Glucose control in the early phase of hospitalization is associated with severe prognosis in coronavirus disease 2019 (COVID-19) patients with diabetes in Japan.

We investigated the association of glycemic control in the early phase of hospitalization with the prognosis of COVID-19 in patients with diabetes. We analyzed the relationship between various clinical indices, including preprandial blood glucose levels measured by self-monitoring devices in the early phase after admission, and severe prognosis in 189 patients with complicated diabetes who were admitted to our hospital between February 22, 2020 and June 20, 2021. Enrolled patients had a median age of 72 years, median body mass index of 24.7, median HbA1c of 7.1%, and median mean preprandial capillary glucose (PPCG) of 179.1 mg/dL. Sixty-six patients progressed to severe disease, and the mean PPCG in severe cases was significantly higher than that in non-severe cases, 195.2 vs 167.8 mg/dL (p = 0.005). Analysis of the receiver operating characteristic curve showed that 179 mg/dL was the cut-off value, and the risk of severity was significantly higher in patients with a mean PPCG of 180 mg/dL or higher (odds ratio (OR) 3.210, p = 0.017) in multiple regression analysis. In this study, we found that the risk of severe COVID-19 increased in patients with a high mean PPCG in the early phase of hospitalization, suggesting that good glucose control in the early phase of COVID-19 with diabetes may be effective in preventing disease severity. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00656-8.

Obesity, glucose intolerance, advanced age, and lymphocytopenia are independent risk factors for oxygen requirement in Japanese patients with Coronavirus disease 2019 (COVID-19).

At the current time of rising demand for hospital beds, it is important to triage COVID-19 patients according to the treatment needed during hospitalization. The need for oxygen therapy is an important factor determining hospital admission of these patients. Our retrospective study was designed to identify risk factors associated with the progression to oxygen requirement in COVID-19 patients. A total of 133 patients with laboratory-confirmed COVID-19 were admitted to our hospital from February 22, 2020, to August 23. After excluding asymptomatic, non-Japanese, pediatric, pregnant patients and also those who needed oxygen immediately at admission, data of the remaining 84 patients were analyzed. The patients were separated into those who required oxygen after admission and those who did not, and their characteristics were compared. Age, body mass index (BMI), lymphocyte count, C-reactive protein (CRP), lactate dehydrogenase, estimated glomerular filtration rate, glucose intolerance, hypertension, and dyslipidemia were significantly different between the two groups. Multivariate analysis identified four significant and independent risk factors of oxygen requirement, including advanced age, obesity, glucose intolerance and lymphocytopenia. Dividing the patients into subgroups according to the number of these risk factors found in each patient indicated that the need for oxygen increased with higher number of these risk factors in the same individual. Our results suggest that the presence of higher number of these risk factors in COVID-19 patients is associated with future oxygen requirement and that this index can be potentially useful in triaging COVID-19 patients staying home in the context of need for hospitalization.

Early clinical factors predicting the development of critical disease in Japanese patients with COVID-19: A single-center, retrospective, observational study.

The factors predicting the progression of coronavirus disease-2019 (COVID-19) from mild to moderate to critical are unclear. We retrospectively evaluated risk factors for disease progression in Japanese patients with COVID-19. Seventy-four patients with laboratory-confirmed COVID-19 were hospitalized in our hospital between February 20, 2020, and June 10, 2020. We excluded asymptomatic, non-Japanese, and pediatric patients. We divided patients into the stable group and the progression group (PG; requiring mechanical ventilation). We compared the clinical factors. We established the cutoff values (COVs) for significantly different factors via receiver operating characteristic curve analysis and identified risk factors by univariate regression. We enrolled 57 patients with COVID-19 (median age 52 years, 56.1% male). The median time from symptom onset to admission was 8 days. Seven patients developed critical disease (PG: 12.2%), two (3.5%) of whom died; 50 had stable disease. Univariate logistic analysis identified an elevated lactate dehydrogenase (LDH) level (COV: 309 U/l), a decreased estimated glomerular filtration rate (eGFR; COV: 68 ml/min), lymphocytopenia (COV: 980/µl), and statin use as significantly associated with disease progression. However, in the Cox proportional hazards analysis, lymphocytopenia at admission was not significant. We identified three candidate risk factors for progression to critical COVID-19 in adult Japanese patients: statin use, elevated LDH level, and decreased eGFR.

First Report of Sublingual Gland Ducts: Visualization by Dynamic MR Sialography and Its Clinical Application.

This study was done to determine whether the sublingual gland ducts could be visualized and/or their function assessed by MR sialography and dynamic MR sialography and to elucidate the clinical significance of the visualization and/or evaluation of the function of sublingual gland ducts by clinical application of these techniques. In 20 adult volunteers, 19 elderly volunteers, and 7 patients with sublingual gland disease, morphological and functional evaluations were done by MR sialography and dynamic MR sialography. Next, four parameters, including the time-dependent changes (change ratio) in the maximum area of the detectable sublingual gland ducts in dynamic MR sialographic images and data were analyzed. Sublingual gland ducts could be accurately visualized in 16 adult volunteers, 12 elderly volunteers, and 5 patients. No significant differences in the four parameters in detectable duct areas of sublingual glands were found among the three groups. In one patient with a ranula, the lesion could be correctly diagnosed as a ranula by MR sialography because the mass was clearly derived from sublingual gland ducts. This is the first report of successful visualization of sublingual gland ducts. In addition, the present study suggests that MR sialography can be more useful in the diagnosis of patients with lesions of sublingual gland ducts.

Anti-proteinase 3-positive Eosinophilic Granulomatosis with Polyangiitis Revealed by Cardiac Tamponade.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic vasculitis characterized by asthma, eosinophilia, and diffuse eosinophilic infiltration. Although cardiovascular involvement is common and a leading cause of EGPA-related mortality, severe pericarditis-led cardiac tamponade occurs rarely. We herein report a 72-year-old man with anti-proteinase 3 (anti-PR3) anti-neutrophil cytoplasmic antibody (ANCA)-positive EGPA diagnosed by the presence of cardiac tamponade, which responded quickly to pericardiocentesis and a single administration of prednisolone. This is the first case of anti-PR3 ANCA-positive EGPA with cardiac tamponade; the patient displayed clinical features of both ANCA-positive and ANCA-negative cases.

Extracranial meningiomas concurrently found in the lung and vertebral bone: a case report.

BACKGROUND: Primary pulmonary meningiomas are very rare, and primary intraosseous meningiomas outside the head and neck region have not yet been reported. We report an extremely unusual case of concurrent meningiomas arising in the pulmonary parenchyma and vertebral bone. CASE PRESENTATION: A 40-year-old Asian woman presented with a destructive lesion of the lumbar vertebral bone and a small nodule in the right lung. Five years later, both lesions slightly increased in size. To evaluate both the pulmonary and vertebral lesions, video-assisted thoracic surgery and curettage of the lytic lesion were performed. Both lesions showed similar histopathological findings corresponding to an intracranial meningioma of World Health Organization grade 1. The patient made good postoperative progress and remained free from disease at 41 months after the operation. CONCLUSIONS: Our patient presented with almost synchronous pulmonary and lumbar vertebral intraosseous meningiomas. Regarding the relationship between the two lesions, there are two possibilities: Independent tumors occurred coincidentally or the primary pulmonary meningioma metastasized to the vertebral bone despite its bland morphology. It is important to keep in mind the exceptionally rare condition of extracranial meningioma.

Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan.

OBJECTIVE: To report the clinical features of myasthenia gravis (MG) induced by treatment with immune checkpoint inhibitors using 2-year safety databases based on postmarketing surveys in Japan. METHODS: We studied 10,277 patients with cancer who had received monotherapy with either nivolumab or ipilimumab between September 2014 and August 2016. As the control group, 105 patients with idiopathic MG were used. RESULTS: There were 12 MG cases (0.12%) among 9,869 patients with cancer who had been treated with nivolumab, but none among 408 patients treated with ipilimumab. These 12 patients included 6 men and 6 women with a mean age of 73.5 ± 6.3 years. MG onset occurred in the early phase after nivolumab treatment and rapidly deteriorated. Nivolumab-related MG (nivoMG) included 4 patients with mild involvement and 8 patients with severe involvement. Bulbar symptoms and myasthenic crisis were observed more frequently in nivoMG than idiopathic MG. Ten patients were positive for anti-acetylcholine receptor antibodies. Serum creatine kinase levels were markedly elevated to an average level of 4,799 IU/L. Among the 12 patients with nivoMG, 4 had myositis and 3 had myocarditis, with 1 of these patients having both. Immunosuppressive therapy was effective. Postintervention status showed that pharmacologic remission or minimal manifestations were obtained in 4 patients; however, 2 patients died. Immune-related adverse events triggered by nivolumab impaired the patients' daily living activity. CONCLUSIONS: The prompt and correct recognition of MG following treatment with immune checkpoint inhibitors in patients with cancer is important.

Overcoming chemoresistance of small-cell lung cancer through stepwise HER2-targeted antibody-dependent cell-mediated cytotoxicity and VEGF-targeted antiangiogenesis.

Small-cell lung cancer (SCLC) easily recurs with a multidrug resistant phenotype. However, standard therapeutic strategies for relapsed SCLC remain unestablished. We found that human epidermal growth factor receptor 2 (HER2) is not only expressed in pretreated human SCLC specimens, but is also upregulated when HER2-positive SCLC cells acquire chemoresistance. Trastuzumab induced differential levels of antibody-dependent cell-mediated cytotoxicity (ADCC) to HER2-positive SCLC cells. Furthermore, as a mechanism of the differential levels of ADCC, we have revealed that coexpression of intracellular adhesion molecule (ICAM)-1 on SCLC cells is essential to facilitate and accelerate the trastuzumab-mediated ADCC. Although SN-38-resistant SCLC cells lacking ICAM-1 expression were still refractory to trastuzumab, their in vivo growth was significantly suppressed by bevacizumab treatment due to dependence on their distinctive and abundant production of vascular endothelial growth factor. Collectively, stepwise treatment with trastuzumab and bevacizumab is promising for the treatment of chemoresistant SCLC.

Drug-induced thrombotic thrombocytopenic purpura successfully treated with recombinant human soluble thrombomodulin.

A 61-year-old woman with recurrent non-small cell lung cancer presented with thrombocytopenia, microangiopathic hemolytic anemia, neurological abnormalities, renal failure and a fever that appeared during chemotherapy with gemcitabine and bevacizumab. She was diagnosed with drug-induced thrombotic thrombocytopenic purpura (TTP). After the discontinuation of chemotherapy, the administration of recombinant human soluble thrombomodulin and fresh-frozen plasma rapidly ameliorated the TTP. Hypertension preceded the onset of TTP and required the administration of quadruple therapy on admission. However, after three months, the hypertension was controllable without anti-hypertensive drugs. Twelve months later, the ninth course of vinorelbine was administered safely, preventing the patient's lung cancer from progressing.

Polymorphisms of CYP2D6 gene and gefitinib-induced hepatotoxicity.

INTRODUCTION: Gefitinib induces severe hepatotoxicity in approximately a quarter of Japanese patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Gefitinib is metabolized by cytochrome P450 (CYP) enzymes--including CYP3A4/5, CYP1A1, and CYP2D6--in the liver. We hypothesized that polymorphisms of the CYP2D6 gene may account for gefitinib-induced hepatotoxicity. PATIENTS AND METHODS: Polymorphisms of the CYP2D6 gene were analyzed in 55 patients with NSCLC who experienced grade ≥ 2 transaminase elevation from gefitinib. The distribution of the CYP2D6 genotype was compared with that of the healthy Japanese population. The correlations between the nonfunctional allele *5 or the reduced-function allele *10 and hepatotoxicity-related clinical factors were also examined. RESULTS: The distribution of the CYP2D6 genotype in the study participants was not different from that of the general Japanese population, reported previously. Existence of allele *5 or *10 did not correlate with clinical factors such as onset of hepatotoxicity within 2 months, grade ≥ 3 serum transaminase elevation, and tolerability to dose reduction or rechallenge of gefitinib. However, in 7 patients taking CYP3A4-inhibitory drugs, rechallenge of gefitinib again caused hepatotoxicity in 4 patients with allele *5 or *10 but not in 3 patients with normal alleles (P = .029). Moreover, switching to erlotinib did not cause hepatotoxicity in any of 17 patients with allele *5 or *10 but did in 3 of 8 patients without these alleles (P = .024). CONCLUSION: Reduced function of CYP2D6 may partly account for gefitinib-induced hepatotoxicity when CYP3A4 is inhibited. Erlotinib could be safely used in patients with decreased CYP2D6 activity even after they experienced gefitinib-induced hepatotoxicity.

Deletion of tetraspanin CD9 diminishes lymphangiogenesis in vivo and in vitro.

Tetraspanins have emerged as key players in malignancy and inflammatory diseases, yet little is known about their roles in angiogenesis, and nothing is known about their involvement in lymphangiogenesis. We found here that tetraspanins are abundantly expressed in human lymphatic endothelial cells (LEC). After intrathoracic tumor implantation, metastasis to lymph nodes was diminished and accompanied by decreased angiogenesis and lymphangiogenesis in tetraspanin CD9-KO mice. Moreover, lymphangiomas induced in CD9-KO mice were less pronounced with decreased lymphangiogenesis compared with those in wild-type mice. Although mouse LEC isolated from CD9-KO mice showed normal adhesion, lymphangiogenesis was markedly impaired in several assays (migration, proliferation, and cable formation) in vitro and in the lymphatic ring assay ex vivo. Consistent with these findings in mouse LEC, knocking down CD9 in human LEC also produced decreased migration, proliferation, and cable formation. Immunoprecipitation analysis demonstrated that deletion of CD9 in LEC diminished formation of functional complexes between VEGF receptor-3 and integrins (α5 and α9). Therefore, knocking down CD9 in LEC attenuated VEGF receptor-3 signaling, as well as downstream signaling such as Erk and p38 upon VEGF-C stimulation. Finally, double deletion of CD9/CD81 in mice caused abnormal development of lymphatic vasculature in the trachea and diaphragm, suggesting that CD9 and a closely related tetraspanin CD81 coordinately play an essential role in physiological lymphangiogenesis. In conclusion, tetraspanin CD9 modulates molecular organization of integrins in LEC, thereby supporting several functions required for lymphangiogenesis.

Suppression of metastases of small cell lung cancer cells in mice by a peptidic CXCR4 inhibitor TF14016.

CXCL12 is a chemokine essential for the organ-specific spread of a variety of cancers including small cell lung cancer (SCLC). Here, we examined the anti-metastatic efficacy of TF14016, a small peptidic inhibitor of CXCL12 receptor CXCR4, in SCLC. Treatment of mice with TF14016 significantly suppressed pulmonary metastases of CXCR4-expressing SCLC in size and number. Furthermore, histological examination revealed that the expression of vascular endothelial cell growth factor and the density of CD31-positive microvessels in metastatic foci were both significantly reduced in TF14016-treated mice. Collectively, CXCR4 could be an attractive target for anti-metastatic and anti-angiogenic therapy in SCLC.

HER2 as therapeutic target for overcoming ATP-binding cassette transporter-mediated chemoresistance in small cell lung cancer.

Small cell lung cancer (SCLC) easily acquires multidrug resistance after successful initial therapy. Overexpression of ATP-binding cassette (ABC) transporters is important for the multidrug resistance. Among them, ABCB1 and ABCG2 are known to be upregulated in chemoresistant SCLC cells. We found that human epidermal growth factor receptor 2 (HER2) expressions are also upregulated in chemoresistant SBC-3/ETP, SBC-3/SN-38, and SBC-3/CDDP cells, compared with chemosensitive SBC-3 cells. Lapatinib, a tyrosine kinase inhibitor of HER2, could not suppress proliferation of these HER2-positive SCLC cells alone but successfully restored chemosensitivity to etoposide and SN-38 with a clinically applicable concentration. The reversal effect of lapatinib was thought to be caused by inhibition of drug efflux pump functions of ABC transporters, although lapatinib itself has been reported to be a substrate for them. Moreover, knocking down of HER2 by an short interfering RNA weakened the effect of lapatinib on ABCB1, indicating the involvement of HER2 in the inhibitory mechanisms. Notably, we showed that caveolin-1 and Src play key roles in modulating ABCB1 function via HER2 inactivation. In SBC-3/ETP cells, dephosphorylation of HER2 by lapatinib activates Src and successively leads to increased caveolin-1 phosphorylation. Through this process, caveolin-1 dissociates from HER2 and strengthens association with ABCB1, and finally impairs the pump functions. Furthermore, we showed that treatment by lapatinib in combination with etoposide or irinotecan significantly suppresses the growth of subcutaneous SBC-3/ETP and SBC-3/SN-38 tumors in mice, respectively. Collectively, these results indicate that combination therapy with lapatinib and cytotoxic agents could conquer ABC transporter-mediated chemoresistance especially in HER2-positive SCLC.

Cell surface tetraspanin CD9 mediates chemoresistance in small cell lung cancer.

Small cell lung cancer (SCLC) is an aggressive malignancy with extremely high mortality due to the appearance of widespread metastases early in its clinical course and rapid acquisition of chemoresistance after initial therapy. A theory of cell adhesion-mediated drug resistance is thought to be a principal mechanism in which extracellular matrix proteins provide a survival advantage against cytotoxic drug-induced apoptosis. We found that the tetraspanin family member CD9 was expressed preferentially in SCLC tumors and metastases from three of seven relapsed patients, whereas chemonaïve primary tumors from 16 patients were CD9 negative with only one exception. Additionally, CD9 was highly expressed on SCLC cell lines rendered resistant to cisplatin or etoposide, and was upregulated in parental chemosensitive cells within 48 hours after exposure to either of these compounds. CD9-expressing chemoresistant SCLC cells adhered more tightly to fibronectin via ß1 integrin, but they were less motile than the respective chemosensitive parental lines. Notably, treatment of the chemoresistant cells with chemokine CXCL12 downregulated CD9 and transiently restored motility. Moreover, selective targeting of CD9 by treatment with specific monoclonal antibody ALB6 or a small interfering RNA triggered apoptosis in the chemoresistant cells. Taken together, our findings implicate CD9 in the cell adhesion-mediated drug resistance mechanism, highlighting CD9 as an attractive therapeutic target to improve therapeutic outcomes in SCLC.

[Two cases of severe myelosuppression from amrubicin in previously-treated small cell lung cancer].

The patients were a 59-year-old man and 68-year-old man with previously-treated small cell lung cancer (extensive disease). Amrubicin (40 mg/m(2) and 45 mg/m(2)) was administered for 3 days after brain irradiation. Severe neutropenia continued for nine days from day 8 following administration. Although both patients had an infection, it improved by granulocyte-colony stimulating factor (G-CSF), and antibiotics, plus a blood transfusion. Particular attention for severe myelosuppression should be given to amrubicin therapy with previously-treated small cell lung cancer. However, a detailed blood test in course 1 and early administration of drugs such as G-CSF make this therapy feasible. In addition, to control the condition of patients, repeated administration of amrubicin with dose reduction is recommended.

Marked hyperglycemia after androgen-deprivation therapy for prostate cancer and usefulness of pioglitazone for its treatment.

Here we demonstrate 2 patients who showed marked hyperglycemia after androgen-deprivation therapy for prostate cancer and the efficacy of the thiazolidinedione pioglitazone on their glycemic control. Case 1 was a 61-year-old man diagnosed with prostate cancer who had type 2 diabetes mellitus for 7 years. His glycemic control had been good for the previous 5 years because of diet therapy and acarbose administration. He was given the gonadotropin-releasing hormone agonist leuprolide acetate and the androgen receptor antagonist flutamide for the treatment of prostate cancer. After the second injection of leuprolide acetate, fasting glucose and hemoglobin A1c (HbA1c) levels were found to be markedly elevated (22.8 mmol/L and 10.5%, respectively). Case 2 was an 81-year-old man whose fasting glucose and HbA1c had been normal 10 months ago. He was injected with leuprolide acetate for the treatment of prostate cancer. Six months after starting the leuprolide treatment, the patient complained of thirst and weight loss and was diagnosed with diabetes mellitus with a fasting glucose of 19.4 mmol/L and HbA1c of 9.9%. The correct homeostasis model assessment evaluation indexes for pancreatic beta-cell function (HOMA-%beta )A and for insulin sensitivity (HOMA-%S) were reduced in these 2 patients compared with control men. Their serum testosterone and 17beta -estradiol concentrations were depressed. After improvement of hyperglycemia by insulin treatment, their glycemic control remained good after treatment with pioglitazone without use of insulin. The values of HOMA-%beta and HOMA-%S increased to control ranges. Insulin resistance after the androgen-deprivation therapy might lead to marked hyperglycemia in these patients.