Esophageal Carcinoma in Children: Report of 2 Cases and a Review of the Literature.

Esophageal carcinoma in children and adolescents is extremely rare. Here, we report 2 cases of pediatric esophageal carcinoma presenting with progressive dysphagia. There was not any underlying specific risk factor in our cases. The histopathological subtypes were adenocarcinoma in one and squamous cell carcinoma in another case. Response to combined modality treatment was good in the case of adenocarcinoma, while the patient with squamous cell carcinoma was unresponsive to treatment and died of the progressive disease. We reviewed the pediatric cases of esophageal carcinoma reported in the literature. Progressive dysphagia was observed in 89% of these cases. One third of pediatric cases had underlying risk factors. Squamous cell carcinoma is a more common type of childhood esophageal carcinoma. In contrast to adults, pediatric esophageal squamous cell carcinoma may distribute throughout the esophagus. Esophageal adenocarcinoma was seen in the distal esophagus in pediatric cases. Metastatic disease was found in 48% of pediatric patients at presentation, and the prognosis is poor. Collaborative efforts are needed for success in the treatment of esophageal carcinoma.

Precursor B-cell Lymphoblastic Lymphoma in Children: Hacettepe Experience.

The purpose of the study was to review the clinical and pathologic characteristics and treatment results of children with precursor B-cell lymphoblastic lymphoma. Of 530 children diagnosed with non-Hodgkin lymphomas between 2000 and 2021, 39 (7.4%) were identified as having precursor B-cell lymphoblastic lymphoma. Clinical characteristics, pathologic, radiologic, laboratory data, treatments, responses, and overall outcomes were recorded from hospital files and analyzed. The median age of 39 patients (males/females, 23/16) was 8.3 years (range 1.3 to 16.1). The most common sites of involvement were the lymph nodes. At a median follow-up of 55.8 months, 14 patients (35%) had a recurrence of disease (11 stage IV, 3 stage III); 4 were in complete remission with salvage therapies, 9 died of progressive disease and one died due to febrile neutropenia. Five-year event-free survival and overall survival rates were 65.4% and 78.3% for all cases, respectively. Survival rates were higher in patients with a complete remission at the end of induction therapies. The survival rates were lower in our study compared with other studies, which could be explained by the high relapse rate and higher incidence of advanced-stage disease due to bone marrow involvement. We demonstrated a prognostic impact of treatment response at the end of the induction phase. Cases with a disease relapse have poor prognosis.

Primary Paraspinal and Spinal Epidural Non-Hodgkin Lymphoma in Childhood.

Primary paraspinal/spinal epidural lymphoma (PPSEL) is rare in childhood. Here, we retrospectively evaluated patients with PPSEL treated in our department. We also reviewed the cases reported in the literature. Fifteen of 1354 non-Hodgkin lymphoma cases diagnosed over a 38-year period were PPSEPL. There were 11 male individuals and 4 female individuals with a median age of 13 years. Most common symptoms were pain and limb weakness. Physical examination revealed spinal cord compression in 80% of patients. The most common tumor location was the lumbar region. Histopathologic subtypes were lymphoblastic lymphoma in 6 and Burkitt lymphom in 5 patients. Subtotal or near-total excision of the tumor with laminectomy was performed in 6 patients. Thirteen and 9 patients received chemotherapy and radiotherapy, respectively. Neurologic recovery was observed in 70% of patients. Seven patients were alive without disease at a median of 88 months. Overall and event-free survival rates were 61.7% and 50.1%, respectively. We reviewed clinical features, treatment, and outcome of 69 PPSEL cases reported in the literature. Neurologic recovery and long-term survival was achieved in 66.7% of them. Heterogeneity in diagnostic methods and treatment have made it difficult to establish the prognostic indicators for neurologic outcome and survival. Multicenter prospective studies with more cases are necessary to determine the prognostic factors.

Primary gastric lymphoma: A report of 16 pediatric cases treated at a single institute and review of the literature.

Gastrointestinal tract is the most common extranodal site for childhood non-Hodgkin lymphomas (NHLs). However, primary gastric lymphoma (PGL) is very rare. We report our experience with PGL. Between 1972 and 2019, patients with PGL among 1696 NHL cases were evaluated retrospectively. Patient characteristics, treatments, and survival rates were recorded. We also reviewed the cases reported in literature. There were 16 PGL (11 males, five females) cases with a median age of 10 years. Most frequent complaints, similarly to the literature, were pain and vomiting. Hematemesis/melena and anemia were present in 20% of patients. Most common tumor location was antrum. Histopathological subtypes were Burkitt and non-Burkitt B-cell lymphoma in 43.75% and marginal zone lymphoma (MZL) in 6.25% of cases while mucosa-associated lymphoid tissue (MALT) and low-grade lymphomas constitute 15.3% of cases reported in the literature. In our series, Helicobacter pylori (H. pylori) was analyzed in only the case with MZL and found to be positive. However, H. pylori positivity was reported in 75% of the cases in the literature. H. pylori eradication, chemotherapy, and radiotherapy were applied in one, 14, and five patients. Subtotal gastrectomy with gastroduodenostomy/jejunostomy was performed in three patients. Gastrojejunostomy was done without tumor resection in two patients. Nine patients lived without disease for a median of 59 (12-252) months. Five-year EFS and OS were 69.6% and 64.3%, respectively. PGL constitutes 0.94% of our NHL cases. Interestingly, most of the cases in the literature were from Turkey. While adult PGL is mostly MALT lymphoma, most pediatric cases had high-grade histopathology. Although surgery and radiotherapy were applied earlier, chemotherapy alone is sufficient.

FAB LMB 96 Regimen for Newly Diagnosed Burkitt Lymphoma in Children: Single-center Experience.

BACKGROUND/OBJECTIVES: The outcome of Burkitt lymphoma has improved by over 90%. In this study, demographic characteristics and outcomes of 57 patients with Burkitt lymphoma treated with FAB LMB 96 regimen are presented. MATERIALS AND METHODS: Standard intensity arms were selected for all risk groups. Clinical characteristics, response to treatment, and outcome were evaluated. RESULTS: The median age of 48 boys and 9 girls was 8.2 years. There were 2 (3%), 41 (72%), and 14 (25%) patients in the low, intermediate, and high-risk groups, respectively. Patients were followed-up for a median of 50 months. The 5-year overall survival and event-free survival rates for the study group were 90.8% and 87.4%, respectively. Two patients in the low-risk group are still alive without evidence of disease for 17 and 57 months. The 5-year overall survival rates were 95% and 78% for intermediate and high-risk patients, and the 5-year event-free survival rates were 93% and 62%, respectively. At the end of induction, 58% of patients had complete response, and 42% (n=24) had residual tumors. A total of 16 of 24 patient biopsies showed no viable tumors. CONCLUSIONS: Our results confirm the previously published survival results of FAB LMB 96. The regimen is an effective regimen for mature B-cell non-Hodgkin lymphoma without radiotherapy or surgery even in central nervous system-positive patients. The most important prognostic factor is the complete response after induction chemotherapy. However, residual tumor at the end of consolidation might not always be a sign for unresponsive tumor. Tumoral residue should be radiologically well evaluated and biopsied if possible for viability before intensifying treatment.

Denosumab treatment in aneurysmal bone cyst: Evaluation of nine cases.

BACKGROUND: Aneurysmal bone cyst (ABC) is a benign bone tumor. Curettage and bone grafting is the common treatment. Here, we retrospectively evaluate nine patients treated with denosumab. PROCEDURE: Nine patients with ABC, mostly pelvic and vertebral, treated with denosumab were analyzed retrospectively. A 70 mg/m2 denosumab dose was used weekly in the first month, and then monthly. Clinical and radiological responses to treatment were evaluated. RESULTS: In all patients, clinical symptoms including pain and limping regressed completely within 3 months. Radiological evaluation revealed changes in lesion size and content. In six patients, overall volume reduction in the range of 18-82% was detected. Decreases in the size and number of cysts were detected in eight patients. In five patients, fat signal appeared on follow-up imaging. No major side effects were observed during treatment. Median follow-up time after treatment was 15 months. At 5 months, severe hypercalcemia was observed in two patients due to rebound increase in osteoclastic activity. Subsequent to denosumab treatment, three patients underwent surgery for clinical or radiological recurrence. CONCLUSIONS: Our results showed that denosumab provided a meaningful clinical and radiological improvement in ABC. It may be a treatment option, especially in spinal and pelvic tumors with potentially high surgical morbidity. However, late rebound hypercalcemia may restrict its use. Studies with more cases are required for routine use of denosumab in ABC.

Primary Osteosarcoma of the Rib: A Case Report and Review of the Literature.

Osteosarcoma is the most common primary malignant tumor of the bone. The most common sites of osteosarcoma in children are the metaphysis of long bones, especially the distal femur, proximal tibia, and proximal humerus. It occurs very rarely in flat bones. Here we report a 14-year-old adolescent boy with primary osteosarcoma of the fifth rib and a review of literature.

Lipoblastoma in children: Review of 12 cases.

BACKGROUND: Lipoblastoma is a rare benign mesenchymal tumor of infancy and early childhood. Symptoms vary depending on localization, and signs of compression of adjacent organs may be seen. METHODS: A total of 12 children with pathologically proven lipoblastoma from 2000 to 2014 were reviewed retrospectively for their clinical features, treatment and follow up. RESULTS: There were seven boys and five girls between 7.5 months and 7.5 years of age. The most common symptom was painless rapid-growing mass. The tumors were located in the neck, the abdomen, the groin, pelvis, axilla, glutea, labium majus, thigh and trunk. The largest tumor was in a retroperitoneal location and was 13 × 10 cm in size. Complete resection was performed in 10 patients. All of these patients were followed without any evidence of recurrence. Subtotal excision was performed in two patients. At a median follow up of 38 months (range, 1.8 months-10 years), all patients were disease free. CONCLUSIONS: Lipoblastoma should be considered in the differential diagnosis of rapidly growing mass in patients <3 years of age. Total excision is the treatment of choice with preservation of vital organs. The prognosis is excellent despite large tumor size and local invasion. Recurrence rate is high in incompletely resected tumors. Regular follow up is important for early detection of recurrence.

Outcome of autologous hematopoietic stem cell transplantation in children and adolescents with relapsed or refractory Hodgkin's lymphoma.

This study evaluates the outcome of 66 pediatric patients with rrHL who underwent autoHSCT. Twenty-nine patients experienced early relapse, and 19 patients experienced late relapse. Of 18 newly diagnosed with HL, 13 were primary refractory disease and five had late responsive disease. At the time of transplantation, only 68% of the patients were chemosensitive. The majority of patients received BCNU + etoposide + ara-C + melphalan for conditioning (45/66), and peripheral blood (56/66) was used as a source of stem cells. After a median follow-up period of 39 months, 46 patients were alive. At five yr, the probabilities of OS, EFS, the relapse rate, and the non-relapse mortality rate were 63.1%, 54.3%, 36.4%, and 9.1%, respectively. The probability of EFS in chemosensitive and chemoresistant patients at five yr was 72.3% and 19%, respectively (p < 0.001). Multivariate analysis showed that chemoresistant disease at the time of transplantation was the only factor predicting limited both OS (hazard ratio = 4.073) and EFS (hazard ratio = 4.599). AutoHSCT plays an important role for the treatment of rrHL in children and adolescents, and survival rates are better for patients with chemosensitive disease at the time of transplantation.

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.

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 nitric oxide in Doxorubicin-induced cardiotoxicity: experimental study.

OBJECTIVE: We evaluated the myocardial damage in rats treated with doxorubicin (DOX) alone and in combination with nitric oxide synthase (NOS) inhibitors. MATERIALS AND METHODS: Twenty-four male Sprague Dawley rats (12 weeks old, weighing 262±18 g) were randomly assigned into 4 groups (n=6). Group I was the control group. In Group II, rats were treated with intraperitoneal (ip) injections of 3 mg/kg DOX once a week for 5 weeks. In Group III, rats received weekly ip injections of 30 mg/kg L-NAME (nonspecific NOS inhibitor) 30 min before DOX injections for 5 weeks. In Group IV, rats received weekly ip injections of 3 mg/kg L-NIL (inducible NOS inhibitor) 30 min before DOX injections for 5 weeks. Rats were weighed 2 times a week. At the end of 6 weeks, hearts were excised and then fixed for light and electron microscopy evaluation and tissue lipid peroxidation (malondialdehyde). Blood samples were also obtained for measuring plasma lipid peroxidation. RESULTS: Weight loss was observed in Group II, Group III, and Group IV. Weight loss was statistically significant in the DOX group. Findings of myocardial damage were significantly higher in animals treated with DOX only than in the control group. Histopathological findings of cardiotoxicity in rats treated with DOX in combination with L-NAME and L-NIL were not significantly different compared with the control group. The level of plasma malondialdehyde in the DOX group (9.3±3.4 µmol/L) was higher than those of all other groups. CONCLUSION: Our results showed that DOX cardiotoxicity was significantly decreased when DOX was given with NO synthase inhibitors.

Safety and efficacy of COVID-19 vaccines in children and adolescents with cancer.

BACKGROUND: Children with cancer have a higher morbidity and mortality due to COVID-19. Vaccination of children with cancer is important. In this study, we aimed to investigate the effectiveness and side effects of the COVID-19 vaccines in children and adolescents with cancer. METHODS: Fifty-eight patients from four centers were included in the study. Antibodies to the SARS-CoV-2 spike protein levels were measured. Vaccine-related complaints were recorded. RESULTS: There were 33 male and 25 female patients. The mean age was 16.9±2.3 years. In 58.6% of cases, the diagnosis was hematological malignancies. Twenty patients were currently under treatment, while 38 had completed the treatment. Forty-eight patients received chemotherapy ± radiotherapy, 13 received immunotherapy, and 3 underwent stem cell transplantation. CoronoVac© and BNT162b2© vaccines were administered in 24% and 76%, respectively. The mean antibody level was lower in patients who received CoronaVac© than that of BNT162b2©, although the difference was not significant. The levels were within the protective limits in both groups. No significant difference was found in antibody levels according to diagnostic subgroups, treatment status, type of treatment, line of treatment, disease status and time between vaccines and measurement of antibody level. The most common side effects were pain at the injection site (37.9%) and malaise/weakness (17.2%), which were similar for both vaccines. CONCLUSIONS: Our study showed that both mRNA and inactivated vaccines elicit an immune response in children with cancer. However, the seroconversion rate is significantly higher in mRNA vaccines. Side effects were similar to those seen in healthy children.

Ganglioneuromas in Childhood: Hacettepe Experience With 70 Cases.

BACKGROUND: Ganglioneuromas (GNs) are rare benign peripheral neuroblastic tumors (PNTs). We shared our institutional experience with childhood GNs. METHODS: Records of the children with PNTs between January 1995 and December 2021 were reviewed, and cases with histopathological diagnoses of GN were identified. Clinical, laboratory, radiological, and histopathological findings, image-defined risk factors (IDRFs), procedures, and overall outcomes were recorded. RESULTS: Of 668 cases with PNTs, 70 (10.4%) had GNs. The median age was 7.4 years (range, 2.6-15.7 years) (girls/boys, 41/29). Common presenting complaints were abdominal pain and cough; 33/70 cases (47.1%) were diagnosed incidentally. Primary tumors were in the abdomen in 41/70, the thorax in 25/70, the neck in 3 cases, and the pelvis in one. The median tumor size was 6.5 cm (range, 1.4-17). Fifty cases (71.4%) were staged as INRG-L1; 20 cases with IDRFs (15 single, five >1) were staged as INRG-L2. Complete and partial tumor resections were performed in 58/70 and 6/70 cases, while 6 had no resection. The overall complication rate was 17.1% (11/64). At a median follow-up of 9 years, five were lost to follow-up; 65 were alive. One patient with gross residue underwent total resection due to progression 13 years after the surgery, and one in the unresected group was lost to follow-up. Ten other cases without a complete resection experienced no tumor progression. CONCLUSIONS: Ganglioneuromas are benign PNTs, and most are free of IDRFs. Even without complete resection, long-term outcomes are excellent. Guidelines should be devised considering the high surgical complication rates and benign course of GNs. LEVEL OF EVIDENCE: Case series, IV.

Indolent B-cell non-Hodgkin lymphomas in children: high association with inborn errors of immunity.

Indolent lymphomas are rare in children and mostly consist of pediatric type follicular (PTFL) and pediatric marginal zone lymphomas (PMZL) and extranodal marginal zone lymphoma (ENMZL). Twenty children with indolent lymphoma (10 PTFL, 6 PMZL, 3 ENMZL, 1 mixed type) among 307 Non-Hodgkin Lymphoma (NHL) were retrospectively evaluated. The mean age of the entire group was 10.4 ± 4.4 and was significantly lower in PTFL than in PMZL. Seven patients (35%) had an associated inborn error of immunity (IEI) which was higher than that seen in aggressive lymphomas (5.9%) (p < 0.0001). Seventeen patients (85%) had stage I/II disease. Two patients received no treatment after surgery. Eleven patients were treated only with 3-6 courses of rituximab. Four patients received 3-6 courses of R-CHOP protocol. The prognosis was excellent Five years overall and event-free survivals were 100% and 85%, respectively.

The role of radiotherapy in multimodal treatment of non-rhabdomyosarcoma soft tissue sarcomas in children: A real life report from a tertiary center.

OBJECTIVE: The current treatment of pediatric non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) is a multimodal risk-based approach. Today, smaller fields and lower doses of radiotherapy (RT) have become standard. In this study, it was aimed to evaluate the treatment outcomes and toxicity profile in children with NRSTS that received RT as a part of multimodal therapy. METHODS: Twenty-nine patients with pediatric NRSTS treated with neoadjuvant or adjuvant RT between 1998 and 2022 were evaluated retrospectively. Kaplan-Meier method was used for survival analyses. RESULTS: Median follow-up was 36 months (range, 6-291 months). The median neoadjuvant and adjuvant RT doses were 50 Gy (range, 45-66 Gy) and 54 Gy (45-66 Gy), respectively. During follow-up, six (21%) patients developed a local recurrence and 10 (35%) had distant metastasis. The 5-year local control, overall survival (OS), local recurrence-free survival, and distant metastasis-free survival rate was 79%, 67%, 59%, and 61%, respectively. In multivariate analysis, a ≤5-cm tumor, gross tumor resection, Children's Oncology Group (COG) low-risk group, and absence of neoadjuvant chemotherapy were independent favorable prognostic factors for OS. Severe (≥ grade 3) late toxicity was observed in 6 (20%) patients. CONCLUSIONS: RT is a crucial component in the multimodal risk-based treatment approach for pediatric NRSTS. However, late toxicity rates are still high and should be improved. Patients with a ≤5-cm tumor, COG low-risk group and treated with gross tumor resection have increased survival rates.

Pulmonary involvement in children with Langerhans cell histiocytosis.

BACKGROUND: Pulmonary Langerhans cell histiocytosis (pLCH) is a rare disease, mostly a component of multisystemic LCH. We aimed to investigate the clinical features and treatment results in children with pLCH. METHODS: We retrospectively reviewed the clinical, radiological, and treatment data of 37 patients with pLCH, diagnosed from 1974 to 2022. RESULTS: 10% (n=37) of 367 patients with LCH had lung involvement. The median age was 1.8 years (range: 0.4 & 17.7) with a male-to-female ratio of 2.3. At admission 29.7% (n=11) presented with respiratory symptoms. Imaging showed a spectrum from nodular opacities to multiple cysts. All but one patient had multisystem disease. Twenty-nine received vinblastine-containing therapy. Ten-year event-free (EFS) and overall survival (OS) rates were 47.8% and 63.3%, respectively. In children younger and older than two years of age, the 10-year EFS was 53.3% vs. 40.2% and the 10-year OS was 58.7% vs. 68.8%, respectively. In children with and without risk organ involvement, 10-year EFS was 51.9% vs. 46.3% and 10-year OS was 51.9% vs. 73.7%. CONCLUSIONS: Lung and multisystem involvement are significant concerns in LCH, highlighting the need for careful management to reduce morbidity and mortality.

Primary ovarian tumors in children: a single center experience of 124 patients.

BACKGROUND: Primary ovarian tumors are rare in the pediatric age group. We reviewed our 40-year experience with ovarian tumors to evalute the clinical features and treatment results in a single institution. METHODS: Between January 1975 and October 2015, 124 girls with primary ovarian tumor were diagnosed and treated in our center. Tumors were identified with biopsy or total resection and/or serum markers. Seventy four children were included in the treatment analysis. RESULTS: Median age for 124 children was 11.0 years (0.73-17.63). The main complaint was abdominal pain in 85 patients (68.5%). One hundred and five patients (84.6%) had total one-sided salpingo-oophorectomy and five patients had bilateral salpingo-oophorectomy. Amongst 124 cases, 29 patients had mature teratoma, which was the most common tumor in this study. Dysgerminoma (n=21) was the most common malignant histopathologic type. Stage I disease was diagnosed in 57.2% and stage IV in 6.6% of the patients. Five year overall survival (OS) and event-free survival (EFS) for 124 children were 82.5% and 76.3% respectively. For 74 children who received treatment, 5-year OS and EFS were 75.2% and 67.1%, respectively. Age (p < 0.017), histopathological subgroup (p < 0.001), stage (p =0.003) and chemotherapy protocols (p =0.049) were significant prognostic factors for OS. CONCLUSIONS: The survival rates in children with ovarian tumors were comparable with studies in the literature. Although patients treated with platin based regimens had better survival rates, prognosis was still poor for the patients in advanced stages. This should be the focus for further studies and improvements.

Small Cell Carcinoma of Ovary, Hypercalcemic Type: A Rare Case Report.

BACKGROUND: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare neoplasm that occurs mostly in women younger than 40 years of age. The unknown histogenesis makes the diagnosis of SCCOHT difficult. SCCOHT was recently shown to be associated with SMARCA4 gene mutation. Serum calcium levels can be used as a marker of treatment response and relapse in SCCOHT. CASE REPORT: Here we report on a 16-year-old girl who presented with pelvic mass and hypercalcemia. SCCOHT was diagnosed histopathologically. However, loss of neither BRG1 nor INI1 expression was detected. SUMMARY AND CONCLUSION: The diagnosis of SCCOHT should be among the differential diagnoses in adolescents presenting with pelvic mass and hypercalcemia. We would like to share our experience with this rare case, discuss recent management, and emphasize the importance of a multidisciplinary approach. Although it is known that almost all cases have a loss of BRG1 expression and a small group exhibit loss of INI1, our patient indicates that there could be exceptional cases with hitherto undescribed genetic abnormalities.