Evaluation of surgical strategies and long-term outcomes in pediatric hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC), the second most common pediatric malignant liver tumor after hepatoblastoma, represents 1% of all pediatric tumors. METHODS: A retrospective study was conducted on children with HCC treated at our center from March 2002 to October 2022, excluding those with inadequate follow-up or records. Demographic data, initial complaints, alpha-fetoprotein (AFP) values, underlying disease, size and histopathological features of the masses, chemotherapy, and long-term outcomes were analyzed. RESULTS: Fifteen patients (8 boys, 7 girls) with a mean age of 11.4 ± 4.1 years (0.8-16.4 years) were analyzed. The majority presented with abdominal pain, with a median AFP of 3.9 ng/mL. Hepatitis B cirrhosis in one patient (6.6%) and metabolic disease (tyrosinemia type 1) in two patients (13.3%) were the underlying diseases. Histopathological diagnoses were fibrolamellar HCC (n:8; 53.3%), HCC (n:6; 40%). Four of the 15 patients underwent liver transplantation, and 9 underwent surgical resection. Due to late diagnosis, two patients were considered inoperable (13.3%). The survival rate for the four patients who underwent liver transplantation was found to be 75%. CONCLUSION: Surgical treatment of various variants of HCC can be safely performed in experienced centers with a multidisciplinary approach, and outcomes are better than in adults.

Timing of Central Venous Line Insertion During Induction in Children With Acute Lymphoblastic Leukemia.

PURPOSE: Central venous lines (CVL) in children with acute lymphoblastic leukemia (ALL) provide comfortable administration of intensive chemotherapy and blood sampling. The optimal time for the insertion of CVL in patients with ALL during induction therapy is controversial. This study aimed to investigate the frequency of CVL-related complications in children with ALL concerning the time of CVL insertion. PATIENTS AND METHODS: We reviewed the records of 52 pediatric ALL patients with CVL. CVL placement before or on treatment day 15 was defined as "early insertion", and after treatment day 15 was defined as "late insertion". Demographics, preoperative blood counts, type of central line, time of CVL placement, CVL-related complications, and blood counts during complications were all noted. All the data were collected from those with the first catheter use. RESULTS: CVL was placed ≤15 days in 26 patients (50%) and after 15 days in 26 patients (50%). Regarding the infection rates, no statistical difference was found between early and late CVL-inserted groups ( P =n.s.). Five patients developed thrombosis, and risk was found to be similar between early and late CVL-inserted groups ( P =n.s.). Catheter-related mechanical complications were recorded in 7 patients (3 in early and 4 in late CVL-inserted group, ( P =n.s.). CONCLUSION: The present study showed no relation between the timing of CVL placement during induction therapy and the occurrence of infection and thrombosis. Our results suggest that CVL can be placed safely at the time of diagnosis or early induction treatment to provide a comfortable administration of chemotherapy and decrease painful blood samplings.

Dysembryoplastic neuroepithelial tumors of childhood: Ege University experience.

BACKGROUND: Dysembryoplastic neuroepithelial tumors (DNETs) are rare, low-grade tumors of the central nervous system (CNS) of childhood. It is an important cause of intractable epilepsy, and it is surgically curable. We aimed to review our institutional experience with DNET in children. METHODS: Medical records of children aged less than 18 years of age diagnosed with DNET between 2009 and 2020 at Ege University Hospital were reviewed. Clinical features of the patients including age, gender, initial symptoms, duration of symptoms, medical treatments, age at the time of surgery, tumor location, degree of surgical resection, and outcome of the patients were documented. RESULTS: We reviewed the records of 17 patients with DNETs. Twelve of them were male (70%), 5 of them female (30%). The median age was 11 years (19 months-17 years). The major symptom was a seizure in all of the patients. Thirteen patients presented with complex partial seizures, whereas 2 had a simple partial seizure, and 2 generalized tonic-clonic seizures. Seven patients had drug resistant epilepsy and had received at least two anti-epileptic drugs before surgery. The median duration of symptoms was 6.6 months (0-48 months). In surgery, total surgical resection was performed in 15 patients, and 2 patients underwent partial resection. From these 15 patients, seven patients underwent lesionectomy of the tumor while the other eight patients had extended lesionectomy. The mean follow-up time was 107 months (54-144 months), the seizure control was achieved in 14 patients (82.4%) after surgery, but 3 patients experienced tumor recurrence in the follow-up. CONCLUSION: In DNETs, the complete total resection of the lesion is generally associated with seizure-free outcomes. In the patients with partial resection and lesionectomy, MRI follow-up is recommended for recurrence.

Ifosfamide-related encephalopathy with severe clinical presentations in children with cancer.

INTRODUCTION: Ifosfamide is an alkylating agent, mostly used against variety of solid tumors in pediatric oncology practice. Although hemorrhagic cystitis is known as a common adverse effect, encephalopathy is the another one that should be kept in mind. It may occur in 2-5% of the children, and manifested by different clinical spectrums such as somnolence, lethargy, irritability, excitement, disorientation, confusion, weakness, hallucinations, seizures, movement disorders, and coma. CASE REPORT: Herein, we present two patients who developed generalized seizure activity and one who developed coma during ifosfamide infusion.Management and outcome: In the first two patients, ifosfamide infusion was discontinued and intravenous diazepam was given. Their seizure stopped in a few minutes and neurological examination was back to normal, and no focal deficits were observed. In the third patient, ifosfamide infusion was discontinued, methylene blue and thiamine were given. After the tenth dose of methylene blue, she became neurologically normal, without any mental and motor deficit. Nevertheless, later she developed febrile neutropenia, septic shock and she died. DISCUSSION: These cases highlight that pediatric oncologists and hematologists should be aware of possibility of severe neurological toxicity after administration of ifosfamide in adolescent patients. Apart from seizure, clinicians should also be prepared to notice drowsiness during ifosfamide infusions in children. Most of the time cessation of ifosfamide and hydration is enough. However, in severe toxicities there is a risk of irreversible neurological damage, and for these patients methylene blue (MB) and thiamine treatment should be kept in mind.

Successful treatment of congenital systemic juvenile xanthogranulomatosis with pulmonary involvement.

Juvenile xanthogranuloma (JXG) is a common form of non-Langerhans cell histiocytosis, which usually presents with spontaneously regressing skin lesions. Systemic involvement is rare and mostly seen in patients with multiple skin nodules. It can spontaneously regress, but sometimes systemic involvement can cause life-threatening symptoms and can be fatal. Herein, we report a case of congenital systemic JXG with multiple skin nodules, soft tissue and pulmonary involvement. She was successfully treated with chemotherapy according to Langerhans cell histiocytosis treatment protocol IV of the Histiocyte Society (LCH-IV).

Combined immunodeficiency with marginal zone lymphoma due to a novel homozygous mutation in IL-21R gene and successful treatment with hematopoietic stem cell transplantation.

Mutations in the interleukin-21 receptor (IL-21R) gene are recently defined as primary immunodeficiency diseases. IL-21R defects result in combined immunodeficiency by affecting the functions of innate and adaptive immune system components.A six-year-old girl was admitted to our hospital with complaints of chronic diarrhea that started after the newborn period and generalized rash over the last three months. She had severe respiratory distress due to Cytomegalovirus (CMV) pneumonia requiring mechanical ventilation and was diagnosed as combined immunodeficiency at another hospital at the age of four. Her physical examination on admission revealed erythematous rash on cheeks, extremities, gluteal region, and lymph node enlargements in cervical, axillary, and inguinal regions. CMV DNA and stool Cryptosporidium parvum were positive. Marginal zone lymphoma -negative for Epstein-Bar virus- was reported in the lymph node biopsy. Targeted next-generation sequencing Ion AmpliSeq™ primary immunodeficiency panel revealed a novel homozygous IL21R c.132delC (p.Ser45fs) mutation.This case is presented to emphasize that IL21R defects should be considered in the differential diagnosis of the patients with recurrent respiratory infections, chronic diarrhea, C. parvum infection, chronic liver disease, sclerosing cholangitis, and malignancy where early hematopoietic stem cell transplantation (HSCT) is life-saving. A total of eight cases with IL21R gene defects have been reported so far. The significance of this case is that it is the first case of malignancy among the published IL-21R deficient patients successfully treated with HSCT.

Intracellular localization of beta-catenin expression plays a possible prognostic role on the outcome of hepatoblastoma patients.

PURPOSE: Wnt/Beta-catenin pathway plays an essential role in liver development and regeneration. Abnormal activation in this pathway leads to development of hepatoblastoma (HB). Although its importance has invoked attention, its prognostic role is debatable. We aimed to evaluate the significance of intracellular localization of beta-catenin (BC) expression in the outcome of hepatoblastoma patients. METHODS: Medical records of HB patients between 2004 and 2018 were reviewed. Patients were grouped according to intracellular localization of BC expression by immunohistochemistry as being cytoplasmic or nuclear. Demographics, radiological images, PRETEXT classifications, vascular involvement, risk groups, chemotherapy responses, and survival rates were analyzed and compared between groups. RESULTS: There were 41 patients. Thirteen patients were excluded for unavailability of records in four, negative/unclear BC expressions in seven. Cytoplasmic expression of BC was observed in 17 patients whereas 13 patients displayed nuclear expression. Demographics were similar in both groups. Cytoplasmic BC expression was associated with poor chemotherapy response (p = 0.001) and increased vascular involvement (p = 0.0162) requiring more extensive surgeries (p = 0.039). CONCLUSION: Although the numbers are limited in our series, the intracellular localization of BC expression has been found to be a promising determining factor for hepatoblastoma prognosis. With larger patient series, more reliable results can be achieved.

Refugee children with beta-thalassemia in Turkey: Overview of demographic, socioeconomic, and medical characteristics.

AIM: Since the beginning of the Syrian civil war, more than 3.5 million Syrians have been under temporary protection status in Turkey. Because beta-thalassemia (BT) is a prevalent disorder in the Mediterranean countries, we decided to estimate the prevalence of and make an overview of the demographic, socioeconomic, medical characteristics, and healthcare problems of refugee children with BT. PATIENTS: Eighteen Turkish Pediatric Hematology Oncology Centers (PHOC) with 318 refugee children from 235 families participated in the study. The mean age of the patients was 8.1 ± 4.8 years (0.5-21 years). The mean time after immigration to Turkey was 2.5 ± 1.5 years (range, 0.1-7 years). Seventy-two (22.6%) of them were born and diagnosed with BT in Turkey. On physical examination, 82 patients (26%) were underweight and 121 patients (38%) were stunted. The appearance of a thalassemic face was reported for 207 patients (65.1%). Hepatomegaly and splenomegaly were reported in 217 (68.2%) and 168 (52.8%) patients, respectively. The median ferritin level was 2508 ng/mL (range, 17-21 000 ng/mL) at the first admission, and 2841 ng/mL (range, 26-12 981 ng/mL) at the last visit after two years of follow-up in a PHOC (P > 0.05). The most frequently encountered mutation was IVSI-110 (G>A) (31%). Before immigration, only 177 patients (55.6%) reported the use of chelators; after immigration it increased to 268 (84.3%). CONCLUSION: Difficulties in communication, finding a competent translator capable in medical terminology, nonregular use of medications, and insensitivity to prenatal diagnosis were preliminary problems. The current extent of migration poses emerging socioeconomic and humanitarian challenges for refugee patients with BT.

Neurotoxicity Associated With Dimethyl Sulfoxide Used in Allogeneic Stem Cell Transplantation.

Dimethyl sulfoxide (DMSO) is a cryoprotective agent used in storage of frozen stem cells in stem cell transplantation. Central nervous system side effects of DMSO such as epileptic seizures, stroke, transient global amnesia, and temporary leucoencephalopathy are rarely seen. Here, we report a pediatric patient who developed seizures after DMSO-cryopreserved stem cell infusion and whose magnetic resonance imaging of the brain demonstrated parietal and occipital focal cortical T2-signal intensity increase. DMSO toxicity should be kept in mind in patients who received cryopreserved stem cell infusion and magnetic resonance imaging may be helpful in differential diagnosis of central nervous system involvement.

CANDLE syndrome: a recently described autoinflammatory syndrome.

CANDLE syndrome (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature) is a recently described autoinflammatory syndrome characterized by early onset, recurrent fever, skin lesions, and multisystemic inflammatory manifestations. Most of the patients have been shown to have mutation in PSMB8 gene. Herein, we report a 2-year-old patient with young onset recurrent fever, atypical facies, widespread skin lesions, generalized lymphadenopathy, hepatosplenomegaly, joint contractures, hypertrglyceridemia, lipodystrophy, and autoimmune hemolytic anemia. Clinical features together with the skin biopsy findings were consistent with the CANDLE syndrome. The pathogenesis and treatment of this syndrome have not been fully understood. Increased awareness of this recently described syndrome may lead to recognition of new cases and better understanding of its pathogenesis which in turn may help for development of an effective treatment.

What has changed in the last 25 years in osteosarcoma treatment? A single center experience.

BACKGROUND: Osteosarcoma is the most common type of primary malignant bone tumor in the extremities. The main purpose of this study was to determine clinical features, prognostic factors, and treatment results of patients with osteosarcoma at our center. METHODS: We retrospectively analyzed the medical records of children with osteosarcoma between the years 1994-2020. RESULTS: 79 patients were identified (54.4% male, 45.6% female). The most common primary site was the femur (62%). Twenty-six of them (32.9%) had lung metastasis at diagnosis. The patients were treated between 1995- 2013 according to the Mayo Pilot II Study protocol, while the others were treated with the EURAMOS protocol between the years 2013-2020. Sixty-nine patients underwent limb salvage surgery as a local treatment, whereas seven underwent amputation. The median follow-up time was 53 months (2.5-265 months). The event-free survival (EFS) and overall survival (OS) rates at 5 years were 52.1% and 61.5%. The 5-year EFS and OS rates were 69.4% and 80% in females; 37.1% and 45.5% in males (p=0.008/p=0.001). The 5-year EFS and OS rates of the patients without metastasis were 63.2% and 66.3%; with metastasis 28.8% and 51.8% (p=0.002/p=0.05). For good-responders, the 5-year EFS and OS rates were 80.2% and 89.1%; while for poor-responders, 35% and 46.7% (p=0.001). Mifamurtide was used in addition to chemotherapy as of the year 2016 (n=16). The 5-year EFS and OS rates were 78.8% and 91.7%, respectively for the mifamurtide group; 55.1% and 45.9%, respectively for the non-mifamurtide group (p=0.015, p=0.027). CONCLUSIONS: Metastasis at diagnosis and poor response to preoperative chemotherapy were the most important predictors of survival. Females had a better outcome than males. In our study group, the mifamurtide group`s survival rates were significantly higher. Further large studies are needed to validate the efficacy of mifamurtide.

Extranodal Ocular Adnexal Marginal Zone Lymphoma in a Ten-Year-Old Child

A 10-year-old girl was brought to the clinic with the complaint of a salmon-colored conjunctival lesion for 1 month. With the aid of histopathological evaluation and other tests, extranodal ocular adnexal marginal zone lymphoma was diagnosed. The patient was graded as T1bN0M0 according to AJCC and Stage 1 according to Ann Arbor classification. She was treated with external radiotherapy at 1.8 Gy/day for 17 days for a total dose of 36 Gy. She is in remission for 26 months and still being followed up.

FLAG Regimen with or without Idarubicin in Children with Relapsed/Refractory Acute Leukemia: Experience from a Turkish Pediatric Hematology Center.

INTRODUCTION: The optimal therapy to achieve higher rates of survival in pediatric relapsed/refractory acute leukemia (AL) is still unknown. In developing countries, it is difficult to obtain some of the recent drugs for optimal therapy and mostly well-known drugs proven to be effective are used. We assessed the efficacy of the combination of fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor (FLAG regimen) with or without idarubicin (IDA) in children with relapsed/refractory acute lymphoblastic leukemia and acute myeloid leukemia. METHODS: Between September 2007 and May 2015, 18 children with refractory/relapsed AL attending our center, treated with a FLAG regimen with or without IDA, were included. The primary end point was the remission status of the bone marrow sampled after the first/second course of chemotherapy. The second end point was the duration of survival after hematopoietic stem cell transplantation (HSCT). RESULTS: Complete remission (CR) was achieved in 7 patients (38.8%) after the first cycle, and at the end of the second cycle the total number of patients in CR was 8 (42.1%). All patients in CR underwent HSCT. The CR rate in patients who had IDA in combination therapy was 28.6%, and it was 50% in patients treated without IDA (p=0.36). Mean survival duration in transplanted patients was 24.7±20.8 months (minimum-maximum: 2-70, median: 25 months), and it was 2.7±1.64 months (minimum-maximum: 0-5, median: 3 months) in nontransplanted patients. Five of them (27.7%) were still alive at the end of the study and in CR. The median time of follow-up for these patients was 33 months (minimum-maximum: 25-70 months). CONCLUSION: FLAG regimens with or without IDA produced a CR of >24 months in 27.7% of children with relapsed/refractory AL and can be recommended as therapeutic options prior to HSCT in developing countries.

Child with RET proto-oncogene codon 634 mutation.

Ince D, Demirag B, Ataseven E, Oymak Y, Tuhan H, Karakus OZ, Hazan F, Abaci A, Özer E, Mutafoglu K, Olgun N. Child with RET proto-oncogene codon 634 mutation. Turk J Pediatr 2017; 59: 590-593. Herein we reported a 7-year-old child with RET proto-oncogene c634 mutation. Her mother had been diagnosed with medullary thyroid carcinoma (MTC), and treated six years ago. Heterozygous mutation of the RET proto-oncogene at c634 had been detected in her mother. Genetic analysis showed the presence of the same mutation in our patient. Thyroid functions were normal. Serum calcitonin level was found mildly elevated. Parathormone (PTH) and carcinoembrionic antigen (CEA) levels were normal. Prophylactic thyroidectomy and sampling of cervical lymph nodes were performed. Histopathologic examination revealed hyperplasia in thyroid C cells, and reactive lymphadenopathy. The risk of MTC has been reported 100% through the life of patients with RET proto-oncogene mutation. It has been reported that particularly patients with c634 mutation have more risk of occurence of metastatic and progressive/recurrent MTC. Prophylactic `thyroidectomy, cervical lymph node dissection` before 5-years-of-age should be considered for these patients.