Lepidic Pulmonary Metastasis from Pancreatic Carcinoma Mimicking Organizing Pneumonia, Diagnosed by a Transbronchial Cryobiopsy.

A 78-year-old man with a history of pancreatic carcinoma underwent chest computed tomography (CT), which revealed a slowly enlarging consolidation in the right lower lobe. Forceps and percutaneous CT-guided lung biopsies showed no evidence of malignancy; therefore, organizing pneumonia was suspected. However, the patient's serum carbohydrate antigen 19-9 levels increased monthly, raising concerns about malignant lesions. A transbronchial cryobiopsy (TBCB) was performed to confirm the diagnosis of pulmonary metastasis of the pancreatic carcinoma. Pulmonary metastasis is an important differential diagnosis when chest CT shows consolidation, mimicking organized pneumonia. In addition, a TBCB can be a useful diagnostic tool for detecting lepidic growth patterns.

Successful treatment of type B2 thymoma with steroid and radiotherapy.

An 86-year-old woman with leg edema and dyspnea on exertion was admitted to our hospital. Chest computed tomography (CT) revealed a mass in the anterior mediastinum with pericardial invasion. Histological examination with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) led to the diagnosis of Masaoka stage IVa type B2 thymoma. For palliation, radiotherapy (32 Gy/16 fractions) and prednisolone (30 mg/day) were administered and tapered. After treatment, both the pericardial effusion and tumour size decreased. Combination therapy with steroids and radiotherapy may be effective for treating thymomas.

Safety and efficacy of airway stent placement following bronchial artery embolization: A retrospective study at a single institute.

BACKGROUND: Airway stenting is an established procedure for treating oncological emergencies in patients with airway disorders. In patients with airway hemorrhage, respiratory conditions may worsen during stenting. Bronchial artery embolization (BAE) is useful to prevent bleeding from the bronchus. We aimed to evaluate the efficacy and safety of airway stenting after BAE in patients with malignant airway disorders. METHODS: The medical records of all patients who underwent airway stenting following BAE at the National Hospital Organization Okayama Medical Center between 2016 and 2023 were retrospectively reviewed. RESULTS: Thirteen procedures (11 silicone Y stents, one hybrid stent, and one self-expandable metallic stent) were performed. The median duration from BAE to airway stenting was one day (range: 1-5 days). Nine patients experienced tumor shrinkage, and none experienced severe bleeding after BAE during the stent procedure. No other major complications were associated with the stent placement. The median survival time after stenting was 169 days (range; 24-1086). No serious complications caused by BAE, such as spinal cord infarction, were observed. CONCLUSIONS: Airway stent placement was safely performed after BAE without severe bleeding or acute respiratory failure. BAE, followed by airway stenting, is useful.

Granular Cell Tumor Mimicking Breast Carcinoma: A Report of Two Cases.

Granular cell tumor (GCT) of the breast is a rare neoplasm that can mimic the clinical and radiological features of breast carcinoma. This paper presents two case reports - a rare male case and a more common female case - to underline the diagnostic challenges posed by GCT in the breast. The male patient was initially suspected of having a breast tumor based on mammography and ultrasound findings. The female patient also exhibited radiological signs suggestive of breast cancer. In both cases, the mammograms showed irregular lesions, while ultrasounds revealed solid masses with posterior shadowing and echogenic halos, mimicking carcinoma. Dynamic contrast-enhanced magnetic resonance imaging (MRI) suggested benign patterns in both cases, but only histopathologic examination post-core needle biopsy confirmed the diagnosis of GCT. These cases highlight the variability of GCT imaging presentations and the potential for misdiagnosis as breast carcinoma. The tumors exhibited distinct histopathological features, such as large polygonal cells with granular eosinophilic cytoplasm and S100 protein, differentiating them from breast carcinoma. However, imaging alone proved insufficient for diagnosis, emphasizing the need for histopathologic confirmation. The report discusses the importance of including GCT in differential diagnoses and utilizing core needle biopsy for accurate evaluation. Both cases had no recurrence during follow-up after wide resection, indicating a favorable prognosis for GCT when properly managed.

Airway stenosis secondary to mediastinal lymph node metastasis of lung adenocarcinoma treated with AERO stent and osimertinib: A case report.

A woman in her mid-50s was admitted to our hospital with airway stenosis secondary to mediastinal lymph node enlargement. An AERO stent was placed under rigid bronchoscopy. Immediately after stent placement, tissue sampling was performed on the lymph nodes. Metastatic lesions were found to have an EGFR mutation (exon 19 deletion). Consequently, osimertinib treatment was initiated 15 days after stent placement. The tumour partially responded to osimertinib, and the airway stenosis improved. The patient underwent stent removal 66 days after stent placement. Our findings indicate that temporary oncological emergencies due to airway stenosis may be bridged by airway stenting.

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.

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.

Granulocyte-Colony Stimulating Factor (G-CSF)-Induced Aortitis: A Case Report.

Pegylated granulocyte colony-stimulating factor (G-CSF), commonly used in chemotherapy-induced neutropenia, has been associated with rare instances of aortitis. This study describes a 67-year-old female patient with estrogen receptor (ER)-positive, human epidermal growth factor receptor-2-positive breast cancer, undergoing chemotherapy with an epirubicin/cyclophosphamide (EC) regimen (epirubicin, cyclophosphamide) and pegylated G-CSF for neutropenia prophylaxis. Post-treatment, she developed symptoms including intermittent fever and severe arthralgia. Laboratory tests revealed an elevated white blood cell count, C-reactive protein levels, and erythrocyte sedimentation rate, while a computed tomography scan showed thickening in the aortic arch and descending aorta. Given the clinical presentation and exclusion of other potential causes, pegylated G-CSF-induced aortitis was suspected. The patient's symptoms improved significantly following the cessation of pegylated G-CSF, aiding in the differentiation from other types of aortitis. This study highlights the importance of considering pegylated G-CSF as a potential cause of aortitis in patients presenting with unexplained symptoms of fever and inflammation after chemotherapy. The rapid improvement upon discontinuation of the drug is a key feature distinguishing it from other aortitis causes. In conclusion, while rare, aortitis should be considered in the differential diagnosis of patients treated with pegylated G-CSF who exhibit relevant clinical symptoms. Early detection and management, including the discontinuation of the causative agent, are crucial for patient recovery and prognosis.

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.

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.

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, 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. 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.

Effect of lemborexant on pharmacokinetics of clozapine: A potential drug-drug interaction mediated by time-dependent inhibition of CYP3A4.

Clozapine (CLZ) is extensively used for treatment-resistant schizophrenia (TRS) with caution to avoid serious adverse events such as agranulocytosis and drug-drug interactions (DDIs). In the current report, we present a case of a 35-year-old male non-smoking TRS patient whose steady-state plasma trough concentrations (Ctrough ) of CLZ and its active metabolite, N-desmethylclozapine (NDMC), were significantly increased after initiating oral administration of lemborexant (LEM), a dual orexin receptor antagonist, for the treatment of insomnia. The patient experienced oversedation with sleepiness and fatigue while maintaining high levels of Ctrough of CLZ. The increased concentrations of CLZ returned to normal ranges after the discontinuation of LEM dosing, implying a pharmacokinetic DDI between CLZ and LEM. To gain insight into possible mechanisms, we performed in vitro assays of CYP1A2- and CYP3A4-mediated CLZ metabolism by measuring the formations of NDMC and clozapine N-oxide (CNO). In accordance with previous studies, the incubation of CLZ with each enzyme resulted in the production of both metabolites. LEM had only a weak inhibitory effect on CYP1A2- and CYP3A4-mediated CLZ metabolism. However, the preincubation of LEM with CYP3A4 in the presence of NADPH showed a significant enhancement of inhibitory effects on CLZ metabolism with IC50 values for the formations of CNO and NDMC of 2.8 µM and 4.1 µM, respectively, suggesting that LEM exerts as a potent time-dependent inhibitor for CYP3A4. Taken together, the results of the current study indicate that co-medication of CLZ with LEM may lead to increase in exposure to CLZ and risks of CLZ-related adverse events.

Risk factors for late recurrence and postrelapse survival in estrogen receptor (ER)-positive, human epidermal growth factor receptor (HER) 2-negative breast cancer after 5 years of endocrine therapy.

It is unclear which patients with ER-positive, HER2-negative breast cancer benefit from extended endocrine therapy beyond 5 years. Prognostic factors for late-recurring breast cancer postrelapse survival have been reported. We retrospectively analyzed data from 892 patients with ER-positive and HER2-negative invasive breast cancer who were disease-free after completing a 5-year adjuvant endocrine therapy. Patients were then classified as high-risk (positive lymph nodes, large tumor size, high tumor grade) or low-risk. High-risk patients were divided into extended endocrine therapy and stop groups. Comparisons were made using propensity score matching, and the benefits of extended endocrine therapy for high-risk patients and prognostic factors for postrelapse survival were assessed. The high- and low-risk groups comprised 444 and 448 patients, respectively. The 10-year distant disease-free survival (DDFS) rates were 96.3 % (95 % confidence interval [CI] 0.912-0.985) and 86.5 % (95 % CI 0.798-0911) in the extended and stop groups, respectively (P = 0.00382). Cox proportional hazards model revealed that extended endocrine therapy promoted greater reduction in distant metastasis risk than 5-year endocrine therapy in high-risk populations (hazard ratio [HR] 0.27; 95 % CI 0.11-0.68; P = 0.0054). Postrelapse survival was significantly different in patients with DDFS ≥7 years (HR 0.24; 95 % CI 0.072-0.81; P = 0.021) and those with better response to first-line treatment (HR 0.072; 95 % CI, 0.058-0.90; P = 0.041). Patients with risk factors for late recurrence should be considered for extended endocrine therapy. Longer DDFS and response to first-line treatment may be a prognostic factor for postrelapse survival after late recurrence.

Public RNA-seq data-based identification and functional analyses reveal that MXRA5 retains proliferative and migratory abilities of dental pulp stem cells.

Dental pulp stem cells (DPSC) usually remain quiescent in the dental pulp tissue; however, once the dental pulp tissue is injured, DPSCs potently proliferate and migrate into the injury microenvironment and contribute to immuno-modulation and tissue repair. However, the key molecules that physiologically support the potent proliferation and migration of DPSCs have not been revealed. In this study, we searched publicly available transcriptome raw data sets, which contain comparable (i.e., equivalently cultured) DPSC and mesenchymal stem cell data. Three data sets were extracted from the Gene Expression Omnibus database and then processed and analyzed. MXRA5 was identified as the predominant DPSC-enriched gene associated with the extracellular matrix. MXRA5 is detected in human dental pulp tissues. Loss of MXRA5 drastically decreases the proliferation and migration of DSPCs, concomitantly with reduced expression of the genes associated with the cell cycle and microtubules. In addition to the known full-length isoform of MXRA5, a novel splice variant of MXRA5 was cloned in DPSCs. Recombinant MXRA5 coded by the novel splice variant potently induced the haptotaxis migration of DPSCs, which was inhibited by microtubule inhibitors. Collectively, MXRA5 is a key extracellular matrix protein in dental pulp tissue for maintaining the proliferation and migration of DPSCs.

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.

Efficient drug delivery to lymph nodes by intradermal administration and enhancement of anti-tumor effects of immune checkpoint inhibitors.

Immune checkpoint inhibitors are novel immunotherapy drugs that have improved cancer treatments. Yet only a small percentage of patients experience durable responses to immune checkpoint inhibitors. Recently, it has been suggested that lymph nodes are important for the efficacy of immunotherapy. However, it is still unclear whether the efficient anti-PD-L1 antibody delivery to tumor-draining lymph nodes improves drug efficacy. In this study, we first characterized lymphatic drug delivery by intradermal administration compared with conventional subcutaneous and systemic administration in rodents and non-human primates. The results confirmed that intradermal administration of immune checkpoint inhibitors is suitable for efficient delivery to the tumor-draining lymph node. In FM3A and EMT6 tumor mice models with different PD-L1 expressions in tumor, efficient delivery of anti-PD-L1 antibody to tumor-draining lymph node by intradermal administration resulted in efficient inhibition of tumor growth in both models. The intradermal administration of low-dose anti-PD-L1 antibody also significantly suppressed tumor growth compared to intraperitoneal administration. It also suppressed tumor growth regardless of PD-L1 expression in tumors, suggesting the importance of blocking PD-L1 in tumor-draining lymph nodes. Hence, efficient delivery by intradermal administration of anti-PD-L1 antibody to tumor-draining lymph node might to be helpful to enhance drug efficacy and potentially reduce adverse events.

Congenital Anomalies in Infants in Fukushima from 2011 to 2014: The Japan Environment and Children's Study.

Introduction: This study aimed to assess congenital anomalies among infants from 2011 to 2014 in Fukushima and compare the assessment with that from other geographical regions in Japan. Methods: We used the dataset of the Japan Environment and Children's Study (JECS), which is a nationwide prospective birth cohort study. For the JECS, participants were recruited through 15 regional centers (RC), including Fukushima. Pregnant women were recruited between January 2011 and March 2014. The Fukushima RC recruited all municipalities in the Fukushima Prefecture, from where we compared congenital anomalies in infants from the Fukushima RC to those in the infants from 14 other RCs. Crude and multivariate logistic regression analyses were also performed, with the multivariate logistic regression analysis being adjusted for maternal age, maternal body mass index (kg/m2), infertility treatment, multiple pregnancies, maternal smoking, maternal alcohol consumption, pregnancy complications, maternal infection, and infant sex. Results: In the Fukushima RC, 12,958 infants were analyzed, and 324 infants were diagnosed with major anomalies (2.50%). In the remaining 14 RCs, 88,771 infants were analyzed and 2,671 infants were diagnosed with major anomalies (3.01%). Crude logistic regression analysis demonstrated that the odds ratio for the Fukushima RC was 0.827 (95% confidence interval, 0.736-0.929) using the other 14 RCs as a reference. Multivariate logistic regression analysis also demonstrated that the adjusted odds ratio was 0.852 (95% confidence interval, 0.757-0.958). Conclusions: Fukushima Prefecture was found not to be an area at high risk for the occurrence of congenital anomalies in infants compared nationwide in Japan from 2011 to 2014.

Pharmacological Activation of YAP/TAZ by Targeting LATS1/2 Enhances Periodontal Tissue Regeneration in a Murine Model.

Due to their multi-differentiation potential, periodontal ligament fibroblasts (PDLF) play pivotal roles in periodontal tissue regeneration in vivo. Several in vitro studies have suggested that PDLFs can transmit mechanical stress into favorable basic cellular functions. However, the application of mechanical force for periodontal regeneration therapy is not expected to exhibit an effective prognosis since mechanical forces, such as traumatic occlusion, also exacerbate periodontal tissue degeneration and loss. Herein, we established a standardized murine periodontal regeneration model and evaluated the regeneration process associated with cementum remodeling. By administering a kinase inhibitor of YAP/TAZ suppressor molecules, such as large tumor suppressor homolog 1/2 (LATS1/2), we found that the activation of YAP/TAZ, a key downstream effector of mechanical signals, accelerated periodontal tissue regeneration due to the activation of PDLF cell proliferation. Mechanistically, among six kinds of MAP4Ks previously reported as upstream kinases that suppressed YAP/TAZ transcriptional activity through LATS1/2 in various types of cells, MAP4K4 was identified as the predominant MAP4K in PDLF and contributed to cell proliferation and differentiation depending on its kinase activity. Ultimately, pharmacological activation of YAP/TAZ by inhibiting upstream inhibitory kinase in PDLFs is a valuable strategy for improving the clinical outcomes of periodontal regeneration therapies.

Real world research on transcranial magnetic stimulation treatment strategies for neuropsychiatric symptoms with long-COVID in Japan.

The number of patients suffering from long-COVID is currently increasing rapidly, even after the acute symptoms of COVID-19 have improved. The objective of this study was to investigate the effects of a pilot transcranial magnetic stimulation (TMS) treatment on neuropsychiatric symptoms caused by long-COVID. In this study, we examined the efficacy of the TMS treatment protocol, which has been established to be effective in refractory depression, by applying it to patients who sought TMS treatment for neuropsychiatric symptoms caused by long-COVID at TMS clinics in Tokyo, Japan in the context of the real world TMS registry study in Japan. Of the 23 patients (13 females) with long-COVID included in this case series, the main neuropsychiatric symptoms were chronic fatigue (n = 12) and cognitive dysfunction (n = 11), but most patients also showed mild depressive symptoms. The mean score on the Montgomery-Åsberg Depression Rating Scale before TMS treatment was 21.2, which improved to 9.8 after treatment. Similarly, the score on the Performance Status, which assesses the degree of fatigue, improved from 5.4 to 4.2, and the score on the Perceived Deficits Questionnaire-Depression 5-item, which reflects cognitive function, improved from 10.0 to 6.3. Although a few patients complained of pain at the stimulation site during the TMS as a side effect, there were no serious adverse events. Despite the limitations of this open-label pilot study, the TMS protocol implemented in this study may have beneficial effects on neuropsychiatric symptoms caused by long-COVID, including depressive symptoms, chronic fatigue, and cognitive impairment. These preliminary findings warrant further validation in randomized controlled trials.

Tobacco Exposure During Pregnancy and Infections in Infants up to 1 Year of Age: The Japan Environment and Children's Study.

BACKGROUND: Tobacco exposure during pregnancy is associated with several adverse outcomes in infants. We investigated the association between tobacco exposure during pregnancy (both active and second-hand) and various infections in infants up to 1 year. METHODS: This prospective cohort study used a fixed dataset (jecs-an-20180131) from the Japan Environment and Children's Study of registered births in Japan during 2011-2014 that included 104,065 fetal records from enrolled pregnant women. Based on the participants' responses to the questionnaire on smoking status, mothers were first divided into "never smoked," "quit smoking," and "current smoker" groups and then into "no second-hand smoking (SHS)" and "SHS" groups. Infectious diseases included central nervous system infection, otitis media (OM), upper respiratory tract infection (URTI), lower respiratory tract infection (LRTI), gastroenteritis (GI), and urinary tract infection. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated using logistic regression analysis and adjusted for maternal, socioeconomic, and postnatal confounding factors. RESULTS: Among the 73,205 newborns enrolled, multivariable analysis revealed that the aOR of LRTI and GI was 1.20 (95% CI, 1.07-1.33) and 1.18 (95% CI, 1.04-1.35), respectively, for the "current smoker with/without SHS" group compared with the "never smoked without SHS" group. "Quit smoking without SHS" was not associated with the risk of LRTI. SHS was associated with an increased risk of OM, URTI, LRTI, and GI, especially with LRTI and GI. CONCLUSION: Exposure to tobacco smoke during pregnancy was associated with an increased risk of OM, URTI, LRTI, and GI in infants during their first year of life.