Number Of Liver Tumors Research Articles

The Japanese Nationwide Cohort Data of Proton Beam Therapy for Liver Oligometastasis in Breast Cancer Patients

A nationwide multicenter cohort study on particle therapy was launched by the Japanese Society for Radiation Oncology (JASTRO) in Japan. We analyzed the outcome of proton beam therapy (PBT) for liver oligometastasis in breast cancers. Cases in which PBT was performed at all Japanese proton therapy facilities between May 2016 and February 2019 were enrolled. The patients were selected based on the following criteria: the primary cancer was controlled, liver recurrence without extrahepatic tumors, and no more than three liver lesions. The treatment indication and strategy were discussed at cancer boards in each institution. The dose and fraction of PBT were determined by referring to the unified treatment policy established by JASTRO. We used the following protocol: 64 gray (Gy) (relative biological effectiveness [RBE])/8 fraction (fr) for the hepatic periphery area away from the GI tract, and 72.6 GyE/22 fr for the adjacent hilar region type. Regarding safety, the HCC irradiation protocols of 66 GyE/10 fr, 72.6-76 GyE/20-22 fr, and 74-76 GyE/37-38 fr could be used. The local control (LC), overall survival (OS), and progression free survival (PFS) rates were calculated using the Kaplan-Meier method. Factors possibly related to OS, such as tumor size, number of liver tumors, intervention of chemotherapy, and/or hormone therapy, were investigated. The cut-off values were estimated using the receiver operating characteristic curve and area under the curve. Univariate analysis was performed using the log-rank test. Fourteen females, with a median age of 57 (range, 44-73) years and twenty-two lesions were included. Nine patients had one lesion, two patients had two lesions, and three patients had three lesions. PBT was selected because nine patients had underlying disease and five patients had general conditions (age, etc.). The median lesion size, fraction size, and biological effective dose using the linear-quadratic model with α/β = 10 Gy ((BED)10) were 44 (20-130) mm, 6.6 (2-8) (relative biological effectiveness [RBE])/fraction (fr), and 109.6 (52.7-115.2) Gy, respectively. The median follow-up period of breast cancers was 22.8 (4-54) months. The 1-, 2-, and 3-year LC rates of liver metastasis from breast cancers were 100% for all. The 1-, 2-, and 3-year OS rates were 85.7%, 62.5%, and 62.5%, respectively. The 1-, 2-, and 3-year PFS rates were 50.0%, 33.3%, and 16.7%, respectively, and median PFS time was 16 months. Tumor size, the number of liver tumors, and the intervention of chemotherapy and/or hormone therapy at any time were not significantly related to the OS. Only one patient did not complete PBT due to current disease progression. The other patients completed PBT without interruption. One patient had grade 3 radiation-induced dermatitis. Based on the low incidence of adverse events and the high LC rate, PBT appears to be a feasible option for liver oligometastasis in breast cancer patients.

The Japanese Nationwide Cohort Data of Particle Beam Therapy for Liver Oligometastasis in Esophagogastric Cancer Patients

A nationwide multicenter cohort study on particle therapy was launched by the Japanese Society for Radiation Oncology (JASTRO) in Japan in May 2016. We analyzed the outcome of proton beam therapy (PBT) for liver oligometastasis of esophagogastric cancers. Cases in which PBT was performed at all PBT facilities in Japan between May 2016 and February 2019 were enrolled. The patients were selected based on the following criteria: controlled primary cancer; liver recurrence without extrahepatic tumors; and no more than three liver lesions. The dose and fraction of PBT were determined using unified treatment policy established by JASTRO. We used the following protocol, 64 gray (relative biological effect) (Gy (RBE))/8 fractions (fr) for the peripheral region, and 72.6 GyE/22fr for the central region. For safety aspect, the hepatocellular carcinoma irradiation protocols of 66 Gy (RBE)/10fr, 72.6-76 Gy (RBE)/20-22fr, and 74-76 Gy (RBE)/37-38fr could be allowed. The overall survival (OS), local control (LC), and adverse events (AEs) were examined. The OS and LC rates were calculated using the Kaplan-Meier method. Factors possibly related to OS, such as tumor size (for multiple lesions, the largest size), number of liver tumors, as well as the presence or absence of prior, concurrent, and post-PBT chemotherapy, were investigated. The cut-off values were estimated using the receiver operating characteristic curve and area under the curve. Univariate analysis was performed using the log-rank test. Statistical significance was P-values < 0.05. Twenty-three males and two females with a median age of 69 (range, 52-80) years and 36 lesions were included. This study included six patients with esophageal and 19 patients with gastric cancer. The median lesion size, fraction size, and biological effective dose (BED)10 were 31 (7-104) mm, 3.8 gray (relative biological effect)/fractions (Gy (RBE)/fr) (2-8 Gy (RBE)/fr), and 96.9 (88.8-115.2) Gy, respectively. The median follow-up period was 18 (4-47) months. The 1-, 2-, and 3-year OS rates were 76.0, 49.5, and 43.3%, respectively, and the median OS was 19 months. The 1-, 2-, and 3-year OS rates of esophageal cancer were 83.3% for all. The 1-, 2-, and 3-year OS rates of gastric cancer were 73.7, 40.2, and 32.2%, respectively, and the median OS was 18 months. The 1-, 2-, and 3-year LC rates were 96.3, 91.5, and 91.5%, respectively. The 1-, 2-, and 3-year LC rates of esophageal cancer were 100% for all. The 1-, 2-, and 3-year LC rates of gastric cancers were 94.7, 88.0, and 88.0%, respectively. Tumor size was the only significant OS-related factor (P < 0.01). No grade 3 or higher adverse events were observed. Owing to the low incidence of adverse events and the high LC rate, PBT is a feasible option for liver oligometastasis of esophagogastric cancers.

Abstract 1821: SPTBN1 Is a potential target to prevent progression of steatohepatitis to hepatocellular carcinoma

Abstract Background: Nonalcoholic steatohepatitis (NASH) is a risk factor for the development of hepatocellular carcinoma (HCC). β-spectrin, encoded by SPTBN1, is associated with HCC. The goal of this study was to evaluate the hepatocyte-specific roles of SPTBN1 in NASH and HCC using mouse models. Methods: We investigated the effect of knocking out Sptbn1 specifically in the liver in mice (LSKO mice). We examined the effect of diets that promote NASH—a high-fat diet (HFD) or Western diet (WD)— and the outcomes of HCC induced by diethylnitrosamine (DEN). Based on the phenotypes of these mice, we examined the therapeutic effects of knocking down Sptbn1 using siRNA. Results: We found LSKO mice were protected from HFD-induced obesity and NASH. Control mice administered siRNA targeting Sptbn1 were protected from developing NASH when placed on a HFD, and NASH phenotypes triggered by WD were reduced by administration of siRNA targeting Sptbn1. LSKO mice appeared to be protected from HFD-induced HCC: One of four HFD control mice developed liver tumors, but none of the three LSKO mice did. HFD-induced HCC is rare in mice, therefore we evaluated DEN-induced HCC. LSKO mice subjected to DEN with or without WD had less severe cancer than did wild-type mice. Compared to the HCC in the control mice, the number of liver tumors in the LSKO mice was lower, the size of the tumors was smaller, and the tumors were less proliferative based on KI67 staining intensity. Furthermore, overall liver pathology was reduced. Conclusions: These data suggest that SPTBN1 is a potential target for therapeutic intervention to treat NASH and prevent progression to HCC. Because other injected siRNA therapies are approved to treat liver diseases, a siRNA-based therapy targeting SPTBN1 could translate into clinical trials. Citation Format: Xiaochun Yang, Shuyun Rao, Xiyan Xiang, Kazufumi Ohshiro, Patricia Latham, Kirti Shetty, Lopa Mishra. SPTBN1 Is a potential target to prevent progression of steatohepatitis to hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1821.

1170-P: Dapagliflozin, a Sodium Glucose Cotransporter 2 Inhibitor, Attenuates the Development of Nonalcoholic Steatohepatitis-Associated Hepatocellular Carcinoma

Nonalcoholic steatohepatitis (NASH) is the most prevalent chronic liver disease worldwide and increases the risk for hepatocellular carcinoma (HCC) in developed countries. However, no medications have been approved to protect against NASH-driven HCC. Dapagliflozin, a sodium glucose cotransporter-2 (SGLT-2) inhibitor, improves hyperglycemia by promoting glycosuria. We investigated whether dapagliflozin prevents NASH-driven HCC using a mouse model. Diethylnitrosamine (25 mg/kg) was intraperitoneally injected into 2-week-old C57BL6/J male mice, followed by either normal chow diet or 60% high-fat diet (HFD) for 30 weeks with or without dapagliflozin, 0.003% (w/w). HFD-fed mice without dapagliflozin had an increased number of tumor on liver surface compared with chow-fed mice (77.0 vs. 12.5/per mouse; n=6 per group; p=0.01). The number of liver tumors was significantly lower in dapagliflozin treated group (19.5/per mouse in dapagliflozin-treated HFD-fed mice; n=6) than that in HFD-fed mice without dapagliflozin (p=0.03). Dapagliflozin treatment numerically reduced body weight and fasting blood glucose compared with HFD-fed mice without dapagliflozin (41.0 vs. 40.2 g, p=0.94 for body weight, and 196.3 vs. 170.8 mg/dL, p=0.34 for fasting blood glucose). In addition, several human HCC cell lines (Huh 7, HepG2, and Hep3B) expressed SGLT-2 protein. Thus, it is possible that dapagliflozin might directly modulate HCC development via SGLT-2 inhibition. In conclusion, dapagliflozin attenuates NASH-associated HCC development possibly via its direct effect on HCC. Disclosure M. Lee: None. H. Lee: None. E. Kang: None. Y. Kim: None. S. Lee: None. H. Kim: None. S. Lee: None. J. Kim: None. S. Kim: None. R. Kim: None. H. Park: None.

Sinusoidal Obstruction Syndrome Promotes Liver Metastatic Seeding of Colorectal Cancer Cells in a Rat Model.

Sinusoidal obstruction syndrome (SOS) after neoadjuvant chemotherapy with oxaliplatin for colorectal liver metastases (CRLM) has been reported to lead to early recurrence. This study investigated the effects of SOS on the development of CRLM in a rat model. RCN-H4 cells were injected into the spleen or liver of ten monocrotaline-treated (SOS group) and ten untreated (control group) rats. The number and size of liver tumors were compared between the groups. The number of liver tumors in the splenic RCN-H4 injection model was significantly higher in the SOS group than in the control group (332±213 vs. 16±5, p=0.029); however, the largest tumor diameter in the hepatic model was similar between groups (6.2±1.8 vs. 6.4±2.4 mm, p=0.87). SOS promotes CRLM development by splenic RCN-H4 cell injection. This might be due to the higher incidence of cancer cell implantation into the liver.

The role of indocyanine green fluorescence imaging in laparoscopic liver surgery

Purpose: Indocyanine fluorescence imaging (ICGFI) is increasingly being used to identify biliary anatomy, demarcation of liver transection margins, and blood supply to the remnant liver. However, the role of ICGFI in the identification of site, size and the number of liver tumours is not well established. The purpose of this study is to present our initial experience with ICGFI in laparoscopic liver surgery (LLS). Methods: We present our experience with ICGFI (Stryker Spy Fluorescence technology) guided LLS in four patients between July and November 2020. All patients received a bolus dose of 0.2-0.3ml/kg of ICG intravenously 3-4 hours before surgery Results: Four male patients with a median age of 73.1 (range: 30.6 -85.8) years underwent ICGF guided LLS surgery during the study period. The indication for liver resection was colorectal metastases (CRLM, n=3) and hepatoma (n=1). Patient with HCC had underlying liver fibrosis. ICGFI identified the exact location, size and the number of tumours (median 1; range 1-2). In all four patients the tumour had signet ring appearance (see photo). The tumour's final histology confirmed CRLM in two, the necrotic lesion in one, and HCC in the fourth patient. Interestingly, all three tumours were well to moderately differentiated tumours. ICGFI did not identify any additional lesions. Conclusions: Our initial experience confirms that ICGFI helps identify the site, size, and the number of superficially located colorectal metastasis/hepatomas.

Depression and stress levels increase risk of liver cancer through epigenetic downregulation of hypocretin

Recent studies suggest that Hypocretin (HCRT, Orexin) are involved in stress regulation of depression through the hypothalamic-pituitary-adrenal (HPA) axis. However, the molecular mechanism by which Hypocretin regulate neurobiological responses is unknown. Herein, the effects of chronic stress on the epigenetic modification of HCRT and its association with depression were explored with regard to a potential role in cancer progression. In the study, Sprague Dawley (SD) rats were used to establish an animal model of cancer with depression by administrating n-nitrosodiethylamine (DEN) and chronic unpredictable mild stress (CUMS). RNA-sequencing was used to detect differentially expressed genes in the hippocampus of rats and quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the results of RNA-sequencing. The status of HCRT promoter methylation was assessed by methylation specific polymerase chain reaction. Behavioral tests showed that rats exposed to CUMS had significant depressive-like behaviors. The number of liver tumors and tumor load in depressed rats exposed to CUMS was higher than in SD rats without CUMS. RNA-sequencing revealed that HCRT was one of the most siginificantly downregulated gene in the hippocampus of SD rats with CUMS compared to non-stressed group, which was validated by qRT-PCR. HCRT mRNA expression was downregulated and the promoter for HCRT was hyper-methylated in those with depression. These results identified a critical role for chronic psychological stressors in tumorigenesis and cancer progression, via epigenetic HCRT downregulation. Such epigenetic downregulation may be the molecular basis for the association of cancer with depression.

Canagliflozin, an SGLT2 inhibitor, attenuates the development of hepatocellular carcinoma in a mouse model of human NASH

Sodium glucose cotransporter 2 (SGLT2) inhibitors, an antidiabetic drug, promotes urinary excretion of glucose by blocking its reabsorption in the renal proximal tubules. It is unclear whether SGLT2 inhibition could attenuate nonalcoholic steatohepatitis (NASH) and NASH-associated hepatocellular carcinoma. We examined the preventive effects of an SGLT2 inhibitor canagliflozin (CANA) in Western diet (WD)-fed melanocortin 4 receptor-deficient (MC4R-KO) mice, a mouse model of human NASH. An eight-week CANA treatment attenuated hepatic steatosis in WD-fed MC4R-KO mice, with increased epididymal fat mass without inflammatory changes. CANA treatment for 20 weeks inhibited the development of hepatic fibrosis in WD-fed MC4R-KO mice. After one year of CANA treatment, the number of liver tumors was significantly reduced in WD-fed MC4R-KO mice. In adipose tissue, CANA suppressed the ratio of oxidative to reduced forms of glutathiones (GSSG/GSH) in WD-fed MC4R-KO mice. Treatment with GSH significantly attenuated the H2O2-induced upregulation of genes related to NADPH oxidase in 3T3-L1 adipocytes, and that of Il6, Tgfb, and Pdgfb in RAW264.7 cells. This study provides evidence that SGLT2 inhibitors represent the unique class of drugs that can attenuate or delay the onset of NASH and eventually hepatocellular carcinoma, at least partly, through “healthy adipose expansion”.

Trans-arterial chemoperfusion for the treatment of liver metastases of breast cancer and colorectal cancer: Clinical results in palliative care patients.

AIMTo evaluate the clinical value and efficiency of trans-arterial chemoperfusion (TACP) in patients with liver metastases from breast cancer (BC) and colorectal cancer (CRC).METHODSWe treated 36 patients with liver metastases of BC (n = 19, 19 females) and CRC (n = 17; 8 females, 9 males) with repeated TACP. The treatment interval was 4 wk. TACP was performed with gemcitabine (1000 mg/m2) and mitomycin (10 mg/m2), administered within 1 h after positioning the catheter tip in the hepatic artery. Before treatment, the size, location, tumour volume, vascularization and number of liver tumours were evaluated using magnetic resonance imaging (MRI). Tumour response was evaluated according to the Response Evaluation Criteria in Solid Tumors guidelines.RESULTSTACP using gemcitabine and mitomycin for metastases from CRC and BC was performed without any serious side effects. The follow-up MRI showed a therapeutic response in 84.2% of the BC patients - stable disease 47.4% and partial response 36.8%. A progression was seen in 15.8%. CRC patients showed a therapeutic response in 52.9% of cases. A progression of the disease was documented in 47.1% of the patients with CRC. These data show that TACP in patients with liver metastases of BC leads to a significantly better therapeutic response compared with CRC patients (P = 0.042). The median survival time was 13.2 mo for the BC patients, which is significantly longer than for CRC patients at 9.3 mo (P = 0.001).CONCLUSIONTACP for liver metastases of BC appears to be a safe and effective palliative treatment with improved outcomes in comparison to patients with CRC.

Local Control by Radiofrequency Thermal Ablation Increased Overall Survival in Patients With Refractory Liver Metastases of Colorectal Cancer.

Radiofrequency thermal ablation (RFA) is widely used for local solitary liver tumor control. However, the benefit of RFA for colorectal cancer with liver metastases, which is refractory to chemotherapy, remains unknown.We retrospectively enrolled 70 consecutive colorectal adenocarcinoma patients, who had synchronous liver metastases, who were refractory to chemotherapy, and whose life expectancy was >6 months, into this study to investigate the outcomes of RFA and associated prognostic factors. RFA was introduced to all of these patients during the enrollment. The time interval from RFA to recurrence of liver metastases and overall survival was recorded. Age, sex, carcinoembryonic antigen level, primary tumor location, postoperative adjuvant chemotherapy regimens, and the size and number of metastatic liver lesions were recorded. Cox regression analysis was used to determine the prognostic significance.Thirty-nine patients accepted RFA during chemotherapy, whereas 31 chose to receive chemotherapy alone. Patients with ≤5 and >5 liver metastases had median survival durations of 28 and 17 months, respectively (P = 0.018). The dominant liver tumor size (<5 vs ≥5 cm) was significantly associated with median survival (30 vs 17 months, respectively; P = 0.038), as was the carcinoembryonic antigen level (35 vs 16 months for ≤200 vs >200 ng/mL respectively; P = 0.029). Besides, radiofrequency thermal ablation plus chemotherapy was associated with a better median overall survival than chemotherapy alone (29 vs 12 months, respectively; P = 0.002). In multivariate analysis, only radiofrequency thermal ablation treatment and number of liver tumors were significant prognostic factors for survival. Our result further revealed that patients treated with radiofrequency thermal ablation had longer progression-free intervals than those treated with chemotherapy alone (18 vs 9 months, respectively; P = 0.001). Hence, radiofrequency thermal ablation is a safe and effective adjunct treatment to chemotherapy.

880 Concomitant Surgical Management of Synchronous Colorectal Cancer and Liver Metastases: A Comparison of Open and Laparoscopic Approaches

Purpose: There are controversies in the simultaneous management of synchronous colorectal cancer and liver metastases. Although, open surgery has been traditionally performed to resect both the primary and the liver tumors, minimally invasive options have recently emerged. The aim of this study was to compare the peri-operative and oncologic outcomes of open and laparoscopic approaches for concomitant management of synchronous colorectal cancer and liver metastases. Materials and methods: Between 2000 and 2014, all patients diagnosed with synchronous colorectal cancer liver metastases were retrospectively reviewed and those undergoing combined surgical treatment of colon and liver tumors were included in the study (n=63). Three groups were identified: patients undergoing open colorectal and liver resection (group 1), laparoscopic colorectal and liver resection (group 2) and laparoscopic colorectal resection and liver radiofrequency ablation (group 3). These 3 groups were compared regarding clinical, perioperative and oncologic data. Data were obtained from an IRB approved database. Statistical analysis was performed using t-test, chi square, and Kaplan-Meier survival. Continuous data are expressed as mean ± standard deviation. Results: There were 41 patients in group 1, and 11 each in groups 2 and 3. The groups were similar regarding demographics, and colonic or rectal primary. For groups 1, 2 and 3, the size (3.5±2.4 cm, 2.5±2.8 cm, and 3.1 ± 1.4 cm, respectively, p=0.459) and number of liver tumors treated (2.1 ± 1.3, 1.6 ± 1.0, 2.1±1.4, respectively, p=0.487) were similar. The type of colorectal procedure performed (low anterior resection, hemicolectomy vs. abdominopelvic resection) was similar between the 3 groups (p=0.225). The type of liver resections performed (minor vs. major) between group1 and 2 was also similar (p=0.931). Estimated blood loss was higher in group 1 (731±659 ml) compared to group 2 (197±171 ml) and group 3 (5±5.2 ml) (p=0.0003). Hospital stay was higher in group 1(11.4±7.6 days) versus group 2 (6.5±3.5 days) and 3 (6.7±2.9 days) (p=0.024). Morbidity was 48.7%, 9% and 18.1% ( p=0.020) and there was one mortality in Group 1 due to postoperative stroke related to deep venous thrombosis.Disease-free survival (10.4, 14.6, vs 14.1 months, respectively, p= 0.177) and overall-survival (40.9, 36.0, vs 38.5 months, respectively, p=0.181) were similar between the same study groups. Conclusion: This study suggests that 1-stage minimally invasive management of synchronous colorectal cancer with liver metastases is feasible, with improved perioperative outcomes to open surgery. The hospital stay is significantly reduced and the oncologic outcomes are not compromised with minimally invasive approaches.

Effects of curcumin supplementation on iron overload and liver cancer in a mouse model of hereditary hemochromatosis (829.8)

Curcumin, a key bioactive component of the dietary spice turmeric, is an antioxidant iron chelator with cancer prevention potential. The aim of this study was to investigate curcumin and turmeric for iron depletion and chemoprevention of diethylnitrosamine (DEN)‐induced liver cancer in a mouse model of hemochromatosis. C3H/HeJ wild type and hfe ‐/‐ male mice were given a single IP injection of DEN at 5 weeks of age and then fed diets containing 40 ppm iron, +/‐ 2% curcumin or 5% turmeric (≍0.2% curcumin). At 36 weeks of age the hfe ‐/‐ mice showed 3‐fold higher levels of liver iron but similar incidence of DEN‐induced cancer vs.wild type. Dietary curcumin did not alter body weights, liver iron, or incidence of cancer (≍77% in all hfe ‐/‐ groups). However the number of liver tumors per animal were increased 2.8x in the curcumin group (p&lt;0.01) and 2.3x in the turmeric group (p&lt;0.05). Liver/body weight ratios increased in both groups (p&lt;0.001). There was no effect of diet on oxidative damage (TBARS) in tumor‐free liver tissue. Western blots suggested increased liver redox defenses (GST‐α and heme oxygenase‐1) in animals fed turmeric. We conclude that addition of curcumin near the maximum achievable in the diet was not effective in decreasing iron overload in this mouse model of hemochromatosis. High levels of dietary curcumin and turmeric appeared to increase, rather than protect against, the hepatocarcinogenic effects of DEN.Grant Funding Source: NIH #AT003448

Complementary Use of Resection and Radiofrequency Ablation for the Treatment of Colorectal Liver Metastases: An Analysis of 395 Patients

Liver resection and radiofrequency ablation (RFA) are two surgical options in the treatment of patients with colorectal liver metastases (CLM). The aim of this study was to analyze patient characteristics and outcomes after resection and RFA for CLM from a single center. Between 2000 and 2010, 395 patients with CLM undergoing RFA (n = 295), liver resection (n = 94) or both (n = 6) were identified from a prospective IRB-approved database. Demographic, clinical and survival data were analyzed using univariate and multivariate analyses. RFA patients had more comorbidities, number of liver tumors and a higher incidence of extrahepatic disease compared to the Resection patients. The 5-year overall actual survival was 17 % in the RFA, 58 % in the Resection group (p = 0.001). On multivariate analysis, multiple liver tumors, dominant lesion >3 cm, and CEA >10 ng/ml were independent predictors of overall survival. Patients were followed for a median of 20 ± 1 months. Liver and extrahepatic recurrences were seen in 69 %, and 29 % of the patients in the RFA, and 40 %, and 19 % of the patients in the Resection group, respectively. In this large surgical series, we described the characteristics and oncologic outcomes of patients undergoing resection or RFA for CLM. By having both options available, we were able to surgically treat a large number of patients presenting with different degrees of liver tumor burden and co-morbidities, and also manage liver recurrences in follow-up.

The Value of Intraoperative Liver Ultrasound Assessment Using an Intraabdominal Probe During Laparotomy Performed for Oncological Reasons

The quality of liver assessment in an oncological patient plays an important role in the selection of a proper type of medical intervention. Diagnostic techniques commonly used in liver imaging are still far from perfect. Intraoperative liver evaluation using an intraabdominal ultrasound probe remains an important tool for proper assessment of this organ. The aim of the study was to evaluate suitability of this intraoperative diagnostic method for detection of primary and secondary neoplastic pathologies of the liver. Between March 2010 and the end of December 2011, we performed intraoperative ultrasound examinations of the liver during 220 of 461 laparotomies carried out for oncological reasons. In 72 patients (33%), intraoperative ultrasonography using an intraabdominal probe revealed neoplastic pathologies in the liver. In 16 patients (7%), the pathologies had not been observed in the preoperative imaging examinations. In 7 cases (3%), the detected tumors were impalpable and invisible in macroscopic examination routinely performed during laparotomy. The time of performing preoperative liver examinations did not affect the detection of previously unrecognized liver tumors (p > 0.05). We found progression in the number of liver tumors in 28 patients (39%). In 20 patients (9%), the primary surgical plans were changed intraoperatively. Liver examination using an intraabdominal ultrasound probe is a useful tool for assessment of neoplastic disease progression. The procedure allows proper choice of an optimal treatment regime and decreases the risk of performing an unnecessary oncological invasive procedure.

Possibility of sandwiched liver surgery with molecular targeting drugs, cetuximab and bevacizumab on colon cancer liver metastases: a case report

A 31-year-old man with sigmoid colon cancer with concomitant simultaneous multiple liver metastases had received FOLFIRI (leucovorin, fluorouracil and irinotecan) and FOLFOX6 (leucovorin, fluorouracil and oxaliplatin) after an ordinary sigmoidectomy. However, his serum carcinoembryonic antigen (CEA) level increased rapidly during the fifteen months after the operation while he was on FOLFOX6. Abdominal computed tomography revealed expanding multiple liver tumors. As the third line chemotherapy, a combination therapy of cetuximab with irinotecan was given, which markedly reduced his levels of serum CEA, and the size and number of liver tumors. He underwent lateral segmentectomy of the liver and microwave coagulation of the liver metastases in the remnant liver. Thereafter, a good quality of life with tumor dormancy was obtained for 6 months. However, his serum CEA started to rise again in the absence of liver tumors. Therefore, FOLFOX6 with bevacizumab was chosen as the fourth line chemotherapy, and the serum CEA was reduced with tumor dormancy. A good quality of life was obtained again at 3 years after the first surgery. This report indicates the effectiveness of sandwiched liver surgery with the molecular targeting drugs cetuximab and bevacizumab on multiple liver metastases of colon cancer, and suggests the possibility of a regimen consisting of bevacizumab following cetuximab.

Prognostic value of the number and volume of liver tumours on portal vein embolization outcomes.

Portal vein embolization (PVE) extends the resecability of liver tumours.The issue of PVE is an insufficient growth of the liver parenchyma or a tumour progression in some patients. We evaluated the effect of the volume and the number of liver tumours on the effect of PVE. PVE was performed in 40 patients with liver tumours due to an insufficient future remnant liver volume. The number and the volume of the tumours were evaluated and compared with the final PVE effect. In patients without any increase of the liver volume after PVE (n=3) the number and the volume of the tumours before PVE were 2.7±2.1 and 2205.1±2432.7mm3, respectively. In patients with sufficient growth of the liver (n=22) it was 3.8±2.2 (NS) and 1164.9±1392.1mm3 (NS), respectively. In patients with tumour progression (n=11) it was 5.6±2.2 and 6971.4±5189.5mm3, respectively (p<0.04 and p<0.005, respectively). Four patients were treated by radiofrequency ablation only due to worsening of their health state. Patients with >4 foci (OR 4.7) and a tumour volume >400mm3 (OR=13.0) had a higher probability of cancer progression or insufficient growth of the liver tissue. Patients with <6 foci and a tumour volume <3100mm3 had an 87.5% probability of a successful liver hypertrophy after PVE. The tumour number and volume were crucial for progression of a malignant disease and growth of the liver parenchyma after PVE.

RETRACTED: Loss of Metallothionein Predisposes Mice to Diethylnitrosamine-Induced Hepatocarcinogenesis by Activating NF-κB Target Genes

Metallothioneins (MT) are potent scavengers of free radicals that are silenced in primary hepatocellular carcinomas (HCC) of human and rodent origin. To examine whether loss of MT promotes hepatocarcinogenesis, male Mt-1 and Mt-2 double knockout (MTKO) and wild-type (WT) mice were exposed to diethylnitrosamine (DEN) and induction of HCC was monitored at 23 and 33 weeks. The size and number of liver tumors, the ratio between liver and body weight, and liver damage were markedly elevated in the MTKO mice at both time points compared with the WT mice. At 23 weeks, MTKO mice developed HCC whereas WT mice developed only preneoplastic nodules suggesting that loss of MT accelerates hepatocarcinogenesis. MTKO tumors also exhibited higher superoxide anion levels. Although NF-κB activity increased in the liver nuclear extracts of both genotypes after DEN exposure, the complex formed in MTKO mice was predominantly p50/65 heterodimer (transcriptional activator) as opposed to p50 homodimer (transcriptional repressor) in WT mice. Phosphorylation of p65 at Ser276 causing its activation was also significantly augmented in DEN-exposed MTKO livers. NF-κB targets that include early growth response genes and proinflammatory cytokines were significantly upregulated in MTKO mice. Concurrently, there was a remarkable increase (∼100-fold) in Pai-1 expression; significant increase in c-Jun, c-Fos, c-Myc, Ets2, and ATF3 expressions; and growth factor signaling that probably contributed to the increased tumor growth in MTKO mice. Taken together, these results demonstrate that MTs protect mice from hepatocarcinogen-induced liver damage and carcinogenesis, underscoring their potential therapeutic application against hepatocellular cancer.

Impact of the Degree of Liver Resection on Survival for Patients with Multiple Liver Metastases from Colorectal Cancer

Although the degree of hepatic resection has been found to be a key aspect of tumor stimulation, the differences in clinical outcome between a massive liver resection and a less extensive resection for multiple colorectal metastases have not been well studied. The purpose of this study was to clarify the impact of the extent of liver resection on survival outcome. Clinicopathologic data were available for 85 patients who were surgically treated for four or more liver metastases. Forty-nine patients who underwent a major hepatic resection were compared with patients who underwent minor hepatic resections (n = 36). As the patients undergoing major resection were more likely to have multiple (p = 0.014) and large tumors (p = 0.021) compared to the minor-resection patients, their overall survival was worse (p = 0.046) and the disease-free rate tended to be poorer. By multivariate analysis of the cohorts, the only independent factor affecting survival was the number of liver tumors (< or =5 or > or =6; relative risk [RR] = 0.427; p = 0.014). When patients with six or more metastases were selected and analyzed, the overall survival of patients who had a major resection was significantly poorer than those who had minor resections (p = 0.028), although the clinical characteristics were comparable between the two groups. Although the extent of hepatectomy was not an independent prognosticator, minor resections for multiple colorectal metastases may offer a long-term survival advantage compared to a major resection.

Coagulation abnormalities in patients with metastatic colon cancer on bevacizumab therapy

14578 Background: Bevacizumab (Avastin) is a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF) that functions as an anti-angiogenic agent. VEGF is a glycoprotein, important for regulation of angiogenesis in normal and pathologic cells and is required for the maintenance of immature blood vessels, found in tumors. In addition to direct antiangiogenic effects, bevacizumab improves chemotherapy delivery by altering tumor vasculature as well as decreasing the size and number of liver tumors in mouse xenograft model of human colon cancer metastases. This study aimed to look for predictors of the development of major toxicities such as bleeding and clotting that would increase the incidence of such events in patients with metastatic colorectal carcinoma on Bevacizumab therapy. Methods: The study was a retrospective analysis over the past 2 years, reviewing the charts of 59 successive patients receiving bevacizumab in our institution. Particular emphasis was placed on age, gender, tumor type and location, location of metastases, chemotherapy regiment/number of cycles, past medical history, hemoglobin/hematocrit values, PT/INR values, liver function tests and albumin values at the time of the diagnosis and event. Utilizing univariant and multivariant analysis the goal was to determine contributing risk factors for increased incidence of bleeding and clotting. Results: 20.3% of the patients were found to have a major complication, such as clotting or bleeding. Once analyzed, there were four statistically significant indicators (p &lt; 0.05) that predicted for the incidence of either one of the events. They included older patient age, low albumin values at the time of the event (as defined by the institution value of less than 3.6), location of the tumor (cecum, ascending colon and sigmoid colon were predominant), and the site of the metastasis (liver and lung). Conclusions: Clotting and bleeding complications in patients on Bevacizumab are not uncommon. It is clear that age, low albumin values, metastatic site and tumor location contribute to an increased incidence of such events in patients with metastatic colon cancer on Bevacizumab therapy. [Table: see text]

Amelioration of carcinogen-induced toxicity in mice by administration of a potentized homeopathic drug, natrum sulphuricum 200.

To examine if a potentized homeopathic drug, Natrum Sulphuricum 200 (Nat Sulph-200) has protective potentials against hepatocarcinogenesis, liver tumors were induced in mice through chronic feeding of P-dimethylaminoazobenzene (p-DAB; initiator of hepatocarcinogenesis) and phenobarbital (PB; promoter). Mice were divided into five sub-groups: fed normal low protein diet (Gr. I, normal control); fed normal low protein plus alcohol-200 (vehicle of the homeopathic remedy) (Gr. II); fed diet mixed with 0.06% p-DAB plus 0.05% PB (Gr. III); fed diet and carcinogens like Gr.III, plus alcohol 200 (positive control for drug fed mice) (Gr. IV) and fed diet and carcinogens like Gr. III, plus Natrum Sulphuiricum-200 (Gr. V; drug fed). Mice were sacrificed at day 7, 15, 30, 60, 90 and day 120 for study of cytogenetical endpoints like chromosome aberrations (CA), micronuclei (MN), mitotic index (MI) and sperm head anomaly (SHA) and biochemical toxicity parameters like aspartate amino transferase (AST), alanine amino transferase (ALT), acid (AcP) and alkaline (AlkP) phosphatases, lipid peroxidation (LPO) and reduced glutathione (GSH) content. Less number of liver tumors were observed in Gr. V (drug fed) mice. Administration of Nat Sulph 200 reduced genomic damage, activities of AcP, AlkP, AST, ALT, LPO and increased GSH content. Therefore, independent replication of the study by others is encouraged.