Cancer of unknown primary eventually diagnosed as poorly differentiated prostate cancer: a case report.

BACKGROUND: Prostate cancer has been well known to have a high prevalence among middle-aged and older men, with high incidence of metastases to the bone-the main metastatic site. However, prostate cancer among those less than 50 years of age is extremely rare, and neck swelling is seldom the initial symptom. CASE PRESENTATION: We herein report case of a 47-year-old Japanese male with poorly differentiated prostate cancer that had been initially diagnosed as a cancer of unknown primary with multiple lymph node and bone metastases before reaching a definitive diagnosis. The patient has been started on endocrine therapy and is currently alive without progression. DISCUSSION AND CONCLUSION: When locating the primary lesion in men with cancer of unknown primary, it is important to consider the possibility of prostate cancer, confirm serum prostate-specific antigen levels, and perform local prostate evaluation.

Targeted next-generation sequencing for detection of PIK3CA mutations in archival tissues from patients with Klippel-Trenaunay syndrome in an Asian population : List the full names and institutional addresses for all authors.

BACKGROUND: Klippel-Trenaunay syndrome (KTS) is a rare slow-flow combined vascular malformation with limb hypertrophy. KTS is thought to lie on the PIK3CA-related overgrowth spectrum, but reports are limited. PIK3CA encodes p110α, a catalytic subunit of phosphatidylinositol 3-kinase (PI3K) that plays an essential role in the PI3K/AKT/mammalian target of rapamycin (mTOR) signaling pathway. We aimed to demonstrate the clinical utility of targeted next-generation sequencing (NGS) in identifying PIK3CA mosaicism in archival formalin-fixed paraffin-embedded (FFPE) tissues from patients with KTS. RESULTS: Participants were 9 female and 5 male patients with KTS diagnosed as capillaro-venous malformation (CVM) or capillaro-lymphatico-venous malformation (CLVM). Median age at resection was 14 years (range, 5-57 years). Median archival period before DNA extraction from FFPE tissues was 5.4 years (range, 3-7 years). NGS-based sequencing of PIK3CA achieved an amplicon mean coverage of 119,000x. PIK3CA missense mutations were found in 12 of 14 patients (85.7%; 6/8 CVM and 6/6 CLVM), with 8 patients showing the hotspot variants E542K, E545K, H1047R, and H1047L. The non-hotspot PIK3CA variants C420R, Q546K, and Q546R were identified in 4 patients. Overall, the mean variant allele frequency for identified PIK3CA variants was 6.9% (range, 1.6-17.4%). All patients with geographic capillary malformation, histopathological lymphatic malformation or macrodactyly of the foot had PIK3CA variants. No genotype-phenotype association between hotspot and non-hotspot PIK3CA variants was found. Histologically, the vessels and adipose tissues of the lesions showed phosphorylation of the proteins in the PI3K/AKT/mTOR signaling pathway, including p-AKT, p-mTOR, and p-4EBP1. CONCLUSIONS: The PI3K/AKT/mTOR pathway in mesenchymal tissues was activated in patients with KTS. Amplicon-based targeted NGS could identify low-level mosaicism from low-input DNA extracted from FFPE tissues, potentially providing a diagnostic option for personalized medicine with inhibitors of the PI3K/AKT/mTOR signaling pathway.

Case of needle tract seeding during preoperative neoadjuvant chemotherapy for resectable pancreatic cancer.

Reports of needle tract seeding (NTS) as a complication of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) have been increasing. To date, most of the reported cases of NTS have been diagnosed during the postoperative follow-up period. Herein, we report a case of NTS that occurred during preoperative neoadjuvant chemotherapy after EUS-FNA for resectable pancreatic cancer. The patient underwent transgastric EUS-FNA for a pancreatic tail tumor. He was diagnosed as having resectable pancreatic cancer and received preoperative neoadjuvant chemotherapy. After completion of the chemotherapy, computed tomography showed a thick-walled cyst-like structure appearing between the pancreas and the gastric wall. Combined resection revealed adenocarcinoma invasion into the cyst-like structure. Based on the clinical course, and surgical and pathological findings, the condition was diagnosed as NTS. It is thus crucial that after EUS-FNA, a detailed review of the imaging findings be conducted in the preoperative period. If adhesions between the stomach and the pancreas are observed after transgastric EUS-FNA, combined resection of the gastric wall should be considered.

Comparison of clinicopathological features and long-term prognosis between mixed predominantly differentiated-type and pure differentiated-type early gastric cancer.

BACKGROUND: Recent studies have shown that mixed predominantly differentiated-type (MD) early gastric cancer (EGC) might have more malignant potential than pure differentiated-type (PD) EGC. However, no study has analyzed all differentiated-type EGC cases treated endoscopically and surgically. This study aimed to compare the differences in clinicopathological features and long-term prognosis between MD- and PD-EGC. METHODS: We evaluated all patients with differentiated-type EGCs who were treated endoscopically and surgically in our hospital between January 2010 and October 2014. The clinicopathological features and long-term prognosis of MD-EGC were compared with those of PD-EGC. RESULTS: A total of 459 patients with 459 lesions were evaluated in this study; of them, 409 (89.1%) and 50 (10.9%) were classified into the PD and MD groups, respectively. Submucosal invasion was found in 96 (23.5%) patients of the PD group and in 33 (66.0%) patients of the MD group (p < 0.01). The rates of positive lymphatic and vascular invasion and ulceration were significantly higher in the MD group than in the PD group (p < 0.01). The proportion of patients with lymph node metastasis was also significantly higher in the MD group than in the PD group (5 (10%) vs 6 (1.5%), p < 0.01). The 5-year overall and EGC-specific survival rates in the PD group were 88.3 and 99.5%, respectively, while they were 94.0 and 98.0% in the MD group, respectively. CONCLUSIONS: MD-EGC has more malignant potential than PD-EGC. However, the long-term prognosis of MD-EGC is good and is not significantly different from that of PD-EGC when treated appropriately.

Association of Epstein-Barr virus with regression after withdrawal of immunosuppressive drugs and subsequent progression of iatrogenic immunodeficiency-associated lymphoproliferative disorders in patients with autoimmune diseases.

Patients with autoimmune diseases (AIDs) may develop lymphoproliferative disorders (LPDs) during treatment with immunosuppressive agents (IS) such as methotrexate (MTX), biological agents, or tacrolimus. Some LPDs in patients with AIDs (AID-LPDs) regress after withdrawal of IS, and a high incidence of Epstein-Barr virus (EBV) positivity in such patients has been reported. To identify characteristics and factors predictive of the response to treatment and disease progression, we retrospectively analyzed clinical and histopathological data for 81 patients with AID-LPDs. Almost all of them (96%) had been treated with MTX. Diffuse large B cell lymphoma was the most common LPD type (61%) and seven patients (9%) had classical Hodgkin lymphoma (CHL). EBV was detected by in situ hybridization with an EBV-encoded small RNA (EBER) probe in 43% of the examined cases. In 59 patients, IS was discontinued as the initial treatment, resulting in regression of LPDs in 69% of them, and multivariate analysis showed that EBER positivity was an independent factor predictive of such regression (p = 0.022). Two-year progression-free survival (PFS) and overall survival for the patients overall were 63% and 83%, respectively. Poor PFS was associated with advanced stage (p = 0.024), worse performance status (PS, p = 0.031), CHL histology (p = 0.013), and reactivation of EBV-related antibodies (p = 0.029). In conclusion, EBV positivity demonstrated using an EBER probe is useful for prediction of successful regression after withdrawal of IS in patients with AID-LPDs. Patients with advanced stage disease, worse PS, CHL histology, or reactivation of EBV-related antibodies should be closely monitored after initial treatment.

Endoscopic submucosal dissection for early squamous cell carcinoma in the anal canal and Lugol chromoendoscopy for assessment of the lateral margin.

A 66-year-old man underwent follow-up colonoscopy after colon polypectomy. The retroflexed view of the anal canal with white-light imaging revealed a whitish, slightly elevated lesion on the dentate line and an ill-defined flat lesion. A biopsy of the whitish elevation revealed squamous cell carcinoma (SCC), and endoscopic submucosal dissection (ESD) was planned. The lateral margin of the SCC was identified by spraying with Lugol's iodine, and the tumor was resected en bloc with no complications. The pathological findings were SCC in situ with parakeratosis in the whitish elevation and high-grade intraepithelial neoplasia in the ill-defined flat lesion, which exhibited a wide iodine-unstained area by chromoendoscopy. Early SCC in the anal canal is a rare gastrointestinal cancer, and Lugol chromoendoscopy helped visualize the tumor margin for ESD.

Atypical presentation of a cushion sign-positive stomach gastrointestinal stromal tumor with cystic formation: A case report.

Gastrointestinal stromal tumors (GIST) typically appear as solid masses, and cystic formation is uncommon. Most stomach GISTs with cystic formation progress outside the gastric wall and are frequently misdiagnosed as epigastric cystic tumors derived from pancreas or liver. An asymptomatic 72-year-old male underwent esophagogastroduodenoscopy, which revealed a submucosal tumor (SMT), approximately 50 mm in diameter, at the anterior wall of the gastric angle. The SMT was very soft with positive cushion sign. Endoscopic ultrasonography and contrast-enhanced computed tomography revealed that the SMT was a cystic tumor with solid component. Laparoscopic and endoscopic cooperative surgery were performed to remove the tumor. Histopathological analysis revealed that the tumor was a GIST with cystic formation. To the best of our knowledge, this the first documented case of a cushion sign-positive stomach GIST with cystic formation, which had mainly developed inside the stomach. This case suggests that we should keep in mind the possibility of cystic formation of GIST when the tumor has a solid component, even if it appears as a cushion sign-positive SMT.

Enhanced expression of IL-34 in an inflammatory cyst of the submandibular gland: a case report.

BACKGROUND: Cysts of the salivary glands are common lesions that occur in the context of various etiologies. Although the diagnostic importance of cysts in salivary gland diseases has been well studied, molecular mechanisms that control the related pathological process remain largely unknown. IL-34 is a novel cytokine that was discovered recently as a tissue-specific ligand of colony stimulating factor-1 receptor. Since its discovery, accumulating evidence has revealed emerging roles of IL-34 in various pathological conditions and has been suggested to correlate remarkably with inflammation. In this study, we report a medical case of an inflammatory cyst within the submandibular gland, through which evaluating the possible involvement of IL-34 in salivary gland disorders. CASE PRESENTATION: A 37-year-old male patient suffered from a sudden swelling in the right submandibular region, started initially small and had gradually increased in size to reach 3-4 cm in 1 week, accompanied by pain and local fever. Ultrasonography and MRI imaging revealed the existence of a well-defined cystic lesion with sharp borders measuring 39.8 mm × 19.7 mm within the right submandibular gland. The cyst was removed surgically, and the diagnostic decision was determined based on histopathological observations as an inflammatory cyst in the submandibular gland. Sections were generated from different regions of the surgically resected inflammatory cyst and used to examine IL-34 expression by immunohistochemistry compared to normal salivary gland tissues. Immunohistochemical staining showed enhanced expression of IL-34 in the ductal epithelial cells and endothelial cells of blood vessels, with a tendency to be accompanied with high infiltration of immune cells, which suggests a possible involvement of IL-34 in the pathogenesis of salivary gland inflammation. CONCLUSIONS: In this report, we introduce interesting findings of enhanced IL-34 expression in a case of an inflamed submandibular gland. Our findings emphasize the pathological roles of IL-34 as an inflammation amplifier and angiogenic enhancer in inflammatory conditions, such as in salivary gland disorders.

Immunoglobulin G4-related disease presenting as a pulmonary nodule with an irregular margin.

We report a case of immunoglobulin G4 (IgG4)-related lung disease presenting as a solitary pulmonary nodule with an irregular margin on computed tomography. The nodule showed a high standardized uptake value on positron emission tomography. A malignant pulmonary tumour could not be excluded. Middle lobectomy was performed. Histological analysis revealed marked lymphoplasmacytic infiltration and storiform fibrosis. Immunostaining indicated the presence of IgG4-positive plasma cells. A definitive diagnosis of IgG4-related disease was confirmed.

Risk factors and management for gastric stenosis after endoscopic submucosal dissection for gastric epithelial neoplasm.

BACKGROUND: Only a few studies have reported treatment options for stenosis after endoscopic submucosal dissection (ESD) for gastric neoplasms. This study aimed to identify the risk factors for and evaluate the management of stenosis after ESD for gastric epithelial neoplasms in the cardia and antrum. METHODS: We retrospectively reviewed 1218 patients (1447 gastric epithelial neoplasms) who underwent ESD at Tonan Hospital from June 2004 to November 2015. Post-ESD stenosis was defined when a standard endoscope could not be passed through the site. RESULTS: Post-ESD stenosis occurred in 10 (21.3%) of the 47 cardia cases and 14 (3.2%) of the 432 antrum cases. A wide resection of more than three fourths of the circumferential extent was the sole significant risk factor related to post-ESD stenosis in both cardia and antrum. Prophylactic endoscopic balloon dilation (EBD) was performed in 3 of 10 patients with cardiac stenosis and 4 of 14 with antral stenosis. Post-EBD bleeding occurred in one cardia (10%) and one antrum (7.1%) case each and was endoscopically treated. Perforation during EBD occurred in two (14.3%) antrum cases, both of which required emergency open surgery. All complications were observed in patients with conventional EBD, and no complications were associated with prophylactic EBD. CONCLUSIONS: A wide resection of more than three fourths of the circumferential extent was the significant risk factor for post-ESD stenosis in both cardia and antrum, and prophylactic EBD could be a promising procedure for the management of post-ESD stenosis.

Short- and long-term outcomes of endoscopic submucosal dissection for early gastric cancer in elderly patients aged 75 years and older.

BACKGROUND: Only a few studies have reported long-term outcomes for endoscopic submucosal dissection (ESD) of early gastric cancer (EGC) in elderly patients. The aim of this study was to evaluate the efficacy of ESD for EGC in elderly patients ≥75 years with respect to both short- and long-term outcomes. METHODS: We reviewed the clinical data of elderly patients ≥75 years who had undergone ESD for EGC at Tonan Hospital from January 2003 to May 2010. RESULTS: A total of 177 consecutive patients, including 145 with curative resection (CR) and 32 with noncurative resection (non-CR), were examined. Of the 32 patients with non-CR, 15 underwent additional surgery, and lymph node metastases were found in 3 patients. The remaining 17 patients were followed without additional surgery because of advanced age or poor general condition. Procedure-related complications, such as post-ESD bleeding, perforation and pneumonia, were within the acceptable range. The 5-year survival rates of patients with CR, those with additional surgery after non-CR, and those without additional surgery after non-CR were 84.6, 73.3, and 58.8 %, respectively. No deaths were attributable to the original gastric cancer; patients succumbed to other illnesses, including malignancy and respiratory disease. CONCLUSIONS: In elderly patients, ESD is an acceptable treatment for EGC in terms of both short- and long-term outcomes. Careful clinical assessment of elderly patients is necessary before ESD. After ESD, medical follow-up is important so that other malignancies and diseases that affect the elderly are not overlooked.

Double Extramedullary Plasmacytoma of the Stomach with a Long-term Endoscopic Follow-up.

A 56-year-old woman was referred to our hospital with a growing gastric submucosal tumor. An upper endoscopic examination revealed two gastric tumors, an original polypoid tumor and a newly diagnosed superficial tumor. Boring biopsied specimens of the submucosal tumor showed gastric plasmacytoma; however, the other specimens showed no malignancy. Blood diseases were ruled out using various examinations; therefore, we diagnosed the tumor as extramedullary gastric plasmacytoma. The patient underwent laparoscopic distal gastrectomy, and both tumors were thus revealed to be plasmacytomas. We experienced a rare case with two differently shaped extramedullary gastric plasmacytomas without significant morphologic change during the follow-up.

Unusual Development of Pulmonary Tumor Embolism from Controlled Liver Metastases of Transitional Cell Carcinoma: An Autopsy Case.

Clinicians generally suspect pulmonary tumor embolism (PTE) with uncontrolled carcinomas which often spread to lungs. We, however, experienced an autopsy case of diffuse microscopic PTE despite controlled liver metastases of transitional cell carcinoma (TCC). A 66-year-old man with progressing respiratory symptoms showed almost normal chest findings on computed tomography. Although liver metastases were successfully shrunk by chemotherapy, the patient died from aggressive respiratory failure. An autopsy revealed small pulmonary vessels showing diffuse tumor emboli. TCC can cause PTE even if liver metastases are controlled. We must therefore be aware that PTE can manifest as respiratory symptoms without any computed tomography findings.

Paraneoplastic Erythrocytosis of Colon Cancer, with Serum Erythropoietin within the Normal Reference Range.

BACKGROUND: Paraneoplastic erythrocytosis can be brought on by ectopic erythropoietin production usually in kidney, brain, and liver tumor with increase of serum erythropoietin level. We report here a paraneoplastic erythrocytosis of colon cancer with serum erythropoietin within the normal reference, which required an immunohistologic test for erythropoietin-antibody to be diagnosed. CASE REPORT: Our case report was of a 75-year-old woman with erythrocytosis. Her hemoglobin and serum erythropoietin levels were 191 g/dL and 12.6 IU/L (reference range, 9.1-32.8), respectively. Colonoscopy revealed an advanced sigmoid colon tumor 20 mm in diameter. She underwent colectomy, and immunohistochemical examination showed the colon adenocarcinoma was focally positive for erythropoietin-antibody. One month after the surgery, her hemoglobin level decreased to 117 g/L. CONCLUSIONS: Colon cancer can cause paraneoplastic erythrocytosis, and it is important to consider not simply the absolute serum erythropoietin level but also the serum erythropoietin level relative to simultaneously measured hemoglobin level. We should include paraneoplastic erythrocytosis as a differential diagnosis in cases of high hemoglobin level unexplained by other diseases.

Conversion therapy of gastric cancer with massive malignant ascites and ovarian metastases by systemic and intraperitoneal chemotherapy.

Intravenous and intraperitoneal paclitaxel with S-1 is showing promising results in gastric cancer with peritoneal metastases. We herein report a successful conversion of unresectable to resectable disease using combination chemotherapy with trastuzumab. The patient was a 39-year-old woman with human epidermal growth factor receptor 2-positive gastric cancer with peritoneal, pulmonary and bilateral ovarian metastases. After 6 cycles of S-1 plus cisplatin with trastuzumab, followed by 15 cycles of intravenous and intraperitoneal paclitaxel with S-1 and trastuzumab, the pulmonary and peritoneal metastases exhibited complete response and no evidence of malignancy was found on diagnostic laparoscopy. We performed metastasectomy of the bilateral sizeable ovaries, followed by total gastrectomy. The patient had no recurrence for 16 months after the gastrectomy. Therefore, satisfactory response to systemic and intraperitoneal chemotherapy may convert unresectable to resectable disease, and primary tumor resection with ovarian metastasectomy may prolong survival. This combination chemotherapy has the potential of becoming a conversion therapy for gastric cancer with peritoneal metastases, even if ascites and ovarian metastases are extensive.

Conversion therapy for pancreatic cancer with peritoneal metastases using intravenous and intraperitoneal paclitaxel with S-1.

Combination chemotherapy consisting of systemic and intraperitoneal agents against peritoneal metastases from several types of cancer has shown promising results. We herein report a case in which combination therapy with intravenous and intraperitoneal paclitaxel with S-1 converted an unresectable pancreatic cancer with peritoneal metastases into a resectable one. The patient was a 65-year old woman with recurrent pancreatitis for 5 months. Endoscopic ultrasonography-guided fine-needle aspiration revealed minute epithelial masses composed of cells with irregular nuclei in the pancreatic body. The patient underwent abdominal surgery, but no excision was performed, as two peritoneal metastases in the bursa omentalis were detected. Combination therapy was initiated, consisting of intravenous and intraperitoneal paclitaxel with S-1 as a single-center clinical trial. The regimen consisted with 2-week administration of S-1 (80 mg per day) followed by 1 week of rest, intravenous paclitaxel 50 mg/m2, and intraperitoneal paclitaxel 20 mg/m2 by a peritoneal access device on days 1 and 8. Over the seven cycles of the chemotherapy, the primary lesion did not change in size, and peritoneal lavage cytology remained negative. After confirming the disappearance of the peritoneal lesions by exploratory laparoscopy, the patient underwent distal pancreatectomy combined with resection of the transverse mesocolon and stomach wall. Thus, the 2-way chemotherapy of intravenous and intraperitoneal paclitaxel with S-1 was well-tolerated and was able to convert pancreatic cancer with peritoneal metastases to resectable disease.

Connexin expression and gap-junctional intercellular communication in ES cells and iPS cells.

Pluripotent stem cells, i.e., embryonic stem (ES) and induced pluripotent stem (iPS) cells, can indefinitely proliferate without commitment and differentiate into all cell lineages. ES cells are derived from the inner cell mass of the preimplantation blastocyst, whereas iPS cells are generated from somatic cells by overexpression of a few transcription factors. Many studies have demonstrated that mouse and human iPS cells are highly similar but not identical to their respective ES cell counterparts. The potential to generate basically any differentiated cell types from these cells offers the possibility to establish new models of mammalian development and to create new sources of cells for regenerative medicine. ES cells and iPS cells also provide useful models to study connexin expression and gap-junctional intercellular communication (GJIC) during cell differentiation and reprogramming. In 1996, we reported connexin expression and GJIC in mouse ES cells. Because a substantial number of papers on these subjects have been published since our report, this Mini Review summarizes currently available data on connexin expression and GJIC in ES cells and iPS cells during undifferentiated state, differentiation, and reprogramming.

Regulation of connexin expression by transcription factors and epigenetic mechanisms.

Gap junctions are specialized cell-cell junctions that directly link the cytoplasm of neighboring cells. They mediate the direct transfer of metabolites and ions from one cell to another. Discoveries of human genetic disorders due to mutations in gap junction protein (connexin [Cx]) genes and experimental data on connexin knockout mice provide direct evidence that gap junctional intercellular communication is essential for tissue functions and organ development, and that its dysfunction causes diseases. Connexin-related signaling also involves extracellular signaling (hemichannels) and non-channel intracellular signaling. Thus far, 21 human genes and 20 mouse genes for connexins have been identified. Each connexin shows tissue- or cell-type-specific expression, and most organs and many cell types express more than one connexin. Connexin expression can be regulated at many of the steps in the pathway from DNA to RNA to protein. In recent years, it has become clear that epigenetic processes are also essentially involved in connexin gene expression. In this review, we summarize recent knowledge on regulation of connexin expression by transcription factors and epigenetic mechanisms including histone modifications, DNA methylation, and microRNA. This article is part of a Special Issue entitled: The communicating junctions, roles and dysfunctions.

[A case of primary unknown cancer responding to CDGP/S-1].

A 77-year-old woman visited our hospital with the chief complaint of left supraclavicular lymph node redness and swelling. Needle biopsy revealed metastatic, epithelial, undifferentiated carcinoma. However, the primary tumor remained unknown despite further thorough examinations, FDG-PET showed abnormal FDG accumulation at the lymph nodes of para-aortic and left external iliac artery area in addition to left supraclavicular lymph node. However, CT and MRI showed no lymph node swelling in the peritoneal cavity. Nedaplatin (CDGP) combined with S-1 therapy was carried out for this primary unknown cancer with lymph node metastases. Three months after CDGP/S-1 therapy was begun, the swollen left supraclavicular lymph node was obviously reduced by 42.5%. Moreover, abnormal FDG accumulation at left supraclavicular and para-aortic lymph nodes dramatically decreased and that at the left external iliac artery area disappeared. The anti-tumor effect was evaluated as a partial response by use of Response Evaluation Criteria in Solid Tumors (RECIST). Standard treatment for primary unknown cancer was not established, because it includes various carcinomas. Here we report a case of primary unknown cancer successfully treated with CDGP/S-1. This combined therapy was considered to be one of the promising strategies for a primary unknown cancer.

Regulation of connexin expression.

Gap junctions contain cell-cell communicating channels that consist of multimeric proteins called connexins and mediate the exchange of low-molecular-weight metabolites and ions between contacting cells. Gap junctional communication has long been hypothesized to play a crucial role in the maintenance of homeostasis, morphogenesis, cell differentiation, and growth control in multicellular organisms. The recent discovery that human genetic disorders are associated with mutations in connexin genes and experimental data on connexin knockout mice have provided direct evidence that gap junctional communication is essential for tissue functions and organ development. Thus far, 21 human genes and 20 mouse genes for connexins have been identified. Each connexin shows tissue- or cell-type-specific expression, and most organs and many cell types express more than one connexin. Cell coupling via gap junctions is dependent on the specific pattern of connexin gene expression. This pattern of gene expression is altered during development and in several pathological conditions resulting in changes of cell coupling. Connexin expression can be regulated at many of the steps in the pathway from DNA to RNA to protein. However, transcriptional control is one of the most important points. In this review, we summarize recent knowledge on transcriptional regulation of connexin genes by describing the structure of connexin genes and transcriptional factors that regulate connexin expression.