Evaluation of late effects during a 21-year follow-up of pediatric Hodgkin lymphoma survivors: Experience of a pediatric cancer center in Turkey, as a developing country model.

BACKGROUND: Long-term survivors of Hodgkin lymphoma (HL) are at risk of developing a range of late effects, with a second malignant neoplasm and cardiovascular diseases being the leading causes of death in these patients. The present study aims to evaluate the late side effects in children with HL. MATERIALS AND METHODS: Out of 53 HL patients, we assessed the long-term effects of childhood HL survivors (HLSs; n = 50) diagnosed between 1998 and 2019. Patient data related to chronic health conditions, and sociodemographic characteristics were compared with their siblings ( n = 56). RESULTS: The cumulative overall survival (OS) at 1, 5, and 10 years from diagnosis was 98.1 ± 1.9%, 93.3 ± 3.8%, and 93.3 ± 3.8%, respectively. Groups of HLSs and their siblings were matched according to age and gender. Compared with siblings, survivors had will be changed as 'a higher frequency of nephrotoxicity ( P = 0.02)', cardiotoxicity ( P = 0.12), thyroid dysfunction ( P = 0.001), health care service usage ( P < 0.01), limitation of physical function ( P = 0.01), and pulmonary disease ( P = 0.01). The control group of siblings had a higher incidence of marital status ( P < 0.01), parenthood ( P = 0.01), and smoking habit ( P = 0.03). Thyroid dysfunction was associated with neck radiotherapy ( P < 0.01). No secondary neoplasm was detected. In relapsed, refractory setting ( n = 10), autologous transplantation ( n = 9) is performed after a complete remission. Brentuximab vedotin with or without bendamustine and rituximab is also used in selected patients. CONCLUSIONS: Increased number of chronic health conditions and social problems point to the significance of long-term follow-up of HLSs. We are currently preparing a survivorship guideline appropriate for Turkey's conditions. IMPLICATIONS FOR CANCER SURVIVORS: Renal, heart, pulmonary impairment, thyroid dysfunction, limitation in physical functioning, and deterioration in social status (marriage, having children, education).

Assessment of metabolic syndrome parameters in pediatric acute lymphoblastic leukemia survivors.

Objective: This study aims to demonstrate the prevalence of metabolic syndrome parameters and to investigate their relationship with body mass index in pediatric acute lymphoblastic leukemia survivors. Methods: The cross-sectional study was conducted between January and October 2019 at the Department of Pediatric Hematology and comprised acute lymphoblastic leukemia survivors who had been treated between 1995 and 2016 and had been off treatment for at least 2 years. The control group included 40 healthy participants who were matched for age and gender. The two groups were compared in terms of various parameters (BMI [body mass index], waist circumference, fasting plasma glucose, HOMA-IR [Homeostatic Model Assessment-Insulin Resistance], etc.). Data were analyzed using Statistical Package for the Social Sciences (SPSS) 21. Results: Of the 96 participants, 56 (58.3%) were survivors and 40 (41.6%) were controls. Among the survivors, there were 36 (64.3%) men, whereas the control group had 23 (57.5%) men. The mean age of the survivors was 16.67 ± 3.41 years, whereas the mean age of the controls was 15.51 ± 4.2 years (P > 0.05). Multinomial logistic regression analysis showed that cranial radiation therapy and female gender were associated with overweight and obesity (P < 0.05). A significant positive correlation was found between BMI and fasting insulin, in survivors (P < 0.05). Conclusion: Disorders of the metabolic parameter were found to be more common among acute lymphoblastic leukemia survivors than among healthy controls.

Diagnosis and genetic analysis of polycythemia in children and a novel EPAS1 gene mutation.

BACKGROUND: Unlike in adults, there is no consensus on management and diagnosis of polycythemia in children. This study aims to evaluate the diagnosis and verify the algorithm in children with polycythemia. METHODS: Seventy-nine children with polycythemia were followed-up in our pediatric hematology-oncology clinic between December 15, 2019, and July 15, 2021. After eliminating secondary causes (hypoxia, pulmonary, cardiac diseases), we checked for genetic mutations, including congenital erythrocytosis gene panel (JAK, EPOR, EPAS1, EGNL1, HBB, HBA, BPGM, and VHL). We also compared parameters for secondary and idiopathic polycythemia groups. RESULTS: Of the 79 children, thirty-five had secondary polycythemia (hypoxia, pulmonary, cardiac diseases), and one was diagnosed with a novel likely pathogenic mutation c.2089C  >  G; p.Pro697Ala in exon 13 of EPAS1 gene. Others (n = 35) had persistent and idiopathic polycythemia. Here, we compared the idiopathic and secondary cases. We found that the ratio of family history of polycythemia (n = 4 (9.5%) vs 0%, respectively) was higher in the second group (p = 0.009). In addition, the mean age (14.7 ± 3.52 vs 13.4 ± 4.67 respectively) (p = 0.042) and the ratio of erythroid hyperplasia in bone marrow [n = 3 (8.6%) vs 0% respectively] (p = 0.003) was higher in the idiopathic polycythemia group, compared to secondary polycythemia patients. CONCLUSION: Finding the genetic defect in polycythemia is a significant issue. Due to being a rarity in children, the first line JAK mutation analysis should be performed in selected cases. This study is the first description of a Turkish patient with EPAS1 p.Pro697Ala mutation, thereby expanding our knowledge about the clinical features of the disease. However, new investigations are required to confirm its function.

Late outcomes in children and adolescents with non-Hodgkin lymphoma: A single-center experience.

Background: Non-Hodgkin lymphoma (NHL) includes pathologies of different clinical courses, treatments, outcomes. Our study aims to investigate the late effects of NHL survivors (NHLS). Materials and Methods: Among 59 NHL cases, 50 survivors completed their NHL treatment between 2003 and 2019. Out of 59 patients, the cumulative survival rates and event-free survival rates after 10 years since diagnosis were 82.9% ±5.2% and 84.1% ±5.2%, respectively. In addition, we compared the data related to chronic health and psychosocial conditions with their siblings (n = 61). Results: The age and gender ratios were similar in the NHLS (n = 50) and the control group (n = 61). The rate of nephrotoxicity (P = 0.02) and the frequency of admission to the hospital (P < 0.01) were significantly higher in the survivors than in the control group. Cardiotoxicity is detected in 3 (6%) of NHLS with cumulative anthracycline dose <300 mg/m2. The social status (being married [P < 0.01], having children [P = 0.003]) is impaired in NHLS. The alcohol and smoking habits, education status, and health conditions (endocrinologic, cardiac, neurological, and pulmonary) were similar in both groups. One patient had acute myeloid leukemia as a secondary malignancy. Twenty NHLS took rituximab, two of them took brentuximab vedotin plus chemotherapy. NHLS have impairment in health status, social life. Conclusion: Nephrotoxicity is a statistically more common late effect than the others in the survivors. We observe cardiotoxicity in low cumulative doses of anthracycline. A more significant number of patients is required to reveal late side effects on novel drugs.

Endoscopic endonasal approach to the cavernous sinus Epstein-Barr virus-positive B cell non-Hodgkin lymphoma in a child: case report.

Cavernous sinus (CS) lymphoma without paranasal sinuses involvement is extremely rare in pediatric population and remains a diagnostic challenge due to its similarity to other tumors located in this area. An 8-year-old boy presented with a 6-day history of gradually developing ptosis in the right eyelid. After admission, his symptoms progressed within 24 h to include right-sided ophthalmoplegia consisting of oculomotor and abducens nerve palsies. Endoscopic endonasal approach (EEA) was performed urgently to decompress the CS and to obtain a diagnosis. The postoperative course was uneventful, and there was no complication related to the surgical approach. No immunodeficiency was identified. The histopathological diagnosis was an Epstein-Barr virus (EBV)-positive high-grade mature B cell non-Hodgkin lymphoma. He was initiated chemotherapy according to COG ANHL01P1 protocol. Two months after surgery, the third and sixth nerve palsies had resolved completely. Currently, he is well and has no clinical or radiological recurrence. This is the first pediatric case with EBV-positive CS lymphoma that underwent EEA for the diagnosis and decompression. In the pediatric population, EEA enables minimally invasive access to the CS and can play an alternative role in the management of CS lesions, either through biopsy or debulking.

Proton MR spectroscopic features of the cisternal segment of the trigeminal nerve in patients with trigeminal neuralgia: A pilot study.

PURPOSE: To investigate normal quantitative proton magnetic resonance spectroscopy (MRS) features of the cisternal segment of the trigeminal nerve and evaluate possible metabolite concentration differences in the affected and unaffected nerves of trigeminal neuralgia patients. MATERIAL AND METHODS: A total of 33 consecutive patients who underwent a MR study of the internal auditory canal/posterior fossa and dedicated trigeminal nerve multivoxel MRS were enrolled. Measurements of N-acetyl aspartate (NAA), creatine (Cr), choline (Cho), myoinositol (mI), glutamate-glutamine (Glx) concentrations, and ratios of NAA-to-Cr, Cho-to-Cr, and Cho-to-NAA were automatically calculated by the dedicated software. Vascular conflicts were also recorded. RESULTS: The mean Cr concentration was significantly higher on the affected sides in all parts of the nerve (p < 0.05), while the mean NAA concentration was significantly higher in only the distal portion (p = 0.04). Mean mI concentration was significantly higher in the middle and distal parts (p < 0.05). NAA-to-Cr ratio was significantly higher in the proximal and middle parts (p < 0.05), while Cho-to-Cr ratio was significantly higher only in the middle portion (p = 0.028). Finally, the Cho-to-NAA ratio was significantly higher only in the distal portion (p = 0.04). Vascular conflicts were observed in 24 patients (72.7%), and in 20 of them (60.6%) the conflict was on the same side as the neuralgia symptoms. CONCLUSION: Although the detected statistical relationships were variable in the spectroscopic measurements, metabolite concentrations and ratios were successfully exhibited in all patients. Features of a normal trigeminal nerve were able to determine by MRS. All calculated metabolite concentrations were higher in the affected nerves; however, only some of them were statistically significant. No statistically significant relationships were found between the MRS measurements and nerves with and without vascular compression.

Two Subsequent Metachroneus Solid Tumors: Oncocytic Variant Adrenocortical Carcinoma and Rhabdomyosarcoma of Childhood: Case Report and Literature Review

Most cases of malignancies appear to be sporadic, but some syndromes are associated with malignancies with germline variants. Herein, a child with an unusual association of oncocytic variant adrenocortical carcinoma (ACC) and rhabdomyosarcoma (RMS) was presented. An 18-month-old-boy was admitted with virilization of the genital area, penis enlargement and erection, which had begun six months earlier. Serum total testosterone (457 ng/dL; NR <10), androstenedione (3.35 ng/mL; NR <0.5) and dehydroepiandrosterone-SO4 (206 mcg/dL; NR<35) were above the normal ranges. Right adrenal mass was detected. After adrenalectomy, histopathological examination revealed an oncocytic variant ACC. Three-month after surgery, he then presented with 6x8 cm sized swelling of the left leg. Histopathological examination revealed embryonal RMS. Testing for tumor protein (TP53) variant by DNA sequence analysis was positive; however; fluorescence in situ hybridization analysis was negative. After chemotherapy and local radiotherapy, the patient is in good condition without tumor recurrence. Only about one-third of these tumors have a variant of TP53. This status also applies to other genetic variants related to cancer. However, a significant association of malignancies strongly suggests a problem in tumor suppressor genes or new variants. Another as yet unidentified suppressor gene may also be present and effective in this locus. The occurrence of ACC as a part of a syndrome and positive family history of malignancies in patients are clinically important. These patients and their families should be scanned for genetic abnormalities. The patient with ACC should be followed-up carefully for other tumors to detect malignancy early.

Muramyl Tripeptide Plus Chemotherapy Reduces Metastasis in Non-Metastatic Osteosarcoma: A Single-Center Experience.

BACKGROUND: The immunomodulator mifamurtide plus a chemotherapy regimen has been shown to significantly improve the outcome in non-metastatic osteosarcoma patients. We report the results of the addition of mifamurtide to chemotherapy in newly diagnosed patients with osteosarcoma. METHODS: A total of 36 children with osteosarcoma without detectable metastasis were treated between November 2010 and April 2018 at the Ankara University Department of Pediatric Oncology. Mifamurtide was added to the chemotherapy regimen in 17 patients while the remaining 19 did not receive mifamurtide. The probabilities of metastasis and overall survival were compared between the groups. RESULTS: The 43-month survival rate was 87.5% and 89.9% in the patients who received and did not receive mifamurtide, respectively (p=0.65). Common side effects of mifamurtide were chills and fever. The addition of mifamurtide in the high-risk group with ≤95% necrosis tended to decrease the probability of distant metastasis (36.4% vs. 58.3%) (p=0.39). The time to metastasis in the group with positive surgical margins (4 months in one patient in the non-mifamurtide group, 7 and 20 months in the mifamurtide group) was also longer in the mifamurtide group. During the 43-month follow up period, median time to metastasis was longer in the mifamurtide group (20 vs. 5 months). In addition, mifamurtide plus chemotherapy decreased the risk of metastasis in the cases with primary site relapse. CONCLUSIONS: The addition of mifamurtide to chemotherapy might improve event-free survival by decreasing the probability of distant metastasis in bad histologic responders, and also by increasing the time to distant metastasis in the surgical margin positive group. Additional clinical studies are necessary to determine the long-term effects of mifamurtide on metastatic disease.
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Diferenciación entre linfadenopatía cervical benigna y maligna mediante ecografía en niños / Differentiation of benign from malignant cervical lymphadenopathy by ultrasonography in children

Introducción. Las causas más frecuentes de la linfadenopatía cervical son las afecciones inflamatorias y reactivas; solo unos pocos casos representan una patología seria. El objetivo fue evaluar la relación entre los hallazgos ecográficos y el diagnóstico histopatológico. Población y métodos. Este estudio retrospectivo abarcó la linfadenopatía cervical en los menores de 20 años seguidos en nuestro centro, entre enero de 2007 y diciembre de 2016. Según los informes anatomopatológicos, se dividió a los pacientes en dos grupos: benigno y maligno. Se compararon los resultados anatomopatológicos y los hallazgos ecográficos. Resultados. Después del análisis de los resultados histopatológicos y los hallazgos ecográficos, se incluyó a 107 pacientes con linfadenopatía cervical persistente (44 casos malignos; 63, benignos). La media de edad de los grupos maligno y benigno fue de 14 ± 6,1 años y de 11,9 ± 4,8 años, respectivamente. La presencia de vascularidad hiliar fue estadísticamente significativa (p < 0,0001) en la linfadenopatía benigna, mientras que el flujo periférico y la vascularidad mixta lo fueron (p < 0,05) en la linfadenopatía maligna. No se observó una diferencia significativa en el diámetro máximo (27,3 ± 11,1 mm y 29,8 ± 12,3 mm, respectivamente), pero sí en el diámetro mínimo entre los grupos benigno y maligno (13,7 ± 7,3 mm y 18,7 ± 8,8 mm, respectivamente). Conclusiones. Este estudio sugiere que existe una relación entre los hallazgos ecográficos y de la biopsia para la diferenciación entre la linfadenopatía benigna y maligna, en especial, en el patrón vascular intraganglionar y el hilio ganglionar.

Introduction. The most common causes of cervical lymphadenopathy (LAP) are inflammatory and reactive conditions; only a small proportion have serious pathology, such as malignancy. The objective of this study was to evaluate the relationship between USG findings and histopathological diagnosis of the cervical LAP. Population and Methods. This retrospective study comprised the cases of cervical LAP in patients aged under 20 years old followed in our center between January 2007 to December 2016. Based on pathology reports, we divided the patients into two groups: benign and malignant. Pathology results and USG findings were compared. Results. After the analyze of the histopathological results and USG findings, 107 patients with persistent cervical LAP (44 malignant; 63 benign) were included in the study. Mean age of malignant and benign group were 14 ± 6.1; 11.9 ± 4.8 years, respectively. Hilar vascularity for benign LAP was highly statistically significant (P < 0.0001) and peripheral flow and mixed vascularity for malignant LAP were also statistically significant (p < 0.05). There was not a significant difference in the maximum diameter (27.3 ± 11.1 mm and 29.8 ± 12.3 mm, respectively), however, there was a significant difference in the minimum diameter between benign and malignant groups (13.7 ± 7.3 mm and 18.7 ± 8.8 mm, respectively).Conclusions. The present study suggests that there is a relationship between US and biopsy findings for the differentiation of benign from malignant LAP, especially in terms of nodal hilus and intranodal vascular pattern.

Differentiation of benign from malignant cervical lymphadenopathy by ultrasonography in children. / Diferenciación entre linfadenopatía cervical benigna y maligna mediante ecografía en niños.

INTRODUCTION: The most common causes of cervical lymphadenopathy (LAP) are inflammatory and reactive conditions; only a small proportion have serious pathology, such as malignancy. The objective of this study was to evaluate the relationship between USG findings and histopathological diagnosis of the cervical LAP. POPULATION AND METHODS: This retrospective study comprised the cases of cervical LAP in patients aged under 20 years old followed in our center between January 2007 to December 2016. Based on pathology reports, we divided the patients into two groups: benign and malignant. Pathology results and USG findings were compared. RESULTS: After the analyze of the histopathological results and USG findings, 107 patients with persistent cervical LAP (44 malignant; 63 benign) were included in the study. Mean age of malignant and benign group were 14 ± 6.1; 11.9 ± 4.8 years, respectively. Hilar vascularity for benign LAP was highly statistically significant (P < 0.0001) and peripheral flow and mixed vascularity for malignant LAP were also statistically significant (p < 0.05). There was not a significant difference in the maximum diameter (27.3 ± 11.1 mm and 29.8 ± 12.3 mm, respectively), however, there was a significant difference in the minimum diameter between benign and malignant groups (13.7 ± 7.3 mm and 18.7 ± 8.8 mm, respectively). CONCLUSIONS: The present study suggests that there is a relationship between US and biopsy findings for the differentiation of benign from malignant LAP, especially in terms of nodal hilus and intranodal vascular pattern.

Introducción: Las causas más frecuentes de la linfadenopatía cervical son las afecciones inflamatorias y reactivas; solo unos pocos casos representan una patología seria.El objetivo fue evaluar la relación entre los hallazgos ecográficos y el diagnóstico histopatológico. Población y métodos: Este estudio retrospectivo abarcó la linfadenopatía cervical en los menores de 20 años seguidos en nuestro centro, entre enero de 2007 y diciembre de 2016. Según los informes anatomopatológicos, se dividió a los pacientes en dos grupos: benigno y maligno. Se compararon los resultados anatomopatológicos y los hallazgos ecográficos. Resultados: Después del análisis de los resultados histopatológicos y los hallazgos ecográficos, se incluyó a 107 pacientes con linfadenopatía cervical persistente (44 casos malignos; 63, benignos). La media de edad de los grupos maligno y benigno fue de 14 ± 6,1 años y de 11,9 ± 4,8 años, respectivamente. La presencia de vascularidad hiliar fue estadísticamente significativa (p < 0,0001) en la linfadenopatía benigna, mientras que el flujo periférico y la vascularidad mixta lo fueron (p < 0,05) en la linfadenopatía maligna. No se observó una diferencia significativa en el diámetro máximo (27,3 ± 11,1 mm y 29,8 ± 12,3 mm, respectivamente), pero sí en el diámetro mínimo entre los grupos benigno y maligno (13,7 ± 7,3 mm y 18,7 ± 8,8 mm, respectivamente). Conclusiones: Este estudio sugiere que existe una relación entre los hallazgos ecográficos y de la biopsia para la diferenciación entre la linfadenopatía benigna y maligna, en especial, en el patrón vascular intraganglionar y el hilio ganglionar.

Posterior Reversible Encephalopathy Syndrome in a Normotensive Child after Allogeneic Hematopoietic Stem Cell Transplantation.

Posterior reversible encephalopathy syndrome (PRES) is an uncommon clinicoradiological syndrome that is characterized by acute neurological symptoms such as headache, convulsion, visual disturbance, and altered consciousness. The characteristic magnetic resonance (MR) finding is vasogenic edema, predominantly in the subcortical areas of the posterior parietal and occipital lobes on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences. Herein, we described a rare case of PRES induced by cyclosporine (CsA) after an allogeneic hematopoietic stem cell transplantation (HSCT) from a sibling donor.

Bilateral Optic Neuritis Secondary to Nivolumab Therapy: A Case Report.

Pediatric glioblastoma multiforme is an uncommon and highly mortal brain cancer. New therapeutic treatments are being intensively investigated by researchers in order to extend the survival of patients. The immune checkpoint inhibitor nivolumab in the treatment of pediatric glioblastoma multiforme is currently under review; it is a human immunoglobulin G4 monoclonal antibody that works against the programmed cell death protein 1 receptor, designed to enhance an immunologic reaction against cancer cells. Herein, we describe the first report of a bilateral optic neuritis induced by nivolumab in a grade 4 glioblastoma multiforme patient.

Time dependent impact of perinatal hypoxia on growth hormone, insulin-like growth factor 1 and insulin-like growth factor binding protein-3.

Hypoxic-ischemia (HI) is a widely used animal model to mimic the preterm or perinatal sublethal hypoxia, including hypoxic-ischemic encephalopathy. It causes diffuse neurodegeneration in the brain and results in mental retardation, hyperactivity, cerebral palsy, epilepsy and neuroendocrine disturbances. Herein, we examined acute and subacute correlations between neuronal degeneration and serum growth factor changes, including growth hormone (GH), insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) after hypoxic-ischemia (HI) in neonatal rats. In the acute phase of hypoxia, brain volume was increased significantly as compared with control animals, which was associated with reduced GH and IGF-1 secretions. Reduced neuronal survival and increased DNA fragmentation were also noticed in these animals. However, in the subacute phase of hypoxia, neuronal survival and brain volume were significantly decreased, accompanied by increased apoptotic cell death in the hippocampus and cortex. Serum GH, IGF-1, and IGFBP-3 levels were significantly reduced in the subacute phase of HI. Significant retardation in the brain and body development were noted in the subacute phase of hypoxia. Here, we provide evidence that serum levels of growth-hormone and factors were decreased in the acute and subacute phase of hypoxia, which was associated with increased DNA fragmentation and decreased neuronal survival.

Low Vitamin D Levels: Are Associated with Both Iron Deficiency and Anemia in Children and Adolescents?

We have read, with great interest, the recent article by Lee. In this excellent study, the authors investigated the association between vitamin D deficiency and anemia in a nationally representative sample of Korean children and adolescents. They concluded that vitamin D deficiency is associated with increased risk of anemia, especially iron deficiency anemia, in healthy female children and adolescents. We appreciate and congratulate the authors for having addressed such an important issue. However, we have some concerns regarding this report, which we would like to share with you. As a result, further studies are needed for the association between vitamin D deficiency and anemia. Factors affecting Vitamin D status and anemia such as measurement method, nutrition, medications, and infections should be considered to conclude an association between vitamin D and anemia. Therefore, we think that considering these confounders would add value to this well-written article.