Can peripheral blood monocyte percentage and lymphocyte monocyte ratio at diagnosis predict survival in pediatric neuroblastoma patients?

BACKGROUND: Previous studies have shown that the immune system plays a critical role in cancer pathogenesis. The lymphocyte monocyte ratio (LMR) and monocyte percentage (MP) have been found to be prognostic factors in various types of adult cancers. But studies about pediatric tumors are scarce and to our knowledge, there are no studies evaluating the immune system effect in pediatric neuroblastoma patients. The aim of this study was to assess whether LMR and MP at diagnosis may have an effect on prognosis in neuroblastoma patients. METHODS: We retrospectively analyzed MP and LMR at diagnosis in 71 pediatric neuroblastoma patients treated between 2002 and 2016. RESULTS: The optimal cut-off values of LMR and MP were determined using the receiver operating characteristics curves (ROC) and area under the curve (AUC). We found that a low LMR (≤3.5) and a high MP (≥7.5%) were correlated with worse overall survival and shorter event-free survival in univariate analysis. Multivariate analysis revealed that elevated LMR was an independent factor for better OS and EFS. CONCLUSIONS: In conclusion, LMR and MP might be valuable prognostic factors for predicting OS in neuroblastoma patients. Multicenter and prospective studies are warranted to confirm this hypothesis.

Impact of the HEAD-US Scoring System for Observing the Protective Effect of Prophylaxis in Hemophilia Patients: A Prospective, Multicenter, Observational Study

Objective: This study aimed to observe the preventive effect of prophylactic treatment on joint health in people with hemophilia (PwH) and to investigate the importance of integration of ultrasonographic examination into clinical and radiological evaluation of the joints. Materials and Methods: This national, multicenter, prospective, observational study included male patients aged ≥6 years with the diagnosis of moderate or severe hemophilia A or B from 8 centers across Turkey between January 2017 and March 2019. Patients were followed for 1 year with 5 visits (baseline and 3th, 6th, 9th, and 12th month visits). The Hemophilia Joint Health Score (HJHS) was used for physical examination of joints, the Pettersson scoring system was used for radiological assessment, point-of-care (POC) ultrasonography was used for bilateral examinations of joints, and the Hemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) score was used for evaluation of ultrasonography results. Results: Seventy-three PwH, of whom 62 had hemophilia A and 11 had hemophilia B, were included and 24.7% had target joints at baseline. The HJHS and HEAD-US scores were significantly increased at the 12th month in all patients. These scores were also higher in the hemophilia A subgroup than the hemophilia B subgroup. However, in the childhood group, the increment of scores was not significant. The HEAD-US total score was significantly correlated with both the HJHS total score and Pettersson total score at baseline and at the 12th month. Conclusion: The HEAD-US and HJHS scoring systems are valuable tools during follow-up examinations of PwH and they complement each other. We suggest that POC ultrasonographic evaluation and the HEAD-US scoring system may be integrated into differential diagnosis of bleeding and long-term monitoring for joint health as a routine procedure.

Retrospective Evaluation of Relationship Between Iron Overload and Transplantation Complications in Pediatric Patient Who Underwent Allogeneic Stem Cell Transplantation Due to Acute Leukemia and Myelodysplastic Syndrome.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a curative therapy option for hematologic malignancies. Iron overload is common in this patient group and can impact short-term and long-term nonrelapse mortality. STUDY DESIGN: Retrospective observational cohort study. AIMS: To evaluate the effect of iron load on early and late HSCT outcomes in patients with acute leukemia and myelodysplasia to assess the necessity of reducing iron load. PATIENTS AND METHODS: Sixty patients who underwent HSCT in pediatric stem cell transplantation unit between 2000 and 2012 were evaluated retrospectively. The patients were divided into those with pretransplantation serum ferritin levels above and below the median value of 1299 ng/mL. RESULTS: Forty-two (70%) of the patients were male, mean ages of the low and high ferritin groups were 85.43±9.42 and 118.56±10.04 months, respectively. Acute graft-versus-host disease (GVHD) within the first 100 days and acute liver GVHD were significantly more common in the high ferritin group (P<0.011 for both). Ferritin level was not associated with rates of engraftment syndrome, veno-occlusive disease, early/late infection, relapse, or overall and disease-free survival. CONCLUSIONS: In our study, significant result especially in terms of acute liver GVHD, was important to emphasize the need to be more careful in terms of acute liver GVHD risk in early liver pathologies in patients with high levels of ferritin after transplantation. In future large studies may be helpful to explain the relationship between acute liver GVHD and high ferritin levels.

Factor 8 Gene Mutation Spectrum of 270 Patients with Hemophilia A: Identification of 36 Novel Mutations

Objective: Hemophilia A (HA) is the most severe X-linked inherited bleeding disorder caused by hemizygous mutations in the factor 8 (F8) gene. The aim of this study is to determine the mutation spectrum of the F8 gene in a large HA cohort from Turkey, and then to establish a phenotype-genotype correlation. Materials and Methods: All HA cases (270 patients) analyzed molecularly in the Ege University Pediatric Genetics Molecular Laboratory between March 2017 and March 2018 were included in this study. To identify intron 22 inversion (Inv22), intron 1 inversion (Inv1), small deletion/insertions, and point mutations, molecular analyses of F8 were performed using a sequential application of molecular techniques. Results: The mutation detection success rate was 95.2%. Positive Inv22 was found in 106 patients (39.3%), Inv1 was found in 4 patients (1.5%), and 106 different disease-causing sequence variants were identified in 137 patients (50.6%). In 10 patients (3.7%), amplification failures involving one or more exonic regions, considered to be large intragenic deletions, were identified. Of 106 different F8 mutations, 36 were novel. The relationship between F8 genotype and inhibitor development was considered significant. Conclusion: A high mutation detection rate was achieved via the broad molecular techniques applied in this study, including 36 novel mutations. With regard to mutation types, mutation distribution and their impact on clinical severity and inhibitor development were found to be similar to those previously reported in other hemophilia population studies.

Pediatric Tonsillar Synovial Sarcoma- Very Rare Localization: A Case Report and Review of the Literature.

Tonsillar synovial sarcoma is an extremely rare entity and only 9 adult patients have been reported up to now. Here, we describe the first pediatric tonsillar synovial sarcoma of the literature in a patient who presented with a 2-month history of dysphagia and snoring. Clinical and radiological examinations showed that the tumor arose from the right palatine tonsil and narrowed the parapharyngeal space. An incisional biopsy from the palatine tonsil revealed the diagnosis of synovial sarcoma. The patient has underwent total tonsillectomy and received radiotherapy and chemotherapy because of the positive surgical margins. The patient is clinically in good condition and free of tumor 30 months after the initial diagnosis. We achieved a long-term complete remission with a combination of surgery, radiotherapy and chemotherapy in our case. Tonsillar synovial sarcoma should be kept in mind while dealing with tonsillar masses. We can conclude that a multidisciplinary approach is warranted while treating synovial sarcoma with this localization.

Homozygous c.130-131 ins A (pW44X) mutation in the HAX1 gene as the most common cause of congenital neutropenia in Turkey: Report from the Turkish Severe Congenital Neutropenia Registry.

BACKGROUND: Severe congenital neutropenia is a rare disease, and autosomal dominantly inherited ELANE mutation is the most frequently observed genetic defect in the registries from North America and Western Europe. However, in eastern countries where consanguineous marriages are common, autosomal recessive forms might be more frequent. METHOD: Two hundred and sixteen patients with severe congenital neutropenia from 28 different pediatric centers in Turkey were registered. RESULTS: The most frequently observed mutation was HAX1 mutation (n = 78, 36.1%). A heterozygous ELANE mutation was detected in 29 patients (13.4%) in our cohort. Biallelic mutations of G6PC3 (n = 9, 4.3%), CSF3R (n = 6, 2.9%), and JAGN1 (n = 2, 1%) were also observed. Granulocyte colony-stimulating factor treatment was given to 174 patients (80.6%). Two patients died with infectious complications, and five patients developed myelodysplastic syndrome/acute myeloblastic leukemia. The mean (± mean standard error) follow-up period was 129.7 ± 76.3 months, and overall survival was 96.8% (CI, 94.4-99.1%) at the age of 15 years. In Turkey, severe congenital neutropenia mostly resulted from the p W44X mutation in the HAX1 gene. CONCLUSION: In Turkey, mutation analysis should be started with HAX1, and if this is negative, ELANE and G6PC3 should be checked. Because of the very high percentage of consanguineous marriage, rare mutations should be tested in patients with a negative mutation screen.

Results of Allogenic Hematopoietic Stem Cell Transplantation in Fanconi Anemia Caused by Bone Marrow Failure: Single-Regimen, Single-Center Experience of 14 Years.

Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for bone marrow failure (BMF) in patients with Fanconi anemia (FA). We retrospectively analyzed the records of patients with FA who underwent HSCT with a radiation-free, reduced-intensity conditioning regimen (fludarabine, cyclophosphamide, and antithymocyte globulin) along with an unmanipulated graft infusion between 2004 and 2018. A total of 44 patients underwent HSCT during the study period. Median age at transplantation was 121 months. Regarding the donor source, 22 transplants (50%) were collected from matched related donors (MRDs), and 22 transplants (50%) were collected from alternative donors (ADs). The median infused CD34+ cell dose was 4.7 × 106/kg (range, 0.8 to 23) in bone marrow or peripheral blood stem cell recipients and 1.2 × 105/kg (range, 1.1 to 3.6) in umbilical cord blood recipients. All but 2 patients achieved primary neutrophil engraftment (95%). In a median follow-up of 36 months (range, 1 to 159), 3-year overall survival was 70.5% in the entire group and 91% in the MRD recipients. Primary causes of death were infections (n = 5), acute grade 3 to 4 graft-versus-host disease (n = 4), and hemorrhagic cystitis (n = 3). All surviving patients have full (n = 29) and acceptable mixed (n = 2) donor chimerism and good clinical status. Our results showed an excellent outcome with unmanipulated grafts using a fludarabine-based, radiation-free preparative regimen for MRD recipients. Even though primary neutrophil engraftment rates were good in AD recipients, intervening complications increased mortality in these patients. In clinics where T cell depletion is not feasible, more effort is warranted to improve outcomes for AD recipients.

An infant with intradural extramedullary synovial sarcoma: the youngest case in the literature.

Yalçin K, Tüysüz G, Kazan S, Gürer EI, Karaali K, Küpesiz A, Güler E. An infant with intradural extramedullary synovial sarcoma: the youngest case in the literature. Turk J Pediatr 2019; 61: 765-770. Spinal cord involvement of synovial sarcoma is extremely rare. So far only two cases have been reported. Herein we describe the youngest case in the literature. She is 14-month-old and first presented with difficulty in walking ongoing for a week. Imagining showed a spinal cord mass at C5-T3 levels. The patient had gone under Decompressive surgery and histopathologic examination of the specimen revealed the presence of synovial sarcoma. Although the tumor regressed after chemotherapy, she was lost due to viral pneumonia. Synovial sarcoma should be kept in mind while evaluating spinal tumors even in infantile group.

Health-related Quality of Life and its Predictors Among Transfusion-dependent Thalassemia Patients.

PURPOSE: With regular blood transfusions and modern medical management strategies, transfusion-dependent thalassemia (TDT) patients are currently living into adulthood, but they still suffer from the chronicity of the disease and its complications. This study was aimed to assess the health-related quality of life (HRQoL) scores in pediatric TDT patients compared with healthy controls. PATIENTS AND METHODS: The PedsQL 4.0 Generic Core Scales were administered to 80 pediatric TDT patients (aged 5 to 18 y, child self-report) and their parents (parent-proxy report), as well as age-matched and sex-matched healthy controls (80 participants and their parents). RESULTS: Patients with TDT and their parents rated lower HRQoL scores in all domains (physical, emotional, social, and school functioning) compared with the healthy population (P<0.01). The univariate analysis indicated that the total HRQoL score for children's self-reports was negatively predicted by high ferritin levels and the presence of any complication. The only negative predictor of the total HRQoL score in multivariate analyses was a high ferritin level (>1800 ng/dL). CONCLUSIONS: This study showed that thalassemia has a negative impact on HRQoL when compared with a healthy population. For a better quality of life, intensive treatment should be applied for complications and high ferritin levels.

A Translocation Renal Cell Carcinoma with Skeletal Muscle Metastasis in a Child.

Renal cell carcinoma is a tumor that is well known for a high rate of metastasis to several locations like the lung, liver and bones. Skeletal muscle is a rare location for dissemination of the disease. Herein, we describe a 7-year-old boy who presented with flank pain. On physical examination, an abdominal mass located on the left kidney as well as a solid palpable lesion on the left upper arm were detected. Total nephrectomy with subsequent excision of the arm mass was performed. Pathology examination revealed presence of translocation renal cell carcinoma. The patient received α-interferon followed by multikinase inhibitor (Sorafenib) treatment but was lost due to progressive disease. This is the first description of a pediatric patient with skeletal muscle metastases of translocation renal cell carcinoma in the literature.

Febrile neutropenia in children with acute lymphoblastic leukemia: single center experience.

AIM: An important life-threatening complication of intensive chemotherapy administered in children with leukemia is febrile neutropenia. The objective of this study was to evaluate the clinical features and consequences of febrile neutropenia attacks in children who were treated for acute lymphoblastic leukemia. MATERIAL AND METHODS: Nighty-six children who received chemotherapy for acute lymphoblastic leukemia in our center between January 1995 and December 2010 were included in the study. The data related to demographic characteristics, treatment features, relapse and febrile neutropenia incidences, risk factors, culture results and prognosis were retrospectively evaluated from the patients' files. RESULTS: A total of two hundred-ninety nine febrile neutropenia attacks observed in the patients during initial treatment and relapse treatment were evaluated. When the incidence of febrile neutropenia was evaluated by years, it was observed that the patients treated after year 2000 had statistically significantly more febrile neutopenia attacks compared to the patients treated before year 2000. When the incidences of febrile neutropenia during initial treatment and during relapse treatment were compared, it was observed that more febrile neutropenia attacks occured during relapse treatment. Fifty-nine percent of all febrile neutropenia attacks were fever of unknown origin. Eighty microorganisms grew in cultures during febrile neutropenia throughout treatment in 75 patients; 86% were bacterial infections (50% gram positive and 50% gram negative), 8% were viral infections and 6% were fungal infections. Coagulase negative staphylococcus (n=17) was the most frequent gram positive pathogen; E. Coli (n=17) was the most commonly grown gram negative pathogen. CONCLUSIONS: In this study, it was found that an increase in the incidence of febrile neutropenia occured in years. Increments in treatment intensities increase the incidence of febrile neutropenia while improving survival. Evaluation of febrile neutropenia results by hematology-oncology units in years will be directive in early and successful treatment.

Childhood mastocytosis: results of a single center.

AIM: We aimed to retrospectively evaluate histopathological, demographic and clinical findings of children with mastocytosis diagnosed with mastocytosis in our clinic. MATERIAL AND METHODS: The files of 21 patients diagnosed with mastocytosis between 2000 and 2014 in our clinic were retrospectively analyzed. RESULTS: All patients had cutaneous mastocytosis, 19 patients had urticaria pigmentosa and 2 patients had mastocytoma. The male-female ratio was: 1/1.6. The median age for onset of disease was 12.1 months and the disease occured in the newborn period in 3 patients. While all patients had eruption, 10 patients had pruritis, 1 patient had a bullous formation, 1 patient had abdominal pain and 1 patient had attacks of redness throughout the body and a sense of burning in the chest. Two patients had a positive familial history. The diagnosis was confirmed with skin biopsy in all patients. The median follow up time of the patients were 5 years. The patients were treated with H1, H2 antihistaminics, local moisturizing creams and topical corticosteroid drugs. The lesions resolved completely in 4 patients who reached to puberty and 7 patients had marked improvement in a 5.5 year-follow-up period. Ten patients had stabile lesions in a 3.6 year-follow-up period. CONCLUSIONS: Most cases of childhood mastocytosis are observed in the form of cutaneous mastocytosis. The prognosis is good; the disease limits itself and is prone to regress in the adolescent period.

A case of xanthogranulomatous pyelonephritis mimicking Wilms tumor.

Xanthogranulomatous pyelonephritis (XGPN) is a very rare, unusual variant of pyelonephritis characterized by destruction of renal parenchyma. It usually occurs in adults with a history of recurrent urinary tract infections. The condition is rare in children and the disease can imitate renal tumors. Here, we describe a 12-year-old boy who presented with abdominal pain. He did not have any history of urinary tract infection. Computed tomography and magnetic resonance imaging showed a cystic lesion in the left upper kidney. The patient underwent radical nephrectomy with a provisional diagnosis of Wilms tumor however histopathological examination of specimen revealed XGPN. Xanthogranulomatous pyelonephritis should be kept in mind in the differential diagnosis of renal lesions in childhood, during surgery if any suspicion from the diagnosis, a frozen biopsy should have been taken.

Isolated central nervous system relapse in a child with non- Hodgkin lymphoma during treatment.

Isolated central nervous system (CNS) relapse of non-Hodgkin lymphoma (NHL) is very rare. We report a five-year-old boy with T-cell lymphoblastic lymphoma (T-LBL), who developed CNS relapse under treatment when the primary tumor was in complete remission. The patient presented initially with persistent cough and an anterior mediastinal mass and had no bone marrow or CNS involvement at diagnosis. During re-induction treatment, a routine lumbar puncture revealed blasts in the cerebrospinal fluid (CSF). The patient developed neurological signs and symptoms consequently. Craniospinal radiotherapy followed by BFM (Berlin-Frankfurt-Münster) high-risk chemotherapy protocol was initiated. Despite complete response after three courses, the patient experienced CNS relapse and expired due to disease progression. In the treatment of a NHL patient, routine CSF analysis should be done for tumor cells even when the primary disease is in complete remission.

Successful management of hepatic mucormycosis in an acute lymphoblastic leukaemia patient: a case report and review of the literature.

We present a case of hepatic mucormycosis in a 9-year-old boy with acute lymphoblastic leukaemia. Despite long-term use of combined liposomal amphotericin B and posaconazole therapy, the lesion persisted and could only be treated by surgical excision. After surgery, antifungal treatment was continued with posaconazole. On follow-up, the patient had two episodes of ascending cholangitis which were responsive to intravenous antibiotics. He is doing well at the moment in remission for 2.5 years. Mucormycosis was long regarded as a fatal infection with poor prognosis. With early medical and surgical management, survival rates increase. Isolated hepatic mucormycosis is rare and only seven cases were reported in the literature up to now. We wanted to emphasise the role of early surgery in patients with hepatic mucormycosis in view of the literature.

Voriconazole induced bradycardia.

Voriconazole is a triazole antifungal drug that is used to treat invasive fungal infections, especially aspergillus. Here, we report two children who had severe bradycardia associated with voriconazole at a dose of 12 mg/kg per day. Bradycardia resolved in 24 hours in both after decreasing the dose to 10 mg/kg per day. Heart rates were in normal limits on follow-up. Bradycardia may be a side effect of voriconazole treatment in children under immunosuppressive treatment. Heart rate should be monitored in patients receiving voriconazole and other triazole treatments.

Prognostic significance of NOTCH1 and FBXW7 mutations in pediatric T-ALL.

The NOTCH signaling pathway plays important role in the development of multicellular organisms, as it regulates cell proliferation, survival, and differentiation. In adults, it is essential for the T- or B-lymphocyte lineage commitment. NOTCH1 and FBXW7 mutations both lead the activation of the NOTCH1 pathway and are found in the majority of T-ALL patients. In this study, the mutation analysis of NOTCH1 and FBXW7 genes was performed in 87 pediatric T-ALLs who were treated on the ALL-BFM protocols. In 19 patients (22%), activating NOTCH1 mutations were observed either in the heterodimerization domain or in the PEST domain and 7 cases (10%) demonstrated FBXW7 mutations (2 cases had both NOTCH1 and FBXW7 mutations). We also analyzed the relationship of the mutation data between the clinical and biological data of the patients. NOTCH1 and FBXW7, NOTCH1 alone were found correlated with lower initial leucocyte counts which was independent from the sex and T- cell immunophenotype. However, NOTCH1 and FBXW7 mutations were not predictive of outcome in the overall cohort of pediatric T-ALLs.