Hematopoietic stem cell transplantation does not increase the risk of infection-related complications for pediatric patients with Hodgkin and non-Hodgkin lymphomas: A multicenter nationwide study.

BACKGROUND: Hodgkin (HL) and non-Hodgkin lymphoma (NHL) represent a spectrum of lymphoid malignancies that are often curable with currently applied treatment regimens; however, 15%-30% of lymphoma patients still suffer from relapsed or refractory (rel/ref) disease. Although hematopoietic stem cell transplantation (HSCT) improves outcomes of second-line therapy for lymphoma in childhood, the complication rates in this group of patients, especially infectious complications (IC), remain unclear. OBJECTIVE: The aim of this population-based cohort study was a retrospective analysis of incidence, epidemiology and profile of bacterial infections (BI), invasive fungal disease (IFD), and viral infections (VI) in primary or rel/ref lymphoma patients, both HL and NHL. PATIENTS AND METHODS: We subdivided lymphoma patients into three groups: patients with primary conventional chemotherapy/radiotherapy regimens (group A), patients with rel/ref lymphoma treated with second-line chemotherapy (group B), and rel/ref lymphoma patients who underwent HSCT (group C). The medical records of the patients were biannually reported by each pediatric oncology center, and the data were analyzed centrally. RESULTS: Within 637 patients with primary lymphoma, at least one IC was diagnosed in 255 (40.0%), among 52 patients with rel/ref lymphoma 24 (46.2%) ICs were observed, and in transplanted group, 28 (57.1%) out of 49 children were diagnosed with IC (P = .151). The distribution of etiology of IC differed between the patient groups (A, B, C), with a predominance of BI in group A (85.6% vs 72.0% and 47.9%, respectively), VI in group C (9% and 16.0% vs 46.6%, respectively), and IFD in group B (5.4% vs 12.0% vs 5.5%, respectively). Overall, 500 (68.0%) episodes of bacterial IC were diagnosed in the entire group. Apart from HL patients treated with chemotherapy, in all the other subgroups of patients Gram-positives were predominant. The rate of multidrug-resistant bacteria was high, especially for Gram-negatives (41.1% in group A, 62.5% in group B, and 84.6% in group C). The infection-related mortality was comparable for each group. CONCLUSIONS: The incidence of IC was comparable during first- and second-line chemotherapy and after HSCT, but their profile was different for primary or re/ref lymphoma and depended on the type of therapy.

Adenovirus infection among pediatric patients with cancer and in pediatric recipients of hematopoietic stem cell: A multicenter nationwide study.

The aim was to evaluate the incidence, clinical course, and outcome of adenoviral infection (AdVI) in pediatric patients diagnosed and treated due to cancer and in pediatric recipients of hematopoietic stem cell. Over a 72-month period, all-in 5599 children with cancer: 2441 patients with hematological malignancy (HM) and 3158 with solid tumors (ST), and 971 patients after transplantation: 741 after allogeneic (allo-HSCT) and 230 after autologous (auto-HSCT) were enrolled into the study. Among cancer patients, 67 episodes of AdVI appeared in 63 (1.1%) children, including 45 (1.8%) with HM and 18 (0.6%; P < .001) with ST. Within transplanted patients, AdVIs were responsible for 88 episodes in 81 (8.3%) children (P < .001), including 78 (10.5%) patients after allo-HSCT and 3 (1.3%) after auto-HSCT. Time to develop AdVI was short, especially after allo-HSCT. The most common clinical manifestation in cancer patients was enteritis diagnosed in 63 (94.0%) cases, while among HSCT recipient asymptomatic adenoviremia was found in 36 (40.9%) cases and the most common clinical manifestation was urinary tract infection. Cancer patients with disseminated disease, as well as HSCT recipients with either asymptomatic viremia or disseminated disease, received antiviral treatment. The most commonly used first-line therapy was cidofovir. None of the cancer patients died due to AdVI, while within HSCT recipients three patients developed disseminated adenoviral disease and died despite antiviral treatment. In cancer patients, AdVIs are rare and associated with very good prognosis even without specific treatment. However, in allo-HSCT recipients, disseminated disease with fatal outcome is more likely to occur.

Incidence, course, and outcome of Clostridium difficile infection in children with hematological malignancies or undergoing hematopoietic stem cell transplantation.

Clostridium difficile infection (CDI) is one of the most common causes of nosocomial infectious diarrhea in children during anticancer therapy or undergoing hematopoietic stem cell transplantation (HSCT) in Europe. Immunosuppression in these patients is a risk factor for CDI. Malignant diseases, age, acute graft-versus-host disease (aGVHD), HLA mismatch, or use of total body irradiation may play an important role in CDI course. The aim of this study was to evaluate the incidence, course, and outcome of CDI in children treated for malignancy or undergoing HSCT. Between 2012 and 2015, a total number of 1846 patients were treated for malignancy in Polish pediatric oncological centers (PHO group) and 342 underwent transplantation (HSCT group). In PHO group, episodes of CDI occurred in 210 patients (14%). The incidence of CDI was higher in patients with hematological malignancies in comparison to that with solid tumors. Patients with acute myeloblastic leukemia had shorter time to episode of CDI than those with acute lymphoblastic leukemia. Patients over 5 years and treated for acute leukemia had more severe clinical course of disease in PHO group. In HSCT group, CDI occurred in 29 (8%) patients. The incidence of CDI was higher in patients transplanted for acute leukemia. The recurrence rate was 14.7% in PHO and 20.7% in HSCT patients. CDI incidence was highest in patients with hematological malignancies. Most of patients experienced mild CDI. Age < 5 years and diagnosis other than acute leukemia were the positive prognostic factors influencing clinical CDI course.

Identification of a novel inherited ALK variant M1199L in the WNT type of medulloblastoma.

Rearrangements involving the ALK gene were identified in a variety of cancers, including paediatric tumour neuroblastoma where presence of ALK expression is also associated with adverse prognosis. Microarrays data indicate that ALK is expressed in another paediatric tumour - medulloblastoma. Therefore, we investigated if the ALK gene is mutated in medulloblastoma and performed simultaneously the molecular profiling of tumours. Tumours from sixty-four medulloblastoma patients were studied for detection of ALK alterations in exons 23 and 25 using Sanger method. The molecular subtypes of tumours were identified by detection of mutations in the CTNNB1 gene, monosomy 6 and by immunohistochemistry using a panel of representative antibodies. Among three ALK variants detected two resulted in intron variants (rs3738867, rs113866835) and the third one was a novel heterozygous variant c.3595A>T in exon 23 identified in the WNT type of tumour. It resulted in methionine to leucine substitution at codon position 1199 (M1199L) of the kinase domain of ALK protein. Results of analysis using three in silico algorithms confirmed the pathogenicity of this single nucleotide variation. The same gene alteration was detected in both patient and maternal peripheral blood leukocytes indicating an inherited type of the detected variant. Presence of ALK expression in tumour tissue was confirmed by immunohistochemistry. The tumour was diagnosed as classic medulloblastoma, however with visible areas of focal anaplastic features. The patient has been disease free for 6 years since diagnosis. This is the first evidence of an inherited ALK variant in the WNT type of medulloblastoma, what altogether with presence of ALK expression may point towards involvement of the ALK gene in this type of tumours.

Increased risk of infections and infection-related mortality in children undergoing haematopoietic stem cell transplantation compared to conventional anticancer therapy: a multicentre nationwide study.

This nationwide multicentre study analysed the epidemiology of bacterial, viral and fungal infections in paediatric haematopoietic stem cell transplantation (HSCT) and paediatric haematology and oncology (PHO) patients over a period of 24 consecutive months, including incidence, hazard risk and outcome of infections as well as occurrence of multidrug-resistant bacteria. During this period, 308 HSCTs were performed and 1768 children were newly diagnosed for malignancy. Compared to PHO, the risk in HSCT patients was significantly higher for all infections (hazard ratio (HR) 2.7), bacterial (HR 1.4), fungal (HR 3.5) and viral (HR 15.7) infections. The risk was higher in allo- than auto-HSCT for bacterial (HR 1.4), fungal (HR 3.2) and viral (HR 17.7) infections. The incidence of resistant bacteria was higher in HSCT than in PHO patients for both G-negative (72.5% vs. 59.2%) and G-positive (41.4% vs. 20.5%) strains. Cumulative incidence of bacterial, fungal and viral infections in HSCT patients was 33.9, 22.8 and 38.3%, respectively. Cumulative incidence of viral infections in allo-HSCT was 28.0% for cytomegalovirus, 18.5% for BK virus, 15.5% for Epstein-Barr virus, 9.5% for adenovirus, 2.6% for varicella zoster virus, 0.9% for influenza, 0.9% for human herpesvirus 6 and 0.3% for hepatitis B virus. Survival rates from infections were lower in HSCT than in PHO patients in bacterial (96.0 vs. 98.2%), fungal (75.5 vs. 94.6%) and most viral infections. In conclusion, the risk of any infections and the occurrence of resistant bacterial strains in allo-HSCT patients were higher than in auto-HSCT and PHO patients, while the outcome of infections was better in the PHO setting.

Liver transplantation in children with hepatocellular carcinoma. Do Milan criteria apply to pediatric patients?

HCC constitutes 25-30% of primary malignant liver tumors in children. Conventional surgical excision is not possible in more than 50% of patients. LTx has recently become an important therapeutic option for adults and children with primary liver tumors. The aim of this study was a retrospective analysis of the clinical and pathological data of children with HCC treated with LTx in relation to Milan criteria assessed at diagnosis and then immediately before transplantation, in comparison with a group of patients treated conventionally. Between 1990 and 2007 we have treated 21 children diagnosed with HCC. Patients were divided into two groups: group I, 10 children treated conventionally and group II, 11 children treated with LTx regardless of previous therapy. The outcome of our patients treated conventionally with resection and chemotherapy is very poor--the disease-free survival rate is 30%. In contrast, despite that only 3 children having fulfilled adult Milan criteria, early clinical results of LTx are much superior. Total hepatectomy followed by LTx is the main treatment option for the majority of children with HCC. Decisions on the type of surgical treatment is made individually, but very early in the course of treatment.

Postural sway in children and young adults, survivors of CNS tumours.

PURPOSE: Brain tumours are the most common solid tumours in children and adolescents. The increasing survival rate of these patients makes their follow-up and quality of life assessment an important task. The evaluation of the negative influence of anti-cancer treatment on their balance is the aim of this study. MATERIAL AND METHODS: The balance assessment was performed on patients who completed the treatment of CNS tumours and were disease-free at the time of the study. Eighty-eight patients aged 5 to 24 years participated in the study. Postural sway was recorded using Kistler force plate. Balance test parameters from two conditions: eyes open and eyes closed were calculated and compared with reference data. The severity of the balance disorders was scored for both conditions. RESULTS: The balance disorders were generally not dependent on the localisation of the tumour. Only patients treated for posterior fossa tumours had a higher score (indicating pronounced balance deficit) in eyes closed condition comparing to others. The patients treated for spinal cord tumours seemed to have increased total sway path in comparison to others. The severity of the balance deficits tended to diminish in time. CONCLUSIONS: These results suggest that the repair mechanisms of the CNS could overcome the problems inflicted by the illness and therapy.

Risk factors of recurrence in 157 MB/PNET patients treated in one institution.

To evaluate the risk factors for recurrence of MB/PNET we analyzed the medical records of 157 patients treated at the Children's Memorial Health Institute between February 1981 and February 1997. The following factors were evaluated: age at diagnosis, gender, tumor size, tumor cells in the CSF, postoperative status, extent of resection and methods of treatment. We evaluated chemotherapy (CHT) doses, interval between courses, interval between surgery (S) and first course of CHT, interval between S and radiotherapy (RTX), and breaks during RTX. We divided patients into six groups: S alone, S+CHT, S+RTX, S+CHT+ RTX, S+RTX+CHT, S+CHT+RTX+ CHT. Age at diagnosis, gender, tumor size, extent of resection, postoperative status, intervals between courses of CHT, between S and the first course of CHT, and between S and RTX, and breaks during RTX had no statistical influence on relapse occurrence. Tumor cells in CSF were routinely checked for from January 1992 onward. In this group of 75 patients, 40 had tumor cells positive at surgery (28 relapsed), while in the group of 35 patients with negative tumor cells 14 relapsed (P=0.004). Out of 26 patients treated with S+RTX alone, 13 relapsed. Among 14 patients treated with S+RTX and prolonged CHT 6 relapsed. Out of 14 patients treated with S+CHT 13 relapsed; among 49 who received S+CHT+RTX 35 relapsed; and out of 51 patients treated with S+CHT+RTX+CHT 30 relapsed. In the multivariate analysis of treatment methods chemotherapy implemented after radiotherapy had a positive, though not statistically significant, influence on outcome (P=0.06). Among those receiving CHT the mean percentage of the ideal dose administered had a statistically significant influence on relapse: in the group of relapsed patients the mean dose was 76.1%, while in the group in continuous remission it was 83.7% (P=0.0013). On the basis of our data, we conclude that the presence of tumor cells in the CSF had a significant influence on the occurrence of relapse. Administration of appropriate doses of chemotherapy is extremely important for the occurrence of relapse and the final outcome of treatment. Prolonged adjuvant chemotherapy after radiotherapy seems to lower the risk of recurrence.

[Progress in the treatment of children with Wilms' tumor in the Department of Pediatric Oncology at the Institute of Mother and Child]. / Postepy w leczeniu guzów Wilmsa u dzieci w Klinice Onkologii Dzieci i Mlodziezy Instytutu Matki i Dziecka.

A retrospective analysis of treatment results of 242 children with Wilms tumor treated in the years 1962-1989 is presented. The patients (pts) were divided into 4 groups according to methods of treatment that changed with the time. Group I consisted of patients treated between 1962-1965. Surgery followed by radiotherapy (RTX) and monochemotherapy (CHT) (ACTD) were the main treatment methods. Group II consisted of 68 patients treated between 1966-1974. In this group, surgery was followed by RTX and CHT (multiple courses of ACTD + VCR). Group III included 68 patients treated between 1975-1982. Preoperative RTX (20 Gy) and CHT (ACTD) were administered. RTX (total 35 Gy) and adjuvant CHT were continued after surgery. Group IV consisted of 62 patients treated in 1982-1989. Preoperative CHT (ACTD, VCR +/- ADR) was introduced. Adjuvant treatment depended on stage and histology of the tumor. The treatment results were as follows: 27, 66.1, 38.2 and 85.4% of survival, respectively. This points to the beneficial role of induction CHT, delayed surgery with adjusting the intensity of further adjuvant treatment to stage and tumor histology.

[Progress in the treatment of 155 children with rhabdomyosarcoma obtained in one center between 1962-1990]. / Postep w leczeniu rhabdomyosarcoma uzyskany w jednym osrodku u 155 dzieci w latach 1962-1990.

The results of treating 155 children with rhabdomyosarcoma using protocols that (RMS) changing over the years between 1962-1990 in reported to progress in chemotherapy (CHT), introduction of megavoltage radiotherapy (RTX) and conservative surgery with attempts to preserve vital organs are presented. In the first period between 1962-1980 when mainly surgery was applied with orthovoltage RTX and low intensity CHT, only 20 of 74 children (27%) survived. In the second period 1981-1985 systemic CHT containing new cytostatic, megavoltage RTX and limited surgery applied in advanced cases after induction of CHT were introduced. Nineteen of 46 children (41.3%) survived. In the last period a 1986-1990 more intensive CHT with an own modified protocol VACA/VAIA and intensification phases containing cisplatinum, etoposide and/or carboplatinum were introduced. Twenty seven of 35 patients (60%) survived. Comparative analysis of the last two periods pointed to significant progress in treatment in III clinical group (IRS classification), (20.7% vs 62.9%) and parameningeal RMS (0% vs 58%). Meaningful improvement concerned also young children below 5 years of age (42.8% vs 73.9%). The main prognostic factors and treatment failures of the recent years were analyzed.

[Preliminary evaluation of individualized use of large doses of methotrexate for treatment of osteosarcoma in children and adolescents]. / Wstepna ocena zastosowania indywidualizowanych duzych dawek metotreksatu w leczeniu miesaka kosciopochodnego u dzieci i mlodziezy.

To improve the final treatment results in children with osteosarcoma, we applied after French DD-11 protocol HD MTX increasing with the younger age of patients, modified next on the basis of maximal serum drug concentrations (Cmax) as feed-back dosing. Toxic side effects were analysed according to WHO grading correlated with MTX elimination. We administered 39 HD MTX courses in 13 patients with osteosarcoma: aged 7-20 yrs (median 12 yrs). We performed 301 measurements of MTX concentration using the method of fluorescence polarisation. Therapeutic Cmax of 1000 microM/L and higher were obtained in 20 courses, the mean of lower values was 770 microM/L. We modified the next MTX doses in 23.7% of courses. Drug elimination was good in the majority of cases: in 34 of 39 courses at 24 hrs, in 36 of 39 at 48 hrs. Nevertheless, III and IV degree toxic side-effects accompanied about half of the courses and could not be predicted by MTX serum level measurements. HD MTX therapy with monitoring MTX serum levels proved feasible with acceptable toxicity. Therapeutic MTX levels were obtained in about 60% of cycles in patients with a favourable course of the disease in comparison with 25% in patients with an unfavorable course but the beneficial effect of age-tailored MTX and feed-back dosing on the treatment results will be possible to assess in the next 3 years.