EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment.

BACKGROUND: Four international study groups undertook a large study in resectable osteosarcoma, which included two randomised controlled trials, to determine the effect on survival of changing post-operative chemotherapy based on histological response. PATIENTS AND METHODS: Patients with resectable osteosarcoma aged ≤40 years were treated with the MAP regimen, comprising pre-operatively of two 5-week cycles of cisplatin 120 mg/m(2), doxorubicin 75 mg/m(2), methotrexate 12 g/m(2) × 2 (MAP) and post-operatively two further cycles of MAP and two cycles of just MA. Patients were randomised after surgery. Those with ≥10% viable tumour in the resected specimen received MAP or MAP with ifosfamide and etoposide. Those with <10% viable tumour were allocated to MAP or MAP followed by pegylated interferon. Longitudinal evaluation of quality of life was undertaken. RESULTS: Recruitment was completed to the largest osteosarcoma study to date in 75 months. Commencing March 2005, 2260 patients were registered from 326 centres across 17 countries. About 1334 of 2260 registered patients (59%) were randomised. Pre-operative chemotherapy was completed according to protocol in 94%. Grade 3-4 neutropenia affected 83% of cycles and 59% were complicated by infection. There were three (0.13%) deaths related to pre-operative chemotherapy. At definitive surgery, 50% of patients had at least 90% necrosis in the resected specimen. CONCLUSIONS: New models of collaboration are required to successfully conduct trials to improve outcomes of patients with rare cancers; EURAMOS-1 demonstrates achievability. Considerable regulatory, financial and operational challenges must be overcome to develop similar studies in the future. The trial is registered as NCT00134030 and ISRCTN 67613327.

Pretreatment for bilateral nephroblastomatosis is an independent risk factor for progressive disease in patients with stage V nephroblastoma.

BACKGROUND: Treatment of stage V nephroblastoma is less established and more complex than in unilateral nephroblastoma. METHODS: Retrospective analysis of 121 consecutive patients with stage V nephroblastoma registered from January 1989 to May 2005. Registration, prospective data collection and treatment were carried out within the framework of 3 consecutive SIOP/GPOH-nephroblastoma-trials. RESULTS: 19 patients had metastasis and 29 syndromes at diagnosis. 13 patients had been pretreated for bilateral nephroblastomatosis. 1 patient was not treated and 17 patients had upfront surgery. Preoperative treatment duration ranged from 1-12 weeks (n=103). 1-3 preoperative treatment-cycles resulted in average tumor-volume-reduction of 45%. 1 patient underwent bilateral nephrectomy. 52% of the patients had 2 functioning kidneys after the end of treatment. 20 patients had died after mean follow-up of 8.6 years. 5y-Progression-Free (PFS) and Overall-Survival (OS) were excellent for patients having a localized disease without pretreatment for nephroblastomatosis (5yPFS/OS: 80±4%/93±3%). Metastasis at diagnosis (51±12%/56±12%; p=0.003) and pretreatment for nephroblastomatosis (37±14%/67±13%; p<0.001) were associated with significantly poorer outcome. Cox-regression analysis revealed an independent influence of pretreatment for nephroblastomatosis, metastasis and syndromes on PFS. The latter 2 as well as anaplasia and age (<2 years or >3 years) had an independent influence on OS. CONCLUSIONS: Pretreatment for nephroblastomatosis, metastasis and syndromes are independent risk factors. 1-3 preoperative treatment-cycles are sufficient to achieve save nephron-sparing-surgery in most patients.

[Chemotherapeutic concepts for bone sarcomas]. / Chemotherapeutische Konzepte bei Knochensarkomen.

BACKGROUND: Osteosarcoma and Ewing sarcoma are the most common chemosensitive sarcomas of the bone. AIM: Development in chemotherapeutic concepts as well as current and future treatment strategies in osteosarcoma and Ewing sarcoma are presented. METHODS: A PubMed search for "Osteosarcoma" and "Ewing sarcoma" was performed, and pertinent results were summarized. RESULTS: In both osteosarcoma and Ewing sarcoma, outcomes achieved with multimodal treatment concepts combining conventional chemotherapy and local treatment have reached a plateau of about 70% for 5-year survival rates. DISCUSSION: Improved insights into the molecular biology and genetics of the diseases as well as insights into the interactions between sarcoma cells and the micro-environment and the immune system are necessary to identify novel therapeutic targets in bone sarcomas. Because of the rarity of the diseases, multinational cooperation is essential to evaluate novel therapies in prospective randomized trials.

Osteosarcoma of the mobile spine.

BACKGROUND: The aims of this analysis were to investigate features and outcome of high-grade osteosarcomas of the mobile spine. PATIENTS AND METHODS: Since 1977, 20 Cooperative Osteosarcoma Study Group patients had a diagnosis of high-grade osteosarcomas of the mobile spine and were included in this retrospective analysis of patient-, tumor- and treatment-related variables and outcome. RESULTS: The median age was 29 years (range 5-58). Most frequent tumor sites were thoracic and lumbar spine. All but three patients had nonmetastatic disease at diagnosis. Treatment included surgery and chemotherapy for all patients, 13 were also irradiated. Eight patients failed to achieve a macroscopically complete surgical remission (five local, one primary metastases, two both), six died, two are alive, both with radiotherapy. Of 12 patients with complete remission at all sites, three had a recurrence (two local, one metastases) and died. The median follow-up of the 11 survivors was 8.7 years (range 3.1-22.3), 5-year overall and event-free survival rates were 60% and 43%. Age <40 years, nonmetastatic disease at diagnosis and complete remission predicted for better overall survival (OS, P < 0.05). CONCLUSIONS: Osteosarcomas of the mobile spine are rare. With complete resection (and potentially radiotherapy) and chemotherapy, prognosis may be comparable with that of appendicular osteosarcomas.

The influence of tumor- and treatment-related factors on the development of local recurrence in osteosarcoma after adequate surgery. An analysis of 1355 patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols.

BACKGROUND: Local recurrence (LR) in osteosarcoma is associated with very poor prognosis. We sought to evaluate which factors correlate with LR in patients who achieved complete surgical remission with adequate margins. PATIENTS AND METHODS: We analyzed 1355 patients with previously untreated high-grade central osteosarcoma of the extremities, the shoulder and the pelvis registered in neoadjuvant Cooperative Osteosarcoma Study Group trials between 1986 and 2005. Seventy-six patients developed LR. RESULTS: Median follow-up was 5.56 years. No participation in a study, pelvic tumor site, limb-sparing surgery, soft tissue infiltration beyond the periosteum, poor response to neoadjuvant chemotherapy, failure to complete the planned chemotherapy protocol and biopsy at a center other than the one performing the tumor resection were significantly associated with a higher LR rate. No differences were found for varying surgical margin widths. Surgical treatment at centers with small patient volume and additional surgery in the primary tumor area, other than biopsy and tumor resection, were significantly associated with a higher rate of ablative surgery. CONCLUSIONS: Patient enrollment in clinical trials and performing the biopsy at experienced institutions capable of undertaking the tumor resection without compromising the oncological and functional outcome should be pursued in the future.

Genomic strategies to improve outcome and individualize therapy in cancer: the paradigm of childhood acute lymphoblastic leukemia.

Childhood acute lymphoblastic leukemia (ALL) is the classic example for a drug-responsive malignancy, and contemporary risk-directed therapies cure more than 80% of children with ALL in industrialized countries. Antileukemic medications, however, can cause significant adverse drug reactions. Moreover, some children have leukemia cell clones which are resistant to current antileukemic treatment. As ALL is still among the leading causes of death from disease in children aged one to 15 years, further improvement of childhood ALL therapy is urgently needed. The aim of pharmacogenomics is to elucidate functionally relevant genomic determinants for drug disposition and response in order to optimize drug therapy based on a patient's genomic profile. Pharmacogenomics has evolved from the study of single candidate genes to large-scale genome-wide strategies. Results from recent pharmacogenomic investigations in children with ALL hold promise to improve ALL therapy in the near future; and can serve as a model to improve drug therapy in other malignancies as well.

[Diagnostic image (316). A woman who died despite resuscitation. Pulmonary bone marrow embolism secondary to a sternum fracture]. / Diagnose in beeld (316). Een vrouw overleden ondanks reanimatie.

A 75-year-old woman was unsuccessfully resuscitated. Post-mortem investigation showed pulmonary bone marrow embolism secondary to a sternum fracture probably caused by the external cardiac massage.

Management of chronic immune thrombocytopenia in children and adolescents: lessons from an Austrian national cross-sectional study of 81 patients.

Chronic immune thrombocytopenia (cITP) is often associated with an underlying predisposition towards autoimmunity, recognition of which is relevant to guide treatment. International recommendations on diagnostic steps and therapeutic measures of cITP in childhood exist. However, due to the low prevalence (1-2/100,000) and a variation of availability of immunological and hematological tests and treatments across pediatric units, we postulated that these guidelines are not uniformly adhered to and that immune dysregulation syndromes remained undiscovered. To delineate the current management of children and adolescents with cITP in Austria, we performed a nationwide cross-sectional study. Between 2011 and 2014, 81 children with cITP were seen at seven centers (median age 8.75 years; range 1-17; female:male ratio 47:34) at 641 visits during 180 patient years after diagnosis of cITP (>12 months ITP duration). Additional diagnoses were noted, most frequently immune or autoimmune disorders, hematologic diseases, or infections (in 37.3%, including Evans syndrome, autoimmune lymphoproliferative syndrome, systemic lupus erythematosus, and Fanconi anemia), or other symptoms like bi- or pancytopenia (n=9), lymphoproliferation or granulomatous inflammation (n = 3). Both decision to treat as well as choice of treatment varied: smaller centers tended to observe more frequently, larger centers applied a pattern of treatment modalities that appeared to depend less on bleeding tendency than on center policy. More than 50% of therapeutic interventions occurred in bleedings scores ≤2 (of 5), suggesting a strong psychosocial intention to treat. Platelet increment upon 479 therapeutic interventions of eight types was evaluated, with multiple treatment approaches being pursued sequentially in refractory patients. These data confirm the hypothesis of heterogeneous diagnostic and therapeutic management of cITP in Austrian children and corroborate the need for (1) a precise panel of parameters to exclude underlying disorders and (2) for biomarkers to predict treatment response.

Differences at the receptor and postreceptor levels between human omental and subcutaneous adipose tissue in the action of insulin on lipolysis.

The possible existence of regional differences in the antilipolytic action of insulin in human adipose tissue was investigated in vitro. Insulin-induced inhibition of glycerol release and insulin binding, measured in terms of receptor number, receptor affinity, and dissociation rates, were determined in omental and subcutaneous adipose tissue segments and isolated fat cells of 16 nonobese subjects who were undergoing elective abdominal surgery but were otherwise healthy. The sensitivity of the antilipolytic effect of insulin was higher in subcutaneous than in omental adipose tissue; the half-maximal effect was obtained with 1 and 3 microU/ml of insulin, respectively (P less than 0.01). Responsiveness of the antilipolytic effect of insulin was threefold higher in the subcutaneous than in the omental region (P less than 0.005). Insulin receptor affinity was significantly higher in subcutaneous than in omental fat cells, but there was no difference in receptor number (about 300,000 sites/cell). 125I-insulin dissociated more rapidly from omental than from subcutaneous adipocytes in both the absence and the presence of excess native insulin. The data suggest that significant regional differences exist in the antilipolytic action of insulin in man; omental fat being less responsive than subcutaneous fat. The difference involves the insulin receptor affinity, which is caused at least partly by variations in the insulin dissociation rate but is also due to differences in insulin action at the postreceptor level.

Utilization and metabolic effects of a conventional and a single-solution regimen in postoperative total parenteral nutrition.

A comparison was made of the effects of two intravenous regimens for postoperative total parenteral nutrition, namely, a conventional (control) regimen (group I) and a single-solution regimen of the same composition (group II). The effects examined were: hemoglobin concentration, prothrombin time, serum protein and electrolyte concentrations, and nitrogen and electrolyte balances. The 18 patients undergoing abdominal surgery were allocated at random to the two groups and the experiment was run for 3 days. During the day of the operation and the next 3 days both groups showed a decrease in the hemoglobin concentration and in the serum levels of iron, albumin, transferrin and cholesterol, while the asparagine aminotransferase increased. During total parenteral nutrition the prothrombin time and erythrocyte sedimentation rate increased in both groups. The nitrogen balance improved gradually in both groups and on the 3rd day was positive in group II. The calcium and magnesium balances indicated a higher retention and the phosphate balance a lower retention of these ions in group II than in group I. The urinary phosphate excretion rate during total parenteral nutrition decreased in both groups. This study indicates that the single-solution regimens used in intravenous nutrition caused no adverse metabolic effects and was used as efficiently as a conventional regimen in the early postoperative period.

Impact of antimicrobial agents on the gastrointestinal microflora and the risk of infections.

The most common and significant cause of disturbances in the normal gastrointestinal microflora is the administration of antimicrobial agents. The microflora can be influenced by antimicrobial agents because of incomplete absorption of any orally administered antimicrobial agent, secretion of an antimicrobial agent by the salivary glands and in the bile, or secretion from the intestinal mucosa. In most cases the influence is not beneficial to the patient because suppression of the indigenous microorganisms often permits potential pathogens to overgrow and cause septic conditions, diarrhea, or colitis. Antimicrobial agents that influence the normal microflora also promote the emergence of antimicrobial-resistant strains. The authors' experience on the impact of different beta-lactams, erythromycin, clindamycin, tetracycline, and nitroimidazoles on the gastrointestinal microflora and the risk of infections when these agents are used is reviewed.

Regional differences in the control of lipolysis in human adipose tissue.

Omental fat cells were 30% smaller than those in subcutaneous regions. In omental fat cells with a mean diameter of 95 mu, the basal cAMP concentration was 50% lower, but the basal rate of glycerol release was three times as rapid as in subcutaneous (epigastric) fat cells of identical size. Added at maximal effective concentration, noradrenaline increased the level of cAMP and the rate of glycerol release more markedly in the omental than in the subcutaneous adipocytes, whereas the response to isopropyl noradrenaline was similar. Before starvation the lipolytic effects of noradrenaline and isopropyl noradrenaline, respectively, were identical in the two regions of subcutaneous adipose tissue investigated (femoral and hypogastric). The findings were well related to the tissue levels of cAMP induced by the two agents. During starvation noradrenaline and isopropyl noradrenaline increased the cAMP level and the rate of lipolysis in fat cells obtained from the hypogastric region, whereas noradrenaline decreased these parameters in femoral adipocytes. Starvation was associated with a more prominent inhibitory effect of phenylephrine on basal and isopropyl-noradrenaline-induced lipolysis in femoral than in hypogastric adipose tissue. In conclusion, differences exist between different regions of adipose tissue in their lipolytic responsiveness to noradrenaline, which seems related to the balance between alpha- and beta-adrenergic receptor response.

Reduction of catheter-associated thrombosis in parenteral nutrition by intravenous heparin therapy.

A prospective trial was carried out to test the hypothesis that therapy with intravenous (IV) heparin sodium reduces the incidence of thrombotic complications related to the use of central venous catheters for parenteral nutrition. The patients studied were randomly allocated either to a group given heparin sodium, at a dosage of 5,000 IU/6 hr, or to a control group that received no heparin prophylaxis. The heparin group comprised 23 catheter periods (22 patients), and the control group 26 catheter periods (25 patients). In five of the 23 catheters in te heparin group and 14 of the 26 in the control group, catheter phlebography revealed thrombus formation in association with the catheter when this was removed. The results indicated that the use of IV heparin as prophylaxis against thrombosis reduced the risk of thrombus formation on the central venous catheter.

Effects of antimicrobial prophylaxis on colonization resistance.

The effect of antimicrobial agents on the intestinal microflora of patients undergoing colorectal surgery was examined. Two narrow spectrum agents, clindamycin and aztreonam, disturbed colonization resistance. This was preserved with the broad spectrum compound, imipenem. Ecological effects are difficult to predict and clinical studies of new antibiotics should include investigations of their impact on the normal human intestinal flora.

Septic complications in relation to factors influencing the gastric microflora in patients undergoing gastric surgery.

Postoperative septic complications and micro-organisms found in primary infections were studied in 750 gastric operations performed between 1972 and 1986. The overall rate of primary infections was 23%. The infection rates were related to the diagnosis and to factors that could influence the colonization of the stomach. No significant differences in the rates of postoperative infections were found between patients who had received preoperative antibiotic prophylaxis and those who had not. In all groups of patients, aerobic and anaerobic gram-positive and gram-negative bacteria and yeasts were isolated in primary infections. Enterobacteriaceae, enterococci and Bacteroides fragiis were more frequent in patients with gastric bleeding or carcinoma.

Antimicrobial activity of dactimicin against aerobic and anaerobic bacteria isolated from intra-abdominal infections.

The in vitro antimicrobial activity of dactimicin against aerobic and anaerobic bacteria isolated from intra-abdominal infections was compared to those of gentamicin and metronidazole. The data obtained show that dactimicin is a promising new aminoglycoside covering aerobic bacteria and that it may be used together with an antianaerobic agent in the treatment of these infections.

Impact of cefbuperazone on the colonic microflora in patients undergoing colorectal surgery.

Cefbuperazone was given intravenously in a dose of 1 g at induction of anaesthesia, followed by a subsequent dose of 1 g 12 h after the first dose, to 10 patients undergoing colorectal surgery. A series of serum and faecal specimens were taken for analysis of cefbuperazone concentrations. Tissue samples from the gut wall were taken at surgery. The maximum serum concentrations (mean value 98.6 +/- 9.1 mg/l) during surgery were reached 30 min after cefbuperazone administration. The cefbuperazone concentration in the tissue samples varied between 7.3 and 40.5 mg/kg and the concentration in the faecal samples between 0 and 27.0 mg/kg. Faecal samples were also collected during the investigation period for cultivation of aerobic and anaerobic bacteria. The aerobic bacteria--streptococci, enterococci and enterobacteria--were suppressed significantly during the prophylaxis period. Among the anaerobic bacteria, cocci, bifidobacteria, eubacteria, lactobacilli, clostridia, fusobacteria and bacteroides decreased markedly during the same period. After four weeks the microflora was normalized in all patients. No postoperative infections occurred.