Hepatitis B Virus Seropositivity Is a Poor Prognostic Factor of Pediatric Hepatocellular Carcinoma: a Population-Based Study in Hong Kong and Singapore.

BACKGROUND: Hepatocellular carcinoma (HCC) is a rare hepatic malignancy in children. Hepatitis B virus (HBV) infection is a key predisposing factor in endemic regions but its impact on outcome has not been studied. We aim to evaluate the prognostic implication of HBV seropositivity and role of cancer surveillance in children with HCC from East Asian populations with national HBV vaccination. METHODS: Review of population-based databases for patients (< 18 years old) diagnosed with HCC from 1993 to 2017 in two Southeast Asian regions with universal HBV vaccination (instituted since 1988 and 1987 in Hong Kong and Singapore, respectively). RESULTS: Thirty-nine patients were identified (Hong Kong, 28; Singapore, 11). Thirty were male; median age at diagnosis was 10.8 years (range, 0.98-16.6). Abdominal pain was the commonest presentation while five patients were diagnosed through surveillance for underlying condition. Alpha-fetoprotein was raised in 36 patients (mean, 500,598 ng/ml). Nineteen had bilobar involvement, among the patients in whom pretreatment extent of disease (PRETEXT) staging could retrospectively be assigned, 3 had stage I, 13 had stage II, 4 had stage III, and 11 had stage IV disease. Seventeen had distant metastasis. HBsAg was positive in 19 of 38 patients. Two patients had fibrolamellar HCC. Upfront management involved tumor resection in 16 (liver transplantation, 2), systemic chemotherapy in 21, interventional procedures in 6 [transarterial chemoembolization (TACE), 5, radiofrequency ablation (RFA), 1], and radiotherapy in 4 (selective internal radiation, 3, external beam radiation, 1). Five-year event-free survival (EFS) and overall survival (OS) were 15.4 ± 6.0 and 26.1 ± 7.2%, respectively. Patient's HBsAg positivity, metastatic disease and inability to undergo definitive resection represent poor prognostic factors in univariate and multivariable analyses. Patients diagnosed by surveillance had significantly better outcome. CONCLUSION: Pediatric HCC has poor outcome. HBV status remains relevant in the era of universal HBV vaccination. HBV carrier has inferior outcome and use of surveillance may mitigate disease course.

Treatment outcome and pattern of failure in hepatoblastoma treated with a consensus protocol in Hong Kong.

BACKGROUND AND AIM: We reviewed the results and pattern of failure of the consensus HB/HCC 1996 treatment protocol for pediatric hepatoblastoma (HB) in Hong Kong. The role of SIOPEL and Children's Hepatic tumors International Collaboration (CHIC) risk stratification was evaluated. METHODS: Patients enrolled on the protocol from 1996 to 2014 were included. PRETEXT staging, SIOPEL, and CHIC risk groups were retrospectively assigned. RESULTS: Sixty patients were enrolled with median age at diagnosis of 1.1 years and median follow-up time of 6.8 years. Alpha-fetoprotein (AFP) was raised (>100 ng/mL) in 58 (97%) patients. Five (8%) had metastases at presentation and 7 (12%) experienced tumor rupture prior to or during treatment. Twenty-nine patients (48%) received a first-line cisplatin, 5-fluorouracil, and vincristine regimen only while 23 (38%) also had alternative chemotherapeutic agents. Hepatic resection could be performed in 48 (80%) patients. Three (5%) patients underwent upfront liver transplantation. Five-year event-free survival and overall survival rates were 69.2% ± 6.1% and 77.6% ± 5.5% respectively. Among the 16 patients with relapse/progression, 9 had intrahepatic failure only, 5 had distant failure only, and 2 had combined local and distant failure. Predictors of inferior outcome included advanced Evans staging, disease involving both lobes, rupture, low AFP, and suboptimal response to first-line chemotherapy. Assigned in 44 patients, PRETEXT staging, SIOPEL, and CHIC risk groups significantly predicted EFS and OS. CONCLUSIONS: Although the consensus HB/HCC 1996 protocol led to cure in three-quarters of pediatric HB patients, an upfront risk stratification system is required to identify and improve the outcome of high-risk patients.

Site-specific tryptophan oxidation induced by autocatalytic reaction of polysorbate 20 in protein formulation.

PURPOSE: Tryptophan (Trp) oxidation leading to atypical degradation of a protein (Fab) formulated with polysorbate 20 (PS20) was investigated. Such atypical Trp oxidation was discussed in relation to a kinetic model that involves initiation of oxidizing free radical through an autocatalytic reaction. METHODS: Ion-exchange chromatography and peptide mapping were used to determine Trp oxidation. Peroxides in PS20 and free radicals in Fab samples were detected by fluorometric assay and electron paramagnetic resonance (EPR), respectively. RESULTS: PS20 with increased peroxides level led to degradation of Fab stored at 30°C. Degradation was characterized as Trp50 oxidation, which was not observed in a Fab variant where His31 was replaced. EPR peaks related to known spin adducts of 5,5 dimethylpyrroline N-oxide were detected in Fab exhibiting Trp oxidation, indicating free radicals were present. Trp oxidation of Fab observed in several drug product lots with different degradation rates fits an autocatalytic reaction model that involves free radicals. EDTA, catalase, and free tryptophan prevented oxidation. CONCLUSIONS: A metal-binding amino acid, His31, was responsible for Trp50 oxidation of Fab induced by peroxides in PS20 present in the protein formulation. Oxidation was induced by autocatalytic degradation of PS20 and could be inhibited by antioxidants.

Hypertrophic pyloric stenosis in a newborn: a diagnostic dilemma.

Infants with hypertrophic pyloric stenosis typically present at 2 to 4 weeks of age with nonbilious projectile vomiting. Hypertrophic pyloric stenosis is exceedingly rare in newborn infants and is scarcely reported in literature. Also, the diagnostic criteria for ultrasonographic measurements in newborn infants have yet to be determined. This report is of a newborn infant with hypertrophic pyloric stenosis. The patient presented with high-volume non-bile-stained output from a nasogastric tube and a dilated gastric bubble on abdominal radiograph. Contrast study ruled out intestinal malrotation. Two ultrasound tests showed that the pyloric muscle thickness and pyloric canal length were within normal limits. Subsequent laparotomy showed a thickened pylorus and pyloromyotomy was performed. The patient showed marked improvement in feeding postoperatively. A high index of suspicion is required for newborn infants presenting with gastric outlet obstruction. Ultrasound and contrast studies provide additional information, but definitive diagnosis may only be available intra-operatively.

Root Cause Investigation of Rubber Seal Cracking in Pre-filled Cartridges: Ozone and Packaging Effects.

Pre-filled syringes/cartridges as primary packaging for parenterally delivered biopharmaceutical liquids consist of multiple components, including containers made of glass or plastic, and stoppers/plungers and disk seals (septa) made of rubber materials. Cracking of rubber components may be cosmetically unacceptable and in extreme cases may compromise enclosure integrity. The purpose of this study was to investigate the root cause of septum cracking and evaluate parameters/solutions to delay or prevent cracking from occurring. Custom-made chambers capable of tightly controlling ozone levels were assembled to deliberately create septum cracks. Cracks were qualitatively assessed by optical microscopy and quantified using image analysis by ImageJ. The results confirmed that ozone attack is the root cause of septum cracking during storage, and the stress-the result of crimping on the glass cartridge by the aluminum lined seal-made the septum particularly vulnerable to ozone attack. Ozone concentration as low as 10-40 ppb (levels routinely detected on a busy street) could crack the stressed septum in hours while days of ozone exposure at 50 ppm could not cause the unstressed septum to crack. Under ozone attack cracks initially grow in length and width uniformly across the stressed area and then stop progressing, perhaps due to residual stress release. Although the use of impermeable barriers could prevent cracking completely, this study suggested that any form of packaging barriers, including a highly permeable Tyvek® sheet, could postpone cracking by slowing down ozone diffusion and convection. We demonstrate that simple double packaging-placing the Tyvek®-lidded blister tray in a cardboard carton-could sufficiently protect the stressed septum for years in a surrounding environment with ozone at normal indoor levels (≤2 ppb). LAY ABSTRACT: Pre-filled syringes/cartridges as primary packaging for parenterally delivered biopharmaceutical liquids contain multiple components, including a disk seal (septum) made of rubber materials. Cracking of rubber components may be cosmetically unacceptable and in extreme cases may compromise enclosure integrity. The septum, if not appropriately packaged, might crack under uncontrolled storage environment. The purpose of this study was to investigate the root cause of septum cracking and evaluate parameters/solutions to delay or prevent cracking from occurring. Custom-made chambers capable of tightly controlling ozone levels were assembled to deliberately create septum cracks. The results confirmed that ozone attack is the root cause of septum cracking during storage, and the stress-the result of crimping on the glass cartridge by the aluminum lined seal-made the septum particularly vulnerable to ozone attack. Ozone concentration as low as 10-40 ppb (levels routinely detected on a busy street) could crack the stressed septum in hours. Although the use of impermeable barriers could prevent cracking completely, this study suggested that any form of packaging barriers, including a highly permeable Tyvek® sheet, could postpone cracking by slowing down ozone diffusion and convection. This investigation will raise awareness of manufacturers of pre-filled cartridge/syringe parenteral products to storage and packaging requirements for the long-term physical stability of cartridge components as small as the rubber septum.

Otogenic tension pneumocephalus caused by therapeutic lumbar CSF drainage for post-traumatic hydrocephalus: a case report.

Tension pneumocephalus occurs when a continuous flow of air accumulates in the intracranial cavity and produces a mass effect on the brain. We describe a case in which tension pneumocephalus was caused by the performance of continuous lumbar CSF drainage in a middle-aged man who had experienced a temporal bone fracture. Continuous lumbar CSF drainage is commonly performed in patients with temporal bone or basilar skull fractures to treat concomitant post-traumatic CSF rhinorrhea, CSF otorrhea, and/or hydrocephalus. However; to the best of our knowledge, there has been no previously reported case of tension pneumocephalus occurring as a complication of this procedure in a patient with a temporal bone fracture.

A hormonal association between estrogen metabolism and proliferative thyroid disease.

OBJECTIVE: To illustrate a relationship between proliferative thyroid disease and estrogen metabolism through the analysis of urinary estrogen metabolites. STUDY DESIGN AND SETTING: Case-control study of 49 subjects with proliferative thyroid disorders and matching them to 49 controls. Urinary estrogen metabolite ratios were obtained, measuring 2-hydroxyestrone, an anti-proliferative metabolite, to 16alpha-hydroxyestrone, a proliferative metabolite. The patients were stratified into low (0 to 1.00), medium (1.01 to 2.00), or high (>2.00) groups according to their estrogen metabolite ratio. RESULTS: Fifty-one percent (25 of 49) of the cases had a low 2/16 ratio compared to 31% (15 of 49) in the control group while 20% (10 of 49) of the control group had a high 2/16 ratio as compared to 8% (4 of 49) in the case group (P value < 0.05). CONCLUSIONS: Increased 16alpha-hydroxyestrone activity compared to 2-hydroxyestrone activity appears to be associated with proliferative thyroid disease. SIGNIFICANCE: Further study of estrogen metabolites in relation to proliferative thyroid disease is warranted and may lead to implications for new treatment modalities for proliferative thyroid disease. EBM RATING: B-3b.

Combined anterior-to-posterior and posterior-to-anterior approach to paranasal sinus surgery: an update.

OBJECTIVES: To develop an anatomically and functionally based approach to endoscopic intranasal ethmoidectomy; to develop such an approach using the salient features of the anterior-to-posterior (AP) and posterior-to-anterior (PA) intranasal sinus operations; to assess the safety of this form of ethmoidectomy in a patient population. STUDY DESIGN: Retrospective chart review of patients undergoing ethmoidectomy by the authors or by residents under their direct supervision. SETTING: University teaching hospital. RESULTS: Two thousand three hundred and forty-four patients underwent either unilateral or bilateral ethmoidectomies between April 1992 and August 2005. A complication rate of 0.34% was observed. CONCLUSIONS: Combining an AP approach to conserve sinus anatomy with a PA approach to avoid surgery directed toward the skull base provides a functional and safe procedure, as demonstrated by the reported results.