Effects of 12-week resistance training during radiotherapy in breast cancer patients.

Exercise is considered to be an effective supportive treatment approach in breast cancer (BC) patients. We conducted a randomized controlled trial to assess the efficacy of a 12-week PRT during radiotherapy. Strength performance was assessed by maximal isokinetic peak torque (MIPT) in two different angular velocities (60°/s and 180°/s) and maximal voluntary isometric contraction for shoulder external and internal rotation, as well as for knee extension and flexion were assessed pre- and post-intervention in 146 patients randomized to PRT or a control group. Statistical analyses were based on analysis of covariance models for the individual changes from baseline to week 13. Intention-to-treat analyses showed significant between-group differences favoring the exercise group (EX) for MIPT in knee flexion and shoulder internal and external rotation (P < 0.05). Subgroup analyses showed borderline significant differences with regard to pretreatment history, revealing that pretreated chemotherapy patients tend to benefit more from PRT than patients without chemotherapy (P = 0.06). Strength gain at the operated arm was significantly higher than at the non-operated arm in EX. PRT was efficacious in increasing upper and lower limb strength in BC patients undergoing adjuvant radiotherapy. Patients with restrictions due to breast cancer-related surgery and pretreated with chemotherapy might benefit the most.

Randomized, controlled trial of resistance training in breast cancer patients receiving adjuvant radiotherapy: results on cancer-related fatigue and quality of life.

BACKGROUND: Exercise has been reported to decrease cancer-related fatigue and to increase quality of life (QoL) in various breast cancer (BC) populations. However, studies investigating exercise during radiotherapy or resistance training are scarce. We conducted a randomized, controlled trial (BEST study) to assess the efficacy of 12-week resistance training on fatigue beyond possible psychosocial effects of a group-based intervention. PATIENTS AND METHODS: One hundred sixty patients with BC stage 0-III were randomly assigned to a 12-week progressive resistance training (2 times/week) or a 12-week relaxation control (RC, 2 times/week). Both interventions were group-based. The primary end point fatigue was assessed with a 20-item multidimensional questionnaire, QoL with EORTC questionnaires. Statistical analyses were based on analysis of covariance models for the individual changes from baseline to week 13. RESULTS: Adherence to the intervention program as well as the completion rate (97%) for the primary outcome variable fatigue was high. In intention-to-treat analyses for the N = 155 patients, significant between-group mean differences (MD) favoring the exercise group (EX) were observed for general fatigue (P = 0.044), especially for the subscale physical fatigue [MD = -0.8; 95% confidence interval -1.5 to -0.2, P = 0.013], but not for affective (P = 0.91) or cognitive fatigue (P = 0.65). For QoL, significantly larger improvements regarding the role function (P = 0.035) and pain (P = 0.040) were noted among exercisers compared with RCs. Future perspective improved significantly stronger in the RC group compared with the EX group (P = 0.047). CONCLUSIONS: The 12-week resistance training program was a safe, feasible and efficacious strategy to improve cancer-related fatigue and components of QoL in BC patients during adjuvant radiotherapy. As exercise was compared with another group-based intervention, results indicate that resistance training effects on fatigue and QoL go beyond psychosocial benefits, and that the clinically relevant overall benefit of resistance exercise compared with usual care can be assumed to be higher. TRIAL REGISTRATION: ClinicalTrials.gov NCT01468766.

Prophylaxis of acute radiation dermatitis with an innovative FDA-approved two-step skin care system in a patient with head and neck cancer undergoing a platin-based radiochemotherapy: a case report and review of the literature.

Radiodermatitis is a very common side effect in cancer treatment often leading to therapy delays and diminution of the patients' health state and quality of life. Despite a wide range of supportive strategies, radiodermatitis is still a major problem necessitating further improvements in prevention and treatment. Lactokine is a milk-based protein shown to assist in the reduction of skin redness. The treatment is a unique FDA-approved skin care system (R1 and R2). In this case presentation we describe the prophylactic use of R1 and R2 in a 63-year-old, female patient with a squamous cell carcinoma of the hypopharynx undergoing a platin-based chemoradiation. The application was feasible and safe and the patient developed only a slight radiodermatitis. To our knowledge this is the first report in the literature on the prophylactic use of R1 and R2. Further evidence will be provided by a prospective, clinical trial we have launched (CREAM-1; study registration in ISRCTN Registry: ISRCTN87302591). We also review the literature to give an overview about common strategies in the management of radiodermatitis.

Differentiation of irradiation and cetuximab induced skin reactions in patients with locally advanced head and neck cancer undergoing radioimmunotherapy: the HICARE protocol (head and neck cancer: immunochemo and radiotherapy with erbitux) - a multicenter phase IV trial.

BACKGROUND: In order to improve the clinical outcome of patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) not being capable to receive platinum-based chemoradiation, radiotherapy can be intensified by addition of cetuximab, a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR). The radioimmunotherapy with cetuximab is a feasible treatment option showing a favourable toxicity profile. The most frequent side effect of radiotherapy is radiation dermatitis, the most common side effect of treatment with cetuximab is acneiform rash. Incidence and severity of these frequent, often overlapping and sometimes limiting skin reactions, however, are not well explored. A clinical and molecular differentiation between radiogenic skin reactions and skin reactions caused by cetuximab which may correlate with outcome, have never been described before. METHODS/DESIGN: The HICARE study is a national, multicenter, prospective phase IV study exploring the different types of skin reactions that occur in patients with LASCCHN undergoing radioimmun(chemo)therapy with the EGFR inhibitor cetuximab. 500 patients with LASCCHN will be enrolled in 40 participating sites in Germany. Primary endpoint is the rate of radiation dermatitis NCI CTCAE grade 3 and 4 (v. 4.02). Radioimmunotherapy will be applied according to SmPC, i.e. cetuximab will be administered as loading dose and then weekly during the radiotherapy. Irradiation will be applied as intensity-modulated radiation therapy (IMRT) or 3D-dimensional radiation therapy. DISCUSSION: The HICARE trial is expected to be one of the largest trials ever conducted in head and neck cancer patients. The goal of the HICARE trial is to differentiate skin reactions caused by radiation from those caused by the monoclonal antibody cetuximab, to evaluate the incidence and severity of these skin reactions and to correlate them with outcome parameters. Besides, the translational research program will help to identify and confirm novel peripheral blood based molecular predictors and surrogates for treatment response and resistance. TRIAL REGISTRATION: Clinical Trial Identifier, NCT01553032 (clinicaltrials.gov)EudraCT number: 2010-019748-38.

Remission of refractory Crohn's disease by high-dose cyclophosphamide and autologous peripheral blood stem cell transplantation.

BACKGROUND: Despite advances in immunosuppressive therapy, up to 10% of patients with severe Crohn's disease (CD) remain refractory to conventional treatment. Limited evidence from pilot trials suggests that high-dose immunosuppression and autologous peripheral blood stem cell transplantation (autoPBSCT) may induce remission in these patients, but there is substantial controversy regarding the safety and efficacy of this approach. AIM: To address this issue, a monocentre phase I/II trial of autoPBSCT was performed in patients with refractory CD in our hospital. METHODS: Here, we report on the outcome of 12 patients with refractory CD treated with autoPBSCT. Briefly, CD34(+) -selected PBSCs were harvested after mobilisation therapy with cyclophosphamide and granulocyte-colony stimulating factor. Later, immunoablative conditioning therapy with high-dose cyclophosphamide followed by autoPBSCT was applied and clinical and endoscopic responses were analysed after a mean follow-up of 3.1 years (range 0.5-10.3 years). RESULTS: PBSC harvest following mobilisation chemotherapy was successful in 11/12 patients and resulted in a clinical and endoscopic improvement in 7/12 patients. Subsequent conditioning and autoPBSCT were performed in nine patients and were relatively well tolerated. Among those, five patients achieved a clinical and endoscopic remission within 6 months after autoPBSCT. However, relapses occurred in 7/9 patients during follow-up, but disease activity could be controlled by low-dose corticosteroids and conventional immunosuppressive therapy. CONCLUSION: Immunoablation by cyclophosphamide and autologous peripheral blood stem cell transplantation is safe and effective to induce remission of refractory Crohn's disease, and should be further evaluated in randomised controlled trials.

Endoscopic diagnosis of acute intestinal GVHD following allogeneic hematopoietic SCT: a retrospective analysis in 175 patients.

Diagnosis of acute intestinal GVHD (aGVHD) following allogeneic hematopoietic cell transplantation is based on clinical symptoms and histological lesions. This retrospective analysis aimed to validate the 'Freiburg Criteria' for the endoscopic grading of intestinal aGVHD. Grade 1: no clear-cut criteria; grade 2: spotted erythema; grade 3: aphthous lesions; and grade 4: confluent defects, ulcers, denudation of the mucosa. Having excluded patients with infectious diarrhea, we evaluated 175 consecutive patients between January 2001 and June 2009. Setting a cutoff between grade 1 (no change in therapy) and grade 2 (intensification of immunosuppression), macroscopy had a sensitivity of 89.2% (95% confidence interval (CI): 80.4-94.9%), a specificity of 79.4% (95% CI: 69.6-87.1%), a positive-predictive value of 79.6% (95% CI: 70.0-87.2%) and a negative-predictive value of 89.0% (95% CI: 80.2-94.9%). In all, 20% of patients with aGVHD in the lower gastrointestinal tract (GIT) had lesions only in the terminal ileum. In all patients with aGVHD ≥2 of the upper GIT, typical lesions were also found in the lower GIT. Ileo-colonoscopy showed the highest diagnostic yield for aGVHD. In conclusion, the 'Freiburg Criteria' for macroscopic diagnosis of intestinal aGVHD provide high accuracy for identifying aGVHD ≥2.

Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion.

BACKGROUND: Anti-epidermal growth factor receptor treatment strategies, i.e. monoclonal antibodies such as cetuximab and panitumumab, or epidermal growth factor receptor (EGFR) small molecule tyrosine kinase inhibitors, such as erlotinib and gefitinib, have expanded the treatment options for different tumor types. Dermatologic toxic effects are the most common side-effects of EGFR inhibitor therapy. They can profoundly affect the patient's quality of life. PURPOSE: The aim of this study was to provide interdisciplinary expert recommendations on how to treat patients with skin reactions undergoing anti-EGFR treatment. MATERIAL AND METHODS: An expert panel from Germany with expertise in medical oncology, dermatology or clinical pharmacology was convened to develop expert recommendations based on published peer-reviewed literature. RESULTS: The expert recommendations for the state-of-the-art treatment of skin reactions induced by EGFR inhibitor therapy include recommendations for diagnostics and grading as well as grade-specific and stage-adapted treatment approaches and preventive measures. It was concluded that EGFR-inhibitor-related dermatologic reactions should always be treated combining basic care of the skin and a specific therapy adapted to stage and grade of skin reaction. For grade 2 and above, specific treatment recommendations for early- and later-stage skin reactions induced by EGFR-inhibitor therapy were proposed. CONCLUSION: This paper presents a German national expert opinion for the treatment of skin reactions in patients receiving EGFR inhibitor therapy.

Cure of ventriculitis and central nervous system shunt infection by Staphylococcus epidermidis with vancomycin by intraventricular injection in a liver transplant recipient.

A 19-year-old female underwent orthotopic liver transplantation for acute hepatic failure because of fulminant Wilson's disease. Three months post transplantation she developed systemic fungal meningoencephalitis and obstructive hydrocephalus that required cerebrospinal fluid (CSF) shunting by a ventriculo-atrial shunt. Subsequently, she contracted Staphylococcus epidermidis bacteremia, ventriculitis, and shunt infection. Treatment with vancomycin either by conventional intravenous (i.v.) or continuous i.v. injection proved ineffective because of insufficient drug concentrations in the CSF. Eradication of S. epidermidis from CSF and cure of chronic ventriculitis and shunt infection was readily achieved by delivering vancomycin by intraventricular injection (5 mg/24 h) via an extraventricular drain together with continuous i.v. infusion (4 g/24 h) over a period of 18 days. This treatment was well tolerated and free of untoward side effects despite the patient's chronic immunosuppression subsequent to liver transplantation. Intraventricular injection of vancomycin is an effective and safe procedure to eradicate S. epidermidis from the central nervous system when i.v. vancomycin treatment fails.

Microcosm studies for neutralization of hypolimnic acid mine pit lake water (pH 2.6).

Ten microcosms of 0.088 m3 water volume (0.3 m i.d. and 1.20 m height) were designed for neutralization studies representing hypolimnic ecosystem models for acid mine pit lakes. Sediment and water were collected from an acid lignite mine pit lake (Brandenburg, Germany) and filled into the microcosms. To determine the efficacy of controlled in situ organic carbon amendments as a possible neutralization method, sediment and water were treated with ethanol and Carbokalk with and without wheat straw. The water chemistry was monitored for 1 yr. At start-up and end of the experiments, the sedimentwas characterized. Iron and sulfate were removed with varying intensity from the water phase as a result of microbial iron and sulfate reduction together with a subsequent precipitation of unsoluble sulfide minerals to the sediment. The pH rose, and alkalinity generation and bacterial growth were observed. Neutralization rates were calculated using equivalents of accumulated total reduced inorganic sulfur together with the nonsulfidic reactive ferrous iron in the sediment. In the treated microcosms, the neutralization rates were between 6 and 15 equiv m(-2) a(-1). Carbokalk was most effective in stimulating growth of sulfate-reducing bacteria and probably also served as inoculum. With Carbokalk together with wheat straw, the pH increased from 2.6 to around 6.5 within the whole microcosm. The critical revision of the results indicates that the application of Carbokalk (approximately 3.9 kg m(-2)) together with the application of wheat straw (approximately 9.3 kg m(-2)) is most suitable for further experiments in outdoor enclosures (mesocosms). For that case, the prediction of the water quality for a lake water column after multiple lake turnover events is presented based on batch reaction simulation using the geochemical model PHREEQC.

Complete remission of Crohn's disease after high-dose cyclophosphamide and autologous stem cell transplantation.

In a 36-year-old male with ileocolic Crohn's disease (CD) no long-lasting remission was obtained by treatment with corticosteroids, mesalazine, azathioprine and antibiotics. Surgical interventions due to relapsing fistulae and abscesses resulted in the removal of >1.5 m of small bowel and left only 40 cm of large bowel. In July 2000, a new fistula and abscess developed. The combination of corticosteroids, mesalazine, ciprofloxacin, metronidazol, azathioprine, formula diet and anti-TNF-alpha antibody largely reduced clinical activity, and resection of fistula and abscess were successful. Despite clinical remission, histology showed activity in the small bowel and the colon. In March 2001, stem cell mobilization chemotherapy with cyclophosphamide was performed. It induced an endoscopic remission for 9 months, which was maintained on azathioprine and corticosteroids. After relapse, in March 2002, high-dose chemotherapy with cyclophosphamide and reinfusion of T-cell-depleted autologous peripheral CD34+ blood stem cells were performed. This led to a complete clinical, endoscopical and histological remission for 9 months without any treatment. Thereafter, endoscopy showed initial aphthous lesions with minimal histological signs of inflammation. The patient is asymptomatic, but low-dose prednisolone and methotrexate are prophylactically given. Immunoablative chemotherapy followed by autologous peripheral blood stem cell transplantation may be a beneficial therapeutic option in complicated refractory CD.

Influence of recombinant human granulocyte colony-stimulating factor (filgrastim) on hematopoietic recovery and outcome following allogeneic bone marrow transplantation (BMT) from volunteer unrelated donors.

Effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF, filgrastim) on hematopoietic recovery and clinical outcome in patients undergoing allogeneic bone marrow transplantation (BMT) from volunteer unrelated donors (VUD) were analyzed retrospectively. Additionally, the influence of baseline patient and transplant characteristics on hematopoietic recovery was evaluated. From January 1994 to March 1996, 47 consecutive adult patients received VUD-BMT. GVHD prophylaxis was cyclosporin A/short course methotrexate/prednisolone, and in four patients additional ATG. Post-transplantation, cohorts of patients received rhG-CSF (5 microg/kg/day) (n = 22) or no rhG-CSF (n = 25) in a non-randomized manner. The patient groups with and without rhG-CSF were rather comparable with respect to baseline patient and transplant characteristics. Median time to neutrophil counts (ANC) >500/microl was 14 days with rhG-CSF vs 16 days without rhG-CSF (P = 0.048), to ANC >1000/microl was 15 vs 18 days (P = 0.084). Neutrophil recovery was accelerated in patients receiving more than the median MNC dose of 2.54 x 10(8)/kg with a median time to ANC >1000/microl of 13 days vs 19 days (P = 0.017). RhG-CSF did not influence platelet recovery and incidence of infectious complications. Incidence of acute GVHD II-IV was 50% with rhG-CSF and 28% without rhG-CSF (P = 0.144), but death before acute GVHD II-IV occurred in 9% of patients with and 20% of patients without rhG-CSF. The median follow-up time was 38 and 36 months in patients with and without rhG-CSF, respectively. Survival at 2 years post-transplant was 39% (95% confidence interval (18%, 60%)) in patients with rhG-CSF and 24% (95% confidence interval (7%, 41%)) in patients without rhG-CSF. Administration of rhG-CSF after VUD-BMT may lead to more rapid neutrophil recovery, but did not influence the incidence of infectious complications. Patients receiving rhG-CSF showed a slightly higher incidence of acute GVHD II-IV. Higher numbers of MNC in the marrow graft accelerated hematopoietic engraftment.

Phylogenetic Composition, Spatial Structure, and Dynamics of Lotic Bacterial Biofilms Investigated by Fluorescent in Situ Hybridization and Confocal Laser Scanning Microscopy.

> Abstract The phylogenetic composition, three-dimensional structure and dynamics of bacterial communities in river biofilms generated in a rotating annular reactor system were studied by fluorescent in situ hybridization (FISH) and confocal laser scanning microscopy (CLSM). Biofilms grew on independently removable polycarbonate slides exposed in the reactor system with natural river water as inoculum and sole nutrient and carbon source. The microbial biofilm community developed from attached single cells and distinct microcolonies via a more confluent structure characterized by various filamentous bacteria to a mature biofilm rich in polymeric material with fewer cells on a per-area basis after 56 days. During the different stages of biofilm development, characteristic microcolonies and cell morphotypes could be identified as typical features of the investigated lotic biofilms. In situ analysis using a comprehensive suite of rRNA-targeted probes visualized individual cells within the alpha-, beta-, and gamma-Proteobacteria as well as the Cytophaga-Flavobacterium group as major parts of the attached community. The relative abundance of these major groups was determined by using digital image analysis to measure specific cell numbers as well as specific cell area after in situ probing. Within the lotic biofilm community, 87% of the whole bacterial cell area and 79% of the total cell counts hybridized with a Bacteria specific probe. During initial biofilm development, beta-Proteobacteria dominated the bacterial population. This was followed by a rapid increase of alpha-Proteobacteria and bacteria affiliated to the Cytophaga-Flavobacterium group. In mature biofilms, alpha-Proteobacteria and Cytophaga-Flavobacteria continued to be the prevalent bacterial groups. Beta-Proteobacteria constituted the morphologically most diverse group within the biofilm communities, and more narrow phylogenetic staining revealed the importance of distinct phylotypes within the beta1-Proteobacteria for the composition of the microbial community. The presence of sulfate-reducing bacteria affiliated to the Desulfovibrionaceae and Desulfobacteriaceae confirmed the range of metabolic potential within the lotic biofilms.http://link.springer-ny.com/link/service/journals/00248/bibs/37n4p225.html

Busulfan/cyclophosphamide in volunteer unrelated donor (VUD) BMT: excellent feasibility and low incidence of treatment-related toxicity.

An increasing number of volunteer unrelated donor bone marrow transplantations (VUD-BMT) are performed every year for hematological malignancies due to the availability of a large donor pool. Here we show the results of 36 VUD transplants from our institution using a chemotherapy-only conditioning regimen comprising busulfan 4 x 4 mg/kg and cyclophosphamide 2 x 60 mg/kg. All patients received heparin 200 IU/kg bw continuous i.v. infusion starting the day before conditioning until day +30. Thirty-four of 36 patients (94%) engrafted and no secondary graft failure was observed. The two non-engraftments occurred in patients with CML in blast crisis with extensive myelofibrosis. All 34 engrafted patients (100%) were in complete remission on day +30 as shown by bone marrow biopsy and cytogenetic examinations. No life-threatening treatment-related morbidity or mortality (TRM) were observed, in particular, no severe veno-occlusive disease (VOD) of the liver and no fatal pulmonary complication. Use of G-CSF significantly shortened the time of neutropenia by 5 days. GVHD prophylaxis consisted of CsA/methylprednisolone with or without MTX. Acute GVHD grade II-IV was observed in 18/34 patients (53%) and cGVHD in 12/27 patients (45%), who survived to day +100. In seven patients (four with HLA class I or II mismatch) anti-T-lymphocyte globulin (ATG) was added for acute GVHD prophylaxis. One of seven had aGVHD grade II and none developed grade III to IV GVHD or graft failure. We conclude that Bu/CY is a feasible, save and sufficiently immunosuppressive regimen for VUD transplantation. Severe acute GVHD might be avoided by additional use of ATG in GVHD prophylaxis.

TNF activates NF-kappa B by phosphatidylcholine-specific phospholipase C-induced "acidic" sphingomyelin breakdown.

In this paper, we describe a phospholipid transmission pathway mediating tumor necrosis factor (TNF) activation of the nuclear transcription factor kappa B (NF-kappa B). Central to this TNF signaling route is the second messenger-like molecule ceramide, which is generated by sphingomyelin (SM) breakdown catalyzed by a sphingomyelinase (SMase). SMase activation is secondary to the generation of 1,2-diacylglycerol (DAG) produced by a TNF-responsive PC-specific phospholipase C (PC-PLC). The functional coupling of these two C type phospholipases is revealed by D609, a selective inhibitor of PC-PLC. SMase itself, or SMase-inducing regimens such as exogenous PLC or synthetic DAGs, induces NF-kappa B activation at pH 5.0, suggesting the operation of an acidic SMase. A model is proposed in which a TNF-responsive PC-PLC via DAG couples to an acidic SMase, resulting in the generation of ceramide, which eventually triggers rapid induction of nuclear NF-kappa B activity.

[Spontaneous secretion of growth hormone in children with constitutional delay of growth and adolescence and with early normal puberty (author's transl)]. / Die Spontansekretion des Wachstumshormons bei der konstitutionellen Entwicklungsverzögerung und der frühnormalen Pubertät.

The spontaneous secretion of hGH (plasma-hGH levels, 1/2-hourly determined) during the first 5 1/2 h of sleep was measured in 18 prepubertal children with constitutional delay of growth and adolescence (cDGA), in 14 controls (matched pairs) and 1 girl with early normal puberty (enP). The mean value of the highest individual peaks of the children with cDGA as well as their planimetrically assessed total secretion of hGH amounted to 56% of that of the controls (p less than 0.01 and less than 0.001). The girl with enP showed enhanced hGH maxima and an increased total secretion. Therapeutic trials with hGH, 10 i.u./m2/week lead to a growth velocity twice as fast as before. Treatment with a long acting testosterone preparation caused a manifold increase of the hGH-secretion.