[Results of Watch and Wait after Chemoradiotherapy for Locally Advanced Rectal Cancer].

BACKGROUND: Watch and wait(W & W)for rectal cancer after chemoradiotherapy(CRT)is attracting attention. PURPOSE: To examine regimens and indications from the results of follow-up of cases undergoing W & W in our department. MATERIALS AND METHODS: CRT(SOX therapy 2-5 cycles, 45 Gy)was performed on patients with lower rectal cancer over a period of 2016 to 2020, and 7 patients with clinical complete response(cCR)were followed up. RESULTS: With a median follow-up of 33 months(10-74), 4 of 7 patients(57.1%)remained in cCR. Two patients had local relapse more than a year after the start of treatment, were able to undergo salvage surgery, and are alive after surgery. Patients with lateral lymph node metastasis before CRT had para-aortic lymph node metastasis at 8 months. CONCLUSIONS: Patients with maintained cCR were those with localized, node-negative disease. On the other hand, in patients with lymph node metastasis, including lateral metastasis, it was not possible to perform salvage surgery due to distant metastasis. Careful case selection and follow-up are necessary in the future.

[A Case of the Huge GIST in the Transverse Colon Mesentery with Intra-Tumoral Hemorrhage and Jejunal Infiltration].

A 38-year-old woman was admitted to our hospital due to severe anemia. CT showed a 13×12 cm tumor with moderately enhanced wall thickening in the right upper abdomen. The huge tumor located adjacent to the jejunum and compressed the right transverse colon. Hemorrhagic necrosis and air were observed within the tumor, suspecting tumor penetration into the jejunum. The patient was diagnosed with abdominal GIST with jejunal infiltration. Laparotomy revealed a 13× 11 cm solid mass with intra-tumoral hemorrhage and invasion into the jejunum, located in the transverse mesocolon. Tumor resection combined with partial jejunectomy and transverse colectomy were performed. Immunohistochemical findings of the resected specimen was positive for c-kit and DOG-1, and the MIB-1 positive rate was 10%. Three weeks after the operation, re-anastomosis was performed due to transverse colon anastomotic stricture. She was discharged 45 days after first operation. Currently, 9 months after the operation, patient has been prescribed imatinib and is alive without recurrence.

[A Case of Pancreatic Tail Cancer Causing Gastrointestinal Hemorrhage Due to Transverse Colon Invasion].

An 81-year-old woman was admitted to our hospital due to frequent bleeding and hemorrhagic shock. Blood tests revealed anemia and contrast-enhanced abdominal CT revealed a pancreatic tail tumor with a diameter of 60 mm. The boundary between pancreatic tumor and the transverse colon, stomach and spleen was unclear, and invasion of the transverse colon as well as the stomach and spleen was suspected. Hemorrhage due to colon invasion of the pancreatic tail cancer and intra-tumoral hemorrhage were suspected. Due to persistent bleeding, the patient had emergency surgery to control bleeding. The pancreatic tail tumor invaded not only the colon but also stomach and spleen, distal pancreatectomy, partial gastrectomy and splenectomy was performed in combination with resection of the transverse colon, and transverse colon colostomy. We report a case of gastrointestinal bleeding caused by transverse colon invasion of pancreatic tail cancer, which resulted in emergency surgery.

[A Case of Perihilar Cholangiocarcinoma with Postoperative Hepatic Encephalopathy Due to Portosystemic Shunt Treated by Percutaneous Embolization].

An 83-year-old woman developed jaundice, and was diagnosed as perihilar cholangiocarcinoma. Abdominal contrast- enhanced CT revealed coexisting portosystemic shunt between portal vein and inferior vena cava, however, her blood ammonia level was normal. She underwent right hemihepatectomy and caudate lobectomy combined with extrahepatic bile duct resection and portal vein resection. Postoperatively, hyperammonemia refractory to conservative treatment was observed. The blood ammonia level increased to 180µg/dL and she was suffered from grade Ⅲ hepatic encephalopathy on the 20th postoperative day. CT showed an increase in the diameter of the portosystemic shunt, while there was only a slight increase in the remnant left lobe of the liver. These findings indicated that hepatic encephalopathy was caused by increased portosystemic shunt blood flow and decreased portal venous flow. Hepatic encephalopathy was rapidly improved by percutaneous transhepatic portosystemic shunt obliteration.

Sphingosine-1-phosphate Receptor-1 Promotes Vascular Invasion and EMT in Hepatocellular Carcinoma.

BACKGROUND: It remains unknown whether epithelial-mesenchymal transition (EMT)-mediated vascular invasion and cancer stemness are associated with sphingosine-1-phosphate receptor-1 (S1PR1) expression in human hepatocellular carcinoma (HCC). The aim of this study was to investigate the correlation between S1PR1 expression and prognosis of patients with primary HCC and to define the potential of S1PR as a therapeutic target. MATERIALS AND METHODS: We investigated 108 patients who underwent primary surgical resection for HCC treatment. Expression of S1PR1 and EMT markers was analyzed to predict prognosis of patients with HCC. Furthermore, three-dimensional organotypic culture, anoikis assay, and cell invasion were performed to validate the association of S1PR1 with EMT and cancer stemness. RESULTS: Among patients with HCC, the high S1PR1 expression group had significantly shorter overall survival than the low expression group. Moreover, high S1PR1 expression was significantly associated with shorter recurrence-free survival, increased risk of portal and hepatic vein invasion, and intrahepatic metastasis. Multivariate analyses revealed that S1PR1 overexpression was an independent prognostic factor in patients with HCC. S1PR1 overexpression positively correlated with vimentin and MMP-9 expression and negatively correlated with E-cadherin. In addition, S1PR1 overexpression induced EMT and enhanced tumor invasion and cancer stemness. CONCLUSIONS: S1PR1 overexpression, via EMT-induced vascular invasion and increased cancer stem cell properties, establishes a metastatic niche, enhances the capacity of hematogenous metastasis, and associates with poor outcomes in patients with HCC. Hence, S1PR1 may serve as a therapeutic target for patients with HCC with vascular invasion.

Comparing prognostic factors of Glut-1 expression and maximum standardized uptake value by FDG-PET in patients with resectable pancreatic cancer.

BACKGROUND: This study aimed to assess the prognostic values of preoperative maximum standardized uptake value (SUVmax) of primary pancreatic tumors and Glut-1 expression in patients with resectable pancreatic ductal adenocarcinoma (R-PDAC), and to investigate whether Glut-1 expression is more effective than SUVmax in predicting survival in patients with R-PDAC. METHODS: We investigated 101 R-PDAC patients who underwent pancreatectomy for pancreatic cancer treatment. SUVmax analyzed through 18F-fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT), and Glut-1 expression, were assessed for predicting the prognosis of patients with R-PDAC. RESULTS: In patients with R-PDAC, the high SUVmax group (≥4.25) had significantly shorter overall survival (OS) and disease-free survival (DFS) than the low SUVmax group (＜4.25). Surprisingly, Glut-1 expression was not significantly correlated with SUVmax. Moreover, the high Glut-1 expression group, which was related to higher levels of CA 19-9, had significantly shorter OS and DFS than the low Glut-1 expression group. Furthermore, among the high SUVmax group, OS and DFS were significantly shorter in the high Glut-1 expression group. Multivariate analyses revealed that Glut-1 overexpression was an independent prognostic factor in patients with R-PDAC. Glut-1 knockdown also induced cell cycle arrest in PDAC cells in vitro. CONCLUSIONS: The study determined that Glut-1 overexpression is a more powerful prognostic factor than SUVmax for predicting OS and higher risk of recurrence in R-PDAC patients. Glut-1 overexpression is also more likely to be associated with malignant activity in PDAC patients.

[A Case of Anaplastic Carcinoma with Osteoclastlike Giant Cells of the Pancreas Concomitant with Lung Recurrence of Solitary Fibrous Tumor].

A 32-year-old woman presented with epigastric pain and an abdominal mass. Abdominal CT showed a 130mm pancreatic tail mass with an enhanced rim, central necrosis, and small calcification. A 6mm lung tumor was also found via chest CT. Her medical history included surgical resection of cerebral solitary fibrous tumor when she was 24 years old. When she was 31 years old, it had recurred but was cured by gamma knife radiosurgery. We performed distal pancreatectomy and splenectomy with lymph node dissection. According to pathological and immunohistochemical findings, it was diagnosed as an anaplastic carcinoma with osteoclast-like giant cells. She underwent surgical resection of the lung tumor 2 months after pancreatic resection and was diagnosed with metastasis from the solitary fibrous tumor. Fourteen months since undergoing pancreatectomy, the patient experienced no recurrence from both diseases. We report a rare resected case of anaplastic carcinoma of pancreas concomitant with recurrent solitary fibrous tumor.

Roles of Pin1 as a Key Molecule for EMT Induction by Activation of STAT3 and NF-κB in Human Gallbladder Cancer.

BACKGROUND: Despite developments in multidisciplinary treatment, the prognosis for advanced gallbladder cancer (GBC) still is poor because of its rapid progression. Epithelial-mesenchymal transition (EMT) plays a central role in promoting tumor invasion and metastasis in malignancies thorough signal transducer and activator of transcription-3 (STAT3) and nuclear factor κB (NF-κB) activation. Whereas Pin1 mediates STAT3 and NF-κB activation, the involvement of Pin1 in GBC progression is unclear. METHODS: Factors regulating Pin1-related STAT3 and NF-κB activation were evaluated using surgical specimens collected from 76 GBC patients, GBC cells, and orthotopic GBC xenograft mice. RESULTS: In the patients with GBC, high Pin1 expression in GBC was associated with aggressive tumor invasion and increased tumor metastasis, and was an independent factor for a poor prognosis. Pin1 expression was correlated with phosphorylation of STAT3(Ser727) and NF-κB-p65(Ser276), thereby activating STAT3 and NF-κB in GBC. Pin1-mediated STAT3 and NF-κB activation induced EMT in GBC. When Pin1 knockdown was performed in GBC cells, the phosphorylation of STAT3(Ser727) and NF-κB-p65(Ser276) was inhibited, and STAT3 and NF-κB activation was suppressed. Inactivation of STAT3 and NF-κB in Pin1-depleted cells decreased snail and zeb-2 expression, thereby reducing the rate of mesenchymal-like cells, suggesting that EMT was inhibited in GBC cells. PiB, a Pin1-specific inhibitor, inhibited EMT and reduced tumor cell invasion by inactivating STAT3 and NF-κB in vitro. Moreover, PiB treatment inhibited lymph node metastasis and intrahepatic metastasis in orthotopic GBC xenograft tumor in vivo. CONCLUSIONS: Pin1 accelerates GBC invasion and metastasis by activating STAT3 and NF-κB. Therefore, Pin1 inhibition by PiB is an excellent therapy for GBC by safely inhibiting its metastasis.

Geometrical Conversion of the EGFR Extracellular Domain by Adiabatic Mapping Combining Normal Mode Analysis of the Elastic Network Model and Energy Optimization.

The activation of epidermal growth factor receptor (EGFR) involves the geometrical conversion of the extracellular domain (ECD) from the tethered to the extended forms with the dynamic rearrangement of the relative positions of four subdomains (SDs); however, this conversion process has not yet been thoroughly understood. We compare the two different forms of the X-ray crystal structures of ECD and simulate the ECD conversion process using adiabatic mapping that combines normal mode analysis of the elastic network model (ENM-NMA) and energy optimization. A comparison of the crystal structures reveals the rigidity of the intradomain geometry of the SD-I and -III backbone regardless of the form. The forward mapping from the tethered to the extended forms retains the intradomain geometry of the SD-I and -III backbone and reveals the trends to rearrange the relative positions of SD-I and -III and to dissociate the C-terminal tail of SD-IV from the hairpin loop in SD-II. The reverse mapping from the extended to the tethered forms complements the promotion of ECD conversion in the presence of epidermal growth factor (EGF).

[Anaplastic Carcinoma of the Pancreas of the Spindle Cell Type with Rapid Growth and Liver Metastases after Resection-A Case Report].

An 81-year-old man was referred to our department because of rapid progression of a cystic lesion in the pancreatic tail. Abdominal CT revealed a heterogeneously enhancing tumor, measuring 70mm in diameter, in the pancreatic tail, encompassing a low-density area with calcification and directly invading the spleen. We diagnosed the patient with malignant transformation of solid-pseudopapillary neoplasm and performed distal pancreatectomy with splenectomy, partial transverse colectomy, and partial resection of the diaphragm. Histopathological examination revealed anaplastic carcinoma of the pancreas of the spindle cell type, and R0 resection was achieved. Anastomotic leakage of the transverse colon occurred on postoperative day 4, and ileostomy was performed. Multiple liver metastases were observed on postoperative day 27, and the patient was orally administered with S-1. Although he was discharged on postoperative day 50, he died of cancer on postoperative day 61. Anaplastic carcinoma of the pancreas has a poor prognosis, and an early multidisciplinary treatment should be performed.

[Surgical Cases of Rupture of Hepatocellular Carcinoma after Transcatheter Arterial Embolization].

Rupture of hepatocellular carcinoma(HCC)is a disease wherein the prognosis is poor. In this study, we investigated cases of rupture of HCC that we encountered over 18 years. The age of onset ranged 48-76 years(67 years on average). The patients included 5 males and 1 female. All the cases experienced onset with rapid abdominal pain or loss of consciousness. Shock conditions appeared in 3 cases. Arrest of bleeding was possible by transcatheter arterial embolization(TAE)in all the cases. Subsequently, systemic search and evaluation of hepatic functional reserve were conducted. Hepatectomy was performed in all the cases. No notable complications occurred after the surgery. Two patients with recurrent peritoneal dissemination died of the original disease within 2 years. In the other 3 patients, recurrence has not occurred, and 2 of them have achieved long-term recurrence-free survivals for 4 years or longer. Therefore, based on the findings, we consider that longterm survival can be expected, depending on individual cases.

[Surgical Treatment for Liver Metastases of Gastric Cancer].

At present, there is no apparent consensus about the indications for hepatectomy for liver metastases of gastric cancer. In this study, we identified factors of poor prognosis to investigate the indications for hepatectomy in 24 cases of hepatectomy for liver metastases of gastric cancer at our hospital during a period from August 2001 to September 2017. The 1-, 3-, and 5- year survival rates in all 24 cases were 63%, 21%, and 17%, respectively. Single variable analysis revealed that significant factors of poor prognosis were 3 or more liver metastases, synchronous liver metastasis, and positive surgical margin. Multivariable analysis revealed that significant independent factors of poor prognosis were synchronous liver metastases(HR 4.71, 95%CI: 1.08-21.79, p=0.040)and positive surgical margin(HR 5.95, 95%CI: 1.56-25.81, p=0.009). These findings indicated that, in cases of metachronous tumors and negative surgical margin, favorable prognosis can be expected following surgical resection for liver metastases of gastric cancer.

Duffy antigen receptor for chemokines (DARC) expressing in cancer cells inhibits tumor progression by suppressing CXCR2 signaling in human pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Chemokines play important roles in the progression of many malignancies; however, the role of chemokine receptor expression in clinical cases of PDAC is unclear. Moreover, little is known about DARC, a decoy receptor of CXC chemokines, in the regulation of tumor progression. METHODS: Functions of chemokine receptors were evaluated using surgical specimens collected from PDAC patients, and PDAC cell lines. RESULTS: CXCR2 expression had no impacts on predicting prognosis, but low DARC expression in cancer cells was an independent risk factor for poor prognosis. In PDAC with low DARC expression, tumor sizes were larger and vascular invasion was increased. High CXCR2 expression was a significant predictor for poor prognosis, only in PDAC patients with low DARC expression. CXCR2 signaling induced STAT3 activation in PDAC, resulting in promoting cell cycle progression, inhibiting apoptosis, inducing angiogenesis, and enhancing invasiveness. DARC inhibited STAT3 activation by down-regulating CXCR2 signaling. These effects were confirmed by EMSA in vitro. DARC knockdown significantly increased cell proliferation in CFPAC-1 cells with high DARC expression, by activating STAT3. In contrast, CXCR2 knockdown inhibited the proliferative effects of IL-8 in MIA PaCa-2 cells with low DARC expression. Moreover, the inhibitory effect of CXCR2 antagonist on PDAC cell proliferation was more powerful in MIA PaCa-2 cells than CFPAC-1 cells. CONCLUSIONS: DARC expressing in cancer cells inhibits PDAC progression by suppressing STAT3 activation through the inhibition of CXCR2 signaling. Therefore, DARC is a novel prognostic predictor and a potential therapeutic target for PDAC.

Hepatocyte exosomes mediate liver repair and regeneration via sphingosine-1-phosphate.

BACKGROUND & AIMS: Exosomes are small membrane vesicles involved in intercellular communication. Hepatocytes are known to release exosomes, but little is known about their biological function. We sought to determine if exosomes derived from hepatocytes contribute to liver repair and regeneration after injury. METHODS: Exosomes derived from primary murine hepatocytes were isolated and characterized biochemically and biophysically. Using cultures of primary hepatocytes, we tested whether hepatocyte exosomes induced proliferation of hepatocytes in vitro. Using models of ischemia/reperfusion injury and partial hepatectomy, we evaluated whether hepatocyte exosomes promote hepatocyte proliferation and liver regeneration in vivo. RESULTS: Hepatocyte exosomes, but not exosomes from other liver cell types, induce dose-dependent hepatocyte proliferation in vitro and in vivo. Mechanistically, hepatocyte exosomes directly fuse with target hepatocytes and transfer neutral ceramidase and sphingosine kinase 2 (SK2) causing increased synthesis of sphingosine-1-phosphate (S1P) within target hepatocytes. Ablation of exosomal SK prevents the proliferative effect of exosomes. After ischemia/reperfusion injury, the number of circulating exosomes with proliferative effects increases. CONCLUSIONS: Our data shows that hepatocyte-derived exosomes deliver the synthetic machinery to form S1P in target hepatocytes resulting in cell proliferation and liver regeneration after ischemia/reperfusion injury or partial hepatectomy. These findings represent a potentially novel new contributing mechanism of liver regeneration and have important implications for new therapeutic approaches to acute and chronic liver disease.

Comprehensive analysis of the Co-structures of dipeptidyl peptidase IV and its inhibitor.

BACKGROUND: We comprehensively analyzed X-ray cocrystal structures of dipeptidyl peptidase IV (DPP-4) and its inhibitor to clarify whether DPP-4 alters its general or partial structure according to the inhibitor used and whether DPP-4 has a common rule for inhibitor binding. RESULTS: All the main and side chains in the inhibitor binding area were minimally altered, except for a few side chains, despite binding to inhibitors of various shapes. Some residues (Arg125, Glu205, Glu206, Tyr662 and Asn710) in the area had binding modes to fix a specific atom of inhibitor to a particular spatial position in DPP-4. We found two specific water molecules that were common to 92 DPP-4 structures. The two water molecules were close to many inhibitors, and seemed to play two roles: maintaining the orientation of the Glu205 and Glu206 side chains through a network via the water molecules, and arranging the inhibitor appropriately at the S2 subsite. CONCLUSIONS: Our study based on high-quality resources may provide a necessary minimum consensus to help in the discovery of a novel DPP-4 inhibitor that is commercially useful.

[A Rare Complication of Transcatheter Arterial Injection for Multiple Liver Metastases of Rectal Neuroendocrine Tumor - A Case Report].

A 50-year-old man was diagnosed with multiple bilobar liver metastases of rectal neuroendocrine tumor(NET). Although he received octreotide for 6 months and everolimus for 10 months, the liver metastases gradually increased in size. Therefore, we decided to perform transcatheter arterial infusion(TAI)with miriplatin. The serum total bilirubin level increased to 13.1 mg/dL 9 days after treatment, and it took 2 months to return to the normal range. CT scan demonstrated that most of the liver tumors had remarkably shrunk 4 months after treatment, and the patient has no sign of tumor regrowth even 12 months after treatment. Retrospective analysis of our cases(98 procedures of[transcatheter arterial chemoembolization: TACE]or TAI for liver tumors performed at the Department of General Surgery, Chiba University from 2012 to 2015)revealed that serum biliary enzymes levels 7 days after TACE were significantly higher in patients with metastatic liver tumors than those in patients with hepatocellular carcinoma. These data suggest that the TACE procedure might lead to severe damage of the biliary system in patients with metastatic liver tumors. Although the morbidity rate of TAI is very low, the procedure should be performed with caution, especially for patients with liver metastases.

[A Radically-Resected Case of Ruptured IPMC of the Pancreas after Abscess Drainage Using an Endoscopic Naso-Pancreatic Drainage Tube].

A 79-year-old man was referred to our hospital because of sudden upper abdominal pain. Enhanced computed tomography revealed a huge multilocular cystic tumor with a thickened wall, which was connected with the main pancreatic duct of the pancreatic body. Abscess formation was seen inside the omental bursa; however, there were no signs of direct invasion of the cystic tumor into the stomach or transverse colon. Therefore, we performed emergency endoscopic naso-pancreatic drainage(ENPD)under the diagnosis of an intraperitoneal abscess caused by rupture of intraductal papillary mucinous carcinoma(IPMC). Four weeks later, distal pancreatectomy with omentectomy was performed to achieve curative resection of the ruptured IPMC. The postoperative course was uneventful and the patient was discharged on postoperative day 14. The pathological diagnosis was noninvasive IPMC. No signs of recurrence were seen until 12 months after surgery. Rupture of IPMC into the intraperitoneal space is rare; however, the prognosis is relatively poor because of the difficulty of curative resection. ENPD drainage before surgery is potentially useful for patients with ruptured IPMC to control local inflammation, which improves surgical curability.

[Two Cases of Remnant Pancreatic Cancer Treated Using Remnant Pancreatectomy Combined with Hepatic Arterial Resection].

Case 1: A 40-year-old man was diagnosed with remnant pancreatic cancer invading the celiac axis 8 months after pancreaticoduodenectomy for pancreatic head cancer. As his gastroduodenal artery had been resected, the patient underwent preoperative coil embolization of the common hepatic artery for the development of extrahepatic collaterals. Eighteen days after the coil embolization, remnant pancreatectomy combined with celiac axis resection without reconstruction was performed. The patient was discharged without postoperative hepatic complications. Case 2: A 62-year-old woman was diagnosed with remnant pancreatic cancer 13 months after distal pancreatectomy with celiac axis resection for pancreatic body cancer. As the coil that had accidentally migrated to the proper hepatic artery during preoperative coil embolization for initial surgery remained, the flow to the liver through the gastroduodenal artery had weakened. In contrast, collateral flow from the right inferior phrenic artery to the right hepatic artery had increased. Remnant pancreatectomy with gastroduodenal artery resection was performed with no postoperative hepatic complications. Changes in the hemodynamics of the liver, resulting from preoperative coil embolization, may reduce the risk of postoperative hepatic ischemia after remnant pancreatectomy combined with hepatic arterial resection.

[A Case of Early-Onset Rapidly Progressive Cerebral Infarction with Trousseau's Syndrome in a Patient with Pancreatic Cancer Undergoing Surgery].

Trousseau's syndrome refers to cerebral infarction associated with hypercoagulability caused by cancer. Here, we report a case of Trousseau's syndrome in a patient with pancreatic cancer undergoing surgery. A 71-year-old woman was diagnosed with pancreatic head cancer with portal vein invasion; she underwent pancreaticoduodenectomy combined with portal vein resection. Pathological examination showed poorly differentiated adenocarcinoma with para-aortic lymph nodal metastasis. Although the patient had an uneventful postoperative course, she suddenly developed right hemiplegia and dysarthria 6 weeks after surgery, resulting in multiple cerebral infarctions scattered over both hemispheres. Owing to elevated D-dimer and CA125 levels as well as multiple liver metastases, the patient was diagnosed with Trousseau's syndrome and treated using heparin-based anticoagulant therapy. However, her cerebral infarction progressed rapidly and she died within 35 days of admission. Therefore, Trousseau's syndrome should be suspected when a patient with cancer is diagnosed with cerebral infarction, and anticoagulation therapy with heparin should be promptly initiated.

CXC chemokine receptor-4 signaling limits hepatocyte proliferation after hepatic ischemia-reperfusion in mice.

The role of stromal cell-derived factor-1 (SDF-1 or CXCL12) and its receptor CXC chemokine receptor-4 (CXCR4) in ischemic liver injury and recovery has not been studied. Some reports suggest that this chemokine may aid in liver regeneration, but others suggest that it may be profibrotic through its activation of hepatic stellate cells. In this study we sought to elucidate the role of SDF-1 and its receptor CXCR4 during liver injury, recovery, and regeneration 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. CXCR4 was expressed constitutively in the liver, and hepatic levels of SDF-1 peaked 8 h after reperfusion but remained significantly increased for 96 h. Treatment of mice with the CXCR4 antagonist AMD3100 or agonist SDF-1 had no effect on acute liver injury assessed 8 h after I/R. However, treatment with AMD3100 increased hepatocyte proliferation after 72 and 96 h of reperfusion and reduced the amount of liver necrosis. In contrast, treatment with SDF-1 significantly decreased hepatocyte proliferation. These effects appeared to be dependent on the presence of liver injury, as AMD3100 and SDF-1 had no effect on hepatocyte proliferation or liver mass in mice undergoing 70% partial hepatectomy. The data suggest that signaling through CXCR4 is detrimental to liver recovery and regeneration after I/R and that clinical therapy with a CXCR4 antagonist may improve hepatic recovery following acute liver injury.