[Breastfeeding Rates and Duration in Germany - A Systematic Review]. / Stillhäufigkeit und Stilldauer in Deutschland ­ eine systematische Übersicht.

Aim: 20 years after establishment of the National Breastfeeding Committee, the present work, based on published data on breastfeeding, is aimed at providing insight into the development of breastfeeding behaviour in Germany. Methods: To identify relevant publications, a comprehensive literature search was conducted in PubMed and Web of Science using the search terms "breast feeding" or "breastfeeding" in combination with "Germany". The publication period was limited to the period 1995-2014. Results: A total of 35 studies with data on breastfeeding for the birth cohorts of 1990-2012 were identified. Most of the data had been collected in regional or local surveys, often retrospectively. About 60% of the studies had been conducted with the primary aim of collecting data on breastfeeding or infant nutrition. Over the past 2 decades, breastfeeding rates were always relatively high at the beginning (72-97%). However, they declined significantly within the first 2 months, and by the age of 6 months, only about 50% of infants were still breastfed. Conclusion: Breastfeeding support and early assistance should be offered to a greater extent in order to achieve sustainable improvement of breastfeeding frequency and duration in Germany. Regarding the quality of data collected on breastfeeding, it seems crucial to implement standardised approaches to monitor breastfeeding in Germany.

SS18-SSX fusion protein-induced Wnt/ß-catenin signaling is a therapeutic target in synovial sarcoma.

Synovial sarcoma is a high-grade soft tissue malignancy characterized by a specific reciprocal translocation t(X;18), which leads to the fusion of the SS18 (SYT) gene to one of three SSX genes (SSX1, SSX2 or SSX4). The resulting chimeric SS18-SSX protein is suggested to act as an oncogenic transcriptional regulator. Despite multimodal therapeutic approaches, metastatic disease is often lethal and the development of novel targeted therapeutic strategies is required. Several expression-profiling studies identified distinct gene expression signatures, implying a consistent role of Wnt/ß-catenin signaling in synovial sarcoma tumorigenesis. Here we investigate the functional and therapeutic relevance of Wnt/ß-catenin pathway activation in vitro and in vivo. Immunohistochemical analyses of nuclear ß-catenin and Wnt downstream targets revealed activation of canonical Wnt signaling in a significant subset of 30 primary synovial sarcoma specimens. Functional aspects of Wnt signaling including dependence of Tcf/ß-catenin complex activity on the SS18-SSX fusion proteins were analyzed. Efficient SS18-SSX-dependent activation of the Tcf/ß-catenin transcriptional complex was confirmed by TOPflash reporter luciferase assays and immunoblotting. In five human synovial sarcoma cell lines, inhibition of the Tcf/ß-catenin protein-protein interaction significantly blocked the canonical Wnt/ß-catenin signaling cascade, accompanied by the effective downregulation of Wnt targets (AXIN2, CDC25A, c-MYC, DKK1, CyclinD1 and Survivin) and the specific suppression of cell viability associated with the induction of apoptosis. In SYO-1 synovial sarcoma xenografts, administration of small molecule Tcf/ß-catenin complex inhibitors significantly reduced tumor growth, associated with diminished AXIN2 protein levels. In summary, SS18-SSX-induced Wnt/ß-catenin signaling appears to be of crucial biological importance in synovial sarcoma tumorigenesis and progression, representing a potential molecular target for the development of novel therapeutic strategies.

[Molecular pathology of sarcomas. Update on the research group "Molecular Diagnosis of Sarcomas"]. / Molekularpathologie von Sarkomen. Erste Ergebnisse des Sarkomforschungsverbundes KoSar.

To establish precise diagnostic algorithms and standardised treatment of sarcomas in specialized centers, the interdisciplinary research group KoSar (sarcoma competence network) has been funded by German Cancer Aid. A sarcoma tissue repository and a diagnostic reference center have been set up, presently containing about 1000 accurately diagnosed sarcomas of different entities. Significant gene expression profiles for synovial sarcomas, leiomyosarcomas, myxoid liposarcomas and a small profile for myxofibrosarcomas as well as a new classification of angiosarcomas were defined. We systematically searched for activated signal transduction pathways in sarcoma cell lines and xenograft transplant models and candidate targets for molecular therapies were identified. Based on these results first clinical studies have been initiated by the German Interdisciplinary Sarcoma Study Group (GISG).

[Amphetamine misuse in suspected adult ADHS syndrome]. / Amphetaminmissbrauch bei angeblichem adultem Aufmerksamkeitsdefizit/Hyperaktivitätssyndrom.

Methylphenidate is increasingly used in adults with attention deficit/hyperactivity syndrome (ADHS). We report two cases of amphetamine misuse in patients with suspected ADH syndrome. In both cases the diagnoses had not been made in childhood. The interrelationship between substance use and adult ADHS is discussed.

[Public opinion on breast-feeding and infant nutrition: results of a questionnaire in North Rhine-Westphalia]. / Die Einstellung der Bevölkerung zum Stillen und zur Säuglingsernährung - Bevölkerungsbefragung in Nordrhein-Westfalen.

AIM: With the intention to create a basis for interventions on the promotion of breast-feeding, the public opinion on breast-feeding and infant nutrition in NRW was assessed. METHODS: A two-stage random sample of interviewees was drawn for a computer-assisted telephone survey (CATI). Methods applied on the selection of: 1. Households: 1.1. Gabler-Häder (n=1 811); 1.2. Onomastik (n=200); participants with a Turkish background of migration interviewed in German or Turkish language, alternatively: 2. Interviewees: Last Birthday method (n=2 011), age > or =18 years. RESULTS: Breast milk is the nutrition preferably recommended in the first six months, the knowledge of adjacent issues of infant nutrition has to be improved. The majority accepts supportive measures for breast-feeding. Different sources of information were assessed in Turkish and German participants. CONCLUSION: The survey supplies the background for the development of target group-specific information strategies which take specifically into account of issues attributable to ethnic differences and to reach the relatives and friends of young families, too.

Activated gammadelta T cells express the natural cytotoxicity receptor natural killer p 44 and show cytotoxic activity against myeloma cells.

gammadelta T cells account for up to 10% of T lymphocytes in the peripheral blood of healthy donors. They can be activated by cytokines such as interleukin (IL)-2, IL-12 and IL-15, express natural killer (NK) cell markers such as NKG2D and show cytotoxic activity against several tumour cells, including multiple myeloma. Here, we present activated polyclonal gammadelta T cells from healthy donors with an NK T cell-like phenotype expressing the natural cytotoxicity receptor NKp44. Natural cytotoxicity receptors NKp30, NKp44 and NKp46 have been regarded as specific NK receptors; only two gammadelta T cell clones described so far expressed NKp 44. Isolated polyclonal gammadelta T cells cultured for 7 days according to the cytokine-induced killer cell (CIK) protocol with additional IL-15 revealed a surface expression of NKp44 of 8+/-7% (n=22). This could be confirmed by detection of NKp 44 mRNA by reverse transcription-polymerase chain reaction (RT-PCR). gammadelta T cells exhibited a marked cytotoxic activity against myeloma cells, which could be reduced by inhibition of NKp44. To our knowledge, this is the first description of the expression of NKp44 on polyclonal gammadelta T cells.

A recombinant anti-carcinoembryonic antigen immunoreceptor with combined CD3zeta-CD28 signalling targets T cells from colorectal cancer patients against their tumour cells.

BACKGROUND AND AIMS: The prognosis of metastatic colorectal cancer is still poor, raising the need for alternative therapeutic approaches, particularly by manipulating the antitumour immune response. Advanced tumour stages, however, are frequently accompanied by functional T cell defects which may be critical for a T cell based anticancer immunotherapy. The aim of this study was to address whether T cells from colorectal cancer patients with advanced tumour stages can be specifically antigen activated against their autologous tumour cells. METHODS: T cells were isolated from colorectal cancer patients and retrovirally transduced to express a recombinant immunoreceptor that has an extracellular binding domain for carcinoembryonic antigen (CEA) and an intracellular CD3zeta signalling domain with and without CD28 costimulation for T cell activation. RESULTS: Peripheral blood T cells from colorectal cancer patients were successfully engineered to express the anti-CEA immunoreceptor on the cell surface. On coincubation with autologous CEA(+) tumour cells, T cells with anti-CEA immunoreceptor are specifically activated to secrete interferon gamma (IFN-gamma) and to lyse autologous tumour cells whereas T cells without immunoreceptor are not. T cells equipped with combined CD3zeta-CD28 signalling receptor are more efficiently activated to secrete IFN-gamma compared with T cells with CD3zeta signalling receptor. Induction of interleukin 2 secretion on targeting towards autologous tumour cells requires triggering of T cells by the CD3zeta-CD28 costimulatory receptor. CONCLUSIONS: T cells from advanced colorectal cancer patients can be tumour specifically activated with high efficiency by engraftment with a combined CD3zeta-CD28 immunoreceptor to break tolerance against autologous tumour cells.

Coculture with dendritic cells promotes proliferation but not cytotoxic activity of gamma/delta T cells.

T cells bearing the gamma9/delta2 T cell receptor (TCR) have recently raised interest as non-MHC restricted effector cells against multiple myeloma. They are described to be stimulated by phosphoantigens without the need of antigen presenting cells. However, in the past a positive effect of cells of the monocyte lineage on activation of gamma/delta T cells has been shown. Monocyte derived dendritic cells (DC) are professional antigen presenting cells widely investigated as stimulators of alpha/beta T cells. But only little is known about the interaction of gamma/delta T cells and monocyte derived DC. Here, we investigated the effect of coculture of mature DC unpulsed or pulsed with ibandronate on the proliferation and cytotoxic activity of isolated gamma/delta T cells. After coculturing monocyte derived DC with isolated gamma/delta T cells, proliferation of gamma/delta T cells was enhanced as determined by the (3)H thymidine uptake assay. Also, IFN-gamma secretion was increased after coculture with DC. As DC are well known to induce activation of alpha/beta T cells we investigated whether the cytotoxic activity of gamma/delta T cells could be increased by coculture with DC. We found no difference in cytotoxic activity of gamma/delta T cells alone or cocultured with unpulsed or pulsed mature DC. Also, sensitizing of myeloma cells by addition of ibandronate could not increase lysis by gamma/delta T cells. In conclusion, monocyte derived DC are capable of stimulating proliferation and secretion of IFN-gamma of gamma/delta T cells but do not exert an effect on cytotoxic activity of gamma/delta T cells against myeloma cells.

The impact of peripartum factors on the onset and duration of lactation.

Knowledge of peripartum indicators of those mother-infant pairs that are at increased risk of early failure of lactation may improve specific support of breastfeeding. Mode of delivery, labor complications, hyperbilirubinemia, milk intake and weight development were evaluated in healthy term infants in a hospital (n = 338). Delayed onset of lactation was observed in primiparae and in study participants with peripartum complications. The quantitative intake of human milk, assessed by test weighing 0-24 h and 24-48 h after the onset of lactation, was not significantly different between these groups. In addition, volume intake, weight gain and lactation success were tracked in 77 infants. Partial feeding of infant formula or an intake of <150 g of human milk per day 24-48 h after the onset of lactation was linked to weaning within 4 weeks. Ninety-one percent of the infants were exclusively breastfed at discharge; this value had declined to 49, 35 and 20% at 4, 12 and 20 weeks, respectively. Peripartum factors may contribute to early lactation failure; the long-term success of breastfeeding was predominantly determined outside the hospital.

Antibody-targeted chemotherapy of older patients with acute myeloid leukemia in first relapse using Mylotarg (gemtuzumab ozogamicin).

We analyzed the safety and efficacy of Mylotarg (gemtuzumab ozogamicin, an antibody-targeted chemotherapy consisting of a humanized anti-CD33 antibody linked to calicheamicin, a potent antitumor antibiotic) in the treatment of 101 patients > or =60 years of age with acute myeloid leukemia (AML) in untreated first relapse in three open-label trials. Mylotarg is administered as a 2-h intravenous infusion at 9 mg/m(2) for two doses with 14 days between doses. The overall remission rate was 28%, with complete remission (CR) in 13% of patients and complete remission with incomplete platelet recovery (CRp) in 15%. Median survival was 5.4 months for all patients and 14.5 months and 11.8 months for patients achieving CR and CRp, respectively. CD33 antigen is present on normal hematopoietic progenitor cells; thus, an expected high incidence of grade 3 or 4 neutropenia (99%) and thrombocytopenia (99%) was observed. The incidences of grade 3 or 4 elevations of bilirubin and hepatic transaminases were 24% and 15%, respectively. There was a low incidence of grade 3 or 4 mucositis (4%) and infections (27%) and no treatment-related cardiotoxicity, cerebellar toxicity, or alopecia. Mylotarg is an effective treatment for older patients with CD33-positive AML in first relapse and has acceptable toxicity.

Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukaemia in first relapse.

Gemtuzumab ozogamicin (CMA-676, Mylotarg, an antibody-targeted chemotherapy agent, was recently approved by the FDA for the treatment of patients with CD33+ acute myeloid leukaemia (AML) in first relapse who are 60 years of age or older and who are not considered candidates for other types of cytotoxic chemotherapy. In combined Phase II studies of 142 patients with CD33+ AML in first relapse, gemtuzumab ozogamicin monotherapy was associated with a 30% overall response rate. While treated patients had relatively high incidences of myelosuppression, grade 3 or grade 4 hyperbilirubinaemia (23%) and elevated hepatic transaminases (17%), the incidences of grade 3 or grade 4 mucositis (4%) and infections (28%) were low compared with what might be expected in association with conventional chemotherapeutic treatment. In contrast with the usual in-patient administration of cytarabine and anthracycline-containing induction regimens, a large number of patients were treated with gemtuzumab ozogamicin as outpatients (38% and 41% for the first and second doses, respectively). Two prognostic factors for patients with AML in first relapse, age and duration of complete remission, had relatively little effect on response rates to gemtuzumab ozogamicin. Preliminary data in pediatric patients also suggest the immunoconjugate to be reasonably well tolerated. Studies of gemtuzumab ozogamicin in combination with anthracycline and cytarabine are underway. Gemtuzumab ozogamicin, administered to patients with CD33+ AML in first relapse, has shown overall response rates comparable to conventional agents and a safety profile that appears to be favourable.

Molybdenum in infancy: balance studies in patients with intestinal stomata.

UNLABELLED: This study investigated the supply of the essential trace element molybdenum (Mo) in infants with preternatural anus. It was divided into two separate investigations: (A) the complete fecal excretion of nine patients was collected in fractions over 24 h; and (B) 72 h balance studies and parallel plasma analysis were conducted in five infants and complemented by the longitudinal comparison of one of these patients with his (otherwise healthy) premature sister. Atomic absorption spectroscopy (balance studies) and high-resolution inductively coupled plasma mass spectrometry (HR-ICP-MS, plasma) were used for analysis. The following results were obtained. (A) The fecal Mo concentration ranged from 1.98 to 42.02 nmol Mo g(-1) dry fecal weight. (B) The daily intake in the balance studies was 43.2 (11.33-100.5) nmol Mo kg(-1) and the median retention was -2.91 (-32.45 to 48.6) nmol Mo kg(-1). In the premature twins the boy with an intestinal stoma had a negative balance and lost -3.32 micromol within 32 d, while his sister retained +0.45 micromol Mo in the same period. Plasma Mo ranged between 9.4 and 46.7 nmol l(-1). CONCLUSION: The negative Mo balance results may indicate an increased risk of Mo deficiency in infants requiring a long-term preternatural anus.

Mylotarg: antibody-targeted chemotherapy comes of age.

Mylotarg (gemtuzumab ozogamicin, CMA-676; Wyeth-Ayerst Laboratories, Philadelphia, PA) recently was approved by the US Food and Drug Administration for the treatment of patients with CD33-positive acute myeloid leukemia in first relapse, age 60 years or older, who are not considered candidates for other types of cytotoxic chemotherapy. In combined phase II studies of 142 patients with CD33-positive acute myeloid leukemia in first relapse, Mylotarg monotherapy was associated with a 30% overall response rate. Although treated patients had relatively high incidences of myelosuppression, hyperbilirubinemia, and elevated hepatic transaminases, the incidences of severe mucositis and infections were low compared with what might be expected in association with conventional chemotherapeutic treatment. Preliminary data in pediatric patients also suggest that the immunoconjugate is reasonably well tolerated. Studies of Mylotarg in combination with anthracycline, cytarabine, and agents that inhibit P-glycoprotein are underway.

Targeted therapies for high-risk acute myeloid leukemia.

Approximately half of children with acute myeloid leukemia (AML) can be cured with contemporary chemotherapy regimens; however, various forms of drug resistance pose considerable obstacles for curing the remaining patients. Recent advances in immunology, cytogenetics, and cellular and molecular biology have provided new insights into fundamental biological differences between leukemic myeloid blasts and their normal counterparts. This article focuses on new technologies involving: (1) antibody- or growth factor-mediated targeting of antigens or growth factor receptors found on AML blasts and restricted sub-groups of normal cells, (2) pharmacologic targeting of the pathologic t(15;17) translocation of acute promyelocytic leukemia with all-trans retinoic acid, (3) pharmacologic and immunologic targeting of mutant RAS oncogenes and related aberrant signaling in AML blasts, and (4) targeting of pathological signaling of the Bcr-Abl oncoprotein and c-kit tyrosine kinase in myeloid leukemias. These advances herald an exciting new era of AML-specific therapies.

United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia.

PURPOSE: To determine the safety and efficacy of arsenic trioxide (ATO) in patients with relapsed acute promyelocytic leukemia (APL). PATIENTS AND METHODS: Forty patients experiencing first (n = 21) or > or = second (n = 19) relapse were treated with daily infusions of ATO to a maximum of 60 doses or until all leukemic cells in bone marrow were eliminated. Patients who achieved a complete remission (CR) were offered one consolidation course of ATO that began 3 to 4 weeks later. Patients who remained in CR were eligible to receive further cycles of ATO therapy on a maintenance study. RESULTS: Thirty-four patients (85%) achieved a CR. Thirty-one patients (91%) with CRs had posttreatment cytogenetic tests negative for t(15;17). Eighty-six percent of the patients who were assessable by reverse transcriptase polymerase chain reaction converted from positive to negative for the promyelocytic leukemia/retinoic acid receptor-alpha transcript by the completion of their consolidation therapy. Thirty-two patients received consolidation therapy, and 18 received additional ATO as maintenance. Eleven patients underwent allogeneic (n = 8) or autologous (n = 3) transplant after ATO treatment. The 18-month overall and relapse-free survival (RFS) estimates were 66% and 56%, respectively. Twenty patients (50%) had leukocytosis (> 10,000 WBC/microL) during induction therapy. Ten patients developed signs or symptoms suggestive of the APL syndrome and were effectively treated with dexamethasone. Electrocardiographic QT prolongation was common (63%). One patient had an absolute QT interval of > 500 msec and had an asymptomatic 7-beat run of torsades de pointe. Two patients died during induction, neither from drug-related causes. CONCLUSION: This study establishes ATO as a highly effective therapy for patients with relapsed APL.

Multidrug-resistance phenotype and clinical responses to gemtuzumab ozogamicin.

Expression of multidrug resistance (MDR) features by acute myeloid leukemia (AML) cells predicts a poor response to many treatments. The MDR phenotype often correlates with expression of P-glycoprotein (Pgp), and Pgp antagonists such as cyclosporine (CSA) have been used as chemosensitizing agents in AML. Gemtuzumab ozogamicin, an immunoconjugate of an anti-CD33 antibody linked to calicheamicin, is effective monotherapy for CD33(+) relapsed AML. However, the contribution of Pgp to gemtuzumab ozogamicin resistance is poorly defined. In this study, blast cell samples from relapsed AML patients eligible for gemtuzumab ozogamicin clinical trials were assayed for Pgp surface expression and Pgp function using a dye efflux assay. In most cases, surface expression of Pgp correlated with Pgp function, as indicated by elevated dye efflux that was inhibited by CSA. Among samples from patients who either failed to clear marrow blasts or failed to achieve remission, 72% or 52%, respectively, exhibited CSA-sensitive dye efflux compared with 29% (P =.003) or 24% (P <.001) among samples from responders. In vitro gemtuzumab ozogamicin--induced apoptosis was also evaluated using an annexin V--based assay. Low levels of drug-induced apoptosis were associated with CSA-sensitive dye efflux, whereas higher levels correlated strongly with achievement of remission and marrow blast clearance. In vitro drug-induced apoptosis could be increased by CSA in 14 (29%) of 49 samples exhibiting low apoptosis in the absence of CSA. Together, these findings indicate that Pgp plays a role in clinical resistance to gemtuzumab ozogamicin and suggest that treatment trials combining gemtuzumab ozogamicin with MDR reversal agents are warranted. (Blood. 2001;98:988-994)

Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse.

PURPOSE: Three open-label, multicenter trials were conducted to evaluate the efficacy and safety of single-agent Mylotarg (gemtuzumab ozogamicin; CMA-676; Wyeth Laboratories, Philadelphia, PA), an antibody-targeted chemotherapy agent, in patients with CD33-positive acute myeloid leukemia (AML) in untreated first relapse. PATIENTS AND METHODS: The study population comprised 142 patients with AML in first relapse with no history of an antecedent hematologic disorder and a median age of 61 years. All patients received Mylotarg as a 2-hour intravenous infusion, at a dose of 9 mg/m(2), at 2-week intervals for two doses. Patients were evaluated for remission, survival, and treatment-emergent adverse events. RESULTS: Thirty percent of patients treated with Mylotarg obtained remission as characterized by 5% or less blasts in the marrow, recovery of neutrophils to at least 1,500/microL, and RBC and platelet transfusion independence. Although patients treated with Mylotarg had relatively high incidences of myelosuppression, grade 3 or 4 hyperbilirubinemia (23%), and elevated hepatic transaminase levels (17%), the incidences of grade 3 or 4 mucositis (4%) and infections (28%) were relatively low. There was a low incidence of severe nausea and vomiting (11%) and no treatment-related cardiotoxicity, cerebellar toxicity, or alopecia. Many patients received Mylotarg on an outpatient basis (38% and 41% of patients for the first and second doses, respectively). Among the 142 patients, the median total duration of hospitalization was 24 days; 16% of patients required 7 days of hospitalization or less. CONCLUSION: Administration of the antibody-targeted chemotherapy agent Mylotarg to patients with CD33-positive AML in first relapse induces complete remissions with what appears to be a favorable safety profile.