Lymphopoiesis in transgenic mice over-expressing Artemis.

Artemis is a factor of the non-homologous end joining pathway involved in DNA double-strand break repair that has a critical role in V(D)J recombination. Mutations in DCLRE1C/ARTEMIS gene result in radiosensitive severe combined immunodeficiency in humans owing to a lack of mature T and B cells. Given the known drawbacks of allogeneic hematopoietic stem cell transplantation (HSCT), gene therapy appears as a promising alternative for these patients. However, the safety of an unregulated expression of Artemis has to be established. We developed a transgenic mouse model expressing human Artemis under the control of the strong CMV early enhancer/chicken beta actin promoter through knock-in at the ROSA26 locus to analyze this issue. Transgenic mice present a normal development, maturation and function of T and B cells with no signs of lymphopoietic malignancies for up to 15 months. These results suggest that the over-expression of Artemis in mice (up to 40 times) has no deleterious effects in early and mature lymphoid cells and support the safety of gene therapy as a possible curative treatment for Artemis-deficient patients.

An open-label study of vandetanib with pemetrexed in patients with previously treated non-small-cell lung cancer.

BACKGROUND: Vandetanib (ZACTIMA; ZD6474) is a once-daily, oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling. The safety and tolerability of vandetanib plus pemetrexed was assessed in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with previously treated NSCLC (stage IIIB/IV) received once-daily oral vandetanib (100 or 300 mg) with pemetrexed (500 mg/m(2) i.v. infusion every 21 days). RESULTS: Patients received vandetanib 100 mg + pemetrexed (n=10) or vandetanib 300 mg + pemetrexed (n=11). The protocol definition of a tolerable dose [vandetanib-related dose-limiting toxicity (DLT) in less than 2 patients] was met in both dose cohorts, with one DLT reported in each: asymptomatic QTc prolongation (>100 ms increase from baseline, but absolute QTc<500 ms) in the 100 mg cohort and interstitial lung disease, which resolved after steroid therapy, in the 300 mg cohort. The most common adverse events were rash, anorexia, fatigue and diarrhea (all n=10). CONCLUSION: Vandetanib and pemetrexed in combination were generally well tolerated in patients with advanced NSCLC.

[Primary chemotherapy of metastatic breast carcinoma with bendamustine hydrochloride, methotrexate and fluorouracil versus cyclophosphamide, methotrexate and fluorouracil]. / Primäre Chemotherapie des metastasierenden Mammakarzinoms mit Bendamustinhydrochlorid, Methotrexat und Fluorouracil versus Cyclophosphamid, Methotrexat und Fluorouracil.

The combination bendamustine/methotrexate/fluorouracil (BMF) was proven versus cyclophosphomide/methotrexate/fluorouracil (CMF) in a stratified randomized pilot study as primary chemotherapy in 61 patients with metastatic breast cancer. Bendamustine was given in a dose of 240 mg/m2 and cyclophosphamide in a dose of 960 mg/m2 per therapy-cycle. The doses of methotrexate (40 mg/m2 i.v., day 1 and 8) and fluorouracil (500 mg/m2 i.v., day 1 and 8) were identical in both groups. 25 patients in the BMF- and 24 patients in the CMF-group were evaluable. The remission rates were 52% vs. 46%. The median duration of remission was 15.2 months (ranging from 8.1 to 19.7 months) in the BMF-group and 6.2 months (ranging from 1.9 to 11.1 months) in the CMF-group. The aim of this study was to identify the main criterion for further randomized studies. The results of this pilot study indicate, that it is possible to prolong the median duration of remission without changing the antineoplastic activity by replacing cyclophosphamide with bendamustine.

[Proof of drug hypersensitivity using an in vivo leukocyte migration inhibition test]. / Nachweis der arzneimittelüberempfindlichkeit mit einem in-vivo-leukozytenmigrationshemmtest

22 chloramphenicol allergics, 10 penicillin allergics and 6 patients with a chromate eczema as well as altogether 34 non-allergic control persons with healthy skin were examined according to the skin chamber method. After addition of the adequate antigen (chloramphenicol, penicillin, ammonium bichromate) into one of the two simultaneously applied skin chambers in sensitized persons an inhibition of the leucocyte migration in the antigen chamber develops. The polymorphonuclear neutrophilic granulocytes mobilised into the inflammation field were regarded as indicator cells. 5 chloramphenicol allergics with eczematous skin abnormalities and all control persons were negative. The investigation method is simply to be performed and therefore it is particularly suitable for clinical routine work.

[The detection of chloramphenicol allergy by leucocyte migration inhibition test in the skin chamber (author's transl)]. / Der Nachweis der Chloramphenikol-Allergie mit den Leukozyten-Migrations-Hemmtest in der Hautkammer.

In the leucocyte migration inhibition test in the skin chamber under in vivo conditions an immune reaction is induced, which influences the migration of polymorphonuclear neutrophilic leucocytes into the chamber in a characteristic way. An inhibition of the migration of leucocytes above 40 per cent is considered positive. In 16 out of 17 patients with chloramphenicol exanthema the test was positive. Five allergic patients with eczematous skin lesions presented negative results. In 14 controlpatients chloramphenicol caused a negative result, too. The mechanical irritation of the skin and the immune response produce different mechanisms, which promote and inhibit migration. The observed influence of the number of leukocyte in the skin chamber is the result of these mechanisms.

Prospective study of the quality of life of cancer patients after intraoral tumor surgery.

PURPOSE: The aim of this prospective study was to determine the quality of life of patients with oral cancer after intraoral ablative surgery. PATIENTS AND METHODS: Eighty-five consecutive patients with squamous cell carcinoma of the floor of the mouth were enrolled in the study. Reconstruction of intraoral soft tissues was accomplished by local tissue (67.8%), jejunal grafts (16.9%), and cutaneous and myocutaneous flaps (15.3%). Soft tissue resections were combined with resections of the alveolar process of the mandible in 35.0% and mandibular discontinuity resections in 31.7% of the cases. A self-administered, standard questionnaire consisting of 22 visual analog scale items with a maximum index value of 154 was used to determine the physical functional status, the psychological status, and social functioning of cancer patients (Functional Living Index--Cancer). The questionnaire was administered preoperatively and 3, 6, and 12 months postoperatively. RESULTS: The Functional Living Index score increased significantly toward the end of the first postoperative year because of an increase in all three factors of the scale. All modes of soft tissue reconstruction achieved nearly equal levels of life quality in patients with median or lateral defects at the end of the observation period. Only patients with large bilateral defects exhibited lower preoperative and postoperative values because of extensive loss of functionally important soft tissue. Patients with discontinuity resections of the mandible took longer to regain the same level of life quality as patients without bone resections. Persistence of dysphagia, reflux of liquids, limitations to liquid food, and sleep disorders had a significant negative effect on the score. CONCLUSIONS: It is concluded that rehabilitation of oral cancer patients is particularly difficult in the case of large soft tissue defects and is not always accomplished completely even with primary microsurgical tissue repair.

[The value of the free hydroxyproline and the N-acetyl-beta- glucosaminidase for the observation of the course of malignant tumors]. / Wertigkeit des freien Hydroxyprolins und der N-Acetyl-beta-Glukosaminidase für die Verlaufsbeobachtung von malignen Tumoren.

In 172 patients with various malign tumours the free hydroxyprolin (HP) and N-acetyl-beta-glucosaminidase (beta-NAG) in the serum were determined. The established values were analysed according to the kind of tumour, spread of tumour, behaviour of growth and histological classification and statistically evaluated. In mamma carcinoma progressively metastasing into bones HP is significantly increased in its mean value. 71.4 per cent of the patients have pathological values. The parameter for bone-marrow diagnostics failed in 28.6 per cent. Increases may only occur until 9 weeks before traditional diagnostics of metastases. beta-NAG values lie within the normal range for clinically not metastasing mamma carcinoma. The enzyme level will increase significantly after each tumour progression into an organ. The diagnostic sensitivity for the general diagnostics of metastases amounts to 97.7 per cent. Increases without any evidence of metastases are either due to other diseases with connective tissue changes or to occult micrometastases. An exact control is required for these patients. Likewise, HP and beta-NAG have a prognostic importance for malign testicle tumours from nonseminomes character and malign lymphomas, because with tumour progression they will turn into pathological ones. Cytostatics have no direct impact on the serum level of HP and beta-NAG.

[Hairy cell leukemia. Light and microscopic and electron microscopic examinations (author's transl)]. / Die Haarzell-Leukämie. Lichtmikroskopische und elektronenmikroskopische Untersuchungen.

Two cases of a typical hairy cell leukemia are presented. The light microscopic findings within the bone marrow, lymph nodes and spleen are documented. The hairy configuration of tumor cells can best be seen in semithin sections of white cells of the peripheral blood. Electron microscopically, the organelle composition of hairy cells (including the characteristic ribosome lamellae complex) is demonstrated. The significance of morphological observations for the diagnosis of hairy cell leukemia and the differential diagnosis of this tumor disease are discussed. From the electron microscopic observations of intercellular cross-banded structures it seems possible that the increase of intercellular material demonstrable light microscopically by silver impregnation is the consequence of synthesis of collagen type IV. The conclusion is drawn from findings in our cases and from reports in the literature that hairy cell leukemia is a clinically and structurally defined syndrome rather than a pathological entity.

[Leukocyte migration inhibition test in skin chamber--an in-vivo method]. / Leukozyten-Migrations-Hemmtest in der Hautkammer--eine In-vivo-Methode

For the demonstration of a cell-mediated sensitisation, tuberculin allergics, chromate allergics, penicillin allergics, and controls were investigated. The method used was the measurement of leukocyte migration inhibition in a Teflon skin chamber with and without addition of antigen, which approaches to testing under in vivo conditions. In 10 of 11 tuberculin allergics, 6 of 7 chromate allergics, and 7 penicillin allergics, a clear inhibition of leucocyte migration after addition of antigen could be observed (maximum 16 h after addition of antigen). In 16 unsensitised controls no significant migration inhibition appeared. Possible advantages of this method over in vitro methods and intracutaneous tests are discussed.

Influence of recombinant human erythropoietin therapy on in vivo chemotaxis and in vitro phagocytosis of polymorphonuclear cells of hemodialysis patients.

Recombinant human erythropoietin (rhu-EPO) mainly stimulates erythropoiesis, but also influences the production and function of polymorphonuclear granulocytes (PAN). We evaluated the influence of rhu-EPO therapy in patients on maintenance hemodialysis without iron overload on both phagocytic and chemotactic activity of polymorphonuclear leukocytes (PMN) obtained from blood and a skin chamber. The study comprised 28 dialysis patients (15 females, 13 males, age 22-78 years, dialysis sessions three times weekly 4-5 h, mean duration of dialysis treatment 4-99 months) and 20 healthy subjects (9 females, 11 males, age 18-56 years). The absolute number of leukocytes in the peripheral blood, the leukocyte mobilization (chemotactic activity) and the phagocytic activity of PMNs were tested in patients before (n = 28), and after (n = 18) reaching the target hematocrit of 30% and during the follow-up period. No alteration in the total leukocyte number (PMN, monocytes, lymphocytes) in the peripheral blood during rhu-EPO therapy could be seen. The phagocytic activity of PMNs slightly improved during the follow-up period whereas the decreased chemotactic activity remained unchanged.

Results of treating stage III and IV malignant non-Hodgkin's lymphomas (NHL).

Malignant non-Hodgkin's lymphoma (NHL) patients were enrolled and analyzed retrospectively in 2 successive study groups. The first group consisted of 57 patients divided into low- and high-grade malignant NHL according to the Kiel classification, the second one included 104 patients divided into low-, intermediate-, and high-grade malignant NHL. The more individualized and more intensive polychemotherapy of the 2nd group yielded clearly better treatment results compared to the first group, especially in high-grade malignant NHL. The complete remissions rose from 32% to 59%, the recurrence rates fell from 62% to 20%, the 5-year survival time of patients under age 30 increased from 0 to 48%. In intermediate-grade malignant NHL, intensive therapy yield results that are as beneficial as those of mild therapy in low-grade malignant NHL (5-year survival rate 62% and 65%, respectively).

[Malignant lymphomas: involvement and complications of the gastro-intestinal tract (author's transl)]. / Maligne Lymphome: Manifestationen und Komplikationen im Gastrointestinaltrakt.

Among 100 patients with malignant lymphomas we found 7 with primary involvement of the gastrointestinal tract and 2 with secondary affection. 2 patients suffered from M. Hodgkin and 7 from non-Hodgkin-lymphoma. The absence of characteristic diagnostic data may lead to incorrect results, as shown. There false diagnoses cannot be excluded neither by endoscopy nor by histology of biopsy material. Every operation on the gastrointestinal tract under the suspicion of a malignant lymphoma should be improved used for the staging. A radio- and/or polychemotherapy has stage depending to follow. On the other hand these are followed by a high percentage of gastrointestinal complications (6% incomplete ileus) which require a gastrointestinal intensive care.

[Results of treatment following stage-dependent therapy of non-seminomatous testicular tumors]. / Behandlungsergebnisse nach stadiengerechter Therapie nichtseminatöser Hodentumoren.

The results of the treatment of 194 patients with non-seminomas were analyzed and statistically registered. The therapeutic approach is described and the cumulative probability of survival is compared according to the stages. For the total number of these tumours a cumulative 5-year-survival probability of 68.6% was calculated. In detail it reaches from 100% in clinical stage I to 39.7% in clinical stage III. The decisive change of the prognosis is between the clinical stages IIb and IIc. An adjuvant cytostatic therapy should, if performed, be aggressive. Relapses in the clinical stage I are possible and call for a critical valuation of the primary stage. A retarded cytostatic polychemotherapy should be performed only under certain conditions.