Hans-Heinrich Kreipe

The phenotype of human STK4 deficiency.

We describe a novel clinical phenotype associating T- and B-cell lymphopenia, intermittent neutropenia, and atrial septal defects in 3 members of a consanguineous kindred. Their clinical histories included recurrent bacterial infections, viral infections, mucocutaneous candidiasis, cutaneous warts, and skin abscesses. Homozygosity mapping and candidate gene sequencing revealed a homozygous premature termination mutation in the gene STK4 (serine threonine kinase 4, formerly having the symbol MST1). STK4 is the human ortholog of Drosophila Hippo, the central constituent of a highly conserved pathway controlling cell growth and apoptosis. STK4-deficient lymphocytes and neutrophils exhibit enhanced loss of mitochondrial membrane potential and increased susceptibility to apoptosis. STK4 deficiency is a novel human primary immunodeficiency syndrome.

Virus-associated hemophagocytic syndrome as a major contributor to death in patients with 2009 influenza A (H1N1) infection

IntroductionVirus-associated hemophagocytic syndrome (VAHS) is a severe complication of various viral infections often resulting in multiorgan failure and death. The purpose of this study was to describe baseline characteristics, development of VAHS, related treatments and associated mortality rate of consecutive critically ill patients with confirmed 2009 influenza A (H1N1) infection and respiratory failure.MethodsWe conducted a prospective observational study of 25 critically ill patients with 2009 influenza A (H1N1) infection at a single-center intensive care unit in Germany between 5 October 2009 and 4 January 2010. Demographic data, comorbidities, diagnosis of VAHS, illness progression, treatments and survival data were collected. The primary outcome measure was the development of VAHS and related mortality. Secondary outcome variables included duration of mechanical ventilation, support of extracorporeal membrane oxygenation and duration of viral shedding.ResultsVAHS developed in 9 (36%) of 25 critically ill patients with confirmed 2009 influenza A (H1N1) infection, and 8 (89%) of them died. In contrast, the mortality rate in the remaining 16 patients without VAHS was 25% (P = 0.004 for the survival difference in patients with or without VAHS by log-rank analysis). The patients were relatively young (median age, 45 years; interquartile range (IQR), 35 to 56 years of age); however, 18 patients (72%) presented with one or more risk factors for a severe course of illness. All 25 patients received mechanical ventilation for severe acute respiratory distress syndrome and refractory hypoxemia, with a median duration of mechanical ventilation of 19 days (IQR, 13 to 26 days). An additional 17 patients (68%) required extracorporeal membrane oxygenation for a median of 10 days (IQR, 6 to 19 days).ConclusionsThe findings of this study raise the possibility that VAHS may be a frequent complication of severe 2009 influenza A (H1N1) infection and represents an important contributor to multiorgan failure and death.

Interactions among HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF-triggered granulopoiesis.

We found that hematopoietic cell–specific Lyn substrate 1 (HCLS1 or HS1) is highly expressed in human myeloid cells and that stimulation with granulocyte colony-stimulating factor (G-CSF) leads to HCLS1 phosphorylation. HCLS1 binds the transcription factor lymphoid-enhancer binding factor 1 (LEF-1), transporting LEF-1 into the nucleus upon G-CSF stimulation and inducing LEF-1 autoregulation. In patients with severe congenital neutropenia, inherited mutations in the gene encoding HCLS1-associated protein X-1 (HAX1) lead to profound defects in G-CSF–triggered phosphorylation of HCLS1 and subsequently to reduced autoregulation and expression of LEF-1. Consistent with these results, HCLS1-deficient mice are neutropenic. In bone marrow biopsies of the majority of tested patients with acute myeloid leukemia, HCLS1 protein expression is substantially elevated, associated with high levels of G-CSF synthesis and, in some individuals, a four-residue insertion in a proline-rich region of HCLS1 protein known to accelerate intracellular signaling. These data demonstrate the importance of HCLS1 in myelopoiesis in vitro and in vivo.

Dynamic of Bone Marrow Fibrosis Regression Predicts Survival after Allogeneic Stem Cell Transplantation for Myelofibrosis

We correlate regression of bone marrow fibrosis (BMF) on day 30 and 100 after dose- reduced allogeneic stem cell transplantation (allo-SCT) in 57 patients with primary or post-essential thrombocythemia/polycythemia vera myelofibrosis with graft function and survival. The distribution of International Prognostic Scoring System (IPSS) risk score categories was 1 patient with low risk, 5 patients with intermediate-1 risk, 18 patients with intermediate-2 risk, and 33 patients with high risk. Before allo-SCT, 41 patients (72%) were classified as XXX [myclofibrosis (MF)]-3 and 16 (28%) were classified as MF-2 according to the World Health Organization criteria. At postengraftment day +30 (±10 days), 21% of the patients had near-complete or complete regression of BMF (MF-0/-1), and on day +100 (±20 days), 54% were MF-0/-1. The 5-year overall survival rate at day +100 was 96% in patients with MF-0/-1 and 57% for those with MF-2/-3 (P = .04). There was no difference in BMF regression at day +100 between IPSS high-risk and low/intermediate-risk patients. Complete donor cell chimerism at day +100 was seen in 81% of patients with MF-0/-1 and in 31% of those with MF-2/-3. Patients with MF-2/-3 at day +100 were more likely to be transfusion-dependent for either RBCs (P = .014) or platelets (P = .018). Rapid BMF regression after reduced-intensity conditioning allo-SCT resulted in a favorable survival independent of IPSS risk score at transplantation.

Contact endoscopy for the evaluation of the pharyngeal and laryngeal mucosa

Contact endoscopy is a noninvasive tool that allows in vivo and in situ examination of superficial mucosa. Its use for early diagnosis of cancerous lesions of the oropharynx and larynx has not been evaluated. The aim of the study was to validate contact endoscopy for the examination of pharyngeal and laryngeal mucosa.

Pathological characteristics of a series of rare chronic histiocytic intervillositis of the placenta

Chronic histiocytic intervillositis of the placenta (CHI) is a rare and poorly understood pathology which may occur in all trimesters. The most conspicuous feature is a histiocytic infiltration of the intervillous space without involvement of the villous parenchyma. In this report on CHI, we re-evaluate a series of four cases and focus on histological, immunohistological and fluorescence in situ hybridisation-derived findings, fetal status and clinical data for previously unrecognised CHI-associated features. Our approach revealed that assisted reproduction-induced pregnancy had been performed in 2 of 4 CHI cases, but other factors and comorbidities are likely to contribute to CHI.

High reproducibility of adhesion formation in rat with meso-stitch approximation of injured cecum and abdominal wall.

Objective: Peritoneal adhesions following surgery are a common, serious pathology with severe complications. Appropriate animal adhesion models are essential for the assessment of adhesion preventing medical devices. This study introduces a variation of an established rat model in which highest degree adhesions are induced with excellent reproducibility (OPAM = optimized peritoneal adhesion model). Thus, this model seems to be eligible to study effects of adhesion preventing devices. Methods: 24 Lewis male rats were divided into four groups (OPAM, WSFX, sham-OPAM, sham-WSFX). The OPAM technique comprised cecal abrasion, creation of an abdominal wall defect plus approximation of injured areas by a suture, which was compared to a setting of lesions without suture fixation (WSFX). All rats were sacrificed at day 7. Macroscopic and histopathological evaluations were performed. Results were statistically analyzed using ANOVA and Dunnetts test. Results: In OPAM rats macroscopic analyses revealed a 90% incidence adhesion of cecum to the abdominal wall, all adhesions imposing as complete agglutination. In WSFX animals incidence of adhesions formation was 75%, while in both sham groups there were no adhesions at all. Histology showed the structure of adhesions with merged smooth muscle of colon and skeletal muscle of abdominal wall in all cases. Conclusion: OPAM technique provides adhesions of injured areas with a better probability than with conventional methods. All OPAM adhesions impressed as highest degree adhesions, i.e. agglutination. Due to high reproducibility in incidence and extend of adhesion formation, the OPAM is recommended for testing of adhesion prevention medical devices.

[Transplant-associated lymphoproliferation].

ZusammenfassungDie Transplantation von soliden Organen und Knochenmark erfordert zur Verhinderung einer Abstoßungsreaktion eine medikamentöse Immunsuppression, die dosis- und medikamentenabhängig die Entstehung von Epstein-Barr-Virus- (EBV-)assoziierten Posttransplantationslymphoproliferationen („post-transplant lymphoproliferative disease“, PTLD) begünstigt. Dabei gibt es ein Spektrum von Läsionen, die von der Hyperplasie bis zum manifesten Lymphom reichen. Letzteres wird als monomorphe PTLD bezeichnet. Hyperplastische Veränderungen, die von viralen Reaktionen nicht zu unterscheiden sind, werden als frühe oder Mononukleose-ähnliche Läsionen bezeichnet, solche, bei denen die Lymphknotenarchitektur aufgehoben ist oder extranodale Herde entstehen, ohne dass ein lymphomartiger Phänotyp nachweisbar ist, als polymorphe PTLD. Bei den monomorphen PTLD handelt es sich entweder um hochmaligne B-Zell-Lymphome, Plasmazellneoplasien oder Hodgkin-Lymphome und nur sehr selten um T-Zell-Lymphome. Niedrig maligne B-Zell-Lymphome treten nicht auf. Eine Reduktion der Immunsuppression kann bei einem Teil der Fälle einschließlich der monomorphen PTLD den Prozess zum Stillstand bringen.AbstractTransplantation of solid organs and haematopoietic stem cells requires immunosuppressive drug therapy in order to prevent rejection or graft-versus-host disease. Depending on dosage and type of drug, the risk of developing an Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) is increased. The lesion spectrum ranges from hyperplastic lesions to manifest lymphomas, the latter being classified as monomorphic PTLD. Hyperplastic changes, which are not distinguishable from viral reactions, comprise early or mononucleosis-like lesions. Those with effaced lymph node architecture or extranodal manifestation without a lymphoma-like phenotype are designated polymorphic PTLD. Monomorphic PTLD are either high grade B cell lymphomas, plasma cell neoplasms or Hodgkin lymphomas and only very rarely T cell lymphomas. Low grade B cell lymphomas do not occur. In a subfraction of cases, including even monomorphic PTLD, reduction of immunosuppression alone is sufficient to induce remission of the pathological process.

PSMA Expression in Tumor Neovasculature Endothelial Cells of Follicular Thyroid Adenoma as Identified by Molecular Imaging Using 68Ga-PSMA Ligand PET/CT.

The prostate-specific membrane antigen (PSMA) is expressed by both prostate cancer and other neoplasms. We report the case of a 65-year-old man with castration-resistant metastatic prostate cancer who underwent Ga-PSMA ligand PET/CT for restaging of disease. Ga-PSMA ligand accumulation was noted in a thyroid lesion, suspicious for thyroid malignancy on complementary ultrasound. Subsequent resection and histopathological analysis showed follicular thyroid adenoma with PSMA expression in tumor neovasculature endothelial cells, but not in thyroid epithelial cells. It is important to be aware that both malignant and benign thyroid neoplasms may show PSMA expression to avoid misinterpretation.

The new liver allocation score for transplantation is validated and improved transplant survival benefit in Germany but not in the United Kingdom.

Prognostic models for the prediction of 90‐day mortality after transplantation with pretransplant donor and recipient variables are needed to calculate transplant benefit. Transplants in adult recipients in Germany (Hannover, n = 770; Kiel, n = 234) and the United Kingdom (Birmingham, n = 829) were used for prognostic model design and validation in separate training and validation cohorts. The survival benefit of transplantation was estimated by subtracting the observed posttransplant 90‐day mortality from the expected 90‐day mortality without transplantation determined by the Model for End‐Stage Liver Disease (MELD) score. A prognostic model called the liver allocation score (LivAS) was derived using a randomized sample from Hannover using pretransplant donor and recipient variables. This model could be validated in the German training and validation cohorts (area under the receiver operating characteristic curve [AUROC] > 0.70) but not in the English cohort (AUROC, 0.58). Although 90‐day mortality rates after transplantation were 13.7% in Hannover, 12.1% in Kiel, and 8.3% in Birmingham, the calculated 90‐day survival benefits of transplantation were 6.8% in Hannover, 7.8% in Kiel, and 2.8% in Birmingham. Deployment of the LivAS for limiting allocation to donor and recipient combinations with likely 90‐day survival as indicated by pretransplant LivAS values below the cutoff value would have increased the survival benefit to 12.9% in the German cohorts, whereas this would have decreased the benefit in England to 1.3%. The English and German cohorts revealed significant differences in 21 of 28 pretransplant variables. In conclusion, the LivAS could be validated in Germany and may improve German allocation policies leading to greater survival benefits, whereas validation failed in England due to profound differences in the selection criteria for liver transplantation. This study suggests the need for national prognostic models. Even though the German centers had higher rates of 90‐day mortality, estimated survival benefits were greater. Liver Transplantation 22 743–756 2016 AASLD.