DASC-21: a novel geriatric assessment for discriminating best supportive care in older patients with inoperable advanced non-small cell lung cancer.

OBJECTIVE: This study investigated whether the Dementia Assessment Sheet for the Community-based Integrated Care System is useful for decision-making or problem detection in the treatment and care of older patients with inoperable advanced non-small cell lung cancer compared with the current standard model using performance status. METHODS: This study retrospectively examined 1595 cases admitted to the Department of Respiratory Medicine at the Tokyo Metropolitan Geriatric Hospital between 26 July 2016 and 28 January 2020. Among these, 29 and 31 patients who received pharmacotherapies and best supportive care were extracted, respectively. The performance in identifying best supportive care using the Dementia Assessment Sheet for the Community-based Integrated Care System was evaluated in comparison with performance status. The ability to detect impairments in each Dementia Assessment Sheet for the Community-based Integrated Care System domain was also assessed. RESULTS: The Dementia Assessment Sheet for the Community-based Integrated Care System total score had an area under the curve of 0.831 (95% confidence interval, 0.694-0.914), which was statistically equivalent to performance status. The discriminatory cut-off value for identification of best supportive care was set at 29 with a sensitivity and specificity of 0.742 and 0.897, respectively. Dementia Assessment Sheet for the Community-based Integrated Care System total score showed good concordance with performance status especially when reported by family members or caregivers. Deficits other than activities of daily living were recognized (2.8-19.4%) in patients with good performance status. Impairments were more frequently detected when reported by family members or caregivers. CONCLUSIONS: The Dementia Assessment Sheet for the Community-based Integrated Care System discriminates the best supportive care for older patients with inoperable advanced non-small cell lung cancer. Moreover, it can identify vulnerabilities especially when reported by family members or caregivers that cannot be detected by performance status.

Dapagliflozin Influences Ventricular Hemodynamics and Exercise-Induced Pulmonary Hypertension in Type 2 Diabetes Patients　- A Randomized Controlled Trial.

BACKGROUND: This prospective randomized multicenter open-label trial evaluated whether sodium-glucose cotransporter-2 inhibitor (SGLT2-i) improves left ventricular (LV) pump function and suppresses elevation of LV filling pressure (LVFP) and right ventricular systolic pressure (RVSP) during exercise in type 2 diabetes mellitus (T2DM) patients.Methods and Results:Based on HbA1c and LV ejection fraction, 78 patients with poorly controlled T2DM were randomly assigned to D-group (dapagliflozin 5 mg/day add-on) or C-group (conventional therapy add-on). Physical examination, home and office blood pressure examination, blood tests, and echocardiography at rest and during ergometer exercise were performed at baseline and at 1.5 and 6 months after treatment. The primary endpoint was defined as the change in RVSP (mmHg) between baseline and 6-month follow up. The secondary endpoints were changes in LVFP (ratio), stroke volume index (SVi; mL/m2), and cardiac index (CI; L/min/m2). Both RVSP and LVFP during exercise significantly decreased from baseline to 6 months after starting treatment in the D-group (P<0.001). No changes to either parameter was observed in the C-group. The SVi and CI did not improve in either group. Both home and office blood pressure significantly decreased in the D-group. Decreases in HbA1c were somewhat greater in the C-group. CONCLUSIONS: Dapagliflozin significantly improved RVSP and LVFP during exercise in patients with T2DM and cardiovascular risk, which may contribute to favorable effects on heart failure.

[An elderly case of squamous cell lung cancer treated continuously with pembrolizumab without any decline in the life function].

BACKGROUND: Whether or not immune checkpoint inhibitors are safe and effective for the elderly remains unclear, even though these drugs were approved two years ago for the treatment of advanced non-small cell lung cancer in Japan. Older cancer patients are vulnerable to chemotherapy, so their life function should be closely monitored before starting, continuing, or discontinuing cancer treatment. CASE: An 85-year-old man showed a wedge-shaped shadow in the apical portion of the left lung on chest computed tomography. Unfortunately, repeated bronchoscopy revealed no malignancy. The shadow progressed over about one year, so a third bronchoscopy was performed, leading to a diagnosis of squamous-cell carcinoma (cT3N2M1a, stage IVA). Because PD-L1 immunohistochemical staining was positive for 80%-90% of the tumor cells, the patient was treated with pembrolizumab as the first-line therapy, and the tumor dramatically regressed, notably without any decline in the patient's life functions. CONCLUSION: An elderly case of squamous-cell lung cancer was treated continuously with pembrolizumab without any decline in the patient's life function.

[Spontaneous regression of lung cancer in an elderly patient: a case report].

An 82 year-old male was referred to us because of a nodule in the upper lobe of his right lung, which was incidentally found by computed tomography (CT) carried out in the course of treating pneumonia. The nodule was identified as non-keratinizing squamous cell carcinoma of the lung by bronchoscopy. A close investigation revealed the tumor to be cT1bN3M1b, clinical Stage IV. Although we only adopted a wait-and-see approach because of his age and his suspected myelodysplastic syndrome, the nodule had regressed on CT images after a year. Fluorodeoxyglucose-positron emission tomography showed apparently decreased uptakes in the lymph nodes and adrenal gland. We considered this to be a systemic observation of spontaneous regression of carcinoma.

Effect of Luseogliflozin, a Sodium-Glucose Cotransporter 2 Inhibitor, and Dipeptidyl-Peptidase 4 Inhibitors on the Quality-of-Life and Treatment Satisfaction of Patients With Type 2 Diabetes Mellitus: A Subanalysis of a Multicenter, Open-Label, Randomized-Controlled Trial (J-SELECT Study).

INTRODUCTION: The effects of dipeptidyl peptidase-4 inhibitors (DPP-4is) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) on quality of life (QOL) and treatment satisfaction have not been directly compared. This sub-analysis of a randomized-controlled trial with an SGLT2i, luseogliflozin, and DPP-4is compared their effects on QOL and treatment satisfaction of patients. METHODS: This study recruited 623 patients with type 2 diabetes mellitus who were drug-naïve or treated with antidiabetic agents other than SGLT2is and DPP-4is. The patients were randomized into luseogliflozin or DPP-4i group and followed for 52 weeks. This sub-analysis assessed QOL and treatment satisfaction using Oral Hypoglycemic Agent Questionnaire (OHA-Q) version 2 in the drug-naïve subgroup who were drug-naïve at baseline and with monotherapy with luseogliflozin or DPP-4i throughout the observation period (256 patients) at 24 and 52 weeks and in the add-on subgroup who were treated with OHAs other than SGLT2is and DPP-4is (204 patients) at baseline, 24 and 52 weeks. RESULTS: In the drug-naïve subgroup, total (50.8 ± 8.2 in luseogliflozin group and 53.1 ± 10.0 in DPP-4i group, p = 0.048) and somatic symptom scores (22.4 ± 5.0 in luseogliflozin group and 24.4 ± 5.8 in DPP-4i group, p = 0.005) at 52 weeks (but not at 24 weeks) were significantly higher in DPP-4i group than in luseogliflozin group. In add-on subgroup, changes in total (3.3 ± 7.8 in luseogliflozin group and 0.9 ± 7.6 in DPP-4i group, p = 0.030) and treatment convenience (1.2 ± 3.9 in luseogliflozin group and - 0.6 ± 4.2 in DPP-4i group, p = 0.002) from baseline to 24 weeks (but not at 52 weeks) were significantly greater in luseogliflozin group than in DPP-4i group. The QOL related to safety or glycemic control was comparable between the groups. CONCLUSIONS: Physicians should pay attention to side effects of SGLT2is to maintain the patients' QOL when SGLT2is are initiated or added-on. Add-on of luseogliflozin increased patients' QOL more than DPP-4is. Considering patients' QOL and treatment satisfaction is important for selecting SGLT2is or DPP-4is. TRIAL REGISTRATION: UMIN000030128 and jRCTs031180241.

Overall Efficacy and Safety of Sodium-Glucose Cotransporter 2 Inhibitor Luseogliflozin Versus Dipeptidyl-Peptidase 4 Inhibitors: Multicenter, Open-Label, Randomized-Controlled Trial (J-SELECT study).

INTRODUCTION: Evidence of a direct comparison between dipeptidyl-peptidase 4 inhibitors (DPP-4is) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) remains lacking, and no clear treatment strategy or rationale has been established using these drugs. This study aimed to compare the overall efficacy and safety of DPP-4is and the SGLT2i luseogliflozin in patients with type 2 diabetes mellitus (T2DM). METHODS: Patients with T2DM who had not used antidiabetic agents or who had used antidiabetic agents other than SGLT2is and DPP-4is were enrolled in the study after written informed consent had been obtained. The enrolled patients were subsequently randomly assigned to either the luseogliflozin or DPP-4i group and followed up for 52 weeks. The primary (composite) endpoint was the proportion of patients who showed improvement in ≥ 3 endpoints among the following five endpoints from baseline to week 52: glycated hemoglobin (HbA1c), weight, estimated glomerular filtration rate (eGFR), systolic blood pressure, and pulse rate. RESULTS: A total of 623 patients were enrolled in the study and subsequently randomized to either the luseogliflozin or DPP-4i groups. The proportion of patients who showed improvement in ≥ 3 endpoints at week 52 was significantly higher in the luseogliflozin group (58.9%) than in the DPP-4i group (35.0%) (p < 0.001). When stratified by body mass index (BMI) (< 25 or ≥ 25 kg/m2) or age (< 65 or ≥ 65 years), regardless of BMI or age, the proportion of patients who achieved the composite endpoint was significantly higher in the luseogliflozin group than in the DPP-4i group. Hepatic function and high-density lipoprotein-cholesterol were also significantly improved in the luseogliflozin group compared with the DPP-4i group. The frequency of non-serious/serious adverse events did not differ between the groups. CONCLUSION: This study showed the overall efficacy of luseogliflozin compared with DPP-4is over the mid/long term, regardless of BMI or age. The results suggest the importance of assessing multiple aspects regarding the effects of diabetes management. TRIAL REGISTRATION NUMBER: jRCTs031180241.

Copulatory courtship behavior and sine song as a mate recognition cue in Drosophila lini and its sibling species.

Most Drosophila species sing species-specific pulse songs during their "precopulatory courtship." Three sibling species of the Drosophila montium species subgroup performed "copulatory courtship": males generated courtship songs by vibrating either wing only after mounting and during copulation. In these three species, strong sexual isolation was detected between D. ohnishii and D. lini and between D. ohnishii and D. ogumai, but not between D. lini and D. ogumai. Female showed strong repelling behavior when they were mounted by a heterospecific male in the species combinations including D. ohnishii, resulting in failure of the copulation attempt of the male. Acoustic analyses of courtship songs revealed that the pulse song was irregular, without any species-specific parameters, but that the frequency of the sine song was different among the three species in accordance with the modes of sexual isolation between them; it was significantly lower in D. ohnishii (mean ± SE = 193.0 ± 1.7 Hz) but higher in D. lini (253.4 ± 2.7 Hz) and D. ogumai (246.7 ± 5.3 Hz). We suggest that this difference in the sine song frequency is a sexual signal in the Specific Mate Recognition System (SMRS) among these three Drosophila species.

Development of an L-type Ca2+ channel-dependent Ca2+ transient during the radial migration of cortical excitatory neurons.

Increasing evidence has shown that voltage-gated L-type Ca2+ channels (LTCCs) are crucial for neurodevelopmental events, including neuronal differentiation/migration and neurite morphogenesis/extension. However, the time course of their functional maturation during the development of excitatory neurons remains unknown. Using a combination of fluorescence in situ hybridization and in utero electroporation-based labeling, we found that the transcripts of Cacna1c and Cacna1d, which encode the LTCC pore-forming subunits, were upregulated in the intermediate zone (IZ) during radial migration. Ca2+ imaging using GCaMP6s in acute brain slices showed spontaneous Ca2+ transients in migrating neurons throughout the IZ. Neurons in the IZ upper layer, especially in the multipolar-to-bipolar transition layer (TL), exhibited more frequent Ca2+ transients than adjacent layers and responded to FPL64176, a potent activator of LTCC. Consistently, nimodipine, an LTCC blocker, inhibited spontaneous Ca2+ transients in neurons in the TL. Collectively, we showed a hitherto unknown increased prevalence of LTCC-dependent Ca2+ transients in the TL of the IZ upper layer during the radial migration of excitatory neurons, which could be essential for the regulation of Ca2+-dependent neurodevelopmental processes.

Calcium signalling: a key regulator of neuronal migration.

Neuronal migration is a crucial event in neuronal development for the construction of brain architecture and neuronal networks. Newborn neurons proliferate in the germinal zone and start migration toward their final destination. Migrating neurons adopt different routes, cell shapes and migratory modes depending on extracellular factors and outer physical substrates. Intracellular Ca2+ is an essential second messenger that regulates diverse cellular functions by activating Ca2+-dependent signalling molecules that underlie Ca2+-responsive cellular functions. Neuronal migration during brain architecture construction is no exception. Spontaneous Ca2+ transients are observed in several types of migrating neurons, and a series of Ca2+-dependent signalling molecules governing neuronal migration has been identified. In this review, we first summarize the molecular mechanisms that trigger intracellular Ca2+ elevation in migrating neurons. In the latter half of this review, we provide an overview of the literature on Ca2+-dependent signalling molecules underlying neuronal migration.

A strategy for screening an inhibitor of viral silencing suppressors, which attenuates symptom development of plant viruses.

To find out whether we can control plant virus diseases by blocking viral RNA silencing suppressors (RSSs), we developed a strategy to screen inhibitors that block the association of RSSs with siRNAs using a surface plasmon resonance assay. The screened chemicals were tested in competition with RSSs for binding to siRNAs using a mobility shift assay. We then confirmed that tested chemicals actually inhibited the RSS activity in vivo using a protoplast assay which was developed for this purpose. This entire system can be adapted to screening inhibitors of not only plant viruses but also some animal viruses possessing RSSs.

IgE- and FcepsilonRI-mediated enhancement of surface CD69 expression in basophils: role of low-level stimulation.

Surface-expressed CD69 is a recently recognized activation marker for basophils and is reported to be strongly induced in vitro by IL-3. In this study, we investigated whether IgE- and high-affinity receptor for IgE (FcepsilonRI)-dependent stimuli can affect basophil CD69 expression. Highly purified basophils were cultured for 24 h in the presence of anti-FcepsilonRI alpha-chain mAb, CRA-1 and IL-3, and surface CD69 expression was analyzed by flow cytometry. CRA-1 mAb at 1 ng/ml or lower concentrations, levels too low to provoke direct histamine release, dose-dependently enhanced surface CD69 expression in the presence of IL-3, although low-dose CRA-1 mAb failed to induce CD69 expression in the absence of IL-3. Recombinant Der f 2 at 10 to 100 pg/ml enhanced CD69 levels in the presence of IL-3 in basophils from mite-sensitive subjects. These results suggest that allergens may influence basophil CD69 expression even when the levels of the antigens are too low to trigger direct degranulation. Upregulated CD69 expression on locally accumulated basophils in bronchial asthma may be attributed at least in part to a combination of local cytokines, especially IL-3, plus exposure to low levels of IgE-crosslinking allergens.

Salvage surgery for primary lung cancer after chemotherapy in octogenarians.

An 81-year-old female patient was admitted to our institute because of abnormal X-ray results. Chest computed tomography showed a 7.7 × 5.3 cm mass located in the left lower lobe and multiple swollen lymph nodes. 18F-fluorodeoxyglucose-positron emission tomography indicated high standard uptake values in the mass and swollen lymph nodes. The patient was diagnosed with stage cT3N2M0-IIIA squamous cell carcinoma. Although the patient had multiple lymph node metastases and severe obstructive pulmonary function, four cycles of platinum doublet chemotherapy were initially performed and no side effect greater than grade 3 was experienced. As the lung cancer was downstaged to ycT2aN0M0-IB and pulmonary function had improved, a bronchodilating preparation, an uneventful left lower lobectomy, and a lymphadenectomy were performed. The patient was discharged 39 days after surgery and exhibited good health for a year at pathological stage ypT1aN0M0-IA (Ef2).

Evaluation of human thymus and activation-regulated chemokine concentrations in blood using a new sandwich ELISA based on monoclonal antibodies.

BACKGROUND: CC chemokine TARC (thymus and activation-regulated chemokine), a potent chemoattractant for Th2 lymphocytes, is thought to play important roles in inflammatory diseases. We developed a new sensitive enzyme-linked immunoassay (ELISA) for human TARC (hTARC) to accurately measure and evaluate its concentrations in blood. METHODS: An ELISA was developed using two established monoclonal antibodies against hTARC. Using this assay, we observed changes of hTARC concentrations in serum and plasma obtained from individual subjects. Improvements to the assay were made to allow use for the clinical evaluation of samples from atopic dermatitis (AD). RESULTS: The lower detection limit of the ELISA was 1.4 pg/ml for a 25 microl sample volume. Other assay characteristics were enough to satisfactorily measure hTARC in biological fluids. This ELISA revealed that changes in serum and plasma concentrations were related to sample handling before separation from blood. With appropriate sample preparation, significant increases of hTARC were observed in patients with AD in comparison with normal subjects. CONCLUSIONS: Appropriate sample preparation is important for clinical studies on hTARC. Accurate measurement using our ELISA method offers a suitable clinical index for evaluating the severity of allergic diseases of Th2-dominant disorders, such as AD.

Female mate recognition and sexual isolation depending on courtship song in Drosophila sechellia and its siblings.

In Drosophila sechellia, females accept males that sing heterospecific songs less than those that do not sing, whereas in D. melanogaster and D. simulans, females accept males that sing heterospecific song more than those that do not sing. Here we studied the sexual isolation of D. sechellia and its siblings using interspecific hybrids to reveal the mechanisms underlying female mate recognition. The females of hybrids mated more with winged males of the parent species than with wingless ones, suggesting that the discrimination against heterospecific songs by D. sechellia females is recessive. Female preference for courtship songs seems to be inherited additively or semidominantly. In addition, we examined female receptivity without the stimuli of courtship songs by comparing the mating frequencies between the crosses using wingless males and found that it is also inherited additively or semidominantly.

Search for species-specific mating signal in courtship songs of sympatric sibling species, Drosophila ananassae and D. pallidosa.

Sexual isolation is one of the most important mechanisms that may lead to speciation. Drosophila ananassae and D. pallidosa are useful for the study of sexual isolation, because of their sympatric distribution and no postmating isolation between them. Courtship songs are considered to play a crucial role in sexual isolation between D. ananassae and D. pallidosa. We recorded and analyzed male courtship songs of D. ananassae and D. pallidosa for eight and four geographical strains, respectively. Courtship behaviors of the two species were consistent with those previously described, however, male's middle leg shaking, which had not before been described, was observed in both species. Males sing by wing vibration only during courtship. Their song oscillograms were distinct between species, but those of conspecific strains were very similar, in spite of their different geographical derivation. We found species-specificity in burst length, pulse length, cycle number in a pulse, and frequency spectra of bursts; these results suggest that these song parameters may play a role in mate recognition that enforces their sexual isolation. The specific values of interpulse interval, cycle number in a pulse and intrapulse frequency were involved with the determination of specificity in frequency spectra of bursts. We discussed the possibility that the specific frequency spectra of bursts are recognized by females as the species-specific signal rather than each parameter individually.

Influence of inhaled corticosteroids on community-acquired pneumonia in patients with bronchial asthma.

OBJECTIVE: The aim of the present study was to evaluate the influence of inhaled corticosteroids (ICS) on community-acquired pneumonia (CAP) in patients with asthma. PATIENTS AND METHODS: All asthmatic patients who required hospitalization for CAP from the beginning of 1989 through December 2001 were enrolled in this retrospective study. Patients who used oral corticosteroids daily were excluded. Patients were divided into two groups based on whether or not they used ICS, and we analyzed clinical characteristics of the pneumonia. Sixty-two patients (28 males, 34 females; mean age, 54.5 years) were enrolled in this study. Thirty-seven of 62 patients used ICS, with the mean dosage being 777.9 microg/day. RESULTS: We found no significant differences between the two groups with regard to mean age, serum albumin level, duration of asthma, pulmonary function and frequency of intravenous infusion of corticosteroids in the outpatient department. There were no significant differences in body temperature, white blood cell count, and CRP value upon admission between the two groups. Differences were not significant in the period of resolution of the pneumonia or in the frequency of pathogens identified between the two groups. CONCLUSION: ICS therapy appears to have no influence on CAP in patients with asthma. We recommend that ICS should be continued to control asthma with adequate antibiotic therapy when asthmatic patients have CAP.

[Clinical properties of community-acquired pneumonia in patients with asthma].

PURPOSE: Many reports were found on the clinical properties of community-acquired pneumonia. The clinical properties of community-acquired pneumonia in patients with asthma have not been elucidated, and we therefore investigated such properties. MATERIALS AND METHODS: Asthmatic patients who required hospitalization for community-acquired pneumonia from the beginning of 1989 through the end of 2001 were enrolled in this study. We performed the study in a retrospective manner. Patients were divided into two groups based on severity of their asthma (mild to moderate asthma vs severe asthma), and we studied the clinical properties of the pneumonia. RESULT: No significant difference was seen in body temperature, white blood cell counts, or CRP value on admission between the two groups. No significant difference was seen in the resolving period of the pneumonia. The frequency of common pathogens (Streptococcus pneumoniae + Haemophilus influenzae) was lower in patients with severe asthma. Asthmatic patients not taking daily oral corticosteroids were divided into two groups based on whether or not they were using a inhaled corticosteroid, and we examined the frequency of pathogendetection. The percentage of common pathogens was almost the same in the two groups. CONCLUSION: The frequency of common pathogens was lower in patients with severe asthma than in those with mild to moderate asthma. This fact is worth considering when empiric therapy for pneumonia is performed in patients with asthma. Inhaled corticosteroid therapy seems to have no influence on the pathogens of pneumonia in patients with asthma.

[A case of eosinophilic gastroenteritis: observation of serum IL-5 and sIL-2R levels before and after remission].

56 years-old man was admitted to our hospital because of severe diarrhea and hypereosinophilia. There was tenderness in the middle part of his abdomen. Laboratory examination revealed elevation of serum IL-5 and serum IL-2R value. No pathogens were detected from his stool specimen. An abdominal CT showed neither ascites nor thickening of intestinal wall. Pathological finding showed marked eosinophil infiltration in gastric and colonic mucosa. Eosinophilic gastroenteritis was diagnosed. His symptom was gradually improved spontaneously at the point of diagnosis. But administration of suplatast tosilate was stared because patients with this disease often relapse. Abdominal symptom was completely disappeared and value of serum IL-5 and sIL-2R was decreased at the end of September. This finding may imply pathogenesis of this disease.

[Acute exacerbation of interstitial pneumonia associated with active systemic lupus erythematosus in a patient with rheumatoid arthritis].

A 36-year-old woman with rheumatoid arthritis was admitted to our hospital for evaluation of newly developed active systemic lupus erythematosus (SLE). After hospitalization, she showed progressive respiratory failure. Chest CT revealed exacerbation of interstitial pneumonia, showing acute development of air-space consolidation and ground-glass opacity in addition to intensified reticular shadows. Administration of high-dose corticosteroids and cyclosporine A resulted in recovery from respiratory failure, accompanied by obvious improvement in the chest radiographs and CT, as demonstrated by the disappearance of air-space consolidation and ground-glass opacity. Clinically, the exacerbation of her interstitial pneumonia was compatible with acute lupus pneumonitis, a rare complication with active SLE.