Carnosol suppresses interleukin-6 production in mouse lungs injured by ischemia-reperfusion operation and in RAW264.7 macrophages treated with lipopolysaccharide.

Carnosol is a naturally occurring herbal compound, known for its antioxidative properties. We previously found that carnosol protected mouse lungs from ischemia-reperfusion injury in ex vivo cultures. To elucidate the molecular mechanisms underpinning carnosol-mediated lung protection, we analyzed modes of interleukin-6 (IL-6) gene expression, which is associated with lung ischemia-reperfusion injury. Microarray analysis of mouse lungs suggested that IL-6 mRNA levels were elevated in the mouse lungs subjected to clamp-reperfusion, which was associated with elevated levels of other inflammatory modulators, such as activating transcription factor 3 (ATF3). Carnosol pretreatment lowered the IL-6 protein levels in mouse lung homogenates prepared after the clamp-reperfusion. On the other hand, the ATF3 gene expression was negatively correlated with that of IL-6 in RAW264.7 cells. IL-6 mRNA levels and gene promoter activities were suppressed by carnosol in RAW264.7 cells, but rescued by ATF3 knockdown. When RAW264.7 cells were subjected to hypoxia-reoxygenation, carnosol treatment lowered oxygen consumption after reoxygenation, which was coupled with a correlation with a transient production of mitochondrial reactive oxygen species and following ATF3 gene expression. These results suggest that carnosol treatment could be a new strategy for protecting lungs from ischemia-reperfusion injury by modulating the ATF3-IL-6 axis.

Disseminated Penicillin-Resistant Streptococcus pneumoniae Infection: A Case Report.

An invasive pneumococcal disease involving sternoclavicular joint arthritis, lumbar spondylodiscitis, and muscular abscesses caused by penicillin-resistant Streptococcus pneumoniae has not been reported previously. We successfully treated a 57-year-old man with this condition using surgical drainage and debridement, and laminectomy/fenestration, in combination with the administration of two IV antimicrobial drugs based on blood culture results. Clinical resolution was obtained after decompression of the lumbar spine, with minimal restriction of the left lower limb. This treatment approach should be considered depending on the pathogen, underlying host factors, and the severity of the disease.

Possible thoracic metastasis from squamous cell carcinoma of the external auditory canal: A case report.

An 80-year-old never-smoking woman, who underwent radiotherapy in combination with simultaneous intra-arterial chemotherapy for external auditory canal squamous cell carcinoma (SCC) 10 years ago, was referred to our department due to a painful huge chest wall tumor. We conducted surgical resection combined with the right upper lobe and chest wall including the 3rd to 5th ribs and affected serratus anterior muscle. Histologically, atypical keratotic cells with the same morphology as external auditory canal SCC proliferated without the figure of carcinoma in situ or squamous dysplasia of the bronchial epithelium of the lung parenchyma adjacent to the tumor. Take Home Message: If long-term imaging follow-up had been performed, it would have been easier to detect it early and differentiate it from metastasis or primary lung cancer.

Malignant involvement of the iliopsoas muscle associated with non-small cell lung cancer: Two case reports.

Under the current progression of molecular targeting or immune therapy, early detection and radiation therapy of iliopsoas metastasis will not only improve performance status but also enable the continuation of effective systemic cancer treatment.

Long-term treatment with ALK inhibitors for postoperative recurrence of ALK-rearranged lung cancer.

We encountered a 40-year-old female patient who developed, in chronological order, carcinomatous pleuritis and lymphangitis, multiple lymph node metastases, brain metastases, and intramedullary spinal cord metastases after resection of lung adenocarcinoma followed by adjuvant chemotherapy. Echinoderm microtubule-associated protein-like 4 (EML4) and the anaplastic lymphoma kinase (ALK) fusion gene, variant 2 was identified in her cancer cells. By changing the ALK inhibitors from the 1st to 3rd generation each time when metastases were identified and incorporating local treatments in a timely fashion, such as metastasectomy or radiation therapy, she has survived for more than 11 years since the start of treatment, while maintaining a good Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score of 0. To our knowledge, this is the first reported case in which ALK fusion variant 2 was identified and prolonged disease control was achieved with the continuous prescription of ALK tyrosine kinase inhibitors (TKIs) and timely consolidative treatments.

[A case of liver tumor diagnosed 5 years after gastrectomy against gastric cancer].

A-62-year-old man with gastric cancer underwent gastrectomy 5 years ago, and an abdominal computed tomography scan detected a 15 mm early enhanced lesion located liver (S8) in 2008. Although primary or metastatic were unclear, we underwent partial hepatectomy( S8) as it was an isolated liver tumor. Pathological finding showed adenocarcinoma, and immunostaining was negative for cytokeratin (CK) 7 and positive for CK20 which was the same in primary gastric cancer, so it was diagnosed liver metastasis of gastric cancer. The patient was living at the time, but he passed away 24 months after hepatectomy. We report herein the case of resectable case of liver tumor 5 years after gastrectomy against gastric cancer.

The histological diagnosis and molecular testing of lung cancer by surgical biopsy for intrathoracic lesions.

OBJECTIVES: Accurate histological diagnosis and molecular testing using a sufficient tumor sample of advanced lung cancer, especially non-small cell lung cancer (NSCLC), are crucial for precision medicine. The aim of this study was to assess the feasibility and safety of surgical biopsy for intrathoracic lesions, and, in addition, overall survival after surgical biopsy. METHODS: One hundred-one patients who underwent surgical biopsy for intrathoracic lesions of lung cancer at our hospital between 2011 and 2019 were retrospectively reviewed. Their clinical and pathologic records were reviewed. In addition to evaluating the oncologic safety of the surgical biopsy, the overall survival based on the biopsy results was estimated. RESULTS: The total number of surgical sites of the 101 patients was 131, and common biopsy sites were the lungs (82, 62.6%) followed by hilar/mediastinal lymph nodes (27, 20.6%). There were 13 postoperative complications (12.9%) without surgery-related deaths. The median time from surgical biopsy to the initiation of treatment was 27 days. Appropriate amounts of specimens for diagnosis and molecular testing were obtained from all patients (100%). When limited to treatment-naïve patients with stage IV adenocarcinoma, patients treated with tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs) based on molecular testing had a better prognosis. CONCLUSIONS: Surgical biopsy for intrathoracic lesions of lung cancer may be a safe and effective method to make a definitive diagnosis, including companion diagnostics for advancing precision therapy in selected patients with inoperable advanced NSCLC.

[Idiopathic thrombocytopenic purpura during chemotherapy for liver metastasis of rectal cancer].

UNLABELLED: Neoadjuavnt chemotherapy for liver metastasis of colorectal cancer implies issues about timing for resection and management for adverse events due to chemotherapy. CASE: A 50-year-old male patient with synchronous liver metastasis from rectal cancer had a surgery for primary lesion followed by neo-adjuvant chemotherapy for liver resection. Chemotherapy of bevacizumab + mFOLFOX6 achieved a partial response for liver metastasis. When we planned a liver resection, platelet count decreased to 1.4 × 10(4)/µL. The patient was diagnosed as idiopathic thrombocytopenic purpura (ITP) by several examinations but medical control including steroids failed. Partial splenic artery embolization could recover platelet count successfully. However, during the period of therapy for ITP, liver metastasis became unresectable. The patient is currently treated by FOLFIRI and with stable disease for three months. CONCLUSION: NeoPyloriadjuvant chemotherapy for respectable liver metastasis should be considered carefully in terms of timing for resection and prompt management for adverse events.

Surgery to avoid fatal complications and secure radicality after definitive chemoradiotherapy for clinical T4N2M0 stage IIIB non-small cell lung cancer: a case report.

BACKGROUND: Chemoradiotherapy (CRT) is the standard treatment for c-stage IIIB non-small cell lung cancer (NSCLC); however, patients who respond to CRT are at risk of developing fatal complications such as massive hemoptysis or infection. In such cases, surgery is an alternative option. Currently, there are limited reports on surgery for complications arising during definitive CRT for locally advanced NSCLC. We report a case of hemoptysis after definitive CRT for c-T4N2M0 stage IIIB NSCLC that was successfully treated with lower bilobectomy combined with left atrial resection. CASE PRESENTATION: A 72-year-old man with c-T4N2M0 stage IIIB NSCLC with left atrial invasion developed hemoptysis during CRT, which was discontinued to control hemoptysis. Chest computed tomography revealed a regressed and cavitated tumor. Three weeks after discontinuation of CRT, surgery was performed to avoid fatal complications and secure radicality. We performed lower bilobectomy combined with partial left atrial resection, which was performed using an automatic tri-stapler. The bronchial stump was covered with an omental flap. The resected specimen pathologically showed complete response with fistula between the intermediate bronchus and necrotic cavity in the tumor. His postoperative course was uneventful, and the patient was disease free at 10 months after surgery. CONCLUSIONS: We successfully performed surgery after definitive CRT in a patient with c-T4N2M0 stage IIIB NSCLC. Partial left atrial resection was safely performed with an automatic tri-stapler. A complete pathological response to CRT was achieved. In a case with a chance of complete (R0) resection, when the risk of developing fatal complications might outweigh the risk of post-CRT surgery perioperative complications, surgery should be considered as a treatment option.

Efficient Differentiation of Mouse Induced Pluripotent Stem Cells into Alveolar Epithelium Type II with a BRD4 Inhibitor.

Regenerative medicine has continued to progress for lung biology and lung diseases. Efforts have focused on a variety of different applications for pluripotent stem cells. Several groups have reported successful methods for inducing differentiation of induced pluripotent stem cells (iPSCs) into the airway epithelium such as alveolar epithelium type II (ATII). However, differentiation efficiency varies among reports and improvements are needed. In the present paper, we propose a novel method for elimination of residual undifferentiated murine iPSCs using JQ1, a potent inhibitor of bromodomain (BRD) and extraterminal domain (BET) family proteins, for efficient differentiation into ATII. First, the murine iPSC line 20D-17 was induced to differentiate into ATII over a period of 26 days (days 0-26) using previously reported embryoid body seeding and stepwise differentiation methods. mRNA expressions of differentiation markers including surfactant protein C (Sftpc) were confirmed by real-time reverse transcription-polymerase chain reaction (RT-PCR) results, and 17% of the cells were shown positive for prosurfactant protein C (proSPC) in flow cytometry analysis. Next, those cells were cultured three-dimensionally in Matrigel for an additional 14 days (days 26-40), during which JQ1 was added for 4 days (days 28-32) to remove residual undifferentiated iPSCs. As a result, on day 40, the mRNA expression level of Sftpc in the three-dimensional culture was maintained at the same level as on day 26 and shown to be further increased by the addition of JQ1, with 39% of the cells found to express proSPC, showing that differentiation efficiency could be further increased. Three-dimensional culture with BRD4 inhibition by JQ1 improved the differentiation induction efficiency to ATII by removing residual undifferentiated murine iPSCs during the differentiation induction process.

Adipose Tissue-Derived Stem Cells Have the Ability to Differentiate into Alveolar Epithelial Cells and Ameliorate Lung Injury Caused by Elastase-Induced Emphysema in Mice.

Chronic obstructive pulmonary disease is a leading cause of mortality globally, with no effective therapy yet established. Adipose tissue-derived stem cells (ADSCs) are useful for ameliorating lung injury in animal models. However, whether ADSCs differentiate into functional cells remains uncertain, and no study has reported on the mechanism by which ADSCs improve lung functionality. Thus, in this study, we examined whether ADSCs differentiate into lung alveolar cells and are able to ameliorate lung injury caused by elastase-induced emphysema in model mice. Here, we induced ADSCs to differentiate into type 2 alveolar epithelial cells in vitro. We demonstrated that ADSCs can differentiate into type 2 alveolar epithelial cells in an elastase-induced emphysematous lung and that ADSCs improve pulmonary function of emphysema model mice, as determined with spirometry and 129Xe MRI. These data revealed a novel function for ADSCs in promoting repair of the damaged lung by direct differentiation into alveolar epithelial cells.