Outcomes of Early Versus Delayed Anemia Treatment in Nondialysis-Dependent CKD.

Introduction: The association of hemoglobin level at treatment initiation with renal and cardiovascular outcomes in patients with anemia in nondialysis-dependent (NDD) chronic kidney disease (CKD) is unclear. Methods: This retrospective cohort study utilized 2 Japanese databases (Medical Data Vision Co. Ltd., Tokyo, Japan [MDV]; and Real World Data Co. Ltd, Kyoto, Japan [RWD]). Patients initiated on long-acting erythropoiesis-stimulating agent (ESA) treatment were divided into early (hemoglobin levels ≥9.0 g/dl) and delayed (<9.0 g/dl) treatment groups. The primary outcome was a renal composite (renal replacement therapy, ≥50% estimated glomerular filtration rate [eGFR] reduction, eGFR <6.0 ml/min per 1.73 m2, and all-cause mortality), and secondary outcomes were a cardiovascular composite (hospitalization by ischemic heart disease, including myocardial infarction, hospitalization by stroke and heart failure, and cardiovascular death) and components of the composite outcomes. Results: After propensity score matching, 1472 (MDV) and 1264 (RWD) patients were evaluated. Delayed treatment was not associated with a risk of the renal composite outcome (MDV: hazard ratio [HR]: 1.15, 95% confidence interval [CI]: 0.99-1.33; RWD: HR: 1.08, 95% CI: 0.92-1.28). However, delayed treatment was associated with higher risks of the cardiovascular composite outcome (MDV: HR: 1.47, 95% CI: 1.16-1.84; RWD: HR: 1.34, 95% CI: 1.09-1.64), heart failure (MDV: HR: 1.50, 95% CI: 1.13-2.00; RWD: HR: 1.53, 95% CI: 1.20-1.96) and all-cause mortality (MDV: HR: 1.83, 95% CI: 1.32-2.54; RWD: HR: 1.64, 95% CI: 1.21-2.22). Conclusion: Although the risk of renal events was not increased following delayed treatment of anemia in patients with NDD-CKD, the risks of cardiovascular events and all-cause mortality were increased, suggesting the importance of early intervention before hemoglobin falls below 9.0 g/dl.

Two Cases of Monozygotic Twins with Early-onset Isolated (DYT1) Dystonia Effectively Treated with Bilateral Globus Pallidus Internus Stimulation.

Early-onset isolated (DYT1) dystonia is one of the most common forms of primary dystonia in childhood, and deep brain stimulation of the globus pallidus internus (GPi-DBS) is a highly effective treatment for it. However, the effectiveness of GPi-DBS in monozygotic twins with DYT1 dystonia has never been reported globally. Here, we report the cases of monozygotic twins with DYT1 dystonia who were treated using GPi-DBS, and we include a literature review. The younger brother showed an abnormal gait, with external rotation of the right lower leg at 6 years old. The symptoms gradually became so severe that he had difficulty walking on his own at 9 years of age. Treatment with levodopa-carbidopa partially resolved his symptoms, but most of the symptoms remained. Meanwhile, the older brother developed dystonia in both upper limbs at 8 years of age, with gradual symptom progression. At 13 years of age, they were diagnosed with DYT1 dystonia. Bilateral GPi-DBS was performed in both patients at 16 years of age. Their symptoms remarkably improved after surgery. The Burke-Fahn-Marsden dystonia rating scale (BFMDRS) movement score was reduced from 52 to 2 points for the younger brother and from 35 to 1 point for the older brother. Even if monozygotic twins have the same genes, the onset and severity of symptoms might vary in accordance with differences in epigenomic profiles. However, GPi-DBS treatment was very effective for the two cases; thus, we should consider the surgical interventions for each patient.

[False-Positive ¹²³I-Metaiodobenzylguanidine Scan in a Patient with Adrenocortical Cancer].

A 59-year-old woman presented with a left adrenal tumor 4 cm in diameter. The ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy showed apparent accumulation in the left adrenal tumor. However, the patient had no sign or symptoms suggesting pheochromocytoma. No biochemical evidence of catecholamine excess was noticed. Computed tomography (CT) revealed relatively strong enhancement in the arterial phase, which persisted until the portal phase. The computed tomography (CT) and magnetic resonance imaging showed 2 liver nodule suspected to be metastatic tumors. No ¹²³I-MIBG accumulation was seen in these nodules. CT also showed thyroid nodules with calcification, which suggested papillary thyroid cancer. Based on the findings, open left adrenalectomy, partial hepatectomy and segmentectomy were performed under the clinical diagnosis of pheochromocytoma and metastatic liver tumors. Histopathological diagnosis was adrenocortical cancer. There was only lymphocyte infiltration in the liver nodules. Postoperative recovery was uneventful, and the patient underwent partial thyroidectomy 6 months later. The pathological diagnosis was papillary thyroid cancer. She has been without recurrence or metastases for 18 months after adrenalectomy. We found only 6 cases of MIBG scintigraphy-positive adrenocortical cancer in the literature. The mechanisms for MIBG uptake in adrenocortical cancer are discussed with a review of the literature.

In Vitro and Clinical Pharmacokinetic Studies of the Effects of Iron-containing Agents on Vadadustat, an Oral Hypoxia-inducible Factor-Prolyl Hydroxylase Inhibitor.

PURPOSE: Vadadustat is an oral hypoxia-inducible factor-prolyl hydroxylase inhibitor approved in Japan for the treatment of anemia in chronic kidney disease. This study investigated drug-drug interactions between vadadustat and oral iron supplements or iron-containing phosphate binders commonly used in Japanese clinical practice by conducting in vitro mechanistic and clinical pharmacokinetic studies. METHODS: In the in vitro assessment, chelate formation of vadadustat with iron-containing agents was investigated in water and in a fed-state simulated intestinal fluid. Chelate formation was assessed by observation of a chelate-specific color, and the concentration of vadadustat was determined. In the single-dose, open-label, randomized, crossover clinical study, healthy male participants received 150 mg of vadadustat with or without oral iron-containing agents. Pharmacokinetic data were collected for up to 24 hours after vadadustat administration. Participants were monitored for adverse events during the study. FINDINGS: Vadadustat formed a chelate precipitate with ferrous sulfate and ferric nitrate, as shown by development of a specific bright orange color in water. The proportions of vadadustat dissolved in the supernatant were 2% and 18%, respectively. Vadadustat did not form a chelate precipitate in a fed-state simulated intestinal fluid in the presence of sodium ferrous citrate, ferric citrate hydrate, or sucroferric oxyhydroxide; the proportion of vadadustat in supernatant ranged from 63% to 89%. In the clinical pharmacokinetic study, coadministration of vadadustat with sodium ferrous citrate, ferric citrate hydrate, sucroferric oxyhydroxide, or ferrous sulfate decreased the AUC0-∞ by 54.0% to 89.7% and Cmax by 42.1% to 91.9%. No serious adverse events were reported. IMPLICATIONS: Chelate formation of vadadustat with iron-containing agents was confirmed by in vitro analysis and depended on the type of iron-containing agent. The AUC0-∞ and Cmax of vadadustat decreased when coadministered with oral iron-containing agents. Our data suggest that the decreases in AUC0-∞ and Cmax are a result of chelation in the gastrointestinal tract; therefore, coadministration of iron-containing agents with vadadustat should use a dosing interval. ClinicalTrials.gov Identifier: NCT03645863.

[Metachronous Development of Mantle Cell Lymphoma during Active Surveillance in a Patient with Stage I Testicular Cancer].

A 78-year-old man presented with swelling of para-aortic and left iliac lymph nodes (LNs). He had undergone left high orchiectomy 10 years ago. He was diagnosed with stage I seminoma, and was managed with active surveillance. Eight years later, the follow-up computed tomography (CT) revealed para-aortic LN swelling, but the patient refused further treatment. He complained of left lower extremity edema 10 years after orchiectomy. CT showed enlargement of both LNs, especially, diameter of left iliac lymph nodes was up to 9 cm. He was referred to our hospital. LDH was slightly increased to 261 IU/1, but α-fetoprotein, and total and free beta human chorionic gonadotropin were within normal limits. Results of pathological review of the testicular tumor was also seminoma. The treatment with etoposide and cisplatin (EP) was started under the diagnosis of late relapse of seminoma. However, CT after 1 course of EP showed no shrinkage of LN metastases. At this time, soluble interleukin-2 receptor (sIL-2R) was elevated up to 5,090 U/ml (normal range: 613 U/ml). Needle biopsy from pelvic LN was performed on suspicion of metachronous malignant lymphoma. The pathological diagnosis was mantle cell lymphoma. The patient was transferred to the department of hematology, and treated successfully with rituximab and bendamustine. When LN swelling is seen after long-term active surveillance, there is a possibility of late relapse. However, metachronous malignant lymphoma also should be considered in an elderly patient.

[Solitary Bladder Metastasis of Chromophobe Renal Cell Carcinoma: Report of a Case].

Bladder metastasis of renal cell carcinoma (RCC) is relatively rare, and only 43 cases have been reported in the Japanese literature. In most cases, the histology of the primary site was clear cell type. Here, we report a case of bladder metastasis of chromophobe RCC. A 74-year-old man presented with asymptomatic gross hematuria. He had a history of chromophobe RCC treated with radical nephrectomy 11 years previously. Since cystoscopy revealed a papillary pedunculated tumor, he underwent transurethral resection of the bladder tumor (TUR-Bt). The pathological diagnosis was chromophobe RCC because the histological findings were similar to those of nephrectomized specimens. Four years after TUR-Bt, the patient received bacillus Calmette-Guérin (BCG) therapy under the diagnosis of carcinoma in situ of urothelial cancer of the bladder but not chromophobe RCC. There was no recurrence of chromophobe RCC within 5 years follow-up after TUR-Bt. To the best of our knowledge, there has been only one other case report of bladder metastasis of chromophobe RCC in the Japanese literature.

Successful re-administration of imatinib without recurrence of tumor lysis syndrome in a patient with peritoneal gastrointestinal stromal tumor.

A 69-year-old man with disseminated peritoneal gastrointestinal stromal tumor (GIST) developed tumor lysis syndrome (TLS) during imatinib therapy. Although the TLS improved after imatinib therapy was discontinued, the tumor growth accelerated. Therefore, imatinib therapy was restarted at a reduced dose, and a TLS prevention strategy was implemented that involved aggressive hydration and therapy with rasburicase and allopurinol. The tumor almost completely diminished without recurrence of TLS, and the patient has been in remission for 26 months. In the 2 previously reported cases of GIST with TLS, none of the patients survived. Our case report suggests that a TLS prevention strategy could be effective when restarting imatinib chemotherapy in sensitive solid tumors like GISTs.

Diet modification and its influence on metabolic and related pathological alterations in the SHR/NDmcr-cp rat, an animal model of the metabolic syndrome.

SHR/NDmcr-cp (SHR/NDcp) rats, which carry a nonsense mutation of the leptin receptor gene, are known to spontaneously develop hypertension, obesity and hyperlipidemia, and have therefore found use as an animal model of the metabolic syndrome and type 2 diabetes. However, some recent studies on SHR/NDcp rats revealed only mild elevation of blood glucose levels. To investigate whether metabolic factors including blood glucose and histopathological alterations of SHR/NDcp rats deteriorate with a diabetogenic diet, biochemical and histopathological examinations were conducted with animals fed normal or diabetogenic diets for 20 weeks. SHR/NDcp rats receiving the normal diet displayed obesity, hypertension, hyperlipidemia, and mild elevation of blood glucose and HbA1c levels. Urinary glucose excretion was noted in only 1 out of 6 animals. Histologically, macro- and micro-vesicular steatosis in the liver, glomerular and tubular damages in the kidney and islet hyperplasia mainly of beta cells in the pancreas were characteristically noted. In SHR/NDcp rats fed the diabetogenic diet, obesity was more severe, with higher blood glucose and HbA1c levels, increased numbers of animals with urinary glucose excretion, and more pronounced hepatic steatosis and renal tubular changes. However, elevation of blood glucose levels and urinary glucose excretion proved transient. These observations indicate that the diabetic state and associated histopathological alterations in SHR/NDcp rats are exacerbated by feeding a diabetogenic diet, but the effects are limited. Elevated islet function with compensative insulin secretion might be related to amelioration of the hyperglycemic state. Further diet modification could be needed to induce a more prominent and persistent diabetic state in SHR/NDcp rats.

A Hepatocellular Adenoma in a Diet-induced Obese Mouse.

A hepatic nodule was noted in a C57BL/6J mouse with diet-induced obesity at 53 weeks of age. Macroscopically, a protruding yellowish white nodule was observed on the visceral surface of the left lateral lobe. Light microscopy demonstrated clear demarcation from the compressed adjacent parenchyma, with loss of the distinct lobular pattern. The proliferating cells of the lesion varied in shape and showed cellular atypia and prominent nucleoli along with vacuoles of various sizes. Some of the cells contained various-sized eosinophilic inclusion bodies in their cytoplasm, and electron microscopy revealed the presence of lipid droplets in the rough endoplasmic reticulum. Eosinophilic inclusions were observed as electron dense granular material in the rough endoplasmic reticulum, with one or a few low density central cores. A diagnosis of hepatocellular adenoma was made based on these findings.

Analysis of voice source characteristics using a constrained polynomial representation of voice source signals.

To analyze the characteristics of voice source signals from speech, a model is presented in the form of polynomial function by expanding the definition of the Rosenberg model. In combination with the all-pole assumption of the vocal-tract filter, methods are described for the pitch-synchronous speech analysis and temporal search of the glottal opening and closing instants. Because the source and filter models are both linear, the parameter estimation problem can be conveniently solved. In addition, the temporal search method can refine the locations of the glottal events and improve the accuracy of the parameter estimation. Analyses of non-nasalized voiced speech are conducted using an electroglottographic device from which the initial estimate of the temporal information is given.

The activity of matrix metalloproteinases (MMPS) and tissue inhibitors of metalloproteinases (TIMPs) in mammary tumors of dogs and rats.

We conducted zymography for detecting the activity of matrix metalloproteinases (MMPs) and reverse zymography for the activity of tissue inhibitors of metalloproteinases (TIMPs) in canine spontaneous and rat 7, 12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumor tissues. The activities of MMPs of canine mammary tumors were quite higher than those of the rat chemically induced tumors. The activities of MMPs were significantly higher in malignant tissues than in benign ones of canine tumors, whereas the activity of only MMP-2 was higher in both benign and malignant rat tumors compared to normal tissues. There were no differences of MMPs activities between benign and malignant rat tumors. The results of reverse zymography indicated that the activities of TIMP-1, -2 and -3 were strikingly higher in rat tumors than in canine tumors. The activities were higher in malignant tissues than in benign ones of dogs, and higher in tumor tissues than in normal mammary tissues of rats. The results of film in situ zymography for tissue localization of gelatinolytic activity showed that the digested area was more extended in malignant tumors than in benign ones of dogs. However, the area was similarly extended in both benign and malignant rat tumors. These results may indicate that the canine spontaneous malignant mammary tumors possess more aggressive nature than the rat chemically induced counterpart, resulting from the high level of MMPs and low level of TIMPs activities of the tumor tissues.

Phase I study of autologous tumor vaccines transduced with the GM-CSF gene in four patients with stage IV renal cell cancer in Japan: clinical and immunological findings.

We produced lethally irradiated retrovirally GM-CSF-transduced autologous renal tumor cell vaccines (GVAX) from six Japanese patients with stage IV renal cell cancer (RCC). Four patients received GVAX ranging from 1.4 x 10(8) to 3.7 x 10(8) cells on 6-17 occasions. Throughout a total of 48 vaccinations, there were no severe adverse events. After vaccination, DTH skin tests became positive to autologous RCC (auto-RCC) in all patients. The vaccination sites showed significant infiltration by CD4(+) T cells, eosinophils, and HLA-DR-positive cells. The kinetic analyses of cellular immune responses using peripheral blood lymphocytes revealed an enhanced proliferative response against auto-RCC in four patients, and cytotoxicity against auto-RCC was augmented in three patients. T cell receptor beta-chain analysis revealed oligoclonal expansion of T cells in the peripheral blood, skin biopsy specimens from DTH sites, and tumors. Western blot analysis demonstrated the induction of a humoral immune response against auto-RCC. Two of the four patients are currently alive 58 and 40 months after the initial vaccination with low-dose interleukin-2. Our results suggest that GVAX substantially enhanced the antitumor cellular and humoral immune responses, which might have contributed to the relatively long survival times of our patients in the present study.

Circadian rhythm of stem and fruit diameter dynamics of Japanese persimmon (Diospyrus kaki Thunb.) is affected by deficiency of water in saline environments.

Early diagnosis of water deficiency is essential to mitigate salt stress injury in plants. The effects of salt stress during the fruit growth stage on stem and fruit diameters of Japanese persimmon trees (Diospyrus kaki Thunb.) were measured by a micromorphometric technique under greenhouse conditions. This technique is less cumbersome and more precise in comparison to measurement of water potential in a small pressure chamber. The effect of stress was measured on photosynthetic rate, pre-dawn water potential, stomatal conductance, transpiration and Na+ and K+ contents of the stem and leaves. Salt stress was imposed by irrigating the plants with NaCl solution. Stem and fruit diameters of the plants given the control treatment started to decrease around 0600 h and reached a minimum at 1400 h. Salt stress did not change the diurnal pattern of response in stem and fruit diameter dynamics, but decreased the amplitude of the circadian rhythm by influencing both declining and recovery phases. The effect of salt stress on stem diameter appeared after 1 d of treatment, and on the third day in the fruit. Salt stress also reduced water potential, photosynthesis, transpiration and stomatal conductance, and increased concentrations of Na and K in the plant parts. Most of these effects were expressed after a lag period of 5 d of salt application. Utilization of micromorphometric techniques for early diagnosis of water deficiency in salt-prone environments is recommended based on results of this study.