Response-adapted omission of radiotherapy in children and adolescents with early-stage classical Hodgkin lymphoma and an adequate response to vincristine, etoposide, prednisone, and doxorubicin (EuroNet-PHL-C1): a titration study.

BACKGROUND: Children and adolescents with early-stage classical Hodgkin lymphoma have a 5-year event-free survival of 90% or more with vincristine, etoposide, prednisone, and doxorubicin (OEPA) plus radiotherapy, but late complications of treatment affect survival and quality of life. We investigated whether radiotherapy can be omitted in patients with adequate morphological and metabolic responses to OEPA. METHODS: The EuroNet-PHL-C1 trial was designed as a titration study and recruited patients at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed stage IA, IB, and IIA classical Hodgkin lymphoma younger than 18 years of age were assigned to treatment group 1 to be treated with two cycles of OEPA (vincristine 1·5 mg/m2 intravenously, capped at 2 mg, on days 1, 8, and 15; etoposide 125 mg/m2 intravenously, on days 1-5; prednisone 60 mg/m2 orally on days 1-15; and doxorubicin 40 mg/m2 intravenously on days 1 and 15). If no adequate response (a partial morphological remission or greater and PET negativity) had been achieved after two cycles of OEPA, involved-field radiotherapy was administered at a total dose of 19·8 Gy (usually in 11 fractions of 1·8 Gy per day). The primary endpoint was event-free survival. The primary objective was maintaining a 5-year event-free survival rate of 90% in patients with an adequate response to OEPA without radiotherapy. We performed intention-to-treat and per-protocol analyses. The trial was registered at ClinicalTrials.gov (NCT00433459) and with EUDRACT, (2006-000995-33) and is completed. FINDINGS: Between Jan 31, 2007, and Jan 30, 2013, 2131 patients were registered and 2102 patients were enrolled onto EuroNet-PHL-C1. Of these 2102 patients, 738 with early-stage disease were allocated to treatment group 1. Median follow-up was 63·3 months (IQR 60·1-69·8). We report on 714 patients assigned to and treated on treatment group 1; the intention-to-treat population comprised 713 patients with 323 (45%) male and 390 (55%) female patients. In 440 of 713 patients in the intention-to-treat group who had an adequate response and did not receive radiotherapy, 5-year event-free survival was 86·5% (95% CI 83·3-89·8), which was less than the 90% target rate. In 273 patients with an inadequate response who received radiotherapy, 5-year event-free survival was 88·6% (95% CI 84·8-92·5), for which the 95% CI included the 90% target rate. The most common grade 3-4 adverse events were neutropenia (in 597 [88%] of 680 patients) and leukopenia (437 [61%] of 712). There were no treatment-related deaths. INTERPRETATION: On the basis of all the evidence, radiotherapy could be omitted in patients with early-stage classical Hodgkin lymphoma and an adequate response to OEPA, but patients with risk factors might need more intensive treatment. FUNDING: Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder, Gießen, Kinderkrebsstiftung Mainz of the Journal Oldtimer Markt, Tour der Hoffnung, Menschen für Kinder, Mitteldeutsche Kinderkrebsforschung, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.

Response-adapted omission of radiotherapy and comparison of consolidation chemotherapy in children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma (EuroNet-PHL-C1): a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial.

BACKGROUND: Children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma achieve an event-free survival at 5 years of about 90% after treatment with vincristine, etoposide, prednisone, and doxorubicin (OEPA) followed by cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) and radiotherapy, but long-term treatment effects affect survival and quality of life. We aimed to investigate whether radiotherapy can be omitted in patients with morphological and metabolic adequate response to OEPA and whether modified consolidation chemotherapy reduces gonadotoxicity. METHODS: Our study was designed as a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial, and was carried out at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed intermediate-stage (treatment group 2) and advanced-stage (treatment group 3) classical Hodgkin lymphoma who were younger than 18 years and stratified according to risk using Ann Arbor disease stages IIAE, IIB, IIBE, IIIA, IIIAE, IIIB, IIIBE, and all stages IV (A, B, AE, and BE) were included in the study. Patients with early disease (treatment group 1) were excluded from this analysis. All patients were treated with two cycles of OEPA (1·5 mg/m2 vincristine taken intravenously capped at 2 mg, on days 1, 8, and 15; 125 mg/m2 etoposide taken intravenously on days 1-5; 60 mg/m2 prednisone taken orally on days 1-15; and 40 mg/m2 doxorubicin taken intravenously on days 1 and 15). Patients were randomly assigned to two (treatment group 2) or four (treatment group 3) cycles of COPP (500 mg/m2 cyclophosphamide taken intravenously on days 1 and 8; 1·5 mg/m2 vincristine taken intravenously capped at 2 mg, on days 1 and 8; 40 mg/m2 prednisone taken orally on days 1 to 15; and 100 mg/m2 procarbazine taken orally on days 1 to 15) or COPDAC, which was identical to COPP except that 250 mg/m2 dacarbazine administered intravenously on days 1 to 3 replaced procarbazine. The method of randomisation (1:1) was minimisation with stochastic component and was centrally stratified by treatment group, country, trial sites, and sex. The primary endpoint was event-free survival, defined as time from treatment start until the first of the following events: death from any cause, progression or relapse of classical Hodgkin lymphoma, or occurrence of secondary malignancy. The primary objectives were maintaining 90% event-free survival at 5 years in patients with adequate response to OEPA treated without radiotherapy and to exclude a decrease of 8% in event-free survival at 5 years in the embedded COPDAC versus COPP randomisation to show non-inferiority of COPDAC. Efficacy analyses are reported per protocol and safety in the intention-to-treat population. The trial is registered with ClinicalTrials.gov (trial number NCT00433459) and EUDRACT (trial number 2006-000995-33), and is closed to recruitment. FINDINGS: Between Jan 31, 2007, and Jan 30, 2013, 2102 patients were recruited. 737 (35%) of the 2102 recruited patients were in treatment group 1 (early-stage disease) and were not included in our analysis. 1365 (65%) of the 2102 patients were in treatment group 2 (intermediate-stage disease; n=455) and treatment group 3 (advanced-stage disease; n=910). Of these 1365, 1287 (94%) patients (435 [34%] of 1287 in treatment group 2 and 852 [66%] of 1287 in treatment group 3) were included in the titration trial per-protocol analysis. 937 (69%) of 1365 patients were randomly assigned to COPP (n=471) or COPDAC (n=466) in the embedded trial. Median follow-up was 66·5 months (IQR 62·7-71·7). Of 1287 patients in the per-protocol group, 514 (40%) had an adequate response to treatment and were not treated with radiotherapy (215 [49%] of 435 in treatment group 2 and 299 [35%] of 852 in treatment group 3). 773 (60%) of 1287 patients with inadequate response were scheduled for radiotherapy (220 [51%] of 435 in the treatment group 2 and 553 [65%] of 852 in treatment group 3. In patients who responded adequately, event-free survival rates at 5 years were 90·1% (95% CI 87·5-92·7). event-free survival rates at 5 years in 892 patients who were randomly assigned to treatment and analysed per protocol were 89·9% (95% CI 87·1-92·8) for COPP (n=444) versus 86·1% (82·9-89·4) for COPDAC (n=448). The COPDAC minus COPP difference in event-free survival at 5 years was -3·7% (-8·0 to 0·6). The most common grade 3-4 adverse events (intention-to-treat population) were decreased haemoglobin (205 [15%] of 1365 patients during OEPA vs 37 [7%] of 528 treated with COPP vs 20 [2%] of 819 treated with COPDAC), decreased white blood cells (815 [60%] vs 231 [44%] vs 84 [10%]), and decreased neutrophils (1160 [85%] vs 223 [42%] vs 174 [21%]). One patient in treatment group 2 died of sepsis after the first cycle of OEPA; no other treatment-related deaths occurred. INTERPRETATION: Our results show that radiotherapy can be omitted in patients who adequately respond to treatment, when consolidated with COPP or COPDAC. COPDAC might be less effective, but is substantially less gonadotoxic than COPP. A high proportion of patients could therefore be spared radiotherapy, eventually reducing the late effects of treatment. With more refined criteria for response assessment, the number of patients who receive radiotherapy will be further decreased. FUNDING: Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder Gießen, Kinderkrebsstiftung Mainz, Tour der Hoffnung, Menschen für Kinder, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.

SPTB related spherocytosis in a three-generation family presenting with kidney failure in adulthood due to co-occurrence of UMOD disease causing variant / Esferocitosis relacionada con SPTB en tres generaciones de una familia con insuficiencia cardíaca en la edad adulta debido a la presentación conjunta de la variante de UMOD causante de la enfermedad

BACKGROUND: Hereditary spherocytosis is clinically and genetically heterogeneous disorder and its clinical characteristics are spherocytosis, anaemia, jaundice and splenomegaly. The aetiology is associated to the genes encoding proteins involved in the interaction between the erythrocyte membrane and the lipid bilayer. Causative variants in BetaI-spectrin (SPTB) gene presenting as mild to moderately severe disease are responsible for approximately 25% cases in the USA and Europe. Among kidney disease, isolated cases of nephrotic syndrome due to membranoproliferative glomerulonephritis and macroscopic haematuria with proteinuria due to IgA nephropathy were previously reported in patients with SPTB deficiency. OBJECTIVE: Seven patients from the same family with spherocytosis were evaluated to assess the kidney failure presented in all affected adult patients. METHODS: Clinical, radiological and laboratory investigations were issued to evaluate the spherocytosis and kidney disease. In selected patients, we also performed genetics testing with next generation sequencing of genes related to hereditary spherocytosis, inherited glomerular disorders and tubulo-interstitial kidney disease. RESULTS: Among the family members with spherocytosis, two adults had end-stage kidney disease and one chronic kidney disease stage 4 with unspecific histopathological findings of interstitial fibrosis/tubular atrophy and glomerulosclerosis. At the time, there were no signs of kidney disease present in four paediatric patients. Novel nonsense variant in SPTB gene (NM_001024858; c.4796G>A; p.Trp1599Ter) was detected in all family members with spherocytosis and was predicted to be disease causing. Furthermore, all adult patients with kidney failure and two paediatric cousins of the index patients were heterozygous for the UMOD gene variant (NM_003361.3:c.552G > C, NP_003352.2:p.Trp184Cys) previously reported in patients with tubulo-interstitial kidney disease. UMOD variant was not present in the index patients. CONCLUSIONS: The co-occurrence of any two rare inherited disorders is extremely rare, while to our knowledge the co-occurrence of genetically confirmed HS and autosomal dominant tubulo-interstitial kidney disease (ADTKD) has previously not been reported. It is not possibly to evaluate whether the haemolytic crises due to HS are influencing the progression of the UMOD related renal disease, since the UMOD related ADTKD characteristics in general and in here presented family are extremely variable. Nevertheless, the observed kidney disease in the family is warranting the regular nephrological examinations in UMOD positive paediatric patients in the family in order to recognise hyperuricemia and treat it as early as possible. This is emphasising the importance of serum uric acid detection in routine laboratory screening of paediatric patients in order to identify early signs of tubular injury indicating possible ADTKD

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SPTB related spherocytosis in a three-generation family presenting with kidney failure in adulthood due to co-occurrence of UMOD disease causing variant.

BACKGROUND: Hereditary spherocytosis is clinically and genetically heterogeneous disorder and its clinical characteristics are spherocytosis, anaemia, jaundice and splenomegaly. The aetiology is associated to the genes encoding proteins involved in the interaction between the erythrocyte membrane and the lipid bilayer. Causative variants in ßI-spectrin (SPTB) gene presenting as mild to moderately severe disease are responsible for approximately 25% cases in the USA and Europe. Among kidney disease, isolated cases of nephrotic syndrome due to membranoproliferative glomerulonephritis and macroscopic haematuria with proteinuria due to IgA nephropathy were previously reported in patients with SPTB deficiency. OBJECTIVE: Seven patients from the same family with spherocytosis were evaluated to assess the kidney failure presented in all affected adult patients. METHODS: Clinical, radiological and laboratory investigations were issued to evaluate the spherocytosis and kidney disease. In selected patients, we also performed genetics testing with next generation sequencing of genes related to hereditary spherocytosis, inherited glomerular disorders and tubulo-interstitial kidney disease. RESULTS: Among the family members with spherocytosis, two adults had end-stage kidney disease and one chronic kidney disease stage 4 with unspecific histopathological findings of interstitial fibrosis/tubular atrophy and glomerulosclerosis. At the time, there were no signs of kidney disease present in four paediatric patients. Novel nonsense variant in SPTB gene (NM_001024858; c.4796G>A; p.Trp1599Ter) was detected in all family members with spherocytosis and was predicted to be disease causing. Furthermore, all adult patients with kidney failure and two paediatric cousins of the index patients were heterozygous for the UMOD gene variant (NM_003361.3:c.552G>C, NP_003352.2:p.Trp184Cys) previously reported in patients with tubulo-interstitial kidney disease. UMOD variant was not present in the index patients. CONCLUSIONS: The co-occurrence of any two rare inherited disorders is extremely rare, while to our knowledge the co-occurrence of genetically confirmed HS and autosomal dominant tubulo-interstitial kidney disease (ADTKD) has previously not been reported. It is not possibly to evaluate whether the haemolytic crises due to HS are influencing the progression of the UMOD related renal disease, since the UMOD related ADTKD characteristics in general and in here presented family are extremely variable. Nevertheless, the observed kidney disease in the family is warranting the regular nephrological examinations in UMOD positive paediatric patients in the family in order to recognise hyperuricemia and treat it as early as possible. This is emphasising the importance of serum uric acid detection in routine laboratory screening of paediatric patients in order to identify early signs of tubular injury indicating possible ADTKD.

Effect of Repeated Antimicrobial Photodynamic Therapy in Treatment of Periodontitis Associated with Fanconi Anemia.

BACKGROUND AND OBJECTIVE: Periodontal disease is one of common oral manifestations in patients with Fanconi anemia (FA). The aim of the study was to evaluate the effect of photodynamic therapy (PDT) on periodontal clinical and microbial parameters in a patient with FA. MATERIALS AND METHODS: For a 16-year-old girl, diagnosed with having FA and periodontal disease, the protocol treatment with duration of 10 months was designed. Every 2 months, thorough oral cavity disinfection was followed by PDT, using photosensitizer phenothiazine chloride activated by a diode laser light. During each visit, periodontal parameters were evaluated: plaque index (PI), gingival index (GI), probing pocket depth (PPD), bleeding on probing (BOP), and clinical attachment level. Simultaneously, the presence of Candida albicans and of five periodontal pathogens was evaluated. RESULTS: Clinical results showed improvement in GI, BOP, and PPD during this 10-month period. BOP subsequently reduced from 100% to 79%, 72%, and 60% at 6, 8, and 10 months, respectively. The proportion of sites with PPD of ≥4 mm decreased from 38.7% at the baseline to zero after 10 months. Further, all five bacterial species and C. albicans were reduced significantly. CONCLUSIONS: PDT effectively influences periodontal healing and reduces periodontopathogenic bacteria without damaging the patient's tissues.

Polymorphisms in GRIA1 gene are a risk factor for asparaginase hypersensitivity during the treatment of childhood acute lymphoblastic leukemia.

l-asparaginase is an effective antineoplastic agent used in chemotherapy of acute lymphoblastic leukemia. The drug effect may be compromised by an elicited immune response, resulting in the production of anti-asparaginase antibodies causing an anaphylactic reaction or silent inactivation of the enzyme. To elucidate possible genetic predisposition for inter-individual differences in asparaginase hypersensitivity, we studied single nucleotide polymorphisms (SNPs) in the GRIA1 gene in 146 pediatric patients treated with l-asparaginase. Allergic reaction to l-asparaginase occurred in 49.3% of patients. We observed a statistically significant association between SNPs in the GRIA1 gene and the occurrence of asparaginase allergy: rs4958351 with p = 0.003, rs4958676 with p = 0.005, rs6889909 with p = 0.005, rs6890057 with p = 0.005 and rs10070447 with p = 0.006. We found a statistically significant correlation between asparaginase allergy and event-free survival (p-value 0.005).

Treatment of severe human metapneumovirus (hMPV) pneumonia in an immunocompromised child with oral ribavirin and IVIG.

BACKGROUND: The clinical manifestations of human metapneumovirus (hMPV) infection resemble those of respiratory syncytial virus with the most severe disease occurring in infants, the elderly, chronically ill, and immunocompromised hosts. OBSERVATION: We present a case of a 2-year-old girl undergoing intensive chemotherapy for Burkitt lymphoma who developed severe hMPV pneumonia. Rapid and complete recovery was observed after treatment with oral ribavirin and intravenous immunoglobulin. CONCLUSION: As hMPV can cause severe pneumonia in immunocompromised patients and due to the reports of effective treatment with ribavirin, clinical studies to elucidate the role of ribavirin in treatment of hMPV pneumonia may be needed.

Treatment of sepsis and ARDS with extracorporeal membrane oxygenation and interventional lung assist membrane ventilator in a patient with acute lymphoblastic leukemia.

We report an 18-year-old ice skater with acute lymphoblast leukemia. She developed Staphylococcus epidermidis bacteremia, severe sepsis, septic shock, and ARDS following chemotherapy-induced severe bone marrow failure. She was successfully treated with extraordinary life support measures, which included extracorporeal membrane oxygenation, double lumen lung ventilation for management of hemoptysis, and lung assist membrane ventilation. After 57 days of ICU treatment and a year of rehabilitation, the patient has fully regained her functional status, is now finishing high school, and is ice skating again.

Influence of the polymorphism in candidate genes on late cardiac damage in patients treated due to acute leukemia in childhood.

Anthracyclines have contributed significantly to the increased cure rate in pediatric oncology. Cardiac toxicity is an important late effect after anthracycline treatment and is thought to occur by reactive oxygen species mediated cardiac damage. We hypothesized that deactivating variants of superoxide dismutase II (SOD2) [rs4880 (-9Val > Ala)], catalase (CAT) [rs1001179 (-262C > T) and rs10836235 (c.66 + 78C > T)], GSTT1, and GSTM1 may increase the risk of developing cardiac toxicity, in patients exposed to anthracyclines. The hypothesis was tested in a cohort of 76 long-term survivals of acute lymphoblastic leukemia in childhood. Cardiac damage was evaluated as an attributive variable and compared to gene polymorphisms. In our study group, we show statistically significant correlation between CC homozygosity for CAT (rs10836235 (c.66 + 78C > T)) and cardiac damage after anthracycline exposure (p = 0.020). We found no statistically significant correlation between cardiac damage after anthracycline exposure and deactivating variants of SOD2 [rs4880 (-9Val > Ala)], CAT [rs1001179 (-262C > T), GSTT1, and GSTM1.