Safety and efficacy of acalabrutinib and obinutuzumab in treatment-naive chronic lymphocytic leukemia: a Japanese phase 1 study.

This report focuses on part 3 of a multicenter, open-label, phase 1 study (NCT03198650) assessing the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of acalabrutinib plus obinutuzumab in Japanese patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL). Ten patients were included; median age was 68 years. With a median treatment duration of 27.2 months, treatment-emergent adverse events (AEs) occurred in all patients (grade ≥3, 70%), and the most common AEs were anemia and headache (40% each). One patient had a grade 4 AE of neutropenia (the only dose-limiting toxicity). PK results suggested no marked effects of concomitant obinutuzumab treatment on the exposure of acalabrutinib. PD assessment indicated that combination therapy provided >98% Bruton tyrosine kinase (BTK) occupancy. Overall response rate (ORR) was 100% with median duration of response (DoR) and median progression-free survival (PFS) not reached. Treatment with acalabrutinib plus obinutuzumab was generally safe and efficacious in adult Japanese patients with TN CLL.

Suppression of Type I Interferon Signaling in Myeloid Cells by Autoantibodies in Severe COVID-19 Patients.

PURPOSE: Auto-antibodies (auto-abs) to type I interferons (IFNs) have been identified in patients with life-threatening coronavirus disease 2019 (COVID-19), suggesting that the presence of auto-abs may be a risk factor for disease severity. We therefore investigated the mechanism underlying COVID-19 exacerbation induced by auto-abs to type I IFNs. METHODS: We evaluated plasma from 123 patients with COVID-19 to measure auto-abs to type I IFNs. We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from the patients with auto-abs and conducted epitope mapping of the auto-abs. RESULTS: Three of 19 severe and 4 of 42 critical COVID-19 patients had neutralizing auto-abs to type I IFNs. Patients with auto-abs to type I IFNs showed no characteristic clinical features. scRNA-seq from 38 patients with COVID-19 revealed that IFN signaling in conventional dendritic cells and canonical monocytes was attenuated, and SARS-CoV-2-specific BCR repertoires were decreased in patients with auto-abs. Furthermore, auto-abs to IFN-α2 from COVID-19 patients with auto-abs recognized characteristic epitopes of IFN-α2, which binds to the receptor. CONCLUSION: Auto-abs to type I IFN found in COVID-19 patients inhibited IFN signaling in dendritic cells and monocytes by blocking the binding of type I IFN to its receptor. The failure to properly induce production of an antibody to SARS-CoV-2 may be a causative factor of COVID-19 severity.

Optimization of electrode positions for equalizing local spatial performance of a tomographic tactile sensor.

A tomographic tactile sensor based on the contact resistance of conductors is a high sensitive pressure distribution imaging method and has advantages on the flexibility and scalability of device. While the addition of internal electrodes improves the sensor's spatial resolution, there still remain variations in resolution that depend on the contact position. In this study, we propose an optimization algorithm for electrode positions that improves entire spatial resolution by compensating for local variations in spatial resolution. Simulation results for sensors with 16 or 64 electrodes show that the proposed algorithm improves performance to 0.81 times and 0.93 times in the worst spatial resolution region of the detection area compared to equally spaced grid electrodes. The proposed methods enable tomographic tactile sensors to detect contact pressure distribution more accurately than the conventional methods, providing high-performance tactile sensing for many applications.

A case report of neuromyelitis optica spectrum disorder induced by pembrolizumab treatment for lung adenocarcinoma: a clinical and immunohistochemical study.

BACKGROUND: We report a case of neuromyelitis optica spectrum disorders (NMOSD), who developed after the pembrolizumab treatment, an immune checkpoint inhibitor, against lung adenocarcinoma. The present case is discussed with the lung adenocarcinoma specimen which was stained by aquaporin-4 (AQP4) and with literature review of NMOSD linked to immune checkpoint inhibitors. CASE PRESENTATION: A 62-year-old Japanese man presented with acute diencephalic syndrome, left optic neuritis, and myelitis 5 months after initiation of pembrolizumab treatment for lung adenocarcinoma. He was diagnosed with NMOSD based on serum anti-aquaporin-4 (AQP4) antibody positivity. Immunohistochemistry of lung biopsy samples showed AQP4 expression on CD68+ cells. This is the fifth reported case of AQP4+ NMOSD triggered by an immune checkpoint inhibitor and the first with a brain lesion. Four out of five NMOSD cases, including the present case and one case with lung metastasis, had lung cancer. CONCLUSIONS: Immune checkpoint inhibitors may trigger AQP4+ NMOSD owing to their molecular similarity to AQP4 expressed in lung and glial tissues. Prompt brain/spinal cord imaging and anti-AQP4 antibody testing may facilitate early diagnosis of immune-mediated adverse event in central nervous system associated with immune checkpoint inhibitors.

Thermal and Optical Properties of Porous Nanomesh Structures for Sensitive Terahertz Bolometric Detection.

Terahertz (THz) electromagnetic waves are attractive for use in nondestructive and biocompatible sensing applications. Thermal sensors are widely used for THz detection owing to the small photon energies of THz radiation, where this requires materials with low thermal conductivity and a small heat capacity to ensure the sensitive and fast operation of the sensors. In this study, we investigated the thermal and optical properties of porous nanomesh structures for sensitive THz bolometric detection. Nanometer (nm)-scale hole array structures were formed on gallium arsenide (GaAs) microelectromechanical system (MEMS) beams to improve their thermal properties. The thermal conductance of the porous MEMS beams was obtained by measuring their thermal bandwidths; it was found to decrease by as much as ~90% when the porosity (P) of the porous nanostructure was increased to ~0.69. We also measured the THz absorptance of the porous hole array structure. The results show that although the porous nanostructure has a much smaller area than the bulk material, it maintained a high coefficient of THz absorptance because the featured size was much smaller than the THz wavelength. The measured absorptance agreed well with that calculated by using the Drude model. These results demonstrate that the porous nanomesh structure is promising for developing highly sensitive THz thermal sensors.

Elevated Myl9 reflects the Myl9-containing microthrombi in SARS-CoV-2-induced lung exudative vasculitis and predicts COVID-19 severity.

The mortality of coronavirus disease 2019 (COVID-19) is strongly correlated with pulmonary vascular pathology accompanied by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-triggered immune dysregulation and aberrant activation of platelets. We combined histological analyses using field emission scanning electron microscopy with energy-dispersive X-ray spectroscopy analyses of the lungs from autopsy samples and single-cell RNA sequencing of peripheral blood mononuclear cells to investigate the pathogenesis of vasculitis and immunothrombosis in COVID-19. We found that SARS-CoV-2 accumulated in the pulmonary vessels, causing exudative vasculitis accompanied by the emergence of thrombospondin-1-expressing noncanonical monocytes and the formation of myosin light chain 9 (Myl9)-containing microthrombi in the lung of COVID-19 patients with fatal disease. The amount of plasma Myl9 in COVID-19 was correlated with the clinical severity, and measuring plasma Myl9 together with other markers allowed us to predict the severity of the disease more accurately. This study provides detailed insight into the pathogenesis of vasculitis and immunothrombosis, which may lead to optimal medical treatment for COVID-19.

Vision Improvement after Osimertinib Treatment in Paraneoplastic Optic Neuropathy Associated with Lung Adenocarcinoma.

Treatments for paraneoplastic optic neuropathy (PON), a tumor-related autoimmune disease, include immunosuppression, plasma exchange, and immunoglobulin therapies, as well as treatment of the underlying disease. Herein, we describe the clinical course of an older adult patient with PON whose loss of vision improved after switching between epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatments for cancer. A 76-year-old woman, who had been treated with gefitinib for lung adenocarcinoma for two years, presented with acute bilateral visual disturbances. Her decimal best-corrected visual acuity (BCVA) was 0.3 in the right eye (RE) and 0.7 in the left eye (LE). Slit-lamp examination and funduscopy showed no abnormal findings. Two weeks later, her BCVA decreased to 0.2 in the RE and 0.01 in the LE. Goldman's perimetry showed a defect in the lower nasal RE and extensive visual-field loss in the LE. Single-flash electroretinograms showed normal amplitudes. Magnetic resonance imaging revealed left optic neuritis and showed neither metastatic cancer nor multiple sclerosis. Pattern-reversal visual evoked potentials showed decreased P100 amplitudes in both eyes (BE). Based on a diagnosis of PON from clinical findings, methylprednisolone pulse treatment was administered. However, her BCVA became no light perception in BE two months after the first visit. Because the tumor tissue was found to be positive for the EGFR T790M resistance mutation by bronchoscopy, the EGFR-TKI treatment was changed to osimertinib, decreasing the size of the lung cancer lesions. Her BCVA improved to hand motion in BE. Her final BCVA was 0.01 in the RE, counting fingers 10 cm in the LE. She died at the age of 79 years. To our knowledge, no reports have shown improvement in BCVA in patients with PON after changing EGFR-TKI treatments. This report indicates that some patients may develop severe visual dysfunction without early treatment for the primary tumor.

[Portal vein thrombosis associated with idiopathic hypereosinophilic syndrome].

A 35-year-old man who previously underwent splenectomy for hereditary spherocytosis at age 29 visited our hospital complaining of fatigue that had started 7 days ago and right upper abdominal pain. Laboratory data showed increased white blood cell and eosinophil count accompanied by severe transaminitis and clotting abnormalities. Computed tomography scan showed multiple embolisms in the portal vein, superior mesenteric vein, right pulmonary artery, and inferior vena cava. Severe liver damage presumably caused by portal vein thrombosis was also observed. Anticoagulant therapies consisting of continuous arterial infusion of urokinase from the superior mesenteric artery and an intravenous infusion of recombinant human thrombomodulin and heparin dissolved the systemic thrombosis. Concurrently administered prednisone decreased the eosinophil count. With regard to eosinophilia, we were unable to find any connective tissue diseases, antibodies to parasites, or genetic anomalies including PDGFRA, PDGFRB, and FGFR1. Hence we diagnosed the patient with idiopathic hypereosinophilic syndrome (HES). Although thromboembolisms in patients with HES have been reported, the literature on portal vein thrombosis associated with HES is scarce. In the present case, the previous splenectomy may have contributed to the portal vein thrombosis.

Successful Treatment of Adolescents and Young Adults with Philadelphia-Negative Acute Lymphoblastic Leukemia by Novel L-Asparaginase-Intensified Induction Therapy and Cord Blood Transplantation: A Single-Center Decade Report.

A novel induction therapy, including intensive L-asparaginase, was designed in 2007 for patients aged <45 years with Philadelphia-negative acute lymphoblastic leukemia (ALL). We analyzed seven de novo cases and one case of recurrence who received this treatment. The median age was 21 years (range: 16-35 years). Four patients had T-ALL and the others had B-ALL. All the patients achieved complete remission and proceeded to cord blood transplantation. In the median 72-month follow-up, there were no cases of observed mortality or recurrence. Our results indicate scope for further development of both induction therapy and postremission therapy.

Hepatocyte growth factor promotes lung carcinogenesis in transgenic mice treated with diethylnitrosamine.

BACKGROUND: Hepatocyte growth factor (HGF) was initially discovered as a mitogen for hepatocytes, but it is also known to be related to carcinogenesis in many other organs. However, the role of HGF in lung carcinogenesis is not fully-understood. In this study, we investigated the role of HGF in lung carcinogenesis using HGF transgenic mice. MATERIALS AND METHODS: To elucidate the role of HGF in lung carcinogenesis, 5 µg/g body weight diethylnitrosamine (DEN) were administered intraperitoneally to HGF transgenic (TG) mice and wild-type (WT) mice at 15 days of age. The incidence and number of lung tumors, the expression of HGF and of its receptor (c-Met) were compared between HGF TG and WT mice. RESULTS: HGF overexpression accelerated DEN-induced lung carcinogenesis. Seventy-six percent of TG mice (versus 50% of WT mice) developed malignant lung tumors by 48 weeks. The incidence of lung tumors was significantly higher in the TG mice in comparison with WT mice (p<0.05). Furthermore, the mean diameter and number of tumors in each mouse were significantly higher in the TG mice compared to the WT mice (p<0.01). The northern blotting analyses revealed that there was overexpression of the HGF transgene in the lung tumors of TG mice in comparison with the surrounding non-tumorous lesions. The western blotting analyses of the tumor lesions revealed increased phosphorylation of c-Met. CONCLUSION: Our results suggest that HGF promotes lung carcinogenesis through the autocrine activation of the HGF/c-Met signaling pathway. The HGF/c-Met signaling pathway appears to have vital roles in lung carcinogenesis.

Interferon treatment for patients with chronic hepatitis C complicated with chronic renal failure receiving hemodialysis.

BACKGROUND AND AIMS: The Japan Society for Dialysis Therapy established "Guidelines for the Treatment of Hepatitis C Virus Infection in Dialysis Patients." We evaluated the status of HCV infection and the treatment of hemodialysis patients in Gunma prefecture. METHODS: Questionnaires concerning the infection rate, recognition of the guidelines, and treatment status were sent to all 64 hospitals/clinics that had hemodialysis systems in Gunma prefecture. The hepatitis C virus-infected hemodialysis patients who received pegylated interferon (peg-IFN) were analyzed at Gunma University Hospital. RESULTS: The positive rate for hepatitis C virus antibody was 256/2582 hemodialysis patients (9.9%). The positive rate varied between institutions (range 0-40.0%; median 9.0%). All institutes recognized the establishment of the guidelines. Conventional or peg-IFN treatment was being given at 37.5% of the institutions. The other 62.5% institutions answered that they intended to provide the treatment in the future if collaboration with a hepatologist could be arranged. The most common answers regarding the indication for IFN treatment were as follows: few complications, under 60 years of age, more than 10 years of survival expected on hemodialysis. Eighteen patients received peg-IFN treatment. The sustained virological response rate of all patients was 33.3%, 0% in 1b/high viral titer, 50% in genotype 2, and 100% in genotype 2/low viral titer. The sustained virological response rate was worse in the patients with 1b/high viral load and diabetic nephropathy (P < 0.05). CONCLUSIONS: Recognition of the publication of the guidelines was high. However, the number of patients treated with peg-IFN was still low. Further enlightenment and cooperation between hemodialysis teams and hepatologists are therefore needed.

Bortezomib-induced posterior reversible encephalopathy syndrome in a patient with newly diagnosed multiple myeloma.

Posterior reversible encephalopathy syndrome (PRES) is a known but extremely rare side effect of bortezomib therapy. An unusual case of PRES possibly caused by bortezomib during induction treatment in a patient with multiple myeloma is reported. The patient experienced neither hypertensive crisis nor uremic encephalopathy at the onset of PRES, which are both well-known etiologies of PRES. The patient's PRES-related symptoms resolved completely after discontinuation of bortezomib and administration of a bulk dose of corticosteroids. The importance of early recognition of this potential neurological complication must be emphasized because this new drug is being increasingly prescribed.

Voltammetric detection of biological molecules using chopped carbon fiber.

Voltammetric detection of biological molecules was carried out using chopped carbon fibers produced from carbon fiber reinforced plastics that are biocompatible and inexpensive. Because chopped carbon fibers normally are covered with a sizing agent, they are difficult to use as an electrode. However, when the surface of a chopped carbon fiber was treated with ethanol and hydrochloric acid, it became conductive. To evaluate the functioning of chopped carbon fibers, voltammetric measurements of [Fe(CN)(6)](3-) were carried out. Redoxes of FAD, ascorbic acid and NADH as biomolecules were recorded using cyclic voltammetry. The sizing agents used to bundle the fibers were epoxy, polyamide and polyurethane resins. The peak currents were the greatest when using the chopped carbon fibers that were created with epoxy resins. When the electrode response of the chopped carbon fibers was compared with that of a glassy carbon electrode, the peak currents and the reversibility of the electrode reaction were sufficient. Therefore, the chopped carbon fibers will be useful as disposable electrodes for the sensing of biomolecules.

Efficacy of idebenone for respiratory failure in a patient with Leigh syndrome: a long-term follow-up study.

Respiratory failure can be the direct cause of death in patients with Leigh syndrome. Unfortunately, no effective treatment strategy is available. Here, we report successful treatment of a patient with Leigh syndrome using idebenone, a derivative of coenzyme Q-10. The patient's brainstem function, especially respiratory function, improved after idebenone treatment. Idebenone may be worth trying in patients with Leigh syndrome.

Primary liver cancers with nonalcoholic steatohepatitis.

Nine patients with hepatocellular carcinoma (HCC) in nonalcoholic steatohepatitis (NASH) (six men and three women, median age 71.5 years) and one patient with intrahepatic cholangiocarcinoma (ICC), a 50-year-old man, in NASH are described. Most patients were associated with obesity, diabetes, hypertension, hypercholesterolemia, or hypertriglyceridemia. Seven patients showed insulin resistance and hyperinsulinemia. All patients except one met the criteria for metabolic syndrome. An HCC or ICC diagnosis was confirmed by tumor biopsy, surgery or autopsy except in two patients, who were diagnosed by computed tomography or hepatic angiography. The underlying liver disease was liver cirrhosis in six patients and chronic liver disease including mild hepatic fibrosis in four patients. The treatment of liver cancers consisted of surgery, radio-frequency ablation (RFA), transcatheter arterial embolization and transcatheter arterial infusion. Although the follow-up period was relatively short (median 27.5 months, average 32.1 months), all postoperative and post-RFA patients have not had a recurrence of HCC to date, except for one patient who had a palliative operation with intra-arterial infusion of anticancer drugs through an implanted reservoir port. Older age and liver cirrhosis are considered risk factors for HCC in NASH, and regular screening of these patients is necessary. Diabetes may contribute to the development of ICC in NASH. Curative therapy (surgery or RFA) and weight loss by the active therapeutic intervention (nutritional care and exercise therapy) after curative therapy may help us improve the prognosis of HCC in NASH.

Systemic sclerosis after interferon alphacon-1 therapy for hepatitis C.

A 66-year-old woman developed systemic sclerosis (SSc) after receiving interferon alphacon-1 (IFNalphacon-1; consensus interferon) therapy for chronic hepatitis C. She suffered from Raynauds phenomenon about 1 year after a course of IFNalphacon-1 therapy. The combination of proximal scleroderma, Raynauds phenomenon, and ANA positivity led to a diagnosis of systemic sclerosis (SSc). IFN has multiple effects on the immune system and is known to trigger the development of autoantibodies, as well as the onset or exacerbation of autoimmune disease. We suspect that the immunomodulatory effects of IFNalphacon-1 triggered the clinical manifestations of SSc in this patient. To our knowledge this is only the third case of SSc after IFNalpha therapy, and it is the first case associated with IFNalphacon-1 therapy.

Hepatocellular carcinoma with portal vein tumor thrombosis: clinical characteristics, prognosis, and patient survival analysis.

Hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is associated with a poor prognosis. New therapeutic modalities, such as continuous hepatic arterial infusion chemotherapy (CHAIC), have recently been reported to be promising strategies. The aim of this study was to evaluate the clinical characteristics, prognosis, and survival of patients with PVTT according to treatment regimen. One hundred ninety-three patients with HCC complicated with PVTT at the time of diagnosis were included in this study. All patients were newly diagnosed to have HCC and were observed from January 1992 to December 2003. CHAIC was performed using an implanted drug delivery system with low-dose cisplatin and 5-fluorouracil. Clinical characteristics, prognosis, and patient survival were analyzed by the Kaplan-Meier method and Cox's proportional hazards model. The mean age of the patients complicated with PVTT was 64.3+/-10.3 years (range, 20-88 years). The survival of the 193 patients with PVTT was 37.5%, 24.0%, 18.9%, and 8.3% at 1, 2, 3, and 5 years, respectively. According to treatment, the survival of patients who underwent surgical treatment was the best, followed by CHAIC, transcatheter arterial infusion/embolization, and supportive care. The 3-year survivals for each treatment regimen were 53.0%, 19.3%, 15.0%, and 4.0%, respectively. Although the survival of patients who received surgical treatment was best, such patients were restricted. There was no difference in survival between treated and untreated patients demonstrating Child-Pugh grade C. In Child B patients, treatment for HCC significantly increased survival (P<0.01). Cox's proportional hazards model revealed the Child-Pugh classification to be an independent prognostic factor for patients with HCC and PVTT (P<0.01). We conclude that the prognosis of HCC with PVTT was quite poor. The treatment did not improve the survival of Child C patients. As a result, the prevention, early diagnosis, and development of new treatment strategies are required.

Hepatocellular carcinoma in young adults: the clinical characteristics, prognosis, and findings of a patient survival analysis.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. However, HCC is rare in young Japanese patients and the clinical features of young patients with HCC have not yet been fully studied. This study was designed to determine the clinical characteristics and prognosis of patients with HCC who are younger than aged 40 years. A retrospective analysis was performed for patients newly diagnosed with HCC and observed from January 1990 to December 2003 at our hospitals. Patients younger than aged 40 years at the diagnosis of HCC were defined as the young group and were reviewed. There were 20 patients (16 males) with HCC who were younger than aged 40 years. The mean age at diagnosis was 33.6 (range, 20-39) years. Fifteen of 20 patients were positive for hepatitis B surface antigen (HBsAg) and 2 patients were positive for hepatitis C virus antibody. According to the Child-Pugh grading, the liver function was relatively good in all patients. Because most of the patients did not receive periodic follow-up, this disease often was discovered at an advanced stage, usually after the appearance of some symptoms. Although intensive treatment was performed for such young patients, the survival was nevertheless poor. Most patients died from this cancer within 1 year. However, one patient who received periodic follow-up and also was in relatively good physical condition had a better prognosis, and he survived for 88 months. Young patients with HCC tended to have a poor prognosis because of advanced stage of HCC, despite a well-preserved liver function and aggressive treatment. Screening for HCC and an early diagnosis is needed for such patients to demonstrate an improved prognosis, especially for HBsAg-positive patients.