Pulmonary function in patients with transfusion-dependent thalassemia and its associations with iron overload.

In patients with transfusion-dependent thalassemia (TDT), pulmonary function impairment has been reported but data are conflicting. Moreover, it remains unclear whether pulmonary dysfunction is associated with iron overload. This study aimed to evaluate the pulmonary function in patients with TDT and to investigate the associations between pulmonary dysfunction and iron overload. It was a retrospective observational study. 101 patients with TDT were recruited for lung function tests. The most recent ferritin levels (pmol/L) and the magnetic resonance imaging (MRI) measurements of the myocardial and liver iron status, as measured by heart and liver T2* relaxation time (millisecond, ms) respectively, were retrieved from the computerized medical records. Only data within 12 months from the lung function measurement were included in the analysis. The serum ferritin, and the cardiac and liver T2* relaxation time were the surrogate indexes of body iron content. The threshold of abnormality in lung function was defined as under 80% of the predicted value. 101 subjects were recruited with a mean age of 25.1 years (standard deviation (SD) 7.9 years). Thirty-eight (38%) and five (5%) demonstrated restrictive and obstructive lung function deficits, respectively. A weak correlation of FVC %Predicted and TLC %Predicted with MRI myocardial T2* relaxation time (rho = 0.32, p = 0.03 and rho = 0.33, p = 0.03 respectively) was observed. By logistic regression, MRI cardiac T2* relaxation time was negatively associated with restrictive lung function deficit (B - 0.06; SE 0.03; Odds ratio 0.94; 95% confidence interval (CI) 0.89-0.99; p = 0.023) after adjusting for age, sex and body mass index. Restrictive pulmonary function deficit was commonly observed in patients with TDT, and the severity potentially correlates with myocardial iron content. Monitoring of lung function in this group of patients, particularly for those with iron overload, is important.

Outcomes of adolescents with acute lymphoblastic leukaemia.

INTRODUCTION: Compared with young children who have acute lymphoblastic leukaemia (ALL), adolescents with ALL have unfavourable disease profiles and worse survival. However, limited data are available regarding the characteristics and outcomes of adolescents with ALL who underwent treatment in clinical trials. The aim of this study was to investigate the causes of treatment failure in adolescents with ALL. METHODS: We retrospectively analysed the outcomes of 711 children with ALL, aged 1-18 years, who were enrolled in five clinical trials of paediatric ALL treatment between 1993 and 2015. RESULTS: Among the 711 children with ALL, 530 were young children (1-9 years at diagnosis) and 181 were adolescents (including 136 younger adolescents [10-14 years] and 45 older adolescents [15-18 years]). Compared with young children who had ALL, adolescents with ALL were less likely to have favourable genetic features and more likely to demonstrate poor early response to treatment. The 10-year overall survival and event-free survival rates were significantly lower among adolescents than among young children (77.9% vs 87.6%, P=0.0003; 69.7% vs 76.5%, P=0.0117). There were no significant differences in the 10-year cumulative incidence of relapse, but the 10-year cumulative incidence of treatment-related death (TRD) was significantly greater among adolescents (7.2%) than among young children (2.3%; P=0.002). Multivariable analysis showed that both younger and older adolescents (vs young children) had worse survival and greater incidence of TRD. CONCLUSION: Adolescents with ALL had worse survival because they experienced a greater incidence of TRD. There is a need to investigate optimal treatment adjustments and novel targeted agents to achieve better survival rates (without excessive toxicity) among adolescents with ALL.

Successful haploidentical hematopoietic stem cell transplantation (HSCT) and durable engraftment by repeated donor lymphocyte infusions for a Chinese patient with transfusion-dependent hemoglobin (Hb) Hammersmith and massive splenomegaly.

BACKGROUND: Hemoglobin (Hb) Hammersmith is a rare form of unstable ß-chain hemoglobinopathy causing hemolytic anemia. This rare event led to a more serious transfusion-dependent phenotype in a patient. It was successfully cured by haploidentical hematopoietic stem cell transplantation (HSCT). METHODS AND RESULTS: A 9-year-old mainland Chinese male with a history of neonatal unconjugated hyperbilirubinemia was diagnosed to have hemoglobin (Hb) Hammersmith. He required regular blood transfusion but was unable to be transfused to desired parameters for 8 years prior to transplant due to social and geographical reasons. He subsequently developed marrow hyperplasia and progressive splenomegaly (down to umbilicus level), suggestive of extramedullary hematopoiesis. Eventually, the family came to Hong Kong and complied to a more intensive transfusion regimen and preconditioning chemotherapy 3 months prior to transplant. He underwent haploidentical HSCT using paternal TCRαß/CD45RA-depleted graft but suffered from graft rejection, despite splenic irradiation for massive splenomegaly. It was successfully salvaged with second HSCT with unmanipulated graft from the same donor with additional serotherapy and donor lymphocyte infusions. CONCLUSION: Allogenic haploidentical HSCT for hemoglobin Hammersmith is feasible but adequate immunosuppression during conditioning is crucial. Precise adoptive cell therapy can promote durable engraftment.

Optimization of a solid culture medium based on Monochamus alternatus for Cordyceps militaris fruiting body formation.

Monochamus alternatus (Coleoptera: Cerambycidae; M. alternatus), popularly known as the Japanese pine sawyer, is a vector of pinewood nematode (Bursaphelenchus xylophilus) that causes pine wilt disease. A solid medium culture with M. alternatus produced Cordyceps militaris fruiting bodies with the longest strips and the highest biological efficiency. Supplementing the original form of M. alternatus with oats resulted in slightly enhanced fruiting body production. The original form of M. alternatus showed higher production than its powder form. The solid culture medium was optimized using a response surface methodology, and the optimal medium contained the following: 8·5 g per bottle of M. alternatus and 11·5 g per bottle of oats mixed with 22·4 ml of water in a 300-ml cylindrical plastic bottle. The optimal culturing period for the fruiting body formation was 37·1 days. Under these conditions, a fruiting body dry weight of 38·0 g per bottle (actual value) was attained. The fruiting body produced using a solid culture medium based on M. alternatus had a cordycepin content of about 25 µg g-1 . The solid culture medium containing M. alternatus is highly efficient and eco-friendly, and its effectiveness in large-scale fruiting body production from C. militaris has been demonstrated.

Outcomes of allogeneic transplantation for hemoglobin Bart's hydrops fetalis syndrome in Hong Kong.

BACKGROUND: Hemoglobin Bart's hydrops fetalis syndrome (BHFS) was once considered a fatal condition universally. Medical advances over the past three decades have resulted in increasing numbers of BHFS survivors. This retrospective review summarized local territory-wide experience and outcomes of BHFS patients who received allogeneic hematopoietic stem cell transplantation (HSCT) in Hong Kong. METHODS: All BHFS patients who underwent allogeneic HSCT in Hong Kong, either in one of the two former pediatric transplant centers (Queen Mary Hospital and Prince of Wales Hospital) on or before 2019 or in the single territory-wide pediatric transplant center (Hong Kong Children's Hospital) since 2019, from January 1, 1996, till December 31, 2020, were included. Basic demographic data, perinatal history, transplant details, long-term outcomes, and morbidities were reviewed. RESULTS: Total five allogeneic HSCT were performed in two males and three females at a median age of 22 months, which include one 8/8 matched-sibling bone marrow transplant, one 5/6 matched-sibling cord blood transplant with HLA-DR antigenic mismatch, two 12/12 matched-unrelated peripheral blood stem cell transplant (PBSCT), and one haploidentical PBSCT with TCRαß/CD45RA depletion from maternal donor. Neutrophil and platelet engrafted (>20 × 109 /L) at a median of 15 and 22 days, respectively. All achieved near full donor chimerism at 1 month. All patients survived and remained transfusion-independent without significant morbidities with median follow-up duration of 10 years. CONCLUSION: To conclude, local data demonstrated favorable outcome of allogeneic HSCT for BHFS patients, but sample number is small. Non-directive approach in counseling and international collaboration is recommended.

Severe cytomegalovirus gastritis after pembrolizumab in a patient with melanoma.

Immunotherapy has emerged as a standard of cancer treatment, with an increasing number of indications. Recently, opportunistic infections have been reported in several cases in which immunotherapy has led to an increased susceptibility to infection. The present case is the first report of cytomegalovirus (cmv) gastritis occurring in a patient with melanoma during immunotherapy without immune-related adverse events (iraes) and without the use of immunosuppressant agents. A 43-year-old woman presented with stage iii malignant melanoma. She underwent wide excision of skin, with lymph node dissection, and she started immunotherapy with a 3-week cycle of pembrolizumab. The patient demonstrated stable disease response, and no iraes were observed during her initial treatment courses. However, after the 9th treatment cycle, she began to experience epigastric pain that worsened significantly, requiring a visit to the emergency centre. Imaging by computed tomography (ct) and integrated positron-emission tomography/ct revealed severe diffuse gastroduodenitis with acute pancreatitis. Esophagogastroduodenoscopy showed diffuse oozing, hemorrhagic, edematous, and exfoliative mucosa involving the entire gastric wall, defined as acute hemorrhagic gastritis. Biopsies of the gastric wall revealed cmv infection. Those findings were consistent with a diagnosis of cmv gastritis, and the patient received antiviral therapy with ganciclovir. After treatment, she recovered enough to resume immunotherapy. This case report presents a rare occurrence of cmv gastritis related to immunotherapy. As more patients are treated with immunotherapy, incidences of cmv infections are expected to increase; a high index of clinical suspicion is therefore needed in symptomatic patients.

Outcomes and morbidities of patients who survive haemoglobin Bart's hydrops fetalis syndrome: 20-year retrospective review.

INTRODUCTION: Haemoglobin Bart's hydrops fetalis syndrome was once considered a fatal condition. However, advances over the past two decades have enabled survival of affected patients. Data relating to their morbidities and outcomes will help medical specialists formulate a management plan and parental counselling. METHODS: All babies with the syndrome who survived beyond the neonatal period and were subsequently managed long-term in eight public hospitals in Hong Kong from 1 January 1996 to 31 December 2015 were included. Patient and parent characteristics, antenatal care, reasons for continuation of pregnancy, intrauterine interventions, perinatal course, presence of congenital malformations, stem-cell transplantation details, and long-term neurodevelopmental outcomes were reviewed. RESULTS: A total of nine patients were identified, of whom five were female and four male. The median follow-up duration was 7 years. All were Chinese and were homozygous for the Southeast Asian α-thalassaemia deletion. Five of the nine mothers received antenatal care at a public hospital and opted to continue the pregnancy after antenatal diagnosis and counselling. Despite intrauterine transfusions, all babies were born with respiratory depression and required intubation and mechanical ventilation during the neonatal period. Hypospadias was identified in all four male infants. Growth retardation, global developmental delay, and residual neurological deficits were noted in two-thirds of the patients. Haematopoietic stem-cell transplantation was performed in two patients, who became transfusion-independent. CONCLUSIONS: Survival of patients with Bart's hydrops fetalis syndrome is possible but not without short- and long-term complications; local epidemiology is comparable to that documented for an international registry. Detailed antenatal counselling of parents with a non-judgemental attitude and cautious optimism are imperative.

Autonomic function test in progressive lacunar infarction.

OBJECTIVE: Neurological progression is a major problem in managing the patients with acute lacunar infarction. The purpose of this was to investigate whether autonomic dysfunction is associated with neurological progression in patients with acute lacunar infarction. MATERIALS AND METHODS: The study comprised 60 patients with acute lacunar infarction. All enrolled subjects underwent autonomic function tests including the 30° head-up tilt test, Valsalva test, heart rate response to deep breathing, and sympathetic skin response. The primary endpoint is the neurological progression, and the secondary endpoint is the 3-month outcome. RESULTS: Increased initial National Institute of Health stroke scale (NIHSS), decreased time to admission from onset, decreased rise of heart rate in the 30° head-up tilt test, abnormal blood pressure response in the Valsalva test, and decreased rise of systolic blood pressure in stage IV of the Valsalva test are associated with neurological progression of acute lacunar infarction; an abnormal blood pressure response in the Valsalva test is significant in logistic regression analysis of neurological progression. Advanced age, increased initial NIHSS and modified Rankin scale, decreased expiration/inspiration ratio of heart rate to deep breathing, decreased rise of systolic blood pressure in stage IV of the Valsalva test, and neurological progression were associated with an unfavorable 3-month outcome; neurological progression was significant in logistic regression analysis of 3-month outcome. CONCLUSIONS: An abnormal blood pressure change in the Valsalva test is associated with neurological progression in patients with acute lacunar infarction, and neurological progression can induce an unfavorable 3-month outcome.

Progressive topological disorganization of brain network in focal epilepsy.

OBJECTIVE: Increasing evidence has suggested that epilepsy is a network disease. Graph theory is a mathematical tool that allows for the analysis and quantification of the brain network. We aimed to evaluate the influences of duration of epilepsy on the topological organization of brain network in focal epilepsy patients with normal MRI using the graph theoretical analysis based on diffusion tenor imaging. METHODS: We prospectively enrolled 66 patients with focal epilepsy (18/66 patients were newly diagnosed) and 84 healthy subjects. All of the patients with epilepsy had normal MRI on visual inspection. All of the subjects underwent diffusion tensor imaging that was analyzed using graph theory to obtain network measures. RESULTS: The measures of characteristic path length and small-worldness in the patients with focal epilepsy were significantly decreased, even after multiple corrections (P < .01). Moreover, the measures including mean clustering coefficient and global efficiency in the patients with epilepsy had strong tendency to decrease compared to those in healthy subjects (P = .0153 and P = .0138, respectively). When comparing the measures among the patients with newly diagnosed/chronic epilepsy and healthy subjects using ANOVA, the characteristic path length (P = .006), small-worldness (P = .032), and global efficiency (P = .004) were significantly different. In addition, the duration of epilepsy was negatively correlated with global efficiency (r = -.249, P = .0454). CONCLUSIONS: We newly found a progressive topological disorganization of the brain network in focal epilepsy. In addition, we demonstrated disrupted topological organization in focal epilepsy, shifting toward a more random state.

Comparison of the paediatric blade of the Pentax-AWS and Ovassapian airway in fibreoptic tracheal intubation in patients with limited mouth opening and cervical spine immobilization by a semi-rigid neck collar: a randomized controlled trial.

BACKGROUND: We compared the performances of the paediatric blade of a Pentax Airway Scope and an Ovassapian airway in fibreoptic tracheal intubation in patients whose necks were stabilized by semi-rigid neck collars. METHODS: Ninety patients were enrolled in this prospective, open-label, randomized controlled trial. Patients were randomly allocated to one of two groups (Group OVA-FOB and Group AWS-FOB). The time to tracheal intubation, success rate of tracheal intubation, number of optimization manoeuvres (jaw thrust), and difficulty of manipulation of the fibreoptic bronchoscope were compared between the groups. RESULTS: The time to tracheal intubation was significantly shorter (32 vs 50 s; median difference 19 s; 95% confidence interval 14-25 s; P<0.001) and manipulation of the fibreoptic bronchoscope was significantly easier for Group AWS-FOB. Optimization manoeuvres were rarely required to facilitate fibreoptic tracheal intubation in Group AWS-FOB [jaw thrust, 0 (0%); jaw thrust with anterior neck collar removal, 1 (2%)] compared with that required in Group OVA-FOB [jaw thrust, 39 (87%); jaw thrust with anterior neck collar removal, 2 (4%)]. There was no significant difference in the success rate of tracheal intubation on the first attempt between groups [Group AWS-FOB, 45 (100%); Group OVA-FOB, 44 (98%)]. CONCLUSIONS: Combined use of the paediatric blade of a Pentax Airway Scope and a fibreoptic bronchoscope enabled rapid tracheal intubation, minimizing the use of external manoeuvres of the airway, in patients with limited mouth opening and cervical spine immobilization by semi-rigid neck collars, compared with use of the Ovassapian airway and the fibreoptic bronchoscope. CLINICAL TRIAL REGISTRATION: NCT02827110.

Effective connectivity in temporal lobe epilepsy with hippocampal sclerosis.

OBJECTIVE: We hypothesized that temporal lobe epilepsy (TLE) patients with and without hippocampal sclerosis (HS) showed differences in their limbic networks. This study aimed to evaluate the role of the thalamus in TLE patients with HS. MATERIALS AND METHODS: Twenty-nine TLE patients with HS and 30 controls were enrolled in this study. In addition, we included eight TLE patients without HS as a disease control group. Using whole-brain T1-weighted MRIs, we analyzed the volumes of the limbic structures, including the hippocampus, thalamus, and total cortex, with FreeSurfer 5.1. We also investigated the effective connectivity among these structures using SPSS Amos 21 based on these volumetric measures. Moreover, we quantified correlations between epilepsy duration and the volumes of these structures. RESULTS: There was a statistically significant effective connectivity from the hippocampus to the thalamus in TLE patients with HS. Moreover, the volumes of the left and right thalamus were negatively correlated with epilepsy duration (r=-.42, P=.0315 and r=-.52, P=.0062, respectively). However, neither TLE patients without HS nor normal controls had a significant effective connectivity from the hippocampus to the thalamus. CONCLUSIONS: The limbic networks of TLE patients with and without HS could be different, and the thalamus might play a critical role in TLE patients with HS.

Inhibitor development after liver transplantation in congenital factor VII deficiency.

Congenital factor VII (FVII) deficiency is the commonest type of the rare bleeding disorders. Very few cases of congenital FVII deficiency developed inhibitor and liver transplant is considered as definitive treatment. In the literature, twelve patients with congenital FVII deficiency developed inhibitors. Two had spontaneous resolution of inhibitors and one did not respond to high dose recombinant factor VIIa (rFVIIa) and died. Regarding liver transplant in congenital FVII patients, seven patients underwent liver transplant with good prognosis. We report a 5-year-old girl with confirmed severe congenital FVII deficiency since neonatal period. She suffered from recurrent intracranial bleeding despite rFVIIa replacement. After auxiliary liver transplant at the age of 4, she continued to show persistent deranged clotting profile and was found to have inhibitor towards FVII. Interestingly, she was still responsive to rFVIIa replacement.

Cyclosporin A for persistent or chronic immune thrombocytopenia in children.

Twenty percent of children with immune thrombocytopenia (ITP) develop a chronic course where treatment strategy is less established. Cyclosporin A (CSA) has been shown to be effective in small series of children with chronic ITP and might reduce the need for chronic steroid therapy and/or splenectomy. We reviewed consecutive patients below 18 years old with persistent or chronic ITP treated with CSA in our unit between January 1998 and June 2015. Thirty patients (14 boys and 16 girls) were included. The median age at initial diagnosis of ITP was 5 years (range 0.5-16.2 years). CSA was started at a median of 13.9 months (range 3.4-124 months) after initial diagnosis and given for a median duration of 9.3 months (range 0.2-63.9 months). The median platelet count before commencement was 12 × 10(9)/L (range 4-199 × 10(9)/L). The median dose of CSA was 6 mg/kg/day (range 2.4-7.5 mg/kg/day). Complete response (CR) or response (R) was achieved in 17 patients (57 %), and 7 (23 %) had sustained response. Side effects (most commonly hirsutism) were tolerable and reversible. CSA appeared effective in about half of persistent or chronic ITP patients and safe as a second-line agent in managing these children.

Remission With Donor Lymphocyte Infusion in a Child With Marrow Relapse After Haploidentical Stem Cell Transplantation for Relapsed Stage 4 Neuroblastoma.

A 7-year-old male with Stage 4 neuroblastoma was treated with chemotherapy and autologous hematopoietic stem cell transplantation (HSCT), resulting in partial response with residual bone and marrow disease. He proceeded to haploidentical-HSCT with his mother as donor and achieved remission. The patient developed marrow relapse 2 years after haploidentical-HSCT with cytopenia and dropping donor chimerism. Donor lymphocyte infusion (DLI) using mother's whole blood was given resulting in clearance of marrow disease, resolution of cytopenia, and full donor chimerism. This is the first report of successful treatment for neuroblastoma relapse after haploidentical-HSCT using DLI alone, supporting the role of adoptive cell therapy post-HSCT in neuroblastoma.

Cerebral hemodynamics in orthostatic intolerance with normal head-up tilt test.

OBJECTIVES: Orthostatic hypotension (OH) and postural orthostatic tachycardia syndrome (POTS) are well-known causes of orthostatic intolerance (OI). In addition, there are OI patients who are characterized by the symptoms of OI and lack of abnormal findings in head-up tilt (HUT) test. The aim of this study was to determine the cerebral hemodynamic changes in HUT test of OI patients with normal HUT (OINH). MATERIALS AND METHODS: Two hundred and sixty-one OI patients and 50 healthy controls were enrolled in this study. All subjects underwent transcranial Doppler test while performing the HUT test. Forty-five patients had OH, 33 patients had POTS, and 183 patients had OINH. Blood pressures, heart rate, cerebral blood flow velocities (CBFVs), end-tidal carbon dioxide (ET-PCO2 ), cerebral critical closing pressure (CCP), cerebral perfusion pressure (CPP), and cerebral vascular resistance (CVR) were measured during HUT test. We compared the hemodynamic parameters of OINH with those of OH, POTS, and healthy controls. RESULTS: Reduced CBFVs, CPP, and ET-PCO2 and elevated CCP were observed in the HUT test of all four groups. CVR was reduced in three OI patients. The drops in systolic CBFV, CPP, and CVR of OINH patients were greater than those of healthy controls. The changes in parameters in the HUT test of OINH group were not different from those of OH and POTS groups except prominent decrements of CPP and CVR in OH group. CONCLUSION: Our findings suggest that OINH is true OI sharing the common pathomechanism of OH and POTS.

Brain morphology in juvenile myoclonic epilepsy and absence seizures.

OBJECTIVE: We evaluated the differences in brain morphology among patients with juvenile myoclonic epilepsy according to the occurrence of absence seizures. MATERIALS AND METHODS: Twenty-one juvenile myoclonic epilepsy patients with (n = 6) and without (n = 15) absence seizures were enrolled. We analyzed whole-brain T1-weighted magnetic resonance imaging using FreeSurfer 5.1. Measures of cortical morphology, such as thickness, surface area, volume, and curvature, and the volumes of subcortical structures, the cerebellum, and cerebrum, were compared between the groups. Moreover, we quantified correlations between clinical variables and each measures of abnormal brain morphology. RESULTS: Compared to normal controls, patients without absence seizures demonstrated thinning of the cortical thickness in the right hemisphere, including the post-central, lingual, orbitofrontal, and lateral occipital cortex. Compared to normal controls, patients with absence seizures had more widespread thinning of the cortical thickness, including the right post-central, lingual, orbitofrontal, and lateral occipital cortexes as well as the right inferior temporal cortex. Additionally, the volume of cerebellar white matter in patients without absence seizures was significantly smaller than that in normal controls. Patients with absence seizures had a much smaller cerebellar white matter volume than normal controls or patients without absence seizures. Moreover, there was significantly positive correlation between the age of seizure onset and the volume of cerebellar white matter in patients with juvenile myoclonic epilepsy. CONCLUSIONS: We demonstrated that there were significant brain morphology differences in patients with juvenile myoclonic epilepsy according to the presence of absence seizures. These findings support the hypothesis that juvenile myoclonic epilepsy may be a heterogeneous syndrome.

Refractory acute lymphoblastic leukemia in Chinese children: bridging to stem cell transplantation with clofarabine, cyclophosphamide and etoposide.

Refractory or relapsed acute lymphoblastic leukemia (r/r ALL) represents the leading cause of cancer mortality in children. Clofarabine is effective in inducing remission thus enabling bridging to hematopoietic stem cell transplantation (HSCT). We report the results in treating Hong Kong Chinese pediatric patients with r/rALL by clofarabine/cyclophosphamide/etoposide (CLO-218) combination therapy. A retrospective review of patients treated between January 2009 and December 2014 in the two tertiary referral pediatric oncology units in Hong Kong. Thirteen patients were identified. All were Chinese and seven were male. Median age at clofarabine treatment was 8 years and the median duration of follow-up was 10 months. Nine patients had B-ALL and four had T-ALL. All were refractory to the preceding regimen(s). The median number of prior treatment regimens was 2; two patients had previous HSCT. Complete remission (CR) was achieved in five patients, Complete remission with incomplete counts (CRi) in two, PR in two, and non-remission (NR) in two. All four patients with T-ALL responded with three patients achieving CR. Eight out of nine patients who responded could be bridged to HSCT. Among those who were transplanted, four remained alive and in remission, three relapsed post-HSCT, and one died from transplant-related mortality. Treatment toxicities were common including febrile neutropenia in all subjects and culture-proven bacteremia in five patients. Hepatotoxicity was mild and reversible with no case of veno-occlusive disease. The clofarabine-based regimen is a promising strategy to induce disease remission in r/rALL and bridge to HSCT. Septic complications are, however, frequent necessitating prompt management with adequate supportive care in specialized centers.