Hintergrund: Die MAHO-Studien erfassten zwischen 1982 bis 1/2001 260 Patienten. 54 % der Patienten hatten Dottersacktumoren (YST), 22 % reife oder unreife Teratome, 8 % maligne Mischtumoren, 7 % Chorionkarzinome (Chorio), 8 % embryonale Karzinome (EC) und 1 % Seminome. Ziele der Studien waren: 1. Verzicht auf Chemotherapie bei YST-Stadium I A (zunächst nur bei Patienten < 2 Jahren, ab 1988 bis 16 Jahren). 2. Verzicht auf modifizierte Lymphadenektomie (RPL) zur Sicherung des Stadium I bei Nicht-YST-Tumoren. 3. Schrittweise Reduzierung der Therapie bei niedrigen bzw. Intensivierung in den höheren Stadien. Die Standardchemotherapie bestand aus 4 Kursen PVB, ab dem Stadium II C BEP. Bei persistierendem vitalen Tumor wurde zusätzlich die Salvage-Therapie (PEI) gegeben. Ergebnisse: Nur 75/260 Patienten benötigten aufgrund des Stadiums und der Histologie eine Chemotherapie. Von 140 Patienten mit YST überlebten 139. Bei dem "watch and wait"-Programm mussten 16 Patienten 6 - 60 Wochen nach Operation eine verzögerte Chemotherapie erhalten (13 %). Patienten mit reifen und unreifen Teratomen (40 bzw. 19 Patienten): Diese Patienten wurden durch alleinige ablatio testis geheilt. Maligne nicht seminomatöse Tumoren (EC, Chorio, Mischtumoren) wurden bei 59 Patienten diagnostiziert; 20 dieser Patienten hatten ein klinisches Stadium I, 5 davon ein pathologisches Stadium I A (nach modifizierter Lymphadenektomie), 15 erhielten adjuvante Chemotherapie, alle 20 Patienten überlebten rezidivfrei. Von 22 Patienten des Stadiums II erhielten 8 Standardchemotherapie und nach der Reevaluierung Salvage-Therapie, 21 der 22 Patienten überlebten rezidivfrei. 17 Patienten hatten ein Stadium III oder IV, 5 davon verstarben trotz zusätzlicher Salvage-Therapie. 9 überlebten rezidivfrei, drei Patienten sind in Teilremission. Zwei Patienten mit Seminomen, beide Stadium I, überlebten rezidivfrei. Die Wahrscheinlichkeit des rezidivfreien Überlebens aller 260 Patienten beträgt nach einer mittleren Beobachtungszeit von 60 Monaten 96,5 %. Schlussfolgerung: Bei malignen Hodentumoren im Kindesalter kann bei Tumormarker-produzierenden YST des Stadium I A nach Semikastration eine "watch and wait"-Strategie durchgeführt werden. Nur bei 13 % dieser Patienten muss für einen kurativen Ansatz zu einem späteren Zeitpunkt eine Chemotherapie verabreicht werden. Bei allen höheren Stadien von YST und allen anderen malignen Hodentumoren gleich welchen Stadiums ist die Chemotherapie so effizient, dass Bestrahlung oder Lymphadenektomie heute nicht mehr erforderlich sind.
Gastric infection by Helicobacter pylori (Hp) is associated with development of gastritis, ulcerations and gastric adenocarcinoma. Production and secretion of the vacuolating cytotoxin (VacA) is an essential Hp virulence factor. VacA is a multifunctional toxin, which exerts immunosuppressive effects on human T lymphocytes via inhibition of cell proliferation and Interleukin-2 (IL-2) signalling. This latter effect of VacA is dependent on the β2-integrin subunit CD18, acting as a receptor for intracellular uptake of VacA. In this study, we investigated the mechanism of endocytosis of VacA into primary human T lymphocytes. A screen with chemical inhibitors for different sets of kinases identified Ser/Thr kinases of the protein kinase C (PKC) family as crucial. Specific inhibitory peptides blocking PKCη or PKCζ-phosphorylating activity, but not PKCα/β specific peptides, resulted in a strong reduction or complete block of VacA uptake. Thus the phosphorylating activity of PKCη and PKCζ is essential for the induction of VacA endocytosis. Furthermore, mimicking of a possible PKC-mediated threonine (T(758)) phosphorylation of the CD18 cytoplasmic tail in resting primary T cells induced VacA endocytosis via activation of the small GTPases Cdc42 and Rac-1. We conclude that VacA is endocytosed into primary T cells via a clathrin-independent pathway.
Sixty-six adult patients were treated for relapsing or refractory acute lymphocytic leukemia (ALL). The induction treatment consisted in a (1) first phase with vindesine 3 mg/m2 intravenously (IV) on days 1, 8, and 15; daunorubicin 45 mg/m2 IV on days 1, 8, and 15; erwinia-asparaginase 10,000 U/m2 IV on days 7, 8, 14, and 15; and prednisone 60 mg/m2 orally on days 1 to 21 and a (2) second phase with cytarabine 3000 mg/m2 as a 3-hour infusion two times a day on days 1 to 4 (in patients greater than 50 years of age we used 1000 mg/m2), and etoposide 100 mg/m2 IV on days 1 to 5. Side effects of induction Phase I were predominantly hematologic with subsequent infections. In Phase II, some patients additionally had gastrointestinal, cutaneous, ocular, and hepatic toxicity. Five patients died during Phase I and another died during Phase II. Five of these patients had T-cell ALL. Thirty-four (64%) of 54 patients in their first relapse had a complete remission (CR) with a median disease-free survival (DFS) of 2.9 months. The median overall survival (OAS) was 6.6 months. Seven of 12 patients with primary refractory disease, a second relapse, or relapse after bone marrow transplantation (BMT) had a CR. The CR rate and survival after first relapse was significantly better in patients with a preceding CR of more than 18 months compared with those with a shorter preceding remission. The leukocyte count was a second significant but not independent risk factor. There was a negative correlation between the leukocyte count and the duration of the preceding CR. The duration of the preceding CR was the major prognostic factor for survival in multivariate analysis. Twenty-two patients received BMT. None of nine patients with autologous BMT is alive and disease-free; 5 of 13 who underwent allogeneic BMT are. It was concluded that this treatment efficiently induced remission with tolerable toxicity. The remission duration should be improved by optimized consolidation treatment.
Background: Primary adrenal lymphoma (PAL) is a rare lymphoid malignancy that primarily involves the adrenal gland(s) in patients without a previous history of lymphoma. Aims: To refine the clinical picture of primary adrenal lymphoma Methods: We retrospectively analyzed clinical and pathological features of 97 patients from 14 centers in Europe, Canada and the United States. PAL was defined as histologically proven extra‐nodal lymphoma that primarily affects the adrenal gland(s). If there was involvement of other organs and/or lymph nodes, the diagnosis of PAL was accepted only in case of unequivocal dominant involvement of the adrenal gland(s). We divided the disease into two subtypes: cases with synchronous extra‐adrenal involvement at diagnosis (PAL+), and cases with isolated involvement of the adrenal(s) (iPAL). Statistical analyses were carried out using the Fisher exact test, Kaplan‐Meier method, log‐rank test, and Cox proportional hazard models. Results: Median age at diagnosis was 66 (25–89) years, and the male/female ratio was 2.3. 19/81 (23%) patients with available imaging data had isolated adrenal involvement (iPAL), while the other 62 (77%) had additional extra‐adrenal involvement (PAL+). The most common manifestations of PAL were B symptoms (55%), fatigue (45%), and abdominal pain (35%). With a median follow‐up of 41.6 months, the 3‐year progression‐free survival (PFS) and overall survival (OS) were 35.5% and 39.4%, respectively. Immunochemotherapy according to the R‐CHOP protocol showed no significant difference in outcome compared to other treatment regimens. On multivariate analysis of variables including age, tumor size, uni‐ vs. bilateral involvement, histopathology of B cell lymphoma, elevated LDH, adrenal insufficiency, and iPAL versus PAL+, iPAL was the only factor with independent, statistically significant impact on PFS. The hazard ratios of iPAL for PFS and OS were 40.1 (95% CI: 2.63–613.7, p = 0.008) and 2.69 (95% CI: 0.61–11.89, p = 0.191), respectively. PFS was much shorter in iPAL versus PAL+ (median 4 months vs. not reached, p = 0.006), and there was a trend for shorter OS (median 16 vs. not reached, p = 0.16). Isolated PAL was more frequent in females (OR = 3.81; P = 0.01) and less frequently associated with B symptoms at diagnosis (OR = 0.159; p = 0.004). Summary/Conclusion: Comprehensive characterization of rare diseases is facilitated by multi‐institutional collaboration. Our retrospective analysis of 97 patients from fourteen centers is the largest analysis of PAL so far. We showed for the first time that PAL is a heterogeneous disease, which comprises cases with isolated involvement of adrenal tissue (iPAL) and cases with additional extra‐adrenal organ manifestations (PAL+). Unexpectedly, patients with iPAL showed an unusual male/female ratio, less B symptoms and significantly worse clinical outcome than those with involvement of additional, extra‐adrenal sites. This finding should stimulate further investigation to see whether the clinical distinction between iPAL and PAL+ is corroborated by differences in molecular biology. image
Abstract Helicobacter pylori displays a worldwide infection rate of about 50%. The Gram‐negative bacterium is the main reason for gastric cancer and other severe diseases. Despite considerable knowledge about the metabolic inventory of H. pylori, carbon fluxes through the citrate cycle (TCA cycle) remained enigmatic. In this study, different 13 C‐labeled substrates were supplied as carbon sources to H. pylori during microaerophilic growth in a complex medium. After growth, 13 C‐excess and 13 C‐distribution were determined in multiple metabolites using GC–MS analysis. [U‐ 13 C 6 ]Glucose was efficiently converted into glyceraldehyde but only less into TCA cycle‐related metabolites. In contrast, [U‐ 13 C 5 ]glutamate, [U‐ 13 C 4 ]succinate, and [U‐ 13 C 4 ]aspartate were incorporated at high levels into intermediates of the TCA cycle. The comparative analysis of the 13 C‐distributions indicated an adaptive TCA cycle fully operating in the closed oxidative direction with rapid equilibrium fluxes between oxaloacetate—succinate and α‐ketoglutarate—citrate. 13 C‐Profiles of the four‐carbon intermediates in the TCA cycle, especially of malate, together with the observation of an isocitrate lyase activity by in vitro assays, suggested carbon fluxes via a glyoxylate bypass. In conjunction with the lack of enzymes for anaplerotic CO 2 fixation, the glyoxylate bypass could be relevant to fill up the TCA cycle with carbon atoms derived from acetyl‐CoA.
Abstract Helicobacter pylori is a gram-negative, spiral-shaped bacterial pathogen and the causative agent for gastritis, peptic ulcer disease and classified as a WHO class I carcinogen. While the prevalence of H. pylori infections in Africa is among the highest in the world, the incidence of gastric cancer is comparably low. Little is known about other symptoms related to the H. pylori infection in Africa and the association with certain phenotypes of bacterial virulence. We established a network of study sites in Nigeria (NG) and South Africa (ZA) to gain an overview on the epidemiological situation. In total 220 isolates from 114 patients were analyzed and 118 different patient isolates examined for the presence of the virulence factors cagA, vacA, dupA , their phylogenetic origin and their resistance against the commonly used antibiotics amoxicillin, clarithromycin, metronidazole and tetracycline. We report that H. pylori isolates from Nigeria and South Africa differ significantly in their phylogenetic profiles and in their expression of virulence factors. VacA mosaicism is intensive, resulting in m1-m2 vacA chimeras and frequent s1m1 and s1m2 vacA subtypes in hpAfrica2 strains. Gastric lesions were diagnosed more frequent in Nigerian versus South African patients and H. pylori isolates that are resistant against one or multiple antibiotics occur frequently in both countries.
