An Ex Vivo Human Kidney Perfusion Model Confirms Larger Microwave Ablation Dimensions After Transarterial Embolization.

PURPOSE: To utilize a novel ex vivo perfused human renal model and quantify microwave ablation (MWA) size differences in renal tissue when combining MWA with transarterial embolization (TAE). MATERIALS AND METHODS: Human kidneys (n = 5) declined for transplantation were obtained and connected to a fluoroscopic-compatible ex vivo perfusion system. Two ablations-1 standard MWA, 1 TAE-MWA-were performed in each kidney for 2 minutes at 100 Watts using a MWA system (Solero Angiodynamics). MWA alone was performed in the upper pole. In the lower pole, MWA was performed after TAE with M0 LUMI microspheres (Boston Scientific) to achieve angiographic stasis. Ablation zones of coagulative necrosis were sectioned along the long axis and segmented for maximal short axis diameter (SAD) and long axis diameter (LAD) measurements. RESULTS: A total of 10 ablations (5 MWA, 5 TAE-MWA) were performed in five human kidneys. TAE-MWA resulted in significantly increased SAD, LAD, volume, and sphericity compared to standard MWA + SD with mean measurements as follows (5 standard MWA + SD vs 5 TAE-MWA, two-tailed t-test): SAD, 1.8 ± 0.1 cm vs 2.5 ± 0.1 cm (p < 0.001); LAD, 2.9 ± 0.3 cm vs 3.2 ± 0.1 cm (p = 0.039); volume, 5.0 ± 0.5 mL vs 11.0 ± 0.7 mL (p < 0.001); sphericity, 0.4 ± 0.2 vs 0.6 ± 0.1 (p = 0.049). Histology demonstrated no differences in TAE-MWA other than concentrated microspheres. CONCLUSION: This study utilized a novel ex vivo human kidney perfusion model to confirm combined MWA-TAE significantly increases ablation size and spherical shape.

Creation of an Ex Vivo Renal Perfusion Model to Investigate Microwave Ablation.

This study hypothesized that an ex vivo renal perfusion model can create smaller microwave ablation (MWA) measurements during perfused states compared with nonperfused states across multiple device settings. Nine bovine kidneys, a fluoroscopic compatible perfusion model, and a commercially-available clinical MWA system were used to perform 72 ablations (36 perfused and 36 nonperfused) at 9 different device settings. Comparing perfused and nonperfused ablations at each device setting, significant differences in volume existed for 6 of 9 settings (P < .05). Collapsed across time settings, the ablation volumes by power were the following (perfused and nonperfused, P value): 60 W, 2.3 cm3 ± 1.0 and 7.2 cm3 ± 2.7, P < .001; 100 W, 5.4 cm3 ± 2.1 and 11.5 cm3 ± 5.6, P < .01; and 140 W, 11.2 cm3 ± 3.7 and 18.7 cm3 ± 6.3, P < .01. Applied power correlated with ablation volume: perfused, 0.021 cm3/W and R = 0.462, P = .004, and nonperfused, 0.029 cm3/W and R = 0.565, P < .001. These results support that an ex vivo perfused organ system can evaluate MWA systems and demonstrate heat sink perfusion effects of decreased ablation size.

The frequencies of very long-chain acyl-CoA dehydrogenase deficiency genetic variants in Japan have changed since the implementation of expanded newborn screening.

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency has been a target of expanded newborn screening (ENBS) using tandem mass spectrometry in Japan. Since the implementation of ENBS, a number of novel ACADVL variants responsible for VLCAD deficiency have been identified. In this study, genotypic differences in Japanese patients with VLCAD deficiency were investigated before and after ENBS. The ACADVL variants in 61 subjects identified through ENBS (ENBS group) and in 40 patients who subsequently developed clinical symptoms without undergoing ENBS (pre-ENBS group) were compared. Subjects in the ENBS group underwent genetic testing and/or VLCAD enzyme activity measurements. Patients in the pre-ENBS group were stratified into three clinical phenotypes and underwent genetic testing. This study revealed that the variants p.K264E, p.K382Q and c.996dupT were found in both groups, but their frequencies were lower in the ENBS group (5.2%, 3.1% and 4.2%, respectively) than in the pre-ENBS group (16.5%, 12.7% and 10.1%, respectively). In addition, p.C607S, p.T409M, p.M478I, p.G289R, p.C237R, p.T260M, and p.R229* were exclusively identified in the ENBS group. Among these variants, p.C607S exhibited the highest frequency (18.8%). The patients who were heterozygous for p.C607S demonstrated 7-42% of control enzyme activity. p.C607S is suspected to be unique to Japanese individuals. According to a comparison of enzyme activity, patients with the p.C607S variant may exhibit higher enzyme activity than those with the p.A416T, p.A180T, p.R450H, and p.K264E variants, which are responsible for the myopathic form of the disease. The VLCAD deficiency genotypes have changed since the initiation of ENBS in Japan.

CaO-B2O3-SiO2 glass fibers for wound healing.

It was reported by Jung and Day in 2011 that a cotton-like glass fiber pad made of borate glass 13-93B3 demonstrated a remarkable wound healing effect. It was approved for sale as a novel wound dressing in the management of acute and chronic wounds in 2016. However, the detailed mechanism of its wound healing effect has not been reported. In the present study, glass fibers of different composition in the system CaO-B2O3-SiO2 were prepared and their in vitro properties investigated to determine the role of the constituent components in wound healing. Fine glass fibers that were 0.6-2.0 µm in diameter were obtained by a melt blown method. However, these fibers were accompanied by small glass beads because of the low viscosity of the glass melts. 13-93B3 glass released an appreciable amount of borate and calcium ions into simulated body fluid (SBF). The amounts of these released ions decreased with partial replacement of the B2O3 in 13-93B3 with SiO2. The addition of large amounts of the borate and calcium ions into the culture medium decreased the viability of the L929 fibroblasts. Partial replacement of the B2O3 in 13-93B3 with SiO2 induced the formation of an apatite-like phase amenable to the adsorption of biological components on its surface in SBF. The wound healing effect of these glass fibers of different composition is worth examining in future animal experiments.

Factors significantly associated with COVID-19 severity in symptomatic patients: A retrospective single-center study.

INTRODUCTION: The severity of coronavirus disease (COVID-19) in Japanese patients is unreported. We retrospectively examined significant factors associated with disease severity in symptomatic COVID-19 patients (COVID-Pts) admitted to our institution between February 20 and April 30, 2020. METHODS: All patients were diagnosed based on the genetic detection of severe acute respiratory syndrome coronavirus 2. Information on the initial symptoms, laboratory data, and computed tomography (CT) images at hospitalization were collected from the patients' records. COVID-Pts were categorized as those with critical or severe illness (Pts-CSI) or those with moderate or mild illness (Pt-MMI). All statistical analyses were performed using R software. RESULTS: Data from 61 patients (16 Pt-CSI, 45 Pt-MMI), including 58 Japanese and three East Asians, were analyzed. Pt-CSI were significantly older and had hypertension or diabetes than Pt-MMI (P < 0.001, 0.014 and < 0.001, respectively). Serum albumin levels were significantly lower in Pt-CSI than in Pt-MMI (P < 0.001), whereas the neutrophil-to-lymphocyte ratio and C-reactive protein level were significantly higher in Pt-CSI than in Pt-MMI (P < 0.001 and P < 0.001, respectively). In the CT images of 60 patients, bilateral lung lesions were more frequently observed in Pt-CSI than in Pt-MMI (P = 0.013). Among the 16 Pt-CSI, 15 received antiviral therapy, 12 received tocilizumab, five underwent methylprednisolone treatment, six received mechanical ventilation, and one died. CONCLUSIONS: The illness severity of Japanese COVID-Pts was associated with older age, hypertension and/or diabetes, low serum albumin, high neutrophil-to-lymphocyte ratio, and C-reactive protein.

The prognostic impact of immune-related adverse events in metastatic renal cell carcinoma patients treated with nivolumab: a real-world multi-institutional retrospective study.

BACKGROUND: Recent studies have shown that immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) were correlated with favorable clinical outcome in patients with melanoma. However, in metastatic renal cell carcinoma (mRCC) patients, there have been few reports about the correlation between irAEs and clinical efficacy of anti-programmed cell death protein-1 (PD-1) therapy. METHODS: We retrospectively investigated 160 mRCC patients who started nivolumab monotherapy between September 2016 and July 2019. IrAEs were defined as patients' AEs having a potential immunological basis that required close follow-up, or immunosuppressive therapy. We compared the data of patients who received nivolumab into two groups based on the occurrence of irAEs and assessed clinical efficacy in both groups. RESULTS: Of all mRCC patients, 47 patients (29.4%) developed irAEs. In patients who developed irAEs, the objective response rate and disease control rate were 38.8% and 77.6%, which were significantly higher when compared to that in patients without irAEs (p = 0.012 and p < 0.001, respectively). Furthermore, the incidence of irAEs was significantly associated with an increase in progression-free survival (PFS) [Hazard ratio (HR) = 0.4867; p = 0.0006] and overall survival (OS) (HR = 0.526; p = 0.0252). Importantly, PFS and OS seemed to be similar in patients who discontinued treatment because of irAEs and in those who did not discontinue because of irAEs (p = 0.36 and p = 0.35, respectively). CONCLUSION: Development of irAEs strongly correlates with clinical benefit for mRCC patients receiving nivolumab monotherapy in real-world settings.

[A Case of Bilateral Ureteral Stenosis Treated by Upper Urinary Tract Reconstruction Using an Ileal Ureter].

A 41-year-old female who suffered local recurrence of cervical cancer after receiving chemoradiotherapy underwent radical hysterectomy, radical vaginal resection, and pelvic and paraaortic lymph node dissection. After surgery, bilateral hydronephrosis due to right ureteral stenosis and left uretero-vaginal fistula occurred. We therefore placed a bilateral ureteral stent. Thereafter, we continued to replace the bilateral ureteral stent once every 3 months, but the replacement of the right ureteral stent became impossible three years after the initial placement. We thus performed bilateral upper urinary tract reconstruction using an ileal ureter with the aim of both eliminating the left ureteral vaginal fistula and resolving the right ureteral stricture.

[Robot-Assisted Partial Nephrectomy for Renal Cell Carcinoma Complicated by Leriche Syndrome : A Case Report].

A 71-year-old man was referred to our hospital for treatment of a 2 cm-sized right renal mass incidentally found by computed tomography (CT) and was diagnosed with right renal cell carcinoma cT1aN0M0. Contrast-enhanced CT revealed that the aorta was completely occluded below the inferior mesenteric artery origin, and Leriche syndrome was diagnosed. CT angiography showed several collateral arteries along the abdominal wall. A robot-assisted laparoscopic partial nephrectomy was performed to treat renal cell carcinoma. Preoperatively, we marked the collateral arteries using ultrasonography to avoid injury during trocar insertion. We did not observe any decrease in blood flow in the right leg during the operation. The pathological diagnosis was clear cell renal cell carcinoma. Leriche syndrome is a chronic occlusive disease involving the infrarenal aorta and the iliac arteries. Since lower limb blood flow is dependent on collateral circulation, it is important to avoid injuring the collateral arteries during surgery.

Advances in glycosaminoglycan detection.

BACKGROUND: Glycosaminoglycans (GAGs) are negatively charged long linear (highly sulfated) polysaccharides consisting of repeating disaccharide units that are expressed on the surfaces of all nucleated cells. The expression of GAGs is required for embryogenesis, regulation of cell growth and proliferation, maintenance of tissue hydration, and interactions of the cells via receptors. Mucopolysaccharidoses (MPS) are caused by deficiency of specific lysosomal enzymes that result in the accumulation of GAGs in multiple tissues leading to organ dysfunction. Therefore, GAGs are important biomarkers for MPS. Without any treatment, patients with severe forms of MPS die within the first two decades of life. SCOPE OF REVIEW: Accurate measurement of GAGs is important to understand the diagnosis and pathogenesis of MPS and to monitor therapeutic efficacy before, during, and after treatment of the disease. This review covers various qualitative and quantitative methods for measurement of GAGs, including dye specific, thin layer chromatography (TLC), capillary electrophoresis, high-performance liquid chromatography (HPLC), liquid chromatography-tandem mass spectrometry (LC-MS/MS), gas chromatography, ELISA, and automated high-throughput mass spectrometry. Major conclusion: There are several methods for GAG detection however, specific GAG detection in the various biological systems requires rapid, sensitive, specific, and cost-effective methods such as LC-MS/MS. GENERAL SIGNIFICANCE: This review will describe different methods for GAG detection and analysis, including their advantages and limitation.

Newborn screening of mucopolysaccharidoses: past, present, and future.

Mucopolysaccharidoses (MPS) are a subtype of lysosomal storage disorders (LSDs) characterized by the deficiency of the enzyme involved in the breakdown of glycosaminoglycans (GAGs). Mucopolysaccharidosis type I (MPS I, Hurler Syndrome) was endorsed by the U.S. Secretary of the Department of Health and Human Services for universal newborn screening (NBS) in February 2016. Its endorsement exemplifies the need to enhance the accuracy of diagnostic testing for disorders that are considered for NBS. The progression of MPS disorders typically incudes irreversible CNS involvement, severe bone dysplasia, and cardiac and respiratory issues. Patients with MPS have a significantly decreased quality of life if untreated and require timely diagnosis and management for optimal outcomes. NBS provides the opportunity to diagnose and initiate treatment plans for MPS patients as early as possible. Most newborns with MPS are asymptomatic at birth; therefore, it is crucial to have biomarkers that can be identified in the newborn. At present, there are tiered methods and different instrumentation available for this purpose. The screening of quick, cost-effective, sensitive, and specific biomarkers in patients with MPS at birth is important. Rapid newborn diagnosis enables treatments to maximize therapeutic efficacy and to introduce immune tolerance during the neonatal period. Currently, newborn screening for MPS I and II has been implemented and/or in pilot testing in several countries. In this review article, historical aspects of NBS for MPS and the prospect of newborn screening for MPS are described, including the potential tiers of screening.

Deficiency of 3-hydroxybutyrate dehydrogenase (BDH1) in mice causes low ketone body levels and fatty liver during fasting.

d-3-Hydroxy-n-butyrate dehydrogenase (BDH1; EC 1.1.1.30), encoded by BDH1, catalyzes the reversible reduction of acetoacetate (AcAc) to 3-hydroxybutyrate (3HB). BDH1 is the last enzyme of hepatic ketogenesis and the first enzyme of ketolysis. The hereditary deficiency of BDH1 has not yet been described in humans. To define the features of BDH1 deficiency in a mammalian model, we generated Bdh1-deficient mice (Bdh1 KO mice). Under normal housing conditions, with unrestricted access to food, Bdh1 KO mice showed normal growth, appearance, behavior, and fertility. In contrast, fasting produced marked differences from controls. Although Bdh1 KO mice survive fasting for at least 48 hours, blood 3HB levels remained very low in Bdh1 KO mice, and despite AcAc levels moderately higher than in controls, total ketone body levels in Bdh1 KO mice were significantly lower than in wild-type (WT) mice after 16, 24, and 48 hours fasting. Hepatic fat content at 24 hours of fasting was greater in Bdh1 KO than in WT mice. Systemic BDH1 deficiency was well tolerated under normal fed conditions but manifested during fasting with a marked increase in AcAc/3HB ratio and hepatic steatosis, indicating the importance of ketogenesis for lipid energy balance in the liver.

Expression of Nectin-4 and PD-L1 in Upper Tract Urothelial Carcinoma.

Enfortumab vedotin is a novel antibody-drug conjugate targeting Nectin-4, which is highly expressed in urothelial carcinoma. However, the expression status of Nectin-4 in upper tract urothelial carcinoma (UTUC) remains unclear. The relationship between Nectin-4 and Programmed Death Ligand 1 (PD-L1) in UTUC is also ambiguous. We performed immunohistochemical analysis of 99 UTUC tissue microarray to assess the expression of Nectin-4 and PD-L1 in UTUC. Nectin-4-positivity was detected in 65 (65.7%) samples, and PD-L1 was detected in 24 (24.2%) samples. There was no correlation between the expression of Nectin-4 and PD-L1. Patients with strong Nectin-4-expressing tumors had a significantly higher risk of progression (p = 0.031) and cancer-specific mortality (p = 0.036). Strong Nectin-4 expression was also an independent predictor of disease progression in the high-risk group (pT3 ≤ or presence of lymphovascular invasion or lymph node metastasis) (Hazard ratio, 3.32 [95% confidence interval, 1.20-7.98; p = 0.027]). In conclusion, we demonstrated that Nectin-4 expression rate in UTUC was 65.7% and independent of PD-L1 expression. Strong Nectin-4 expression was associated with worse progression-free survival in high-risk UTUC. These findings suggested that enfortumab vedotin may be effective in a broad range of patients with UTUC, regardless of PD-L1 expression.

Validation of Liquid Chromatography-Tandem Mass Spectrometry-Based 5-Plex Assay for Mucopolysaccharidoses.

Mucopolysaccharidoses (MPSs) are rare lysosomal storage diseases caused by the accumulation of undegraded glycosaminoglycans in cells and tissues. The effectiveness of early intervention for MPS has been reported. Multiple-assay formats using tandem mass spectrometry have been developed. Here, we developed a method for simultaneous preparation and better measurement of the activities of five enzymes involved in MPSs, i.e., MPS I, MPS II, MPS IIIB, MPS IVA, and MPS VI, which were validated using 672 dried blood spot samples obtained from healthy newborns and 23 patients with MPS. The mean values of the enzyme activities and standard deviations in controls were as follows: α-iduronidase (IDUA), 4.19 ± 1.53 µM/h; iduronate-2-sulfatase (I2S), 8.39 ± 2.82 µM/h; N-acetyl-α-glucosaminidase (NAGLU), 1.96 ± 0.57 µM/h; N-acetylgalactosamine-6-sulfatase (GALNS), 0.50 ± 0.20 µM/h; and N-acetylgalactosamine-4-sulfatase (ARSB), 2.64 ± 1.01 µM/h. All patients displayed absent or low enzyme activity. In MPS I, IIIB, and VI, each patient group was clearly separated from controls, whereas there was some overlap between the control and patient groups in MPS II and IVA, suggesting the occurrence of pseudo-deficiencies. Thus, we established a multiplex assay for newborn screening using liquid chromatography tandem mass spectrometry, allowing simultaneous pretreatment and measurement of five enzymes relevant to MPSs.

[Primary Ureteral Small Cell Carcinoma with Multiple Recurrences and Metastases in the Early Postoperative Period : A Case Report].

A 79-year-old woman who presented with right hydronephrosis was referred to our hospital. Abdominal computed tomography (CT) showed a right ureteral tumor (cT3N0M0). Right nephroureterectomy and partial cystectomy were performed. Pathological examination revealed small cell carcinoma (mixed type ; INFb, pT3, ly1, v1, u-rt0, ur0, RM0). Cystoscopy showed intravesical recurrence of the tumor 3 months after the surgery. Transurethral resection was performed, and histopathological examination revealed small cell carcinoma (pT2). We recommended postoperative chemotherapy ; however, the patient and her family refused consent for chemotherapy. Liver and lymph node metastases developed, and the patient died 2 months after the transurethral resection.

[Rituximab Chemotherapy for Primary Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma of the Urinary Bladder : A Case Report].

An 84-year-old man consulted a local physician for asymptomatic macrohematuria. Abdominal ultrasonography revealed thickening ofthe bladder wall from the triangular part ofthe bladder to the posterior wall, and he was referred to our department. Cystoscopy showed extensive bladder wall thickening with edema ofthe mucosa. Abdominal contrast-enhanced computed tomography (CT) showed extensive bladder wall thickening and right external iliac lymphadenopathy accompanied by a contrast effect suspected ofbeing extravesical invasion. We performed transurethral resection ofthe bladder tumor and made the diagnosis ofmucosa associated lymphoid tissue (MALT) lymphoma. Our diagnosis made from positron emission tomography-CT performed after surgery was primary MALT lymphoma of the bladder and metastasis to the right external iliac lymph node. We administered rituximab 375 mg/m2 once a week for four times in total. CT after rituximab administration showed that the tumor and right external iliac lymph nodes had shrunk significantly, and no recurrence was present at 18 months after treatment.

Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency.

Mitochondrial acetoacetyl-CoA thiolase (T2, encoded by the ACAT1 gene) deficiency is an inherited disorder of ketone body and isoleucine metabolism. It typically manifests with episodic ketoacidosis. The presence of isoleucine-derived metabolites is the key marker for biochemical diagnosis. To date, 105 ACAT1 variants have been reported in 149 T2-deficient patients. The 56 disease-associated missense ACAT1 variants have been mapped onto the crystal structure of T2. Almost all these missense variants concern residues that are completely or partially buried in the T2 structure. Such variants are expected to cause T2 deficiency by having lower in vivo T2 activity because of lower folding efficiency and/or stability. Expression and activity data of 30 disease-associated missense ACAT1 variants have been measured by expressing them in human SV40-transformed fibroblasts. Only two variants (p.Cys126Ser and p.Tyr219His) appear to have equal stability as wild-type. For these variants, which are inactive, the side chains point into the active site. In patients with T2 deficiency, the genotype does not correlate with the clinical phenotype but exerts a considerable effect on the biochemical phenotype. This could be related to variable remaining residual T2 activity in vivo and has important clinical implications concerning disease management and newborn screening.

Critical review of current MPS guidelines and management.

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders that impair degradation of glycosaminoglycans (GAG). The specific GAGs that accumulate depend on the type of MPS, leading to unique characteristic clinical features. Development of guidelines for treatment of MPS has traditionally been multifaceted and largely based on palliative care. In the last three decades, hematopoietic stem cell transplantation and enzyme replacement therapy have been developed based on experimental and clinical studies. Guidelines have been established with the accumulation of the clinical data from natural history of the disease and therapeutic consequences, mainly sponsored by pharmaceutical companies. In recent years, committees in three countries, Australia (2015), Japan (2017), and Brazil (2018) have adopted guidelines for the treatment of MPS II, sponsored and authorized by each government. As novel treatments for MPS including substrate reduction therapy, pharmacological chaperone therapy, and gene therapy become clinically available, it is increasingly necessary to establish the optimal guideline for each type of MPS, considering multiple factors including therapeutic efficacy, adverse effects, age, disease stage, prognosis, feasibility and availability of access to treatment, and cost- performance. In this article, we discuss the historical guidelines for specific MPS types and the most recently adopted guidelines for MPS II and propose the development of future guidelines without conflict of interest and bias leading to mutual benefits to all parties including patients and families, professionals, tax payers, and governments.

The utility of post-test newborn blood spot screening cards for epigenetic association analyses: association between HIF3A methylation and birth weight-for-gestational age.

Identification of disease-associated epigenetic markers in early life might be useful for pre-emptive intervention to prevent diseases. Epigenome-wide association analyses using newborn blood spot screening cards are an anticipated field of research in Japan. Here, in this study, post-test dried blood spot (DBS) samples were anonymized, with only three attributes of gender, gestational age, and birth weight identified. We isolated DNA from DBS (n = 300) archived for more than 3 years. The median DNA yield (ng) per individual was 429 (interquartile range 300-565). In a model epigenetic analysis, we conducted a confirmative study on the known association between birth weight and hypoxia-inducible factor 3A (HIF3A) gene methylation. DNA methylation levels and cis-acting SNP genotypes (rs8102595 and rs3826795) were measured using EpiTYPER and Taqman assays, respectively. HIF3A methylation was positively associated with birth weight-for-gestational age centile (p = 0.021). While HIF3A methylation was associated with cis-genotypes (rs8102595, p = 2.08E-13; rs3826795, p = 3.63E-09), the association with birth weight centile was retained after adjusting for cis-genotypes (p = 0.029). Thus, we successfully reproduced the results reported previously by others, and demonstrated the usefulness of archived DBS in secondary use for epigenetic association analyses.

Enzyme replacement therapy for mucopolysaccharidoses; past, present, and future.

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders, which lack an enzyme corresponding to the specific type of MPS. Enzyme replacement therapy (ERT) has been the standard therapeutic option for some types of MPS because of the ability to start immediate treatment with feasibility and safety and to improve prognosis. There are several disadvantages for current ERT, such as limited impact to the brain and avascular cartilage, weekly or biweekly infusions lasting 4-5 h, the immune response against the infused enzyme, a short half-life, and the high cost. Clinical studies of ERT have shown limited efficacy in preventing or resolving progression in neurological, cardiovascular, and skeletal diseases. One focus is to penetrate the avascular cartilage area to at least stabilize, if not reverse, musculoskeletal diseases. Although early intervention in some types of MPS has shown improvements in the severity of skeletal dysplasia and stunted growth, this limits the desired effect of ameliorating musculoskeletal disease progression to young MPS patients. Novel ERT strategies are under development to reach the brain: (1) utilizing a fusion protein with monoclonal antibody to target a receptor on the BBB, (2) using a protein complex from plant lectin, glycan, or insulin-like growth factor 2, and (3) direct infusion across the BBB. As for MPS IVA and VI, bone-targeting ERT will be an alternative to improve therapeutic efficacy in bone and cartilage. This review summarizes the effect and limitations on current ERT for MPS and describes the new technology to overcome the obstacles of conventional ERT.

Effect of enzyme replacement therapy on the growth of patients with Morquio A.

Mucopolysaccharidosis IVA (MPS IVA) is a degenerative systemic skeletal dysplasia, in which children exhibit marked short stature and become physically handicapped. This study evaluated the growth patterns of patients treated with enzyme replacement therapy (ERT), compared with those of untreated patients. Cross-sectional and longitudinal data of heights and weights were collected from 128 MPS IVA patients and compared with the growth charts of MPS IVA. Twelve patients (six males, six females) starting ERT before 5 years old were treated for at least 2 years. Six out of 12 patients (50%) with ERT over 2 years stopped growing between 94 and 98 cm (mean height of 95.1 ± 2.2 cm) from 5.0 years to 9.0 years of age (mean age of 6.2 ± 1.6 years). The other patients, except one attenuated case, exhibited a marked slow growth velocity from 3.6 years to 7.7 years. Treated and untreated patients with severe phenotype reached their final heights by ~10 years of age. Patients treated with ERT exhibited a reduced pubertal growth spurt analogous to their untreated counterparts, which contributes to the marked short stature associated with MPS IVA. Compared with the growth charts for untreated patients, patients treated with ERT did not show any significant increase in growth in any age group. Overall, ERT-treated patients do not experience growth improvement and continue to exhibit poor growth despite early ERT intervention before 5 years of age. These findings indicate that current intravenous ERT is ineffective at correcting abnormal growth in MPS IVA.