological innovation has led to the development of regenerative therapeutic interventions aimed at halting or reversing the vicious cycle of heart failure progression. Driven by the unmet patient need and fueled by encouraging experimental studies, stem cell-based clinical trials have been launched over the past decade. Collectively, these trials have enrolled several thousand patients and demonstrated the clinical feasibility and safety of cell-based interventions. However, the totality of evidence supporting their efficacy in ischemic heart failure remains limited. Experience from the early randomized stem cell clinical trials underscores the key points in trial design ranging from adequate hypothesis formulation to selection of the optimal patient population, cell type and delivery route. Importantly, to translate the unprecedented promise of regenerative biotherapies into clinical benefit, it is crucial to ensure the appropriate choice of endpoints along the regulatory path. Accordingly, we here provide considerations relevant to the choice of endpoints for regenerative clinical trials in the ischemic heart failure setting.