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Background The frequency of metastasis to the pancreas is very low, and the frequency of metastasis from squamous cell carcinoma of the esophagus is even lower. Although curative resection of these metastatic lesions has been reported for some patients, the survival benefit of these procedures has not yet been clearly determined. Case presentation The patient was a 54-year-old man who was found to have lower thoracic esophageal cancer. Computed tomography showed a 2-cm tumor in the tail of his pancreas. Since no other obvious distal metastases were observed, the patient underwent simultaneous surgical procedures that excised both the esophageal squamous cell carcinoma and the pancreatic metastasis. Histopathologic examination confirmed squamous cell carcinoma in both specimens. The patient has been free of disease for 9 months since the resection. A literature review of all relevant cases to date found that the site of the primaries of all cases of esophageal cancers with metastasis to the pancreas was the lower thoracic esophagus. Conclusion Complete simultaneous resections of esophageal squamous cell carcinoma and a solitary metastasis to the pancreas is beneficial and may produce good outcomes. However, because of the low number of such reports, further studies are needed to confirm the benefits of surgery.

An irreparable scaphoid proximal pole is challenging to treat because of the fragment size and limited blood supply. Salvage surgery, such as partial wrist fusion or proximal row carpectomy, may be performed but is not ideal for young patients. There are few reports of proximal scaphoid reconstruction using rib osteochondral grafts.Four patients were treated with rib osteochondral graft for reconstruction of the scaphoid proximal pole. The patients had a mean postoperative follow-up of 24 months. The mean age at the time of surgery was 30 years. Outcome measurements included total active range of wrist motion arc, grip strength, and wrist function score. We also evaluated the progression of osteoarthritis and changes in carpal height.No complications occurred at the donor site. The range of motion improved from 82° to 95° before and after surgery. Grip strength improved from 22 kg to 33 kg before and after surgery. There was a remarkable improvement in the modified wrist function scores of Green and O'Brien from 40 points to 70 points before and after surgery. No progression of arthrosis was seen on the radiographs of all the patients. There was no significant difference in the carpal height ratio before and after surgery.Proximal scaphoid fractures may require reconstruction of the articular surfaces of the radius, capitate, and lunate. Reconstruction with a rib osteochondral graft is flexible, easy to fabricate, and can reconstruct the three articular surfaces.

BACKGROUND Loss-of-function homozygous or compound heterozygous mutations in IL36RN, which encodes interleukin-36 receptor antagonist (IL-36Ra), has been implicated in the pathogenesis of skin disorders. However, the pathogenic role of IL-36Ra in cutaneous ischemia-reperfusion (I/R) injury remains unclear. OBJECTIVES We investigated the role of IL36Ra in cutaneous I/R injury. METHODS We examined I/R injury in Il36rn-/- mice. The area of wounds, numbers of infiltrated cells, apoptotic cells and neutrophil extracellular trap (NET) formation were assessed. The expression levels of various genes were analysed using real-time RT-PCR. The expression of high mobility group box 1 (HMGB1), an endogenous toll-like receptor (TLR) 4 ligand, was confirmed using immunohistology, and serum HMGB1 levels were measured by ELISA. Cytokine production by stimulated cultured J774A.1 and HaCaT cells was examined. RESULTS IL-36Ra deficiency resulted in significantly delayed wound healing and increased neutrophil and macrophage infiltration into the wound tissues. Il36rn-/- mice had increased mRNA expression levels of CXCL1, CXCL2, CCL4, TNF-α, TGF-β, IL-1β, IL-6 and IL-36γ relative to wild-type mice. Apoptosis was identified in keratinocytes by TUNEL assay. HMGB1 expression in the I/R site was decreased in both keratinocytes and adnexal cells, while serum HMGB1 levels were significantly elevated after reperfusion. The mRNA levels of various cytokines, including IL-1β, were elevated in J774A.1 cells through TLR4 signalling by HMGB1 stimulation. In addition, HaCaT cells stimulated with IL-1β showed significantly increased CXCL1, TNF-α, IL-6, IL-36β and IL-36γ mRNA expression. Furthermore, NET formation was increased by IL-36Ra deficiency. Finally, either the blockade of TLR4 signalling by TAK-242 or inhibition of NET formation by Cl-amidine normalized exacerbated I/R injury in Il36rn-/- mice. CONCLUSIONS This study indicated that IL-36Ra deficiency exacerbates cutaneous I/R injury due to excessive inflammatory cell recruitment, NET formation, and excessive cytokine and chemokine production via the TLR4 pathway by HMGB1 released from epidermal apoptotic cells.

A 67-year-old woman had a painless tumor in the pulp of her left little finger, which was diagnosed as a synovial cyst. She underwent 2 surgeries to remove the cyst; however, she had a third recurrence. Magnetic resonance imaging revealed that the cyst originated from the flexor tenosynovitis associated with degenerative arthritis of the distal radioulnar joint and pisotriquetral joint. We performed flexor tenosynovectomy and a salvage procedure for the degenerative wrist joint with a Sauve-Kapandji procedure for distal radioulnar joint osteoarthritis and pisiformectomy for pisotriquetral joint arthritis. One year after surgery, the synovial cyst had not recurred, and the functional outcomes of the wrist joint were good. Flexor tenosynovectomy and concurrent joint salvage procedure may be good treatment choices for synovial cysts originating from the flexor tenosynovitis associated with a degenerative wrist joint.

Syphilis can cause a wide range of systemic manifestations, such as papular rash, malaise, weight loss, muscle aches, generalized lymphadenopathy, and meningitis. However, pulmonary involvement in patients with secondary syphilis is thought to be relatively rare. Moreover, bone involvement in patients with secondary syphilis is also considered rare, and only a few cases of involvement of lung and bone in such patients have been reported. In this paper, we report a case of secondary syphilis with pulmonary involvement in the form of multiple nodules with low attenuation areas, lymphadenopathy and multiple bone lesions detected on computed tomography and 18F fluorodeoxyglucose-positron emission tomography/computed tomography.

Background: Infiltrative lesions of the skin caused by unresectable malignant tumors reduce the quality of life of patients significantly due to the presence of bleeding, exudate, pain, and/or malodor. Objective: We compared the efficacy of a modified Mohs' technique and topical application of a starch powder containing zinc oxide as palliative treatments for skin lesions caused by unresectable tumors in our hospital. Design: This is a retrospective study. Settings/Subjects: This study included nine patients who were treated for skin-infiltrating lesions caused by unresectable malignant tumors at our hospital in Japan from April 2008 to December 2019. Measurements: Mohs' paste or zinc oxide powder (50%) was applied to the infiltrative skin lesions. Arterial embolization was performed before the application of the Mohs' paste for patients at risk for arterial hemorrhage. Patients were evaluated for pain, tumor size, bleeding, wound exudate, and malodor. Results: Both treatments were useful for alleviating symptoms, such as tumor size, local bleeding, malodor, and exudate in patients with unresectable malignant tumors. Pain was reduced in patients treated with Mohs' paste for 1 hour as compared with those treated for 24 hours. Conclusions: Effective management of skin infiltrative lesions can be achieved by using a modified Mohs' technique, topical application of starch powder containing zinc oxide, and arterial embolization to reduce the vascularization of the tumors.

BackgroundNeuroendocrine tumors of the minor papilla are very rare, and only 20 cases have been reported in the literature. Neuroendocrine carcinoma of the minor papilla with pancreas divisum has not been reported; thus, this report describes the first case. Neuroendocrine tumors of the minor papilla have been reported in association with pancreas divisum in about 50% of cases reported in the literature. We herein present our case of neuroendocrine carcinoma of the minor papilla with pancreas divisum in a 75-year-old male with a systematic literature review of the previous 20 reports of neuroendocrine tumors of the minor papilla.Case presentationA 75-year-old man was referred to our hospital for evaluation of dilation of the main pancreatic duct noted on abdominal ultrasonography. Magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography showed a dilated dorsal pancreatic duct, which was not connected to the ventral pancreatic duct; however, it opened to the minor papilla, indicating pancreas divisum. The common bile duct had no communication with the pancreatic main duct and opened to the ampulla of Vater. A contrast-enhanced computed tomography scan showed a 12-mm hypervascular mass near the ampulla of Vater. Endoscopic ultrasonography showed a defined hypoechoic mass in the minor papilla with no invasion. The biopsies performed at the previous hospital found adenocarcinoma. The patient underwent a subtotal stomach-preserving pancreaticoduodenectomy. The pathological diagnosis was neuroendocrine carcinoma. At the 15-year follow-up visit, the patient was doing well with no evidence of tumor recurrence.ConclusionIn our case, because the tumor was discovered during a medical check-up relatively early in the course of disease, the patient was doing well at the 15-year follow-up visit with no evidence of tumor recurrence. Diagnosing a tumor of the minor papilla is very difficult because of the relatively small size and submucosal location. Carcinoids and endocrine cell micronests in the minor papilla occur more frequently than generally thought. It is very important to include neuroendocrine tumors of the minor papilla in the differential diagnosis of patients with recurrent pancreatitis or pancreatitis of unknown cause, especially for patients with pancreas divisum.

We herein report a 64-year-old man with concomitant pancreatic ductal adenocarcinoma (PDAC) and type 1 autoimmune pancreatitis (AIP). An endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) from the pancreatic head mass revealed level 2 histology of AIP and atypical glands. We diagnosed definitive focal AIP using the clinical diagnostic criteria. Computed tomography revealed that the pancreatic mass had not been reduced by steroid therapy. Surgery was performed after a histological PDAC diagnosis was made via a transpapillary biliary biopsy. The resected specimen revealed PDAC associated with AIP. It is important to consider the cooccurrence of PDAC and AIP even if the histological diagnosis via an EUS-FNB is AIP.

Combination therapy with BRAF and MEK inhibitors (BRAFi/MEKi) have dramatically improved prognosis among patients with BRAF-mutant metastatic melanoma compared with traditional treatment, such as chemotherapy. However, resistance to these targeted agents occurs invariably, thereby limiting their clinical efficacy. Recently, it has been reported that the ligand-independent phosphorylation of erythropoietin-producing hepatocellular receptor A2 (EphA2) at Ser-897 signaling is a driver of BRAF inhibitor resistance in melanoma. A melanoma patient with multiple metastases was treated with dabrafenib plus trametinib therapy and maintained complete remission for more than 2 years. As brain metastasis occurred, we had switched to nivolumab plus ipilimumab therapy. However, new lesions were observed after four cycles of nivolumab plus ipilimumab therapy, she was rechallenged with encorafenib plus binimetinib therapy, and she maintained progression-free status for more than 7 months. We performed immunohistochemical staining of EphA2, phospho-EphA2 (p-EphA2; Ser-897), and epidermal growth factor receptor (EGFR) of melanoma cells before and/or after dabrafenib and trametinib therapy. Immunohistochemical examination showed higher expression of EphA2, p-EphA2, and EGFR in the melanoma cells after dabrafenib plus trametinib therapy as compared with that before therapy. Our results may indicate that EphA2, p-EphA2, and EGFR can be critical factors for resistance and reversible response of BRAFi/MEKi in metastases of melanoma. Our case presents a possible treatment that can help overcome BRAFi/MEKi resistance and improve prognosis of melanoma.

Pancreatic cancer (PaCa) exhibits one of the poorest prognoses among all gastrointestinal cancers due to the rapid development of treatment resistance, which renders chemotherapy and radiotherapy no longer effective. However, the mechanisms through which PaCa becomes resistant to radiotherapy are unknown. Here, we established radiation‑resistant PaCa cell lines to investigate the factors involved in radiation resistance. The role of the C‑X‑C motif chemokine ligand 12 (CXCL12)/C‑X‑C chemokine receptor type 4 (CXCR4) axis in radiation resistance in PaCa and the effects of a CXCR4 antagonist on radiation‑resistant PaCa cell lines were investigated. As confirmed by immunofluorescence staining, reverse transcription quantitative polymerase chain reaction, and western blotting, the expression of CXCR4 was higher in radiation‑resistant PaCa cell lines than that noted in normal PaCa cell lines. The invasion ability of radiation‑resistant PaCa cell lines was greater than that of normal cell lines and was enhanced by CXCL12 treatment and coculture with fibroblasts; this enhanced invasion ability was suppressed by the CXCR4 antagonist AMD070. Irradiation after treatment with the CXCR4 antagonist suppressed the colonization of radiation‑resistant PaCa cell lines. In conclusion, the CXCL12/CXCR4 axis may be involved in the radiation resistance of PaCa. These findings may facilitate the development of novel treatments for PaCa.

We experienced a case of solitary liver tumor that developed after renal cancer surgery. Before the surgery, the tumor was suspected to be hepatocellular carcinoma and was subsequently diagnosed as renal cancer liver metastasis. An 81-year-old man underwent retroperitoneal laparoscopic nephrectomy for left renal cancer in January 2017. After that, the cancer had not recurred, but a follow-up CT examination 1 year after the operation revealed a 42 mm-sized tumor in the liver S6. Liver biopsy was performed for diagnosis, but in histopathological findings, the diagnosis was difficult to make. Eventually, the preoperative final diagnosis was hepatocellular carcinoma. Laparoscopic partial hepatectomy was performed in June 2018, and in the histopathological findings of the resected specimen, the final diagnosis was the liver metastasis from renal cancer. Generally, the prognosis of renal cancer with liver metastasis is poor, but if complete resection is possible, it is recommended in the Clinical Practical Guideline for Renal Cancer. In recent years, the number of minimally invasive laparoscopic surgeries for hepatectomy has increased, and its safety has also improved. Therefore, resection is diagnostic treatment for cases where, like this case, preoperative diagnosis for solitary liver tumor is difficult. Laparoscopic hepatectomy could be one of the effective treatment strategies.

Pancreatic cancer (PaCa) is one of the most aggressive types of cancer. Thus, the development of new and more effective therapies is urgently required. Escin, a pentacyclic triterpenoid from the horse chestnut, has been reported to exhibit antitumor potential by reducing cell proliferation and blocking the nuclear factor-κB (NF-κB) signaling pathway in several types of cancer. Our previous study reported that NF-κB enhanced the secretion of interleukin (IL)-8 and vascular endothelial growth factor (VEGF), thereby inducing angiogenesis in PaCa cell lines. In the present study, it was examined whether escin inhibited angiogenesis by blocking NF-κB activation in PaCa. It was initially confirmed that escin, at concentrations >10 µM, significantly inhibited the proliferation of several PaCa cell lines. Next, using immunocytochemical staining, it was found that escin inhibited the nuclear translocation of NF-κB. Furthermore, ELISA confirmed that NF-κB activity in the escin-treated PaCa cells was significantly inhibited and reverse transcription-quantitative PCR showed that the mRNA expression levels of tumor necrosis factor-α-induced IL-8 and VEGF were significantly suppressed following escin treatment in the PaCa cell lines. ELISA also showed that escin decreased the secretion of IL-8 and VEGF from the PaCa cells. Furthermore, tube formation in immortalized human endothelial cells was inhibited following incubation with the supernatants from escin-treated PaCa cells. These results indicated that escin inhibited angiogenesis by reducing the secretion of IL-8 and VEGF by blocking NF-κB activity in PaCa. In conclusion, escin could be used as a novel molecular therapy for PaCa.

Background The treatment of chronic pancreatitis requires a surgical approach in patients who are refractory to medical therapy. During surgical treatment, ductal decompression is required, but a pancreatectomy is necessary for some patients, such as those with severe stenosis of the pancreatic duct. Indeed, suboptimal procedures lead to recurrent pancreatitis. We used a laparoscopic hybrid approach for patients with severe stenosis of the pancreatic duct. In this report, we present the feasibility and outcomes of our approach. Methods We selected a laparoscopic approach for the distal pancreatectomy, which is relatively safe and the effect of reducing the length of the wound is substantial. We selected an open approach for the Frey procedure because complete ductal compression has a high risk for injury to the vessels posterior to the pancreas. We recorded the operative outcomes, postoperative complications, and recurrence of pancreatitis. Results We performed the laparoscopic hybrid approach on 3patients between January and December 2018. There were no major intraoperative complications (Clavien-Dindo classification IIIa or more) and the postoperative course was uneventful in all patients. There were no recurrences of pancreatitis and no postoperative pain in all patients in > 2 years of follow-up. Conclusion Our hybrid method with a focus on complete ductal compression with safety and minimal invasiveness might be the optimal approach for the surgical treatment of chronic pancreatitis that requires a pancreatectomy with the Frey procedure.

The case is a 59-year-old woman. A medical examination revealed a high CA19-9, she visited a nearby hospital. Abdominal echo showed thickening of the gallbladder wall, and she was referred to our hospital for further examination. EUS-FNA was performed and a biopsy of #12 lymph node revealed undifferentiated cancer, which was diagnosed as gallbladder cancer. FDG-PET showed accumulation of FDG in the gallbladder lumen and swollen lymph nodes around the aorta. Therefore, the cancer was considered unresectable and chemotherapy was performed. FDG-PET was re-examined after 4 courses of gemcitabine plus cisplatin combination chemotherapy. As a result, the lymph node swelling contracted, the accumulation of FDG disappeared, and surgery was scheduled. Extended cholecystectomy and extrahepatic bile duct resection were performed. She was discharged 22 days after the surgery without complications. Histopathological examination showed fibrotic tissue at the gallbladder and lymph nodes, but no residual tumor cells. There are no recurrences 11 months after surgery. Although the prognosis of gallbladder cancer with para-aortic lymph node metastasis is generally poor, it is suggested that conversion surgery with multimodality treatment including preoperative chemotherapy may be a useful therapeutic strategy.

Background: The treatment of chronic pancreatitis requires a surgical approach in patients refractory to medical therapy. During surgical treatment, ductal decompression is required, but a pancreatectomy is necessary for some patients, such as those with severe stenosis of the pancreatic duct. Importantly, inadequate procedures lead to recurrent pancreatitis. We used a minimally invasive approach for patients with severe stenosis of the pancreatic duct. In this report, we aim to present the feasibility and outcomes of our approach. Methods: We selected a laparoscopic approach for the distal pancreatectomy because these parts are relatively safe and the effect of reducing the length of the wound is substantial. We selected an open approach for parts of the Frey procedure because complete ductal compression has a high risk for injury to the vessels posterior to the pancreas. We examined operative outcomes, postoperative complications and recurrence of pancreatitis.Results: Our approach was performed in three patients from January 2018 to December 2018. No intraoperative complications occurred and the postoperative course was uneventful in all patients. There were no recurrence of pancreatitis and no postoperative pain in all patients in the over two years follow-up. Conclusion: Our hybrid method focusing on complete ductal compression with safety and minimal invasiveness is the optimal approach for the surgical treatment of chronic pancreatitis which requires a pancreatectomy with the Frey procedure.

Background: The treatment of chronic pancreatitis requires a surgical approach in patients refractory to medical therapy. During surgical treatment, ductal decompression is required, but a pancreatectomy is necessary for some patients, such as those with severe stenosis of the pancreatic duct. Importantly, inadequate procedures lead to recurrent pancreatitis. We used a novel minimally invasive approach for patients with severe stenosis of the pancreatic duct. In this report, we aim to present the feasibility and outcomes of our approach. Methods: We selected a laparoscopic approach for the distal pancreatectomy because these parts are relatively safe and the effect of reducing the length of the wound is substantial. We selected an open approach for parts of the Frey procedure because complete ductal compression has a high risk for injury to the vessels posterior to the pancreas. We examined operative outcomes, postoperative complications and recurrence of pancreatitis.Results: Our approach was performed in three patients from January 2018 to December 2018. No intraoperative complications occurred and the postoperative course was uneventful in all patients. There were no recurrence of pancreatitis and no postoperative pain in all patients in the over two years follow-up. Conclusion: Our hybrid method focusing on complete ductal compression with safety and minimal invasiveness is the optimal approach for the surgical treatment of chronic pancreatitis which requires a pancreatectomy with the Frey procedure.

Background An epithelial cyst in an intrapancreatic accessory spleen (ECIPAS) is rare. We report a case of ECIPAS that was treated with robot-assisted distal pancreatectomy with splenectomy. Case presentation The case was a 59-year-old woman who was referred to our hospital after a pancreatic tail tumor was found on computed tomography prior to surgery for small bowel obstruction at another hospital. A cystic lesion in the pancreatic tail was discovered and evaluated by magnetic resonance imaging and endoscopic ultrasonography. Based on clinical and radiological features, mucinous cystic neoplasm was included in the differential diagnosis. The patient underwent robot-assisted distal pancreatectomy with splenectomy. The postoperative course was uneventful. Pathological evaluation revealed a 20-mm ECIPAS in the pancreatic tail. Conclusions If a pancreatic tail tumor is present, ECIPAS should be included in the differential diagnosis. However, preoperative diagnosis is difficult, and a definitive diagnosis is often not obtained until after surgery. Surgery should be minimally invasive. Laparoscopic distal pancreatectomy has become a standard surgical procedure because it is minimally invasive. Robot-assisted surgery is not only minimally invasive, but also advantageous, because it has a stereoscopic magnifying effect and allows the forceps to move smoothly. Robot-assisted distal pancreatectomy may be a good option, when performing surgery for a pancreatic tail tumor.

In Internet of Things (IoT) networks, devices use various application protocols, such as MQ telemetry transport (MQTT), constrained application protocol (CoAP), and extensible messaging and presence protocol (XMPP). However, because of the various protocols used, devices adopting different protocols cannot communicate mutually; thus, service interoperability issues arise. To enhance service interoperability, protocol conversion is required. Because different protocols are used in IoT networks, they are required to correspond to various protocols and have high extensibility for protocol conversion. In this paper, a protocol conversion method that satisfies these requirements is proposed. The proposed method converts packets into a middle format before converting them into target protocols. Conversion rules are described for each protocol; thus, the proposed method has high extensibility. We confirmed that clients that use the proposed conversion method could successfully connect to other devices using different protocols and communicate mutually through servers. The protocols included MQTT, CoAP, XMPP, and SMTP. Furthermore, the throughput degradation caused by the conversion process is small.

We investigate the effect of asymmetric deformation dynamics in an amoeboid organism on its search ability using a model amoeba. The model represents the behaviours of the amoeboid organism and its search ability is evaluated by searching for the solution to a Boolean satisfiability problem (SAT). We found that the efficiency of the search is significantly improved by implementing asymmetric delays in response to the feedback signals that increase and decrease the variable under appropriate errors. The results indicate that the model could search around the variable vector space by means of the appropriate combination of the inherent local search in the model and the error-induced global search. The results also show that the asymmetric response delays bias the variable to the values that can satisfy the SAT. We also demonstrate that an analog electronic system implementing the amoeba model with asymmetric dynamics possesses the search characteristics of the model.

Summary Most triacylglycerol-lowering fibrates have been developed in the 1960s–1980s before their molecular target, peroxisome proliferator-activated receptor alpha (PPARα), was identified. Twenty-one ligand-bound PPARα structures have been deposited in the Protein Data Bank since 2001; however, binding modes of fibrates and physiological ligands remain unknown. Here we show thirty-four X-ray crystallographic structures of the PPARα ligand-binding domain, which are composed of a “Center” and four “Arm” regions, in complexes with five endogenous fatty acids, six fibrates in clinical use, and six synthetic PPARα agonists. High-resolution structural analyses, in combination with coactivator recruitment and thermostability assays, demonstrate that stearic and palmitic acids are presumably physiological ligands; coordination to Arm III is important for high PPARα potency/selectivity of pemafibrate and GW7647; and agonistic activities of four fibrates are enhanced by the partial agonist GW9662. These results renew our understanding of PPARα ligand recognition and contribute to the molecular design of next-generation PPAR-targeted drugs., Graphical Abstract, Highlights • X-ray crystallography reveals 34 high-resolution human PPARα-ligand structures • Stearic acid and palmitic acid are presumably physiological PPARα ligands • Coordination to Arm III domain is important for high PPARα potency/selectivity • Agonistic activities of four fibrates are enhanced by the partial agonist GW9662, Biochemistry; Molecular Physiology; Structural Biology; Protein Structure Aspects

Loss-of-function homozygous or compound heterozygous mutations in IL36RN, which encodes interleukin-36 receptor antagonist (IL-36Ra), have been implicated in the pathogenesis of various skin disorders. Previous findings showed that IL-36γ promoted wound healing in mice; however, the pathogenic role of IL-36Ra in wound healing remains unclear. We elucidated the role of IL-36Ra, a regulator of IL-36 in tissue repair by investigating the recruitment of inflammatory cells and cytokine production in the absence of IL-36Ra. Full-thickness excisional wounds were made on the back of Il36rn−/− mice and healing was assessed by monitoring macroscopic wound sizes, numbers of infiltrated cells, and gene expression of inflammatory cytokines. Macroscopic wound healing, re-epithelialization, and granulation tissue formation were delayed by 3 days post-injury in Il36rn−/− mice. This delay was associated with increased infiltrations of neutrophils and macrophages, and increased expression of cytokines, such as IL-36γ, C-X-C motif chemokine ligand 1 (CXCL1), and transforming growth factor (TGF)-β. Importantly, administration of TAK-242, a toll-like receptor 4 (TLR4) inhibitor, caused normalization of wound healing in Il36rn−/− mice, abrogating the initial delay in tissue repair. These results showed that targeting TLR4- mediated infiltrations of immune cells and cytokine production could be beneficial in regulating wound healing in IL-36Ra-deficient skin disorders.

A 60's man came to our hospital for jaundice. Contrast-enhanced CT showed irregular thickening of the hilar bile duct, and the lymph nodes(LN)were swollen from the hilar to the abdominal aorta. These LNs showed similar findings in endoscopic ultrasonography(EUS), and fine needle aspiration cytology(FNA)was performed on the enlarged No.13LN to diagnose LN metastasis of hilar cholangiocarcinoma. Since the peri-aortic LN was also markedly enlarged, it was considered to be metastasis, and was diagnosed as unresectable hilar cholangiocarcinoma with distant LN metastasis. When gemcitabine/cisplatin therapy(GC therapy)was started, tumor markers normalized and LN decreased in 4 months. We performed GC therapy for a total of 12 cycles and did not re-exacerbate. Cholangioscopy revealed that bile duct stenosis at the hilar portion had improved. We have determined that curative resection is possible and performed surgery. We confirmed that No.16b1LN was negative by pathological diagnosis during surgery and performed left hepatic caudate lobectomy, extrahepatic cholangectomy, and biliary reconstruction. Diagnosis was pT2aN1(n8a)M0, fStage ⅢB, and pR0. After surgery, adjuvant chemotherapy with S-1 was continued.