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The number of cancer patients with impairment of activities of daily living (ADLs) has increased. This study aimed to examine associations of perioperative Barthel index score, a validated measure of ADLs, with survival outcomes following hepatectomy for hepatocellular carcinoma (HCC).We analyzed data of 492 consecutive patients who underwent hepatectomy for HCC between 2010 and 2018. Pre- and postoperative ADLs were assessed using the Barthel index (range, 0-100; higher scores indicate greater independence). Preoperative Barthel index score ≤85 or postoperative Barthel index score ≤85 was defined as impairment of perioperative ADLs. Cox proportional hazards regression was used to calculate hazard ratios (HRs) after adjusting for potential confounders.Among the 492 patients, 26 (5.2%) had a preoperative Barthel index score ≤85 and 95 (19%) had a postoperative Barthel index score ≤85. Impairment of perioperative ADLs was independently associated with shorter overall survival (multivariable HR: 1.75, 95% confidence interval [CI]: 1.06-2.81, p = 0.028). The association of impairment of perioperative ADLs with recurrence-free survival was not statistically significant.Impairment of perioperative ADLs is associated with poor prognosis following hepatectomy for HCC. Maintenance and improvement of perioperative ADLs would be important to provide favorable long-term outcomes in patients with HCC.

Fusobacterium nucleatum has been detected in 8%‐13% of human colorectal cancer, and shown to inhibit immune responses against primary colorectal tumors in animal models. Thus, we hypothesized that the presence of F. nucleatum might be associated with reduced T cell density in colorectal cancer liver metastases (CRLM). We quantified F. nucleatum DNA in 181 CRLM specimens using quantitative PCR assay. The densities of CD8+ T cells, CD33+ cells (marker for myeloid‐derived suppressor cells [MDSCs]), and CD163+ cells (marker for tumor‐associated macrophages [TAMs]) in CRLM tissue were determined by immunohistochemical staining. Fusobacterium nucleatum was detected in eight (4.4%) of 181 CRLM specimens. Compared with F. nucleatum‐negative CRLM, F. nucleatum‐positive CRLM showed significantly lower density of CD8+ T cells (P = .033) and higher density of MDSCs (P = .001). The association of F. nucleatum with the density of TAMs was not statistically significant (P = .70). The presence of F. nucleatum is associated with a lower density of CD8+ T cells and a higher density of MDSCs in CRLM tissue. Upon validation, our findings could provide insights to develop strategies that involve targeting microbiota and immune cells for the prevention and treatment of CRLM., Fusobacterium nucleatum was detected in eight (4.4%) of 181 colorectal cancer liver metastasis tissue. We found that the presence of F. nucleatum was associated with lower CD8+ T cell density and greater densities of both myeloid‐derived suppressor cells and tumor‐associated macrophages.

Two‐stage hepatectomy (TSH) is one of the specific surgical techniques that can expand the pool of resectable patients with initially unresectable colorectal liver metastases (CRLM). The indication of TSH for CRLM is only bilateral, multinodular disease, which cannot be resected by a single hepatectomy. TSH is nowadays considered an effective treatment for selected patients, with acceptable morbidity/mortality rates and promising long‐term outcomes. However, not all eligible patients can benefit from the TSH strategy. One of the most important issues is dropout from the strategy (failure to complete both of the two sequential procedures), because the survival of such patients is drastically worse compared with patients who can complete both stages. Another important issue is the early recurrence rate and subsequent poor survival even after completion of TSH. Thus, the selection of appropriate patients who can really benefit from the TSH strategy is crucial. This review discusses the optimal patient selection for TSH, which should be helpful for the development of treatment strategies for patients with extensive CRLM., Although two‐stage hepatectomy (TSH) for extensive colorectal liver metastases (CRLM) is nowadays considered an effective treatment for selected patients, with acceptable morbidity/mortality rates and promising long‐term outcomes, not all eligible patients can benefit from this strategy. In this review, we discuss the optimal patient selection for TSH, which should be helpful for the development of treatment strategies for patients with extensive CRLM.

Portal vein embolization (PVE) for hepatocellular carcinoma (HCC) was first introduced in 1986 and has been continuously developed throughout the years. Basically, PVE has been applied to expand the indication of liver resection for HCC patients of insufficient future liver remnant. Importantly, PVE can result in tumor progression in both embolized and non‐embolized livers; however, long‐term survival after liver resection following PVE is at least not inferior compared with liver resection alone despite the smaller future liver remnant volume. Five‐year disease‐free survival and 5‐year overall survival were 17% to 49% and 12% to 53% in non‐PVE patients, and 21% to 78% and 44% to 72% in PVE patients, respectively. At present, it has proven that PVE has multiple oncological advantages for both surgical and nonsurgical treatments. PVE can also enhance the anticancer effects of transarterial chemoembolization and can avoid intraportal tumor cell dissemination. Additional interventional transarterial chemoembolization and hepatic vein embolization as well as surgical two‐stage hepatectomy and associated liver partition and portal vein ligation for staged hepatectomy can enhance the oncological benefit of PVE monotherapy. Taken together, PVE is an important treatment which we recommend for listing in the guidelines for HCC treatment strategies., Oncological benefits of portal vein embolization (PVE) for hepatocellular carcinoma were summarized. PVE can result in tumor progression in both embolized and non‐embolized livers; however, long‐term survival after liver resection following PVE is at least not inferior compared with liver resection alone despite the smaller future liver remnant volume. Further, PVE has multiple oncological advantages for both surgical and nonsurgical treatments.

Background and Objectives Despite the long-standing consensus on the importance of tumor size, tumor number and carcinoembryonic antigen (CEA) levels as predictors of long-term outcomes among patients with colorectal liver metastases (CRLM), optimal prognostic cut-offs for these variables have not been established. Methods Patients who underwent curative-intent resection of CRLM and had available data on at least one of the three variables of interest above were selected from a multi-institutional dataset of patients with known KRAS mutational status. The resulting cohort was randomly split into training and testing datasets and recursive partitioning analysis was employed to determine optimal cut-offs. The concordance probability estimates (CPEs) for these optimal cut offs were calculated and compared to CPEs for the most widely used cut-offs in the surgical literature. Results A total of 1643 patients who met eligibility criteria were identified. Following recursive partitioning analysis in the training dataset, the following cut-offs were identified: 2.95 cm for tumor size, 1.5 for tumor number and 6.15 ng/ml for CEA levels. In the entire dataset, the calculated CPEs for the new tumor size (0.52), tumor number (0.56) and CEA (0.53) cut offs exceeded CPEs for other commonly employed cut-offs. Conclusion The current study was able to identify optimal cut-offs for the three most commonly employed prognostic factors in CRLM. While the per variable gains in discriminatory power are modest, these novel cut-offs may help produce appreciable increases in prognostic performance when combined in the context of future risk scores. publishedVersion

Background/Purpose We examined therapeutic strategies for pancreatic neuroendocrine neoplasm (pNEN) associated with MEN1 (M‐pNEN) by investigating clinicopathological features and menin expression. Methods Seventy‐seven patients who underwent resection of pNEN at our department from January 2001 to December 2017 were retrospectively analyzed. Immunohistochemical analysis of menin was performed using resected specimens. Results Seven patients (9%) met the diagnostic criteria for MEN1. M‐pNEN had more tumors (P, This study aimed to describe therapeutic strategies for pancreatic neuroendocrine neoplasm associated with multiple endocrine neoplasia type 1 (M‐pNEN) by investigating the clinicopathological features and menin expression. Sonoda and colleagues concluded that minimal resection with strict follow‐up is recommended rather than extensive pancreatic resections for consideration of recurrence in M‐pNEN.

Introduction The objective of this study was to describe the surgical techniques for a thoracoscopic approach to treat hepatocellular carcinoma in the hepatic dome. Also, safety, feasibility, and long-term outcomes were evaluated. Methods Surgical procedures were selected based on liver function, the extent and location of the tumor, and each patient's general condition. Thoracoscopic hepatic resection was performed under direct vision through a diaphragmatic incision. Thoracoscopic radiofrequency ablation (TRFA) was performed either with a transdiaphragmatic puncture for deeply located tumors or under direct vision through a diaphragmatic incision for subcapsular tumors. Results Thoracoscopic surgery was indicated for 107 patients with hepatocellular carcinoma in the hepatic dome. Among these patients, 5 underwent hepatectomy and 102 underwent radiofrequency ablation, which was more frequently employed in patients with impaired liver function. Of the patients who underwent radiofrequency ablation, 43 (42.2%) required a diaphragmatic incision. In the thoracoscopic hepatic resection group and TRFA group, the median operating time was 350 and 197 minutes, the median blood loss was 200 and 5 mL, and the complication rate was 12.7% and 20.0%, respectively. The 5-year overall and disease-free survival rates were 100% and 50.0% in the thoracoscopic hepatic resection group, respectively, and 60.7% and 18.1% in the TRFA group, respectively. Local recurrence after TRFA was observed in 10 patients (9.8%). Conclusion The thoracoscopic approach is safe and feasible, with promising short- and long-term outcomes. It could serve as a treatment option for hepatocellular carcinoma in the hepatic dome.

Although surgical resection is the only treatment of choice that can offer prolonged survival and a chance of cure in patients with colorectal liver metastases (CRLM), nearly 80% of patients are deemed to be unresectable at the time of diagnosis. Considerable efforts have been made to overcome this initial unresectability, including expanding the indication of surgery, the advent of conversion chemotherapy, and development and modification of specific surgical techniques, regulated under multidisciplinary approaches. In terms of specific surgical techniques, portal vein ligation/embolization can increase the volume of future liver remnant and thereby reduce the risk of hepatic insufficiency and death after major hepatectomy. For multiple bilobar CRLM that were traditionally considered unresectable even with preoperative chemotherapy and portal vein embolization, two‐stage hepatectomy was introduced and has been adopted worldwide with acceptable short‐ and long‐term outcomes. Recently, ALPPS (associating liver partition and portal vein ligation for staged hepatectomy) was reported as a novel variant of two‐stage hepatectomy. Although issues regarding safety remain unresolved, rapid future liver remnant hypertrophy and subsequent shorter intervals between the two stages lead to a higher feasibility rate, reaching 98%. In addition, adding radiofrequency ablation and vascular resection and reconstruction techniques can allow expansion of the pool of patients with CRLM who are candidates for liver resection and thus a cure. In this review, we discuss specific techniques that may expand the criteria for resectability in patients with initially unresectable CRLM.

BACKGROUND AND AIM Clinical significance of endoscopic response (ER) after neoadjuvant chemotherapy (NAC) for esophageal cancer has not been fully understood. Thus, the present study aimed to investigate the association between ER to NAC and its clinicopathological outcomes in patients with esophageal squamous cell carcinoma (ESCC). METHODS In total, 141 patients who underwent NAC and subsequent esophagectomy for ESCC were included. ER to NAC was retrospectively evaluated based on macroscopic findings of the primary tumor, which was classified into three categories: endoscopic no response (eNR), endoscopic partial response (ePR), and endoscopic good response (eGR). An endoscopic responder was defined as patients with eGR/ePR. RESULTS Approximately 89.4% of patients had cStage II-III disease, and 7.1% had pathological complete response. Upon ER evaluation, eNR, ePR, and eGR were observed in 46 (32.6%), 54 (38.3%), and 41 (29.1%) patients, respectively. Pathological responders significantly increased as the ER grade became better. Among preoperative clinical factors, only ER significantly correlated with pathological response in univariate and multivariate analysis. Endoscopic responders showed a significantly better prognosis than did eNR patients (P

Chronic inflammation has a crucial role in cancer development and the progression of various tumors, including pancreatic ductal adenocarcinoma (PDAC). The arachidonate cascade is a major inflammatory pathway that produces several metabolites, such as prostaglandin E2. The enzyme 15‐hydroxyprostaglandin dehydrogenase (15‐PGDH) degrades prostaglandin and is frequently decreased in several types of cancer; however, the molecular mechanisms of 15‐PGDH suppression are unclear. The current study was carried out to elucidate the molecular mechanisms and clinical significance of 15‐PGDH suppression in PDAC. Here, we showed that interleukin‐1β (IL‐1β), a pro‐inflammatory cytokine, downregulates 15‐PGDH expression in PDAC cells, and that IL‐1β expression was inversely correlated with 15‐PGDH levels in frozen PDAC tissues. We also found that activated macrophages produced IL‐1β and reduced 15‐PGDH expression in PDAC cells. Furthermore, the number of CD163‐positive tumor‐associated macrophages was shown to be inversely correlated with 15‐PGDH levels in PDAC cells by immunohistochemical staining of 107 PDAC samples. Finally, we found that low 15‐PGDH expression was significantly associated with advanced tumors, presence of lymph node metastasis and nerve invasion, and poor prognosis in PDAC patients. Our results indicate that IL‐1β derived from TAMs suppresses 15‐PGDH expression in PDAC cells, resulting in poor prognosis of PDAC patients.

Background Small hepatocellular carcinomas (HCC ≤3 cm) are generally considered to have low malignant potential; however, some of them display pathological microvascular invasion (MVI). Methods Between 1991 and 2013, 414 patients with a single HCC ≤3 cm underwent curative hepatic resection (HR). Predictors for MVI were identified. Using another cohort (149 patients during 2000‐2014), our predictors for MVI in HCC ≤3 cm were validated. In 428 patients with a single HCC ≤3 cm who had predictors for MVI, survival was compared among anatomical HR (n = 149), partial HR (n = 227), and radiofrequency ablation (RFA) (n = 52). Results The positive rate of MVI reached 40.6% (168/414 patients). Independent predictors for MVI were as follows: tumor diameter ≥2 cm (odds ratio 1.84, P = .0052), alpha‐fetoprotein (AFP) ≥200 ng/mL (odds ratio 1.82, P = .0466), and des‐gamma‐carboxy prothrombin (DCP) ≥40 mAU/mL (odds ratio 1.79, P = .0126). Matching at least one predictor among these three could predict MVI in HCC ≤3 cm well (sensitivity 82.8%, positive predictive value [PPV] 48.7%). This criterion could also predict MVI in HCC ≤3 cm well in another cohort (sensitivity 82.8%, PPV 30.3%). In patients with single HCC ≤3 cm matching our criterion for predicting MVI, anatomical HR led to significantly better survival in both disease‐free (hazard ratio 0.689, P = .0231) and overall (hazard ratio 0.589, P = .0316) survivals. Conclusion Matching at least one factor among three (tumor diameter ≥2 cm, AFP ≥200 ng/mL, or DCP ≥40 mAU/mL) can predict MVI in HCC ≤3 cm. In such patients, anatomical HR would be recommended to improve survival., Matching at least one factor among three (tumor diameter ≥2 cm, AFP ≥200 ng/mL, or DCP ≥40 mAU/mL) can predict MVI in HCC ≤3 cm. In such patients, anatomical HR should be recommended to improve survival.

Postpancreaticoduodenectomy (PD) bleeding, which is reported to occur in 5–7%, is a major complication that often causes life‐threatening secondary events. A transarterial catheter technique with coil embolization is a widespread procedure that could potentially cause massive hepatic infarction and subsequent sepsis with hepatic abscess, which can be a fatal complication. Here, we introduce a new transarterial technique that uses a hemostat with a stent graft, which successfully rescued a patient had suffered post‐PD bleeding., This case demonstrated the successful treatment of a patient with post‐PD bleeding by transarterial stenting. Although sufficient experience and skill in angiographic techniques are required of is mandatory, and the need for a stent is largely determined by the arterial anatomy, we suggest that this technique may be promising for improving short‐term outcomes for post‐PD bleeding.

Aim Postoperative recurrence beyond the Milan criteria is one of poor prognostic factors for hepatocellular carcinoma patients treated with various treatments. We investigated the most useful inflammation-based prognostic score for predicting recurrences beyond the Milan criteria after initial liver resection. Methods From January 2007 to December 2012, 271 consecutive patients with hepatocellular carcinoma undergoing curative liver resection were enrolled. Patients were divided according to the initial recurrence pattern; the recurrence beyond the Milan criteria and the others (recurrence within the Milan criteria and no recurrence). The patients were classified into two groups: low-platelet-to-lymphocyte ratio (PLR) (

Immunotherapy using anti‐PD‐1/PD‐L1 antibodies for several types of cancer has received considerable attention in recent decades. However, the molecular mechanism underlying PD‐L1 expression in pancreatic ductal adenocarcinoma (PDAC) cells has not been clearly elucidated. We investigated the clinical significance and regulatory mechanism of PD‐L1 expression in PDAC cells. Among the various cytokines tested, tumor necrosis factor (TNF)‐α upregulated PD‐L1 expression in PDAC cells through NF‐κB signaling. The induction of PD‐L1 expression was also caused by co‐culture with activated macrophages, and the upregulation was inhibited by neutralization with anti‐TNF‐α antibody after co‐culture with activated macrophages. PD‐L1 expression in PDAC cells was positively correlated with macrophage infiltration in tumor stroma of human PDAC tissues. In addition, survival analysis revealed that high PD‐L1 expression was significantly associated with poor prognosis in 235 PDAC patients and especially in patients harboring high CD8‐positive T‐cell infiltration. These findings indicate that tumor‐infiltrating macrophage‐derived TNF‐α could be a potential therapeutic target for PDAC.

Aim The aim of this study was to determine the predictive factors of pathological vascular invasion as contra-indicators for ablation therapy in patients with hepatocellular carcinoma (HCC) within 3 cm and three nodules without radiological vascular invasion. Methods Two hundred and seventeen patients with HCC within 3 cm and three nodules without radiological vascular invasion who underwent hepatic resection were retrospectively investigated. Results Pathological vascular invasion was positive in 46 patients, consisting of 38 portal vein invasions, three hepatic vein invasions, two hepatic artery invasions, one hepatic duct invasion and two with portal and hepatic vein invasions. In univariate analysis, patients with α-fetoprotein (AFP) of more than 100 ng/mL had higher rates of pathological vascular invasion than those without. In addition, patients with protein induced by vitamin K absence (PIVKA-II) of more than 100 mAU/mL had higher rates of pathological vascular invasion than those without. Multivariate analysis revealed that AFP of more than 100 ng/mL and PIVKA-II of more than 100 mAU/mL were independent predictive factors for pathological vascular invasion. As these patients were treated with hepatic resection, cumulative 5-year recurrence-free and overall survivals were not significantly different between the pathological vascular invasion negative and positive cases. Conclusion AFP of more than 100 ng/mL and PIVKA-II of more than 100 mAU/mL can predict pathological vascular invasion in patients with HCC within 3 cm and three nodules without radiological vascular invasion. In treating such cases, hepatic resection rather than local ablation therapy is recommended.

It has become evident that P-cadherin, one of the classical cadherins, contributes to the malignant behavior of several types of cancer. In this study, we analyzed the expression of P-cadherin and its clinicopathological and prognostic values in intrahepatic cholangiocarcinoma (ICC) and pancreatic cancer. Furthermore, we investigated the functional role of P-cadherin in these cancer cells by knockdown and overexpression in vitro and by analyzing the correlation between the P-cadherin expression and its promoter methylation status. Thirty of 59 ICC cases (51%) and 36 of 73 pancreatic cancer cases (49%) stained positive for P-cadherin with mainly membranous distribution in tumor cells by immunohistochemistry. P-cadherin expression was significantly correlated with several clinicopathological factors, which reflect tumor behavior, and was identified as an independent adverse prognostic factor for disease-free survival in patients with ICC (relative risk [RR] 2.93, P = 0.04) and pancreatic cancer (RR 2.68, P = 0.005) via multivariate analyses. P-cadherin downregulation by siRNA suppressed migration and invasion, and P-cadherin overexpression induced the opposite effects in both ICC and pancreatic cancer cells, without any effects on cell proliferation. P-cadherin expression was related to its promoter methylation status in both cell lines and cancer tissues. In summary, P-cadherin overexpression may serve as a useful biomarker of invasive phenotype and poor prognosis; P-cadherin expression was found to be regulated by its promoter methylation. These results suggest that P-cadherin represents a novel therapeutic target for the treatment of ICC and pancreatic cancer.

AIM The prognostic value of lymphocyte infiltration into hepatocellular carcinoma (HCC) is still controversial, and it has not been reported in hepatitis B virus (HBV)-positive or non-B non-C (NBNC) HCC. The aim of this study is to assess the prognostic significance of lymphocyte infiltrate in tumor for HBV-positive and NBNC HCC patients. METHODS This study investigated 145 HBV-positive or NBNC patients who underwent hepatectomy for HCC between January 2001 and May 2009. Cumulative recurrence rate, overall survival (OS), and clinicopathological parameters were analyzed according to lymphocyte infiltration in tumor. RESULTS In patients with low lymphocyte infiltration, the 5-year recurrence rate was higher and OS was poor (86.4 and 44.1%, respectively) than that of the patients with high lymphocyte infiltration (55.3 and 83.7%, respectively). Multivariate analyses revealed that independent risk factors for recurrence were low albumin value (hazard ratio [HR] 2.33, P = 0.009), high American Joint Committee on Cancer (AJCC) T stage (HR 2.31, P

Metachronous rectal liver metastasis (15 mm in segment 8 ventral) was managed with laparoscopic hepatectomy using segmental blood flow occlusion with radiofrequency ablation. During liver dissection, the ischemic area was visible as a distinct hypoechoic area on intraoperative enhanced ultrasound; with a photodynamic eye camera, it appeared as a discolored lesion. The resection was completed with adequate margins.

Aim Local recurrence of hepatocellular carcinoma (HCC) after local ablation therapy (LAT) is a serious problem; however, the optimal treatment strategy remains unclear. Methods A retrospective analysis was conducted of 50 patients with local recurrence of HCC after LAT that underwent either salvage hepatectomy (n = 23) or radiofrequency ablation (RFA; n = 27). Their background characteristics, intraoperative data, and postoperative short- and long-term outcome were analyzed. Results The RFA group was found to be significantly associated with an impaired liver functional reserve, smaller number and size of tumors. The hepatectomy group showed a significantly longer operation time, greater intraoperative blood loss and more frequent red blood cell transfusion. In-hospital stay mortality and morbidity rate did not significantly differ. The disease-free and overall survival showed no significant difference between the groups. Although local recurrence after salvage treatment was found in zero (0%) for hepatectomy and in seven (25.9%) for RFA, that did not affect the overall survival. The tumor size at the prior LAT was identified as an independent prognostic factor for disease-free survival and serum albumin for overall survival. Conclusion Whereas salvage hepatectomy for local recurrent HCC is recommended for selected patients in terms of its good local control effect, salvage RFA is also acceptable because it is less invasive and also has a reasonable long-term outcome.

Aim Hepatectomy is feasible for patients with hepatocellular carcinoma (HCC) with good hepatic function who meet the Milan criteria. Several studies have indicated that tumor markers of HCC, α-fetoprotein (AFP), Lens culinaris agglutinin-reactive fraction of AFP percentage and protein induced by vitamin K absence/antagonist-II were good predictors of malignant potential. It is important to identify highly malignant cases of HCC, and the aim of this study was to clarify the impact of triple positive tumor markers as the prognostic factors for early stage HCC within the Milan criteria. Methods This study investigated 199 patients who underwent hepatectomy for HCC within the Milan criteria between January 2001 and May 2009. Cumulative recurrence-free survival (RFS), overall survival (OS) and clinicopathological parameters were analyzed according to the number of positive tumor markers. Results In patients with triple positive tumor markers, 5-year RFS and OS was poor (17.1 and 61.4%, respectively). Multivariate analyses revealed independent risk factors for recurrence to be hepatitis C virus antibody positivity, non-initial treatment for HCC and triple positive tumor markers, and the independent risk factors for OS were high indocyanine green retention rate at 15 min value, maximum tumor size and triple positive tumor markers. Pathologically invasive growth, microvascular invasion and moderate to poor differentiation were significantly related to the number of the three tumor markers. Conclusion Triple positive tumor markers for early stage HCC within the Milan criteria showed poor prognosis and malignant characteristics. These markers could be a useful predictor for the degree of malignant potential in early stage HCC.

Background Partial splenic embolization (PSE) for cirrhotic patients has been reported not only to achieve an improvement in thrombocytopenia and portal hypertension, but also to induce PSE-associated fringe benefit such as individual liver functional improvement. The purpose of this study was to clarify the predictive marker of liver functional improvement due from PSE in cirrhotic patients. Methods From April 1999 to January 2009, 83 cirrhotic patients with hypersplenism-induced thrombocytopenia (platelet count 600 ml obtained significantly higher serum albumin and cholinesterase levels at one year after PSE compared to those with less than 600 ml (P-values were 0.029 in both). Conclusion A large preoperative splenic volume was the useful predictive marker for an effective PSE-induced liver functional improvement.

Local ablation therapy (LAT) is a widely used treatment for hepatocellular carcinoma (HCC) because it is less invasive than hepatic resection. The precise molecular mechanism underlying local HCC recurrence after LAT is largely unknown. The CD44 standard isoform (CD44s) is involved in epithelial–mesenchymal transition (EMT) in HCC. We investigate the significance of CD44s expression and EMT expression profile in local HCC recurrence after LAT. We studied the expression levels of CD44s, EMT expression profile (E-cadherinlow/vimentinhigh expression) and their association with clinicopathological factors in 30 HCC samples from patients with locally recurrent HCCs after LAT following hepatic resection. The alterations of CD44s expression was compared with those in initial HCCs from 150 patients without prior any anticancer treatment including LAT. A high CD44s expression was significantly associated with the EMT expression profile (P = 0.002), and it was also detected with a higher frequency in the locally recurrent HCCs after LAT compared to initial HCCs (P

The role of adjuvant chemotherapy for stage IV colorectal cancer has so far been under-investigated. The aim of this study was to assess the feasibility and short-term outcome of adjuvant chemotherapy with the FOLFOX regimen following liver resection for patients with colorectal liver metastasis (CRLM).From May 2005 to September 2010, 86 patients with CRLM underwent hepatic resection in the Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University. Of these patients, 24 received FOLFOX4 or modified FOLFOX6 as postoperative adjuvant chemotherapy.Nineteen male and 5 female patients received adjuvant chemotherapy following liver resection. Twenty-one (87.5 %) of these patients completed 6 cycles of adjuvant chemotherapy. Five patients required a dose reduction due to neutropenia, and the dose intensities of oxaliplatin and 5-FU were 93.6 and 94.1 %, respectively. There were no severe adverse events from the treatments. The median follow-up period was 48.4 months. Recurrences developed in 12 patients, and 3 patients died during the follow-up period. The 3- and 5-year disease-free survival and overall survival were 51.6 and 45.1 % and 95.5 and 76.0 %, respectively.Adjuvant FOLFOX is feasible and might provide a good prognosis for CRLM patients who undergo liver resection.

The present study attempted to identify a useful tumor-associated antigen (TAA) for lung cancer immunotherapy and potential immunogenic peptides derived from the TAA. We focused on cell division cycle 45-like (CDC45L), which has a critical role in the initiation and elongation steps of DNA replication, as a novel candidate TAA for immunotherapy based on a genome-wide cDNA microarray analysis of lung cancer. The CDC45L was overexpressed in the majority of lung cancer tissues, but not in the adjacent non-cancerous tissues or in many normal adult tissues. We examined the in vitro and in vivo anti-tumor effects of cytotoxic T-lymphocytes (CTL) specific to CDC45L-derived peptides induced from HLA-A24 (A*24:02)-positive donors. We identified three CDC45L-derived peptides that could reproducibly induce CDC45L-specific and HLA-A24-restricted CTL from both healthy donors and lung cancer patients. The CTL could effectively lyse lung cancer cells that endogenously expressed both CDC45L and HLA-A24. In addition, we found that CDC45L (556) KFLDALISL(564) was eminent in that it induced not only HLA-A24 but also HLA-A2 (A*02:01)-restricted antigen specific CTL. Furthermore, the adoptive transfer of the CDC45L-specific CTL inhibited the growth of human cancer cells engrafted into immunocompromised mice. These results suggest that these three CDC45L-derived peptides are highly immunogenic epitopes and CDC45L is a novel TAA that might be a useful target for lung cancer immunotherapy.

Insulin-like growth factor-II mRNA binding protein 3 (IMP-3) is an oncofetal protein expressed in various malignancies including lung cancer. This study aimed to identify immunogenic peptides derived from IMP-3 that can induce tumor-reactive and human leukocyte antigen (HLA)-A2 (A*02:01)-restricted cytotoxic T lymphocytes (CTL) for lung cancer immunotherapy. Forty human IMP-3-derived peptides predicted to bind to HLA-A2 were analyzed to determine their capacity to induce HLA-A2-restricted T cells in HLA-A2.1 (HHD) transgenic mice (Tgm). We found that three IMP-3 peptides primed HLA-A2-restricted CTL in the HLA-A2.1 Tgm. Among them, human CTL lines reactive to IMP-3 (515) NLSSAEVVV(523) were reproducibly established from HLA-A2-positive healthy donors and lung cancer patients. On the other hand, IMP-3 (199) RLLVPTQFV(207) reproducibly induced IMP-3-specific and HLA-A2-restricted CTL from healthy donors, but did not sensitize CTL in the HLA-A2.1 Tgm. Importantly, these two IMP-3 peptide-specific CTL generated from healthy donors and cancer patients effectively killed the cancer cells naturally expressing both IMP-3 and HLA-A2. Cytotoxicity was significantly inhibited by anti-HLA class I and anti-HLA-A2 monoclonal antibodies, but not by the anti-HLA-class II monoclonal antibody. In addition, natural processing of these two epitopes derived from the IMP-3 protein was confirmed by specific killing of HLA-A2-positive IMP-3-transfectants but not the parental IMP-negative cell line by peptide-induced CTL. This suggests that these two IMP-3-derived peptides represent highly immunogenic CTL epitopes that may be attractive targets for lung cancer immunotherapy.

Background Many factors may compromise the functional recovery of a harvested potential liver for engraftment. Normothermic machine perfusion (NMP) can revive hepatic metabolism ex vivo enabling subsequent transplantation. In this study, we evaluated the recovery of 11 discarded livers' function utilizing NMP. Materials and methods Eleven consecutive discarded livers underwent NMP for 6 hours. Liver function recovery was defined by lactate levels of ≤3 mmol/L and continuous bile production. Results Ten of 11 livers perfused were fatty. The median percentage of macrosteatosis (MaS) and microsteatosis (MiS) was 40% (10%-90%) and 40% (20%-50%), respectively, based on a review of paraffin-embedded sections of preperfusion biopsies. A discarded "amyloid" liver from an HIV-positive donor was also studied. Recovery of liver function was observed in 4 livers, including that with the amyloid deposition. These livers sustained shorter cold ischemia times and seemed to have increased portal and arterial blood flow. No significant change in MiS or MaS was observed before and after perfusion. Conclusion Our results suggest that some discarded grafts might have been salvaged for transplantation. Further studies utilizing NMP with subsequent transplantation would validate this strategy.

Background Poorly differentiated hepatocellular carcinoma (HCC) has a malignant potential such as frequent microvascular invasion even if the tumor is smaller than 3 cm in diameter. The aim of this study was to clarify the preoperative predictors of poorly differentiated HCC for safe local ablation therapy. Methods Sixty-six patients underwent a hepatic resection for solitary small-sized HCC (≤3 cm) were included in this study. According to the postoperative histological examination, the patients were divided into a “poorly differentiated group” (n = 17) and a “well/moderately differentiated group” (n = 49). This study investigated the clinicopathological factors and imaging findings, and elucidated the predictive factors of the poorly differentiated type. Results In a univariate analysis, serum hepatitis B surface antigen positive, hepatitis C virus antibody negative, alpha-fetoprotein level, des-γ-carboxy prothrombin level, and a high contrast-to-noise ratio (CNR) in T2-weighted MR imaging were significantly associated with the poorly differentiate type. In a multivariate analysis, a high CNR in T2-weighted MR imaging was the only independent predictor of the poorly differentiated type. In the postoperative pathological findings, portal vein invasion and intrahepatic metastasis were significantly frequent in the poorly differentiated group. Conclusions The CNR in T2-weighted MR imaging is a useful tool to predict poorly differentiated HCC preoperatively. J. Surg. Oncol. 2009;100:121–126. © 2009 Wiley-Liss, Inc.