Safety and Effectiveness of Trastuzumab Biosimilar SB3 in Korean Patients, a Post-Marketing Surveillance Study.

INTRODUCTION: SB3 is a trastuzumab biosimilar approved in Australia, Brazil, Canada, the European Union, the Republic of Korea, Switzerland, and the United States. This real-world study evaluated safety and effectiveness of SB3 as part of the Korean post approval safety management system. METHODS: This post-marketing surveillance in Korea included patients in line with approved indications, i.e. patients with early or metastatic breast cancer or metastatic gastric cancer. Safety outcomes were adverse events and adverse drug reactions. Effectiveness outcomes were tumor response and event-free survival. RESULTS: 424 patients were evaluated: 366 patients (86%) with early breast cancer, 53 patients (13%) with metastatic breast cancer, and 5 patients (1%) with metastatic gastric cancer. Among patients with breast cancer, adverse events (mostly mild) and adverse drug reactions were reported by 158 (37.7%) and 57 (13.6%) patients, respectively. Most patients with an AE (141, 75.9%) had no change in treatment schedule. Treatment was temporarily suspended in 14 (8.2%) patients with an AE and completely discontinued in 7 (3.7%). Among patients with early and metastatic breast cancer who were evaluated for efficacy, objective response rates were 82.7% and 38.3%, respectively. Pathological complete response was 64.6% in patients with early breast cancer. DISCUSSION/CONCLUSION: Safety and efficacy of SB3 demonstrated in this real-world study were comparable with previous studies of reference trastuzumab.

Effect of fenofibrate in 1113 patients at low-density lipoprotein cholesterol goal but high triglyceride levels: Real-world results and factors associated with triglyceride reduction.

Fibrates are used in patients with dyslipidemia and high cardiovascular risk. However, information regarding drug response to fibrate has been highly limited. We investigated treatment results and factors associated with triglyceride reduction after fenofibrate therapy using large-scale real-world data. Patients with one or more cardiovascular risk factors, at low-density lipoprotein-cholesterol goal but with triglyceride level ≥150 mg/dL, and undergoing treatment with fenofibrate 135-160 mg for the first time were included in this retrospective observational study. The outcome variable was the percentage changes of TG levels. The achievement rate of triglyceride <150 mg/dL was additionally analyzed. Factors associated with treatment results were also analyzed. Among 2546 patients who were initially screened, 1113 patients were enrolled (median age: 61 years; male: 71%). After median follow-up of 4 months, the median change in triglyceride was -60%, and 49% of the patients reached triglyceride <150 mg/dL. After adjusting for confounding variables, female sex, non-diabetic status, coronary artery disease, lower baseline triglyceride, and no statin use were identified to be independently associated with achievement of triglyceride <150 mg/dL. Among them, female sex, non-diabetic status, and coronary artery disease were also related to median or greater percentage reduction of triglyceride. In conclusion, only half of the study patients reached triglyceride levels <150 mg/dL after real-world fenofibrate therapy. This study indicates that more attention is needed on some subgroups to obtain optimal triglyceride levels when treating with fenofibrate.

A case of parathyroid adenoma adjacent to the thoracic spine in a hemodialysis patient.

Ectopic parathyroid glands are detected occasionally, especially in cases of recurrent hyperparathyroidism after initial parathyroidectomy. Their ectopic locations usually result from faulty migration during embryogenesis. Ectopic parathyroid glands can be found within the thyroid gland, thymus, mediastinum, carotid sheath, or retropharynx, which lie along the path of their normal migration. Here we report a rare case of parathyroid adenoma adjacent to the thoracic spine in a hemodialysis patient who had undergone parathyroidectomy previously. A 67-year-old woman on maintenance hemodialysis since 1993 developed hyperparathyroidism. She underwent total parathyroidectomy with autotransplantation in 2007. Histological examination of the parathyroid glands showed hyperplasia in three glands and adenoma in one. Serum parathyroid hormone levels gradually increased after a year. Ultrasonography of the neck and upper limbs was negative, but technetium-99-sestamibi scanning showed focal uptake in the posterior mediastinum. Computed tomography and magnetic resonance imaging confirmed a tumor adjacent to the left costovertebral junction of the third thoracic vertebra. A tumor resection was performed in 2010, and histopathological examination showed a parathyroid adenoma. Parathyroid adenoma adjacent to the thoracic spine has not been reported previously, and our case suggests that technetium-9-sestamibi scanning is useful for the correct preoperative diagnosis of such rare cases of ectopic parathyroid glands.

Survey of the effects of a column for adsorption of ß2-microglobulin in patients with dialysis-related amyloidosis in Japan.

Dialysis-related amyloidosis is a serious complication of long-term hemodialysis. Its pathogenic mechanism involves accumulation of ß2-microglobulin in the blood, which then forms amyloid fibrils and is deposited in tissues, leading to inflammation and activation of osteoclasts. Lixelle, a direct hemoperfusion column for adsorption of ß2-microglobulin, has been available since 1996 to treat dialysis-related amyloidosis in Japan. However, previous studies showing the therapeutic efficacy of Lixelle were conducted in small numbers of patients with specific dialysis methods. Here, we report the results of a nationwide questionnaire survey on the therapeutic effects of Lixelle. Questionnaires to patients and their attending physicians on changes in symptoms of dialysis-related amyloidosis by Lixelle treatment were sent to 928 institutions that had used Lixelle, and fully completed questionnaires were returned from 345 patients at 138 institutions. The patients included 161 males and 184 females 62.9 ± 7.7 years age, who had undergone dialysis for 25.9 ± 6.2 years and Lixelle treatment for 3.5 ± 2.7 years. Based on self-evaluation by patients, worsening of symptoms was inhibited in 84.9-96.5% of patients. Of the patients, 91.3% felt that worsening of their overall symptoms had been inhibited, while attending physicians evaluated the treatment as effective or partially effective for 72.8% of patients. Our survey showed that Lixelle treatment improved symptoms or prevented the progression of dialysis-related amyloidosis in most patients.

Effectiveness of ß(2)-microglobulin adsorption column in treating dialysis-related amyloidosis: a multicenter study.

BACKGROUND/AIMS: The aim of this study was to determine whether treatment with ß(2)-microglobulin adsorption column (Lixelle) affects bone cysts and clinical symptoms in patients with dialysis-related amyloidosis (DRA). METHODS: Radiographic changes in the number and area of bone cysts of the wrist and the hip joint were compared between 39 hemodialysis (HD) patients treated with Lixelle (Lixelle group) and 28 HD patients treated with conventional therapy as retrospective control (HD group). Clinical symptoms of DRA were also evaluated. RESULTS: In the Lixelle group, the number of bone cysts and the cystic area in wrist joints were significantly decreased, although the changes in these parameters in hip joints were not significant. In the HD group, the corresponding parameters in the hip joints even significantly increased. Clinical symptoms notably improved after Lixelle treatment. CONCLUSION: Treatment with Lixelle reduces the radiolucency of bone cysts in the wrist joints, and improves clinical symptoms associated with DRA.

Clinical efficacy and cost-effectiveness of lanthanum carbonate as second-line therapy in hemodialysis patients in Japan.

BACKGROUND AND OBJECTIVES: Lanthanum carbonate (LC) is a nonaluminum, noncalcium phosphate binder that is effective for hyperphosphatemia in dialysis patients. However, its efficacy and cost-effectiveness as second-line therapy have not been fully examined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We first conducted a multicenter, open-label, 16-week clinical trial to examine the effect of additive LC in 116 hemodialysis patients who had uncontrolled hyperphosphatemia with conventional phosphorus-lowering therapy alone. Based on these clinical data, a state transition model was developed to evaluate the benefits and costs associated with LC as second-line therapy. Reduced risks for cardiovascular morbidity and mortality among patients treated with LC arise through more of the population achieving the target phosphorus levels. Uncertainty was explored through sensitivity analysis. RESULTS: After 16 weeks of additive LC treatment, mean serum phosphorus levels decreased from 7.30 ± 0.90 to 5.71 ± 1.32 mg/dl, without significant changes in serum calcium or intact parathyroid hormone levels. A subsequent cost-effectiveness analysis showed that compared with conventional treatment, additive LC incurred an average additional lifetime cost of $22,054 per person and conferred an additional 0.632 quality-adjusted life years (QALYs). This resulted in an incremental cost-effectiveness ratio of $34,896 per QALY gained. Applying a cost-effectiveness threshold of $50,000 per QALY, a probabilistic sensitivity analysis showed that additive LC had a 97.4% probability of being cost-effective compared with conventional treatment. CONCLUSIONS: Our results indicate that the use of LC as second-line therapy would be cost-effective among hemodialysis patients with uncontrolled hyperphosphatemia in Japan.

Cinacalcet effectively reduces parathyroid hormone secretion and gland volume regardless of pretreatment gland size in patients with secondary hyperparathyroidism.

BACKGROUND AND OBJECTIVES: Cinacalcet is effective in reducing serum parathyroid hormone (PTH) in patients with secondary hyperparathyroidism. However, it has not been proven whether parathyroid gland size predicts response to therapy and whether cinacalcet is capable of inducing a reduction in parathyroid volume. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This 52-week, multicenter, open-label study enrolled hemodialysis patients with moderate to severe secondary hyperparathyroidism (intact PTH >300 pg/ml). Doses of cinacalcet were adjusted between 25 and 100 mg to achieve intact PTH <180 pg/ml. Ultrasonography was performed to measure the parathyroid gland size at baseline, week 26, and week 52. Findings were also compared with those of historical controls. RESULTS: Of the 81 subjects enrolled, 56 had parathyroid glands smaller than 500 mm(3) (group S) and 25 had at least one enlarged gland larger than 500 mm(3) (group L). Treatment with cinacalcet effectively decreased intact PTH by 55% from baseline in group S and by 58% in group L. A slightly greater proportion of patients in group S versus group L achieved an intact PTH <180 pg/ml (46 versus 32%) and a >30% reduction from baseline (88 versus 78%), but this was not statistically significant. Cinacalcet therapy also resulted in a significant reduction in parathyroid gland volume regardless of pretreatment size, which was in sharp contrast to historical controls (n = 87) where parathyroid gland volume progressively increased with traditional therapy alone. CONCLUSIONS: Cinacalcet effectively decreases serum PTH levels and concomitantly reduces parathyroid gland volume, even in patients with marked parathyroid hyperplasia.

Restoration of reversed whole PTH/intact PTH ratio and reduction in parathyroid gland vascularity during cinacalcet therapy for severe hyperparathyroidism in a uraemic patient.

Parathyroid hormone (PTH) levels measured with the intact PTH assays are generally higher than those measured with the whole PTH assay; however, rare exceptions to this rule have been reported in patients with severe hyperparathyroidism associated with N-PTH overproduction. We report a haemodialysis patient with severe secondary hyperparathyroidism, in whom abnormally higher whole PTH levels than intact PTH levels were normalized during cinacalcet therapy. Moreover, we observed a marked reduction in parathyroid gland vascularity during this treatment. Our findings suggested that increased sensitivity of the parathyroid calcium sensing receptor by calcimimetics may modulate the secretion or truncation of N-PTH or other PTH molecules that can be detected by the whole PTH assay but not by the intact PTH assays.

Information-sharing system for disaster recovery of dialysis therapy in Japan.

If a natural disaster or other event causes damage that makes dialysis therapy impossible, what steps should be taken? Many actions will be required, including disaster recovery activities in the affected area as well as the performance of dialysis at substitute dialysis facilities outside the affected area. The Japanese Association of Dialysis Physicians (JADP), in collaboration with the Japan Association for Clinical Engineering Technologists (JACET), operates an "information sharing system" that will be essential when carrying out post-disaster activities. This system consists of a website and mailing lists on the Internet, and it has been used in 11 disasters so far.The JADP is an organization of doctors engaged in dialysis therapy. This association conducts investigation and research, education, and crisis management for dialysis therapy. The JACET is an organization that aims to enhance scientific knowledge and skills and to improve capabilities. This association also pursues improvement of the reliability of medical care involving life support systems and other medical equipment.

Carpal tunnel syndrome and plasma beta2-microglobulin concentration in hemodialysis patients.

As of the end of June 2005, 27 of 96 dialysis outpatients at our clinic had developed carpal tunnel syndrome (CTS). Of 19 patients who had undergone dialysis for 30 years or longer, 15 had CTS, whereas none of the 38 patients who had received dialysis for less than 10 years had CTS. These data reflect trends in CTS development: from 1983 the incidence of CTS increased for many years, but more recently there has been a decline in new cases of CTS. Comparison of the 27 CTS and 69 non-CTS dialysis patients at our clinic showed that those in the CTS group were older and had a longer duration of dialysis. Patients in the CTS group were found to have had a high plasma beta2-microglobulin (BMG) level in the distant past (15-21 years ago), but conversely had a much lower BMG level in recent years. Simple correlation analysis and multiple logistic regression analysis showed that the presence of CTS was correlated with high BMG levels in the distant past, in addition to age and duration of dialysis. These findings suggest that reduction of the plasma BMG level due to advances in dialysis therapy in recent years has contributed to the decreased incidence of CTS.

Determination of Bisphenol A (BPA) in Plasma of Hemodialysis Patients Using Three Methods: LC/ECD, LC/MS, and ELISA.

ABSTRACT Bisphenol A (BPA) values were compared in plasma of hemodialysis patients and in recycling solvents using LC/MS, LC/electrochemical detector (ECD), and enzyme linked immunosorbent assay (ELISA). BPA values in the plasma and the solvent were 0-8.4 ng/ml and 0-0.8 ng/ml for LC/ECD, 0-4.9 ng/ml and 0-0.8 ng/ml for LC/MS, and 0-15.5 ng/ml and 0-3.1 ng/ml for ELISA, respectively. There was no significant difference among BPA values both in the plasma and the solvents using three methods. Single correlation coefficients between LC/ECD and LC/MS, LC/ECD and ELISA, and LC/MS and ELISA were, respectively, 0.373 (p < 0.002), 0.347 (p < 0.002), and 0.945 (p < 0.001) in the plasma (n = 68-109) and 0.916 (p < 0.001), 0.431 (p > 0.05), and 0.332 (p > 0.05) in the solvents (n = 19). An unknown substance present in the plasma of patients but not healthy volunteers influenced the LC/ECD values of plasma repeated freezing and thawing. The results indicate that LC/MS and ELISA are appropriate for BPA analysis in plasma and both LC/MS and LC/ECD in the recycling solvents and handling with plasma before analysis is important to the analysis of BPA in patients' plasma using LC/ECD.

Reversed whole PTH/intact PTH ratio as an indicator of marked parathyroid enlargement: five case studies and a literature review.

Parathyroid hormone (PTH) levels detected by intact PTH assays are generally higher than those detected by the whole PTH assay because the latter does not detect non-(1-84) PTH fragments, mainly PTH (7-84). Rare exceptions to this rule have been reported in patients with severe primary or secondary hyperparathyroidism and parathyroid carcinoma. Overproduction of an N-form of PTH other than PTH (1-84) has been observed in the sera of these patients. We report five additional cases with the reversed whole PTH/intact PTH ratio associated with severe hyperparathyroidism in haemodialysis patients. Three patients demonstrated enlargement of a single hypervascular gland, whereas the other two had undergone surgical parathyroidectomy and later showed recurrent hyperparathyroidism due to progressive autograft hyperplasia. In the case of a single enlarged gland, the pathological pattern and heterogeneous expression of parathyroid adenomatosis 1/cyclin D1 suggested it to be a single nodule of uraemic hyperparathyroidism rather than sporadic primary adenoma. These cases suggested that the reversed whole PTH/intact PTH ratio could be an indicator of marked parathyroid enlargement. Further studies are required to elucidate the clinical significance of the reversed whole PTH/intact PTH ratio in haemodialysis patients.

[2 dialysis cases which came to our clinic for the symptoms caused by hypercalcemia].

We'll report 2 dialysis cases which came to our clinic for the symptoms caused by hypercalcemia. Patients complained of sleeplessness, itching, headache, palpitation, apathy, akinesis, leanness, foot gangrene and so on. Hypercalcemia is one of the complication of vitamin D and calcium carbonate administration in chronic renal failure, though the frequency and risk are not clearly documented. Hypercalcemia aggravates the outcome of patients on dialysis and contributes to vascular calcification in long term. Recently various factors involving cardiovascular calcification are discussed, but first of all we must be very careful for the symptoms of hypercalcemia, and careful monitoring of plasma calcium concentration are recommended.

Bio-intact parathyroid hormone and intact parathyroid hormone in hemodialysis patients with secondary hyperparathyroidism receiving intravenous calcitriol therapy.

Intact parathyroid hormone (iPTH) assay has been the most widely used for the diagnosis of secondary hyperparathyroidism and evaluation of vitamin D therapy. However, 1-84 PTH assay might be a better diagnostic tool since iPTH detects not only 1-84 PTH but also large C-terminal fragments, which would antagonize PTH action. Therefore, we conducted a multicenter study to evaluate the clinical usefulness of a newly developed immunochemiluminometric assay for 1-84 PTH, Bio-Intact PTH (BiPTH). Thirty-five uremic patients with secondary hyperparathyroidism participated in the study. Intravenous calcitriol therapy was continued for 12 months. iPTH and bone-specific alkaline phosphatase (BAP) were monitored at each dialysis center to control the dose of calcitriol. Serum and plasma samples were collected from each center and both iPTH and BiPTH were measured using Allegro-Lite assay reagents from Nichols Institute Diagnostics (San Clemente, CA, USA). Intravenous calcitriol suppressed iPTH after 1 month as well as BiPTH. Bone-specific alkaline phosphatase decreased after 3 months. A high degree of correlation between Nichols iPTH and BiPTH (y = 0.3913 x + 19.517, r = 0.9561) was demonstrated with a BiPTH/iPTH ratio of approximately 0.44. Significant correlation between BAP and iPTH, or between BAP and BiPTH was not observed. Our limited data failed to demonstrate the superiority of BiPTH to iPTH. Therefore, further investigations would be necessary to examine the relationship between BiPTH and bone histomorphometry.

Efficacy of direct injection of calcitriol into the parathyroid glands in uraemic patients with moderate to severe secondary hyperparathyroidism.

INTRODUCTION: Secondary hyperparathyroidism (2HPT) is a common complication in uraemic patients. When medical therapy, including high doses of intravenous calcitriol, fails to suppress the pathological secretion of parathyroid hormone (PTH), one of the newly developed interventional techniques, such as percutaneous ethanol injection therapy (PEIT), is an option before taking the surgical solution. A protocol for direct calcitriol injection therapy and a discussion of its effectiveness and limitations for an enlarged parathyroid gland(s) are presented. METHODS: Nine patients were selected according to the Japanese Guideline for Selective PEIT. Using the same technique as PEIT, a dose of calcitriol that was approximately 200-300% of the calculated volume of the selected parathyroid gland was injected directly into the gland under ultrasonographic guidance. RESULTS: In six cases, the intact PTH concentration decreased to <360 pg/ml. The total volume of the enlarged parathyroid gland(s) also decreased to 54.7% of the initial volume. The blood supply to the treated glands, as evaluated by colour Doppler imaging, appeared to diminish transiently after injection, probably from the volume effect of this procedure. The number of enlarged parathyroid glands was not a limiting factor for this therapy; however, a grossly enlarged parathyroid gland (>2000 mm(3)) appeared to be resistant to this intervention and an intrathoracic parathyroid gland was found in a non-responsive case. None of the patients had any severe complications, such as nerve palsy or massive haemorrhage. CONCLUSION: This new approach to the control of 2HPT is recommended as an alternative pharmacological parathyroidectomy to surgical therapy.