A Pediatric Case of Atypical Chronic Myeloid Leukemia with CSF3R Mutation Not Responding to Ruxolitinib, but Rescued by Allogeneic Transplantation / 임상소아혈액종양

Atypical chronic myeloid leukemia (aCML), BCR-ABL1-negative is a rare myeloid neoplasm, especially in pediatric patients. The mutations identified in aCML have overlapped with those of other myeloid neoplasms. In recent studies, ruxolitinib, a Janus kinase (JAK) inhibitor, was found efficient in some patients of aCML with CSF3R mutation. Here, we report a pediatric case of aCML with CSF3Rmutation who did not respond to ruxoritinib, but was successfully rescued with hematopoietic stem cell transplantation (SCT). A stuporous 13-year-old boy was transferred with leukocytosis.Computed tomography showed an acute lobar intracranial hemorrhage in the left frontal lobe. The bone marrow aspirate demonstrated significant granulocytic proliferations with predominant dysplasia. Hydroxyurea and imatinib were initially administered to reduce leukocytosis. After BCR-ABL1 was found to be negative, imatinib was discontinued. After the identification of CSF3R mutation by customized targeted DNA sequencing (NGeneBio, Seoul, South Korea), ruxolitinib was added. He seemed to have hematologic and clinical responses on 2 months of ruxolitinib treatment, but the blast counts in the bone marrow increased. He underwent a full-matched unrelated peripheral blood SCT successfully 3 months after his diagnosis and has currently been disease-free 8 months since the transplantation. In conclusion, ruxolitinib for aCML with CSF3R mutation might not always induce a significant response but could be used as bridge to hematopoietic SCT.

Better Failure-Free Survival and Graft-versus-Host Disease-Free/Failure Free Survival with Fludarabine-Based Conditioning in Stem Cell Transplantation for Aplastic Anemia in Children

BACKGROUND: This study aimed to assess the outcome of stem cell transplantation (SCT), including overall survival (OS), failure-free survival (FFS) and graft-versus-host disease (GvHD)-free/failure-free survival (GFFS), and to analyze prognostic factors in children with aplastic anemia (AA).METHODS: From 1991 to 2018, 43 allogeneic SCT recipients were enrolled in the study to investigate the demographic characteristics, survival outcomes and prognostic factors.RESULTS: With the median follow-up of 7.1 years, the estimated 10-year OS, FFS, GFFS were 86.0%, 60.5%, and 51.2%, respectively. Matched related donors (MRD, n = 28) showed better 10-year OS than unrelated donors (n = 15) (96.4% vs. 66.7%; P = 0.006). Engraftment failure was seen in 13 patients (30.2%). Donor-type aplasia was seen in 13.8% (4/29) after fludarabine (Flu)-based conditioning (Flu-group), while in 42.6% (6/14) after cyclophosphamide (Cy)-based regimen (Cy-group) (P = 0.035). Six patients died. The 10-year OS in Cy-group was 92.9% (n = 14, all MRD), while that of Flu-group was 82.1% (n = 29; P = 0.367). But Flu-group tended to have better FFS and GFFS than Cy-group, although Flu-group had less MRDs (41.4% vs. 100%; P = 0.019), and higher proportion of previous immunosuppressive treatment (IST; 62% vs. 21.4%, P = 0.012). In MRD transplants, OS was similar between Flu-group (100%, n = 14) and Cy-group (92.9%, n = 14), while FFS (100.0% vs. 42.9%; P = 0.001) and GFFS (85.7% vs. 35.7%; P = 0.006) were significantly better in Flu-group. Stem cell sources, irradiation in the conditioning, and method of GvHD prophylaxis did not significantly influence the outcome.CONCLUSION: This study reviewed SCT outcomes for pediatric AA with changes of transplant strategies over the last 25 years. The FFS and GFFS were higher in Flu-group than in Cy-group, especially in matched related transplantation. Graft failure including donor-type aplasia remains troublesome even with Flu-based conditioning. Further refinement of transplant strategies to ensure better quality-of-life should be pursued.

Better Failure-Free Survival and Graft-versus-Host Disease-Free/Failure Free Survival with Fludarabine-Based Conditioning in Stem Cell Transplantation for Aplastic Anemia in Children

BACKGROUND@#This study aimed to assess the outcome of stem cell transplantation (SCT), including overall survival (OS), failure-free survival (FFS) and graft-versus-host disease (GvHD)-free/failure-free survival (GFFS), and to analyze prognostic factors in children with aplastic anemia (AA).@*METHODS@#From 1991 to 2018, 43 allogeneic SCT recipients were enrolled in the study to investigate the demographic characteristics, survival outcomes and prognostic factors.@*RESULTS@#With the median follow-up of 7.1 years, the estimated 10-year OS, FFS, GFFS were 86.0%, 60.5%, and 51.2%, respectively. Matched related donors (MRD, n = 28) showed better 10-year OS than unrelated donors (n = 15) (96.4% vs. 66.7%; P = 0.006). Engraftment failure was seen in 13 patients (30.2%). Donor-type aplasia was seen in 13.8% (4/29) after fludarabine (Flu)-based conditioning (Flu-group), while in 42.6% (6/14) after cyclophosphamide (Cy)-based regimen (Cy-group) (P = 0.035). Six patients died. The 10-year OS in Cy-group was 92.9% (n = 14, all MRD), while that of Flu-group was 82.1% (n = 29; P = 0.367). But Flu-group tended to have better FFS and GFFS than Cy-group, although Flu-group had less MRDs (41.4% vs. 100%; P = 0.019), and higher proportion of previous immunosuppressive treatment (IST; 62% vs. 21.4%, P = 0.012). In MRD transplants, OS was similar between Flu-group (100%, n = 14) and Cy-group (92.9%, n = 14), while FFS (100.0% vs. 42.9%; P = 0.001) and GFFS (85.7% vs. 35.7%; P = 0.006) were significantly better in Flu-group. Stem cell sources, irradiation in the conditioning, and method of GvHD prophylaxis did not significantly influence the outcome.@*CONCLUSION@#This study reviewed SCT outcomes for pediatric AA with changes of transplant strategies over the last 25 years. The FFS and GFFS were higher in Flu-group than in Cy-group, especially in matched related transplantation. Graft failure including donor-type aplasia remains troublesome even with Flu-based conditioning. Further refinement of transplant strategies to ensure better quality-of-life should be pursued.

Better Failure-Free Survival and Graft-versus-Host Disease-Free/Failure Free Survival with Fludarabine-Based Conditioning in Stem Cell Transplantation for Aplastic Anemia in Children

BACKGROUND@#This study aimed to assess the outcome of stem cell transplantation (SCT), including overall survival (OS), failure-free survival (FFS) and graft-versus-host disease (GvHD)-free/failure-free survival (GFFS), and to analyze prognostic factors in children with aplastic anemia (AA).@*METHODS@#From 1991 to 2018, 43 allogeneic SCT recipients were enrolled in the study to investigate the demographic characteristics, survival outcomes and prognostic factors.@*RESULTS@#With the median follow-up of 7.1 years, the estimated 10-year OS, FFS, GFFS were 86.0%, 60.5%, and 51.2%, respectively. Matched related donors (MRD, n = 28) showed better 10-year OS than unrelated donors (n = 15) (96.4% vs. 66.7%; P = 0.006). Engraftment failure was seen in 13 patients (30.2%). Donor-type aplasia was seen in 13.8% (4/29) after fludarabine (Flu)-based conditioning (Flu-group), while in 42.6% (6/14) after cyclophosphamide (Cy)-based regimen (Cy-group) (P = 0.035). Six patients died. The 10-year OS in Cy-group was 92.9% (n = 14, all MRD), while that of Flu-group was 82.1% (n = 29; P = 0.367). But Flu-group tended to have better FFS and GFFS than Cy-group, although Flu-group had less MRDs (41.4% vs. 100%; P = 0.019), and higher proportion of previous immunosuppressive treatment (IST; 62% vs. 21.4%, P = 0.012). In MRD transplants, OS was similar between Flu-group (100%, n = 14) and Cy-group (92.9%, n = 14), while FFS (100.0% vs. 42.9%; P = 0.001) and GFFS (85.7% vs. 35.7%; P = 0.006) were significantly better in Flu-group. Stem cell sources, irradiation in the conditioning, and method of GvHD prophylaxis did not significantly influence the outcome.@*CONCLUSION@#This study reviewed SCT outcomes for pediatric AA with changes of transplant strategies over the last 25 years. The FFS and GFFS were higher in Flu-group than in Cy-group, especially in matched related transplantation. Graft failure including donor-type aplasia remains troublesome even with Flu-based conditioning. Further refinement of transplant strategies to ensure better quality-of-life should be pursued.

Biphenotypic acute leukemia or acute leukemia of ambiguous lineage in childhood: clinical characteristics and outcome

BACKGROUND: Acute leukemia (AL), not clearly assigned to myeloid, B-lymphoid, or T-lymphoid lineage, is classified as either biphenotypic acute leukemia (BAL) based on the European Group for Immunological Classification of Leukemias (EGIL) or acute leukemia of ambiguous lineage (ALAL) encompassing acute undifferentiated leukemia (AUL) and mixed-phenotype acute leukemia (MPAL) based on the World Health Organization (WHO) criteria. METHODS: Medical records of children newly diagnosed with BAL or ALAL, based on the EGIL or the 2008/2016 WHO criteria, respectively, admitted at Chonnam National University Hospital in 2001–2017 were retrospectively reviewed. RESULTS: Twelve (3.2%) of 377 AL patients satisfied the BAL or ALAL definitions based on the EGIL or the WHO criteria, respectively. Among 12 patients including 11 with BAL and another with undefined case based on the EGIL criteria, 7 (1.9%) had ALAL based on more stringent 2016 WHO criteria (AUL, 2; MPAL, 5). One patient had MPAL with t(9;22)(q34;q11.2), BCR-ABL+, and two had MLL gene abnormality. ALL-directed regimen was associated with better complete remission rate compared with AML-directed regimen (100.0% vs. 16.7%; P=0.015). The 5-year overall survival (OS) and event-free survival (EFS) were 51.1±15.8% and 51.9±15.7%, respectively. AUL was associated with poor OS and EFS compared with MPAL (0.0% vs. 75.0±21.7%; P=0.008). CONCLUSION: Due to the rarity of the cases, future multicenter, prospective studies incorporating large number of cases are urgently warranted to identify the clinical, biologic, and molecular markers for the prediction of prognosis and determine the best tailored therapy for each patient.

Growing Teratoma Syndrome of the Pineal Gland Recognized Very Early during Chemotherapy in a Child with a Non-Germinomatous Germ-Cell Tumor / 임상소아혈액종양

The growing teratoma syndrome (GTS) is defined as the development of mature low-grade elements in the absence of a recurrent non-germinomatous germ-cell tumor (NGGCT) after partial response to multimodal treatment. It is uncommon and may occur in intracranial NGGCTs. Here, we report that a 7-year-old boy with intracranial NGGCT presented with precocious puberty and developed growing teratoma syndrome only 2 weeks after the first cycle of chemotherapy.

Growing Teratoma Syndrome of the Pineal Gland Recognized Very Early during Chemotherapy in a Child with a Non-Germinomatous Germ-Cell Tumor / 임상소아혈액종양

The growing teratoma syndrome (GTS) is defined as the development of mature low-grade elements in the absence of a recurrent non-germinomatous germ-cell tumor (NGGCT) after partial response to multimodal treatment. It is uncommon and may occur in intracranial NGGCTs. Here, we report that a 7-year-old boy with intracranial NGGCT presented with precocious puberty and developed growing teratoma syndrome only 2 weeks after the first cycle of chemotherapy.

Clinical Progress of Epilepsy in Children with Tuberous Sclerosis: Prognostic Factors for Seizure Outcome / 전남의대학술지

The incidence and outcome of epilepsy in tuberous sclerosis (TS) patients have not yet been thoroughly investigated. The aim of this study was to evaluate the clinical features and prognosis of epileptic seizures associated with TS. The medical records of 29 patients who satisfied the diagnostic criteria for TS and were followed up for at least 2 years at the Department of Pediatrics, Chonnam National University Hospital (CNUH), between January 2000 and December 2010 were reviewed. Onset age of seizure, initial electroencephalography (EEG) findings, and efficacy of treatment were evaluated. Brain imaging studies were reanalyzed to determine the number of cortical tubers and subependymal nodules present. A total of 26 (89.6%) cases presented with seizures. In the seizure-controlled group (n=9, 34.6%), the mean number of cortical tubers was 4.5 (range, 0-16) and the mean number of subependymal nodules was 6.2 (range, 0-14). Initial EEG identified epileptiform discharges in 4 (44.5%) of these cases. In the seizure-sustained group (n=17, 58.6%), 10 patients had initial seizures before 1 year of age. In this group, the mean number of cortical tubers was 6.0 (range, 0-20) and the mean number of subependymal nodules was 6.0 (range, 1-11). A total of 15 (88.2%) had epileptiform discharges on their initial EEGs. In three patients who did not show any seizures during the observation period, the mean number of cortical tubers was 1.3 (range, 0-2), and the mean number of subependymal nodules was 4.6 (range, 0-13). Medical intractability of epilepsy in conjunction with TS did not correlate with age at onset of seizure, the number of cortical tubers, or subependymal nodules, but was associated with initial EEG findings.

Clinicopathologic Characteristics and Prognostic Factors of Nonfunctioning Endocrine Tumor of the Pancreas

PURPOSE: Nonfunctioning endocrine tumors of the pancreas have no specific symptoms. Therefore, diagnosis is usually delayed and the malignancy rate at the time of diagnosis is reported to be higher than 50%. However, it is difficult to discriminate malignant from benign nonfunctioning endocrine tumors preoperatively. The purpose of this study was to investigate clinical characteristics of nonfunctioning endocrine tumors of the pancreas, including predictive factors of malignancy and prognostic factors affecting long-term survival. METHODS: Between 1992 and 2010, clinicopathological data of 53 patients with nonfunctioning endocrine tumors proven by surgical pathology were reviewed retrospectively. RESULTS: Of the 53 patients, mean age was 54 years-old and the male to female ratio was 1:1.2 Median follow up was 32.1 months. At the time of diagnosis, liver metastasis was detected in 4 patients. Curative resection was achieved in 49 patients, and 17% of them had recurrence, which was most common in liver. The overall 5-year survival rate was 85.1%. Both the WHO classification (p<0.001) and AJCC staging (p<0.001) correlated well with long-term survival. Univariate analysis revealed preoperative body weight loss (p<0.001), weak enhancement at the early arterial phase (p=0.043), lymph node metastasis (p<0.001), liver metastasis (p=0.001), perineural invasion (p=0.001), or lymphovascular invasion (p=0.010) as prognostic factors. CONCLUSION: Nonfunctioning endocrine tumor of the pancreas has favorable survival outcomes. Lymph node metastasis (p<0.001), liver metastasis (p=0.001), perineural invasion (p=0.001), and lymphovascular invasion (p=0.010) are poor prognostic factors.

Clinical Progress of Epilepsy in Children with Tuberous Sclerosis: Prognostic Factors for Seizure Outcome / 전남의대학술지

The incidence and outcome of epilepsy in tuberous sclerosis (TS) patients have not yet been thoroughly investigated. The aim of this study was to evaluate the clinical features and prognosis of epileptic seizures associated with TS. The medical records of 29 patients who satisfied the diagnostic criteria for TS and were followed up for at least 2 years at the Department of Pediatrics, Chonnam National University Hospital (CNUH), between January 2000 and December 2010 were reviewed. Onset age of seizure, initial electroencephalography (EEG) findings, and efficacy of treatment were evaluated. Brain imaging studies were reanalyzed to determine the number of cortical tubers and subependymal nodules present. A total of 26 (89.6%) cases presented with seizures. In the seizure-controlled group (n=9, 34.6%), the mean number of cortical tubers was 4.5 (range, 0-16) and the mean number of subependymal nodules was 6.2 (range, 0-14). Initial EEG identified epileptiform discharges in 4 (44.5%) of these cases. In the seizure-sustained group (n=17, 58.6%), 10 patients had initial seizures before 1 year of age. In this group, the mean number of cortical tubers was 6.0 (range, 0-20) and the mean number of subependymal nodules was 6.0 (range, 1-11). A total of 15 (88.2%) had epileptiform discharges on their initial EEGs. In three patients who did not show any seizures during the observation period, the mean number of cortical tubers was 1.3 (range, 0-2), and the mean number of subependymal nodules was 4.6 (range, 0-13). Medical intractability of epilepsy in conjunction with TS did not correlate with age at onset of seizure, the number of cortical tubers, or subependymal nodules, but was associated with initial EEG findings.

A sclerosing stromal tumor of the ovary with masculinization in a premenarchal girl / 소아과

A sclerosing stromal tumor of the ovary is an extremely rare benign tumor; it usually is found during the second and third decades of life. Patients present with pelvic pain or a palpable abdominal mass. Hormonal effects such as masculinization are uncommon. Here, an 11-year old premenarchal girl presented with deepening of the voice. In addition, clitoromegaly and hirsutism with a male suprapubic hair pattern were observed. The laboratory findings showed that the testosterone level was elevated to 3.67 ng/mL, andostenedione to above 10 ng/mL, dehydroepiandrosterone-sulfate to 346 microg/dL and 17-hydroxy progesterone (17-OHP) to 11.28 ng/mL. The chromosome evaluation revealed a 46,XX female karyotype. An adrenocorticotropic hormone stimulation test was performed. The 17-OHP to cortisol ratio in 30 minutes was 0.045, which suggested a heterozygote for the 21-hydroxylase deficiency. However, the CYP21A2 gene encoding steroid 21-hydroxylase showed normal. The pelvic ultrasound showed a heterogeneous mass consisting of predominantly solid tissue in the pelvic cavity. The pelvic magnetic resonance imaging revealed an 8.9x6.2x6.6 cm mass of the left ovary. A left oophrectomy was performed and microscopic examination confirmed a sclerosing stromal tumor. Immunohistochemical studies showed that the tumor was positive for smooth muscle actin and vimentin, but negative for S-100 protein and cytokeratin. Following surgery, the hormone levels returned to the normal range and the hirsutism resolved.

A case of imipramine induced toxicity with Brugada electrocardiographic pattern in a toddler / 소아과

Imipramine, a tricyclic antidepressant (TCA), is used for the treatment of non-polar depression and nocturnal enuresis in children in whom an organic pathology has been excluded, anxiety disorders, and neuropathic pain. Clinical toxicity following the treatment of TCAs, including imipramine, is well known. The anticholinergic effects initially present include a dry mouth, ileus, dilated pupils, urinary retention, and mild sinus tachycardia. The central nervous system toxicity includes delirium, agitation, restlessness, hallucinations, convulsions, and CNS depression or coma. However, the most life-threatening toxicity remains the development of cardiac dysrhythmias. Conduction delays such as QRS and corrected QT prolongation, wide QRS complex tachycardia, and the Brugada electrocardiographic pattern have been reported. Sodium bicarbonate decreases QRS widening and suppresses dysrhythmias by providing excess sodium to reverse the TCA-induced sodium-channel blockade and possibly by binding directly to the myocardium. There are no pediatric case reports on imipramine or other TCA associated toxicity in Korea. Here, we describe a patient who presented with convulsions, tachycardia with a wide QRS complex, a Brugada electrocardiographic pattern, and anuresis associated with an accidental overdose of imipramine and the outcome of treatment with sodium bicarbonate.

Dysphagia Following Stroke: Evaluation with Digital Radiography

PURPOSE: To evaluate the usefulness of digital radiography in the assessment of dysphagia following stroke. MATERIALS AND METHODS: Eighteen stroke patients (8 men, 10 women) referred for dysphagia and ten controls without known pharyngeal swallowing difficulty underwent digital radiography using a 1:1 mixture of barium and water. We evaluated oropharyngeal transit time and the location and severity of dysphagia; transit time was defined as the time from the first movement of the bolus to the return of the epiglottis to its original position. We sought to observe specific patterns of oropharyngeal dysfunction; dysphagia was classified as mild, moderate, or severe. RESULTS: In the control group, oropharyngeal transit time was 1.25sec (1.0-1.5sec), and for dysphagia patients, this was 4.32sec (1.75-6.5sec). Eleven patients (61%) had oral dysfunction, and 12 (67%), pharyngeal dysfunction; eight (44%) showed both oral and pharyngeal dysfunction. Mild swallowing difficulties occurred in six patients (33%), moderate dysfunction in six (33%), and severe dysfunction in three (17%). CONCLUSION: The dynamic image of the pharynx, as seen on a digital radiograph, may be diagnostically useful for defining the location and severity of dysphagia; in order to make feeding recommendations, this information is essential.

Usefulness of 3 Dimensional CT Angiography in the Diagnosis of Intracranial Aneurysms: Comparative Study with Conventional Angiography

PURPOSE: To assess the diagnostic capability of three-dimensional CT angiography(3D-CTA) in the diagnosis of intracranial aneurysms, compared with conventional angiography. MATERIALS AND METHODS: Twenty-two patients with intracranial aneurysms were studied using 3D-CTA and conventional angiography. Three-dimensional images were obtained with a helical CT scanner using SSD(shaded surface display) technique. 3D-CTA findings were retrospectively compared with conventional angiography with respect to lesion detection and delineation of the aneurysms. RESULTS: Of the 25 aneurysms demonstrated by conventional angiography, 23(92.0%) were detected by 3D-CTA. Aneurysmal necks were clearly visualized in 17 of 25 aneurysms(68.0%) with conventional angiography, and 19 of 23(82.6%) with 3D-CTA. And 3D-CTA is also superior to conventional angiography in aneurysmal delineation. CONCLUSION: 3D-CTA is thought to be a potential imaging modality in the evaluation of intracranial aneurysm, especially in aneurysmal delineation.

Percutaneous Transluminal Angioplasty of Chronic Arterial Occlusive Disease below the Knee Joint

PURPOSE: The purpose of this study was to determine the safety and efficacy of the percutaneous transluminal angioplasty(PTA) in patients with chronic arterial occlusive disease below the knee joint. MATERIALS AND METHODS: We retrospectively analyzed the results of 36 procedures in 16 patients. There were 15 men and one woman, aged 57-75 years(mean, 62 years). Indications were disabling claudication(SVS/ISCVS grade 1, category 3) in five cases, rest pain(grade 2, category 4) in three cases, and non-healing ulceration or gangrene(grade 3, category 5) ineight cases. PTA was performed by using small vessel balloon catheter of 2-4 mm and 3 mm monorail balloon catheterin tibioperoneal vessels and 5-6 mm balloon catheter in distal popliteal artery and tibioperoneal trunk. Combined thrombolytic therapy with Urokinase was performed in 14 patients. RESULTS: Involved infrapopliteal vessels werefour distal popliteal arteries, 15 tibioperoneal trunks, six anterior tibial arteries, five posterior tibialarteries, and seven peroneal arteries. Technical success was determined when post-PTA angiogram showed less than 30% of residual stenosis. Clinical success was defined as improvement of clinical symptoms, such as disappearance of claudication or rest pain, and healing of ulceration. Technical success was achieved in 30 of 36 arteries(83%). Clinical success was achieved in 12 of 16 patients(75%) at an average follow-up of 13.3 months(range, 2-46 months). Clinical success rate was 100% in grade 1 category 3 patients, 67% in grade 2 category 4 patients, and 63% in grade 3 category 5 patients. Complication included two distal emboli, one vessel rupture, one vessel thrombosis, and one occluding intimal flap. CONCLUSION: PTA was an effective method for treatment of chronicarterial occlusive disease below the knee joint and considered as the procedure of first choice. Severe claudicant(grade 1) should be included in the indication of the tibioperoneal PTA.

The effects of chromium exposure on sister chromatid exchange and concentration of 8-hydroxydeoxyguanosine / 예방의학회지

To elucidate some DNA adducts as a biological marker for workers of chromate pigment, the effects of chromium exposure on the formation of 8-hydroxydeoxyguanosine(8-OH-dG) and sister chromatid exchanges(SCEs) frequency in 38 workers of a pigment plant in Bucheon which utilized lead chromates, were examined. The chromium contents of venous blood and urine were measured as working environmental exposure level. The concentrations of 8-OH-dG in DNA isolated from lymphocytes were determined with high performance liquid chromatography and electrochemical detector and denoted as a molar ratio of 8-OH-dG to deoxyguanosine(dG). The SCEs frequency were analyzed in DNA isolated from lymphocytes. A significant correlation was found between creatinine adjusted urine chromium concentration and the molar ratio of 8-OH-dG to dG(r=0.47, p<0.01). After adjusting the current smoking habit, the correlation coefficient was increased(r=0.62, p<0.05). However, there was no significant correlation between the SCE frequency and chromium exposure. This significant results between molar ratio of 8-OH-dG to dG and chromium exposure are in good agreement with in vitro studies that support the importance of DNA adduct formation for the carcinogenic effect of chromium.