EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks.

BACKGROUND AND AIMS: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. APPROACH AND RESULTS: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. CONCLUSIONS: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies.

Immunologic characterization of COVID-19 patients with hematological cancer.

Not available.

Treatment of graft-versus-host disease with mesenchymal cells as a complication of a liver transplantation.

We present the case of a liver transplant (LT) recipient donor who developed graft versus host disease (GVHD). The main features were cutaneous rash, diarrhea and pancytopenia. Mesenchymal cells were administered as part of the treatment. This is the first case of a patient with GVHD after LT reported to date. Despite the treatment, there was no improvement in aplasia or gastrointestinal symptoms and the patient died due to a disseminated infection.

Renal autotransplant for subsequent endovascular exclusion of the thoracoabdominal aorta.

In the last 20 years, endovascular procedures have radically altered the treatment of diseases of the aorta. The objective of endovascular treatment of dissections is to close the entry point to redirect blood flow toward the true lumen, thereby achieving thrombosis of the false lumen. In extensive chronic dissections that have evolved with the formation of a large aneurysm, the dissection is maintained from the end of the endoprosthesis due to multiple orifices, or reentries, that communicate with the lumens. In addition, one of the primary limitations of this technique is when the visceral arteries have disease involvement. In this report we present a case where, despite having treated the entire length of the descending thoracic aorta, the dissection was maintained distally, leading to progression of the diameter of the aneurysm. After reviewing the literature, and to the best of our knowledge, we describe the first case in which renal autotransplant was performed to allow for subsequent exclusion of the aorta at the thoracoabdominal level using a fenestrated endoprosthesis for the celiac trunk and the superior mesenteric artery.

Long-Term Outcome of Critically Ill Advanced Cancer Patients Managed in an Intermediate Care Unit.

Background: To analyze the long-term outcomes for advanced cancer patients admitted to an intermediate care unit (ImCU), an analysis of a do not resuscitate orders (DNR) subgroup was made. Methods: A retrospective observational study was conducted from 2006 to January 2019 in a single academic medical center of cancer patients with stage IV disease who suffered acute severe complications. The Simplified Acute Physiology Score 3 (SAPS 3) was used as a prognostic and severity score. In-hospital mortality, 30-day mortality and survival after hospital discharge were calculated. Results: Two hundred and forty patients with stage IV cancer who attended at an ImCU were included. In total, 47.5% of the cohort had DNR orders. The two most frequent reasons for admission were sepsis (32.1%) and acute respiratory failure (excluding sepsis) (38.7%). Mortality in the ImCU was 10.8%. The mean predicted in-hospital mortality according to SAPS 3 was 51.9%. The observed in-hospital mortality was 37.5% (standard mortality ratio of 0.72). Patients discharged from hospital had a median survival of 81 (30.75−391.25) days (patients with DNR orders 46 days (19.5−92.25), patients without DNR orders 162 days (39.5−632)). The observed mortality was higher in patients with DNR orders: 52.6% vs. 23.8%, p 0 < 0.001. By multivariate logistic regression, a worse ECOG performance status (3−4 vs. 0−2), a higher SAPS 3 Score and DNR orders were associated with a higher in-hospital mortality. By multivariate analysis, non-invasive mechanical ventilation, higher bilirubin levels and DNR orders were significantly associated with 30-day mortality. Conclusion: For patients with advanced cancer disease, even those with DNR orders, who suffer from acute complications or require continuous monitoring, an ImCU-centered multidisciplinary management shows encouraging results in terms of observed-to-expected mortality ratios.

Therapeutic versus Prophylactic Bemiparin in Hospitalized Patients with Nonsevere COVID-19 Pneumonia (BEMICOP Study): An Open-Label, Multicenter, Randomized, Controlled Trial.

Thromboprophylaxis with low molecular weight heparin in hospitalized patients with COVID-19 is mandatory, unless contraindicated. Given the links between inflammation and thrombosis, the use of higher doses of anticoagulants could improve outcomes. We conducted an open-label, multicenter, randomized, controlled trial in adult patients hospitalized with nonsevere COVID-19 pneumonia and elevated D-dimer. Patients were randomized to therapeutic-dose bemiparin (115 IU/kg daily) versus standard prophylaxis (bemiparin 3,500 IU daily), for 10 days. The primary efficacy outcome was a composite of death, intensive care unit admission, need of mechanical ventilation support, development of moderate/severe acute respiratory distress, and venous or arterial thrombosis within 10 days of enrollment. The primary safety outcome was major bleeding (International Society on Thrombosis and Haemostasis criteria). A prespecified interim analysis was performed when 40% of the planned study population was reached. From October 2020 to May 2021, 70 patients were randomized at 5 sites and 65 were included in the primary analysis; 32 patients allocated to therapeutic dose and 33 to standard prophylactic dose. The primary efficacy outcome occurred in 7 patients (22%) in the therapeutic-dose group and 6 patients (18%) in the prophylactic-dose (absolute risk difference 3.6% [95% confidence interval [CI], -16% -24%]; odds ratio 1.26 [95% CI, 0.37-4.26]; p = 0.95). Discharge in the first 10 days was possible in 66 and 79% of patients, respectively. No major bleeding event was registered. Therefore, in patients with COVID-19 hospitalized with nonsevere pneumonia but elevated D-dimer, the use of a short course of therapeutic-dose bemiparin does not appear to improve clinical outcomes compared with standard prophylactic doses. Trial Registration: ClinicalTrials.gov NCT04604327.

Risk factors of lung, head and neck, esophageal, and kidney and urinary tract carcinomas after liver transplantation: the effect of smoking withdrawal.

Liver transplant recipients have an increased risk of malignancy. Smoking is related to some of the most frequent causes of posttransplant malignancy. The incidence and risk factors for the development of neoplasia related to smoking (head and neck, lung, esophageal, and kidney and urinary tract carcinomas) were studied in 339 liver transplant recipients. Risk factors for the development of smoking-related neoplasia were also studied in 135 patients who had a history of smoking so that it could be determined whether smoking withdrawal was associated with a lower risk of malignancy. After a mean follow-up of 7.5 years, 26 patients were diagnosed with 29 smoking-related malignancies. The 5- and 10-year actuarial rates were 5% and 13%, respectively. In multivariate analysis, smoking and older age were independently associated with a higher risk of malignancy. In the smoker subgroup, the variables related to a higher risk of malignancy were active smoking and older age. In conclusion, smoking withdrawal after liver transplantation may have a protective effect against the development of neoplasia.

Prognosis of hepatocellular carcinoma in relation to treatment across BCLC stages.

BACKGROUND: The Barcelona Clinic Liver Cancer (BCLC) staging system recommends first-line therapy for each tumor stage. We evaluated the effect of compliance with BCLC treatment allocation on the prognosis of patients with hepatocellular carcinoma (HCC). METHODS: We retrospectively analyzed 359 consecutive, newly diagnosed HCC patients treated in our Liver Unit during a 14-year period. For each stage, survival was compared according to whether treatment matched the BCLC recommendation. We also compared the survival of patients in the same BCLC stage who received different treatments, and patients in different BCLC stages receiving the same treatment. RESULTS: BCLC-A patients treated with radical therapies (66%) survived longer (117 vs. 20 months; p < 0.001) than patients (33%) who received locoregional or systemic therapies. Survival of BCLC-B patients treated with locoregional treatments (57%) was shorter (24 vs. 71 months; p < 0.001) than that of patients receiving radical therapies (32%). BCLC-C patients treated with systemic therapy or supportive care survived shorter (6 vs. 11 months; p = 0.003) than those receiving locoregional therapies (39%). Survival of BCLC-D patients receiving systemic therapies or supportive care was significantly lower than that of patients treated by liver transplantation (5 vs. 137 months; p < 0.001). CONCLUSIONS: In addition to BCLC stage, actual treatment determines survival in patients with HCC.

Acquiring sepsis competencies through simulation-based learning bundle during intermediate care unit internship.

ABSTRACT: Intermediate care units (ImCUs) have been shown as appropriate units for the management of selected septic patients. Developing specific protocols for residents in training may be useful for their medical performance. The objective of this study was to analyze whether a simulation-based learning bundle is useful for residents while acquiring competencies in the management of sepsis during their internship in an ImCU.A prospective study, set in a tertiary-care academic medical center was performed enrolling residents who performed their internship in an ImCU from 2014 to 2017. The pillars of the simulation-based learning bundle were sepsis scenario in the simulation center, instructional material, and sepsis lecture, and management of septic patients admitted in the ImCU. Each resident was evaluated in the beginning and at the end of their internship displaying a sepsis-case scenario in the simulation center. The authors developed a sepsis-checklist that residents must fulfill during their performance which included 5 areas: hemodynamics (0-10), oxygenation (0-5), antibiotic therapy (0-9), organic injury (0-5), and miscellaneous (0-4).Thirty-four residents from different years of residency and specialties were evaluated. The total median score (interquartile range) increased significantly after training: 12 (25) vs 23 (16), P = .001. First-year residents scored significantly lower than older residents at baseline: 10 (14) vs 14.5 (19), P = .024. However, the performance at the end of the training period was similar in both groups: 21.5 (11) vs 23 (16), P = 1.000. Internal Medicine residents scored significantly higher than residents from other specialties: 18 (17) vs 10.5 (21), P = .007. Nonetheless, the performance at the end of the training period was similar in both groups: 24.5 (9) vs 22 (13), P = 1.000.Combining medical simulation with didactic lectures and a rotation in an ImCU staffed by hospitalists seems to be useful in acquiring competencies to manage critically ill patients with sepsis. We designed a checklist to assure an objective evaluation of the performance of the residents and to identify those aspects that could be potentially improved.

Immunological Biomarkers of Fatal COVID-19: A Study of 868 Patients.

Information on the immunopathobiology of coronavirus disease 2019 (COVID-19) is rapidly increasing; however, there remains a need to identify immune features predictive of fatal outcome. This large-scale study characterized immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection using multidimensional flow cytometry, with the aim of identifying high-risk immune biomarkers. Holistic and unbiased analyses of 17 immune cell-types were conducted on 1,075 peripheral blood samples obtained from 868 COVID-19 patients and on samples from 24 patients presenting with non-SARS-CoV-2 infections and 36 healthy donors. Immune profiles of COVID-19 patients were significantly different from those of age-matched healthy donors but generally similar to those of patients with non-SARS-CoV-2 infections. Unsupervised clustering analysis revealed three immunotypes during SARS-CoV-2 infection; immunotype 1 (14% of patients) was characterized by significantly lower percentages of all immune cell-types except neutrophils and circulating plasma cells, and was significantly associated with severe disease. Reduced B-cell percentage was most strongly associated with risk of death. On multivariate analysis incorporating age and comorbidities, B-cell and non-classical monocyte percentages were independent prognostic factors for survival in training (n=513) and validation (n=355) cohorts. Therefore, reduced percentages of B-cells and non-classical monocytes are high-risk immune biomarkers for risk-stratification of COVID-19 patients.

Usefulness of a program of neoplasia surveillance in liver transplantation. A preliminary report.

De novo malignancies are frequent complications after liver transplantation. Aim of the study is to evaluate whether a surveillance program for malignancy may improve patient survival. We have compared the survival after the diagnosis of malignancy (excluding cutaneous and hepatobiliary carcinomas and lymphoproliferative disease) of patients with symptomatic or incidental malignancies with patients with neoplasia diagnosed on screening. Two hundred and eighty patients with a follow-up greater than three months were followed for a median of 77.5 months (total follow-up: 1515 patient-yr). Thirty-three patients developed 41 malignancies. When compared with general population, the entire cohort of liver transplant recipients had a significantly higher risk of malignancy (relative risk: 2.34), gastrointestinal tract (relative risk: 2.52), urological tract (relative risk: 2.94) and head and neck cancer (relative risk: 4.14), and cancer-related death (relative risk: 2.35). All nine patients diagnosed with cancer with active screening are currently alive and free of malignancy after a median follow-up of 25 months. By contrast, 18/24 patients with diagnosis of cancer prompted by symptoms or incidentally diagnosed died as a consequence of the cancer (median survival: 13.5 months). The difference in survival between both groups was significant (p = 0.002). In conclusion, a close surveillance protocol for the diagnosis of malignancy could be life-saving in liver transplant recipients.

A retrospective comparative analysis of the effect of Y90-radioembolization on the survival of patients with unresectable hepatocellular carcinoma.

BACKGROUND/AIMS: to determine the impact of Y90-Radioembolization on survival when used as a first-line treatment for unresectable HCC. METHODOLOGY: We retrospectively analyzed 35 consecutive patients with unresectable HCC who received 90Y-labeled resin microspheres as first-line treatment and compared their overall survival from the time of diagnosis with that of a cohort of 43 patients with unresectable HCC that were potential candidates for Y90-Radioembolization but had received conventional care due to unavailability or technical contraindications. Patients in both groups had a similar liver function and tumor burden. RESULTS: Median survival from diagnosis was significantly higher in the radioembolization group compared with controls (16 vs. 8 months; p < 0.05), even after adjusting for cirrhosis, multinodular disease, bilobar involvement or vascular invasion. In a multivariate analysis, treatment by radioembolization was the only prognostic factor independently associated with improved survival. In an intention-to-treat analysis, patients evaluated for radioembolization (finally treated or not) survived longer than controls (13 vs. 10 months; p < 0.05). CONCLUSION: Y90-Radioembolization is likely to improve survival among patients with unresectable HCC compared with conventional treatment. Further prospective studies are needed to evaluate the potential of this new treatment modality in unresectable HCC.

Liver transplantation in patients with hepatocellular carcinoma across Milan criteria.

Milan criteria are the most frequently used limits for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC), but our previous experience with expanded criteria showed encouraging results. The aim of this study was to investigate whether our expanded Clinica Universitaria de Navarra (CUN) criteria (1 nodule up to 6 cm or 2-3 nodules up to 5 cm each) could be used to select patients with HCC for LT. Eighty-five patients with HCC fulfilling CUN criteria were included as candidates for LT. Survival of transplanted HCC patients was compared with survival of patients without HCC (n = 180). After the exclusion of 2 patients with tumor seeding of the chest wall due to pre-LT tumor biopsy, survival and recurrence rates were compared according to tumor staging. Twenty-six out of 85 (30%) patients exceeded Milan criteria. Twelve patients had tumor progression on the waiting list. Patients exceeding Milan criteria had a higher dropout rate due to tumoral progression. One-, 3-, 5-, 7-, and 10-year survival rates of the 73 transplanted HCC patients were 86%, 74%, 70%, 61%, and 50%, respectively. Survival of patients with HCC was significantly lower than that of patients without HCC, but by multivariate analysis, HCC was not associated with lower survival. Tumor recurrence and survival rates were similar for patients fulfilling Milan and CUN criteria. Pathological staging showed 55 patients within Milan criteria, 7 patients exceeding them but within CUN criteria, and 9 patients exceeding CUN criteria. Tumor recurrence rates were 2/55 (4%), 0/7 (0%), and 4/9 (44%) in each of these groups, respectively. In conclusion, following CUN criteria could increase the number of HCC patients who could benefit from LT, without worsening the results. Because of the short number of patients in this series, these data need external validation.

Design and Performance of a New Severity Score for Intermediate Care.

BACKGROUND: Application of illness-severity scores in Intermediate Care Units (ImCU) shows conflicting results. The aim of the study is to design a severity-of-illness score for patients admitted to an ImCU. METHODS: We performed a retrospective observational study in a single academic medical centre in Pamplona, Spain. Demographics, past medical history, reasons for admission, physiological parameters at admission and during the first 24 hours of ImCU stay, laboratory variables and survival to hospital discharge were recorded. Logistic regression analysis was performed to identify variables for mortality prediction. RESULTS: A total of 743 patients were included. The final multivariable model (derivation cohort = 554 patients) contained only 9 variables obtained at admission to the ImCU: previous length of stay 7 days (6 points), health-care related infection (11), metastatic cancer (9), immunosuppressive therapy (6), Glasgow comma scale 12 (10), need of non-invasive ventilation (14), platelets 50000/mcL (9), urea 0.6 g/L (10) and bilirubin 4 mg/dL (9). The ImCU severity score (ImCUSS) is generated by summing the individual point values, and the formula for determining the expected in-hospital mortality risk is: e(ImCUSS points*0.099 - 4,111)/(1 + e(ImCUSS points*0.099 - 4,11)1). The model showed adequate calibration and discrimination. Performance of ImCUSS (validation cohort = 189 patients) was comparable to that of SAPS II and 3. Hosmer-Lemeshow goodness-of-fit C test was χ2 8.078 (p=0.326) and the area under receiver operating curve 0.802. CONCLUSIONS: ImCUSS, specially designed for intermediate care, is based on easy to obtain variables at admission to ImCU. Additionally, it shows a notable performance in terms of calibration and mortality discrimination.

Mortality Prediction in Patients Undergoing Non-Invasive Ventilation in Intermediate Care.

BACKGROUND: Intermediate Care Units (ImCU) have become an alternative scenario to perform Non-Invasive Ventilation (NIV). The limited number of prognostic studies in this population support the need of mortality prediction evaluation in this context. OBJECTIVE: The objective of this study is to analyze the performance of Simplified Acute Physiology Score (SAPS) II and 3 in patients undergoing NIV in an ImCU. Additionally, we searched for new variables that could be useful to customize these scores, in order to improve mortality prediction. DESIGN: Cohort study with prospectively collected data from all patients admitted to a single center ImCU who received NIV. The SAPS II and 3 scores with their respective predicted mortality rates were calculated. Discrimination and calibration were evaluated by calculating the area under the receiver operating characteristic curve (AUC) and with the Hosmer-Lemeshow goodness of fit test for the models, respectively. Binary logistic regression was used to identify new variables to customize the scores for mortality prediction in this setting. PATIENTS: The study included 241 patients consecutively admitted to an ImCU staffed by hospitalists from April 2006 to December 2013. KEY RESULTS: The observed in-hospital mortality was 32.4% resulting in a Standardized Mortality Ratio (SMR) of 1.35 for SAPS II and 0.68 for SAPS 3. Mortality discrimination based on the AUC was 0.73 for SAPS II and 0.69 for SAPS 3. Customized models including immunosuppression, chronic obstructive pulmonary disease (COPD), acute pulmonary edema (APE), lactic acid, pCO2 and haemoglobin levels showed better discrimination than old scores with similar calibration power. CONCLUSIONS: These results suggest that SAPS II and 3 should be customized with additional patient-risk factors to improve mortality prediction in patients undergoing NIV in intermediate care.