Noninvasive diagnosis of significant liver inflammation in patients with chronic hepatitis B in the indeterminate phase.

The presence of significant liver inflammation is an important indication for antiviral treatment in patients with chronic hepatitis B (CHB) in the indeterminate phase. We aimed to establish a non-invasive nomogram to predict significant liver inflammation in these patients. A total of 195 CHB patients in the indeterminate phase were randomly split into training and validation sets. The least absolute shrinkage and selection operator and logistic regression were applied to identify risk factors and establish a predictive model. A calibration curve, decision curve analysis (DCA), and receiver operating characteristic (ROC) curve were applied to assess the performance of the nomogram. The median age was 42.0 y and 59.5% of the patients were male. Alkaline phosphatase, γ-glutamyl transpeptidase, and prothrombin time were independent predictors for significant liver inflammation and selected to establish the AGP-nomogram. The calibration plot demonstrated that the predicted results matched the actual values. The DCA showed a high net benefit when the threshold probability was 25-83% in the training set and 31-100% in the validation set. The areas under ROC curves of AGP-nomogram in predicting significant inflammation were significantly higher than ALT in the training set (0.744 vs. 0.642, P = 0.049) and validation set (0.766 vs. 0.660, P = 0.047). The ability of AGP-nomogram in predicting advanced inflammation was also superior to ALT. The AGP-nomogram can accurately identify significant inflammation in CHB patients in the indeterminate phase, and its application may reduce the need for liver biopsy and help identify candidates for antiviral treatment.Abbreviations: AASLD: American Association for the Study of Liver Diseases; ALB: albumin; ALP: alkaline phosphatase; ALT: alanine aminotransferase; APRI: aspartate aminotransferase-to-platelet ratio index; AST: aspartate aminotransferase; AUROC: area under the receiver operating characteristic curve; CHB: chronic hepatitis B; CI: confidence interval; DCA: decision curve analysis; FIB-4: fibrosis index based on the four factors; GLB: globulin; GGT: γ-glutamyl transpeptidase; HBcAb: hepatitis B core antibody; HBeAg: hepatitis B e antigen; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HIV: human immunodeficiency virus; INR: international-normalized ratio; IQR: interquartile range; LASSO: least absolute shrinkage and selection operator; LB: liver biopsy; LR: Likelihood ratio; NAFLD: non-alcoholic fatty liver disease; NPV: negative predictive value; PLT: platelets; PPV: positive predictive value; PT: prothrombin time; ROC: receiver operating characteristic; TB: total bilirubin; TE: transient elastography; ULN: upper limit of normal.

Prenatal asfotase alfa-mediated enzyme replacement therapy restores delayed calcification in a severe infantile form of hypophosphatasia model mice.

Hypophosphatasia (HPP) is a congenital disorder caused by mutations in the tissue-nonspecific alkaline phosphatase (TNALP) gene. The pathogenesis of HPP varies, ranging from severe cases in which there is total absence of fetal bone calcification, which leads to stillbirth, to relatively mild cases in which the effects are confined to the teeth, such as early loss of the primary teeth. In recent years, the establishment of enzyme supplementation as a treatment method has prolonged survival in patients; however, this approach does not provide sufficient improvement for failed calcification. Furthermore, the effects of enzyme replacement therapy on the jawbone and periodontal tissues have not yet been studied in detail. Therefore, in this study, we investigated the therapeutic effects of enzyme replacement therapy on jawbone hypocalcification in mice. Recombinant TNALP was administered to mothers before birth and newborns immediately after birth, and the effect of treatment was evaluated at 20 days of age. The treated HPP mice had improved mandible (mandibular length and bone quality) and tooth quality (root length of mandibular first molar, formation of cementum), as well as improved periodontal tissue structure (structure of periodontal ligament). Furthermore, prenatal treatment had an additional therapeutic effect on the degree of mandible and enamel calcification. These results suggest that enzyme replacement therapy is effective for the treatment of HPP, specifically in the maxillofacial region (including the teeth and mandible), and that early initiation of treatment may have additional beneficial therapeutic effects.

Asfotase alfa improved skeletal mineralization and fracture healing in a child with MCAHS.

Tissue non-specific alkaline phosphatase (TNSALP) is an enzyme that is tethered to the cell membrane by glycosylphosphatidylinositol (GPI) and converts inorganic pyrophosphate to inorganic phosphate. Inorganic phosphate combines with calcium to form hydroxyapatite, the main mineral in the skeleton. When TNSALP is defective, conversion of inorganic pyrophosphate to inorganic phosphate is impaired and the skeleton is at risk of under-mineralization. Phosphatidylinositol glycan anchor biosynthesis class N (PIGN) is one of more than 20 genes in the GPI-biosynthesis family. Pathogenic variants in PIGN have been identified in multiple congenital anomalies-hypotonia-seizures syndrome (OMIM 614080), although a metabolic bone disease or skeletal fragility phenotype has not been reported. We describe a female child with multiple congenital anomalies-hypotonia-seizures syndrome due to a compound heterozygous pathogenic variant in PIGN who sustained a low-trauma distal femur fracture at age 7.4 years. We hypothesized that the GPI synthesis defect may result in metabolic bone disease from inadequate anchoring of TNSALP in bone and initiated asfotase alfa, a human bone-targeted recombinant TNSALP-Fc-deca-aspartate peptide, as it could bypass the PIGN genetic defect that possibly caused her skeletal fragility. Asfotase alfa was begun at 8.5 years. Baseline X-rays revealed mild rachitic findings of wrists and knees, which resolved by 5 months of treatment. Bone mineral density (BMD) assessed by dual-energy X-ray absorptiometry (DXA) showed mild improvement in spine, hip and total body less head after 16 months of treatment, while radius declined. She sustained additional low trauma fractures at right tibia and left humeral neck at 11 and 15 months into treatment, which healed quickly. Calcium, phosphorus, and parathyroid hormone levels have remained within the normal range over the 18 months of treatment. For adverse effect, she experienced a rash and discomfort in the first week of treatment which resolved with ibuprofen and diphenhydramine. She also developed subcutaneous fat atrophy. Overall, in this child with a compound pathogenic variant in PIGN, off-label use of asfotase alfa has been generally well tolerated with minimal side effects and resolution of rickets, but she continues to remain skeletally fragile.

Antarctic Krill Oil Exhibited Synergistic Effects with Nobiletin and Theanine on Regulating Ligand-Specific Receptor-Mediated Transcytosis in Blood-Brain Barrier by Inhibiting Alkaline Phosphatase in SAMP8 Mice.

Blood-brain barrier (BBB) impairment is related to the development of Alzheimer's disease (AD), which is dependent not only on tight junction but also on transcytosis of brain endothelial cells (BECs) in the BBB. Aging induces the decrease of ligand-specific receptor-mediated transcytosis (RMT) and the increase of non-specific caveolar transcytosis in BECs, which lead to the entry into parenchyma of neurotoxic proteins and the smaller therapeutic index in central nervous system drug delivery, further provoking neurodegenerative disease. A previous study suggests that sea-derived Antarctic krill oil (AKO) exhibits synergistic effects with land-derived nobiletin (NOB) and theanine (THE) on ameliorating memory and cognitive deficiency in SAMP8 mice. However, it is still unclear whether BBB change is involved. Hence, the effects of AKO combined with NOB and THE on aging-induced BBB impairment, including tight junction between BECs, ligand-specific RMT, and non-specific caveolar transcytosis in BECs, are investigated. The results suggest that AKO exhibits synergistic effects with NOB and THE on regulating ligand-specific RMT in BBB by inhibiting alkaline phosphatase (ALPL). The study provides a potential strategy candidate or targeted dietary patterns to prevent and treat AD by improving the BBB function.

Real-world outcomes of abiraterone and enzalutamide in first-line treatment of metastatic castration-resistant prostate cancer: which patients benefit most?

OBJECTIVES: Abiraterone and enzalutamide are two oral novel androgen receptor axis-targeted agents approved for the treatment of castration-resistant prostate cancer (mCRPC). Despite the availability of multiple treatments, there is a need to improve the knowledge and management of these drugs in the real-world setting, especially in patient groups under-represented in clinical trials. Our aim was to review the outcome of patients with chemotherapy-naïve mCRPC treated with abiraterone or enzalutamide in routine clinical practice in order to identify factors that are predictive for response. METHODS: This observational retrospective study was performed in a Spanish tertiary hospital and included men with chemotherapy-naïve mCPRC who started treatment with abiraterone or enzalutamide between September 2012 and November 2018. The study end date was 30 October 2020. RESULTS: Ninety patients with mCRPC were included, 57 with abiraterone and 33 with enzalutamide. Median overall survival (OS) was 26.87 months (95% CI 19.68 to 34.05), with no difference found between the two treatment groups. Nine variables were related to increased OS in the univariate analysis: Eastern Cooperative Oncology Group (ECOG) performance status (0-1 vs 2), pain (need of opioids for cancer pain), visceral disease, ≥3 bone lesions, exclusively lymph node metastases, baseline prostate specific antigen (PSA) (<50 vs ≥50 ng/dL and <20 vs ≥20 ng/dL), haemoglobin (<12 vs ≥12 g/dL) and alkaline phosphatase (≤116 vs >116 IU/L). A PSA response >50% was observed in 65 patients (76.5%). In the multivariate analysis, ECOG performance status, pain, visceral disease and alkaline phosphatase provided independent prognostic information. Median OS by Kaplan-Meier analysis was significantly longer for patients with a PSA response (32.1 vs 17.9 months; HR 0.46, 95% CI 0.27 to 0.78; p=0.003). CONCLUSIONS: This study assessed the efficacy of abiraterone and enzalutamide in a real-world setting, including patients under-represented in pivotal studies. Some clinical factors were correlated with improved OS in chemotherapy-naïve men with mCPRC treated with these drugs.

Health-related quality of life, psychological distress, and fatigue in metastatic castration-resistant prostate cancer patients treated with radium-223 therapy.

BACKGROUND: Radium-223 is a registered treatment option for symptomatic bone metastatic castration-resistant prostate cancer (mCRPC). Aim of this multicenter, prospective observational cohort study was to evaluate health-related quality of life (HR-QoL), psychological distress and fatigue in mCRPC patients treated with radium-223. METHODS: Primary endpoint was cancer-specific and bone metastases-related HR-QoL, as measured by the EORTC QLQ-C30 and BM-22 questionnaires. Secondary endpoints were psychological distress and fatigue, evaluated by the HADS and CIS-Fatigue questionnaires. Outcomes were analyzed for the total cohort and between subgroups (1-3 versus 4-5 versus 6 radium-223 injections). A trajectory analysis was performed to explore HR-QoL patterns over time. RESULTS: In total, 122 patients were included for analysis. Baseline HR-QoL, pain intensity, psychological distress and fatigue were worse in patients who did not complete radium-223 therapy. In patients who completed therapy, stabilization of HR-QoL was perceived and psychological distress and fatigue remained stable, whereas clinically meaningful and statistically significant deterioration of HR-QoL, psychological distress and fatigue over time was observed in patients who discontinued radium-223 therapy. Trajectory analysis revealed that HR-QoL deterioration over time was more likely in patients with baseline opioid use, low hemoglobin and high alkaline phosphatase levels. CONCLUSIONS: Patients who discontinued radium-223 therapy showed worse HR-QoL, psychological distress and fatigue at baseline and more frequent deterioration of HR-QoL, psychological distress and fatigue over time when compared to patients who completed therapy. Specific attention with regard to HR-QoL during follow-up is indicated in patients with opioid use, low hemoglobin and high alkaline phosphatase levels before radium-223 therapy initiation. CLINICAL TRIAL REGISTRATION NUMBER: NCT04995614.

Determinants of Long-Term Survival in Metastatic Choroidal and Ciliary Body Melanoma.

PURPOSE: To build and validate a prognostic model that predicts long-term overall survival (OS) in metastatic choroidal and ciliary body melanoma (CCBM) to facilitate patient counseling and planning, reporting, and interpreting clinical trials. DESIGN: Retrospective cohort study with validation. METHODS: We analyzed predictors of intermediate (IMT; 25-<42 months) and long-term (LT; ≥42 months) OS in a Finnish nationwide cohort of 330 patients with metastatic CCBM. Short-term (<25 months), IMT, and LT survival were compared with pairwise and ordinal logistic regression. A single-center cohort of 259 patients from Italy was used for validation. Models were compared with a deviance test. RESULTS: Median OS was 12 and 17 months in the building and validation datasets, respectively; 40 (12%) and 31 (9%) compared with 44 (17%) and 32 (12%) patients were IMT and LT survivors, respectively. Alkaline phosphatase or lactate dehydrogenase level never exceeded 2 times the upper normal limit (UNL) in either LT cohort. Conditional to both being ≤2 times the UNL, distant metastasis-free interval (DMFI) >42 months (odds ratio [OR] 4.09-4.64; P < .001) paired with age <60 years (OR 3.23; P = .002), having no symptoms (OR 4.19; P = .005), and the largest diameter of the largest metastasis <30 mm (Tumor, Node, Metastasis stage M1a; OR 3.05; P = .001) independently predicted higher odds of surviving longer (IMT or LT) without model preference. These results were confirmed in the validation dataset. CONCLUSIONS: Alkaline phosphatase or lactate dehydrogenase >2 times the UNL essentially precluded LT survival. The most robust predictor otherwise was DMFI >42 months, followed by age <60 years, absence of symptoms, and Tumor, Node, Metastasis stage M1a.

Efficacy of minodronic acid for the prevention of osteoporosis in premenopausal women with gynaecologic disease who undergo bilateral oophorectomy: a single-centre, non-randomised controlled, experimental study.

We evaluated the efficacy of minodronic acid for osteoporosis prevention after bilateral oophorectomy for gynaecologic disease in premenopausal women. Bone mineral density (BMD) and young adult mean (YAM) data from the lumbar vertebrae and femur and bone alkaline phosphatase (BAP)/tartrate-resistant acid phosphatase 5 b (TRACP 5 b) data were obtained for 101 patients. The primary endpoint was the efficacy of minodronic acid for osteoporosis prevention. Fifty-five and 31 patients were assigned to medication and no medication groups, respectively. The decrease in BMD and YAM and the increase in BAP/TRACP-5b were significantly more suppressed in the medication group. There were no significant between-group differences in age at oophorectomy, cancer type, body mass index (BMI), and adjuvant therapy. There were no adverse events due to minodronic acid. Minodronic acid may prevent osteoporosis after oophorectomy in premenopausal women with gynaecologic disease, independent of age at oophorectomy, cancer type, BMI, or adjuvant therapy. Impact statementWhat is already known on this subject? Although the current strategy for osteoporosis prevention after premenopausal bilateral oophorectomy (b-OVX) is hormone therapy (HT), there is no consensus on the treatment duration or adverse events.What do the results of this study add? Therefore, we planned a prospective study to evaluate the efficacy of prophylactic treatment for osteoporosis after b-OVX in premenopausal women with gynaecologic disease using minodronic acid, an oral bisphosphonate, which have a strong evidence of the treatment for osteoporosis. The result showed minodronic acid significantly suppressed the decrease in bone mineral density (BMD) and young adult mean (YAM) and the increase in bone alkaline phosphatase (BAP)/tartrate-resistant acid phosphatase 5b (TRACP 5b). Minodronic acid may prevent osteoporosis after oophorectomy in premenopausal women with gynaecologic disease, independent of age at oophorectomy, cancer type, BMI, or adjuvant therapy.What are the implications of these findings for clinical practice and/or further research? Minodronic acid treatment for osteoporosis prevention after premenopausal b-OVX may be effective as a therapeutic agent after the cessation of HT, or alternative for patients who are contraindicated for HT in breast cancer and thrombosis and should be administered with caution with a history of uterine or ovarian cancer.

Effects of ultra-low dose hormone therapy on biochemical bone turnover markers in postmenopausal women: A randomized, placebo-controlled, double-blind trial.

OBJECTIVE: Evaluate the effects of ultra-low-dose hormone therapy (Ultra-LD HT) with 17ß-estradiol 0.5 mg and norethisterone acetate 0.1 mg (E2 0.5/NETA 0.1) versus placebo on bone turnover markers (BTM) in postmenopausal women. STUDY DESIGN: A multicenter, double-blind, randomized, placebo-controlled study was performed with 107 participants who received one tablet daily of E2 0.5/NETA 0.1 or placebo for 24-weeks. Bone formation markers-N-terminal propeptide of type I procollagen (PINP) and Bone-specific alkaline phosphatase (BSAP), and bone resorption markers-C-telopeptide of type I collagen (CTX-I) and N-telopeptide crosslinked of type I collagen (NTX) were assessed before and at 12 and 24-weeks of treatment. RESULTS: Women treated with E2 0.5/NETA 0.1 had a significant reduction in the PINP marker from baseline (58.49 ± 21.12 µg/L) to week 12 (48.31 ± 20.99 µg/L) and week 24 (39.16 ± 16.50 µg/L). Placebo group, the PINP marker did not differ significantly. The analysis of the BSAP indicated a significant increase in the placebo group (13.8 ± 5.09 µg/L and 16.29 ± 4.3 µg/L, at baseline and week 24, respectively), whereas in the treatment group the values did not change. The analysis of the NTX marker showed a significant reduction only in the treatment group (43.21 ± 15.26 nM/mM and 33.89 ± 14.9 nM/mM, at baseline and week 24, respectively). CTX-I had a significant decrease in the treatment group from baseline (0.3 ± 0.16 ng/L) to week 12 (0.21 ± 0.14 ng/L) and week 24 (0.21 ± 0.12 ng/L). CONCLUSION: Women receiving E2 0.5/NETA 0.1 experienced reductions in bone resorption and formation markers, an expected effect during the anti-resorptive therapy, suggesting a protective bone effect with the Ultra-LD HT.

Osteomalacia as a Complication of Intravenous Iron Infusion: A Systematic Review of Case Reports.

Randomized control trials (RCTs) have shown that certain intravenous iron preparations can induce high levels of fibroblast growth factor 23 (FGF-23) and persistent hypophosphatemia. Repeated iron infusions may lead to prolonged hypophosphatemia and osteomalacia events not captured by RCTs. Several previous case reports have described skeletal adverse effects after repeated iron infusions. To characterize these effects, we conducted a systematic review of case reports. MEDLINE, Embase, Web of Science, and Cochrane databases were searched in March 2021. We selected case reports of patients ≥16 years old. Study quality was assessed using the tool from Murad and colleagues. We report the results in a narrative summary. We identified 28 case reports, reporting 30 cases. Ages ranged from 28 to 80 years (median 50 years). Most patients (n = 18) received ferric carboxymaltose (FCM), whereas 8 received saccharated ferric oxide (SFO) and 3 received iron polymaltose (IPM). All but 2 cases had more than five infusions (range 2 to 198, median 17). The lowest phosphate levels ranged from 0.16 to 0.77 mmol/L (median 0.36 mmol/L). Intact FGF-23 (iFGF-23) was high when measured. Serum 25OH vitamin D was low in 10 of 21 cases measured and 1,25(OH)2 vitamin D in 12 of 18. Alkaline phosphatase was high in 18 of 22 cases. Bone or muscle pain was reported in 28 of the 30 cases. Twenty patients had pseudofractures, 9 had fractures, and 6 patients had both. All 15 available bone scans showed focal isotope uptake. Case reports tend to report severe cases, so potential reporting bias should be considered. Osteomalacia is a potential complication of repeated iron infusion, especially in patients with gastrointestinal disorders receiving prolonged therapy. Pain and fractures or pseudofractures are common clinical findings, associated with low phosphate, high iFGF-23, high alkaline phosphatase, and abnormal isotope bone scan. Discontinuing or switching the iron formulation was an effective intervention in most cases. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Un caso de hipofosfatasia perinatal grave con una mutación novedosa / Severe perinatal hypophosphatasia case with a novel mutation

La hipofosfatasia es un trastorno hereditario raro causado por mutaciones en el gen ALPL. Causa defectos en la mineralización ósea y dental, función respiratoria anormal, convulsiones, hipotonía, dolor óseo y nefrocalcinosis. Las formas clínicas se reconocen según la edad al diagnóstico y la gravedad. Presentamos el caso de una lactante con fontanela anterior agrandada, bóveda craneal blanda, fracturas, dificultad respiratoria y convulsiones. El análisis bioquímico mostró hipercalcemia, fosfato sérico normal y fosfatasa alcalina sérica baja. La radiografía mostró hipomineralización, fracturas y callos. La concentración plasmática de piridoxal-5'-fosfato era de 762 mg/l (intervalo normal: 5-50) y la concentración de fosfoetanolamina en orina era de 1015 mmol/l (intervalo normal: 15-341). El análisis del gen ALPL mostró dos mutaciones heterocigotas compuestas, una de las cuales es novedosa. El diagnóstico y tratamiento tempranos de la hipofosfatasia perinatal podría mejorar los resultados y tener un impacto positivo en la sobrevida.

Hypophosphatasia (HPP) is a rare inherited disorder caused by mutations in the ALPL gene. Mineralization defect in bones and teeth, abnormal respiratory function, seizures, hypotonia, bone pain, and nephrocalcinosis can be observed. Clinical forms are usually recognized based on age at diagnosis and severity of features. We present an infant with an enlarged anterior fontanelle, soft calvarium, fractures, respiratory distress, and seizures. Biochemical analysis showed hypercalcemia, normal serum phosphate, and low serum alkaline phosphatase (ALP) levels. X-ray showed hypomineralization, fractures, and callus formations. Plasma pyridoxal 5'-phosphate (PLP) was 762 mg/L (NV : 5-50) and urine phosphoethanolamine (PEA) was 1015 mmol/L (NV : 15-341) and ALPL gene analysis showed two compound heterozygous mutations, one of which is a novel one. Early diagnosis and treatment of perinatal HPP may improve outcomes and might have a positive impact on survival.

Real-world data prognostic model of overall survival in patients with advanced NSCLC receiving anti-PD-1/PD-L1 immune checkpoint inhibitors as second-line monotherapy.

BACKGROUND AND AIM: The objective of this retrospective, observational, noninterventional cohort study was to investigate prognostic factors of overall survival (OS) in patients with advanced non-small cell lung cancer (aNSCLC) and to develop a novel prognostic model. METHODS: A total of 4049 patients with aNSCLC diagnosed between January 2011 and February 2020 who received atezolizumab, nivolumab, or pembrolizumab as second-line monotherapy were selected from a real-world deidentified database to build the cohort. Patients could not have received first-line treatment with clinical study drug(s) nor immune checkpoint inhibitors including anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1), and anti-cytotoxic T-lymphocyte-associated protein 4 therapies. RESULTS: Patients had a median age of 69 years; 45% were female, 75% White, 70% had stage IV at initial diagnosis, and 70% had nonsquamous histology. A Cox proportional hazards model with lasso regularization was used to build a prognostic model for OS using 18 baseline demographic and clinical factors based on the real-world data cohort. The risk-increasing prognostic factors were abnormally low albumin and chloride levels, Eastern Cooperative Oncology Group performance status score ≥ 2, and abnormally high levels of alkaline phosphatase and white blood cells. The risk-decreasing prognostic factors were PD-L1 positivity, longer time from advanced diagnosis to start of first-line therapy, and higher systolic blood pressure. The performance of the model was validated using data from the OAK trial, and the c-index for the OAK trial validation cohort was 0.65 and 0.67 for the real-world data cohort. CONCLUSIONS: Based on baseline demographic and clinical factors from a real-world setting, this prognostic model was developed to discriminate the risk of death in patients with aNSCLC treated with checkpoint inhibitors as second-line monotherapy, and it performed well in the real-world data and clinical trial cohorts.

Massive calcification around large joints in a patient subsequently diagnosed with adult-onset hypophosphatasia.

We report a 64-year-old Japanese woman with a history of progressive loss of motor function and painful swelling of large joints. At the age of 54, profound calcification appeared around the shoulder and hip joints, which did not heal after repeated surgical resections. Iliac bone biopsy revealed osteomalacic changes. Laboratory data showed low serum alkaline phosphatase (ALP) activity and a high urine phosphoethanolamine (PEA) concentration with normal serum calcium, phosphate, and fibroblast growth factor 23 (FGF23) levels. Subsequent genetic analysis of the ALPL gene confirmed the diagnosis of hypophosphatasia (HPP) with the identification of a heterozygous single nucleotide deletion, c.1559delT (p.Leu520ArgfsX86). We started a mineral-targeted enzyme replacement therapy, asfotase alfa (AA), to treat the patient's musculoskeletal symptoms. A follow-up bone biopsy after 12 months of AA treatment showed improvement of osteomalacia. Calcified deposits around the large joints were unchanged radiographically. To our knowledge, this is the first report of a patient with an adult-onset HPP who presented with profound calcification around multiple joints. Nonspecific clinical signs and symptoms in patients with adult-onset HPP often result in delayed diagnosis or misdiagnosis. We propose that bone biopsy and genetic analysis should be considered along with laboratory analysis for all patients with ectopic calcification around joints of unknown etiology for accurate diagnosis and better treatment.

Risk Factors for and Effects of Persistent and Severe Hypophosphatemia Following Ferric Carboxymaltose.

CONTEXT: Hypophosphatemia, osteomalacia, and fractures are complications of certain intravenous iron formulations. OBJECTIVE: This study investigated risk factors for incident, severe, and persistent hypophosphatemia, and associated alterations in bone and mineral biomarkers following intravenous iron treatment. METHODS: We analyzed data from the PHOSPHARE-IDA randomized clinical trials, comprising 245 patients aged 18 years or older with iron deficiency anemia at 30 outpatient clinics in the United States who received intravenous ferric carboxymaltose (FCM) or ferric derisomaltose (FDI). Outcome measures included serum phosphate, intact fibroblast growth factor-23 (iFGF23), 1,25-dihydroxyvitamin D (1,25(OH)2D), ionized calcium, parathyroid hormone (PTH), and alkaline phosphatase. RESULTS: FCM was the only consistent risk factor for incident hypophosphatemia (< 2.0 mg/dL; odds ratio vs FDI: 38.37; 95% CI: 16.62, 88.56; P < 0.001). Only FCM-treated patients developed severe hypophosphatemia (< 1.0 mg/dL; 11.3%; 13/115) or persistent hypophosphatemia (< 2.0 mg/dL at study end; 40.0%; 46/115). More severe hypophosphatemia associated with significantly greater increases in iFGF23, PTH, and alkaline phosphatase, and more severe decreases in 1,25(OH)2D and ionized calcium (all P < 0.05). Patients with persistent vs resolved hypophosphatemia demonstrated significantly greater changes in iFGF23, PTH, 1,25(OH)2D, and N-terminal procollagen-1 peptide levels (all P < 0.01), but alkaline phosphatase increased similarly in both groups. CONCLUSION: Treatment with FCM was the only consistent risk factor for hypophosphatemia. Patients who developed severe or persistent hypophosphatemia after FCM treatment manifested more severe derangements in bone and mineral metabolism. Changes in bone biomarkers continued beyond resolution of hypophosphatemia, suggesting ongoing effects on bone that may help explain the association of FCM with osteomalacia and fractures.

Is Elevation of Alkaline Phosphatase a Predictive Factor of Response to Alectinib in NSCLC?

In the following report, we describe a case of alkaline phosphatase (ALP) elevation occurring during treatment with alectinib (Alecensa™), which was administered for anaplastic lymphoma kinase (ALK) mutated metastatic non-small cell lung cancer (mNSCLC). A 51 year-old female with widespread metastatic disease exhibited a rapid and significant response within a very short period to alectinib therapy, accompanied by a rapid increase of ALP to more than six times the upper limit of normal (grade 3) ALP, decreasing to within normal limits within 3 weeks after initiation of therapy without any dose modification.

[The results of phase III multicenter open randomized controlled study REM-Chol-III-16 in patients with intrahepatic cholestasis syndrome caused by chronic diffuse liver diseases].

AIM: To assess the safety and efficacy of Remaxol, solution for infusion, compared with parenteral form of S-adenosyl-L-methionine, in the treatment of patients with intrahepatic cholestasis syndrome accompanying chronic diffuse liver diseases of various etiology. MATERIALS AND METHODS: In a multicenter open-label comparative study of the safety and efficacy of Remaxol (inosine + meglumine + methionine + nicotinamide + succinic acid) 317 patients aged 18 to 65 years were randomized into 2 groups: patients of the experimental group (n=168) received intravenous Remaxol, solution for infusion, 400 ml, and patients of the control group (n=149) Heptral (S-adenosyl-L-methionine) 800 mg. The duration of treatment was 10 days. The primary efficacy endpoint was the proportion of patients who responded to therapy, as demonstrated by dynamics of laboratory parameters of liver functional status: decrease in gamma glutamyl transpeptidase level by 40%, and/or alkaline phosphatase level by 30%, and/or decrease total bilirubin level by 30% from baseline by the end of the treatment course. RESULTS: The proportion of responders was 51% in the Remaxol group vs. 44.9% in the Heptral group (p=0.303); the lower limit of the one-sided 95% confidence interval for the difference in the proportions of responders was -4.01%, which exceeds the non-inferiority margin pre-defined by the study protocol, thus, the non-inferiority hypothesis was proven, i.e. Remaxol at a dose of 400 ml/day demonstrates similar efficacy to Heptral at a dose of 800 mg/day in patients with intrahepatic cholestasis syndrome associated with chronic diffuse liver diseases. Similar positive trends in the levels of transaminases, total bilirubin and the severity of pruritus were revealed in both treatment groups. We did not reveal statistically significant between-group differences in the frequency of adverse events definitely related to the study treatment. CONCLUSION: Administration of Remaxol as a part of the pathogenetic therapy of patients with intrahepatic cholestasis syndrome who need hepatoprotection is justified.

Pediatric hypophosphatasia: lessons learned from a retrospective single-center chart review of 50 children.

BACKGROUND: Hypophosphatasia (HPP) is a rare, inherited metabolic disorder caused by loss-of-function mutations in the ALPL gene that encodes the tissue-nonspecific alkaline phosphatase TNAP (ORPHA 436). Its clinical presentation is highly heterogeneous with a remarkably wide-ranging severity. HPP affects patients of all ages. In children HPP-related musculoskeletal symptoms may mimic rheumatologic conditions and diagnosis is often difficult and delayed. To improve the understanding of HPP in children and in order to shorten the diagnostic time span in the future we studied the natural history of the disease in our large cohort of pediatric patients. This single centre retrospective chart review included longitudinal data from 50 patients with HPP diagnosed and followed at the University Children's Hospital Wuerzburg, Germany over the last 25 years. RESULTS: The cohort comprises 4 (8%) perinatal, 17 (34%) infantile and 29 (58%) childhood onset HPP patients. Two patients were deceased at the time of data collection. Diagnosis was based on available characteristic clinical symptoms (in 88%), low alkaline phosphatase (AP) activity (in 96%), accumulating substrates of AP (in 58%) and X-ray findings (in 48%). Genetic analysis was performed in 48 patients (31 compound heterozygous, 15 heterozygous, 2 homozygous mutations per patient), allowing investigations on genotype-phenotype correlations. Based on anamnestic data, median age at first clinical symptoms was 3.5 months (min. 0, max. 107), while median time to diagnosis was 13 months (min. 0, max. 103). Common symptoms included: impairment of motor skills (78%), impairment of mineralization (72%), premature loss of teeth (64%), musculoskeletal pain and craniosynostosis (each 64%) and failure to thrive (62%). Up to now 20 patients started medical treatment with Asfotase alfa. CONCLUSIONS: Reported findings support the clinical perception of HPP being a chronic multi-systemic disease with often delayed diagnosis. Our natural history information provides detailed insights into the prevalence of different symptoms, which can help to improve and shorten diagnostics and thereby lead to an optimised medical care, especially with promising therapeutic options such as enzyme-replacement-therapy with Asfotase alfa in mind.