Autocrine TGF-ß-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis.

The molecular etiology of idiopathic pulmonary fibrosis (IPF) has been extensively investigated to identify new therapeutic targets. Although anti-inflammatory treatments are not effective for patients with IPF, damaged alveolar epithelial cells play a critical role in lung fibrogenesis. Here, we establish an organoid-based lung fibrosis model using mouse and human lung tissues to assess the direct communication between damaged alveolar type II (AT2)-lineage cells and lung fibroblasts by excluding immune cells. Using this in vitro model and mouse genetics, we demonstrate that bleomycin causes DNA damage and activates p53 signaling in AT2-lineage cells, leading to AT2-to-AT1 transition-like state with a senescence-associated secretory phenotype (SASP). Among SASP-related factors, TGF-ß plays an exclusive role in promoting lung fibroblast-to-myofibroblast differentiation. Moreover, the autocrine TGF-ß-positive feedback loop in AT2-lineage cells is a critical cellular system in non-inflammatory lung fibrogenesis. These findings provide insights into the mechanism of IPF and potential therapeutic targets.

Identifying a Lung Stem Cell Subpopulation by Combining Single-Cell Morphometrics, Organoid Culture, and Transcriptomics.

Single-cell RNA sequencing is a valuable tool for dissecting cellular heterogeneity in complex systems. However, it is still challenging to estimate the proliferation and differentiation potentials of subpopulations within dormant tissue stem cells. Here, we established a new single-cell analysis method for profiling the organoid-forming capacity and differentiation potential of tissue stem cells to disclose stem cell subpopulations by integrating single-cell morphometrics, organoid-forming assay, and RNA sequencing, a method named scMORN. To explore lung epithelial stem cells, we initially developed feeder-free culture system, which could expand all major lung stem cells, including basal, club, and alveolar type 2 (AT2) cells, and found that club cells contained a subpopulation, which showed better survival rate and high proliferation capacity and could differentiate into alveolar cells. Using the scMORN method, we discovered a club cell subpopulation named Muc5b+ and large club (ML-club) cells that efficiently formed organoids than other club or AT2 cells in our feeder-free organoid culture and differentiated into alveolar cells in vitro. Single-cell transcriptome profiling and immunohistochemical analysis revealed that ML-club cells localized at the intrapulmonary proximal airway and distinct from known subpopulations of club cells such as BASCs. Furthermore, we identified CD14 as a cell surface antigen of ML-club cells and showed that purified CD14+ club cells engrafted into injured mouse lungs had better engraftment rate and expansion than other major lung stem cells, reflecting the observations in organoid culture systems. The scMORN method could be adapted to different stem cell tissues to discover useful stem-cell subpopulations.

[Laparoscopic Colectomy for a Patient with Transverse Colon Cancer in Situs Inversus Totalis].

A 74-year-old man with situs inversus totalis visited our hospital for a positive fecal occult blood. He was diagnosed with transverse colon cancer by total colonoscopy. We performed laparoscopic partial colectomy. He was discharged on the 8th postoperative day, without postoperative complications. Histopathological examination revealed well differentiated adenocarcinoma, pT1aN0M0, pStage Ⅰ. Preoperative assessment of the anatomical position and vascular malformations, using 3- dimensional computed tomography, was essential for our safe surgical conduct.

[A Case of Small Cell Carcinoma of the Esophagus with Complete Response to Chemoradiotherapy in an Elderly Patient].

Small cell carcinoma of the esophagus is a rare malignancy with a perceived poor prognosis. We report a case of long-term survival using chemoradiotherapy. An 80-year-old man visited our hospital complaining of hiccup. Endoscopic examination showed type 2 lesions in the lower esophagus with a pathological diagnosis of small cell carcinoma. Based on the diagnosis of cStage Ⅲ disease and the patient's age, chemoradiotherapy comprising 3 courses of CDDP and CPT-11 and 45 Gy of irradiation was administered. After treatment completion, the therapeutic effect was evaluated as a complete response through CT, PET-CT, and endoscopic examination. No recurrence has been identified more than 5 years after achieving the complete response.

[A Case of Advanced Gastric Cancer Responding to Neoadjuvant Chemotherapy with Docetaxel, Cisplatin, and 5-Fluorouracil, Leading to a Pathological Complete Response].

We report a 72-year-old woman who was initially diagnosed with locally advanced gastric cancer with involvement of the esophagus and pancreas. She received 3 courses of neoadjuvant chemotherapy(NAC)with docetaxel, cisplatin, and 5- fluorouracil(the DCF regimen)and achieved an excellent response. She underwent total gastrectomy with distal pancreatectomy, splenectomy, and D2 lymphadenectomy. Histological examination confirmed a pathological complete response. NAC chemotherapy can down stage/down size the disease and allow some patients to undergo curative radical surgery.

[A Case of a Metastatic Liver Tumor from a Thymic Carcinoma Detected During a Cesarean Section].

A 40-year-old pregnant woman who had previously been diagnosed with uterine myoma underwent cesarean section. During the operation, a tumor thought to be uterine myoma was found to be an extrauterine tumor arising from the upper abdomen. After the delivery of the fetus, a staging CT scan was performed, which revealed a huge, 18 cm, hepatic tumor in the left lateral segment, a mediastinal tumor with calcification, and multiple lung nodules. She underwent a left hepatic lobectomy and a wedge resection 8 days after the delivery. The initial pathological diagnosis was moderately differentiated neuroendocrine tumor (NET). However, as a primary hepatic NET is extremely rare, further immunohistochemical staining was performed. The tumor was positive for p63, CD5, c-kit, and bcl-2, indicating a diagnosis of thymic carcinoma with liver and lung metastases.

[Successful Surgical Treatment for Hepatocellular Carcinoma with Portal Vein Tumor Thrombus after Favorable Response to Irradiation and Transcatheter Arterial Chemoembolization].

Here, we describe the surgical treatment of a patient with hepatocellular carcinoma(HCC)with portal vein tumor thrombus (PVTT) after irradiation and transcatheter arterial chemoembolization (TACE). A 51-year-old man was being followed-up for HBV-related liver cirrhosis and HCC that was previously treated by radio-frequency ablation (RFA) and TACE. A follow up CT study revealed recurrence of HCC in segment 6 of the liver with PVTT extending to the right branch. As early recurrence was likely after resection and due to insufficient hepatic functional reserve, primary radiotherapy for PVTT was performed followed by TACE. After non-surgical treatment, a favorable tumor response was observed with no evidence of intrahepatic disease within the left lobe of the liver, and the volume of the future liver remnant increased, allowing us to perform splenectomy and right hemihepatectomy combined with portal vein resection/reconstruction.

[Simultaneous Resection of Sigmoid Colon Cancer and Synchronous Liver Metastasis by Laparoscopic Surgery].

We report the case of a patient with sigmoid colon cancer with synchronous liver metastasis who underwent simultaneous sigmoid colectomy and partial hepatectomy by laparoscopic surgery. A 70-year-old man with positive fecal occult blood was diagnosed with sigmoid colon cancer and referred to our hospital. Staging computed tomography (CT) revealed a solitary liver metastasis in segment 6, confirmed by magnetic resonance imaging (MRI). He underwent simultaneous laparoscopic sigmoid colectomy and partial hepatectomy. The patient's postoperative recovery was uneventful and he was discharged 12 days later. The patient was alive without recurrence 4 months after surgery. Laparoscopic surgery is an accepted mode of treatment for colorectal cancer. However, the use of laparoscopy in liver surgery is still limited. There have only been few case reports of combined laparoscopic colorectal and liver resection. Simultaneous laparoscopic colectomy and hepatectomy is feasible for selected colorectal cancer patients with liver metastases. It may provide significant decrease in morbidity, length of hospitalization time, and intraoperative blood loss, without compromising curability or increasing mortality. Further studies are needed to confirm the feasibility of this approach.

A case of basaloid carcinoma of the esophagus with a solitary lung metastasis for which thoracoscopic partial lung resection was performed.

We experienced a case of basaloid carcinoma of the esophagus with a solitary lung metastasis for which thoracoscopic partial lung resection was performed. To the best of our knowledge, this is the first reported case of basaloid carcinoma of the esophagus with lung metastasis for which surgery was performed. There are no evidence-based treatment strategies for postoperative recurrence of basaloid carcinoma of the esophagus. Treatment strategies such as adjuvant therapy centered on chemotherapy and surgical indications should be established.

[Lung metastasis of basaloid-squamous cell carcinoma of the esophagus; report of a case].

A 69-year-old woman had undergone a subtotal esophagectomy for basaloid-squamous cell carcinoma of the esophagus 2 years before (pT3, ly1, v2, pN0, pStage II). Right lung metastasis was detected by follow up chest computed tomography( CT). A partial resection of the right lung was performed. Histopathological diagnosis was basaloid-squamous cell carcinoma. She is doing well 17 months after surgery for metastasis.To our knowledge, no case of radical surgery for the lung metastasis of basaloid-squamous cell carcinoma has not been reported in the Japanese literature to date.

Thoracoscopic esophagectomy in the prone position.

Thoracoscopic esophagectomy performed with the patient in the left lateral position has been occasionally reported since the 1990s, but it has not been established as a standard procedure. This may be because the success of this procedure largely depends on the technical competence of an assistant to secure an adequate field of view during the procedure. Thoracoscopic esophagectomy with the patient in the prone position has recently been introduced and has been consistently shown to be useful. Compared with left lateral thoracoscopic esophagectomy, prone thoracoscopic esophagectomy requires less assistance in exposing the operative field and it is relatively easy to obtain a satisfactory field of view. We performed prone thoracoscopic esophagectomy on 20 patients and were successful in achieving a wide field of view. The postoperative course was remarkably favorable in all patients and the procedure is considered promising for standard thoracoscopic esophagectomy. There are few detailed reports of this procedure; herein, we describe the procedure of prone thoracoscopic esophagectomy employed at our hospital.

A new category for chronic sclerosing sialadenitis as an IgG4 related syndrome.

This report presents three cases of IgG4 related sclerosing disease complicated with chronic sclerosing sialadenitis. The clinical, radiographic and pathologic findings later suggested that the patients had chronic sclerosing sialadenitis. The submandibular gland tumour regressed in two patients. These patients were suspected to have Mikulicz's disease or Sjögren's syndrome, but the diagnostic criteria were not satisfied. The workup for chronic sclerosing sialadenitis revealed a significantly elevated value of serum IgG4. The patient was then diagnosed with IgG4 related sclerosing disease complicated with chronic sclerosing sialadenitis. After administering prednisolone to these patients, the serum IgG4 values decreased after 4 weeks. The current cases may represent a new category for Mikulicz's disease or Sjögren's syndrome as an IgG4 related sclerosing disease.

Isolation of tissue progenitor cells from duct-ligated salivary glands of swine.

Tissue stem cells participate in the repopulation of tissue after injury. Tissue injury stimulates the normally quiescent tissue stem cells to differentiate and proliferate, in the process of replacing and/or repairing the damaged cells, and hence effecting tissue regeneration. The salivary glands retain the ability for frequent regeneration. Previously, we isolated progenitor cells from the injured salivary glands of mice and rats that differentiated into hepatic and pancreatic lineages. The isolated progenitors were CD49f-positive and intracellular laminin-positive, and proliferated on type I collagen while maintaining their multipotency. In this study, we analyzed the tissue stem cells induced by ligating the main excretory duct of the salivary gland in swine. After duct ligation of the gland, acinar cells receded due to apoptosis, and epithelial cells subsequently proliferated. We cultured cells obtained from the duct-ligated salivary gland and purified the cells by limited dilution. The isolated cells were positive for CD29, CD49f, intracellular laminin, AFP, CK19, CK18, and Thy-1(CD90), and weakly positive for c-Kit (CD117). After three-dimensional formation, the cells expressed insulin and albumin. We designated the cells as swine salivary gland-derived progenitor cells. Gene expression of insulin and albumin was significantly increased (five-fold) and that of insulin was also increased (3.8-fold) with differentiation medium with nicotinamide and/or GLP-1 treatment in spherical culture. The expressions of albumin and insulin were 1/10-fold and 1/4-fold compared to porcine hepatocytes and pancreatic endocrine cells. The differentiated SGP cells could release insulin, which were stimulated by glucose and potassium. These results indicate that swine SGP cells could differentiate into hepatocytes and beta-cells, functionally. Swine SGP cells were useful tools for therapy and analyzing endodermal regenerative models in large animals.