T-cell checkpoint inhibition as a cancer treatment approach has been the main breakthrough in cancer treatment during the last years. Since the approval of the first commercial CTLA-4 antibody ...ipilimumab in 2011 for the treatment of melanoma, research and drug development in this field has accelerated massively. In 2014, the US Food and Drug Administration (FDA) approved the first PD-1 targeting agent, namely pembrolizumab, shortly followed by nivolumab. Areas covered: Nivolumab is a fully human immunoglobulin G4 anti-PD-1 monoclonal antibody which is approved for multiple advanced malignancies, including melanoma, non-small cell lung cancer, renal cell cancer, Hodgkin's lymphoma, squamous head and neck cancer, and urothelial carcinoma. In September 2017, nivolumab was approved by the FDA for liver cancer as a second line treatment after failure of sorafenib based on the data of the multi-cohort phase 1/2 trial CheckMate-040. This article reviews the concept of immunotherapy in liver cancer with focus on nivolumab. Expert commentary: Immunotherapy in hepatocellular carcinoma is safe and is a new treatment option for patients with advanced stage disease besides sorafenib and regorafenib in the US. Randomized phase III trials of nivolumab, pembrolizumab, atezolizumab, durvalumab and tislelizumab as mono- or combination-therapy are ongoing.
Background and Aims The continually increasing life expectancy in man comes along with an increasing number of endoscopic interventions performed in patients with advanced or even very advanced age. ...Data on the feasibility and safety of ERCP in elderly patients are relatively scarce. Methods By a systematic query of the University Hospital Frankfurt clinical database, patients undergoing their first ERCP procedure at our center were retrospectively identified. Patients were grouped according to age at the day of the intervention (>80 years, 61-80 years, 40-60 years, and <40 years). Demographic data, indication, outcome, and risk factors were compared among the indicated groups. Results A total of 758 patients who underwent ERCP procedures at our center were identified and included in the study. Main indications for ERCP were intraductal gallstones in 345 patients (45%) and tumor obstruction of the bile ducts (distal common bile duct: n = 126 16.5%, hilar cholangiocarcinoma: n = 89 11.7%, tumor of papilla of Vater: n = 16 2.1%). Gallstones were the most common cause for ERCP in patients aged >80 years (53.8%), and normal findings indicating exclusion of relevant disease were more frequent in patients <80 years (13.4%) compared with older patients (4.3%) ( P < .01). Sedation adverse events were significantly more common in individuals aged >80 years compared with younger patients (3.4% vs 0.5%; P < .01). However, post-ERCP pancreatitis was significantly less frequent in the older patients (>80 years) (0.9% vs 5.3%; P < .05). Other adverse events were equally distributed in all age groups. The ERCP success rate (>80%) was not different among age groups. Conclusions ERCP is safe and efficient in patients aged 80 years or older. However, conscious sedation must be carefully monitored in older patients because risk of sedation adverse events is increased. The incidence of post-ERCP pancreatitis is lower in older patients compared with younger ones.
Vitamin D, best known to regulate bone mineralization, has numerous additional roles including regulation inflammatory pathways. Recently, an increased incidence of 25-hydroxyvitamin D3 (25(OH)D3) ...deficiency has been found in subjects suffering from liver diseases. We here investigated if low vitamin D levels might be associated with prognosis, inflammation and infectious complications in patients with cirrhosis.
We performed a prospective cohort study investigating the relation between 25(OH)D3 levels and stages of cirrhosis, mortality and complications of cirrhosis, including infections.
251 patients with cirrhosis were enrolled into the present prospective cohort study. 25(OH)D3 levels were quantified by radioimmunoassay from serum samples obtained at study inclusion. The mean follow-up time was 411 ± 397 days with a range of 1-1382 days. 30 (12.0%) patients underwent liver transplantation and 85 (33.8%) individuals died within the study. The mean serum 25(OH)D3 concentration was 8.93 ± 7.1 ng/ml with a range of 1.0 to 46.0 ng/ml. 25(OH)D3 levels differed significantly between Child Pugh scores and showed a negative correlation with the model of end stage liver disease (MELD) score. Patients with decompensated cirrhosis and infectious complications, had significantly lower 25(OH)D3 levels compared to subjects without complications. Low 25(OH)D3 was associated with mortality in uni- as well as multivariate Cox regression models.
25(OH)D3 deficiency is associated with advanced liver disease and low 25(OH)D3 levels are an indicator for a poor outcome and are associated with infectious complications.
Summary
Background
Programmed cell death protein‐1‐targeted immunotherapy has shown promising results in phase II studies of hepatocellular carcinoma.
Aim
To evaluate safety and efficacy of nivolumab ...and pembrolizumab in an international, multicentre, real‐world cohort of patients with advanced hepatocellular carcinoma.
Methods
Sixty‐five patients treated with nivolumab (n = 34) or pembrolizumab (n = 31) between July 10, 2015 and December 31, 2018 (data cut‐off) across six centres in Austria and Germany were retrospectively analysed.
Results
Child‐Pugh class A/B/C was 32 (49%)/28 (43%)/5 (8%). Immunotherapy was used as systemic first‐/second‐/third‐/fourth‐line treatment in 9 (14%)/27 (42%)/26 (40%)/3 (5%) patients. Fifty‐four patients had at least one follow‐up imaging and were, therefore, available for radiological response assessment. The overall response and disease control rates were 12% and 49% respectively. Of 52 evaluable patients, four (8%) had hyperprogressive disease. Median time to progression was 5.5 (95% CI, 3.5‐7.4) months, median progression‐free survival was 4.6 (95% CI, 3.0‐6.2) months, and median overall survival was 11.0 (95% CI, 8.2‐13.8) months. Most common adverse events were infections (n = 7), rash (n = 6), pruritus (n = 3), fatigue (n = 3), diarrhoea (n = 3) and hepatitis (n = 3). Efficacy and safety results were comparable between Child‐Pugh A and B patients; however, median overall survival (OS) was shorter in Child‐Pugh B patients (16.7 vs 8.6 months; P = 0.065). There was no difference in terms of efficacy and adverse events between patients who received immunotherapy as first‐/second‐line and third‐/fourth‐line respectively.
Conclusions
Programmed cell death protein‐1‐targeted immunotherapy with nivolumab or pembrolizumab showed promising efficacy and safety in patients with advanced hepatocellular carcinoma, including subjects with Child‐Pugh stage B and patients with intensive pretreatment.
The global spread of multidrug-resistant organisms (MDRO) complicates treatment and isolation measures in hospitals and has shown to increase mortality. Patients with disease- or therapy-related ...immunodeficiency are especially at risk for fatal infections caused by MDRO. The impact of MDRO colonization on the clinical course of AML patients undergoing intensive induction chemotherapy-a potentially curative but highly toxic treatment option-has not been systematically studied.
312 AML patients undergoing intensive induction chemotherapy between 2007 and 2015 were examined for MDRO colonization. Patients with evidence for MDRO before or during the hospital stay of induction chemotherapy were defined as colonized, patients who never had a positive swab for MDRO were defined as noncolonized.
Of 312 AML patients 90 were colonized and 130 were noncolonized. Colonized patients suffered from significantly more days with fever, spent more days on the intensive care unit and had a higher median C-reactive protein value during the hospital stay. These findings did not result in a prolonged length of hospital stay or an increased mortality rate for colonized patients. However, in a subgroup analysis, patients colonized with carbapenem-resistant enterobacteriaceae (CRE) had a significantly reduced 60- and 90-day, as well as 1- and 2-year survival rates when compared to noncolonized patients.
Our analysis highlights the importance of intensive MDRO screening especially in patients with febrile neutropenia since persisting fever can be a sign of MDRO-colonization. CRE-colonized patients require special surveillance, since they seem to be at risk for death.
Vacuolization is a frequently found morphological feature in acute myeloid leukemia (AML) blasts. Subcellular origin and biological function as well as prognostic impact are currently unknown. The ...aim of this study was to evaluate whether vacuolization correlates with clinically relevant AML features.
Bone marrow smears of patients diagnosed with AML at the University Hospital Frankfurt between January 2011 and August 2013 were analyzed for blast vacuolization and correlated with clinically relevant AML features. Patients undergoing standard induction chemotherapy were further analyzed for molecular and cytogenetic features as well as treatment response and survival.
14 of 100 patients diagnosed with AML receiving standard induction chemotherapy had evidence of blast vacuolization. Positivity for vacuolization correlated with a CD15 positive immunophenotype and with a higher incidence of high-risk AML according to the European LeukemiaNet risk stratification. AML patients with blast vacuolization had a poor blast clearance after standard induction chemotherapy and poor survival.
In conclusion, our findings demonstrate that vacuolization can easily be determined in myeloid leukemia blasts and may be a useful biomarker to predict AML risk groups as well as early treatment response rates and survival.
Acute kidney injury (AKI) complicates the clinical course of hospitalized patients by increasing need for intensive care treatment and mortality. There is only little data about its impact on AML ...patients undergoing intensive induction chemotherapy. In this study, we analyzed the incidence as well as risk factors for AKI development and its impact on the clinical course of AML patients undergoing induction chemotherapy. We retrospectively analyzed data from 401 AML patients undergoing induction chemotherapy between 2007 and 2019. AKI was defined and stratified according to KIDGO criteria by referring to a defined baseline serum creatinine measured on day 1 of induction chemotherapy. Seventy-two of 401 (18%) AML patients suffered from AKI during induction chemotherapy. AML patients with AKI had more days with fever (7 vs. 5,
p
= 0.028) and were more often treated on intensive care unit (45.8% vs. 10.6%,
p
< 0.001). AML patients with AKI had a significantly lower complete remission rate after induction chemotherapy and, with 402 days, a significantly shorter median overall survival (OS) (median OS for AML patients without AKI not reached). In this study, we demonstrate that the KIDGO classification allows mortality risk stratification for AML patients undergoing induction chemotherapy. Relatively mild AKI episodes have impact on the clinical course of these patients and can lead to chronic impairment of kidney function. Therefore, we recommend incorporating risk factors for AKI in decision-making considering nutrition, fluid management, as well as the choice of potentially nephrotoxic medication in order to decrease the incidence of AKI.
Hepatitis B virus (HBV) surface proteins (HBsAg) coat the viral particle and form subviral particles (SVPs). Loss of HBsAg represents a functional cure and is an important treatment goal.
We analyzed ...the impact of the HBV genotypes A-E and pre-S mutations on SVP expression in hepatitis B virus e antigen (HBeAg)-negative chronic HBV-infected patients. A HBV genome harboring a preS1-deletion was analyzed in hepatoma cells.
We observed a genotype-specific ratio of the 3 surface proteins (SHBs/MHBs/LHBs), reflecting differences in the morphology and composition of SVPs. Deletions/mutations in the preS1/preS2 domain, detected in released viral genomes, did not affect the molecular weight of MHBs and LHBs in these patients. In contrast, LHB molecular weight was altered in vitro using an HBV genome harboring a preS1-deletion derived from one of these patients.
Differences in composition of SVPs may result in genotype-specific immunogenicity and pathogenesis. In the patients with preS-mutations, secreted HBsAg and released viral genomes cannot be derived from the same genetic source. As viral genomes are derived from covalently closed circular DNA (cccDNA), HBsAg is presumably derived from integrated DNA. This important HBsAg source should be considered for novel antiviral strategies in HBeAg-negative chronic HBV-infected patients.
Myiasis refers to the infestation of living humans and vertebrates with fly larvae that feed on necrotic or vital tissue of the host. Since the invasion of new fly species in Europe is currently ...being observed, which live obligatorily parasitically or are close relatives of such species, the aim of this study is to obtain a global overview of the distribution of myiasis-causing fly species in times of climate change and to assess the possible consequences for Western Europe. A systematic literature search was conducted using Pubmed/Medline for the years 1997 to 2017 and a total of 464 international case reports from 79 countries were evaluated. The described cases were caused by 41 different species. In 99.4% of the cases, it was a colonization by just one species, a maximum of three species were detected in a human. Casuistics from Western Europe mostly describe myiasis as a “holiday souvenir” from tropical regions. Reports of autochthonous cases are rare in comparison to other regions. With regard to rising temperatures and the invasion of new fly species, a noticeable increase in the number of cases in Western Europe is to be assumed, which could be an increasing problem in the clinical area and in care, which is why thorough monitoring for professional identification and treatment seems important in the future.
Background and Aims Treatment of anastomotic biliary strictures (ABSs) after orthotopic liver transplantation by endoscopic insertion of multiple plastic stents (MPSs) is well established. The use of ...covered self-expandable metal stents (cSEMSs) for this indication is less investigated. Methods In an open-label, multicenter, randomized trial, patients with confirmed ABSs were randomly assigned 1:1 to receive either an MPS or a cSEMS. The primary endpoint was the number of endoscopic interventions until ABS resolution. Secondary endpoints were frequency of adverse events, treatment success rates, and time to treatment success and recurrence of ABS during follow-up of at least 1 year. Results Fifty-eight patients were included between 2012 and 2015, and 48 patients completed follow-up. Patients receiving MPS (n = 24) underwent a median of 4 (range, 3-12) endoscopic retrograde cholangiography examinations, whereas those in the cSEMS group (n = 24) underwent a median of 2 (range, 2-12) sessions until ABS resolution ( P < .001). A median of 8 (range, 2-32) stents was used until ABS resolution within the MPS group and 1 (range, 1-24) in the cSEMS group ( P < .0001). cSEMS migration occurred in 8 (33.3%) patients. Treatment duration did not differ significantly. Initial treatment success rates were high with 23 (95.8%) in the MPS group and 24 (100%) for cSEMSs ( P = 1). Five (20.8%) patients in both groups showed stricture recurrence after a median follow-up of 500 days (range, 48-1317 days). Conclusions cSEMSs for treatment of ABSs needed less endoscopic interventions to achieve similar efficacy as MPS and might become a new treatment standard. However, the optimal duration of cSEMS therapy and cost-efficacy have to be evaluated. (Clinical trial registration number: NCT01393067 .)
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