Modal share changes due to COVID-19: The case of Budapest.

The COVID-19 pandemic has had a rapid and significant impact on mobility. One of the most important responses of countries worldwide to slow the spread of the pandemic is to restrict the movement of people, which has had a considerable effect on transport systems. However, the reduction of transport is not identical for all modes of transport: public transport has seen the greatest decline so far. Understanding urban modal share developments during a pandemic situation can help cities better prepare for transport management in the future.

UICC-2002 TNM classification is not suitable for differentiated thyroid cancer in children and adolescents.

BACKGROUND: Recently the UICC-TNM classification for differentiated thyroid cancer (DTC) was changed neglecting the special circumstances for children affected by the disease. While the 1997 TNM classification grouped tumours

Number of genomic imbalances correlates with the overall survival for adrenocortical cancer in childhood.

BACKGROUND: Adrenocortical tumours (ACT) in children are rare and, if malignant, often associated with poor prognosis. Relevant cytogenetic factors for prognosis are hardly available. PROCEDURES: We analysed 14 adrenocortical cancers (ACC) of children by comparative genomic hybridisation (CGH). RESULTS: The total number of genomic imbalances ranged from 1 to 17 in individual tumour samples. The most common imbalances were +1q (57%), +12p (50%), +12q (50%), +1p (43%), +7q (42%), +9q (42%), +15q (42%), and -4q (57%), -11q (57%), -4p (42%), and -16q (42%). The median number of genomic changes was 5.5 (n = 8) in pT1-pT2 and 15.5 (n = 6) in pT3-pT4 tumours. The median number was 4 in the eight patients, who remain in remission more than 51 months and 15.5 in the six patients, who have died from the disease within 44 months. Moreover, all seven patients with less than 10 individual imbalances were in remission (median follow-up 72 months), while all but one patient with 10 and more individual imbalances (n = 7) have died from the disease (median survival time 30 months). Comparison of the data from children and adults revealed characteristic differences. Gain of 1p and loss of 4p, 4q and 16q are frequent in childhood and rare in adults. Inversely, loss of 1p is rare in childhood but frequent in adult ACT. CONCLUSION: The number of CGH imbalances appeared to have a predictive value for overall survival in paediatric ACC.

Longitudinal analysis of Epstein-Barr viral load in plasma and peripheral blood mononuclear cells of transplanted patients by real-time polymerase chain reaction.

BACKGROUND: Posttransplant lymphoproliferative disease (PTLD) is a significant cause of morbidity and mortality in transplant recipients and is caused by iatrogenic suppression of T cell function. Elevations in the Epstein-Barr viral (EBV) load in plasma (>1000 EBV copies/100 microL plasma) or peripheral blood mononuclear cells (PBMC) (>5000 EBV copies/microg PBMC DNA) as determined by real-time quantitative polymerase chain reaction (RQ-PCR) have been shown to be sensitive indicators for the development of PTLD in patients. METHODS: The diagnostic value of frequent monitoring of EB viral load in peripheral blood from 46 patients after heart transplantation was investigated compared with 21 healthy controls in a prospective longitudinal study. EB viral load was detected in PBMC and plasma using real-time quantitative (RQ)- polymerase chain reaction (PCR)-based assays and compared with serological parameters of EBV infection or with the occurrence of CMV reactivations. RESULTS: EB viral load was significantly increased in PBMC and in plasma from transplanted patients compared with healthy controls. Regarding levels and fluctuations of EB viral load in PBMC, patients were grouped in three distinct categories with high, intermediate, or low EB viral load. Although in one patient without PTLD, the EB viral load exceeded the threshold value for PTLD of 5000 EBV copies/microg PBMC DNA, all patients had an EB viral load in plasma of less than 1000 EBV copies/100 microL plasma. No correlation was found between the level of EB viral load and serological parameters of EBV reactivations in patients or in healthy control individuals. EBV and cytomegalovirus reactivations occurred independently in the majority of patients. CONCLUSIONS: EB viral load measurements in plasma and PBMC of patients using RQ-PCR are superior to serology and are a powerful tool for monitoring transplanted patients.

Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignancy, and it was only in 2004 that the International Union Against Cancer (UICC) defined TNM criteria and published the first staging classification. However, to date, the prognostic value of the proposed classification has not been evaluated. METHODS: The German ACC Registry comprising 492 patients was searched for patients who were diagnosed between 1986 and 2007 with detailed information on primary diagnosis and a minimum follow-up of 6 months. Patients were assigned to UICC tumor stage, and disease-specific survival (DSS) was assessed. In addition, the contribution of potential risk factors for DSS was evaluated. RESULTS: In total, 416 patients with a mean follow-up of 36 months met the inclusion criteria (stage I, n=23 patients; stage II, n=176 patients; stage III, n=67 patients; stage IV, n=150 patients). Kaplan-Meier analysis revealed a stage-dependent DSS. However, DSS in patients with stage II ACC did not differ significantly from DSS in patients with stage III ACC (hazard ratio, 1.38; 95% confidence interval, 0.89-2.16). Furthermore, patients who had stage IV ACC without distant metastases had an improved DSS compared with patients who had metastatic disease (P=.004). An analysis of different potential risk factors for defining stage III ACC revealed important roles in DSS for tumor infiltration in surrounding tissue, venous tumor thrombus (VTT), and positive lymph nodes; whereas tumor invasion in adjacent organs carried a prognosis similar to that of infiltration in surrounding tissue only. CONCLUSIONS: The 2004 UICC staging classification for ACC has significant limitations. On the basis of the current analysis, a revised classification with superior prognostic accuracy is proposed (the European Network for the Study of Adrenal Tumors classification). In this system, stage III ACC is defined by the presence of positive lymph nodes, infiltration of surrounding tissue, or VTT; and stage IV ACC is restricted to patients with distant metastasis.

Immunomodulatory effect of vitamin C on intracytoplasmic cytokine production in neonatal cord blood cells.

BACKGROUND: Vitamin C (ascorbic acid) is an essential water-soluble antioxidant in cells and plasma. Besides metabolic functions, vitamin C is also known to contribute to immune homeostasis. Recently, it has been demonstrated that vitamin C has an inhibitory effect on the expression of pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor alpha (TNF-alpha) in adult whole blood cells in vitro. It has been postulated that vitamin C might be an interesting compound for modulation of an over-exuberant immune response, e.g., in patient cohorts susceptible for the development of systemic inflammatory response syndrome such as neonates. It was the aim of this study to investigate the modulatory effects of vitamin C on the production of inflammatory mediators in neonatal cord blood cells. METHODS: The intracytoplasmic production of pro-inflammatory cytokines in neonatal cord blood cells stimulated with lipopolysaccharide or phorbol 12-myristate 13-acetate/ionomycin was assessed by flow-cytometry. RESULTS: In contrast to our previous observations from adult whole blood cells, 20 mM vitamin C mildly stimulated the percentage of neonatal monocytes producing IL-6 after lipopolysaccharide stimulation (e.g., 11.3% increase compared to control, p = 0.005). In the presence of 20 mM vitamin C, even a stronger stimulatory effect was noted for the percentage of IL-8 (e.g., 46.7% increase, p < 0.001) and TNF-alpha producing neonatal monocytes (e.g., 69.2% increase, p = 0.004; n = 20). In accordance with adult data, the percentage of neonatal lymphocytes producing IL-2 after phorbol 12-myristate 13-acetate/ionomycin stimulation was dose-dependently reduced (e.g., 41.3% inhibition, p = 0.001, 20 mM vitamin C), while the percentage of TNF-alpha producing lymphocytes was mildly stimulated (e.g., 20.8% increase, p = 0.003, 20 mM vitamin C). CONCLUSIONS: Interestingly, vitamin C was demonstrated to enhance pro-inflammatory responses in CD14(+) cord blood cells while only intracellular IL-2 production in CD3(+) cells was diminished. These data suggest that vitamin C differentially influences intracytoplasmic cytokine production in adults and neonates, and further studies are needed to elucidate the underlying mechanisms of this selective immunomodulation.

Characteristic genomic imbalances in pediatric pheochromocytoma.

Pheochromocytoma (PCC) in children is rare, genetically not well described, and often related to a poor prognosis. We detected genomic imbalances in all 14 tumors from children analyzed by comparative genomic hybridization. A combinatorial loss of chromatin from 3p and 11p was a common feature in 10 of 14 (72%) patients, which was a result of either a loss of a total chromosome 3 and a total chromosome 11 in 6 of 10 patients, or confined deletions of their p arms in 4 of 10 patients. All patients exhibiting a loss of 3p and 11p carried VHL mutations. The VHL mutations were constitutive in 9 cases and somatic and restricted to tumor DNA in the remaining tumor. On the other hand, VHL mutations were absent in 4 patients, 2 who had other familial syndromes (NF1, SDHD) and 2 with unknown etiology. Our data show that the pattern of imbalances in the tumor DNA of PCC patients strongly correlated with an underlying familial VHL mutation. Furthermore, we show that true sporadic PCC is rare in childhood. Thus, children with PCC should be checked for a related predisposing gene. This would also identify familial syndrome patients requiring long-term monitoring for other syndrome-related malignancies.

Treatment of nasopharyngeal carcinoma in children and adolescents: definitive results of a multicenter study (NPC-91-GPOH).

BACKGROUND: Preliminary results of combined neoadjuvant chemotherapy, radiotherapy, and postradiation interferon beta (IFN-beta) in children and adolescents with nasopharyngeal carcinoma, especially in high-risk patients, have been promising. METHODS: From 1992 to 2003, 59 patients (58 high-risk patients and 1 low-risk patient, median age 13 yrs; range, 8-25 yrs) were treated in the GPOH-NPC-91 study. The Stage II patient received irradiation as initial therapy. Fifty-eight patients received preradiation chemotherapy with methotrexate, cisplatin, and 5-fluorouracil. The cumulative radiation dose to primary sites was 59.4 Gy, a total dose of 45 Gy was delivered to the neck area. After irradiation, all patients were treated with 10(5) U recombinant IFN-beta/kg body weight 3 times a week for 6 months. RESULTS: After combination therapy, complete response was accomplished in 58 patients. In one patient, there was tumor progression during chemotherapy. In 3 patients, distant metastases were observed 14, 15, and 18 months after diagnosis, respectively. One patient had a local relapse 12 months after diagnosis. Fifty-four patients are still in first remission with a median follow-up of 48 months (range, 10-110 mos). Chemotherapy-related toxicity was mucositis Grade II, III, or IV in all patients and acute cardiotoxicity in 2 (3.5%) of the patients. Nephrotoxicity Grade I-II occurred in 8.8% of patients. CONCLUSIONS: The combination of initial chemotherapy, radiotherapy, and IFN-beta results in an excellent outcome. These results strongly support the development of a future treatment strategy along this line.

Effects of vitamin C on intracytoplasmic cytokine production in human whole blood monocytes and lymphocytes.

BACKGROUND: Vitamin C (ascorbic acid) is an essential water-soluble nutrient which primarily exerts its effect on immune homeostasis as physiological antioxidant. However, conflicting data exist regarding the effect of vitamin C on the expression of pro-inflammatory cytokines. METHODS: It was the aim of this study to investigate the impact of vitamin C on intracytoplasmic production of pro-inflammatory cytokines in monocytes and lymphocytes by flow cytometry after human whole blood assay. RESULTS: Vitamin C dose dependently inhibited the LPS-induced number of monocytes producing IL-6 (e.g., 41.0% reduction, p < 0.001, 20 mM vitamin C) and TNF-alpha (e.g., 26.0% reduction, p < 0.005, 20 mM vitamin C). Simultaneously, the number of lymphocytes producing IL-2 after PMA/ionomycin stimulation was dose dependently reduced (e.g., 24.2% inhibition, p < 0.005, 20 mM vitamin C). Notably, the number of IL-1 and IL-8 producing monocytes as well as TNF-alpha and IFN-gamma producing lymphocytes were not significantly affected by 20 mM vitamin C. CONCLUSIONS: These data suggest that vitamin C selectively influences intracytoplasmic cytokine production and therefore, further studies are needed to elucidate the underlying mechanisms of immunomodulation, i.e. regulation of NF kappa B activation which is mandatory for the induction of pro-inflammatory cytokines.

Differential maturation of the innate immune response in human fetuses.

Newborns and especially preterm infants show a unique susceptibility to severe bacterial infections that cause significant morbidity and mortality. As very few data are available on innate immune functions in human fetuses, we conducted a comprehensive study to investigate the expression of several adhesion molecules essentially involved in migration (CD11a, CD11b, CD11c, CD18, and CD62L). Furthermore, phagocytic activity, generation of respiratory burst products, and production of several proinflammatory cytokines were assessed. Various functions of the fetal innate immune system were demonstrated to be essentially different from those observed in term neonates or adults. Expression of several surface markers was significantly diminished on fetal granulocytes. Furthermore, a significantly reduced phagocytic activity of fetal granulocytes and monocytes was found, contrasted by an enhanced generation of reactive oxygen products. In addition, we demonstrate that significant numbers of fetal monocytes are capable of the production of proinflammatory cytokines in response to stimulation. However, the pattern of cytokine production is different from the more mature individuals: the number of IL-6- and tumor necrosis factor-alpha-positive monocytes were significantly diminished, whereas more IL-8-producing monocytes were found compared with adults. The results of our study add significantly to our understanding of the maturation and impairment of the innate immune response.

Influence of specimen age and use of different negative controls in determination of intracytoplasmic levels of cytokines after whole-blood culture assay.

Intracytoplasmic detection of cytokines by flow cytometry has become a powerful tool in the characterization of cytokine-producing cells. However, it is not known to what extent specimen age and the use of various negative controls may influence the amount of cytokine-positive cells. We therefore compared different times of storage and the use of several negative controls in the determination of intracytoplasmic levels of cytokines. There was a substantial decline of interleukin-2- and gamma interferon-positive lymphocytes after 20 h and especially after 48 h of storage. The precision of intracytoplasmic interleukin-6 determination decreases after long-term storage compared to 2 h of storage, whereas the amount of interleukin-8-positive monocytes remained rather stable. Therefore, we recommend performing the analysis as fast as possible after the blood sample is drawn. Under consideration of isotype-matched antibodies and nonstimulated cells as negative controls instead of the purified antibody-blocking control, strikingly higher amounts of interleukin-2-, gamma interferon, interleukin-6-, and interleukin-8-positive cells were found. For a meaningful interpretation of data these differences have to be kept in mind. Further studies should evaluate the exact specificity of these controls.

Enhanced interleukin-6 and interleukin-8 synthesis in term and preterm infants.

There is growing evidence that sepsis-related complications in neonates are crucially mediated by the action of proinflammatory cytokines. It has previously been demonstrated that elevated IL-6 and IL-8 levels can predict brain damage and chronic lung disease in preterm infants. However, it is the current view that neonates have a reduced capability to produce proinflammatory cytokines. To clarify this issue, we analyzed the inflammatory response in term and preterm infants directly at the single cell level by flow cytometry. Endotoxin challenge was performed under defined conditions on monocytes obtained from 50 healthy adults and 119 neonates, which consist of 45 term infants, 63 preterm infants (26.1-36.7 wk of gestational age), and 11 preterm infants with proven infection (24.6-29.9 wk). Our results challenge the existing view of an immature inflammatory response by demonstrating that term infants and preterm infants display a higher percentage of IL-6- and IL-8-positive cells than adults. After preincubation with dexamethasone the number of cytokine-positive cells decreased in all groups, but the number of IL-8-positive cells remained higher in term and preterm infants >32 wk compared with adults. These observations demonstrate not only a well-developed but also an enhanced inflammatory response in term and preterm infants. Under consideration of several detrimental effects of IL-6 and IL-8, our data may have major implications on the pathophysiology of inflammatory-triggered neonatal diseases.

Oral topotecan in children with recurrent or progressive high-grade glioma: a Phase I/II study by the German Society for Pediatric Oncology and Hematology.

BACKGROUND: Continuous oral treatment with topotecan may be more effective than the typical 1-day and 5-day treatment schedules. In previous studies of continuous treatment with topotecan, increased intestinal side effects were reported in adult patients; however, the experience in pediatric patients and patients with high-grade glioma is quite limited. METHODS: Thirty-two pediatric patients with recurrent high-grade glioma (16 females and 16 males; median age, 9.5 years) were enrolled in the current Phase I/II study. Tumor locations included the cerebral cortex (n = 5), pons (n = 18), and other sites (n = 9). An injectable formulation of topotecan was administered orally, in ice-cold orange juice, once daily. The starting dose of 0.4 mg/m(2) per day was escalated on a patient-by-patient basis. At each patient's maximum dose, blood samples were obtained for the determination of plasma hydroxytopotecan and topotecan lactone concentrations and for the calculation of pharmacokinetic quantities. RESULTS: The toxicity criteria for a maximum tolerated topotecan dose were met in only 19 patients. The primary toxicity type was hematologic. The median maximum tolerated dose was 0.9 mg/m(2) per day (n = 19). The calculated maximum total plasma topotecan concentration was 3.8 ng/mL (n = 7), with an area under the concentration-time curve of 38.4 ng. hours/mL and a half-life of 4.1 hours, which would result in the complete disappearance of topotecan from the plasma after 12 hours. Objective responses were observed in 2 of 13 evaluable patients and lasted for 2.5 and 9 months, respectively (continuous clinical remission, 1 of 14 patients; partial response, 2 of 14 patients; stable disease, 7 of 14 patients; progressive disease, 4 of 14 patients). CONCLUSIONS: Oral topotecan (median dose, 0.9 mg/m(2) per day) administered once daily was well tolerated and somewhat effective in children with recurrent high-grade glioma. A schedule in which the daily dose is split so that dosing is performed twice daily may be superior to the current schedule.