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Hintergrund Wir berichten über das gehäufte Auftreten von Riechstörungen bei COVID-19-Patienten in der ersten Gruppe von COVID-19-Patienten in Deutschland (Webasto-Cluster). Methode Über den Verlust des Geruch- und/oder Geschmackssinns berichteten 26 von 63 COVID-19-Patienten (41 %), wobei nur bei 31 % der von Hyposmie Betroffenen gleichzeitig Symptome einer Rhinitis vorlagen. Bei 14 Patienten führten wir einen Riechtest und bei 10 einen Schmecktest durch. Die Messungen fanden innerhalb der Krankenversorgung einer frühen COVID-19-Kohorte statt. Ergebnisse Bei 10/14 Patienten lag sowohl vor als auch nach Abschwellen der Nasenschleimhäute eine Riechstörung vor. Für 2/14 Patienten war die Hyposmie das führende oder sogar das einzige Symptom der SARS-CoV-2-Infektion. Alle Getesteten berichteten über eine Besserung des Geruchs- und/oder Geschmackssinns innerhalb von 8–23 Tagen. Schlussfolgerung Den vorliegenden Daten zufolge a) kann COVID-19 bei einer nennenswerten Anzahl Patienten zu Hyposmie führen, die Inzidenz betrug ca. 30 % in dieser Kohorte; b) war die Riechstörung überwiegend nicht mit rhinitischen Symptomen assoziiert, was auf eine nichtrhinitische, z. B. neurogene Ursache hinweisen kann; und c) erholte das Riechvermögen sich weitgehend im Laufe von 1–3 Wochen nach Beginn der COVID-19-Symptome. Anhaltspunkte für ein gehäuftes Auftreten einer Schmeckstörung ergaben sich nicht. Diese frühen Ergebnisse können sowohl bei der Interpretation der COVID-19-assoziierten Hyposmie als auch für ein beruhigendes Patentengespräch angesichts der hier beobachteten temporären Natur der Hyposmie hilfreich sein. Darüber hinaus kann nach derzeitiger Erfahrung eine plötzlich aufgetretene Hyposmie ohne Vorliegen einer neuen Nasenatmungsbehinderung (Rhinitis) das führende oder sogar einzige Symptom einer SARS-CoV-2-Infektion sein.

Early, risk-adapted treatment with fludarabine in Binet stage A chronic lymphocytic leukemia patients: results of the CLL1 trial of the German CLL study group

Richter transformation (RT) is defined as development of aggressive lymphoma in patients (pts) with CLL. The incidence rates of RT among pts with CLL range from 2 to 10%. The aim of this analysis is to report the frequency, characteristics and outcomes of pts with RT enrolled in trials of the GCLLSG. A total of 2975 pts with advanced CLL were reviewed for incidence of RT. Clinical, laboratory, and genetic data were pooled. Time-to-event data, starting from time of CLL diagnosis, of first-line therapy or of RT diagnosis, were analyzed by Kaplan-Meier methodology. One hundred and three pts developed RT (3%): 95 pts diffuse large B-cell lymphoma (92%) and eight pts Hodgkin lymphoma (8%). Median observation time was 53 months (interquartile range 38.1-69.5). Median OS from initial CLL diagnosis for pts without RT was 167 months vs 71 months for pts with RT (HR 2.64, CI 2.09-3.33). Median OS after diagnosis of RT was 9 months. Forty-seven pts (46%) received CHOP-like regimens for RT treatment. Three pts subsequently underwent allogeneic and two pts autologous stem cell transplantation. Our findings show that within a large cohort of GCLLSG trial participants, 3% of the pts developed RT after receiving first-line chemo- or chemoimmunotherapy. This dataset confirms the ongoing poor prognosis and high mortality associated with RT.

Background Central venous catheter (CVC)-related bloodstream infections (CRBSI) are a frequent cause of morbidity and mortality in patients with chemotherapy-induced neutropenia. Chlorhexidine containing catheter securement dressings may prevent CRBSI. Patients and methods A multicenter randomized, controlled trial was conducted at 10 German hematology departments. We compared chlorhexidine-containing dressings with non-chlorhexidine control dressings in neutropenic patients. The primary end point was the incidence of definite CRBSI within the first 14 days (dCRBSI14) of CVC placement. Secondary end points included combined incidence of definite or probable CRBSI within 14 days (dpCRBSI14), overall (dpCRBSI), incidence of unscheduled dressing changes and adverse events. Results From February 2012 to September 2014, 613 assessable patients were included in the study. The incidence of dCRBSI14 was 2.6% (8/307) in the chlorhexidine and 3.9% (12/306) in the control group (P = 0.375). Both dpCRBSI14 and dpCRBSI were significantly less frequent in the study group with dpCRBSI14 in 6.5% (20/307) of the chlorhexidine group when compared with 11% (34/306) in the control group (P = 0.047), and dpCRBSI in 10.4% (32/307) versus 17% (52/306), respectively (P = 0.019). The frequency of dressing intolerance with cutaneous and soft tissue abnormalities at the contact area was similar in both groups (12.4% and 11.8%; P = 0.901). Conclusions Although the trial failed its primary end point, the application of chlorhexidine containing catheter securement dressings reduces the incidence of definite or probable CRBSI in neutropenic patients. Clinical trials number NCT01544686 (Clinicaltrials.gov).

Eine Vielzahl von Hautveranderungen ist bei malignen hamatologischen Erkrankungen bisher beschrieben worden. In der vorliegenden Ubersichtsarbeit wird versucht, die Thematik durch Einteilung der Hautveranderungen in 3 grosere Gruppen zu strukturieren: 1. Hauterkrankungen durch Gefasveranderungen (Gefasdilatation, Gefasokklusion und entzundliche Gefasprozesse), 2. die Gruppe der unspezifischen (z. B. Blasse, Infektanfalligkeit fur opportunistische Infektionen) und spezifischen Hautveranderungen (z. B. Leukaemia cutis) und 3. die grose Gruppe von paraneoplastischen Erkrankungen. Der Schwerpunkt der Arbeit liegt auf der Beschreibung klinischer Befunde und therapeutischer Optionen fur diese paraneoplastischen Syndrome, die am haufigsten mit malignen hamatologischen Erkrankungen assoziiert sind.

Impact of gender on outcome after chemoimmunotherapy in patients with chronic lymphocytic leukemia: a meta-analysis by the German CLL study group

Hypoxia-induced p38 MAPK activation reduces Mcl-1 expression and facilitates sensitivity towards BH3 mimetics in chronic lymphocytic leukemia

Chemoimmunotherapies like the combination of fludarabine, cyclophosphamide, and rituximab (FCR) achieve response rates as high as 95% in patients with previously untreated chronic lymphocytic leukemia (CLL).1 Further improvements in clinical outcome will therefore mainly depend on attaining more durable remissions in those responders who suffer an early relapse. In general, progression of disease within 24 months after intensive chemoimmunotherapy is regarded as unsatisfactory2 and might be associated with a shortened overall survival (OS).3

Background | Relapsing fever is divided into tick borne relapsing fever (TBRF) and louse borne relapsing fever (LBRF). This report describes 25 refugees from East Africa who were diagnosed to suffer from LBRF within a period of 6 month only at a single hospital in Munich / Germany. MaterialMethods | The aim was to point out common clinical features as well as laboratory findings and clinical symptoms before and after initiation of treatment in 25 patients with louse borne relapsing fever (LBRF) who were diagnosed and treated at Klinikum München Schwabing from August 2015 to January 2016. To the best of our knowledge this is the largest case series of LBRF in the western world for decades. Main focus of the investigation was put on clinical aspects. Results | All 25 patients suffered from acute onset of high fever with chills, headache and severe prostration. Laboratory analysis showed high CRP and a marked thrombocytopenia. A Giemsa blood stain was procured immediately in order to look for malaria. In the blood smear spirochetes with typical shape and aspect of borrelia species could be detected.The further PCR analysis confirmed infection with Borrelia recurrentis. Treatment with Doxycycline was started forthwith. The condition improved already on the second day after treatment was started and all were restored to health in less than a week. Apart from a mild to moderate Jarisch-Herxheimer-reaction we didn`t see any side effects of the therapy. Conclusion | LBRF has to be taken into account in feverish patients who come as refugees from East-Africa. It seems that our patients belong to a cluster which probably has its origin in Libya and more patients are to be expected in the near future. As LBRF might cause outbreaks in refugee camps it is pivotal to be aware of this emerging infectious disease in refugees from East-Africa.

Fludarabine and cyclophosphamide in combination with alemtuzumab in patients with primary high-risk, relapsed or refractory chronic lymphocytic leukemia

Phase 1b trial of atacicept, a recombinant protein binding BLyS and APRIL, in patients with chronic lymphocytic leukemia

The pharmacological induction of apoptosis in neoplastic B cells presents a promising therapeutic avenue for the treatment of chronic lymphocytic leukemia (CLL). We profiled a panel of clinical multi-kinase inhibitors for their ability to induce apoptosis in primary CLL cells. Whereas inhibitors targeting a large number of receptor and intracellular tyrosine kinases including c-KIT, FLT3, BTK and SYK were comparatively inactive, the CDK inhibitors BMS-387032 and flavopiridol showed marked efficacy similar to staurosporine. Using the kinobeads proteomics method, kinase expression profiles and binding profiles of the inhibitors to target protein complexes were quantitatively monitored in CLL cells. The targets most potently affected were CDK9, cyclin T1, AFF3/4 and MLLT1, which may represent four subunits of a deregulated positive transcriptional elongation factor (p-TEFb) complex. Albeit with lower potency, both drugs also bound the basal transcription factor BTF2/TFIIH containing CDK7. Staurosporine and geldanamycin do not affect these targets and thus seem to exhibit a different mechanism of action. The data support a critical role of p-TEFb inhibitors in CLL that supports their future clinical development.

The consensus views of an expert roundtable meeting are presented as updated management guidelines for using alemtuzumab in chronic lymphocytic leukemia. Since the publication of previous management guidelines in 2004, clinical experience with alemtuzumab has grown significantly, especially regarding its efficacy and safety, management of cytomegalovirus (CMV) reactivation, identification of patient subgroups likely to benefit from alemtuzumab therapy and subcutaneous administration of alemtuzumab. The updated recommendations include (1) alemtuzumab monotherapy can be safely used as first-line therapy; (2) suitable patient subgroups for alemtuzumab therapy include elderly patients, patients with 17p deletion, patients with refractory autoimmune cytopenias and patients with profound pancytopenia at baseline due to heavily infiltrated bone marrow; (3) alemtuzumab treatment should be continued for 12 weeks (36 doses) whenever possible, and bone marrow examination may be considered at week 12 to evaluate response; (4) monitoring CMV reactivation by weekly PCR is mandated during therapy; when CMV reactivation becomes symptomatic or viremia increases, alemtuzumab therapy should be interrupted and anti-CMV therapy started; (5) subcutaneous administration is safe, easy to perform and appears equally effective compared with intravenous infusion and (6) our strong recommendation is that alemtuzumab combination therapy and consolidation therapy shall not be used outside carefully controlled clinical studies. Leukemia (2009) 23, 1980-1988; doi: 10.1038/leu.2009.146; published online 23 July 2009

Constitutively activated pathways contribute to apoptosis resistance in chronic lymphocytic leukemia (CLL). Little is known about the metabolism of lipids and function of lipases in CLL cells. Performing gene expression profiling including B-cell receptor (BCR) stimulation of CLL cells in comparison to healthy donor CD5+ B cells, we found significant overexpression of lipases and phospholipases in CLL cells. In addition, we observed that the recently defined prognostic factor lipoprotein lipase (LPL) is induced by stimulation of BCR in CLL cells but not in CD5+ normal B cells. CLL cellular lysates exhibited significantly higher lipase activity compared to healthy donor controls. Incubation of primary CLL cells (n=26) with the lipase inhibitor orlistat resulted in induction of apoptosis, with a half-maximal dose (IC(50)) of 2.35 microM. In healthy B cells a significantly higher mean IC(50) of 148.5 microM of orlistat was observed, while no apoptosis was induced in healthy peripheral blood mononuclear cells (PBMCs; P

This study aimed to assess the frequency of and the contributing factors for second primary malignancies (SPMs) and Richter's transformations (RTs) following first-line treatment of chronic lymphocytic leukemia within four phase II/III trials of the GCLLSG evaluating fludarabine (F) vs F+cyclophosphamide (FC), chlorambucil vs F, FC without or with rituximab, and bendamustine+R (BR). Among 1458 patients, 239 (16.4%) experienced either an SPM (N=191) or a RT (N=75). Solid tumors (N=115; 43.2% of all second neoplasias) appeared most frequently, followed by RTs (N=75; 28.2%). Patients showed a 1.23-fold increased risk of solid tumors in comparison to the age-matched general population from the German cancer registry. Age65 (hazard ratio (HR) 2.1; P0.001), male sex (HR 1.7; P=0.01), co-morbidities (HR 1.6; P=0.01) and number of subsequent treatments⩾1 (HR 12.1; P0.001) showed an independent adverse prognostic impact on SPM-free survival. Serum thymidine kinase10 U/l at trial enrollment (HR 3.9; P=0.02), non-response to first-line treatment (HR 3.6; P0.001) and number of subsequent treatments⩾1 (HR 30.2; P0.001) were independently associated with increased risk for RT.

Numerous cutaneous manifestations have been reported in patients with hematologic malignancies. This review provides an overview on this subject by dividing skin lesions into three main groups: (1) skin disorders due to vascular changes (dilatation, occlusion and inflammation), (2) unspecific (e.g. paleness, opportunistic infections) and specific skin lesions (e.g. leukemia cutis), and (3) the large group of paraneoplastic skin disorders. Emphasis is placed on clinical findings and therapeutic options of those paraneoplastic syndromes that are most frequently found in hematologic malignancies.

While chemotherapy based on alkylating agents has been the standard treatment of chronic lymphocytic leukemia (CLL) for decades, purine analogues and their combinations have emerged as effective new therapies for previously untreated and pretreated patients. As single agents, fludarabine and cladribine are the most promising, showing higher remission rates compared to chlorambucil. For younger and physically fit patients, the combination of fludarabine and cyclophosphamide has shown benefit. Fludarabine plus epirubicin appears equally potent. The addition of monoclonal antibodies, such as rituximab and alemtuzumab, to purine analogues alone or in combination seems to be even more effective for chemotherapy-naive and pretreated CLL patients. Another promising agent in the armamentarium of therapies for CLL is bendamustine, which has properties of both an alkylating agent and a purine analogue. Clinical trials are ongoing with novel drugs that interfere with cell cycle regulation and signaling molecules in CLL, including flavopiridol, UCN-01, bryostatin 1, depsipeptide, and oblimersen. It remains to be seen whether these chemotherapeutic approaches offer real benefit for patients by prolonging survival with an improved quality of life.

A 50-year-old man with HIV infection (first diagnosed20 years ago) presented at our hospital with fulminant oral mucositis. Antiretroviral therapy (tenofovir, emtricitabine, raltegravir) had been started 2 months ago. Previously he had no opportunistic infections and no other pre-existing illnesses. He had not travelled outside Europe but stayed in Spain for several weeks during summer.Physical examination revealed swelling of the lips and severe ulcerative mucositis of the gums and pharynx. The patient complained of painful swallowing. The blood-chemistry showed no abnormalities. The microscopical analysis of a smear and a biopsy of the buccal mucosa revealed amastigotes of leishmania. By means of PCR technique, Leishmania donovani complex was specified.The patient was treated with liposomal amphotericin B (1 mg/kg) for 21 days. Because of the immunosuppression he was put on maintenance therapy afterwards (liposomal amphotericin B every 3 weeks). However, 4 months later there was a clinical relapse of the mucositis and a new cultural and PCR detection of leishmania in a buccal biopsy. After another course of 21 days with liposomal amphotericin B (3 mg/kg) and miltefosine (150 mg/d), the mucositis subsided. Therapy with liposomal amphotericin B (3 mg/kg single dose every 3 weeks) has since been maintained. The antiretroviral therapy was changed meanwhile to lamivudin, abacavir and raltegravir because of kidney failure with elevated urea and creatinine. The patient has been clinically stable ever since without any other HIV-related problems. The latest CD4 count was 456/µl and the HIV load 340 copies/ml.Leishmaniasis is a severe infection in HIV-positive patients. Clinical manifestations can be atypical in immunosuppressed patients and the treatment is complicated with HIV coinfection. This is also due to a lifelong persistence of the parasite with potential reactivation especially in patients with suppressed CD4 cells. Therefore maintenance therapy after standard therapy of leishmaniasis is mandatory at least for a CD4 count below 350/µl. Especially in HIV patients with a leishmaniasis relapse lifelong maintenance therapy should be considered.