Cytotoxic activity of distinct families of phosphonic acid derivatives - A chemocentric approach to assess their molecular action.

Phosphorus containing small molecules (particularly α-aminophosphonates, α-hydroxyphosphonates and bisphosphonates) represent a unique chemical space among the biologically active compounds. We selected 35 diverse compounds that showed remarkable cytotoxicity effects on various cancer cell lines. However, the exact mechanism of action often requires further investigations, in vitro or in silico target identification even though many target-based activity data were gathered for the above cluster of compounds.

N-Functionalization of ß-aminophosphonates: cytotoxic effects of the new derivatives.

ß-Aminophosphonates obtained by the Michael addition of primary amines to the double bond of diethyl vinylphosphonate proved to be suitable starting materials (amine components) in the Kabachnik-Fields reaction with formaldehyde and dialkyl phosphites or secondary phosphine oxides to afford N-phosphonylmethyl- and N-phosphinoylmethyl-ß-aminophosphonates. On the other hand, the starting aminophosphonates were modified by N-acylation using acid chlorides. The N-acyl products were found to exist in a dynamic equilibrium of two conformers as suggested by the broad NMR signals. At 26 °C, there may be rotation around the N-C axis of the acylamide function. At the same time, low-temperature NMR measurements at -5 °C revealed the presence of two distinct rotamers that could be characterized by 31P, 13C and 1H NMR data. The modified ß-aminophosphonic derivatives were subjected to a comparative structure-activity analysis on MDA-MB-231, PC-3, A431 and Ebc-1 tumor cell lines, and in a few cases, significant activity was detected.

Blood tumor mutational burden and response to pembrolizumab plus chemotherapy in non-small cell lung cancer: KEYNOTE-782.

BACKGROUND: First-line pembrolizumab plus chemotherapy has shown clinical benefit in patients with metastatic non-small cell lung cancer (NSCLC) regardless of tissue tumor mutational burden (tTMB) status. Blood tumor mutational burden (bTMB), assessed using plasma-derived circulating tumor DNA (ctDNA), may be a surrogate for tTMB. The KEYNOTE-782 study evaluated the correlation of bTMB with the efficacy of first-line pembrolizumab plus chemotherapy in NSCLC. METHODS: Previously untreated patients with stage IV nonsquamous NSCLC received pembrolizumab 200 mg plus pemetrexed 500 mg/m2 and investigator's choice of carboplatin area under the curve 5 mg/mL/min or cisplatin 75 mg/m2 for 4 cycles, then pembrolizumab plus pemetrexed for ≤31 additional cycles every 3 weeks. Study objectives were to evaluate the association of baseline bTMB with objective response rate (ORR) (RECIST v1.1 by investigator assessment; primary), progression-free survival (PFS; RECIST v1.1 by investigator assessment), overall survival (OS), and adverse events (AEs; all secondary). A next-generation sequencing assay (GRAIL LLC) with a ctDNA panel that included lung cancer-associated and immune gene targets was used to measure bTMB. RESULTS: 117 patients were enrolled; median time from first dose to data cutoff was 19.3 months (range, 1.0-35.5). ORR was 40.2 % (95 % CI 31.2-49.6 %), median PFS was 7.2 months (95 % CI 5.6-9.8) and median OS was 18.1 months (95 % CI 13.5-25.6). Treatment-related AEs occurred in 113 patients (96.6 %; grade 3-5, n = 56 [47.9 %]). Of patients with evaluable bTMB (n = 101), the area under the receiver operating characteristics curve for continuous bTMB to discriminate response was 0.47 (95 % CI 0.36-0.59). Baseline bTMB was not associated with PFS or OS (posterior probabilities of positive association: 16.8 % and 7.8 %, respectively). CONCLUSIONS: AEs were consistent with the established safety profile of first-line pembrolizumab plus chemotherapy in NSCLC. Baseline bTMB did not show evidence of an association with efficacy.

HUNCHEST-II contributes to a shift to earlier-stage lung cancer detection: final results of a nationwide screening program.

OBJECTIVES: The introduction of low-dose CT (LDCT) altered the landscape of lung cancer (LC) screening and contributed to the reduction of mortality rates worldwide. Here we report the final results of HUNCHEST-II, the largest population-based LDCT screening program in Hungary, including the screening and diagnostic outcomes, and the characteristics of the LC cases. METHODS: A total of 4215 high-risk individuals aged between 50 and 75 years with a smoking history of at least 25 pack-years were assigned to undergo LDCT screening. Screening outcomes were determined based on the volume, growth, and volume doubling time of pulmonary nodules or masses. The clinical stage distribution of screen-detected cancers was compared with two independent practice-based databases consisting of unscreened LC patients. RESULTS: The percentage of negative and indeterminate tests at baseline were 74.2% and 21.7%, respectively, whereas the prevalence of positive LDCT results was 4.1%. Overall, 76 LC patients were diagnosed throughout the screening rounds (1.8% of total participants), out of which 62 (1.5%) patients were already identified in the first screening round. The overall positive predictive value of a positive test was 58%. Most screen-detected malignancies were stage I LCs (60.7%), and only 16.4% of all cases could be classified as stage IV disease. The percentage of early-stage malignancies was significantly higher among HUNCHEST-II screen-detected individuals than among the LC patients in the National Koranyi Institute of Pulmonology's archive or the Hungarian Cancer Registry (p < 0.001). CONCLUSIONS: HUNCHEST-II demonstrates that LDCT screening for LC facilitates early diagnosis, thus arguing in favor of introducing systematic LC screening in Hungary. CLINICAL RELEVANCE STATEMENT: HUNCHEST-II is the so-far largest population-based low-dose CT screening program in Hungary. A positive test's overall positive predictive value was 58%, and most screen-detected malignancies were early-stage lesions. These results pave the way for expansive systematic screening in the region. KEY POINTS: • Conducted in 18 medical facilities, HUNCHEST-II is the so far largest population-based low-dose CT screening program in Hungary. • The vast majority of screen-detected malignancies were early-stage lung cancers, and the overall positive predictive value of a positive test was 58%. • HUNCHEST-II facilitates early diagnosis, thus arguing in favor of introducing systematic lung cancer screening in Hungary.

A Study of the Bisphosphonic Derivatives from the Pudovik Reaction of Dialkyl α-Oxophosphonates and >P(O)H Reagents: X-ray Structure and Bioactivity.

New hydroxy-methylenebisphosphonic derivatives were prepared with different P-functions. The outcome of the reaction of α-oxophosphonates (YC(O)P(O)(OR)2) and dialkyl phosphites or diarylphosphine oxides depended on the Y substituent of the oxo-compound, the nature of the P-reagent and the amount of the diethylamine catalyst. Starting from dimethyl α-oxoethylphosphonate, in the presence of 5% of diethylamine, the corresponding Pudovik adduct was the single product. While using 40% of the catalyst, the rearranged species with the >P(O)-O-CH-P(O)< skeleton was the exclusive component. A similar reaction of α-oxobenzylphosphonate followed the rearrangement protocol. X-ray crystallography revealed not only the spatial structures of the three products, but also an intricate pattern evolving from the interplay of slight chemical differences, solvent inclusion and disorder as well as H-bridge patterns, which invite further investigation. In vitro activity of the compounds was assessed on different tumor cell cultures using end-point-type cell tetrazolium-based measurements. These structure-activity studies revealed a cytostatic effect for four rearranged derivatives containing aromatic units. One of them had a pronounced effect on MDA-MB 231 and Ebc-1 cells, showing IC50 = 37.8 and 25.9 µM, respectively.

Superimposed Mosaicism in the Form of Extremely Extended Segmental Plexiform Neurofibroma Caused by a Novel Pathogenic Variant in the NF1 Gene.

Plexiform neurofibromas occurring in approximately 20-50% of all neurofibromatosis type-1 (NF1) cases are histologically benign tumors, but they can be fatal due to compression of vital structures or transformation to malignant sarcomas or malignant peripheral nerve sheath tumors. All sizeable plexiform neurofibromas are thought to result from an early second mutation giving rise to a loss of heterozygosity of the NF1 gene. In this unusual case, a 12-year-old girl presented with a rapidly growing, extremely extensive plexiform neurofibroma with segmental distribution over the entire right arm, extending to the right chest wall and mediastinum, superimposed on classic cutaneous lesions of NF1. After several surgical interventions, the patient was efficiently treated with an oral selective MEK inhibitor, selumetinib, which resulted in a rapid reduction of the tumor volume. Molecular analysis of the NF1 gene revealed a c.2326-2 A>G splice-site mutation in the clinically unaffected skin, peripheral blood sample, and plexiform neurofibroma, which explains the general clinical symptoms. Furthermore, a novel likely pathogenic variant, c.4933dupC (p.Leu1645Profs*7), has been identified exclusively in the girl's plexiform neurofibromas. This second-hit mutation can explain the extremely extensive segmental involvement.

A long-term, prospective, observational cohort study of the safety and effectiveness of etanercept for the treatment of patients with paediatric psoriasis in a naturalistic setting.

BACKGROUND: Psoriasis is a chronic inflammatory skin disorder that affects 125 million people worldwide, with one-third having childhood onset. OBJECTIVES: The PURPOSE study evaluated long-term safety and effectiveness of etanercept in paediatric psoriasis. MATERIALS & METHODS: This observational study enrolled patients with paediatric psoriasis who were prescribed etanercept per routine care in eight EU countries. Patients were followed retrospectively (first dose prior to 30 days before enrolment) or prospectively (first dose within 30 days prior to or any time after enrolment) for five years. Safety endpoints included serious infections, opportunistic infections, malignancies, other serious adverse events (SAEs) and adverse events. Effectiveness endpoints (prospective patients) included treatment patterns, dose change/discontinuation, and physicians' global subjective assessment of change in disease severity from baseline to follow-up. RESULTS: In total, 72 patients were enrolled (32 prospectively, 40 retrospectively), with mean age of 14.5 years and mean disease duration of 7.1 years. No serious or opportunistic infections/malignancies were reported. Psoriasis (n=8) and subcutaneous tissue disorders (system organ class) (erythema nodosum, erythrodermic psoriasis; n=1 for each) were the most frequently reported SAEs, which occurred in six (8.3%) patients with current/recent treatment and four (7.4%) with previous treatment. Of 25 treatment-emergent SAEs, seven (28.0%) were possibly related to etanercept. Assessments of prospective patients revealed that 28 (87.5%) completed 24 weeks, five (15.6%) required at least one subsequent course, and 93.8% experienced decreased disease severity. It is possible that some rare adverse events were not noted in this relatively small sample. CONCLUSION: These real-world data are consistent with the known safety and efficacy profile of etanercept in paediatric patients with moderate to severe plaque psoriasis.

Co-occurrence of neurofibromatosis type 1 and pseudoachondroplasia - a first case report.

BACKGROUND: Neurofibromatosis type 1 and pseudoachondroplasia are both rare autosomal dominant disorders, caused by pathogenic mutations in NF1 and COMP genes, respectively. Both neurofibromin 1 and cartilage oligomeric matrix protein (COMP) play a role in the development of the skeleton. Carrying both germline mutations has not been previously reported; however, it can affect the developing phenotype. CASE PRESENTATION: The index patient, an 8-year-old female presented with several skeletal and dermatologic anomalies resembling the coexistence of multiple syndromes. Her mother had dermatologic symptoms characteristic for neurofibromatosis type 1, and her father presented with distinct skeletal anomalies. NGS-based analysis revealed a heterozygous pathogenic mutation in genes NF1 and COMP in the index patient. A previously unreported heterozygous variant was detected for the NF1 gene. The sequencing of the COMP gene revealed a previously reported, pathogenic heterozygous variant that is responsible for the development of the pseudoachondroplasia phenotype. CONCLUSIONS: Here, we present the case of a young female carrying pathogenic NF1 and COMP mutations, diagnosed with two distinct heritable disorders, neurofibromatosis type 1 and pseudoachondroplasia. The coincidence of two monogenic autosomal dominant disorders is rare and can pose a differential diagnostic challenge. To the best of our knowledge, this is the first reported co-occurrence of these syndromes.

Avelumab in Combination With Cetuximab and Chemotherapy as First-Line Treatment for Patients With Advanced Squamous NSCLC.

Introduction: We present the results of a phase 2a trial of first-line avelumab (anti-programmed death-ligand 1 antibody) plus cetuximab (anti-EGFR antibody) in patients with advanced squamous NSCLC. Methods: Patients with recurrent or metastatic squamous NSCLC received avelumab 800 mg (d 1 and 8), cetuximab 250 mg/m2 (d 1) and 500 mg/m2 (d 8), cisplatin 75 mg/m2 (d 1), and gemcitabine 1250 mg/m2 (d 1 and 8) for four 3-week cycles, followed by avelumab 800 mg and cetuximab 500 mg/m2 every 2 weeks. The primary end point was the best overall response; the secondary end points were progression-free survival, duration of response, overall survival, and safety. Efficacy analyses were reported from an updated data cutoff. Results: A total of 43 patients were enrolled. The median follow-up was 6.6 months for the primary analyses and 9.2 months for the efficacy analyses. In the efficacy analyses, 15 patients had a confirmed partial response (objective response rate, 34.9% [95% confidence interval: 21.0%-50.9%]), and the median duration of response was 7.1 months (95% confidence interval: 4.2-12.5 mo). The median progression-free survival and overall survival were 6.1 months and 10.0 months, respectively. In the safety analyses (primary analysis), 38 patients (88.4%) had a treatment-related adverse event, of whom 24 (55.8%) had a grade 3 or higher treatment-related adverse event. Conclusions: The combination of avelumab + cetuximab and chemotherapy showed antitumor activity and tolerable safety; however, the ORR was not improved compared with those reported for current standards of care (NCT03717155).

COVID-19 mortality is associated with low vitamin D levels in patients with risk factors and/or advanced age.

BACKGROUND & AIMS: Although conclusive evidence is yet lacking, it has been suggested that vitamin D deficiency (VD) may be associated with a more severe course of SARS-CoV-2 Infection (COVID-19). In this retrospective study we assessed the association of VD deficiency with mortality in a group of COVID-19 patients treated in a tertiary referral center. METHODS: Data of 257 Covid-19 patients hospitalized between 30th September 2020 and 2nd March 2021 have been collected retrospectively. The following parameters were collected: age, gender, serum level of 25-OH-Vitamin D3, outcome (survival/death), comorbidities (cancer, diabetes mellitus and chronic obstructive pulmonary disease). Serum VD measurement was done within 3 days of admission. RESULTS: VD levels were significantly lower in patients who did not survive, however, in this patients' group the average age was significantly higher than among those, who survived. After age-matching, in a subgroup of patients with risk factors and/or 60 years of age or older who survived had significantly higher VD level in their serum than those who deceased. Serum C-reactive protein, lactate-dehydrogenase and creatinin-kinase were significantly higher in the group in which the patients died, however these laboratory parameters did not correlate with the VD levels. CONCLUSION: We found that in COVID-19 infection, when old age as risk factor (60 years of age or older) was pooled with risk factors (cancer, diabetes and/or COPD), the VD levels were significantly lower in the patient group, in which the patients did not survive. We suggest further, prospective studies in similar subgroups to explore a possible causal relationship.

Atezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results From the Randomized Phase 3 IMpower132 Trial.

INTRODUCTION: We report the final results of the phase 3 IMpower132 study evaluating atezolizumab plus carboplatin or cisplatin plus pemetrexed (APP) in patients with nonsquamous NSCLC. METHODS: Chemotherapy-naive patients with stage IV nonsquamous NSCLC without sensitizing EGFR or ALK genetic alterations were randomized in a one-to-one ratio to receive four or six cycles of carboplatin or cisplatin plus pemetrexed (PP) or APP every 3 weeks, followed by maintenance therapy with atezolizumab plus pemetrexed or pemetrexed alone. Co-primary end points were overall survival (OS) and investigator-assessed progression-free survival (PFS). RESULTS: The intention-to-treat population included 578 patients (APP, n = 292; PP, n = 286). At the primary PFS analysis (May 22, 2018; median follow-up, 14.8 mo), APP exhibited significant PFS improvement versus PP (median = 7.6 versus 5.2 mo, stratified hazard ratio [HR] = 0.60, 95% confidence interval [CI]: 0.49-0.72, p < 0.0001). OS for the APP group was numerically better but not statistically significant at the interim (May 22, 2018; median = 18.1 versus 13.6 mo, stratified HR = 0.81, 95% CI: 0.64-1.03, p = 0.0797) and final analyses (July 18, 2019; median = 17.5 versus 13.6 mo; stratified HR = 0.86, 95% CI: 0.71-1.06, p = 0.1546). The OS and PFS results favored APP versus PP across subgroups. Grade 3 or 4 treatment-related adverse events occurred in 54.6% (APP) and 40.1% (PP) of patients; grade 5 treatment-related events occurred in 3.8% and 2.9%, respectively. CONCLUSIONS: IMpower132 met its co-primary PFS end point but not its co-primary OS end point, with numerical improvement for OS in the APP arm. APP had a manageable safety profile, with no new or unexpected safety signals identified.

Long-Term Outcomes and Retreatment Among Patients With Previously Treated, Programmed Death-Ligand 1‒Positive, Advanced Non‒Small-Cell Lung Cancer in the KEYNOTE-010 Study.

PURPOSE: In the KEYNOTE-010 study, pembrolizumab improved overall survival (OS) versus docetaxel in previously treated, programmed death-ligand 1 (PD-L1)‒expressing advanced non‒small-cell lung cancer (NSCLC) in patients with a tumor proportion score (TPS) ≥ 50% and ≥ 1%. We report KEYNOTE-010 long-term outcomes, including after 35 cycles/2 years or second-course pembrolizumab. METHODS: Of 1,033 patients randomly assigned (intention to treat), 690 received up to 35 cycles/2 years of pembrolizumab 2 mg/kg (n = 344) or 10 mg/kg (n = 346) every 3 weeks, and 343 received docetaxel 75 mg/m2 every 3 weeks. Eligible patients with disease progression after 35 cycles/2 years of pembrolizumab could receive second-course treatment (up to 17 cycles). Pembrolizumab doses were pooled because no between-dose difference was observed at primary analysis. RESULTS: Pembrolizumab continued to improve OS over docetaxel in the PD-L1 TPS ≥ 50% and ≥ 1% groups (hazard ratio [HR], 0.53; 95% CI, 0.42 to 0.66; P < .00001; and HR, 0.69; 95% CI, 0.60 to 0.80; P < .00001, respectively) after a 42.6-month (range, 35.2-53.2 months) median follow-up. Estimated 36-month OS rates were 34.5% versus 12.7% and 22.9% versus 11.0%, respectively. Grade 3-5 treatment-related adverse events occurred in 16% versus 37% of patients, respectively. Seventy-nine of 690 patients completed 35 cycles/2 years of pembrolizumab; 12-month OS and progression-free survival rates after completing treatment were 98.7% (95% CI, 91.1% to 99.8%) and 72.5% (95% CI, 59.9% to 81.8%), respectively. Seventy-five patients (95%) had objective response (RECIST v1.1, blinded independent central review) and 48 (64%) had ongoing response. Grade 3-5 treatment-related adverse events occurred in 17.7% of patients. Fourteen patients received second-course pembrolizumab: 5 completed 17 cycles, 6 (43%) had partial response, and 5 (36%) had stable disease. CONCLUSION: Pembrolizumab provided long-term OS benefit over docetaxel, with manageable safety, durable responses among patients receiving 2 years of treatment, and disease control with second-course treatment, further supporting pembrolizumab for previously treated, PD-L1‒expressing advanced NSCLC.

Prevalence and impact of risk factors for poor asthma outcomes in a large, specialist-managed patient cohort: a real-life study.

BACKGROUND: Risk factors for poor asthma outcomes may have considerable influence on the control level and medical care of asthmatic patients. Our objective was to conduct a study that provides data on the level of symptom control and the frequency of specific risk factors for poor asthma outcomes on a large patient cohort. METHODS: A cross-sectional, non-interventional real-life study was conducted among asthmatic patients treated by respiratory specialists in Hungary. Asthma control and risk factor assessment were done according to Global Initiative for Asthma guideline (Box 2-2). In the data analysis, phase descriptive statistics, graphical outputs, and Fisher's exact tests were used. RESULTS: Of 12743 patients enrolled by 187 specialists, asthma was well controlled in 36.0%, partially controlled in 29.29%, and uncontrolled in 34.71% of the cases. The most common comorbidities were rhinitis/sinusitis (66.84%), cardiovascular diseases (43.81%), and gastroesophageal reflux disease (20.11%). The following risk factors had the strongest relationship with uncontrolled disease: incorrect inhaler technique causing side effects (odds ratio, OR 4.86, 3.51-6.8), previous severe exacerbation (OR 4.79, 4.02-5.72), high short-acting beta agonist (SABA) use (OR 4.46, 4.03-4.93), incorrect inhaler technique associated with an exacerbation (OR 3.91, 3.06-5.03), and persistently low forced expiratory volume in 1 s (FEV1, OR 3.14, 2.8-3.52). The most frequent risk factors were smoking (OR 1.47, 1.36-1.59) and obesity (OR 1.34, 1.24-1.45). Furthermore, high loss of control was associated with an initial low FEV1 (OR 2.21, 2.01-2.44), frequent oral corticosteroid (OCS) use (OR 1.83, 1.64-2.05), poor adherence to treatment (OR 2.51, 2.21-2.86), and allergen exposure (OR 1.63, 1.47-1.81). CONCLUSIONS: This study indicated that the presence of risk factors for poor asthma outcomes listed by the Global Initiative for Asthma document significantly influenced actual control level in a real-world large patient cohort, with high SABA use, previous severe exacerbation, incorrect inhaler technique, persistently low FEV1, and poor adherence to treatment having the highest impact.

Safety of Systemic Agents for the Treatment of Pediatric Psoriasis.

Importance: Use of systemic therapies for moderate to severe psoriasis in children is increasing, but comparative data on their use and toxicities are limited. Objective: To assess patterns of use and relative risks of systemic agents for moderate to severe psoriasis in children. Design, Setting, and Participants: A retrospective review was conducted at 20 centers in North America and Europe, and included all consecutive children with moderate to severe psoriasis who used systemic medications or phototherapy for at least 3 months from December 1, 1990, to September 16, 2014. Main Outcomes and Measures: The minimal core data set included age, sex, severity of psoriasis, systemic interventions, monitoring, adverse events (AEs), and reason for discontinuation. Results: For 390 children (203 girls and 187 boys; mean [SD] age at diagnosis, 8.4 [3.7] years) with psoriasis who used 1 or more systemic medications, the mean interval between diagnosis and starting systemic therapy was 3.0 years. Methotrexate was used by 270 patients (69.2%), biologic agents (primarily etanercept) by 106 (27.2%), acitretin by 57 (14.6%), cyclosporine by 30 (7.7%), fumaric acid esters by 19 (4.9%), and more than 1 medication was used by 73 (18.7%). Of 270 children taking methotrexate, 130 (48.1%) reported 1 or more AEs associated with methotrexate, primarily gastrointestinal (67 [24.8%]). Folic acid 6 days per week (odds ratio, 0.16; 95% CI, 0.06-0.41; P < .001) or 7 days per week (OR, 0.21; 95% CI, 0.08-0.58; P = .003) protected against gastrointestinal AEs more than once-weekly folic acid, regardless of the total weekly dosage. Methotrexate-associated hepatic transaminase elevations were associated with obesity (35 of 270 patients [13.0%]), but a folic acid regimen was not. Injection site reactions occurred in 20 of 106 patients (18.9%) treated with tumor necrosis factor inhibitors, but did not lead to discontinuation of treatment. Having 1 or more AEs related to medication, gastrointestinal AE, laboratory abnormality, or AE leading to discontinuation of the drug was more likely with methotrexate than tumor necrosis factor inhibitors, but having 1 or more infections related to medication (predominantly upper airway) was less likely. Six patients developed a serious treatment-related AE (methotrexate, 3; fumaric acid esters, 2; and adalimumab, 1), but methotrexate and biologic agents were taken for a mean duration that was 2-fold greater than the mean duration for cyclosporine or fumaric acid esters. No patient developed tuberculosis or a malignant neoplasm. Conclusions and Relevance: Medication-related AEs occur less often with tumor necrosis factor inhibitors than with methotrexate. Folic acid administration 6 or 7 times per week protected more against methotrexate-induced gastrointestinal AEs than did weekly administration. A prospective registry is needed to track the long-term risks of systemic agents for pediatric psoriasis.

A randomized, controlled trial of oral propranolol in infantile hemangioma.

BACKGROUND: Oral propranolol has been used to treat complicated infantile hemangiomas, although data from randomized, controlled trials to inform its use are limited. METHODS: We performed a multicenter, randomized, double-blind, adaptive, phase 2-3 trial assessing the efficacy and safety of a pediatric-specific oral propranolol solution in infants 1 to 5 months of age with proliferating infantile hemangioma requiring systemic therapy. Infants were randomly assigned to receive placebo or one of four propranolol regimens (1 or 3 mg of propranolol base per kilogram of body weight per day for 3 or 6 months). A preplanned interim analysis was conducted to identify the regimen to study for the final efficacy analysis. The primary end point was success (complete or nearly complete resolution of the target hemangioma) or failure of trial treatment at week 24, as assessed by independent, centralized, blinded evaluations of standardized photographs. RESULTS: Of 460 infants who underwent randomization, 456 received treatment. On the basis of an interim analysis of the first 188 patients who completed 24 weeks of trial treatment, the regimen of 3 mg of propranolol per kilogram per day for 6 months was selected for the final efficacy analysis. The frequency of successful treatment was higher with this regimen than with placebo (60% vs. 4%, P<0.001). A total of 88% of patients who received the selected propranolol regimen showed improvement by week 5, versus 5% of patients who received placebo. A total of 10% of patients in whom treatment with propranolol was successful required systemic retreatment during follow-up. Known adverse events associated with propranolol (hypoglycemia, hypotension, bradycardia, and bronchospasm) occurred infrequently, with no significant difference in frequency between the placebo group and the groups receiving propranolol. CONCLUSIONS: This trial showed that propranolol was effective at a dose of 3 mg per kilogram per day for 6 months in the treatment of infantile hemangioma. (Funded by Pierre Fabre Dermatologie; ClinicalTrials.gov number, NCT01056341.).

[Ethiopathogenesis of spontaneous primary pneumothorax. Marijuana: cause or a blame?]. / A spontán primer légmell aetiopathogenesiséhez. Marihuána: ok vagy bunbak?

OBJECTIVE: There are contradictory data on chronic lung injury caused by marijuana, which is partially due to insufficient basic research. Anecdotic reports draw attention to an increased rate of primary spontaneous pneumothorax (PSP) among young marijuana smokers, suggesting a causative link. METHODS: A retrospective analysis of 20 patients treated for PSP in our department in the last two years was performed. Demographics, treatment modality and outcome data were analysed. Chi-square, Mann-Whitney and Fisher tests were applied for statistical evaluation. Gender distribution: 16 male, 4 female, age 23.95 ± 4,57 years: min: 18, max: 32. 13/20 patients admitted to be regular cannabis users (CU), among them 11 male, 2 female, age 24.54 ± 4.77 years. Altogether 7/20 patients had a history of previous pneumo-thorax, with a higher recurrence rate among CU (odds ratio 1.56). RESULTS: In the non-cannabis user group (NCU) 3/7 patients were managed with thoracic drainage alone. 4/7 NCH patients needed major surgery, VATS was performed on all 4 patients. 4/13 CU patients were managed with thoracic drainage, 9/13 patients needed thoracotomy (8 VATS, 1 open thoracotomy). We found a shorter drainage time among NCU patients (4.00 ± 1.00 days NCU vs 4.5 ± 1.73 days CU, p = 0.651). Operative treatment was needed more frequently among cannabis users (69.23% vs NCU 57.14%, p = 0.651) due to impaired lung expansion. Recurrence was detected in 2 patients after drainage, 1 CU, 1 NCU patients, respectively, both of them were managed with VATS. On histological examination there were no major differences between the two groups, 11/13 of operative cases had pulmonary emphysaema . Based on county demographical and clinical data, there's a higher risk for PSP among cannabis users (odds ratio 3.86). CONCLUSIONS: Despite the small sample size, there seems to be a connection between marijuana use and PSP prevalence. It's unclear if marijuana directly contributes to the development of pneumothorax, or just aggravates a fundamentally fragile lung parenchyma condition. In this group of young patients a more aggressive surgical approach is recommended, considering underlying parenchymal impairment and higher recurrence rate.

[Observations on human parvovirus B19 infection diagnosed in 2011]. / A 2011. évi B19 humán parvovírus-fertozésekrol szerzett tapasztalatok.

INTRODUCTION: The incidence of human parvovirus B19 infection is unknown. AIM: A retrospective analysis of clinical and laboratory findings was carried out in patients diagnosed with human parvovirus B19 infection in 2011 in a virologic laboratory of a single centre in Hungary. METHODS: Clinical and laboratory data of patients with proven human parvovirus B19 infection were analysed using in- and out-patient files. RESULTS: In 2011, 72 patients proved to have human parvovirus B19 infection with the use of enzyme immunoassay. The clinical diagnoses of these patients were as follows: human parvovirus B19 infection (30.6%), transient aplastic crisis (16.7%), arthritis (8.3%) and acute hepatitis (4.1%). Symptoms of each of the four phases of the infection occurred in various combinations with the exception of the monophase of cheek exanthema. This occurred without the presence of other symptoms in some cases. Leading symptoms and signs were exanthema (in 74.6% of cases), haematological disorders (in 69% of cases), fever (in 54.9% of cases) and arthritis (in 33.8% of cases). Several atypical dermatological symptoms were also observed. Acute arthritis without exanthema was noted in 8 patients. Of the 72 patients with proven human parvovirus B19 infection there were 7 pregnant women, and one of them had hydrops foetalis resulting spontaneous abortion. In 16 patients (22.5%) human parvovirus B19 IgG was undetectable despite an optimal time for testing. CONCLUSION: The observations of this study may contribute to a better recognition of clinical symptoms of human parvovirus B19 infection.

Propranolol for infantile haemangioma: striking effect in the first weeks.

OBJECTIVE: Discuss effect and dynamics of propranolol (PR) treatment in infantile haemangioma (IH) of head and neck in children during follow-up. METHODS: Between 2010 and 2011, 22 children with head and neck infantile haemangioma (IH) treated by PR were recruited into the study. In a retrospective chart review clinical data were analyzed at 5 consecutive, different check-up time from 1 week to 12-14 months. Effectiveness of PR treatment was assessed by a symptom score method. RESULTS: In the whole series a significant regression was observed in 13 patients (59%) in the first week of the therapy. Further five patients showed this time a marked, two mild improvements, and two children did not respond initially to the PR therapy. In one of them (case #8) later on a mild improvement could be seen too. At the second check-up (1 month after initiating PR therapy) 50% of children showed definitive improvement compared to the first visit. Difference between first and second check-ups was significant, and between the 4th and 5th visits the improvement showed the lowest rate. Comparison of IH regression between the 2nd and the 5th check-ups resulted in a p value a little larger than 0.05. There was not significant correlation between the initial IH severity and the treatment effectiveness at the follow-ups (p>0.05). No significant differences were found in treatment effectiveness concerning the IH localizations, too. CONCLUSION: PR treatment is highly effective in children with IHs. The most striking effect is seen at the first week of treatment; later improvement is much slower, sometimes with periods of stagnations. The cause of this is probably the spectacular early effect of vasoconstriction, though other impacts of PR to the individual molecular markers of IH seemed to be less impressive clinically. However, treatment should be continued for at least 6 months because early cessation can cause a relapse.