[Aggressive B­cell lymphomas : Recommendations from the German Panel of Reference Pathologists in the Competence Network on Malignant Lymphomas on diagnostic procedures according to the current WHO classification, update 2017]. / Aggressive B­Zell-Lymphome : Empfehlungen des Deutschen Panels der Referenzpathologen im Kompetenznetz Maligne Lymphome e. V. zum diagnostischen Vorgehen nach der aktuellen WHO-Klassifikation, Update 2017.

The update of the 4th edition of the WHO classification for hematopoietic neoplasms introduces changes in the field of mature aggressive B­cell lymphomas that are relevant to diagnostic pathologists. In daily practice, the question arises of which analysis should be performed when diagnosing the most common lymphoma entity, diffuse large B­cell lymphoma. We discuss the importance of the cell of origin, the analysis of MYC translocations, and the delineation of the new WHO entities of high-grade B­cell lymphomas.

[Revised version of the 4th edition of the WHO classification of malignant lymphomas : What is new?] / Revidierte Fassung der 4. Ausgabe der WHO-Klassifikation maligner Lymphome : Was ist neu?

After 8 years, the WHO has now published the updated version of the 4th edition of the classification of hematopoietic and lymphoid tumors. This update provides a conceptual rewrite of existing entities as well as some new provisional entities and categories, particularly among the aggressive B­cell lymphomas. Important new diagnostic categories include the high-grade B­cell lymphomas, the large B­cell lymphoma with IRF4 rearrangement, and the Burkitt-like lymphoma with 11q aberrations. Of particular importance, new concepts concerning the taxonomy and classification of early lymphoid lesions or precursor lesions are included, such as the in situ follicular neoplasia or the in situ mantle cell neoplasia. In addition, the concept of indolent lymphoproliferations, such as breast-implant-associated anaplastic large cell lymphoma and the indolent T­cell lymphoproliferative disorder of the gastrointestinal tract, has been strengthened. Finally, diagnostic criteria for existing lymphoma entities have been refined.

Transvaginal Hybrid NOTES Cholecystectomy: A Single-Centre Long-Term Experience on Sexual Function.

INTRODUCTION: Transvaginal hybrid NOTES cholecystectomy is an alternative approach to the traditional laparoscopic technique. Despite increasing data regarding clinical outcomes following transvaginal hybrid NOTES cholecystectomy, there is still a lack of long-term results, particularly with regard to sexual function. Therefore, the aim of this study was to evaluate long-term outcome of a series of transvaginal hybrid cholecystectomy. PATIENTS AND METHODS: Female patients with symptomatic cholecystolithiasis who underwent transvaginal hybrid NOTES cholecystectomy were retrospectively analysed regarding clinical and surgical outcome parameters. Furthermore, all patients received a 17-question survey postoperative with questions about sexual intercourse, the domains satisfaction and pain of the German Female Sexual Function Index. RESULTS: Overall, 47 of 80 patients were included in the study with a completed survey responses (return rate 58.6%), with a mean age of 48 years, mean body mass index of 29 and mean operative time of 47 min. The median follow-up was 40 months. There were no intra- or postoperative complications and no conversion to a laparoscopic or open approach. No significant differences were found for postoperative sexual function (painful intercourse, inability to achieve orgasm), although sexual intercourse was less frequent postoperatively (p = 0.022). Forty-four patients (93.7%) were satisfied with the aesthetic and the overall postoperative result, and 40 patients (85.1%) would recommend the applied surgical technique to friends and family. CONCLUSION: The findings show that transvaginal hybrid NOTES cholecystectomy is a safe procedure for female patients, particularly with regard to sexual function.

Yeast nitrogen catabolite repression is sustained by signals distinct from glutamine and glutamate reservoirs.

Nitrogen catabolite repression (NCR) is a wide transcriptional regulation program enabling baker's yeast to downregulate genes involved in the utilization of poor nitrogen sources when preferred ones are available. Nowadays, glutamine and glutamate, the major nitrogen donors for biosyntheses, are assumed to be key metabolic signals regulating NCR. NCR is controlled by the conserved TORC1 complex, which integrates nitrogen signals among others to regulate cell growth. However, accumulating evidence indicate that the TORC1-mediated control of NCR is only partial, arguing for the existence of supplementary regulatory processes to be discovered. In this work, we developed a genetic screen to search for new players involved in NCR signaling. Our data reveal that the NADP-glutamate dehydrogenase activity of Gdh1 negatively regulates NCR-sensitive gene transcription. By determining the total, cytoplasmic and vacuolar pools of amino acids, we show that there is no positive correlation between glutamine/glutamate reservoirs and the extent of NCR. While our data indicate that glutamine could serve as initial trigger of NCR, they show that it is not a sufficient signal to sustain repression and point to the existence of yet unknown signals. Providing additional evidence uncoupling TORC1 activity and NCR, our work revisits the dogmas underlying NCR regulation.

The importance of infant mental health.

A clear understanding of infant mental health will significantly assist a clinician's ability to provide high-quality paediatric care for children and their families, given the new understanding of its role in overall development. The present commentary describes the mental health needs of children <3 years of age and provides practical suggestions for the office setting.

En raison des nouvelles connaissances sur le rôle de la santé mentale dans le développement global, le clinicien sera mieux en mesure de fournir des soins pédiatriques de qualité aux enfants et à leur famille s'il comprend bien la santé mentale des nourrissons. Le présent commentaire décrit les besoins des enfants de moins de trois ans en matière de santé mentale et contient des suggestions pratiques à utiliser en cabinet.

Accumulation of STIM1 is associated with the degenerative muscle fibre phenotype in ALS and other neurogenic atrophies.

AIM: Upon denervation, skeletal muscle fibres initiate complex changes in gene expression. Many of these genes are involved in muscle fibre remodelling and atrophy. Amyotrophic lateral sclerosis (ALS) leads to progressive neurodegeneration and neurogenic muscular atrophy (NMA). Disturbed calcium homeostasis and misfolded protein aggregation both in motor neurones and muscle fibres are key elements of ALS pathogenesis that are mutually interdependent. Therefore, we hypothesized that the calcium sensor STIM1 might be abnormally modified and involved in muscle fibre degeneration in ALS and other types of NMA. METHODS: We examined ALS and NMA patient biopsy and autopsy tissue and tissue from G93A SOD1 mice by immunohistochemistry and immunoblotting. RESULTS: In normal human and mouse muscle STIM1 was found to be differentially expressed in muscle fibres of different types and to concentrate at neuromuscular junctions, compatible with its known role in calcium sensing. Denervated muscle fibres of sALS and NMA cases and SOD1 mice showed diffusely increased STIM1 immunoreactivity along with ubiquitinated material. In addition, distinct focal accumulations of STIM1 were observed in target structures within denervated fibres of sALS and other NMA as well as SOD1 mouse muscles. Large STIM1-immunoreactive structures were found in ALS-8 patient muscle harbouring the P56S mutation in the ER protein VAPB. CONCLUSION: These findings suggest that STIM1 is involved in several ways in the reaction of muscle fibres to denervation, probably reflecting alterations in calcium homeostasis in denervated muscle fibres.

Pediatric Nodular Lymphocyte-predominant Hodgkin Lymphoma: Treatment Recommendations of the GPOH-HD Study Group.

Nodular lymphocyte-predominant Hodgkin lymphoma (nLPHL) is a very rare disease in childhood and adolescence. In Germany, about 15 newly diagnosed patients present with this disease annually; this number comprises less than 10% of all pediatric Hodgkin lymphoma cases. Since the EuroNet-PHL-LP1 trial for early stage nLPHL patients stopped recruiting in Germany in October 2014, the GPOH-HD writing committee reviewed the literature and decided to deliver treatment recommendations for childhood and adolescent nLPHL patients. These guidelines shall be applicable to young nLPHL patients in European countries that will no longer be able to participate in nLPHL trials for young patients. Therefore, the EuroNet-PHL-nLPHL-registry will be installed to provide quality assured central review of staging and response assessment for registered patients by the Central Review Board of EuroNet-PHL in Halle/Leipzig, Germany.

[Lymphadenopathy: demarcation to malignant lymphomas]. / Lymphadenopathie: Grenzziehung zu malignen Lymphomen.

Recognition of the differential diagnosis between lymphadenitis and malignant lymphoma requires good knowledge of the basic forms of the disease as well in depth knowledge of the structure of the individual compartments. There are defined forms of lymphadenitis where the differential diagnosis to certain lymphoma entities is known. Other reactive structural alterations show indistinct limits so that a decision is only possible after using additional techniques, such as immunohistochemistry and molecular analyses. Finally, there are marginal areas which can only be clarified by including clinical data.

[Round robin test for detection of genomic aberrations in non-Hodgkin lymphoma by in situ hybridization]. / Ringversuch zum Nachweis genomischer Veränderungen bei Non-Hodgkin-Lymphomen mittels In-situ-Hybridisierung.

BACKGROUND: The detection of characteristic genomic aberrations by fluorescence in situ hybridization (FISH) has a high diagnostic impact on lymphomas according to the World Health Organization (WHO). To investigate the reproducibility of non-isotopic ISH results a multicenter trial was carried out involving eight institutes for hematopathology. MATERIAL AND METHODS: Analyses were performed on two diffuse large B-cell lymphomas (DLBCL) without known aberrations, on one follicular lymphoma with a IGH/BCL2 translocation and BCL6 split and on two B-cell lymphomas intermediate between DLBCL and Burkitt's lymphoma with c-MYC and BCL2 rearrangements, one with an additional BCL6 split. Break-apart probes for BCL6 and c-MYC, as well as fusion probes for the c-MYC/IGH and the IGH/BCL2 translocations were used. RESULTS: All aberrations were correctly detected by all centres and no false positive or false negative results were obtained. The numbers of positive cells varied from 25% to 94%. Pearson's correlation coefficient between the centres was always > 0.8. CONCLUSIONS: The ISH analysis of recurrent genomic aberrations in formalin-fixed paraffin-embedded (FFPE) tissue is a highly reproducible technique which yields substantial additive help for lymphoma diagnostics.

[Hyperthyroidism, eosinophilia, and fever in a 64-year-old patient]. / Hyperthyreose, Eosinophilie und Fieber bei einem 64-jährigen Patienten.

We report on a male patient suffering from loss of weight, fatigue, fever, eosinophilia, and hyperthyreoidism. The echocardiogram revealed a left atrial mass originating from the posterior mitral leaflet. In combination with the constitutional symptoms a left atrial myxoma was diagnosed. The tumor was surgically removed. Postoperatively therapy with corticosteroids and thiamazole was stopped. During follow-up, eosinophilia and hyperthyreodism could no longer be detected.

High-dose therapy followed by autologous stem-cell transplantation with and without rituximab for primary treatment of high-risk diffuse large B-cell lymphoma.

BACKGROUND: We aimed to determine safety and efficacy of rituximab (R) in combination with repetitive high-dose therapy (HDT) as primary treatment for diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: Patients aged 18-60 years and elevated lactate dehydrogenase were treated with four cycles of MegaCHOEP and transplantation of autologous stem cells after cycles 2, 3 and 4. Rituximab (375 mg/m²) was given before each cycle and 12 and 33 days after start of the last cycle of chemotherapy. Sixty-four patients given R-MegaCHOEP were compared with 29 patients who had received identical treatment without rituximab. RESULTS: Overall survival (OS) and event-free survival (EFS) after 3 years were significantly improved in patients treated with R-MegaCHOEP (OS: 78.7% versus 55.0%, P = 0.045; EFS: 72.7% versus 47.2%, P = 0.013). In a Cox regression model adjusted for performance status and stage, relative risk of treatment failure was lower (relative risk 0.5, P = 0.041) and OS was better (relative risk 0.4, P = 0.054) for patients given R-MegaCHOEP. Grade 3/4 infections were more frequent in the R-MegaCHOEP group (18.5% versus 6.0%, P = 0.003). CONCLUSIONS: The addition of rituximab to MegaCHOEP significantly improved outcome in young patients with high-risk DLBCL. The higher incidence of grade 3/4 infections needs consideration when rituximab and HDT regimens are combined.

[Vasculitis: histopathology and differential diagnosis]. / Vaskulitis: Histopathologie und Differenzialdiagnose.

A histopathologically confirmed biopsy is the gold standard for the diagnosis of vasculitis. Possible etiologies include primary systemic vasculitis, secondary vasculitis or isolated single organ vasculitis, although on histopathological grounds alone a clear differentiation is frequently not possible. The key criteria of morphological vasculitis work-up include vessel size, type of inflammation (granulomatous, necrotizing and/or leukocytoclastic) as well as the presence or absence of immune complexes and extravascular inflammatory changes. Together with the typical organ involvement and serological data, these criteria constitute the basis of vasculitis classification. Differential diagnostic overlaps and possible discrimination methods are presented. In the same way that the clinical approach of vasculitis patients is an interdisciplinary one, histopathology can only provide a definite diagnosis in combination with clinical and serological data. A conclusive morphological diagnosis depends on the right time of biopsy and the selection of appropriate biopsy material.

Hibernoma-like brown fat in the bone marrow: report of a unique case.

We report on a bone-marrow biopsy of a 61-year-old female patient that was performed because of the clinical suspicion of a myeloproliferative disease. The trephine biopsy showed morphological features that were consistent with an essential thrombocythaemia (ET). The diagnosis of a myeloproliferative disease could be corroborated by demonstration of the V617F mutation of JAK2. Besides the histological features of ET, the marrow showed a peculiar infiltrate that consisted of multivacuolated cells that were immunohistochemically identified as brown adipose tissue with a hibernoma-like picture. To the best of our knowledge, this is the first report on brown adipose tissue in the bone marrow.

Rumination syndrome: an emerging case scenario.

This article describes the case of a 19-year-old woman presenting with repetitive episodes of effortless vomiting, which started within 3 weeks of her naval boot camp training. She underwent a battery of costly investigations before the diagnosis of rumination syndrome could be made. One of the reasons for her delayed diagnosis is that many physicians are unaware of, or are reluctant to make the diagnosis of rumination syndrome. The purpose of this article is to make the general physician aware of the possibility of rumination syndrome in adolescents and adults of normal intelligence, even though it was initially considered only in infants and mentally retarded individuals. The key to diagnosis is a thorough patient history. Reassurance and behavioral therapy is the mainstay of treatment, with a reported success of >80%.

Rearrangement of the beta chain of the T cell antigen receptor and immunoglobulin genes in lymphoproliferative disorders.

55 samples representing Hodgkin's and non-Hodgkin's lymphoma and other hyperplastic lesions of the lymph node were examined for rearrangement of the beta chain of the T cell antigen receptor (TcR) and Ig genes. In non-Hodgkin's lymphoma, rearrangement of TcR beta was found in all 14 T cell lymphomas and in two of the seven B cell lymphomas. Ig gene rearrangement was found in none of the 14 T cell lymphomas and in all seven B cell lymphomas. We also examined DNA from lymph nodes in which the lineage of the malignant cell is not clear. Rearrangement of TcR beta was found in all five lymphoepitheloid cell (Lennert's) lymphomas; four of eight Hodgkin's lymphomas; seven of ten Ki 1+ lymphomas; and all nine cases of angioimmunoblastic lymphoadenopathy (AIL). Ig gene rearrangement was found in none of five lymphoepitheloid cell lymphomas; none of eight Hodgkin's lymphomas; three of ten Ki 1+ lymphomas; and four of nine cases of AIL. These findings indicate that genetic studies of TcR and Ig genes are useful in identifying the presence of a clonal population in a lymph node, in determining the extent of the clonal population, and aid in identifying lineage. Of special interest was the finding that some cases of Hodgkin's lymphoma and AIL contain clonal rearrangement of the TcR genes, which suggests that in those cases the malignant cells may be of T cell origin.

Overexpression of the death-promoting gene bax-alpha which is downregulated in breast cancer restores sensitivity to different apoptotic stimuli and reduces tumor growth in SCID mice.

We have studied the expression of members of the bcl-2 family in human breast cancer. The expression pattern of these genes in breast cancer tissue samples was compared with the expression pattern in normal breast epithelium. No marked difference with regard to bcl-2 and bcl-xL expression was observed between normal breast epithelium and cancer tissue. In contrast, bax-alpha, a splice variant of bax, which promotes apoptosis, is expressed in high amounts in normal breast epithelium, whereas only weak or no expression could be detected in 39 out of 40 cancer tissue samples examined so far. Of interest, downregulation of bax-alpha was found in different histological subtypes. Furthermore, we transfected bax-alpha into breast cancer cell lines under the control of a tetracycline-dependent expression system. We were able to demonstrate for the first time that induction of bax expression in breast cancer cell lines restores sensitivity towards both serum starvation and APO-I/Fas-triggered apoptosis and significantly reduces tumor growth in SCID mice. Therefore, we propose that dysregulation of apoptosis might contribute to the pathogenesis of breast cancer at least in part due to an imbalance between members of the bcl-2 gene family.

Repression of the genes for lysine biosynthesis in Saccharomyces cerevisiae is caused by limitation of Lys14-dependent transcriptional activation.

The product of the LYS14 gene of Saccharomyces cerevisiae activates the transcription of at least four genes involved in lysine biosynthesis. Physiological and genetic studies indicate that this activation is dependent on the inducer alpha-aminoadipate semialdehyde, an intermediate of the pathway. The gene LYS14 was sequenced and, from its nucleotide sequence, predicted to encode a 790-amino-acid protein carrying a cysteine-rich DNA-binding motif of the Zn(II)2Cys6 type in its N-terminal portion. Deletion of this N-terminal portion including the cysteine-rich domain resulted in the loss of LYS14 function. To test the function of Lys14 as a transcriptional activator, this protein without its DNA-binding motif was fused to the DNA-binding domain of the Escherichia coli LexA protein. The resulting LexA-Lys14 hybrid protein was capable of activating transcription from a promoter containing a lexA operator, thus confirming the transcriptional activation function of Lys14. Furthermore, evidence that this function, which is dependent on the presence of alpha-aminoadipate semialdehyde, is antagonized by lysine was obtained. Such findings suggest that activation by alpha-aminoadipate semialdehyde and the apparent repression by lysine are related mechanisms. Lysine possibly acts by limiting the supply of the coinducer, alpha-aminoadipate semialdehyde.

A segment of mRNA encoding the leader peptide of the CPA1 gene confers repression by arginine on a heterologous yeast gene transcript.

The expression of the yeast gene CPA1, which encodes the small subunit of the arginine pathway carbamoylphosphate synthetase, is repressed by arginine at a translational level. CPA1 mRNA contains a 250-nucleotide-long leader which includes a 25-codon upstream open reading frame (uORF). Oligonucleotide site-directed mutagenesis of this uORF as well as sequencing of constitutive cis-dominant mutations has suggested that the leader peptide product of the CPA1 uORF is an essential negative element for repression of the CPA1 gene by arginine. In this work, a series of deletions affecting the regions 5' and 3' to the uORF in the leader sequence was constructed. The arginine-dependent repression of CPA1 was little affected in these constructions, indicating that these regions are not essential for the regulatory response. This conclusion was further supported by the finding that inserting the mRNA segment encoding the leader peptide sequence of CPA1 in the leader sequence of another gene, namely, GCN4, places this gene under arginine repression. Similarly, the behavior of fusions of the leader sequence of CPA1 with those of ARG4 or GAL10 confirmed that the regions of this leader located upstream and downstream from the uORF are dispensable for the regulation by arginine. Finally, a set of substitution mutations which modify the uORF nucleotide sequence while leaving unchanged the corresponding amino acid sequence was constructed. The mutations did not affect the repression of CPA1 by arginine. The data presented in this paper consequently agree with the conclusion that the leader peptide itself is the main element required for the translational repression of CPA1.

Prognostic significance of clusterin immunoreactivity in breast cancer.

Clusterin (CLU) is involved in a variety of biological processes and has been found to be expressed even in many human malignancies, including breast cancer. Currently, there are only few data on the prognostic value of CLU in breast cancer. We therefore evaluated the relationship between CLU expression and clinicopathological parameters as well as relapse-free survival (RFS) and metastasis-free survival (MFS) of 141 breast cancer patients using the monoclonal antibody 7D1. CLU expression was found in 26% of cases and correlated significantly with high histological tumor grade and high Ki-67 labeling index (p=0.026 and p=0.010, respectively). Univariate Cox regression analysis revealed that CLU expression was tendentiously associated with RFS (p=0.068; relative risk [RR]: 1.77) and MFS (p=0.122; RR: 1.57). In a multivariate analysis, tumor grade, stage, estrogen receptor status and patients age (concerning RFS) as well as grade and lymph node status (concerning MFS) were identified as significant independent prognosticators. CLU expression showed an independent prognostic relevance concerning prediction of RFS by trend (p=0.110; RR: 1.81). We conclude from our data that estimation of CLU immunoreactivity may be helpful as a supplementary criterion to better assess the tumors propensity to relapse in selected cases of breast carcinoma.