Anthony Pak-Yin Liu

Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and HPV-6/11/16/18 vaccine administered according to 2- and 3-dose schedules in girls aged 9–14 years: Results to month 12 from a randomized trial

This observer-blind study (clinicaltrials.gov NCT01462357) compared the immunogenicity and safety of 2 doses of the HPV-16/18 AS04-adjuvanted vaccine (HPV-16/18(2D)) vs. 2 or 3 doses of the HPV-6/11/16/18 vaccine (HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D)) in healthy girls aged 9–14 y. Girls were randomized (1:1:1) to receive HPV-16/18(2D) at months (M) 0,6 (N = 359), HPV-6/11/16/18(2D) at M0,6 (N = 358) or HPV-6/11/16/18(3D) at M0,2,6 (N = 358). The primary objective was non-inferiority/superiority of HPV-16/18 antibodies by ELISA for HPV-16/18(2D) vs. HPV-6/11/16/18(2D) at M7 in the according-to-protocol immunogenicity cohort (ATP-I) and total vaccinated cohort, respectively. Secondary objectives included non-inferiority/superiority of HPV-16/18(2D) vs. HPV-6/11/16/18(3D) at M7, non-inferiority/superiority at M12, HPV-16/18 neutralizing antibodies, frequencies of T-cells/B-cells, reactogenicity and safety. Antibody responses at M7 for HPV-16/18(2D) were superior to those for HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D) (lower limit of 95% confidence interval for geometric mean titer ratio (GMR) was >1): HPV-16/18(2D)/HPV-6/11/16/18(2D) GMRs were 1.69 [1.49–1.91] for anti-HPV-16 and 4.52 [3.97–5.13] for anti-HPV-18; HPV-16/18(2D)/HPV-6/11/16/18(3D) GMRs were 1.72 [1.54–1.93] for anti-HPV-16 and 3.22 [2.82–3.68] for anti-HPV-18; p = 0.0001 for all comparisons. Non-inferiority/superiority was also demonstrated at M12. Among initially seronegative girls in the ATP-I, neutralizing antibody titers were at least 1.8-fold higher for HPV-16/18(2D) vs. HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D) at M7 and M12. Frequencies of HPV-16/18-specific T-cells and B-cells were in similar ranges between groups. Reactogenicity and safety were in line with the known profile of each vaccine. In conclusion, superior HPV-16/18 antibody responses were elicited by 2 doses of the HPV-16/18 AS04-adjuvanted vaccine compared with 2 or 3 doses of the HPV-6/11/16/18 vaccine in girls (9–14 years).

Under-recognition of 22q11.2 deletion in adult Chinese patients with conotruncal anomalies: implications in transitional care.

22q11.2 deletion syndrome (22q11.2DS) is a multi-systemic disorder with high phenotypic variability. Under-diagnosis in adults is common and recognition of facial dysmorphic features can be affected by age and ethnicity. This study aims to determine the prevalence of undiagnosed 22q11.2DS in adult Chinese patients with conotruncal anomalies and to delineate their facial dysmorphisms and extra-cardiac manifestations. We recruited consecutively 156 patients with conotruncal anomalies in an adult congenital heart disease (CHD) clinic in Hong Kong and screened for 22q11.2DS using fluorescence-PCR and fluorescence in-situ hybridization. Assessment for dysmorphic features was performed by a cardiologist at initial screening and then by a clinical geneticist upon result disclosure. Clinical photographs were taken and childhood photographs collected. Eighteen patients (11.5%) were diagnosed with 22q11.2DS, translating into 1 previously unrecognized diagnosis of 22q11.2DS in every 10 adult patients with conotruncal anomalies. While dysmorphic features were detected by our clinical geneticist in all patients, only two-thirds were considered dysmorphic by our cardiologist upon first assessment. Evolution of facial dysmorphic features was noted with age. Extra-cardiac manifestations included velopharyngeal incompetence or cleft palate (44%), hypocalcemia (39%), neurodevelopmental anomalies (33%), thrombocytopenia (28%), psychiatric disorders (17%), epilepsy (17%) and hearing loss (17%). We conclude that under-diagnosis of 22q11.2DS in Chinese adults with conotruncal defects is common and facial dysmorphic features may not be reliably recognized in the setting of adult CHD clinic, referral for genetic evaluation and molecular testing for 22q11.2DS should be offered to patients with conotruncal defects.

Timing of adjuvant radiotherapy and treatment outcome in childhood ependymoma

Several trials incorporating adjuvant focal RT for treatment of young children with ependymoma have demonstrated improved survival with acceptable adverse effects. The optimal timing of RT administration is, however, unknown.

A newborn with a 790 kb chromosome 17p13.3 microduplication presenting with aortic stenosis, microcephaly and dysmorphic facial features - is cardiac assessment necessary for all patients with 17p13.3 microduplication?

While deletion of chromosome 17p13.3 (encompassing PAFAH1B1 and YWHAE genes) is known to result in Miller-Dieker syndrome (OMIM 247200), 17p13.3 microduplication gives rise to a condition commonly associated with developmental delay and autism spectrum disorder. We report a Chinese newborn presenting with dysmorphic features, microcephaly and valvar aortic stenosis, who was confirmed to have a 790 kb microduplication in chromosome 17p13.3 by array comparative genomic hybridization (aCGH). The patient passed away at 4 months of age with presumably life-threatening event associated with his cardiac condition. From literature review, congenital heart diseases of various kinds were identified in up to 20% of patients with 17p13.3 microduplication. We propose cardiac assessment should be part of the comprehensive evaluation of these patients.

Expanded Prader–Willi syndrome due to chromosome 15q11.2–14 deletion: Report and a review of literature†

We report on a male infant with de novo unbalanced t(5;15) translocation resulting in a 17.23 Mb deletion within 15q11.2–q14 and a 25.12 kb deletion in 5pter. The 15q11.2–q14 deletion encompassed the 15q11.2–q13 Prader–Willi syndrome (PWS) critical region and the recently described 15q13.3 microdeletion syndrome region while the 5pter deletion contained no RefSeq genes. From our literature review, patients with similar deletions in chromosome 15q exhibit expanded phenotype of severe developmental delay, protracted feeding problem, absent speech, central visual impairment, congenital malformations and epilepsy in addition to those typical of PWS. The patient reported herein had previously unreported anomalies of mega cisterna magna, horseshoe kidney and the rare neonatal interstitial lung disease known as pulmonary interstitial glycogenosis. Precise breakpoint delineation by microarray is useful in patients with atypical PWS deletions to guide investigation and prognostication.

Chinese medical students’ knowledge, attitude and practice towards human papillomavirus vaccination and their intention to recommend the vaccine

The human papillomavirus (HPV) vaccine is effective in preventing cervical cancer, but its global uptake rate in vulnerable populations is unsatisfactory. Physicians recommendation is an important determinant for vaccine uptake, but we have limited understanding on the contributing factors of physicians recommendation. This study investigated whether the knowledge, attitudes and vaccination status of medical students would affect their intention to recommend HPV vaccination.

De novo large rare copy-number variations contribute to conotruncal heart disease in Chinese patients

Conotruncal heart anomalies (CTDs) are particularly prevalent congenital heart diseases (CHD) in Hong Kong. We surveyed large (>500 kb), rare (<1% frequency in controls) copy-number variations (CNVs) in Chinese patients with CTDs to identify potentially disease-causing variations. Adults who tested negative for 22q11.2 deletions were recruited from the adult CHD clinic in Hong Kong. Using a stringent calling criteria, high-confidence CNV calls were obtained, and a large control set comprising 3,987 Caucasian and 1,945 Singapore Chinese subjects was used to identify rare CNVs. Ten large rare CNVs were identified, and 3 in 108 individuals were confirmed to harbour de novo CNVs. All three patients were syndromic with a more complex phenotype, and each of these CNVs overlapped regions likely to be important in CHD. One was a 611 kb deletion at 17p13.3, telomeric to the Miller–Dieker syndrome (MDS) critical region, overlapping the NXN gene. Another was a 5 Mb deletion at 13q33.3, within a previously described critical region for CHD. A third CNV, previously unreported, was a large duplication at 2q22.3 overlapping the ZEB2 gene. The commonly reported 1q21.1 recurrent duplication was not observed in this Chinese cohort. We provide detailed phenotypic and genotypic descriptions of large rare genic CNVs that may represent CHD loci in the East Asian population. Larger samples of Chinese origin will be required to determine whether the genome-wide distribution differs from that found in predominantly European CHD cohorts.

Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and 4vHPV vaccine administered according to two- or three-dose schedules in girls aged 9–14 years: Results to month 36 from a randomized trial

This observer-blind study (clinicaltrials.gov NCT01462357) compared the immunogenicity and safety of two doses (2D) of the HPV-16/18 AS04-adjuvanted vaccine (2D of AS04-HPV-16/18) vs. two or three doses of the 4vHPV vaccine [2D or 3D of 4vHPV] in 1075 healthy girls aged 9-14 years. Girls were randomized (1:1:1) to receive 2D of AS04-HPV-16/18 at months (M) 0, 6 (N = 359), 2D of 4vHPV at M0, 6 (N = 358) or 3D of 4vHPV at M0, 2, 6 (N = 358). 351, 339 and 346 girls, respectively, returned for the concluding visit at M36. Superiority was demonstrated at M7 and M12; comparison of the immune response to both vaccine antigens was made between 2D of AS04-HPV-16/18 and 2D or 3D of 4vHPV at subsequent time points in the according-to-protocol immunogenicity cohort (ATP-I; N = 958 at M36) and the total vaccinated cohort (TVC: N = 1036 at M36). HPV-16/18-specific T-cell- and B-cell-mediated immune responses and safety were also investigated. At M36, anti-HPV-16/18 ELISA responses in the 2D AS04-HPV-16/18 group remained superior to those of the 2D and 3D 4vHPV groups. In the M36 TVC, geometric mean titers were 2.78-fold (HPV-16) and 6.84-fold (HPV-18) higher for 2D of AS04-HPV-16/18 vs. 2D of 4vHPV and 2.3-fold (HPV-16) and 4.14-fold (HPV-18) higher vs. 3D of 4vHPV. Results were confirmed by vaccine pseudovirion-based neutralisation assay. Numbers of circulating CD4+ T cells and B cells appeared similar across groups. Safety was in line with the known safety profiles of both vaccines. In conclusion, superior HPV-16/18 antibody responses were elicited by 2D of the AS04-HPV-16/18 compared with 2D or 3D of the 4vHPV vaccine in girls aged 9-14 years. CLINICAL TRIAL REGISTRATION NCT0146235.

Donor lymphocyte infusion reversed graft rejection in matched-unrelated donor hematopoietic stem cell transplantation for a child with thalassemia

Dear Editor, Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only well-established curative treatment in thalassemia. Transplants with matched-unrelated donors (MUD) resulted in thalassemia-free survival of 70–90% at 2–3 years in pediatric series [1, 2]. Mixed-chimerism, however, occurs in one-third of patients and may herald graft rejection [3]. We report a child who experienced early graft rejection with extremely low level of donor-chimerism salvaged by donor lymphocyte infusion (DLI). A Chinese boy with β-thalassemia major (homozygous IVS-II-654 C > T) was referred to us at 30 months for HSCT. Examination showed hepatomegaly 2 cm below costal margin and splenomegaly 5 cm below costal margin. Deferasirox had been started at 27 months, but there was significant iron overloading with serum ferritin of 11,236 pmol/ L. Chelation was intensified with addition of deferoxamine. He had no sibling, and thus a MUD of the same ethnicity (male, 41 years of age, HLA-A/B/C/DRB1/DQB1 matched at allelic level) was identified. The child was 3.5 years old at the time of HSCT, with a ferritin level of 6495 pmol/L and MRI T2* study showing moderate hepatic iron overloading but no cardiac iron overloading. Preconditioning with hydroxyurea and azathioprine, followed by conditioning with cyclophosphamide, busulphan, and fludarabine were given [2] (Fig. 1). Graft-versus-host disease (GvHD) prophylaxis consisted of thymoglobulin, shortcourse methotrexate, mycophenolate mofetil, and cyclosporin. Bone marrow harvest from donor yielded a stem cell product (post red-cell depletion for major blood group mismatch, B to O) with a total nucleated cell count of 1.6 × 10/kg and CFU-GM of 4.5 × 10/kg. The transplantation course was complicated by mucositis and Stenotrophomonas septicemia. Neutrophil engrafted (>0.5 × 10/L) on day + 24, and platelet engrafted (>20 × 10/L) on day + 45. There was no acute GvHD. Whole-blood chimerism study on day + 30, nevertheless, showed only 53% donor cells. There was progressive drop in donor-chimerism despite trial of increment followed by withdrawal of cyclosporin, the patient remained transfusiondependent (Fig. 1). The first dose of DLI (CD3 dose 1 × 10/kg) was given on day + 94 when the donor granulocyte chimerism reached a nadir of 2%. Two weeks later, a second dose of DLI (CD3 dose 1 × 10/kg) was given. This was followed by pancytopenia, fever, and transaminitis suggestive of hepatic GvHD which settled with introduction of tacrolimus. Concomitant increase in donor-chimerismwas observed, and the patient was rendered transfusion-independent since day + 154. The patient did not develop chronic GvHD. Andreani et al. described the outcome of thalassemia patients with mixed-chimerism post-HSCT [4]. Residual host cells of more than 25%, especially detected within 2 months post-transplantation, were predictive of graft rejection. DLI has been used to salvage a dropping donor-chimerism by enhancement of graft-versus-host alloreactivity, but data is scarce [5, 6]. Treatment with DLI rather than second HSCT obliviates the need for repeat conditioning and practical problems of another stem cell harvest, despite the potential to * Anthony P. Y. Liu apyliu@hku.hk

Central Nervous System Tumors in Chinese Children Under The Age of 3: A Population Study

The management of central nervous system tumors in children below the age of 3 years represents a special challenge to pediatric oncologists with distinctive epidemiology, treatment considerations, and prognosis. Population-based epidemiological data on this particular patient group is lacking in Chinese. We reviewed the population-based pediatric tumor registry in Hong Kong between 1999 and 2011. Eighty-one children with primary central nervous system tumors from 0 to 3 years of age were identified (annual incidence: 4.16 cases per 100,000). Forty-one (50.6%) were male and the mean duration of follow-up was 94 months (±8.1). Primary tumors were infratentorial in 43 (53.1%). The tumor types in decreasing frequency were astrocytoma (n=17), medulloblastoma (n=16), ependymoma (n=13), choroid plexus tumor (n=7), primitive neuroectodermal tumor (n=7), atypical teratoid rhabdoid tumor (n=6), germ cell tumor (GCT, n=5), craniopharyngioma (n=4), and ganglioglioma (n=3). Three patients presented antenatally. Treatment included surgery in 82.7%, chemotherapy in 50.6%, and radiotherapy in 25.9%. There were 29 deaths (35.8%) and 19 relapses (23.5%) during the review period with the 1-year overall survival (OS), 5-year OS, 1-year event-free survival (EFS), and 5-year EFS being 79.4% (±4.6), 63.5% (±5.9), 68.9% (±5.3), and 52.5% (±5.9), respectively. Significantly better OS and EFS were observed in patients who received gross total resection, but those with high-grade tumors, antenatal diagnosis, or atypical teratoid rhabdoid tumor/primitive neuroectodermal tumor had worse outcome. Survival did not differ with age. Comparison with statistics from other studies revealed higher rates of embryonal tumor, GCT, and craniopharyngioma in Hong Kong Chinese. Disease outcome appeared to be better in our cohort comparing to previous reports probably due to the higher proportion of GCT locally.