Clinical Profile and Outcomes of Primary Immunodeficiency and Malignancy in Childhood at a Tertiary Oncology Center in Developing Country.

Primary immune deficiencies are a group of heterogenous genetic disorders characterized by frequent infections, autoimmunity and malignancy. In this study, we aimed to evaluate clinical characteristics, outcomes of children with malignancy developed on background of primary immunodeficiency and compare survival rates of patients between malignant lymphoma with primary immunodeficiency and without immunodeficiency from tertiary oncology center in a developing country. A total 23 patients with primary immunodeficiency and malignancy were evaluated retrospectively. A total of 26 malignancies (first or second) in 23 patients were determined. The median age at the time of the first malignancy was 8 years (ranges 2-18 years) with increased male ratio (M/F:14/9). Non-Hodgkin lymphoma (n = 17; 65%) was the most common malignancy, followed by Hodgkin lymphoma (n = 5), anaplastic ependymoma (n = 1), spinal glioblastoma multiforme (n = 1), retinoblastoma (n = 1) and intracranial hemangiopericytoma (n = 1). The median follow-up time of patients was 25 months (ranges between 1 and 189 months). The 5-year overall survival rate of patients with malignant lymphoma associated with primary immunodeficiency (41%) were lower than immunocompetent patients with malignant lymphoma (80%) (p = 0.000). The 5-year overall survival of patients was diagnosed between 2021 and 2013 years (62%) was higher than previous years (22%) (p = 0.03). In conclusion, non-Hodgkin lymphomas were the most common histopathologic type in patients with malignancy associated with primary immunodeficiency in the present study. The survival of patients with malignant lymphoma associated with primary immunodeficiency has improved in recent years, yet it is still lower than immunocompetent patients with lymphoma and new targeted drugs are required for better survival rates.

Paratesticular Rhabdomyosarcoma Associated with Tuberculosis.

We report a 16-year-old male patient diagnosed with paratesticular rhabdomyosarcoma and mediastinal tuberculous lymphadenitis. The differential diagnosis between high or early stage of rhabdomyosarcoma and tuberculosis (TB) was critical in this patient without a history of TB. Unexpected lymphadenopathies detected during the staging of patients with malignancy should be carefully evaluated, and TB should be taken into consideration in the differential diagnosis especially in underdeveloped and developing countries. Unnecessary additional treatments increase the rate of mortality and morbidity because of upstaging of cancer. Further, TB reactivation can be seen during chemotherapy because of immunosuppression.

Irinotecan and temozolamide treatment for relapsed Ewing sarcoma: a single-center experience and review of the literature.

Long-term survival in relapsed Ewing sarcoma (ES) is less than 20%. Encouraging results have been reported with irinotecan and temozolomide combinations (IRN/TMZ). We aimed to share our experience and compare it with previously published studies using this combination to treat relapsed ES. We retrospectively evaluated 20 patients treated with a combination of IRN (20 mg/m(2)/d × 5 for 2 weeks) and temozolomide (100 mg/m(2)/d × 5). Patients received a total of 97 courses. An objective response was achieved in 11 patients (55%) and maintained for a median of 12 months. Five patients were alive for a median of 12 months. Median time to progression was 5.5 (2-57) months. After the IRN/TMZ treatment, 1-year overall and event-free survival rates were 54.2% and 44.4%, respectively. Grade 3-4 toxicities included diarrhea (9.2%), neutropenia (11.3%), and thrombocytopenia (6.2%). Three retrospective trials were found in our literature review, which used an IRN/TMZ combination to treat ES. There was one other study which retrospectively evaluated the efficacy of vincristine, IRN, and TMZ combination in relapsed ES. A total of 81 patients were treated with IRN/TMZ in four studies including ours. The objective response rate was 55.1%, and median time to progression ranged from 5.5 to 8.3 months. Twenty-six (7.5%) of a total of 346 courses were associated with grade 3-4 diarrhea. Grade 3-4 neutropenia and thrombocytopenia were reported in 9.2% and 7.2% of the courses, respectively. Results showed that an IRN/TMZ combination is effective and tolerable in patients with relapsed ES.

Anthropometric and Biochemical Assessment of Nutritional Status in Pediatric Cancer Patients.

Children are at greater risk for malnutrition due to increased needs of nutrients to obtain appropriate growth, and they exhibit elevated substrate needs due to cancer and its treatment. This study aimed to report anthropometric and biochemical evaluation of nutritional status in children with cancer at initial presentation and during treatment. A prospective, controlled study was performed in the pediatric oncology department of a tertiary care center. Control group consisted of the siblings of patients. Weight, height, body mass index, triceps skinfold thickness, and serum levels of total protein, albumin, prealbumin, serum lipids, trace minerals, C-reactive protein (CRP), and vitamins were compared in patients and controls at initial presentation and at 6th month after the onset of treatment. According to weight for height, the frequency of malnutrition was 16% at initial presentation and 22% at 6th month. Triceps skinfold thickness was significantly thinner in patients than controls at both measurements. Patients had lower levels of prealbumin, albumin, iron, folate, zinc, and vitamin C and higher levels of ferritin, vitamin B12, and copper. Serum CRP levels were significantly higher in cancer patients at initial presentation and seemed to be correlated with copper levels. Compared with other patients, malnourished patients had significantly higher levels of vitamin B12 at 6th month. Results of the current study demonstrate that trace minerals, vitamins, and anthropometric measures may yield important clues for nutritional status and disease activity in pediatric oncology patients. However, validation and updating these potential markers warrant further trials on larger series.

Magnetic Resonance Imaging Findings in Childhood Period Nasopharynx Cancer.

BACKGROUND: Nasopharyngeal carcinoma is a rarely seen tumor in childhood. It is mostly detected late as the clinical features are similar to other childhood tumors which affect the nasopharynx and adenoidal hypertrophy. Therefore, the radiological features of childhood tumors of the nasopharynx must be well known. The aim of this study was to investigate the contribution of MR imaging features of childhood nasopharynx cancer. MATERIAL/METHODS: The study included 10 nasopharyngeal carcinoma patients under the age of 18 years who presented at hospital between February 2008 and March 2014 and who had tissue diagnosis and MRI of the nasopharynx region. The MRI scans were evaluated by two radiologists. Loco-regional spread, asymmetry, signal intensity of the tumors, and lymph nodes were evaluated. RESULTS: In all the patients there was a mass which narrowed the nasopharynx. In all cases, unilateral mastoid opacification was observed. In 9 cases (90%), parapharyngeal extension was found. In 8 cases (80%), the mass showed an extension into the nasal cavity or oropharynx. In 5 cases (50%), there was an involvement of the skull base. In 3 patients (30%), an extension to the masticator space and pterygopalatine fossa was found. There were enlarged cervical lymph nodes bilaterally in 10 cases (100%). In 4 cases (40%), a lateral retropharyngeal lymph node was detected. CONCLUSIONS: Childhood nasopharyngeal cancers are often diagnosed at an advanced stage. MR imaging can be helpful in diagnosis and differential diagnosis of childhood nasopharynx cancer from other diseases of the nasopharynx.

Gastrointestinal stromal tumor in a newborn diagnosed in prenatal period: a case report and review of literature.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. Only 1.5% to 2% of all GISTs are observed in children and adolescents. Most of the pediatric cases are between 10 and 18 years of age, with a median age of 13 years. GIST is extremely rare in the newborn period. We could find only 5 reports on the neonatal cases. Herein, we have reported a case with abdominal tumor that was identified by prenatal ultrasonography and magnetic resonance imaging, and diagnosed as GIST on the seventh day of life. We have also reviewed the neonatal GIST cases reported in the English literature.

The role of proangiogenic cytokines in predicting sepsis in febrile neutropenic children with cancer.

BACKGROUND: We assessed the relationship between sepsis occurrence and the serum levels of angiopoietin (Ang-1, Ang-2), vascular endothelial growth factor (VEGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) in pediatric patients with cancer-related febrile neutropenia. METHODS: Fifty-two children with malignant tumors who experienced 86 episodes of febrile neutropenia (FN) were examined between June 2016 and June 2018. Each FN episode was considered a separate event and the total number of FNs were recorded (86 FN episodes = FN group). The control group consisted of 21 healthy children. Ang-1, Ang-2, VEGF-A and sFlt-1 were measured at the baseline and 48th hour of each FN episode -alongside routine characterization of inflammation (C-reactive protein; white blood cell and absolute neutrophil count). RESULTS: Among the episodes, 29 (34.5%) developed sepsis while 57 were classified as non-complicated FN. The baseline values of patients and controls were significantly different for Ang-1, Ang-2, VEGF and sFlt-1 values (all, p < 0.05). In the subgroup with sepsis, Ang-2 values were higher than in the subgroup without sepsis (p = 0.017). In predicting sepsis, Ang-2 had 60.7% sensitivity and 66.7% specificity at the 74.6 cut-off value (AUC: 0.662 [95%CI: 0.541 - 0.783], p = 0.022), Ang-2 / Ang-1 ratio had 65.5% sensitivity and 60.0% specificity at the 0.405 cut-off value (AUC: 0.633 [95%CI: 0.513 - 0.753], p = 0.046). CONCLUSIONS: Our results reveal that Ang-2 and Ang-2/Ang-1 were higher in the sepsis group and Ang-2 might be a biomarker to indicate the risk of sepsis in patients with FN and/or cancer.

Comparison of filgrastim and lenograstim in pediatric solid tumors.

PURPOSE: Chemotherapy-induced febrile neutropenia (FEN), which causes treatment delays or chemotherapy dose reductions, is a serious side effect of cancer treatment. In Turkey, recombinant G-CSF (rG-CSF) has been used since 2000 to control neutropenia. The purpose of this prospective randomized study is to compare the effectiveness, toxicities and the cost of these two drugs in children. METHODS: Between April and December 2008, 29 patients were administered 40 courses of chemotherapy in each arm. A randomized crossover study was designed. All patients were administered rG-CSF 24 hours after the last day of chemotherapy as a secondary prophylaxis. Complete blood counts as well as peripheral blood progenitor (CD34+) cell levels were measured before G-CSF treatment and on the fifth and the seventh day of treatment. RESULTS: The median duration of neutropenia, FEN, the length of hospitalization, the incidence of FEN, and documented infection was not different between the two rG-CSF treatment groups. Erythrocyte and platelet transfusion rates were also similar. After 7 days, the mean leukocyte (WBC [white blood cell]) and neutrophil count (ANC [absolute neutrophil count]), hemoglobin and platelet levels were not significantly different. However, the CD34+ cell level was significantly higher in the lenograstim group. Lenograstim was also more expensive than filgrastim. No serious side effects were reported for either rG-CSF treatment. CONCLUSIONS: There is no difference following the administration of either lenograstim or filgrastim for the duration of neutropenia, FEN or hospitalization for pediatric cancer patients. For stem cell mobilization, lenograstim was superior to filgrastim.

Treatment results of the Ewing sarcoma of bone and prognostic factors.

BACKGROUND: The purpose of this study is to assess the clinical outcome of patients with ESFT of the bone treated with the European Intergroup Cooperative Ewings Sarcoma Study (EICESS)-92 treatment protocol at a single center, and to identify prognostic factors. METHODS: Ninety-eight patients younger than 18 years of age, diagnosed with ESFT of the bone between 1992 and 2005, were analyzed retrospectively. RESULTS: Eighty-seven patients were treated with the EICESS-92 protocol. The median follow-up was 105 +/- 38 months. The 5-year event-free survival (EFS) survival rate was 40%, the 5-year overall survival (OS) rate was 47%. For non-metastatic disease, the rates of 5-year EFS and OS were 45% and 51%. These rates were 18% and 27%, for metastatic disease. The 5-year EFS and OS rates were 17% and 30%, respectively for females. For males, theses rates were 45% and 48%. Of 87 patients, 52 were admitted with primary extremity lesions. Distant metastasis was detected in 48% of patients with a metaphyseal tumor. In patients with diaphyseal lesions, it was 17%. The 5-year EFS and OS were 35% and 43%, respectively. In non-metastatic disease, these measures were 43% and 50%, whereas in metastatic disease, they were 20% and 27%. In patients with a lesion originating from metaphysis, the 5-year EFS was 17%, and the 5-year OS was 29%, for patients with a diaphyseal lesion, these values were 50% and 54%. CONCLUSION: The presence of metastasis was closely related with metaphyseal tumors. The localization of tumor in the bone (i.e., diaphyseal or metaphyseal) and gender of patients seem to have prognostic importance.

A Rare Malignity of Childhood: Krukenberg Tumor-Case Report and Review of Literature.

Krukenberg tumor (KT) is a rare ovarian carcinoma containing mucin-filled signet ring cells. It accounts for 1%-2% of all ovarian tumors. It is seen at an average age of 40 years. Reported pediatric cases of KT in the literature are very limited. Herein, we present an adolescent with a KT that was compatible with metastatic ring cell colon carcinoma.

Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in Patients With Osteosarcoma.

Importance: Osteosarcoma, the most common malignant bone tumor in children and adolescents, occurs in a high number of cancer predisposition syndromes that are defined by highly penetrant germline mutations. The germline genetic susceptibility to osteosarcoma outside of familial cancer syndromes remains unclear. Objective: To investigate the germline genetic architecture of 1244 patients with osteosarcoma. Design, Setting, and Participants: Whole-exome sequencing (n = 1104) or targeted sequencing (n = 140) of the DNA of 1244 patients with osteosarcoma from 10 participating international centers or studies was conducted from April 21, 2014, to September 1, 2017. The results were compared with the DNA of 1062 individuals without cancer assembled internally from 4 participating studies who underwent comparable whole-exome sequencing and 27 173 individuals of non-Finnish European ancestry who were identified through the Exome Aggregation Consortium (ExAC) database. In the analysis, 238 high-interest cancer-susceptibility genes were assessed followed by testing of the mutational burden across 736 additional candidate genes. Principal component analyses were used to identify 732 European patients with osteosarcoma and 994 European individuals without cancer, with outliers removed for patient-control group comparisons. Patients were subsequently compared with individuals in the ExAC group. All data were analyzed from June 1, 2017, to July 1, 2019. Main Outcomes and Measures: The frequency of rare pathogenic or likely pathogenic genetic variants. Results: Among 1244 patients with osteosarcoma (mean [SD] age at diagnosis, 16 [8.9] years [range, 2-80 years]; 684 patients [55.0%] were male), an analysis restricted to individuals with European ancestry indicated a significantly higher pathogenic or likely pathogenic variant burden in 238 high-interest cancer-susceptibility genes among patients with osteosarcoma compared with the control group (732 vs 994, respectively; P = 1.3 × 10-18). A pathogenic or likely pathogenic cancer-susceptibility gene variant was identified in 281 of 1004 patients with osteosarcoma (28.0%), of which nearly three-quarters had a variant that mapped to an autosomal-dominant gene or a known osteosarcoma-associated cancer predisposition syndrome gene. The frequency of a pathogenic or likely pathogenic cancer-susceptibility gene variant was 128 of 1062 individuals (12.1%) in the control group and 2527 of 27 173 individuals (9.3%) in the ExAC group. A higher than expected frequency of pathogenic or likely pathogenic variants was observed in genes not previously linked to osteosarcoma (eg, CDKN2A, MEN1, VHL, POT1, APC, MSH2, and ATRX) and in the Li-Fraumeni syndrome-associated gene, TP53. Conclusions and Relevance: In this study, approximately one-fourth of patients with osteosarcoma unselected for family history had a highly penetrant germline mutation requiring additional follow-up analysis and possible genetic counseling with cascade testing.

Association of vitamin D receptor gene polymorphisms with osteosarcoma risk and prognosis.

OBJECTIVE: Through its receptor (VDR), vitamin D3 plays an important role in a wide variety of cellular processes. Polymorphisms in VDR gene have been linked to risk of various cancers and their prognoses. We conducted a case-control study to analyze he relationship of VDR gene polymorphisms with the occurrence and prognosis of osteosarcoma. METHODS: Fifty-eight osteosarcoma patients and 75 healthy controls were included in the study. Single nucleotide change polymorphisms (SNPs) in Cdx2, FokI, BsmI, ApaI and TaqI regions of VDR gene were examined with SNaPshot mini-sequencing technique. Allele and genotype frequencies in patients and controls were compared. The association of polymorphic genotypes with osteosarcoma was evaluated. The relationship of the presence of polymorphism to prognostic parameters and survival rates were also analyzed. RESULTS: Allele and genotype frequencies of Cdx2, FokI, BsmI, ApaI and TaqI regions in VDR gene were found to be similar in patients and controls. Polymorphisms in these regions were not associated with osteosarcoma risk. In patients having Cdx2 polymorphic allele, tumor volume was greater (p:0.041), metastasis was more common (p:0.042) and histopathological response to chemotherapy was worse (p:0.044). Good histopathological response was significantly higher in patients with BsmI homozygous polymorphism (p:0.037). In the presence of heterozygous Cdx2 and homozygous a higher three-year overall survival rate was found, while there was a higher event-free survival rate in patients with ApaI polymorphisms. CONCLUSION: Our results suggested that although polymorphisms of VDR gene are not related to the development of osteosarcoma, they may be important for prognosis. Understanding the effect of VDR polymorphisms on osteosarcoma will be important in identifying new prognostic parameters and new targets for treatment.

Genome-wide association study identifies two susceptibility loci for osteosarcoma.

Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. To better understand the genetic etiology of osteosarcoma, we performed a multistage genome-wide association study consisting of 941 individuals with osteosarcoma (cases) and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: a locus in the GRM4 gene at 6p21.3 (encoding glutamate receptor metabotropic 4; rs1906953; P = 8.1 × 10⁻9) and a locus in the gene desert at 2p25.2 (rs7591996 and rs10208273; P = 1.0 × 10⁻8 and 2.9 × 10⁻7, respectively). These two loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma.

The effect of long-term low-dose lead exposure on thyroid function in adolescents.

This study investigated blood lead (Pb-B) levels and Pb-B effects on thyroid functions in long-term low-level-lead-exposed male adolescents who work as auto repairers. Pb-B and ALAD index (logarithm of activated delta-aminolaevulinic acid dehydratase/nonactivated delta-aminolaevulinic acid dehydratase) were measured as indicators of exposure to lead. Thyroid function tests including free thyroxine (FT4), free triiodothyronine (FT3), and thyrotrophin (TSH) were conducted and thyroid ultrasounds were performed in 42 lead-exposed adolescents and 55 healthy control subjects. Mean Pb-B levels and ALAD index were found significantly higher in the study group than in the normal control group (7.3+/-2.92 microg/dl vs. 2.08+/-1.24 microg/dl, P < 0.001 and 0.44+/-0.26 vs. 0.29+/-0.23, P < 0.05, respectively). FT4 levels were found significantly lower in the study group (1.02+/-0.18 mI/mL and 1.12+/-0.14 mIU/mL, P < 0.05). No subject in the control group had an abnormal FT4 level, but FT4 levels were found under normal limits in 11 subjects (26%) in the study group. FT3 and TSH levels in the study and control groups did not differ (P > 0.05). Thyroid volumes in the study and control groups did not exhibit any significant differences (P > 0.05). Pb-B was found to be negatively correlated to FT4 levels (r = -0.20, P = 0.044). This study revealed that long-term low-level lead exposure may lead to reduced FT4 level without significant changes in TSH and T3 levels in adolescents even at low Pb-B levels.

High-dose ifosfamide in relapsed pediatric osteosarcoma: therapeutic effects and renal toxicity.

BACKGROUND: Sixteen pediatric osteosarcoma patients, previously treated with conventional chemotherapy (including ifosfamide (IFX), 9 g/m(2)) were retreated with high-dose ifosfamide (HD-IFX, 14 g/m(2) per course), following relapse or development of a new bone tumor. The objective was to obtain responses and an improved event-free survival (EFS). PROCEDURE: HD-IFX was administered as described by Patel SR: J Clin Oncol 1997;15:2378. Efficacy of treatment was assessed initially after two to four courses. The interval between the courses was 3 to 4 weeks. Provided a response was obtained after two to four courses, treatment was continued for an additional eight courses unless progressive disease or an untoward event, for example, renal failure occurred. Tumor sites were: lung, (10) bone (9), and bone and soft-tissue (1). RESULTS: Response after two to four courses was 62.5%: CR 6 and PR 4. A total of 84 courses were administered to the 16 patients: (range 2-10, median 5.5 per patient). Median interval between courses was 28.5 days (range 15-90). Five patients were disease free at 15+ to 63+ months after induction and maintenance therapy. Fever and neutropenia occurred in 12 courses. Nephrotoxicity was a major toxic event and was characterized by creatinine levels at or above three times the upper limit of normal. It was unpredictable and occurred in four patients: two were reversible. The other two patients developed full-blown renal failure; one was treated with renal dialysis, but both eventually succumbed to osteosarcoma. Our past experience also indicated that two patients treated with IFX (9 g/m(2)/course) developed renal failure: one recovered and the other required a renal transplant. CONCLUSIONS: HD-IFX is effective in patients who have failed conventional chemotherapy including IFX (9 g/m(2)). Improved disease-free survival was achieved in 30% of patients. However, renal failure constitutes an important life-threatening complication and its development is unpredictable.

Quantitative thallium-201 scintigraphy in childhood osteosarcoma: Comparison with technetuim-99m MDP and magnetic resonance imaging in the evaluation of chemotherapeutic response.

The aim of this study was to assess early (15 min) and late 2 h) thallium-201 (201Tl) uptake in children with osteosarcoma and to compare these findings with magnetic resonance imaging (MRI) and technetium-99m methylenediphosphonate (99mTc MDP), with emphasis on evaluating tumor viability before and after chemotherapy. Fifteen patients with biopsy-proven osteosarcoma received standard preoperative chemotherapy with a combination of cisplatin, Adriamycin, and high-dose methotrexate. Their ages ranged between 7 and 18 years (median 14.5 years). All patients had 201Tl, 99mTc MDP, and MRI studies. Thallium scintigraphy was performed at 15 min and 2 h after IV injection of 92 MBq of thallium. Thallium uptake ratio was calculated by dividing the count density of the lesion (L) by that of the controlateral normal (N) area. The percent reduction of 201Tl uptake ratio (alteration ratio) was calculated by [100x(prechemotherapy L/N-postchemotherapy L/N)/prechemotherapy L/N]. Pathologic changes were graded on the basis of % tumor necrosis as defined histologically. Scintigraphic comparisons demonstrated a high-degree of correlation with late 201Tl alteration ration and poor correlation with both early 201Tl and 99mTc MDP alteration ratios. Late 201Tl images were superior to early 201Tl, 99mTc MDP, and MRI in predicting tumor response to chemotherapy as determined by % tumor necrosis (p<.01). The authors found that late 201Tl was an accurate test for evaluating the response to specific therapeutic regimens and it can be useful planning surgery or choosing alternative chemotherapeutic regimens.