[The Usefulness of RFA as a Conversion Therapy after Molecular Targeted Therapy for Advanced Hepatocellular Carcinoma-A Case of Long-Term Survival with Multidisciplinary Treatment].

In this study, we report a case in which molecular-targeted agents have been shown to be effective in the treatment of unresectable hepatocellular carcinoma(HCC), which has enabled a radical treatment, conversion therapy, and long-term survival with multimodality treatment including RFA. Case: A 61-year-old male, abdominal ultrasonography revealed a large liver tumor and multiple lesions mainly in the right lobe of the liver. He was diagnosed as having unresectable HCC, and treatment with sorafenib was initiated. After treatment, the tumor was clearly reduced in size and the lung metastases disappeared. Five years later, recurrence was observed at the treated site of S7/8, and RFA was performed again after TACE. The patient has survived for 8 years without recurrence.

Prospective observational study of the efficacy of oral uracil and tegafur plus leucovorin for stage II colon cancer with risk factors for recurrence using propensity score matching (JFMC46-1201).

BACKGROUND: The efficacy of adjuvant chemotherapy for high-risk stage II colon cancer (CC) has not been well established. We compared the effects of surgery with and without oral uracil and tegafur plus leucovorin (UFT/LV) in patients with high-risk stage II CC, adjusting for potential risk factors. METHODS: We enrolled patients with histologically confirmed stage II colon adenocarcinoma with at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes. Patients chose to be non-randomized or randomized to undergo surgery alone (NR-Group S or R-Group S) or surgery followed by 6 months of UFT/LV (NR-Group U or R-Group U). The primary endpoint was disease-free survival (DFS) after adjusting for previously reported risk factors using propensity score matching (1:2) and inverse probability of treatment weighting (IPTW) in the non-randomized arm. RESULTS: Overall, 1,902 (98%) and 36 (2%) patients were enrolled in the non-randomized and randomized arms, respectively. There were too few patients in the randomized arm and these were therefore excluded from the analysis. Of the 1,902 patients, 402 in NR-Group S and 804 in NR-Group U were propensity score-matched. The 3-year DFS rate (95% confidence interval) was significantly higher in NR-Group U (80.9% [77.9%-83.4%]) than in NR-Group S (74.0% [69.3%-78.0%]) (hazard ratio, 0.64 [0.50-0.83]; P = 0.0006). The 3-year overall survival rate was not significantly different between NR-Group S and NR-Group U. Significantly higher 3-year DFS (P = 0.0013) and overall survival (P = 0.0315) rates were observed in NR-Group U compared with NR-Group S using IPTW. CONCLUSIONS: Adjuvant chemotherapy with UFT/LV showed a significant survival benefit over surgery alone in patients with high-risk stage II CC characterized by at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs031180155 (date of registration: 25/02/2019) (UMIN Clinical Trials Registry: UMIN000007783 , date of registration: 18/04/2012).

Randomized phase II study comparing the efficacy and safety of SOX versus mFOLFOX6 as neoadjuvant chemotherapy without radiotherapy for locally advanced rectal cancer (KSCC1301).

BACKGROUND: Preoperative chemoradiotherapy (CRT), the current standard of care for locally advanced rectal cancer (LARC), is associated with many radiotherapy (RT)-related side effects. We aimed to evaluate whether S-1 and oxaliplatin (SOX) or folinic acid, 5-FU, and oxaliplatin (mFOLFOX6) can be as effective as neoadjuvant chemotherapy (NAC) regimens for LARC without RT. METHODS: Patients with untreated resectable LARC were randomly assigned to receive SOX or mFOLFOX6. The NAC protocol period was 3 months. The primary endpoint was 3-year disease-free survival (DFS), and the secondary endpoints included pathological effects, surgical completion rate, 3-year survival, and safety. RESULTS: From September 2013 to October 2015, 56 and 54 patients were enrolled in the SOX and mFOLFOX6 arms, respectively. The 3-year DFS rates were 69.4% (95% confidence interval [CI] 54.9-83.6) and 73.4% (95% CI 58.7-83.6) in the SOX and mFOLFOX6 arms, respectively; no significant differences were found between the arms (log-rank test; P = 0.5315, hazard ratio: 0.808, 95% CI 0.414-1.578). The 3-year survival rates were 92.3 and 91.8% in the SOX and mFOLFOX6 arms, respectively. The surgical completion rate was 98.1% overall, 100% in the SOX arm, and 96.0% in the mFOLFOX6 arm. The incidences of pathological response rates ≥grade 1b were 41.5 and 43.8% in the SOX and mFOLFOX6 arms, respectively. Both treatments were manageable and tolerable. CONCLUSION: We demonstrated the effectiveness and safety of SOX and mFOLFOX6, both of which may be new neoadjuvant treatment candidates in previously untreated LARC cases. TRIAL REGISTRATION: Date of enrolment of the first participant to the trial: 3rd Oct 2013; This study was registered in the UMIN clinical trials registry on 14th Aug, 2013. (Prospectively registered, UMIN-CTR number UMIN000011486). https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&recptno=R000013441&language=J.

Alox12/15 Deficiency Exacerbates, While Lipoxin A4 Ameliorates Hepatic Inflammation in Murine Alcoholic Hepatitis.

Alcoholism is one of the leading and increasingly prevalent reasons of liver associated morbidity and mortality worldwide. Alcoholic hepatitis (AH) constitutes a severe disease with currently no satisfying treatment options. Lipoxin A4 (LXA4), a 15-lipoxygenase (ALOX15)-dependent lipid mediator involved in resolution of inflammation, showed promising pre-clinical results in the therapy of several inflammatory diseases. Since inflammation is a main driver of disease progression in alcoholic hepatitis, we investigated the impact of endogenous ALOX15-dependent lipid mediators and exogenously applied LXA4 on AH development. A mouse model for alcoholic steatohepatitis (NIAAA model) was tested in Alox12/15+/+ and Alox12/15-/- mice, with or without supplementation of LXA4. Absence of Alox12/15 aggravated parameters of liver disease, increased hepatic immune cell infiltration in AH, and elevated systemic neutrophils as a marker for systemic inflammation. Interestingly, i.p. injections of LXA4 significantly lowered transaminase levels only in Alox12/15-/- mice and reduced hepatic immune cell infiltration as well as systemic inflammatory cytokine expression in both genotypes, even though steatosis progressed. Thus, while LXA4 injection attenuated selected parameters of disease progression in Alox12/15-/- mice, its beneficial impact on immunity was also apparent in Alox12/15+/+ mice. In conclusion, pro-resolving lipid mediators may be beneficial to reduce inflammation in alcoholic hepatitis.

Protocol of the QUATTRO-II study: a multicenter randomized phase II study comparing CAPOXIRI plus bevacizumab with FOLFOXIRI plus bevacizumab as a first-line treatment in patients with metastatic colorectal cancer.

BACKGROUND: First-line treatment with FOLFOXIRI plus bevacizumab (BEV) is highly effective and regarded as one of the standards-of-care for patients with metastatic colorectal cancer (mCRC), despite the high incidence of neutropenia and diarrhea as side effects. AXEPT, an Asian phase III study, showed that modified CAPIRI+BEV [capecitabine (CAP: 1600 mg/m2), irinotecan (IRI: 200 mg/m2), and BEV (7.5 mg/m2)] was non-inferior to FOLFIRI+BEV as a second-line therapy for mCRC patients and was associated with a lower incidence of hematologic toxicities. Thus, a reduced dose of the CAP and IRI regimen in combination with oxaliplatin (OX) and BEV (CAPOXIRI+BEV) may be more feasible than FOLFOXIRI+BEV, without compromising efficacy. METHODS: QUATTRO-II is an open-label, multicenter, randomized phase II study. In Step 1, the recommended doses of OX and IRI will be investigated as a safety lead-in. In Step 2, patients will be randomized to the recommended dose of either CAPOXIRI+BEV or FOLFOXIRI+BEV. Induction triplet chemotherapy plus BEV treatments will be administered for up to 4 months followed by fluoropyrimidine plus BEV maintenance. The primary endpoint is progression-free survival (PFS). The similarity in PFS between the two arms will be evaluated by observing whether the point estimate of hazard ratio (HR) for PFS falls between 0.80 and 1.25. Ensuring a 70% probability that the observed HR will be "0.8 < HR < 1.25" under the assumption of the true HR of 1.0, and 100 patients will be evaluated during the 3-year study period. Secondary endpoints include overall survival, overall response rate, safety, and patient reported outcome (PRO) (FACT/GOG-Ntx4). DISCUSSION: Considering the lower incidence of hematologic toxicities with modified CAPIRI+BEV than with FOLFIRI+BEV, CAPOXIRI+BEV may be a promising treatment option if sufficient efficacy and lower hematologic toxicities are indicated in this study. Additionally, a lower incidence of peripheral sensory neuropathy (PSN) reported following CAPEOX treatment compared to that after FOLFOX in ACHIEVE, an adjuvant phase III trial, suggest that CAPOXIRI+BEV can mitigate OX-induced PSN. TRIAL REGISTRATION: Clinicaltrials.gov NCT04097444 . Registered September 20, 2019, https://clinicaltrials.gov/ct2/show/study/NCT04097444 / Japan Registry of Clinical Trials jRCTs041190072. Registered October 9, 2019.

S-1 and Oxaliplatin Versus Tegafur-uracil and Leucovorin as Postoperative Adjuvant Chemotherapy in Patients With High-risk Stage III Colon Cancer (ACTS-CC 02): A Randomized, Open-label, Multicenter, Phase III Superiority Trial.

BACKGROUND: The efficacy of S-1 plus oxaliplatin (SOX) as postoperative adjuvant chemotherapy for colon cancer has not been established. This randomized phase III study was designed to verify the superiority of SOX over tegafur-uracil and leucovorin (UFT/LV) in patients with high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries). PATIENTS AND METHODS: Patients who underwent curative resection for pathologically confirmed high-risk stage III colon cancer were randomly assigned to receive either UFT/LV (300 mg/m2 of UFT and 75 mg/day of LV on days 1-28, every 35 days, 5 cycles) or SOX (100 mg/m2 of oxaliplatin on day 1 and 80 mg/m2 of S-1 on days 1-14, every 21 days, 8 cycles). The primary endpoint was disease-free survival (DFS). RESULTS: A total of 478 patients in the UFT/LV group and 477 patients in the SOX group were included in the primary analysis. The 3-year DFS was 60.6% (95% confidence interval [CI], 56.0%-64.9%) in the UFT/LV group and 62.7% (95% CI, 58.1%-66.9%) in the SOX group. The stratified hazard ratio for DFS was 0.90 (95% CI, 0.74-1.09; stratified log-rank test, P = .2780). In the N2b subgroup, the 3-year DFS was 46.0% (95% CI, 37.5%-54.0%) in the UFT/LV group and 54.7% (95% CI, 45.7%-62.7%) in the SOX group (hazard ratio, 0.76; 95% CI, 0.55-1.05). CONCLUSION: As postoperative adjuvant chemotherapy, SOX was not superior to UFT/LV in terms of DFS in patients with high-risk stage III colon cancer.

Clinical significance of evaluating endoscopic response to neoadjuvant chemotherapy in esophageal squamous cell carcinoma.

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 < 0.001), although the overall survival (OS) of the patients with eGR and ePR was equivalent. Endoscopic responder, ypT, ypN, and pathological responder were significant predictors of OS in the univariate analysis, and endoscopic responder, ypN, and pathological responder were independent predictors in the multivariate analysis. CONCLUSION: This study suggests that ER can be a simple and important tool to predict the pathological response and survival of patients who undergo NAC for ESCC.

Significance of neoadjuvant therapy for borderline resectable pancreatic cancer: a multicenter retrospective study.

PURPOSE: Neoadjuvant therapy (NAT) is increasingly used to improve the prognosis of patients with borderline resectable pancreatic cancer (BRPC) albeit with little evidence of its advantage over upfront surgical resection. We analyzed the prognostic impact of NAT on patients with BRPC in a multicenter retrospective study. METHODS: Medical data of 165 consecutive patients who underwent treatment for BRPC between January 2010 and December 2014 were collected from ten institutions. We defined BRPC according to the National Comprehensive Cancer Network guidelines, and subclassified patients according to venous invasion alone (BR-PV) and arterial invasion (BR-A). RESULTS: The rates of NAT administration and resection were 35% and 79%, respectively. There were no significant differences in resection rates and prognoses between patients in the BR-PV and BR-A subgroups. NAT did not have a significant impact on prognosis according to intention-to-treat analysis. However, in patients who underwent surgical resection, NAT was independently associated with longer overall survival (OS). The median OS of patients who underwent resection after NAT (53.7 months) was significantly longer than that of patients who underwent upfront (17.8 months) or no resection (14.9 months). The rates of superior mesenteric or portal vein invasion, lymphatic invasion, venous invasion, and lymph node metastasis were significantly lower in patients who underwent resection after NAT than in those who underwent upfront resection despite similar baseline clinical profiles. CONCLUSIONS: Resection after NAT in patients with BRPC is associated with longer OS and lower rates of both invasion to the surrounding tissues and lymph node metastasis.

Controlling Nutritional Status (CONUT) Score Is a Prognostic Marker in Metastatic Colorectal Cancer Patients Receiving First-line Chemotherapy.

BACKGROUND/AIM: The Controlling Nutritional Status (CONUT) score is a useful nutritional evaluation, that is calculated from serum albumin, total cholesterol concentrations, and total lymphocyte count. This study aimed to investigate the association between the CONUT score and prognosis in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: The CONUT score was retrospectively calculated in 211 patients with mCRC receiving first-line chemotherapy. The patients were divided into three groups: the CONUT low-group (0-1), intermediate-group (2-4), and high-group (5-). The associations of the CONUT score with clinicopathological factors and survival outcomes were evaluated. RESULTS: The higher CONUT score was significantly associated with synchronous metastases, and no primary tumor resection. The higher CONUT score group showed a significant shorter progression-free survival (log-rank p<0.05) and overall survival (log-rank p<0.001). CONCLUSION: The CONUT score is a useful prognostic marker for predicting survival outcomes of patients with mCRC.

Hepatic Resection Followed by Hepatic Arterial Infusion Chemotherapy for Hepatocellular Carcinoma with Intrahepatic Dissemination.

BACKGROUND/AIM: To investigate the utility of adjuvant hepatic arterial infusion chemotherapy (HAIC) following hepatectomy for patients with hepatocellular carcinoma (HCC) with intrahepatic dissemination (IHD) after local ablation therapy. PATIENTS AND METHODS: Twelve patients with HCC with IHD were divided into two groups: HAIC group (n=6) underwent hepatectomy followed by HAIC; and the non-HAIC group (n=6) underwent hepatectomy alone. HAIC with cisplatin and 5-fluorouracil was started within a month and was continued for a month: Results: At the first local ablation, tumors close to the major portal vein and insufficient ablation were recognized in eight (67.7%) and six (58.3%) of the patients, respectively. In the HAIC group, the 1-, 3-, and 5-year disease-free and overall survival rates were 50.0%, 16.7%, and 16.7%, and 83.3%, 83.3% and 62.5%, respectively. Three patients in the HAIC group remain alive after 10 years of follow-up. CONCLUSION: Hepatic resection with short-term postoperative HAIC may provide excellent outcomes in patients with HCC and IHD.

Planned Safety Analysis of the ACTS-CC 02 Trial: A Randomized Phase III Trial of S-1 With Oxaliplatin Versus Tegafur and Uracil With Leucovorin as Adjuvant Chemotherapy for High-Risk Stage III Colon Cancer.

BACKGROUND: This trial was designed to verify the superiority of 6 months of postoperative adjuvant chemotherapy with SOX (S-1 with oxaliplatin) with UFT (tegafur and uracil) with LV (leucovorin) in terms of disease-free survival in patients with high-risk stage III colon cancer. We report the results of a planned safety analysis. PATIENTS AND METHODS: Patients who underwent curative resection for high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries) were randomly assigned to receive either UFT/LV (300-600 mg/d UFT with 75 mg/d LV on days 1-28, every 35 days, for 5 cycles) or SOX (100 mg/m2 of oxaliplatin on day 1 with 80-120 mg/d S-1 on days 1-14, every 21 days, for 8 cycles). Treatment status and safety were evaluated. RESULTS: A total of 966 patients were enrolled, and 932 patients were included in safety analyses. The planned 6-month protocol treatment was received by 76.9% of the patients in the UFT/LV group and 65.8% of those in the SOX group. The overall incidence of any Grade adverse events (AEs) were 91.3% in the UFT/LV group and 98.7% in the SOX group, and those of Grade ≥ 3 AEs were 16.1% and 36.1%, respectively. As for Grade ≥ 3 AEs, leukopenia, neutropenia, thrombocytopenia, and sensory neuropathy were more common in the SOX group. The incidence of Grade ≥ 3 sensory peripheral neuropathy was 4.6% in the SOX group. CONCLUSION: The completion rate of adjuvant SOX and its incidence of AEs were acceptable in patients with colon cancer.

Impact of surgical treatment after sorafenib therapy for advanced hepatocellular carcinoma.

BACKGROUND: For advanced hepatocellular carcinoma (HCC), surgical treatment after sorafenib induction has rarely been reported. We examined the survival benefit of additional surgical treatment in sorafenib-treated patients. METHODS: Thirty-two advanced HCC patients were given sorafenib from July 2009 to July 2012, and we statistically analyzed the relevant predictive factors of the long-term survival. The institutional review board of Kumamoto University Hospital approved this study (Approval number 1038). RESULTS: The median duration of sorafenib administration was 56.5 days (range 5-945). The cumulative overall survival rate was 44.6, 33.4, 26.0 and 17.8% at 1, 2, 3 and 5 years, respectively. The median survival time was 11.2 months. A survival of more than 3 years after the initiation of sorafenib induction was observed in seven patients, five of whom were subjected to additional surgical intervention. Additional surgery was the most significant factor predicting a survival exceeding 3 years (P < 0.0001) and represents an independent prognostic factor [hazard ratio (HR) 0.07; P = 0.01], followed by the total dose of sorafenib. The surgical interventions comprised two hepatic resections ± radiofrequency ablation, two radiofrequency ablations and one lung resection. CONCLUSIONS: A long-term survival might be obtained for select HCC patients given adequate additional surgical treatment, even after sorafenib induction.

A long-term survivor of hilar cholangiocarcinoma with resection of recurrent peritoneal dissemination after R0 surgery: a case report.

BACKGROUND: Although hilar cholangiocarcinoma (HCCA) has a very poor prognosis, there are cases in which long-term survival is rarely obtained by multidisciplinary treatment. CASE PRESENTATION: A 61-year-old man diagnosed with HCCA was referred to our hospital. We performed an extended left hemi-hepatectomy and caudate lobectomy with extrahepatic bile duct resection. The tumor stage was T2aN0M0, stage II, based on the TNM classification, seventh edition. R0 resection was successfully performed. Adjuvant chemotherapy was not administered. After 38 months, computed tomography revealed peritoneal dissemination. The patient received chemotherapy with tegafur-gimeracil-oteracil-potassium (S-1) and gemcitabine. The peritoneal dissemination was successfully controlled for more than 50 months. During the treatment, levels of CEA and CA19-9 kept rising slowly, which was followed by bowel obstruction due to peritoneal dissemination of HCCA. The patient underwent resection of transverse colon with tumor nodules, and the tumor was pathologically diagnosed as metastasis of HCCA. Tumor markers decreased to normal levels, and the patient has been free from tumor relapse for 6 months. CONCLUSIONS: We here report a rare case of HCCA patient with recurrent peritoneal dissemination 3 years after R0 surgery which was sensitive to chemotherapy. The patient successfully received resection of peritoneal dissemination 50 months after the induction of chemotherapy and survived for 10 years.

Simultaneously Diagnosed and Successfully Treated Rectovaginal and Vesicovaginal Fistulae after Low Anterior Resection with Concomitant Resection of Female Genitalia.

Rectovaginal fistula (RVF) and vesicovaginal fistula (VVF) are infrequent but distressing complications after pelvic surgery. However, their adequate treatment is not well described. Here, we simultaneously encountered and successfully treated RVF and VVF after radical surgery for rectal cancer. A 70-year-old woman underwent low anterior resection (LAR) combined with resection of the uterus, the bilateral adnexa, and the upper side of the vagina, as well as diverted ileostomy for rectal cancer. A month after the surgery, she developed urinary incontinence and underwent medical treatment, but her symptoms did not improve. Evaluation with contrast enema before stoma closure revealed the presence of RVF and VVF. We repaired the VVF and RVF via transabdominal and transperineal approaches. After 6 months, ileostomy was closed and the patient had no recurrence of cancer and fistula. In LAR with hysterectomy and resection of the vaginal wall, there is a risk of RVF and VVF. The excision and closure of the fistula tract and omental flap can be effective to treat both fistulae.

Bathing in carbon dioxide-enriched water alters protein expression in keratinocytes of skin tissue in rats.

Beneficial effects of balneotherapy using naturally occurring carbonated water (CO2 enriched) have been known since the Middle Ages. Although this therapy is clinically applied for peripheral artery disease and skin disorder, the underlying mechanisms are not fully elucidated.Under controlled conditions, rats were bathed in either CO2-enriched water (CO2 content 1200 mg/L) or tap water, both at 37 °C, for 10 min daily over 4 weeks. Proliferation activity was assessed by Ki67 immunohistochemistry of the epidermis of the abdomen. The capillary density was assessed by immunodetection of isolectin-positive cells. Using cryo-fixed abdominal skin epidermis, follicle cells and stroma tissue containing capillaries were separately isolated by means of laser microdissection and subjected to proteomic analysis using label-free technique. Differentially expressed proteins were validated by immunohistochemistry.Proliferation activity of keratinocytes was not significantly different in the epidermis after bathing in CO2-enriched water, and also, capillary density did not change. Proteomic analysis revealed up to 36 significantly regulated proteins in the analyzed tissue. Based on the best expression profiles, ten proteins were selected for immunohistochemical validation. Only one protein, far upstream element binding protein 2 (FUBP2), was similarly downregulated in the epidermis after bathing in CO2-enriched water with both techniques. Low FUBP2 expression was associated with low c-Myc immune-expression in keratinocytes.Long-term bathing in CO2-enriched water showed a cellular protein response of epithelial cells in the epidermis which was detectable by two different methods. However, differences in proliferation activity or capillary density were not detected in the normal skin.

Statin attenuates cell proliferative ability via TAZ (WWTR1) in hepatocellular carcinoma.

Diabetes and obesity are associated with non-alcoholic steatohepatitis and an increased incidence of hepatocellular carcinoma (HCC). TAZ and YAP are equivalently placed downstream effectors of the Hippo pathway with oncogenic roles in human cancers. Statins are commonly used to patients with metabolic problems as hypercholesterolemia. Statins also have anti-cancer properties, and the cross-talk between mevalonate pathway and Hippo pathway was known. The aim of this study is to confirm the statin's anti-cancer effects on HCC cells and its survival benefits in HCC patients with curative surgery. TAZ expression level in HCC cell lines was analyzed by western blot. Two cell lines (HLF and HuH1) were used in this study. Then the mechanism of statin's anti-proliferative effect was examined in HLF and HuH1 cells. In clinical setting, overall survival and recurrence-free survival (RFS) rate were examined in comparison between statin intake and statin non-intake group. The proliferation assay using four different statins (atorvastatin, pravastatin, fluvastatin, simvastatin). Simvastatin and fluvastatin showed very strong growth suppressive effects, and induced apoptosis in HLF cells, but not HuH1 cells. TAZ expression was suppressed in HLF cells by fluvastatin and simvastatin treatment. The similar change pattern was confirmed in p-ERK1/2 and ERK. In HuH1 cells, such expression change was not confirmed. In clinical setting, statin intake was significantly associated with longer RFS in the HCC patients with hepatectomy (P = 0.038). The statin had the anti-proliferative effects and induced apoptosis in HCC cells and improved the prognosis of HCC patients.

Tumor/normal esophagus ratio in (18)F-fluorodeoxyglucose positron emission tomography/computed tomography for response and prognosis stratification after neoadjuvant chemotherapy for esophageal squamous cell carcinoma.

BACKGROUND: Positron emission tomography (PET) response criteria in solid tumors were recently proposed as a standardized method for the metabolic and quantitative assessment of response to chemotherapy. However, use of these criteria is limited in many institutions because of the need for exclusive software. This study was designed to clarify whether tumor to normal esophageal (T/N) ratio on (18)F-fluorodeoxyglucose PET/computed tomography could predict response to neoadjuvant chemotherapy and stratify prognosis in patients with esophageal squamous cell carcinoma (ESCC). METHODS: Clinicopathological data were collected for 73 patients with ESCC who received neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil followed by curative resection. The right liver lobe and normal esophagus were utilized as reference tissues for diagnosing complete metabolic response (CMR). Statistical methods included Kaplan-Meier analysis and univariate and multivariate Cox proportional hazards regression analyses. RESULTS: CMR was achieved in 24 patients on the basis of maximum standardized uptake value (SUVmax) and in 11 on the basis of SUVmax evaluation with T/N ratio. Although prognosis was poorer in patients who achieved CMR than partial metabolic response based on SUVmax, the responses were significantly correlated with disease-free survival (DFS) based on SUVmax evaluation with T/N ratio (P = 0.0011). Receiver operating characteristic curve analysis showed that SUVmax evaluation with T/N ratio was the best predictor of pGrade 3. Multivariate analysis showed that SUVmax evaluation with T/N ratio was an independent predictor of DFS in patients with pGrade 1 pathologic response. CONCLUSIONS: SUVmax evaluation with T/N ratio is useful for evaluating the effects of neoadjuvant chemotherapy in patients with ESCC.

Treatment Rationale and Study Design for Clinical Trial on the Efficacy of UFT/LV for Stage II Colorectal Cancer With Risk Factors for Recurrence (JFMC46-1201).

BACKGROUND: The usefulness of adjuvant chemotherapy for stage II colon cancer has not been established. Meanwhile, the presence of stage II colon cancer with high-risk factors for recurrence has been reported. To our knowledge, no prospective study of adjuvant chemotherapy for stage II colon cancer with high-risk factors has been implemented to date. PATIENTS AND METHODS: This study is a prospective nonrandomized controlled study based on patients' selection of treatment option, including randomized therapeutic decision-making, to evaluate the usefulness of adjuvant chemotherapy with tegafur-uracil (UFT) with leucovorin (LV) for stage II colon cancer with high-risk factors for recurrence, compared with surgery alone. Five courses of UFT/LV therapy will be given as follows: UFT (300 mg/m(2)/d) with LV (75 mg/d) will be orally administered in 3 doses per day. Treatment will be received daily for 28 days, followed by a 7-day rest or will be received daily for 5 days, followed by a 2-day rest. For both regimens, 1 course will last 5 weeks, and 5 courses will be given. The primary end point is disease-free survival. A propensity score matching will be conducted based on 7 variables that represent risk factors to minimize selection bias in a comparison between the nonrandomized arms. For this nonrandomized comparison, a target sample size is set at 1200 (400 and 800 patients for the surgery alone and UFT/LV groups, respectively) and 1720 patients will be enrolled. In this study we aim to evaluate the therapeutic usefulness of adjuvant chemotherapy with UFT/LV for stage II colorectal cancer with risk factors for recurrence.

Recurrence-free survival of a hepatocellular carcinoma patient with tumor thrombosis of the inferior vena cava after treatment with sorafenib and hepatic resection.

Sorafenib (Nexabar, Bayer, Berlin, Germany), one of multikinase inhibitors, can infrequently downstage advanced hepatocellular carcinoma (HCC). There are some reports that sorafenib in combination with other modalities, such as transcatheter arterial chemoembolization (TACE) or radiation therapy, could represent a bridge to surgery. We have observed a progressive HCC case with hepatic vein tumor thrombosis proceeding to the inferior vena cava (IVC-HVTT) convert to a state of feasible curative resection after a multidisciplinary treatment which included sorafenib. The patient underwent a successful resection in consequence of this therapy. A 45-year-old male with Hepatitis B Virus-associated chronic hepatitis was diagnosed as HCC with IVC-HVTT. To obtain oncological curative resection, we performed TACE, radiation therapy followed by administration of sorafenib (800 mg per day, total 72 g). The tumor including IVC-HVTT remarkably shrank, therefore, an extended posterior sectionectomy and total removal of the IVC-HVTT was successfully performed. The operation time was 736 minutes and the amount of intraoperative hemorrhage was 805 mL. No postoperative complication occurred. Adjuvant therapy with sorafenib was started four weeks after the operation and continued for 6 months (800 mg per day, total 144 g). The patient is alive without recurrence for about 4 years from the initial therapy. Multidisciplinary therapy including sorafenib, TACE, radiation, and hepatic resection may be an effective strategy to treat HCC patients with IVC-HVTT.

Recurrence 11 years after complete response to gemcitabine, 5-Fluorouracil, and Cisplatin chemotherapy followed by radiotherapy in a patient with advanced pancreatic cancer: a case report.

A 63-year-old man diagnosed with locally advanced pancreatic ductal adenocarcinoma (PDAC; stage IIa) was treated with chemotherapy (gemcitabine, 5-fluorouracil and cisplatin) followed by radiotherapy. He had complete response by imaging and relapse-free survival for 11 years. However, he subsequently presented with local tumor recurrence and underwent pancreaticoduodenectomy followed by chemotherapy; a partial response was achieved. As in liver metastasis of colonic cancer, complete response by imaging in PDAC may not mean pathological complete response. We would propose the importance of adjuvant surgery for a patient with PDAC with complete response by imaging after chemoradiotherapy.