Relevance of plasma lenvatinib concentrations and endogenous urinary cytochrome P450 3A activity biomarkers in clinical practice.

Lenvatinib (LEN), a multitarget tyrosine kinase inhibitor used in various cancer treatments, is mainly metabolized by cytochrome P450 3A (CYP3A) enzymes. The importance of therapeutic drug monitoring (TDM) in patients administered LEN has been proposed. Although some biomarkers of endogenous CYP3A activity have been reported, their utility in dosage adjustments has not been well evaluated. This study investigated the correlation between plasma LEN concentrations and endogenous urinary CYP3A biomarkers in clinical practice. Concentrations of plasma LEN (N = 225) and CYP3A biomarkers (cortisol, 6ß-hydroxycortisol, deoxycholic acid, and 1ß-hydroxydeoxycholic acid) in urine (N = 214) from 20 patients (hepatocellular carcinoma, N = 6; thyroid cancer, N = 3; endometrial cancer, N = 8; and renal cell carcinoma, N = 3) collected for consultation for up to 1 year were evaluated using liquid chromatography-tandem mass spectrometry. Moreover, plasma trough LEN concentrations were predicted using a three-compartment model with linear elimination for outpatients administered LEN before sample collection. Moderate correlations were observed between the quantified actual concentrations and the predicted trough concentrations of LEN, whereas there was no correlation with endogenous urinary CYP3A biomarkers. The utility of endogenous urinary CYP3A biomarkers could not be determined. However, TDM for outpatients administered orally available medicines may be predicted using a nonlinear mixed effect model (NONMEM). This study investigated the utility of endogenous urinary CYP3A biomarkers for personalized medicine and NONMEM for predicting plasma trough drug concentrations. These findings will provide important information for further clinical investigation and detailed TDM.

Plasma Venetoclax Concentrations in Patients with Acute Myeloid Leukemia Treated with CYP3A4 Inhibitors.

Venetoclax (VEN) is used in patients with acute myeloid leukemia (AML) and is primarily metabolized by CYP3A4, a major drug-metabolizing enzyme. Patients with AML simultaneously administered VEN and CYP3A4 inhibitors require a more appropriate management of drug-drug interactions (DDIs). Here, we report two cases of patients with AML (54-year-old man and 22-year-old woman) administrated VEN and CYP3A4 inhibitors, such as posaconazole, cyclosporine, or danazol. In the first case, we evaluated the appropriateness of timing for adjusting VEN dosage subsequent to the cessation of posaconazole. Consequently, modifying the VEN dosage in conjunction with the cessation of Posaconazole simultaneously may result in elevated plasma VEN levels. In the second case, plasma VEN concentrations were markedly elevated when co-administered with several CYP3A4 inhibitors. Additionally, in vitro assays were conducted for reverse translational studies to analyze CYP3A4 inhibition. CYP3A4 inhibition by combinatorial administration of cyclosporine A and danazol was demonstrated in vitro, which potentially explains the increasing plasma VEN concentrations observed in clinical settings. Although the acquisition of therapeutic effects is a major priority for patients, frequent therapeutic drug monitoring and dosage adjustments considering DDIs would be important factors in chemotherapy.

Effect of anti-claudin 18.2 monoclonal antibody zolbetuximab alone or combined with chemotherapy or programmed cell death-1 blockade in syngeneic and xenograft gastric cancer models.

The development of targeted cancer therapies based on monoclonal antibodies against tumor-associated antigens has progressed markedly over recent decades. This approach is dependent on the identification of tumor-specific, normal tissue-sparing antigenic targets. The transmembrane protein claudin-18 splice variant 2 (CLDN18.2) is frequently and preferentially displayed on the surface of primary gastric adenocarcinomas, making it a promising monoclonal antibody target. Phase 3 studies of zolbetuximab, a chimeric immunoglobulin G1 monoclonal antibody targeting CLDN18.2, combined with 5-fluorouracil/leucovorin plus oxaliplatin (modified FOLFOX6) or capecitabine plus oxaliplatin (CAPOX) in advanced or metastatic first-line gastric or gastroesophageal junction (G/GEJ) adenocarcinoma have demonstrated favorable clinical results with zolbetuximab. In studies using xenograft or syngeneic models with gastric cancer cell lines, zolbetuximab mediated death of CLDN18.2-positive human cancer cell lines via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in vitro and demonstrated anti-tumor efficacy as monotherapy and combined with chemotherapy in vivo. Mice treated with zolbetuximab plus chemotherapy displayed a significantly higher frequency of tumor-infiltrating CD8+ T cells versus vehicle/isotype control-treated mice. Furthermore, zolbetuximab combined with an anti-mouse programmed cell death-1 antibody more potently inhibited tumor growth compared with either agent alone. These results support the potential of zolbetuximab as a novel treatment option for G/GEJ adenocarcinoma.

A novel breast cancer image classification model based on multiscale texture feature analysis and dynamic learning.

Assistive medical image classifiers can greatly reduce the workload of medical personnel. However, traditional machine learning methods require large amounts of well-labeled data and long learning times to solve medical image classification problems, which can lead to high training costs and poor applicability. To address this problem, a novel unsupervised breast cancer image classification model based on multiscale texture analysis and a dynamic learning strategy for mammograms is proposed in this paper. First, a gray-level cooccurrence matrix and Tamura coarseness are used to transfer images to multiscale texture feature vectors. Then, an unsupervised dynamic learning mechanism is used to classify these vectors. In the simulation experiments with a resolution of 40 pixels, the accuracy, precision, F1-score and AUC of the proposed method reach 91.500%, 92.780%, 91.370%, and 91.500%, respectively. The experimental results show that the proposed method can provide an effective reference for breast cancer diagnosis.

Concomitant use of hydroxyzine and haloperidol did not worsen delirium in patients with cancer: A multicenter, retrospective, observational study.

OBJECTIVES: There is concern that hydroxyzine exacerbates delirium, but a recent preliminary study suggested that the combination of haloperidol and hydroxyzine was effective against delirium. This study examined whether the concomitant use of hydroxyzine and haloperidol worsened delirium in patients with cancer. METHODS: This retrospective, observational study was conducted at 2 general hospitals in Japan. The medical records of patients with cancer who received haloperidol for delirium from July to December 2020 were reviewed. The treatments for delirium included haloperidol alone or haloperidol combined with hydroxyzine. The primary outcome was the duration from the first day of haloperidol administration to the resolution of delirium, defined as its absence for 2 consecutive days. The time to delirium resolution was analyzed to compare the haloperidol group and hydroxyzine combination group using the log-rank test with the Kaplan-Meier method. Secondary outcomes were (1) the total dose of antipsychotic medications, including those other than haloperidol (measured in chlorpromazine-equivalent doses), and (2) the frequencies of detrimental incidents during delirium, specifically falls and self-removal of drip infusion lines. The unpaired t-test and Fisher's exact test were used to analyze secondary outcomes. RESULTS: Of 497 patients who received haloperidol, 118 (23.7%) also received hydroxyzine. No significant difference in time to delirium resolution was found between the haloperidol group and the hydroxyzine combination group (log-rank test, P = 0.631). No significant difference between groups was found in either chlorpromazine-equivalent doses or the frequency of detrimental incidents. SIGNIFICANCE OF RESULTS: This study showed that the concomitant use of hydroxyzine and haloperidol did not worsen delirium in patients with cancer.

Urinary podocyte markers of disease activity, therapeutic efficacy, and long-term outcomes in acute and chronic kidney diseases.

A critical degree of podocyte depletion causes glomerulosclerosis, and persistent podocyte loss in glomerular diseases drives the progression to end-stage kidney disease. The extent of podocyte injury at a point in time can be histologically assessed by measuring podocyte number, size, and density ("Biopsy podometrics"). However, repeated invasive renal biopsies are associated with increased risk and cost. A noninvasive method for assessing podocyte injury and depletion is required. Albuminuria and proteinuria do not always correlate with disease activity. Podocytes are located on the urinary space side of the glomerular basement membrane, and as they undergo stress or detach, their products can be identified in urine. This raises the possibility that urinary podocyte products can serve as clinically useful markers for monitoring glomerular disease activity and progression ("Urinary podometrics"). We previously reported that urinary sediment podocyte mRNA reflects disease activity in both animal models and human glomerular diseases. This includes diabetes and hypertension which together account for 60% of new-onset dialysis induction patients. Improving approaches to preventing progression is an urgent priority for the renal community. Sufficient evidence now exists to indicate that monitoring urinary podocyte markers could serve as a useful adjunctive strategy for determining the level of current disease activity and response to therapy in progressive glomerular diseases.

α-L-iduronidase fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa) for mucopolysaccharidosis type I: A phase 1/2 trial.

Mucopolysaccharidosis type I (MPS I) causes systemic accumulation of glycosaminoglycans due to a genetic deficiency of α-L-iduronidase (IDUA), which results in progressive systemic symptoms affecting multiple organs, including the central nervous system (CNS). Because the blood-brain barrier (BBB) prevents enzymes from reaching the brain, enzyme replacement therapy is effective only against the somatic symptoms. Hematopoietic stem cell transplantation can address the CNS symptoms, but the risk of complications limits its applicability. We have developed a novel genetically modified protein consisting of IDUA fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa; JR-171), which has been shown in nonclinical studies to be distributed to major organs, including the brain, bringing about systemic reductions in heparan sulfate (HS) and dermatan sulfate concentrations. Subsequently, a first-in-human study was conducted to evaluate the safety, pharmacokinetics, and exploratory efficacy of JR-171 in 18 patients with MPS I. No notable safety issues were observed. Plasma drug concentration increased dose dependently and reached its maximum approximately 4 h after the end of drug administration. Decreased HS in the cerebrospinal fluid suggested successful delivery of JR-171 across the BBB, while suppressed urine and serum concentrations of the substrates indicated that its somatic efficacy was comparable to that of laronidase.

Association of Estimated Total Body Iron with All-Cause Mortality in Japanese Hemodialysis Patients: The Miyazaki Dialysis Cohort Study.

Iron deficiency/excess may be associated with worse prognosis in patients undergoing hemodialysis. This study ascertained the association of the estimated total body iron (TBI) with mortality in patients receiving hemodialysis. Multicenter clinical data collected in the Miyazaki Dialysis Cohort Study from 943 patients receiving hemodialysis were analyzed after stratification into tertile categories by baseline TBI-estimated as the heme iron plus iron storage from ferritin levels. The primary outcome was a 5-year all-cause mortality; hazard ratios of the TBI-all-cause mortality association were estimated using Cox models adjusted for potential confounders, including clinical characteristics, laboratory, and drug data, wherein patients with high TBI were the reference category. The receiver operating characteristic (ROC) curve analyses of TBI, serum ferritin levels, and transferrin saturation were performed to predict all-cause mortality; a total of 232 patients died during the follow-up. The low TBI group (<1.6 g) had significantly higher hazard ratios of mortality than the high TBI group (≥2.0 g). As ROC curve analyses showed, TBI predicted mortality more accurately than either levels of serum ferritin or transferrin saturation. Lower TBI increases the mortality risk of Japanese hemodialysis patients, and further studies should examine whether iron supplementation therapy that avoids low TBI improves prognosis.

BCL6B Contributes to Ocular Vascular Diseases via Notch Signal Silencing.

BACKGROUND: Endothelial cell activation is tightly controlled by the balance between VEGF (vascular endothelial cell growth factor) and Notch signaling pathway. VEGF destabilizes blood vessels and promotes neovascularization, which are common features of sight-threatening ocular vascular disorders. Here, we show that BCL6B (B-cell CLL/lymphoma 6 member B protein), also known as BAZF, ZBTB28, and ZNF62, plays a pivotal role in the development of retinal edema and neovascularization. METHODS: The pathophysiological physiological role of BCL6B was investigated in cellular and animal models mimicking 2 pathological conditions: retinal vein occlusion and choroidal neovascularization. An in vitro experimental system was used in which human retinal microvascular endothelial cells were supplemented with VEGF. Choroidal neovascularization cynomolgus monkey model was generated to investigate the involvement of BCL6B in the pathogenesis. Mice lacking BCL6B or treated with BCL6B-targeting small-interfering ribose nucleic acid were examined for histological and molecular phenotypes. RESULTS: In retinal endothelial cells, the BCL6B expression level was increased by VEGF. BCL6B-deficient endothelial cells showed Notch signal activation and attenuated cord formation via blockage of the VEGF-VEGFR2 signaling pathway. Optical coherence tomography images showed that choroidal neovascularization lesions were decreased by BCL6B-targeting small-interfering ribose nucleic acid. Although BCL6B mRNA expression was significantly increased in the retina, BCL6B-targeting small-interfering ribose nucleic acid suppressed ocular edema in the neuroretina. The increase in proangiogenic cytokines and breakdown of the inner blood-retinal barrier were abrogated in BCL6B knockout (KO) mice via Notch transcriptional activation by CBF1 (C promotor-binding factor 1) and its activator, the NICD (notch intracellular domain). Immunostaining showed that Müller cell activation, a source of VEGF, was diminished in BCL6B-KO retinas. CONCLUSIONS: These data indicate that BCL6B may be a novel therapeutic target for ocular vascular diseases characterized by ocular neovascularization and edema.

Evaluation of a Capillary Microsampling Device for Analyzing Plasma Lenvatinib Concentration in Patients With Hepatocellular Carcinoma.

BACKGROUND: The anticancer drug, Lenvima (lenvatinib), has severe side effects. Therapeutic drug monitoring helps ensure its efficacy and safety. Regular and optimally timed blood sampling is tough, especially when lenvatinib is self-medicated. Microsampling using the easy to handle Microsampling Wing (MSW) may help circumvent this problem. However, current lenvatinib detection methods are not sensitive enough to detect its concentrations in microsamples (<50-250 µL). Thus, the aim of this study was 2-fold (1) develop an analytic method to estimate plasma lenvatinib concentrations in microsamples and (2) verify whether this method works on micro (5.6 µL) blood plasma samples obtained clinically through MSW from patients with unresectable hepatocellular carcinoma (HCC). METHODS: A simple, highly sensitive, and specific liquid chromatography-electrospray ionization tandem mass spectrometry method was developed. Using this novel protocol, the trough blood plasma concentration of lenvatinib was measured for both blood sampled conventionally and that using MSW. Thirty-five venous whole blood samples were obtained from 11 patients with HCC. Furthermore, the stability of lenvatinib in MSW samples during storage was evaluated. RESULTS: The mean plasma lenvatinib concentration estimates were not significantly different between the MSW and conventional venous blood samples. CV for interday and intraday assays was low. Up to day 5, the lenvatinib concentration in the MSW samples was 85%-115% of the initial day concentration (when stored at 25°C or 4°C). The interference of endogenous matrix components in the human plasma was low. CONCLUSIONS: These results indicate that the novel mass spectrometry protocol accurately measures lenvatinib in human plasma and is reproducible. Thus, MSW could be a useful microsampling device for lenvatinib therapeutic drug monitoring in patients with HCC when used in combination with this novel liquid chromatography-electrospray ionization tandem mass spectrometry detection method.

The safety and efficacy of hematopoietic stem cell mobilization using biosimilar filgrastim in related donors.

In April 2014, the Japan Society for Hematopoietic Cell Transplantation started a prospective observational study entitled "A short-term follow-up investigation of related hematopoietic stem cell donors receiving biosimilar G-CSF to mobilize peripheral blood stem cells." A total of 106 donors were registered from 25 transplant facilities through the end of March 2017. The study cohort consisted of 47 men and 58 women, and their median age was 38.5 years (range 15-65 years). The mean total count of collected CD34-positive cells/recipient body weight for all 106 donors was 4.40 ± 2.38 × 10 6/kg. The yield of CD34-positive cells was weakly correlated with donor age was observed. However, gender, WBC count on day 4, G-CSF dose reduction, type of apheresis device, collection speed, and treated blood volume had no significant impact on the collection efficacy of CD34-positive cells. The safety profile of biosimilar G-CSF was also acceptable: 126 adverse events in 73 donors were reported, but none was serious. The most common adverse events were low back pain, headache, and bone pain. This prospective study confirmed that biosimilar G-CSF had comparable efficacy and safety to reference G-CSF for CD34-positive cell mobilization in healthy related donors.

Association between oral health and advisability of oral feeding in advanced cancer patients receiving palliative care: a cross-sectional study.

PURPOSE: Maintenance of oral feeding is important in terms of maintaining and improving the quality of life in terminal cancer patients receiving palliative care. Although adequate oral health status is essential for oral feeding in hospitalized patients, the relationship between oral health and oral feeding in patients receiving palliative care remains unclear. This cross-sectional study aimed to examine how the general condition and oral health status of these patients relate to decisions regarding their nutritional intake methods. METHODS: This retrospective cross-sectional study included 103 terminal cancer patients (59 men and 44 women; mean age, 73.8 ± 10.9 years) who received palliative care between April 2017 and August 2019. The nutritional method was assessed using the Functional Oral Intake Scale (FOIS). We assessed two types of nutritional methods: (1) the method advised by the attending physician until the initial dental examination (FOIS-I) and (2) the recommended method based on consultation with a palliative care doctor and dentist after the initial oral examination (FOIS-R). Furthermore, the participants' basic information and Dysphagia Severity Scale (DSS) and Oral Health Assessment Tool (OHAT) scores were assessed. RESULTS: There was a divergence between FOIS-I and FOIS-R. FOIS-R was significantly higher than FOIS-I (p < 0.001). Multiple regression analysis revealed that the time until death, DSS score, and OHAT score had a significant impact on determining the food form for oral feeding. CONCLUSIONS: Appropriate oral health assessment is important in determining the food form and indication for oral feeding among patients receiving palliative care.

Potent bactericidal activity of reduced cryptdin-4 derived from its hydrophobicity and mediated by bacterial membrane disruption.

Defensin is a cysteine-rich antimicrobial peptide with three disulphide bonds under normal oxidative conditions. Cryptdin-4 (Crp4) is a defensin secreted by Paneth cells in the small intestine of mice, and only reduced Crp4 (Crp4red) shows activity against enteric commensal bacteria, although both oxidised Crp4 (Crp4ox) and Crp4red can kill non-commensal bacteria. To investigate the molecular factors that affect the potent antimicrobial activity of Crp4red, the bactericidal activities of Crp4ox and Crp4red, Crp4 with all Cys residues substituted with Ser peptide (6C/S-Crp4), and Crp4 with all thiol groups modified by N-ethylmaleimide (NEM-Crp4) were assessed. All peptides showed bactericidal activity against non-commensal bacteria, whereas Crp4red and NEM-Crp4 showed bactericidal activity against commensal bacteria. These potent peptides exhibited high hydrophobicity, which was strongly correlated with membrane insertion. Intriguingly, Crp4ox formed electrostatic interactions with the membrane surface of bacteria, even without exerting bactericidal activity. Moreover, the bactericidal activity of both oxidised and reduced forms of Crp4 was abolished by inhibition of electrostatic interactions; this finding suggests that Crp4red targets bacterial membranes. Finally, a liposome leakage assay against lipids extracted from commensal bacteria demonstrated a correlation with bactericidal activity. These results suggest that the potent bactericidal activity of Crp4red is derived from its hydrophobicity, and the bactericidal mechanism involves disruption of the bacterial membrane. Findings from this study provide a better understanding of the bactericidal mechanism of both Crp4ox and Crp4red.

Factors affecting the oral health of inpatients with advanced cancer in palliative care.

PURPOSE: Patients with terminal cancer undergoing multidisciplinary palliative care often have oral health problems, but these details are still unclear. This cross-sectional study aimed to elucidate the oral health of patients with terminal-stage cancer who are inpatient recipients of acute-phase palliative care, and to unveil the factors affecting their oral health. METHODS: Participants were 121 patients with terminal-stage cancer (68 males, 53 females, mean age: 73.6 ± 11.1 years) and oral health complaints. They received palliative care at Tokyo Medical and Dental University Medical Hospital between April 2017 and August 2019. Their demographic and medical details were extracted, retrospectively, from their medical records, and their oral health status, such as the number of natural teeth, removable denture usage, Oral Health Assessment Tool (OHAT), and Dysphagia Severity Scale, were evaluated. All outcomes were assessed by a dentist from the palliative care team. RESULTS: The problems with soft tissue, saliva, and oral cleanliness were observed. The absence of posterior occlusal support was common, and the use of removable dentures was often inadequate. In contrast, swallowing function was relatively well-conserved and 46.3% of the participants were capable of nutrition intake solely by mouth. Multiple regression analysis revealed a significant association between total OHAT score and age, consciousness level, prognostic level, and method of nutritional intake. CONCLUSION: The results revealed that the oral health of terminal cancer patients under palliative care declined despite receiving routine oral care from nurses, and suggest the importance of including dental professionals in multidisciplinary palliative care.

Patients with mild cognitive impairment diagnosed at dementia clinic display decreased maximum occlusal force: a cross-sectional study.

BACKGROUND: Previous research indicates that patients with mild cognitive impairment (MCI) are more likely to have poor oral health and impairments in oral functions, which may be due to few remaining teeth and impaired tongue and lip motor function. However, the oral health of those patients following comprehensive cognitive assessment by a dementia specialist has not been sufficiently investigated. Therefore, this study aimed to clarify the oral function of patients with MCI and the association between oral health and lower cognitive function. METHODS: This cross-sectional study included 96 participants (men: 35; women: 61; mean age: 73.3 ± 8.5 years) who visited a dementia clinic between December 2017 and January 2020. Participants' cognitive function was assessed by a dementia specialist using neuropsychological and hematological tests and neuroimaging immediately after enrollment. The participants were divided into the healthy and MCI groups according to comprehensive cognitive assessment. Participants' age, sex, body mass index, primary disease, education level, drinking habits, smoking habits, living environment, employment status, and exercise habits were evaluated. Moreover, oral outcomes, including the number of existing teeth, number of functional teeth (natural and prosthetic teeth which were occluded with antagonists), denture use, oral dryness, tongue and lip motor function, tongue pressure, occlusal force, masticatory ability, and swallowing ability were recorded. The Mann-Whitney U test, χ2, and Fisher's exact tests were used for between-group comparisons. Furthermore, logistic regression analysis using MCI diagnosis as the target variable was performed. RESULTS: A comprehensive evaluation of the cognitive function of the study participants by the dementia specialist revealed that 48 participants (mean age: 69.8 ± 8.8 years) were healthy and 48 (mean age: 76.9 ± 6.7 years) had MCI. MCI participants were significantly older (p < 0.001) and had significantly fewer existing teeth (p = 0.031) and lower maximum occlusal force (p = 0.019) than healthy participants. Age (odds ratio: 1.126, p = 0.002) and maximum occlusal force (odds ratio: 0.978, p = 0.048) were significantly associated with lower cognitive function. CONCLUSIONS: Patients with MCI had poorer oral health than healthy individuals. Decreased maximum occlusal force was independently associated with lower cognitive function, even when adjusted for age and sex.

Dural arteriovenous fistula following cerebral venous sinus thrombosis in a patient with minimal change disease: A case report.

A 78-year-old man presented with nephrotic syndrome and new-onset disorientation. Plasma D-dimer level was increased, and a lower leg deep vein thrombosis was identified on ultrasound. Histopathologic analysis of percutaneous renal biopsy samples confirmed the diagnosis of minimal change disease. Treatment with prednisone (20 mg/day), cyclosporine (50 mg/day), and anticoagulant therapy with edoxaban tosylate hydrate led to the complete resolution of nephrotic syndrome after 4 weeks. Despite this, his disorientation persisted. Head CT and MRI have revealed cerebral venous sinus thrombosis and dural arteriovenous fistula, which was considered a possible complication of nephrotic syndrome. Embolization dramatically improved his disorientation. This paper highlights that cerebral venous sinus thrombosis and dural arteriovenous fistula should always be considered in patients with nephrotic syndrome and new-onset disorientation.

Breast Cancer Detection from a Urine Sample by Dog Sniffing: A Preliminary Study for the Development of a New Screening Device, and a Literature Review.

BACKGROUND: Breast cancer is a leading cause of cancer death worldwide. Several studies have demonstrated that dogs can sniff and detect cancer in the breath or urine sample of a patient. This study aims to assess whether the urine sample can be used for breast cancer screening by its fingerprints of volatile organic compounds using a single trained sniffer dog. This is a preliminary study for developing the "electronic nose" for cancer screening. METHODS: A nine-year-old female Labrador Retriever was trained to identify cancer from urine samples of breast cancer patients. Urine samples from patients histologically diagnosed with primary breast cancer, those with non-breast malignant diseases, and healthy volunteers were obtained, and a double-blind test was performed. Total of 40 patients with breast cancer, 142 patients with non-breast malignant diseases, and 18 healthy volunteers were enrolled, and their urine samples were collected. RESULTS: In 40 times out of 40 runs of a double-blind test, the trained dog could correctly identify urine samples of breast cancer patients. Sensitivity and specificity of this breast cancer detection method using dog sniffing were both 100%. CONCLUSIONS: The trained dog in this study could accurately detect breast cancer from urine samples of breast cancer patients. These results indicate the feasibility of a method to detect breast cancer from urine samples using dog sniffing in the diagnosis of breast cancer. Although the methodological standardization is still an issue to be discussed, the current result warrants further study for developing a new breast cancer screening method based on volatile organic compounds in urine samples.

Impact of polypharmacy on all-cause mortality and hospitalization in incident hemodialysis patients: a cohort study.

BACKGROUND: Polypharmacy (PP) is common in end-stage chronic renal disease patients largely due to the presence of multiple comorbid conditions. Although PP is potentially harmful, its relationship with mortality and morbidity in hemodialysis patients currently remains unclear. METHODS: Study design: cohort study. SETTING: participants: one hundred and fifty-two initial hemodialysis patients (male, 88 patients; mean age, 70.3 years) were enrolled between February 2015 and March 2018 at Nobeoka Prefectural Hospital and Chiyoda Hospital. PREDICTOR: patients were divided into 2 groups according to PP (6 or more drug prescriptions or less) during admission and discharge for the initiation of hemodialysis. OUTCOMES: all-cause mortality and hospitalization during the mean 2.8-year follow-up. MEASUREMENTS: hazard ratios (HRs) were estimated using Cox's model for the relationships between PP and clinical outcomes and adjusted for potential confounders. The group with 5 or less drug prescriptions was set as a reference. RESULTS: The number of prescribed drugs per patient averaged 7.4 at admission and 7.0 at discharge for initial hemodialysis. One hundred (65.8%) and 94 patients (61.8%) had PP at admission and discharge, respectively. During the follow-up, 20 patients died and 71 were hospitalized. PP at admission did not correlate with outcomes, whereas that at discharge correlated with all-cause hospitalization. CONCLUSIONS: PP at discharge may be associated with clinical outcomes. However, it remains unclear whether PP is the direct cause of outcomes or is simply a marker for an increased risk of outcomes.

Development of a novel AlphaLISA ImmunoAssay for Big angiotensin-25.

We previously described the discovery of Big angiotensin-25 (Bang-25), an angiotensin-related peptide isolated from human urine. Bang-25 consists of the first 25 amino acids of the N-terminus of angiotensinogen (Aogen), with N-linked glycosylation on the 14th amino acid and a cysteine conjugated to the 18th amino acid. Bang-25 is rapidly converted into angiotensin II (Ang II) by chymase. Because Bang-25 is widely distributed in human tissues, including islet cells in the pancreas and podocytes in the kidney, we hypothesized that it may participate in the Ang II production system in these tissues. To test this hypothesis, we developed a specific assay for Bang-25 and used it to examine the urinary concentrations of Bang-25 in patients with diabetes mellitus (DM). The assay used the Amplified Luminescent Proximity Homogeneous Assay (Alpha)-based ELISA method (AlphaLISA) of PerkinElmer Japan and included antibodies specific to the N-terminus of Ang II and the C-terminus of Bang-25. The AlphaLISA ImmunoAssay specifically recognized Bang-25 and had no cross-reactivity with Aogen or Ang I. Bang-25 was detected in healthy volunteers' urine samples but not in their plasma samples. In patients with DM, the urinary Bang-25 concentration was significantly higher than in healthy volunteers. Moreover, the results indicated that the Bang-25 concentration in the urine may offer a different perspective on disease status from that provided by urinary albumin. This assay could provide a useful tool for determining urinary Bang-25, which may prove an important biomarker for diabetic kidney disease.

[Acute promyelocytic leukemia recurrence diagnosed due to granulocytic sarcoma of the external auditory canal].

A 47-year-old man was diagnosed with acute promyelocytic leukemia (APL) accompanied by pancytopenia and left forearm swelling. Complete remission was achieved with remission induction therapy using all-trans retinoic acid (ATRA), and consolidation therapy was completed. Three months after the treatment, left ear closure was observed, and a mass lesion was found in the left external auditory canal. An initial tumor biopsy only revealed inflammatory cell infiltration. Moreover, the tumor's rebiopsy performed 3 months later revealed MPO-positive and CD68-positive granulocyte infiltration. Furthermore, the rebiopsy revealed 4.9×105 copies/µgRNA of PML/RARα, the patient was diagnosed with locally recurrent APL. A bone marrow examination 2 weeks later confirmed an increase in myeloblasts and promyelocytes for the first time since the confirmation of remission. Therefore, it was diagnosed as bone marrow recurrence. Reinduction therapy using ATRA and arsenic trioxide again led to complete remission, after which autologous peripheral blood stem cell transplantation was performed. Currently, complete remission is being maintained. In this case, the recurrence of the external auditory canal lesion preceded the bone marrow recurrence. Therefore, it is important to note the nonspecific leukemia recurrence patterns of the external auditory canal.