Central nervous system relapse in high-risk stage 4 neuroblastoma: The HR-NBL1/SIOPEN trial experience.

BACKGROUND: There is rising concern on the impact of new strategies, such as high-dose chemotherapy (HDC) and immunotherapy, on the pattern of relapse in high-risk neuroblastoma (HR-NBL). Our aim is to evaluate the incidence and identify risk factors for first recurrence in the central nervous system (CNS) in HR-NBL. PATIENTS AND METHODS: Data from patients with stage 4V HR-NBL included from February 2002 to June 2015 in the prospective HR-NBL trial of the European International Society of Pediatric Oncology Neuroblastoma Group were analysed. Characteristics at diagnosis, treatment and the pattern of first relapse were studied. CNS imaging at relapse was centrally reviewed. RESULTS: The 1977 included patients had a median age of 3 years (1 day-20 years); 1163 were boys. Among the 1161 first relapses, 53 were in the CNS, with an overall incidence of 2.7%, representing 6.2% of all metastatic relapses. One- and three-year post-relapse overall survival was 25 ± 6% and 8 ± 4%, respectively. Higher risk of CNS recurrence was associated with female sex (hazard ratio [HR] = 2.0 [95% confidence interval {CI}: 1.1-3.5]; P = 0.016), MYCN-amplification (HR = 2.4 [95% CI: 1.2-4.4]; P = 0.008), liver (HR = 2.5 [95% CI: 1.2-5.1]; P = 0.01) or >1 metastatic compartment involvement (HR = 7.1 [95% CI: 1.0-48.4]; P = 0.047) at diagnosis. Neither HDC nor immunotherapy was associated with higher risk of CNS recurrence. Stable incidence of CNS relapse was reported over time. CONCLUSIONS: The risk of CNS recurrence is linked to both patient and disease characteristics, with neither impact of HDC nor immunotherapy. These findings support the current treatment strategy and do not justify a CNS prophylactic treatment.

Absence of respiratory burst in X-linked chronic granulomatous disease mice leads to abnormalities in both host defense and inflammatory response to Aspergillus fumigatus.

Mice with X-linked chronic granulomatous disease (CGD) generated by targeted disruption of the gp91phox subunit of the NADPH-oxidase complex (X-CGD mice) were examined for their response to respiratory challenge with Aspergillus fumigatus. This opportunistic fungal pathogen causes infection in CGD patients due to the deficient generation of neutrophil respiratory burst oxidants important for damaging A. fumigatus hyphae. Alveolar macrophages from X-CGD mice were found to kill A. fumigatus conidia in vitro as effectively as alveolar macrophages from wild-type mice. Pulmonary disease in X-CGD mice was observed after administration of doses ranging from 10(5) to 48 spores, none of which produced disease in wild-type mice. Higher doses produced a rapidly fatal bronchopneumonia in X-CGD mice, whereas progression of disease was slower at lower doses, with development of chronic inflammatory lesions. Marked differences were also observed in the response of X-CGD mice to the administration of sterilized Aspergillus hyphae into the lung. Within 24 hours of administration, X-CGD mice had significantly higher numbers of alveolar neutrophils and increased expression of the proinflammatory cytokines IL-1 beta and TNF-alpha relative to the responses seen in wild-type mice. By one week after administration, pulmonary inflammation was resolving in wild-type mice, whereas X-CGD mice developed chronic granulomatous lesions that persisted for at least six weeks. This is the first experimental evidence that chronic inflammation in CGD does not always result from persistent infection, and suggests that the clinical manifestations of this disorder reflect both impaired microbial killing as well as other abnormalities in the inflammatory response in the absence of a respiratory burst.

Assessment of disease activity in rheumatoid arthritis using a novel folate targeted radiopharmaceutical Folatescan.

OBJECTIVES: Development of a simple and accurate technique for detecting active inflammation in the joints and other tissues of patients with inflammatory disorders is an unmet need in rheumatic diseases. This study is a preliminary assessment of the safety and usage of a radiopharmaceutical, FolateScan (Technetium-99m EC20; 99mTc-EC20), for detecting disease activity in patients with rheumatoid arthritis. METHODS: EC20 is a folate-targeted diagnostic radiopharmaceutical which binds to the folate receptor and is preferentially taken up by activated macrophages. In this open-label, cross-sectional study, a total of 40 patients with RA (26 with one or more swollen joints, 14 with clinically quiescent joint disease; 0/66 joint count) as well as 6 patients with osteoarthritis, 12 patients with other inflammatory conditions and 5 healthy subjects received 0.1 mg of EC20 labeled with 20-25mCi of technetium-99m. Disease activity was scored in each joint and other target tissues by a radiologist blinded to the clinical assessment, and results were compared to the rheumatologist's physical examination, which served as the test standard. RESULTS: The 40 patients (78% female) with RA had a mean age of 56.9 years. Assessment of uptake of 99mTc-EC20 in joints of patients with RA based on image analysis was compared to the clinical examination. FolateScan detected more actively involved joints in 27 patients (68%) than joints recorded as "swollen", and more actively involved joints in 25 patients (63%) than joints recorded as "painful and/or swollen". The number of swollen joints by clinical exam was correlated with ESR (r=0.43; p=0.006) and C-rp (r=0.35; p=0.03). The number of actively involved joints by FolateScan was also correlated with ESR (r=0.47; p=0.002) and C-rp (r=0.36; p=0.02). Joint uptake was also seen in patients with osteoarthritis. CONCLUSION: FolateScan is a potentially useful tool for detection of disease activity in patients with RA and may be more sensitive than the physical examination.

Surround repulsion of spinal sensory axons in higher vertebrate embryos.

We have tested whether the orientation of axons sprouting from bipolar dorsal root ganglion neurons is influenced by diffusible cues from surrounding tissues. Surface ectoderm, dermomyotome, and notochord exert strong chemorepulsion on axons growing in collagen gels, operating at separations beyond those found in vivo and active in cocultures of chick and mouse tissues. Basal and alar plates of the neural tube are devoid of activity, as is the posterior-half-sclerotome, which repels in a contact-dependent manner. When ganglia are sandwiched between dermomyotome and notochord placed at a distance, axon growth is channeled in a bipolar trajectory. These results show that gradients of diffusible repulsion molecules flanking axon pathways can generate linear patterns of axon growth. We suggest that such "surround repulsion" may function generally, in concert with contact-dependent guidance mechanisms, to guide axons in the developing nervous system.

Rhabdomyosarcoma subtyping by immunohistochemical assessment of myogenin: tissue array study and review of the literature.

Myogenin immunostaining has been described as a useful marker of the alveolar subtype of rhabdomyosarcoma and as a tool for distinguishing it from the more common embryonal subtype. To add to the growing body of literature describing this phenomenon we analysed myogenin immunohistochemical staining in 152 tumors using a rhabdomyosarcoma tissue array. Results were analysed blinded to histological type by two independent investigators. Samples were excluded if any samples failed to stain with desmin and/or myogenin. Mean percentage of myogenin positive cells was significantly greater for ARMS (n = 31; mean percentage positivity 59% (95% confidence intervals +/- 7%) than ERMS (n = 41, mean percentage positivity 16%, 95% confidence intervals +/- 4; P < 0.0001). This data is consistent with previously published studies identifying strong nuclear myogenin staining in a high proportion of cells as a marker of alveolar histology.

Preservation of complement-induced lung injury in mice with deficiency of NADPH oxidase.

Mice with chronic granulomatous disease (X-CGD mice) generated by mutating the X-linked gene for a subunit of NADPH oxidase have been analyzed for their ability to respond to intravenous injection of purified cobra venom factor (CVF). This agent in wild-type mice produces a neutrophil-dependent and catalase-sensitive form of lung injury. Lung injury was evaluated by measuring the accumulation of extravascular albumin. Quite unexpectedly, the lungs of X-CGD mice showed no difference in the increased accumulation of extravascular albumin after injection of CVF when compared to wild-type mice. In both X-CGD and wild-type mice, full development of injury required neutrophils. While catalase was highly protective in wild-type mice, its protective effects were completely lost in the X-CGD mice. Furthermore, a competitive antagonist of L-arginine, N(G)-methyl-L-arginine, was protective in X-CGD mice but not in wild-type mice. Allopurinol was protective in both types of mice. Both the basal and the CVF-inducible lung mRNA for inducible nitric oxide synthase and IL-1beta was similar in X-CGD and wild-type mice. These data indicate that oxygen radical production and lung injury in response to injection of CVF occurs through alternative pathways in mice with genetic deletion of NADPH oxidase.

Neurocan is upregulated in injured brain and in cytokine-treated astrocytes.

Injury to the CNS results in the formation of the glial scar, a primarily astrocytic structure that represents an obstacle to regrowing axons. Chondroitin sulfate proteoglycans (CSPG) are greatly upregulated in the glial scar, and a large body of evidence suggests that these molecules are inhibitory to axon regeneration. We show that the CSPG neurocan, which is expressed in the CNS, exerts a repulsive effect on growing cerebellar axons. Expression of neurocan was examined in the normal and damaged CNS. Frozen sections labeled with anti-neurocan monoclonal antibodies 7 d after a unilateral knife lesion to the cerebral cortex revealed an upregulation of neurocan around the lesion. Western blot analysis of extracts prepared from injured and uninjured tissue also revealed substantially more neurocan in the injured CNS. Western blot analysis revealed neurocan and the processed forms neurocan-C and neurocan-130 to be present in the conditioned medium of highly purified rat astrocytes. The amount detected was increased by transforming growth factor beta and to a greater extent by epidermal growth factor and was decreased by platelet-derived growth factor and, to a lesser extent, by interferon gamma. O-2A lineage cells were also capable of synthesizing and processing neurocan. Immunocytochemistry revealed neurocan to be deposited on the substrate around and under astrocytes but not on the cells. Astrocytes therefore lack the means to retain neurocan at the cell surface. These findings raise the possibility that neurocan interferes with axonal regeneration after CNS injury.

Matrix metalloproteases and their inhibitors are produced by overlapping populations of activated astrocytes.

Matrix metalloproteases (MMPs) and tissue inhibitors of metalloproteases (TIMPs) are involved in many cell migration phenomena and produced by many cell types, including neurons and glia. To assess their possible roles in brain injury and regeneration, we investigate their production by glial cells, after brain injury and in tissue culture, and we investigate whether they are capable of digesting known axon-inhibitory proteoglycans. To determine the action of MMPs, we incubated astrocyte conditioned medium with activated MMPs, then did western blots for several chondroitin sulphate proteoglycans. MMP-3 digested all five proteoglycans tested, whereas MMP-2 digested only two and MMP-9 none. To determine whether MMPs or TIMPs are produced by astrocytes in vitro, we tested both primary cultures and astrocyte cell lines by western blotting, and compared them with Schwann cells. All cultures produced at least some MMPs and TIMPs, with no obvious correlation with the ability of axons to grow on those cells. Both MMP-9 and TIMP-3 were regulated by various cytokines. To determine which cells produce MMPs and TIMPs after brain injury, we made lesions of adult rat cortex, and did immunohistochemistry. MMP-2 was seen to be induced in activated astrocytes through the whole thickness of the cortex but not deeper, but MMP-3 was not seen in the injured brain. TIMP-2 and TIMP-3 immunoreactivities were induced in activated astrocytes in deep cortex and the underlying white matter. In situ hybridisation confirmed induction of TIMP-2 in glia as well as neurons, but showed no expression of TIMP-4. These results show that both MMPs and TIMPs are produced by some astrocytes, but TIMP production is particularly strong, especially in deep cortex and white matter which is more inhibitory for axon regeneration. Conversely the MMPs produced may not be adequate to promote migration of cells and axons within the glial scar.

"Legs" technique for management of widely separated coronary arteries during ascending aortic repair.

BACKGROUND: Widely separated coronary arteries with significantly diseased tissue continues to challenge surgeons repairing ascending aortic aneurysms. METHODS: Occasional troublesome leaks around coronary ostial anastomoses and Cabrol graft thrombosis prompted a change of our operative management of this condition. Collagen-impregnated 8-mm "legs" grafts are used to connect the coronary arteries to the composite graft. Ten patients, aged 14 to 70 years, underwent the operation. RESULTS: The first patient is 15 years after the operation and is symptom free. One patient died of an arrhythmia 1 month after discharge. Eight patients are living and well 11/2 to 4 years postoperatively. CONCLUSIONS: Advantages of direct interposition (legs) grafts are as follows: the coronary arteries are separately perfused and the risk of catastrophic thrombosis from a longer high-volume graft is eliminated. Problems with coronary ostial mobilization are avoided. The technique allows full visualization and hemostatic suture line testing with cardioplegia before aortic declamping. Space constraints with reoperations are easily managed, whereas other techniques may result in graft compression on refilling of the heart and termination of bypass. The technique is carried out with ease and reproducibility, and the availability of new graft material has made it our treatment of choice for ascending aortic composite graft replacement.

An earthquake disaster in Turkey: assessment of the need for plastic surgery services in a crisis intervention field hospital.

On August 17, 1999, an earthquake of 7.4 magnitude struck Turkey, resulting in the destruction of the cities Golcuk, Izmit, Adapazari, and Yalova. Three days later, the Israel Defense Force Field Hospital arrived at Adapazari, serving as a reinforcement hospital until the rehabilitation of the local medical facilities. Surgical services in the field hospital were supplied by general, orthopedic, and plastic surgeons. The authors evaluated all soft-tissue injuries managed at the hospital and assessed the need for plastic surgery services in a crisis intervention field hospital. Information was gathered regarding soft-tissue injuries throughout the activity of the hospital. In addition, patients' charts, operations' reports, and entry and evacuation logs were reviewed for all patients accepted and treated in the field hospital. Interviews of patients, local physicians, and citizens of Adapazari were performed to evaluate the medical situation in the first 3 days after the earthquake. A total of 1205 patients were treated by the field hospital in Adapazari; 138 (11.45 percent) of these patients sought aid for isolated soft-tissue injuries, 105 of which (76.09 percent) were earthquake-related. Twenty (51.28 percent) of the operations performed in the hospital were to treat soft-tissue injuries; 1.49 percent of all patients underwent minor surgical manipulations by the plastic surgeon on staff. Plastic surgery patients occupied 13.6 percent of the hospital beds. In conclusion, the authors find it beneficial to supply plastic surgery services at a field hospital in an earthquake situation.

Serotype prevalence and antibiotic resistance in Streptococcus pneumoniae clinical isolates among global populations.

Streptococcus pneumoniae remains a leading cause of disease in children and adults. Serotypes differ in invasiveness, virulence, and antibiotic resistance; therefore, serotype surveillance is necessary to monitor the burden of pneumococcal disease, especially in the setting of pneumococcal vaccination programs. The Tigecycline Evaluation Surveillance Trial, (TEST), is an on-going global antibiotic susceptibility surveillance program. Serotypes and antibiotic susceptibilities of 2173 invasive S. pneumoniae in this existing database during 2004-2008 were evaluated. Worldwide, serotypes 19A (28%), 19F (10%) and 14 (9%) were the most common in children under 5 years. In adults over 16 years, 19A (13%), 3, 6A and 7F (all 7%) were most common. Serotypes 19A, 6A, 19F, 6B, 15A, 9V, and 14 exhibited significantly higher levels of erythromycin resistance (P<0.05), while 19A, 19F, 35B, 6A, 6B, 23A, 9V, 15A, and 14 demonstrated higher rates of penicillin resistance (P<0.05). This analysis of an existing pathogen database provides a snapshot of global serotype data and describes the consequential issue of antibiotic resistance in specific serotypes, many of which are increasingly common causes of invasive pneumococcal disease.

Night-time and daytime atypical manifestations of gastro-oesophageal reflux disease: frequency, severity and impact on health-related quality of life.

BACKGROUND: Respondents with gastro-oesophageal reflux disease (GERD) report having a variety of atypical manifestations. The relationship between these manifestations and disease severity, night-time GERD and functioning has not been determined. AIM: To determine if atypical manifestations are related to increased disease severity, night-time GERD and decreased functioning. METHODS: A web survey among US adults was conducted, using a validated GERD screener. Frequency of night-time and daytime typical symptoms (acid regurgitation and heartburn) and atypical manifestations were assessed. Respondents were classified as night-time GERD or daytime GERD based on typical symptom frequency. Prevalence of frequent atypical manifestations (> or =2 days or nights/week) was assessed. RESULTS: Gastro-oesophageal reflux disease cases had a higher prevalence of each atypical manifestation (P < 0.05 for all) compared with controls. Night-time GERD respondents had a higher prevalence of atypical manifestations compared with daytime GERD respondents (P < 0.05 for most manifestations) and the prevalence of atypical manifestations increased with GERD symptom severity (P < 0.05 for most). Those with atypical manifestations reported lower functioning scores (P < 0.05 for most). CONCLUSIONS: Respondents with typical GERD symptoms commonly report atypical manifestations, especially those with night-time symptoms and those with greater underlying GERD severity. Respondents with GERD and atypical manifestations had more impaired functioning than those with typical symptoms only.

Effect of pantoprazole in older patients with erosive esophagitis.

Several studies suggest that older adults with gastroesophageal reflux disease (GERD) are more likely to develop complications, including erosive esophagitis, but it is unclear whether erosive esophagitis is more difficult to treat in older patients. The purpose of this study was to determine if adults > or = 65 years with erosive esophagitis are more difficult to treat than younger adults. The study was a post hoc analysis of two double-blind, randomized, multicenter trials of patients with erosive esophagitis. Patients received pantoprazole 40 mg once daily, nizatidine 150 mg twice daily or placebo. Patients were evaluated for endoscopic healing at 4 and 8 weeks. Patients recorded typical reflux symptoms using a daily diary to note presence or absence of symptoms. Results showed that 44, 13 and 11 patients > or = 65 years and 210, 69, and 71 patients < 65 received pantoprazole 40 mg daily, nizatidine 150 mg twice daily, or placebo, respectively. Eighty-six percent (86%[76%, 97% CI]) of older and 83% (78%, 88% CI) of younger pantoprazole-treated patients were healed at 8 weeks; 46% (19%, 73% CI) and 35% (24%, 46% CI) of nizatidine-treated and 27% (1%, 54% CI) and 34% (23%, 45% CI) of placebo-treated were healed at 8 weeks. Median time to persistent absence of GERD-related symptoms was similar for older and younger patients treated with pantoprazole. We conclude that older patients with erosive esophagitis do not appear to have more difficult-to-treat disease. Erosive esophagitis is effectively healed and GERD symptoms are controlled in older patients using pantoprazole 40 mg daily.

[Immature-cell leukoses in the adult age]. / Unreifzellige Leukosen im Erwachsenenalter

In form of a survey the author enters into selected questions of the etiopathogenesis, the pre-leucaemic phase, the epidemiology, the cytochemical subdivision, the clinic and therapy of undifferentiated cell leucaemia in adult age. The number of two-year sojourns in a hospital and other data are reported on the basis of an evaluation of the signature ledges of the clinical histories in the district Dresden. A study concerning the therapy carried out on 331 patients from six clinics of the GDR emphasizes the value of the polychemotherapy, in which cases according to the COAP- and ViDaP-scheme the results of the treatment are somewhat more unfavourable, compared with the results in the newest combinations of other authors.

[Paroxysmal supraventricular tachycardia in the delivery room]. / Paroxysmale supraventrikuläre Tachykardie im Kreisssaal.

In case of tachycardia the whole clinical picture should be taken into consideration. After exclusion of other kinds of shock also in the delivery room it should be thought of the rare cardiogenic shock caused by paroxismal supraventricular tachycardia. Stimulation of nervus vagus and/or drugs have good success.

[Course of pulmonary involvement in patients with Hodgkin's disease]. / Verlauf der Lungenbeteiligung bei Patienten mit Morbus Hodgkin.

65 patients with Hodgkin's disease and pulmonary involvement were observed during the fifteen years from 1964 to 1978. Polychemotherapy was administered to 24 patients and monochemotherapy to 28. Six of the 24 patients on polychemotherapy reached the four-year limit after diagnosis of pulmonary involvement. The results in the patients on monochemotherapy were significantly worse. None of the male patients lived longer than 28 months. None of the patients with mixed cellularity and lymphocyte depleted histology had a survival of more than one year after diagnosis of the pulmonary involvement.