Using hemoglobin vesicles to treat operative hemorrhagic shock after pneu- monectomy in dog models: an experimental study.

Hemoglobin vesicles (HbVs), considered as red blood cell substitutes, are liposomes encapsulating purified hemoglobin, with a phospholipid bilayer membrane (diameter: 250 nm; P50, 28 Torr). In this study, we aimed to investigate HbV function during hemorrhagic shock in lung resection and analyze the details of oxygen delivery. Left pneumonectomy was performed in dogs under mechanical ventilation, followed by rapid exsanguination of approximately 30% of the total circulating blood volume, which led to shock, reducing the mean arterial pressure (MAP) by approximately 60% of baseline. Subsequently, either 5% human serum albumin (HSA) or HbVs suspended in 5% HSA were infused for resuscitation. The MAP only recovered to 75% of baseline after HSA administration, but fully recovered (100%) after HbV administration, with significant differences between the groups (P < 0.005). Oxygen delivery was restored in the HbV group and was significantly higher than that in the HSA group (P < 0.0001). The infusion of HbVs dispersed in a 5% HSA solution compensated for the rapid loss of approximately 30% of the total circulating blood volume in a dog pneumonectomy model, even with impaired lung function. Thus, HbVs can be used for resuscitation from hemorrhagic shock during thoracic surgery.

Significance of ZO-1, an Intercellular Adhesion Molecule, as a Prognostic Marker in Lung Adenocarcinoma.

In epithelial tissues, intercellular adhesion structures are formed between adjacent cells via intercellular adhesion factors, such as zonula occludens (ZO-1), to maintain the structure and function of tissues and organs, thereby contributing to homeostasis. Epithelial cells are polarized into apical and basal regions by tight junctions (TJs), a type of intercellular adhesion structure, and thus, their intracellular organelles are asymmetrically distributed. Normal epithelial cells maintain their cellular function by controlling cytoskeletal reorganization, motility, and division by maintaining asymmetry in their intracellular organelles. Among the features common to many cancer tissues are abnormalities in cell polarity and intercellular adhesion. Lung adenocarcinoma consists of a mixture of five different histologic types that can be distinguished in the same section: lepidic, papillary, acinar, micropapillary, and solid patterns. Therefore, it is often difficult to accurately assess histological images because the staining differs according to the histological types. In the present study, we evaluated ZO-1 staining based on histological features observed in a single section and examined its relationship to clinicopathological features. In non-tumor areas, ZO-1 was expressed on the plasma membrane and in the cytoplasm of normal alveolar epithelial cells. However, in tumor areas, ZO-1 staining was mainly localized in the cytoplasm and on the plasma membrane only in a few cells. ZO-1-negative cases tended to have poorer prognoses in all histological types, with a poorer prognosis in the solid pattern. These results suggest that ZO-1 expression in solid-pattern lung adenocarcinoma may be a useful prognostic marker.

Refractory Pneumothorax Due to Cystic Pulmonary Metastasis of a Lowgrade Endometrial Stromal Sarcoma: A Case Report.

Low-grade endometrial stromal sarcoma (LG-ESS) is a rare uterine neoplasm. Computed tomography (CT) revealed the presence of multiple small bilateral pulmonary nodules in a 58-year-old woman 1 year after surgery for LG-ESS; the clinical diagnosis was pulmonary metastasis. Hormone therapy with progesterone was initiated, after which most of the solid nodules disappeared and some transformed into cystic lesions. Seven years after hormone therapy, the patient experienced repeated pneumothorax. The cause of the pneumothorax was perforation of a metastatic focus within the wall of a small subpleural cyst that was not evident on CT images.

Phylogenetic diversity, distribution, and gene structure of the pyruvic oxime dioxygenase involved in heterotrophic nitrification.

Some heterotrophic microorganisms carry out nitrification to produce nitrite and nitrate from pyruvic oxime. Pyruvic oxime dioxygenase (POD) is an enzyme that catalyzes the degradation of pyruvic oxime to pyruvate and nitrite from the heterotrophic nitrifying bacterium Alcaligenes faecalis. Sequence similarity searches revealed the presence of genes encoding proteins homologous to A. faecalis POD in bacteria of the phyla Proteobacteria and Actinobacteria and in fungi of the phylum Ascomycota, and their gene products were confirmed to have POD activity in recombinant experiments. Phylogenetic analysis further classified these POD homologs into three groups. Group 1 POD is mainly found in heterotrophic nitrifying Betaproteobacteria and fungi, and is assumed to be involved in heterotrophic nitrification. It is not clear whether group 2 POD, found mainly in species of the Gammaproteobacteria and Actinobacteria, and group 3 POD, found simultaneously with group 1 POD, are involved in heterotrophic nitrification. The genes of bacterial group 1 POD comprised a single transcription unit with the genes related to the metabolism of aromatic compounds, and many of the genes group 2 POD consisted of a single transcription unit with the gene encoding the protein homologous to 4-hydroxy-tetrahydrodipicolinate synthase (DapA). LysR- or Cro/CI-type regulatory genes were present adjacent to or in the vicinity of these POD gene clusters. POD may be involved not only in nitrification, but also in certain metabolic processes whose functions are currently unknown, in coordination with members of gene clusters.

Minimally invasive surgery for anterior flail chest injury in the acute phase: series of 10 cases.

OBJECTIVE: Anterior flail chest frequency represents a significant case of ventilator insufficiency. Surgical stabilization of acute phase of trauma is considered to effectively shorten the period of ventilation compared to conservative treatment using mechanical ventilation. We have applied minimally invasive surgery to stabilize the injured chest wall. METHODS: Surgical stabilization of predominantly anterior flail chest segments was performed using one or two bars as per the Nuss procedure, during the acute phase of chest trauma. Data from all patients were examined. RESULTS: Ten patients received surgical stabilization using the Nuss method between 1999 and 2021. All patients had already been mechanically ventilated prior to surgery. The mean period from trauma to surgery was 4.2 days (range, 1-8 days). The number of bars used was one for 7 patients, and two for 3 patients. The mean operation time was 60 min (range, 25-107 min). All patients were extubated from artificial respiration without surgical complications or mortality. Mean total ventilation period was 6.5 days (range, 2-15 days). All bars were removed in a subsequent surgery. No collapses or fracture recurrences were observed. CONCLUSION: This method is simple and effective for fixed anterior dominant frail segment.

Protective effect of ebselen on bleomycin-induced lung fibrosis: analysis of the molecular mechanism of lung fibrosis mediated by oxidized diacylglycerol.

The molecular mechanisms underlying the development of pulmonary fibrosis remain unknown, and effective treatments have not yet been developed. It has been shown that oxidative stress is involved in lung fibrosis. Oxidized diacylglycerol (DAG) produced by oxidative stress is thought to play an important role in lung fibrosis. This study assessed the effect of oxidized DAG in an animal model of pulmonary fibrosis induced by aspiration of bleomycin (BLM) into the lungs. The inhibitory effect of ebselen on pulmonary fibrosis was also investigated. In lung fibrotic tissue induced by BLM, an increase in lipid peroxides and collagen accumulation was observed. Moreover, the levels of oxidized DAG, which has strong protein kinase C (PKC) activation activity, were significantly increased over time following the administration of BLM. Western blotting showed that phosphorylation of PKCα and δ isoforms was increased by BLM. Oral administration of ebselen significantly suppressed the increase in oxidized DAG induced by BLM and improved lung fibrosis. PKCα and δ phosphorylation were also significantly inhibited. The mRNA expression of α-smooth muscle actin and collagen I (marker molecules for fibrosis), as well as the production of transforming growth factor-ß and tumor necrosis factor-α(a potentially important factor in the fibrotic process), were increased by BLM and significantly decreased by ebselen. The administration of BLM may induce lipid peroxidation in lung tissue, while the oxidized DAG produced by BLM may induce overactivation of PKCα and δ, resulting in the induction of lung fibrosis.

Development of a Subclinical Dissociation Scale by Comparing Healthy Controls with Patients.

We developed a Subclinical Dissociation Scale by comparing healthy controls with patients with post-traumatic stress disorder (PTSD) or dissociative disorder. The Dissociative Experiences Scale, Subclinical Dissociation Scale, and General Health Questionnaire were completed by 441 healthy Japanese adolescents (mean age, 19.9 years) and 23 psychiatric inpatients (mean age, 28.8 years) diagnosed with PTSD or dissociative disorder. The initial Subclinical Dissociation Scale included 52 items grouped into five factors: F1, absentmindedness (14 items); F2, immersion or preoccupation (15 items); F3, temporary amnesia (10 items); F4, feelings of unreality (eight items); and F5, feelings of alienation (five items). Factor and correlation analyses revealed the validity and reliability of the Subclinical Dissociation Scale. The final version of the scale that comprised three factors (F1, F2, and F4) and 37 items underwent logistic regression and receiver operating characteristic (ROC) curve analyses to compare healthy controls with patients with PTSD or dissociative disorder. The ROC curve analysis using the Youden Index indicated a cut-off score of 18 for the borderline or abnormal range, which was calculated using the following formula: "(F1) + (F4) - (F2)." This study provides evidence of the partial test-retest reliability and con current validity of the Subclinical Dissociation Scale.

Early reperfusion with hemoglobin vesicles into tracheal subepithelial capillaries in a mouse tracheal transplant model.

Hemoglobin vesicles (HbVs), liposomes containing concentrated hemoglobin extracted from outdated human red blood cells (RBC), are artificial oxygen carriers with a small particle size. To evaluate the reperfusion of capillaries with HbVs in a tracheal transplant model and compare it with that of RBC. Isogenic mice were used as donors and recipients in a parallel trachea transplant model. Both ends of the donor trachea were anastomosed end-laterally to the recipient trachea to form in parallel. After transplantation, 0.3 mL of HbV solution (Hb concentration, 10 g/dL) was administered via the tail vein. The recipients were euthanized 1, 4, 6, and 8 h after surgery (n = 5 in each group). The tracheas were harvested, and tracheal subepithelial capillaries (SEC) reperfusion was histologically evaluated. A significant number of particles defined as HbV by electron microscopy were observed in the SEC of the grafted tracheas 4 h after the transplant surgery and HbV administration when no RBC were found in the SECs. The number increased 6 and 8 h later. Our findings suggest that HbVs, which are smaller than RBC, can reperfuse the capillaries of grafts earlier than RBCs after transplantation and contribute to the oxygenation of transplanted tissues.

Thymic Dedifferentiated Liposarcoma Having a Leiomyosarcomatous Dedifferentiated Component.

We report an extremely rare case of 42-year-old man, d iagnosed with thymic dedifferentiated liposarcoma (DDL) having a leiomyosarcomatous dedifferentiated component. The tumor was composed of atypical spindle cells. The morphological atypia was also observed around thymic adipose tissue. Immunohistochemically, the spindle cells were positive for desmin, smooth muscle actin, MDM2 and CDK4. MDM2 and CDK4 were also positive for the thymic adipose tissue. MDM2 amplification was confirmed by fluorescence in situ hybridization. Although there are some reports of mediastinal leiomyosarcoma, DDL may be overlooked. For accurate diagnosis of mediastinal mesenchymal tumor, careful observation of thymic adipose tissue is required with immunohistochemical study.

Enteric-type thymic adenocarcinoma: a case report and literature review focusing on prognosis based on histological subtypes.

Thymic adenocarcinoma is a rare disease and enteric-type thymic adenocarcinoma is even more rarely found. We report a resected case of a non-mucinous, enteric-type thymic adenocarcinoma in a 53-year-old woman. The operation was performed by median sternotomy, and the tumor was stage II in the Masaoka classification. Six months after the operation, recurrence-free follow-up is currently underway. Knowledge of enteric-type thymic adenocarcinoma can prevent misdiagnosis of metastatic tumors. We also determined the prognosis of enteric-type thymic adenocarcinoma based on histological subtypes through our literature review.

A Case of Thoracolithiasis Extracted with a Thoracoscope.

We report on an 81-year-old male patient in whom chest computed tomography during follow-up for extramammary Paget's disease revealed a nodule in the right thoracic cavity. Because he had been taking methotrexate for rheumatoid arthritis, the possibility of methotrexate-associated lymphoproliferative lung disease was considered and methotrexate was discontinued as a precaution. No calcification was found inside the nodule, and there was no change in its size or position for 6 months. The patient had a history of malignant tumor, so thoracoscopic surgery was performed for diagnostic purposes. A free white nodule was found in the right thoracic cavity and was subsequently removed. The pathological diagnosis was thoracolithiasis; although the nodule had not moved since its discovery, movement was suspected to have occurred 3 years prior. Although thoracolithiasis is rare, it should be considered as a differential diagnosis for nodules at the end of the lung field and on the diaphragm.

Pulmonary glomus tumor observed for 6 years: A case report.

Glomus tumors are rarely developed in the lung. We report a case of a pulmonary glomus tumor that was observed for a long period. The patient was a 50-year-old man. Chest computed tomography showed a 6 mm nodule in the left lower lobe. The patient requested follow-up observation. The nodule gradually increased and was resected 6 years later. Pulmonary partial resection was performed thoracoscopy. The lesion was diagnosed as a glomus tumor with no malignant features. Pulmonary glomus tumors are rare and difficult to diagnose before resection. However, care is necessary as they may be malignant.

Introducing a Remote Pre-graduate Medical Education Curriculum Planning Workshop During the COVID-19 Pandemic.

PURPOSE: To conduct a thorough online workshop on infection control under COVID-19 and to conduct a questionnaire survey on the online workshop. OBJECTIVE: The Tokai University School of Medicine has held 39 workshops to acquire the curriculum planning ability required as a faculty member of the School of Medicine. Due to the COVID-19 pandemic, this year (2020) we were unable to hold a workshop. Therefore, we attempted an online workshop using Zoom. METHODS: To shorten the amount of time required for the workshop, we excluded some content that was used the previous year. The day passed without any major problems, and both the participants and the individuals in charge of the workshop filled out a questionnaire at the end of the day. RESULTS: Conclusion: Online workshops appear to be a very useful tool in terms of infection control under the COVID-19 pandemic.

Par3 and ZO-1 Membrane Clustering is an Indicator of Poor Prognosis in Lung Squamous Cell Carcinoma.

Epithelial cells form epithelial tissue structures by joining together via intercellular adhesion structures composed of intercellular adhesion factors such as zona occludins-1 (ZO-1). Epithelial cells are polarized at the apical and basal regions, and are bordered by intercellular adhesion structures called tight junctions; the organelles within epithelial cells are distributed asymmetrically. Maintenance of this asymmetry in normal epithelial cells is essential for normal cytoskeletal remodeling, movement, and cell division. The key factor regulating cell polarity is called partitioning-defective protein 3 (Par3). Abnormalities in cell polarity and intercellular adhesion are common features of many cancer tissues. Mutation and loss of cell polarity regulators contributes to the immortalization of normal cells and to the malignant transformation of cancer cells. In this study, we investigated the relationship between the subcellular localization of Par3 and ZO-1 and clinicopathological features of lung squamous cell carcinoma (lung SqCC). Both molecules were localized to the cell membrane in normal lung tissue, but the levels were lower at this location in pulmonary tumor tissue compared with normal lung tissue. Both Par3 and ZO-1 accumulated in clusters on the cell membrane (hereinafter, "foci"). Tumor size, recurrence rate, and mortality rate were significantly higher in patients with Par3 foci compared to those without Par3 foci. Rates of lymph node metastasis, recurrence, and mortality were significantly higher in patients with ZO-1 foci than in those without ZO-1 foci. The expression of Par3 and ZO-1 mRNA was not s ignificantly different in s amples from p atients with foci versus those without. These results strongly suggest that the presence of Par3 and ZO-1 foci on the membrane may be a useful prognostic marker for lung SqCC.

A surgical Case of Synchronous Multiple Primary Lung Cancers with Small Cell Carcinoma and Squamous Cell Carcinoma.

The incidence of synchronous multiple primary lung cancers has increased in recent years, however, there are few reports of cases involving small cell carcinoma. A 72-year-old man was referred to our department because of an abnormal shadow on chest radiography. He was receiving treatment for pulmonary fibrosis, emphysema, rheumatoid arthritis, and prostate cancer. Computed tomography revealed two lung nodules in the left lower lobe. A definitive diagnosis was unable to be made based on transbronchial lung biopsy. Positron emission tomography demonstrated abnormal fluorodeoxyglucose uptake in the two lung nodules and lung cancer (cT3N0M0) was suspected. Thoracoscopic partial resection of the left lower lobe was performed. As primary lung cancer was diagnosed using the frozen specimen, we performed left lower lobectomy with lymph node dissection. Pathological examination of the S9 and S6 tumors revealed combined small cell carcinoma and squamous cell carcinoma, respectively. Both tumors were separated and diagnosed as synchronous multiple primary lung cancers. No lymph node metastasis was found. We report a rare case of synchronous multiple primary lung cancers, including small cell carcinoma.

A case of JAK2V617F-positive essential thrombocythemia where allele burden was reduced by a PD-1 inhibitor.

The Janus kinase/signal transducers and activators of transcription signaling pathway induces programmed death ligand-1 (PD-L1) expression. JAK2 mutation at position 617 (JAK2V617) is a frequent driver of myeloproliferative neoplasms (MPN) through PD-L1 expression. Although PD-1 inhibitors should be effective against MPN with JAK2V617F mutation, this has not yet been reported in humans. Thus, we assessed the efficacy of a PD-1 inhibitor in a lung cancer patient with JAK2V617F-positive essential thrombocythemia (ET). A 71-year-old man was diagnosed with ET, and with lung carcinoma 3 years later. After right lobectomy and postoperative chemotherapy, pembrolizumab [a PD-1 inhibitor (200 mg, every 3 weeks)] was initiated for refractory lung carcinoma. Lung cancer progression did not occur for 1.5 years under treatment. Most megakaryocytes were PD-L1-positive, and after pembrolizumab initiation, platelet count remained below 45 × 104/µL without the need for other cytoreductive therapies for ET. The JAK2V617F allele burden gradually decreased from 11.5% at diagnosis to 2.9% after 17 months of pembrolizumab treatment. Other peripheral blood lineages did not decrease, and pembrolizumab treatment was continued without any adverse events. This is the first report demonstrating the effectiveness of pembrolizumab in an MPN patient with JAK2V617F mutation.

The Role of Hypertension and Renin-angiotensin-aldosterone System Inhibitors in Bleomycin-induced Lung Injury.

INTRODUCTION: The risk factors for bleomycin-induced lung injury (BLI), a fatal complication of cancer chemotherapy, are not well-established. The renin-angiotensin-aldosterone system (RAAS) has recently been suggested to play a role in the development of lung injury. This study clarified the impact of hypertension (HTN) and the administration of RAAS inhibitors on BLI occurrence in patients treated with bleomycin-containing regimens. PATIENTS AND METHODS: We retrospectively analyzed the data of 190 patients treated with a bleomycin-containing regimen for Hodgkin lymphoma or germ cell tumors at our institutions from 2004 to 2018. RESULTS: Overall, 190 patients received bleomycin, and symptomatic BLI occurred in 21 (11.1%) cases. In the multivariate analysis, age ≥ 65 years (odd ratio, 10.90; 95% confidence interval, 3.72-32.20; P < .001) and history of HTN (odds ratio, 3.32; 95% confidence interval, 1.07-10.30; P = .04) were found to be significant risk factors for BLI onset. BLI occurred in 3.6% (n = 5) of patients with no risk, 11.8% (n = 2) of those whose only risk factor was HTN, 31.6% (n = 6) of those whose only risk factor was age ≥ 65 years, and 57.1% (n = 8) of those with both risk factors (P < .001). BLI-induced mortality rates in each group were 0.0% (n = 0), 5.9% (n = 1), 10.5% (n = 2), and 42.9% (n = 6) (P < .001), respectively. Among 31 patients with HTN, BLI incidence was 12.5% in patients who were administered RAAS inhibitors and 53.3% in those who were not (P = .02). CONCLUSION: Older age and history of HTN were independent risk factors for the development of BLI, and the administration of RAAS inhibitors might reduce the onset of BLI.

Postintubation tracheal stenosis 35 years after neonatal resuscitation.

INTRODUCTION: Postintubation tracheal stenosis involves granulation or cicatrization of the tracheal epithelium. It is progressive and can become life-threatening within a few months after extubation. PRESENTATION OF CASE: We here report a case of tracheal stenosis with a delayed manifestation, presenting 35 years after endotracheal intubation for neonatal resuscitation. A female patient complained of dyspnea during pregnancy. Bronchoscopy revealed 75% constriction of the tracheal lumen by cicatrization, from the 2nd to 4th tracheal rings. After child-birth, the scar tissue was ablated using argon plasma coagulation. DISCUSSION: The patient had no significant medical history, such as severe airway infection or cervical/chest trauma, which might have caused the circumferential cicatricial tracheal stenosis, other than the endotracheal intubation she had undergone for neonatal resuscitation. Therefore, we considered this to reflect postintubation tracheal stenosis with delayed manifestation. CONCLUSION: Delayed postintubation tracheal stenosis should be taken into consideration, when a patient suffers from suffocating tracheal stenosis.

Analysis of key clinical features for achieving complete remission in stage III and IV non-small cell lung cancer patients.

BACKGROUND: Although development of immune checkpoint inhibitors and various molecular target agents has extended overall survival time (OS) in advanced non-small cell lung cancer (NSCLC), a complete cure remains rare. We aimed to identify features and treatment modalities of complete remission (CR) cases in stages III and IV NSCLC by analyzing long-term survivors whose OS exceeded 3 years. METHODS: From our hospital database, 1,699 patients, registered as lung cancer between 1st Mar 2004 and 30th Apr 2011, were retrospectively examined. Stage III or IV histologically or cytologically confirmed NSCLC patients with chemotherapy initiated during this period were enrolled. A Cox proportion hazards regression model was used. Data collection was closed on 13th Feb 2017. RESULTS: There were 164 stage III and 279 stage IV patients, including 37 (22.6%) and 51 (18.3%) long-term survivors and 12 (7.3%) and 5 (1.8%) CR patients, respectively. The long-term survivors were divided into three groups: 3 ≤ OS < 5 years, 5 years ≤ OS with tumor, and 5 years ≤ OS without tumor (CR). The median OS of these groups were 1,405, 2,238, and 2,876 days in stage III and 1,368, 2,503, and 2,643 days in stage IV, respectively. The mean chemotherapy cycle numbers were 16, 20, and 10 in stage III and 24, 25, and 5 in stage IV, respectively. In the stage III CR group, all patients received chemoradiation, all oligometastases were controlled by radiation, and none had brain metastases. Compared with non-CR patients, the stage IV CR patients had smaller primary tumors and fewer metastases, which were independent prognostic factors for OS among long-term survivors. The 80% stage IV CR patients received radiation or surgery for controlling primary tumors, and the surgery rate for oligometastases was high. Pathological findings in the stage IV CR patients revealed that numerous inflammatory cells existed around and inside resected lung and brain tumors, indicating strong immune response. CONCLUSIONS: Multiple line chemotherapies with primary and oligometastatic controls by surgery and/or radiation might achieve cure in certain advanced NSCLC. Cure strategies must be changed according to stage III or IV. This study was retrospectively registered on 16th Jun 2019 in UMIN Clinical Trials Registry (number UMIN000037078).

Congenital cystic adenomatoid malformation in adults: Report of a case presenting with a recurrent pneumothorax and a literature review of 60 cases.

Congenital cystic adenomatoid malformation (CCAM) is a congenital pulmonary cystic disease that is mostly detected and diagnosed prenatally or during the neonatal period, while rarely being observed in adults. Here, we report an adult case of CCAM that was diagnosed following surgery for a recurrent pneumothorax. We further review 60 case reports on adult CCAM that have been previously published. The patient was a 29-year-old woman with a severe left pneumothorax. Her computed tomography scan showed the presence of multiple pulmonary cysts at the base of the left lower lobe. Since she had experienced a left pneumothorax twice previously, surgery was indicated. A wedge lung resection of the pulmonary cysts was performed thoracoscopically. The postoperative pathological diagnosis was type I CCAM. From the review, 7 adult CCAM patients (11.7%) out of 61, including the patient in the present case, presented with pneumothorax, while 21 patients (35%) presented with infection. Thirty-nine foci of CCAM (65%) were located in lower lobes. Moreover, malignancies were associated in 8 cases (13.3%). We propose that if multicystic lung lesions are found in pneumothorax patients, particularly in lower lobes, CCAM should be considered during the differential diagnosis, even in adults.