小西 孝宜

症例は60歳、男性。膵尾部癌に対して脾合併尾側膵切除、胃・空腸・左腎静脈合併切除術を施行した。術後補助化学療法としてS-1内服を1年間行った。術後1年8ヵ月目にCA19-9の上昇を認めたため、gemcitabine(GEM)による化学療法を開始した。以後GEMを継続していたが、術後3年10ヵ月目に腸閉塞で入院となった。保存的治療で改善せず、手術を施行したところ腹膜播種巣が小腸に浸潤していたため、バイパス術、播種巣の生検を施行した。術後FOLFIRINOX療法を開始したが、初回手術より4年8ヵ月目にCA19-9の上昇を認めGEM+nab-paclitaxel療法に変更し、初回手術後6年11ヵ月、腹膜播種再発確認後5年3ヵ月現在、明らかな増悪なく外来化学療法を継続中である。本症例ではいずれのレジメンも長い奏効期間を維持しただけではなく、特筆すべき副作用なく長期継続可能であったことも長期生存に寄与していると考えられた。(著者抄録)

症例は48歳、女性。食後の腹痛、腹部膨満感を主訴に前医を受診し、膵腫瘍を指摘され当科紹介となった。腹部dynamic CT検査で膵尾部に多房性嚢胞性病変を認め、胸部CT検査で右肺S10に3mm、5mm、左肺S8に10mmの小結節影を認めた。膵粘液性嚢胞腺癌(mucinous cystic carcinoma:MCC)、両側多発肺転移の診断で膵切除を先行し、二期的に肺転移巣を切除する方針とした。手術は尾側膵切除術を施行し、病理組織学的診断は膵MCCであった。術後経過は良好で術後第18病日に退院となった。膵切除から2ヵ月後、5ヵ月後にそれぞれ左肺S8+9区域切除、右肺S9+10区域切除を施行し、いずれも膵MCCの肺転移の診断であった。補助化学療法は施行せず経過観察中であり、膵切除後11ヵ月、肺切除後6ヵ月現在、無再発生存中である。(著者抄録)

A 60-year-old man underwent distal pancreatectomy with splenectomy and combined resection partially of the stomach, jejunum, and left renal vein. We administered S-1 adjuvant chemotherapy for 1 year. After its completion, the patient showed no evidence of recurrence. However, his carbohydrate antigen(CA)19-9 level was elevated for 1 year and 8 months postoperatively. We administered gemcitabine chemotherapy. He was admitted for bowel obstruction 3 years and 10 months postoperatively. Conservative treatment with an ileus tube did not improve the bowel obstruction. Therefore, we performed the surgery. Intraoperative findings revealed peritoneal nodules invading the small intestine. We performed a small bowel bypass. Pathological examination revealed the peritoneal nodule of pancreatic cancer. Although we administered FOLFIRINOX chemotherapy postoperatively, his CA19-9 level remained elevated for 4 years and 8 months after the first surgery. Therefore, chemotherapy was changed to gemcitabine and nab-paclitaxel. Six years and 11 months after the first surgery and 5 years and 3 months after the diagnosis of peritoneal dissemination, he survives with recurrence. Herein, there were 2 contributors to long-term survival; the patient not only showed positive responses to each chemotherapy regimen but could also continue chemotherapy without developing significant adverse effects.

A 48-year-old female visited former doctor with abdominal pain and bloating. She was suspected of having pancreatic tumor and referred to our hospital. Abdominal dynamic CT showed multilocular cystic tumor in the pancreatic tail, and chest CT showed multiple lung nodules. From these findings, the patient was diagnosed mucinous cystic carcinoma(MCC)with lung metastases. We performed distal pancreatectomy for the first and lung resection after pancreatectomy. After all, the pathological diagnosis was MCC and metastatic lung cancer from the MCC. The adjuvant chemotherapy was not performed. Eleven months after pancreatectomy and 6 months after lung resection, the patient is still alive without recurrence.

胆嚢癌(疑診例)に対する術中迅速組織診は、癌の存在診断と、深達度診断という二つの側面をもつ。とくに深達度に関しては術式決定にかかわる重要な要素であり、その正確性が常に求められている。しかしながら、術中迅速組織診断はホルマリン固定後標本と異なり、急速凍結された標本であるため、標本の質が固定後標本よりも低く、診断に難渋することも少なくない。われわれの施設では、胆嚢癌疑診例に対しては全例全層胆嚢摘出術に加え術中迅速組織診を施行しているが、癌であった症例の深達度の正診率は90.2%と比較的良好であるものの、他施設の迅速診断と最終診断の乖離例も含めて検討すると、標本の質の問題以外にも癌のRAS進展の問題やサンプリングエラーなどが重要な課題と考えられた。(著者抄録)

BACKGROUND: Conversion chemotherapy may downsize unresectable colorectal liver metastases (CRLMs), but may cause liver injury and splenic enlargement. The effect of preoperative chemotherapy on liver regeneration after liver resection remains undetermined. The aim of this study was to examine whether splenic enlargement induced by preoperative chemotherapy is an indicator to identify high-risk patients for impaired liver regeneration and liver dysfunction after resection. METHODS: We retrospectively reviewed 118 Japanese patients with CRLMs. Fifty-one patients had conversion chemotherapy. The other 67 patients underwent up-front liver resection. We clarified effects of conversion chemotherapy on splenic volume, liver function, and postoperative liver regeneration. Perioperative outcome was also analyzed. RESULTS: A ratio of the splenic volume before and after chemotherapy (SP index) in the oxaliplatin-based chemotherapy group was significantly greater than other chemotherapy groups after 9 or more chemotherapy cycles. Patients whose SP index was 1.2 or more had significantly higher indocyanine green retention rate at 15 min (ICG-R15) than patients without chemotherapy. Analyses of covariance showed liver regeneration rate after resection was decreased in patients whose SP index was 1.2 or more. The incidence of postoperative liver dysfunction in patients whose SP index was 1.2 or more was significantly greater than patients without chemotherapy. Multivariate analysis showed SP index was a significant predictive factor of impaired liver regeneration. CONCLUSIONS: Splenic enlargement induced by preoperative chemotherapy was a useful indicator for impaired liver regeneration after resection and a decision-making tool of treatment strategy for unresectable CRLMs.

Hepatic ischemia-reperfusion (I/R) is a major complication of liver resection, trauma, and liver transplantation; however, liver repair after I/R in diseased liver has not been studied. The present study sought to determine the manner in which the fibrotic liver repairs itself after I/R. Liver fibrosis was established in mice by CCl4 administration for 6 wk, and then liver I/R was performed to investigate liver injury and subsequent liver repair in fibrotic and control livers. After I/R, fibrotic liver had more injury compared with nonfibrotic, control liver; however, fibrotic liver showed rapid resolution of liver necrosis and reconstruction of liver parenchyma. Marked accumulation of hepatic stellate cells and macrophages were observed specifically in the fibrotic septa in early reparative phase. Fibrotic liver had higher numbers of hepatic stellate cells, macrophages, and hepatic progenitor cells during liver recovery after I/R than did control liver, but hepatocyte proliferation was unchanged. Fibrotic liver also had significantly greater number of phagocytic macrophages than control liver. Clodronate liposome injection into fibrotic mice after I/R caused decreased macrophage accumulation and delay of liver recovery. Conversely, CSF1-Fc injection into normal mice after I/R resulted in increased macrophage accumulation and concomitant decrease in necrotic tissue during liver recovery. In conclusion, fibrotic liver clears necrotic areas and restores normal parenchyma faster than normal liver after I/R. This beneficial response appears to be directly related to the increased numbers of nonparenchymal cells, particularly phagocytic macrophages, in the fibrotic liver.NEW & NOTEWORTHY This study is the first to reveal how diseased liver recovers after ischemia-reperfusion (I/R) injury. Although it was not completely unexpected that fibrotic liver had increased hepatic injury after I/R, a novel finding was that fibrotic liver had accelerated recovery and repair compared with normal liver. Enhanced repair after I/R in fibrotic liver was associated with increased expansion of phagocytic macrophages, hepatic stellate cells, and progenitor cells.

The CXC chemokine receptor 2 (CXCR2) is critical for neutrophil recruitment and hepatocellular viability but has not been studied in the context of cholestatic liver injury following bile duct ligation (BDL). The present study sought to elucidate the cell-specific roles of CXCR2 on acute liver injury after BDL. Wild-type and CXCR2-/- mice were subjected BDL. CXCR2 chimeric mice were created to assess the cell-specific role of CXCR2 on liver injury after BDL. SB225002, a selective CXCR2 antagonist, was administrated intraperitoneally after BDL to investigate the potential of pharmacological inhibition. CXCR2-/- mice had significantly less liver injury than wild-type mice at 3 and 14 days after BDL. There was no difference in biliary fibrosis among groups. The chemokines CXCL1 and CXCL2 were induced around areas of necrosis and biliary structures, respectively, both areas where neutrophils accumulated after BDL. CXCR2-/- mice showed significantly less neutrophil accumulation in those injured areas. CXCR2Liver+/Myeloid+ and CXCR2Liver-/Myeloid- mice recapitulated the wild-type and CXCR2-knockout phenotypes, respectively. CXCR2Liver+/Myeloid+ mice suffered higher liver injury than CXCR2Liver+/Myeloid- and CXCR2Liver-/Myeloid+; however, only those chimeras with knockout of myeloid CXCR2 (CXCR2Liver+/Myeloid- and CXCR2Liver-/Myeloid-) showed reduction of neutrophil accumulation around areas of necrosis. Daily administration of SB225002 starting after 3 days of BDL reduced established liver injury at 6 days. In conclusion, neutrophil CXCR2 guides the cell to the site of injury, while CXCR2 on liver cells affects liver damage independent of neutrophil accumulation. CXCR2 appears to be a viable therapeutic target for cholestatic liver injury.NEW & NOTEWORTHY This study is the first to reveal cell-specific roles of the chemokine receptor CXCR2 in cholestatic liver injury caused by bile duct ligation. CXCR2 on neutrophils facilitates neutrophil recruitment to the liver, while CXCR2 on liver cells contributes to liver damage independent of neutrophils. CXCR2 may represent a viable therapeutic target for cholestatic liver injury.

An 80-year-old man was referred to our hospital because of jaundice and fatigue. Abdominal computed tomography(CT) scan revealed an extrahepatic bile duct tumor, and biliary cytology detected adenocarcinoma; therefore, subtotal stomachpreserving pancreaticoduodenectomy was performed. Histological analysis showed that the tumor was a well-differentiated adenocarcinoma without lymph node metastasis. Two years after the initial surgery, blood examination detected an elevated serum CA19-9 level and submucosal tumor which is 2.5 cm diameter with an ulcer at the gastrojejunostomy anastomosis. Tumor biopsy was performed, and histological analysis revealed a recurrent cholangiocarcinoma. The tumor directly invaded the transverse colon mesentery; therefore, distal gastrectomy and right hemicolectomy were performed. The patient survived 12 months postoperatively without recurrence. Gastric metastasis from cholangiocarcinoma rarely occurs. Intraoperative exposure of bile juice may have caused gastric metastasis in this case.

A 78-year-old man was referred to our hospital owing to a pancreatic tumor detected on ultrasonography. He showed weight loss, and his diabetes mellitus had worsened over 3 months. Abdominal contrast-enhanced computed tomography revealed a 3 cm diameter pancreatic head tumor with peripheral enhancement and a dilated pancreatic duct. He underwent subtotal stomach-preserving pancreaticoduodenectomy. Examination of intraoperative frozen sections did not indicate cancer involvement at the edge of the resected pancreatic duct. The tumor was histologically diagnosed as mixed acinar-neuroendocrine carcinoma(MANEC). It was mainly detected in the pancreatic head and was accompanied by intra-ductal growth in the pancreatic duct. The patient has survived for 21 months without recurrence. MANEC is a rare disease associated with intraductal growth. Intraoperative diagnosis of tumor involvement at the edge of the pancreatic duct may be useful for R0 resection in surgery for MANEC.

Liver recovery after hepatic ischemia-reperfusion (I/R) injury is characterized by clearance of dead tissue and its replacement with functional liver parenchyma. Previous reports have observed fibrosis after liver I/R. To determine whether liver fibrosis after I/R was a pathologic consequence of the injury response, we assessed the development of liver fibrosis after I/R and its impact on subsequent insult. A murine model of partial I/R was used to induce liver injury and study the reparative response. During liver remodeling after I/R, expression of the profibrotic genes increased in the ischemic liver. Histologically, α-smooth muscle actin (α-SMA)-positive hepatic stellate cells (HSCs)/myofibroblasts increased, and collagen deposition was enhanced along the injured site. Selective staining experiments showed that HSCs, not portal fibroblasts, were the major source of myofibroblasts. During liver repair after I/R, liver fibrosis was readily observed at the interface between necrotic tissue and regenerating liver in association with HSCs/myofibroblasts. The number of HSCs/myofibroblasts decreasing shortly after the full resolution of necrotic injury and restoration are normal liver architecture. However, liver fibrosis persisted for several more weeks before gradually resolving. Resolution of liver fibrosis was accompanied by upregulated expression of matrix metalloproteinase-13. After resolution of fibrosis, the administration of CCl4 did not result in exacerbated liver injury, suggesting that I/R injury does not predispose the liver to future fibrotic insults. The data suggest that liver fibrosis is a component of tissue repair after I/R, is caused by myofibroblasts derived from HSC, and does not increase susceptibility of the liver to subsequent hepatic injury. NEW & NOTEWORTHY This study is the first to assess pathology of liver fibrosis during the reparative process after ischemia-reperfusion (I/R) injury. Here we show that profibrotic gene expression increased in the liver after I/R, and collagen accumulation produced by hepatic stellate cells (HSCs)/myofibroblasts enhanced at the interface between necrotic tissue and regenerating liver. Liver fibrosis gradually resolved concomitant with decreasing activation of HSC and upregulating matrix metalloproteinase-13. After resolution of fibrosis, the liver was not more susceptible to subsequent hepatic injury.

Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are key regulators of cell proliferation and organ size; however, their physiological contribution after liver injury has not been fully understood. In this study, we sought to determine the role of YAP and TAZ during liver recovery after ischemia-reperfusion (I/R). A murine model of partial (70%) I/R was used to induce liver injury and study the reparative and regenerative response. After liver injury, there was marked activation and proliferation of hepatic stellate cells. The Hippo pathway components, large tumor suppressor 1 (LATS1) and its adapter protein, Mps one binder 1 (MOB1), were inactivated during liver repair, and YAP and TAZ were activated selectively in hepatic stellate cells. Concurrently, the expression of connective tissue growth factor and survivin, both of which are YAP and TAZ target genes, were upregulated. Hepatic stellate cell expansion and concomitant activation of YAP and TAZ occurred only in the injured liver and were not observed in the nonischemic liver. Treatment of mice with verteporfin, an inhibitor of YAP and TAZ, decreased hepatic stellate cell proliferation, survivin, and cardiac ankyrin repeat protein expression. These changes were associated with a significant decrease in hepatocyte proliferation. The data suggest that liver repair and regeneration after I/R injury are dependent on hepatic stellate cell proliferation, which is mediated by YAP and TAZ. NEW & NOTEWORTHY This study is the first to assess the proliferation of hepatic stellate cells (HSCs) after ischemia-reperfusion (I/R) injury and their role in the reparative and regenerative process. Here we show that the Hippo pathway is inactivated after I/R and that Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) activation is detected in HSC. HSC proliferation and expansion are prominent during liver recovery after I/R injury. Inhibition of YAP/TAZ activation with verteporfin reduces HSC proliferation and target gene expression and attenuates hepatocyte proliferation.

Hepatic ischemia/reperfusion (I/R) injury is a major complication of liver surgery, including liver resection, liver transplantation, and trauma surgery. Much has been learned about the inflammatory injury response induced by I/R, including the cascade of proinflammatory mediators and recruitment of activated leukocytes. In this review, we discuss the complex network of events that culminate in liver injury after I/R, including cellular, protein, and molecular mechanisms. In addition, we address the known endogenous regulatory mediators that function to maintain homeostasis and resolve injury. Finally, we cover more recent insights into how the liver repairs and regenerates after I/R injury, a setting in which physical mass remains unchanged, but functional liver mass is greatly reduced. In this regard, we focus on recent work highlighting a novel role of CXC chemokines as important regulators of hepatocyte proliferation and liver regeneration after I/R injury.

Exosomes are small membrane vesicles released by different cell types, including hepatocytes, that play important roles in intercellular communication. We have previously demonstrated that hepatocyte-derived exosomes contain the synthetic machinery to form sphingosine-1-phosphate (S1P) in target hepatocytes resulting in proliferation and liver regeneration after ischemia/reperfusion (I/R) injury. We also demonstrated that the chemokine receptors, CXCR1 and CXCR2, regulate liver recovery and regeneration after I/R injury. In the current study, we sought to determine if the regulatory effects of CXCR1 and CXCR2 on liver recovery and regeneration might occur via altered release of hepatocyte exosomes. We found that hepatocyte release of exosomes was dependent upon CXCR1 and CXCR2. CXCR1-deficient hepatocytes produced fewer exosomes, whereas CXCR2-deficient hepatocytes produced more exosomes compared to their wild-type controls. In CXCR2-deficient hepatocytes, there was increased activity of neutral sphingomyelinase (Nsm) and intracellular ceramide. CXCR1-deficient hepatocytes had no alterations in Nsm activity or ceramide production. Interestingly, exosomes from CXCR1-deficient hepatocytes had no effect on hepatocyte proliferation, due to a lack of neutral ceramidase and sphingosine kinase. The data demonstrate that CXCR1 and CXCR2 regulate hepatocyte exosome release. The mechanism utilized by CXCR1 remains elusive, but CXCR2 appears to modulate Nsm activity and resultant production of ceramide to control exosome release. CXCR1 is required for packaging of enzymes into exosomes that mediate their hepatocyte proliferative effect.

Lesser omental hernia is a rare type of hernia that can cause intestinal obstruction. To our knowledge, there are only 16 documented cases of lesser omental hernia, including the present case. The subject of this case report was a 42-year-old man with a history of total colectomy for colon perforation caused by Crohn's disease 15 years earlier, who presented with epigastralgia and vomiting. Abdominal computed tomography (CT) revealed a distended bowel loop ventral to the stomach and convergence of mesenteric vessels at the lesser curvature of the stomach. Based on a diagnosis of intestinal obstruction caused by a lesser omental hernia, he underwent emergency surgery, which revealed a 150-cm jejunal segment herniating through a 5-cm defect in the lesser omentum from the retrogastric space. We reduced the herniated loop and closed the hernial orifice successfully. We describe the characteristic CT findings, which allowed us to make the preoperative diagnosis, and speculate how the past total colectomy, in which the gastrocolic ligament was isolated and the transverse colon was resected, probably caused by this hernia. This case serves to demonstrate that lesser omental hernia could be a postoperative complication of total colectomy.

With advances in drug treatment of breast cancer, the number of patients experiencing cardiac toxicity or carcinomatous pericarditis is expected to increase. These conditions can cause cardiac tamponade, which is a potentially fatal condition requiring prompt diagnosis and treatment. We experienced 3 breast cancer patients with cardiac tamponade due to carcinomatous pericarditis who survived for prolonged periods after treatment with pericardiocentesis and intrapericardial instillation. The 3 women were 68, 46 and 46 years old, respectively, and receiving treatment for recurrent breast cancer after surgery. They developed dyspnea and cough and were diagnosed with cardiac tamponade by echocardiography. Pericardiocentesis was performed, and cytology of the effusion confirmed the diagnosis of carcinomatous pericarditis. Intrapericardial instillation of cisplatin reduced the cardiac effusion, ameliorating symptoms. The patients died 13, 31 and 14 months later, respectively. In our clinical review of 13 other cases of cardiac tamponade due to breast cancer, 85% achieved local control after the aforementioned local treatments, which were considered to be effective. Although the overall prognosis was poor with a median survival time of only 4 months, some patients were able to survive more than 1 year after local treatment with subsequent systemic therapy.

A 57-year-old man, who was a chronic axillary crutch user as a result of childhood poliomyelitis, was referred to our hospital because of a sudden onset of right forearm ischemia. The right forearm had no pulse, and three-dimensional computed tomography (3DCT) showed an aneurysm of the right brachial artery associated with arterial occlusion. The thrombosed aneurysm of the brachial artery was resected and the brachial artery was successfully revascularized by interposing a saphenous vein graft. Postoperative 3DCT revealed an asymptomatic left brachial artery aneurysm. His postoperative course was uneventful under warfarin anticoagulation therapy.