Autopsy case of meningoencephalitis induced by nivolumab and ipilimumab in a patient being treated for non-small cell lung cancer.

A 75-year-old woman with stage IVB (cT2bN3M1b) lung adenocarcinoma was administered nivolumab, ipilimumab, carboplatin, and paclitaxel. Fourteen days after receiving chemotherapy, she experienced an impaired consciousness and a cerebrospinal fluid analysis revealed high protein levels and pleocytosis. She was diagnosed with nivolumab- and ipilimumab-induced encephalitis and was treated with corticosteroids which were tapered to 10 mg/day, with no symptom recurrence. She died 18 weeks after the initial presentation, as the cancer worsened. An autopsy showed encephalitis and CD8+ lymphocyte infiltration around the blood vessels. Thus, immune-related adverse events should be suspected and treatment should be initiated for patients presenting with an impaired consciousness when concurrently being treated with nivolumab and ipilimumab.

Successful ultrathin bronchoscopy with cryobiopsy for diagnosing and removing mucus plugs in allergic bronchopulmonary mycosis mimicking lung cancer.

In patients presenting with abnormal pulmonary nodules, especially those with a history of asthma, allergic bronchopulmonary mycosis should be considered. Eosinophil counts and IgE levels should be checked in such patients.

Secondary Pulmonary Alveolar Proteinosis Development during the Treatment for Anti-aminoacyl-tRNA Synthetase Antibody-positive Interstitial Lung Disease.

A 70-year-old woman with anti-aminoacyl-tRNA synthetase (ARS) antibody-positive interstitial lung disease (ARS-ILD) received daily medications and regular cyclophosphamide cycles for recurring exacerbations. Approximately four years after immunosuppression initiation, the patient was admitted for progressive dyspnea on exertion. Chest computed tomography (CT) findings were suggestive of acute exacerbation. Despite intensified immunosuppressive treatment, the radiographic findings worsened, and serum Krebs von den Lungen-6 (KL-6) levels increased. A bronchoalveolar lavage fluid (BALF) examination revealed amorphous globules and alveolar macrophages with eosinophilic granules. Owing to negative anti-GM-CSF antibody tests, a diagnosis of secondary pulmonary alveolar proteinosis (PAP) was established.

Image of a thawed frozen specimen obtained using a cryoprobe floated with oil droplets in normal saline: An endobronchial lipomatous hamartoma image.

Hereby, we present a rare case of a resected endobronchial tumour that floated or showed oil droplets in saline. In this study, we report an interesting image related to endobronchial lipomatous hamartoma cryotherapy.

ALLO-1- and IKKE-1-dependent positive feedback mechanism promotes the initiation of paternal mitochondrial autophagy.

Allophagy is responsible for the selective removal of paternally inherited organelles, including mitochondria, in Caenorhabditis elegans embryos, thereby facilitating the maternal inheritance of mitochondrial DNA. We previously identified two key factors in allophagy: an autophagy adaptor allophagy-1 (ALLO-1) and TBK1/IKKε family kinase IKKE-1. However, the precise mechanisms by which ALLO-1 and IKKE-1 regulate local autophagosome formation remain unclear. In this study, we identify two ALLO-1 isoforms with different substrate preferences during allophagy. Live imaging reveals a stepwise mechanism of ALLO-1 localization with rapid cargo recognition, followed by ALLO-1 accumulation around the cargo. In the ikke-1 mutant, the accumulation of ALLO-1, and not the recognition of cargo, is impaired, resulting in the failure of isolation membrane formation. Our results also suggest a feedback mechanism for ALLO-1 accumulation via EPG-7/ATG-11, a worm homolog of FIP200, which is a candidate for IKKE-1-dependent phosphorylation. This feedback mechanism may underlie the ALLO-1-dependent initiation and progression of autophagosome formation around paternal organelles.

Large-vessel vasculitis induced by pegfilgrastim and immune checkpoint inhibitor in a patient with small-cell lung cancer.

A 75-year-old woman with stage IVB (cT3N3M1c) extensive disease small-cell lung cancer was treated with carboplatin, etoposide, and atezolizumab. Ten days after pegfilgrastim initiation, during the second chemotherapy cycle, she experienced back pain. Contrast-enhanced computed tomography revealed soft tissue thickening around the descending aorta and brachiocephalic artery. She was diagnosed with atezolizumab and pegfilgrastim-induced large-vessel vasculitis (LVV) and was treated with prednisolone, which was tapered and discontinued after 14 weeks, with no symptom recurrence. LVV should be included in the differential diagnosis of patients with nonspecific body pain when pegfilgrastim and immune checkpoint inhibitors are used in combination.

Safety and effectiveness of SARS-CoV-2 vaccines for patients with intractable hepatobiliary diseases: A multicenter, questionnaire-based, cross-sectional study.

AIM: There are few data regarding the safety and effectiveness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with intractable hepatobiliary diseases. We conducted a multicenter, questionnaire-based, cross-sectional study to determine the safety and effectiveness of the SARS-CoV-2 vaccines in Japanese patients with intractable hepatobiliary disease. METHODS: Patients aged ≥18 years with autoimmune hepatitis (AIH), primary biliary cholangitis, primary sclerosing cholangitis, Budd-Chiari syndrome, idiopathic portal hypertension, and extrahepatic portal vein obstruction at each center were consecutively invited to join the study. Participants were asked to complete a questionnaire regarding their characteristics, vaccination status, post-vaccination adverse effects, and SARS-CoV-2 infection. Additionally, liver disease status, treatment regimens, and liver function test values pre- and post-vaccination were collected. RESULTS: The survey was conducted from September 2021 to May 2022, and 528 patients (220 AIH, 251 primary biliary cholangitis, 6 AIH- primary biliary cholangitis/primary sclerosing cholangitis overlap, 39 primary sclerosing cholangitis, 4 Budd-Chiari syndrome, 5 idiopathic portal hypertension, and 3 extrahepatic portal vein obstruction) participated in the study. Post-vaccination adverse effects were comparable to those observed in the general population. Post-vaccination liver injuries classified as grade 1 or higher were observed in 83 cases (16%), whereas grades 2 and 3 were observed in only six cases (1.1%); AIH-like liver injury requiring treatment was not observed. Overall, 12 patients (2.3%) were infected with SARS-CoV-2, and only one patient was infected 6 months after the second vaccination. CONCLUSION: SARS-CoV-2 vaccines demonstrated satisfactory safety and effectiveness in Japanese patients with intractable hepatobiliary diseases.

Effectiveness of AERO Stent Placement for Malignant Airway Disorder in Patients with a Poor Performance Status.

Objective Airway stenting is an established procedure for treating various airway disorders. The AERO stent (Merit Medical Systems, South Jordan, UT, USA) is a fully covered self-expandable metallic stent approved for use in Japan in 2014. However, its effectiveness in treating malignant airway disorders in patients with a poor performance status remains unclear. Therefore, we investigated the safety and efficacy of the AERO stent in patients with malignant airway disorders and a poor performance status. Patients and Methods We retrospectively reviewed the medical records of all patients who underwent AERO stent placement at our institute between April 2016 and March 2022, and 21 patients underwent 25 procedures for malignant airway disorders. All AERO stenting procedures were performed using an over-the-wire delivery system with flexible and/or rigid bronchoscopy. Results Eighteen of the 21 patients (85.7%) had a poor general condition (Eastern Cooperative Oncology Group performance status 3 or 4). AERO stents were successfully placed in 23 of the 25 procedures and migrated in the remaining 2 cases. Complications occurred in 10 cases, with infection being the most common (3 cases). Fourteen patients (66.6%) showed an improvement in their performance status. In addition, 5 of the 6 intubated patients were extubated following AERO stenting, and 11 patients subsequently received anticancer treatment. Conclusion The placement of the AERO stent is useful in patients with a poor performance status, including those who are intubated and afflicted with malignant airway disorders.

MARC-3, a membrane-associated ubiquitin ligase, is required for fast polyspermy block in Caenorhabditis elegans.

In many sexually reproducing organisms, oocytes are fundamentally fertilized with one sperm. In Caenorhabditis elegans, chitin layer formation after fertilization by the EGG complex is one of the mechanisms of polyspermy block, but other mechanisms remain unknown. Here, we demonstrate that MARC-3, a membrane-associated RING-CH-type ubiquitin ligase that localizes to the plasma membrane and cortical puncta in oocytes, is involved in fast polyspermy block. During polyspermy, the second sperm entry occurs within approximately 10 s after fertilization in MARC-3-deficient zygotes, whereas it occurs approximately 200 s after fertilization in egg-3 mutant zygotes defective in the chitin layer formation. MARC-3 also functions in the selective degradation of maternal plasma membrane proteins and the transient accumulation of endosomal lysine 63-linked polyubiquitin after fertilization. The RING-finger domain of MARC-3 is required for its in vitro ubiquitination activity and polyspermy block, suggesting that a ubiquitination-mediated mechanism sequentially regulates fast polyspermy block and maternal membrane protein degradation during the oocyte-to-embryo transition.

Successful prolonged treatment with sofosbuvir/velpatasvir for a hepatitis C patient with decompensated cirrhosis and treatment failure after 12-week therapy.

There is no established rescue therapy for hepatitis C patients with decompensated cirrhosis who experience treatment failure on 12-week sofosbuvir (SOF)/velpatasvir (VEL) therapy that is the only approved regimen for decompensated cirrhosis in Japan. We experienced a patient with decompensated cirrhosis who showed virologic relapse at post-treatment week 7 following 12-week SOF/VEL therapy. She had resistance-associated substitutions (RASs) against VEL before therapy but did not achieve new RASs against VEL or SOF after therapy. We considered rescue therapy following strong demand from her and her family. The drug adherence of therapy was 100%, and the treatment was well tolerated. Because we prioritized the safety and drug adherence of the regimen, we performed prolonged 24-week SOF/VEL therapy without ribavirin at her own expense with the approval of the ethics board in the hospital where the first author belongs. Fortunately, a sustained virologic response 24 was achieved without any adverse events. Hepatocellular carcinoma that had developed after 12-week SOF/VEL therapy recurred and was treated near the end of rescue therapy, but hepatic functional reserve improved. Although this was a single case report and was assumed to be very rare, the same regimen might be effective for treatment failure with 12-week SOF/VEL therapy.

Comparative Outcomes of Anterior and Posterior Plating for Distal-Third Humerus Shaft Fractures.

PURPOSE: When treating distal-third humerus shaft fractures (HSFs) surgically, the optimal approach for plating is controversial. We conducted a retrospective multicenter study to investigate and compare the clinical outcomes of anterior and posterior plating in distal-third HSFs and the incidence of complications including iatrogenic radial nerve palsy. METHODS: We identified 116 patients from our multicenter trauma database who were diagnosed as having distal-third HSFs and who underwent surgical treatment, including intramedullary nailing between 2011 and 2020. We analyzed 50 cases treated in one of two ways: open reduction internal fixation with anterior plating (group A: 20 cases) and open reduction internal fixation with posterior plating (group P: 30 cases). RESULTS: The findings were similar in terms of operation time, estimated bleeding, and clinical and radiographic outcomes between the groups. Postoperative radial nerve palsy occurred only in group P (4 cases) and never in group A. CONCLUSIONS: The results of this study suggest that the anterior approach is a safe and effective method for treating distal-third HSFs with satisfactory outcomes. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Successful Treatment with Mepolizumab for Coronary Spastic Angina Associated with Eosinophilic Granulomatosis with Polyangiitis.

A 46-year-old man with a history of bronchial asthma and chronic sinusitis presented to our hospital with chest pain. We suspected angina evoked by epicardial coronary spasm and performed an ergonovine provocation test to diagnose coronary spastic angina (CSA). The patient also met the diagnostic criteria for eosinophilic granulomatosis with polyangiitis (EGPA) and was treated with 60 mg prednisolone (PSL) for EGPA-associated CSA. After PSL administration, eosinophils decreased, and angina attacks disappeared. However, when PSL was tapered to 12.5 mg, chest pain recurred. We administered mepolizumab subcutaneously and chest pain disappeared. Additional mepolizumab may be effective for EGPA with CSA.

Partial liver irradiation in rats induces the hypertrophy of nonirradiated liver lobes through hepatocyte proliferation†.

Irradiation of the liver induces a regenerative response in the nonirradiated part of the liver. It is unclear whether this leads to actual liver enlargement. The aim of this study was to evaluate the weight of compensatory hypertrophy that occurs in nonirradiated livers and to clarify the mechanism of hypertrophy from the viewpoint of hepatocyte proliferation. The anterior liver lobes (anterior lobes) were irradiated with 60 Gy of X-rays (X60 Gy) under opening laparotomy. Body weights and liver lobe weights were measured before and at 1, 4, 8 and 12 weeks after irradiation, and serum and liver tissue samples were analyzed at each time point. The anterior lobes atrophied progressively, whereas the posterior liver lobes (posterior lobes) hypertrophied in the X-ray irradiated (X-irradiated) group. Although temporary liver damage was observed after irradiation, liver function did not decrease at any time point. Hepatocyte degeneration and loss were observed in the anterior lobes of the X-irradiated group, and significant fibrosis developed 8 weeks postirradiation. Following irradiation, the proportion of Ki-67-positive cells in the anterior lobes decreased markedly in the early postirradiation period, whereas the proportion of positive cells in the posterior lobes increased, peaking at 4 weeks postirradiation (P < 0.05). Increased tumor necrosis factor-α expression was observed only in the anterior liver lobes of the X-irradiated group at 1 and 4 weeks postirradiation. Partial liver irradiation with X60 Gy induced compensatory hypertrophy of nonirradiated liver lobes. This study suggests that liver hypertrophy after partial liver irradiation is caused by increased hepatocyte mitosis.

Establishment of prediction equations for subcutaneous tissue thickness in two representative intramuscular deltoid injections.

This study clarifies the predicted subcutaneous shoulder depth and investigates the safety of the conventional (three-finger breadth method) and new (axillary method) intramuscular injection methods. The anatomical features of 245 volunteers who received the COVID-19 vaccination via the conventional method were investigated at the injection site (T point) and the hypothetical injection site using the new method (A point) via ultrasonography. The body mass index (BMI) and subcutaneous thickness at the T point (men: r = 0.75; women: r = 0.45) and the A point (men: r = 0.81; women: r = 0.55) were positively correlated. The upper arm circumference and subcutaneous thickness at the T point (r = 0.51) and the A point (r = 0.58) were correlated in women. Formulas to predict subcutaneous thickness using BMI and upper arm circumference were established: predicted subcutaneous thickness at the A point = 0.62 × BMI - 7.7 mm (R2 = 0.66) in men and 0.658 × BMI - 5.5 mm (R2 = 0.31) in women. This study demonstrates safe intramuscular injection sites and their depth.

Retrospective multicenter (TRON group) study of humeral shaft fragility fractures: Analysis of mortality rates and risk factors.

AIMS: This study aimed to show the mortality rate following humeral shaft fragility fractures (HSFF) in the elderly. The secondary aim was to examine the predictors associated with mortality in elderly patients who have sustained HSFF. METHODS: From 2011 to 2020, all elderly patients aged 65 years and older with HSFF managed at our nine hospitals were retrospectively identified from our TRON database. Patient demographics and surgical characteristics were extracted from medical records and radiographs, and multivariable Cox regression analysis was used to identify factors affecting mortality. RESULTS: In total, 153 patients who sustained HSFF were included. The mortality rate for HSFF in the elderly was 15.7% at 1 year and 24.6% at 2 years. Multivariable Cox regression analysis showed significant differences in survival for the following variables: older age (p < 0.001), underweight (p = 0.022), severely ill (p = 0.025), mobility limited to indoors (p = 0.003), dominant-side injury (p = 0.027), and nonoperative treatment (p = 0.013). CONCLUSION: The outcome following HSFF in the elderly population appears to be relatively grim. The prognosis of elderly patients with HSFF is closely related to their medical history. In the elderly patients with HSFF, operative treatment should be positively considered while taking into account their medical status.

Sec16 and Sed4 interdependently function as interaction and localization partners at ER exit sites.

COPII proteins assemble at ER exit sites (ERES) to form transport carriers. The initiation of COPII assembly in the yeast Saccharomyces cerevisiae is triggered by the ER membrane protein Sec12. Sec16, which plays a critical role in COPII organization, localizes to ERES independently of Sec12. However, the mechanism underlying Sec16 localization is poorly understood. Here, we show that a Sec12 homolog, Sed4, is concentrated at ERES and mediates ERES localization of Sec16. We found that the interaction between Sec16 and Sed4 ensures their correct localization to ERES. Loss of the interaction with Sec16 leads to redistribution of Sed4 from the ERES specifically to high-curvature ER areas, such as the tubules and edges of the sheets. The luminal domain of Sed4 mediates this distribution, which is required for Sed4, but not for Sec16, to be concentrated at ERES. We further show that the luminal domain and its O-mannosylation are involved in the self-interaction of Sed4. Our findings provide insight into how Sec16 and Sed4 function interdependently at ERES.

[A case of extensive digestive tract metastasis from invasive lobular carcinoma of the breast].

A 59-year-old female patient underwent surgery for invasive lobular carcinoma of the right breast 12 years ago. The final diagnosis was invasive lobular carcinoma (T4N1M0 stage IIIB). She underwent chemotherapy, radiotherapy, and hormonal therapy after surgery. She had abdominal bloating and vomiting 12 years after surgery. Contrast-enhanced computed tomography (CECT) and esophagogastroduodenoscopy showed edematous thickening from the stomach to the duodenum and moderate amounts of ascites. Lymph node metastasis was not observed. Biopsy specimens of the stomach revealed signet ring cell carcinoma. Immunochemical studies (ER, GCDFP-15, MUC1, MUC5AC, and MUC6) confirmed gastroduodenal metastasis of invasive lobular carcinoma. Ascites disappeared after she underwent chemotherapy with paclitaxel and bevacizumab; however, wall thickening had spread from the lower esophagus to the stomach, small intestine, colon, and rectum on the CECT. She died 7 months after the diagnosis of gastroduodenal metastasis. Herein, we report a case of invasive lobular carcinoma of the breast with extensive digestive tract metastasis.

A Newly Developed Method-Based Xanthine Oxidoreductase Activities in Various Human Liver Diseases.

Studies evaluating xanthine oxidoreductase (XOR) activities in comprehensive liver diseases are scarce, and different etiologies have previously been combined in groups for comparison. To accurately evaluate XOR activities in liver diseases, the plasma XOR activities in etiology-based comprehensive liver diseases were measured using a novel, sensitive, and accurate assay that is a combination of liquid chromatography and triple quadrupole mass spectrometry to detect [13C2, 15N2]uric acid using [13C2, 15N2]xanthine as a substrate. We also mainly evaluated the association between the plasma XOR activities and parameters of liver tests, purine metabolism-associated markers, oxidative stress markers, and an inflammation marker. In total, 329 patients and 32 controls were enrolled in our study. Plasma XOR activities were generally increased in liver diseases, especially in the active phase, such as in patients with hepatitis C virus RNA positivity, those with abnormal alanine transaminase (ALT) levels in autoimmune liver diseases, and uncured hepatocellular carcinoma patients. Plasma XOR activities were numerically highest in patients with acute hepatitis B. Plasma XOR activities were closely correlated with parameters of liver tests, especially serum ALT levels, regardless of etiology and plasma xanthine levels. Our results indicated that plasma XOR activity might reflect the active phase in various liver diseases.

Platinum-based anticancer drugs-induced downregulation of myosin heavy chain isoforms in skeletal muscle of mouse.

Cisplatin, a platinum-based anticancer drug used frequently in cancer treatment, causes skeletal muscle atrophy. It was predicted that the proteolytic pathway is enhanced as the mechanism of this atrophy. Therefore, we investigated whether a platinum-based anticancer drug affects the expression of the major proteins of skeletal muscle, myosin heavy chain (MyHC). Mice were injected with cisplatin or oxaliplatin for four consecutive days. C2C12 myotubes were treated using cisplatin and oxaliplatin. Administration of platinum-based anticancer drug reduced quadriceps mass and muscle strength compared to the control group. Protein levels of all MyHC isoforms were reduced in the platinum-based anticancer drug groups. However, only Myh2 (MyHC-IIa) gene expression in skeletal muscle of mice treated with platinum-based anticancer drugs was found to be reduced. Treatment of C2C12 myotubes with platinum-based anticancer drugs reduced the protein levels of all MyHCs, and treatment with the proteasome inhibitor MG-132 restored this reduction. The expression of Mef2c, which was predicted to act upstream of Myh2, was reduced in the skeletal muscle of mice treated systemically with platinum-based anticancer drug. Degradation of skeletal muscle MyHCs by proteasomes may be a factor that plays an important role in muscle mass loss in platinum-based anticancer drug-induced muscle atrophy.