Higher Rate Of Liver Metastasis Research Articles

Clinical Characteristics and Special Considerations in the Management of Rare Melanoma Subtypes.

Rare histologic subtypes of melanoma, including acral, mucosal, uveal, and desmoplastic melanomas, only make up 5% of all diagnosed melanomas and are often underrepresented in large, randomized trials. Recent advancements in systemic therapy have shown marked improvement in pathologic response rates, improving progression-free and overall survival among cutaneous melanoma patients, but there are limited data to demonstrate improved survival among rarer subtypes of melanoma. Acral melanoma has a poor response to immunotherapy and is associated with worse survival. Mucosal melanoma has a large variability in its presentation, a poor prognosis, and a low mutational burden. Uveal melanoma is associated with a high rate of liver metastasis; recent adoption of infusion and perfusion therapies has demonstrated improved survival among these patients. Desmoplastic melanoma, a high-risk cutaneous melanoma, is associated with high locoregional recurrence rates and mutational burden, suggesting this melanoma may have enhanced response to immunotherapy. While these variants of melanoma represent distinct disease entities, this review highlights the clinicopathologic characteristics and treatment recommendations for each of these rare melanomas and highlights the utility of modern therapies for each of them.

Art of using maintenance therapy in a patient with metastatic colon cancer harboring RAS-wt/BRAF V600E

Background: Colorectal cancer is one of the most common malignancies with a high rate of liver metastasis, and various gene mutations have been proven to be involved in its pathogenesis. One of them is BRAF gene mutations, the most frequent of which—V600E—has a poor prognosis in patients with colon cancer. Case presentation: By applying the FOLFIRINOX regimen and a specific maintenance strategy containing vemurafenib, we achieved disappearance of metastatic lesions, no recurrence, and good stability in a Kurdish patient with metastatic colon cancer harboring RASwt/ BRAF V600E. Conclusion: Our therapeutic strategy allows the selection of the most appropriate treatment approach for patients.

Analysis of Hepatic Artery Infusion (HAI) Chemotherapy Using Randomized Trials of Floxuridine (FUDR) for Colon Cancer Patients with Multiple Liver Metastases.

Colorectal cancer (CRC) is one of the leading causes of cancer-related death, with most of the people who have the disease developing numerous liver metastases. Sixty percent of colon cancer patients have liver metastases. Only 25% of those with resectable hepatic metastases are alive, and recurrence occurs in nearly half of these cases. Regardless of the fact that left-sided cancer has a higher rate of liver metastases, past study reveals that left- and right-sided liver metastatic colon cancer patients have different survival rates. Hepatic artery infusion (HAI) combined with systemic chemotherapy is a treatment option for patients with unresectable liver-only or liver-dominant colon liver metastases. Although HAI has only been performed in a few locations previously, this study used randomized trials of floxuridine (FUDR) to characterize patient selection and first perioperative results during the deployment of a new HAI program. In this research, we also looked at the technical aspects of placing implantable pumps and catheters for HAI chemotherapy, as well as the efficacy, morbidity, and outcomes of this therapy in colon cancer patients with numerous liver metastases. The parameters like toxicity, overall survival rate, response rate, and progression-free response for the suggested therapy are also analyzed. These findings have important implications for colon cancer adjuvant HAI chemotherapy.

Efficacy and safety of immunotherapy in non-small cell lung cancer patients with poor performance status.

e21601 Background: The introduction of Immunotherapy (IO) has dramatically improved the prognosis of patients (pts) with advanced Non-Small Cell Lung Cancer (NSCLC). However, data regarding the role of IO in ECOG Performance Status (PS) 2 pts are generally limited in randomized trials, and real-world evidences could support clinical decision-making. Methods: We retrospectively analyzed data about pts with stage IV NSCLC treated with IO between April 2013 and December 2019 in two Italian Centers. The aim of our study was to assess the impact of PS status (0-1 vs 2) on disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Response was classified according to RECIST v1.1 criteria. PFS and OS were estimated by the Kaplan-Meier method. Chi-square test was used to compare clinical-pathological variables: gender, age ( < 70, 70-79, ≥80 years-old), smoking status, histology (squamous, non-squamous), PDL1 expression ( < 1%, ≥1%), IO line (1°, ≥2°), number (N) of metastatic sites (1, ≥2), presence of liver and/or brain metastasis. Their impact on survival was evaluated through Cox proportional hazard models. Results: Four-hundred-one pts (35.7% female) with median age of 65.4 years (range 27-88) were studied. Baseline PS was 0 in 134 pts (33.4%), 1 in 209 pts (52.1%) and 2 in 58 pts (14.5%). 312 pts had non-squamous NSCLC, 89 squamous NSCLC. Clinical-pathological variables were uniformly distributed across PS groups except for a higher rate of liver metastasis in PS2 pts ( p= 0.046). Response evaluation was available for 386 pts. DCR was 49.7% in PS0-1 pts and 25.9% in PS2 pts ( p= 0.006). At a median follow-up of 29 months (mos), median PFS was 3.0 mos (95% CI 2.63-4.00) and 2.04 mos (95% CI 1.84-3.00) in pts with PS0-1 and 2 ( p< 0.0001). Median OS was 13.2 mos (95% CI 11.18-15.78) and 4.0 mos (95% CI 2.66-5.62) in pts with PS 0-1 and 2 respectively ( p< 0.0001). Univariate analysis showed significant correlation of PS2 status, negative PDL1, IO line ≥2, N of metastatic sites ≥2 and liver metastasis, for both PFS and OS. Multivariate analysis confirmed an independent association of PS ( p= 0.0013 for PFS, p< 0.0001 for OS), PDL1 ( p= 0.0002 for PFS, p= 0.02 for OS) and liver metastasis ( p= 0.017 for PFS, p= 0.02 for OS). The incidence of Grade 3/4 adverse events was 10.5% in PS 0-1 pts and 13.7% in PS 2 pts ( p= 0.41). Conclusions: Our data confirm reduced efficacy of IO in pts with poor PS, regardless of the N of prior therapy lines or PDL1 expression. Despite IO appears to be safe and tolerable its role remains uncertain in PS2 pts based on worse survival outcomes.

Hepatitis B virus infection specially increases risk of liver metastasis in breast cancer patients: a propensity-matched analysis.

BackgroundBreast cancer and hepatitis B virus (HBV) infection are serious public health issues in China. But the effect of HBV infection on breast cancer remains unclear. The objective was to assess whether HBV infection was associated with prognosis of breast cancer.MethodsA retrospective database of 1,924 invasive breast cancer patients from Sun Yat-sen University Cancer Center from 2008 to 2010 was established. Propensity score matching method was applied to balance baseline parameters. Logistic regression was used for identifying the independent risk factors of liver metastasis. Prognostic outcomes were evaluated via Kaplan-Meier analysis and Cox model.ResultsPrimary evaluation of gross data suggested HBV infection was associated with much higher rate of liver metastasis. 642 patients were matched for analysis. The median follow-up time was about 69 months. Patients with HBV surface antigen (HBsAg) (+) had a specially higher risk of liver metastasis aside of other distant organs than those with HBsAg (−). HBsAg (−/+) was identified to be an independent risk factor of liver metastasis [odds ratio (OR), 2.651; 95% confidence intervals (CI), 1.213–5.796; P=0.015]. HBsAg (+) was associated with liver metastasis significantly in stage III or in estrogen receptor (ER) (+) and/or progesterone receptor (PR) (+), human epidermal growth factor receptor-2 (HER-2) (−) subtype. Meanwhile, patients with HBsAg (+) had significant shorter liver metastasis-free survival (LMFS) compared with HBsAg (−) patients (P=0.041). But the difference of overall survival (OS) between the HBsAg (−) and HBsAg (+) groups reached statistically no significance (P=0.425). The multivariate analysis suggested HBsAg (+) could worsen the outcome of LMFS [hazards ratio (HR), 2.450; 95% CI, 1.169–5.135; P=0.018].ConclusionsIn breast cancer, HBsAg (+) was associated with specially a higher rate of liver metastasis and thus worsened the LMFS. HBsAg (−/+) was an independent risk factor of liver metastasis.

Prediction of tumor biological characteristics in different colorectal cancer liver metastasis animal models using 18F-FDG and 18F-FLT

BackgroundPositron emission tomography (PET) is a noninvasive method to characterize different metabolic activities of tumors, providing information for staging, prognosis, and therapeutic response of patients with cancer. The aim of this study was to evaluate the feasibility of 18F-fludeoxyglucose (18F-FDG) and 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) PET in predicting tumor biological characteristics of colorectal cancer liver metastasis. MethodsThe uptake rate of 18F-FDG and 18F-FLT in SW480 and SW620 cells was measured via an in vitro cell uptake assay. The region of interest was drawn over the tumor and liver to calculate the maximum standardized uptake value ratio (tumor/liver) from PET images in liver metastasis model. The correlation between tracer uptake in liver metastases and VEGF, Ki67 and CD44 expression was evaluated by linear regression. ResultsCompared to SW620 tumor-bearing mice, SW480 tumor-bearing mice presented a higher rate of liver metastases. The uptake rate of 18F-FDG in SW480 and SW620 cells was 6.07% ± 1.19% and 2.82% ± 0.15%, respectively (t = 4.69, P = 0.04); that of 18F-FLT was 24.81% ± 0.45% and 15.57% ± 0.66%, respectively (t = 19.99, P < 0.001). Micro-PET scan showed that all parameters of FLT were significantly higher in SW480 tumors than those in SW620 tumors. A moderate relationship was detected between metastases in the liver and 18F-FLT uptake in primary tumors (r = 0.73, P = 0.0019). 18F-FLT uptake was also positively correlated with the expression of CD44 in liver metastases (r = 0.81, P = 0.0049). ConclusionsThe uptake of 18F-FLT in metastatic tumor reflects different biological behaviors of colon cancer cells. 18F-FLT can be used to evaluate the metastatic potential of colorectal cancer in nude mice.

Tumor Heterogeneity Predicts Metastatic Potential in Colorectal Cancer.

Purpose: Tumors continuously evolve to maintain growth; secondary mutations facilitate this process, resulting in high tumor heterogeneity. In this study, we compared mutations in paired primary and metastatic colorectal cancer tumor samples to determine whether tumor heterogeneity can predict tumor metastasis.Experimental Design: Somatic variations in 46 pairs of matched primary-liver metastatic tumors and 42 primary tumors without metastasis were analyzed by whole-exome sequencing. Tumor clonality was estimated from single-nucleotide and copy-number variations. The correlation between clinical parameters of patients and clonal heterogeneity in liver metastasis was evaluated.Results: Tumor heterogeneity across colorectal cancer samples was highly variable; however, a high degree of tumor heterogeneity was associated with a worse disease-free survival. Highly heterogeneous primary colorectal cancer was correlated with a higher rate of liver metastasis. Recurrent somatic mutations in APC, TP53, and KRAS were frequently detected in highly heterogeneous colorectal cancer. The variant allele frequency of these mutations was high, while somatic mutations in other genes such as PIK3CA and NOTCH1 were low. The number and distribution of primary colorectal cancer subclones were preserved in metastatic tumors.Conclusions: Heterogeneity of primary colorectal cancer tumors can predict the potential for liver metastasis and thus, clinical outcome of patients. Clin Cancer Res; 23(23); 7209-16. ©2017 AACR.

Analysis of 100 consecutive cases of resectable pancreatic neuroendocrine neoplasms: clinicopathological characteristics and long-term outcomes

The incidence rate of pancreatic neuroendocrine neoplasms (pNENs) has increased rapidly in recent years. However, the clinicopathological characteristics of pNENs are poorly understood. Medical records of patients who underwent surgery and were confirmed as pNENs by pathological examination from January 2003 to February 2015 in Qilu Hospital were reviewed retrospectively. A total of 100 patients, 36 males and 64 females, were included with a mean operation age of 46.26 + 13.41 years. Among the 100 cases, 76 had insulinomas and 24 had non-functional pNENs. Tumor size ranged from 0.5 cm to 9 cm, and the mean size was 2.20 + 1.40 cm. The percentages of TNM stages I, II, III, and IV tumors were 89.0%, 8.0%, 0.0%, and 3.0%, respectively. Based on the WHO classification, pNENs were classified into three grades: G1, G2, and G3. G1, G2, and G3 tumors were confirmed in 72.9%, 23.7%, and 3.4% patients, respectively. The positive rates of CgA and Syn immunohistochemical staining were 94.5% (69/73) and 100% (74/74), respectively. Compared with insulinoma, non-functional pNENs have larger tumor sizes, more advanced TNM staging, a higher Ki-67 index, and a higher rate of liver metastasis (P < 0.05). In conclusion, pNENs are heterogeneous tumors with varying clinical manifestations, diverse tumor biological characteristics, and different prognoses. Non-functional pNENs present a more aggressive behavioral model and have poorer prognosis than functional pNENs.

Abstract 1539: Live circulating tumor cells as a predictive biomarker of response to neoadjuvant chemoradiotherapy for resectable pancreatic cancer

Abstract The detection of increase in the number of circulating tumor cells (CTCs) during a patient's clinical course may be a harbinger of forthcoming overt metastasis. To detect live CTCs (l-CTCs) in blood samples of cancer patients (pts), we employed a new genetically modified telomerase-specific replication-selective adenovirous, expressing GFP (TelomeScanF35), containing both type 35 fiber that induce broad infectivity and miR-142-3p target sequence that can prevent a false positive toward blood cells. Recently, we indicated that preoperative chemoradiation therapy comprising gemcitabine and S-1 administration concurrent with full-dose radiation (NACRT) lead to encouraging survival rate in pts with resectable pancreatic cancer. But, NACRT may have disadvantages. NACRT requires several months, potentially delaying surgical resection, and can be waste of time and may result in the pts missing the chance for surgery. We assessed the l-CTCs burden in pts treated with NACRT. This study was approved by the Osaka Police Hospital IRB. Pts with resectable cytologically or histologically proven ductal adenocarcinoma of the pancreas were enrolled. Treatment consisted of an intervenous infusion of Gem 800 mg/m2 on day 1, 8, 22, and 29; and S-1 80 mg/m2 orally on day 1-5, 8-12, 22-26, and 29-33 given concurrently with IMRT to 60 Gy. Surgical exploration was scheduled 4-7 weeks after the final radiation fraction. 7.5 ml of blood samples were obtained from the pts included in this clinical study before NACRT, after 1 month of NACRT, and after 2 months of surgical resection. To distinguish between leucocyte and cells with epithelial origin, cells were stained with anti-CD45 and anti-Cytokeratin Abs. To distinguish cells with mesenchymal origin, cells were labeled with anti-Vimentin Ab. GFP-positive and CD45-negative cells were counted as l-CTC. 16 pts aged 44-78 years (5 males and 11 females) were enrolled. No treatment-related deaths occurred. CA19-9 was reduced to &amp;lt;50% of baseline values in 10 of 12 measureable pts. 13 of 16 enrolled pts successfully underwent surgical resection. 5 of 16 enrolled pts had l-CTCs (1∼4CTCs,Vimentin[+]) detected before NACRT. An increase in CTCs was seen in 4 of 5 pts after NACRT, but no detectable l-CTCs were observed in only 1 pt after NACRT. These 4 CTC-positive pts continuously had CTCs detected after surgery. 2 of 4 CTC-positive pts early developed liver metastasis and died, despite R0 resection. On the contrary, small increase (1∼2CTCs) of CTCs was seen after NACRT in 4 of 11pts, who had no CTCs detected before NACRT. But, no l-CTCs were detected in these 11 pts after surgery and they survived without recurrence. CTC-positive pts before NACRT presented a higher rate of liver metastasis after surgery than CTC-negative pts (50% vs. o%). We may consider surgery first for the CTC-positive pts before NACRT. The capture of l-CTCs may be useful biomarker for prognosis assessment or stratification. Citation Format: Masahiro Tanemura, Kenta Furukawa, Masaki Wakasugi, Kentaro Kishi, Yasuo Urata, Kiyomi Taniyama, Hiroki Akamatsu. Live circulating tumor cells as a predictive biomarker of response to neoadjuvant chemoradiotherapy for resectable pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1539.

Overexpression of eIF4E in colorectal cancer patients is associated with liver metastasis.

PurposeLiver metastasis is one of the leading causes of death in colorectal cancer (CRC) patients. The present study aimed to evaluate the value of eIF4E as a prognostic marker of colorectal liver metastasis (CLM) and identify the functional role of eIF4E in CRC metastasis.Patients and methodsThe expression level of eIF4E in CRC tissues was analyzed by immunohistochemical staining and Western blot. Expression of eIF4E in CRC cell lines was evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot. Cell Counting Kit-8 (CCK-8) and Transwell assays were performed to assess the effects of eIF4E on cell proliferation, migration, and invasion. Western blot was further used to investigate the mechanism of eIF4E in tumor metastasis.ResultsThe upregulation frequency of eIF4E in the CLM group (82.5%) was higher than that in the non-CLM group (65.0%). Of the 80 patients recruited for the follow-up study, 23 were in the low eIF4E group (ratio of tumor to nontumor tissue <twofold), and 57 were in the high eIF4E group (ratio of tumor to nontumor tissue ≥twofold). In addition, the group exhibiting high eIF4E expression had a higher rate of liver metastasis (47.4%) than the group exhibiting low eIF4E expression (13.0%). In CRC cell lines, the expression of eIF4E was higher than in the normal cells. In vitro functional studies indicated that eIF4E knockdown inhibited the proliferation, migration, and invasion of Lovo and SW480 cells, and suppressed the expression of cyclin D1, VEGF, MMP-2, and MMP-9.ConclusionThe results of the present study indicated that high eIF4E levels in CRC patients predicted a high risk of liver metastasis. Knockdown of eIF4E inhibited CRC cell metastasis in part through regulating the expression of cyclin D1, VEGF, MMP-2, and MMP-9.

Pattern of metastasis and outcome in patients with breast cancer.

There is growing evidence about differences in metastatic spread among breast cancer (BC) biologic subtypes (BS). Aim of this study was to analyze the pattern of metastasization according to BS and to explore the corresponding prognosis. A series of 544 consecutive patients receiving anticancer therapy for metastatic BC from 2004 to 2013, was analyzed. BS were defined by immunohistochemistry according to St Gallen 2013 criteria. Association between BS and the different distant localizations was analyzed. Prognosis was described in terms of overall survival (OS), progression free survival (PFS) and post progression survival (PPS). Results were reported taking luminal A BC as reference. Triple negative BC showed a higher tropism for lung (OR 4.30 95% CI 1.41-13.1), while non luminal HER2 subtype was associated with a higher rate of liver metastases (OR 3.61 95% CI 1.36-9.58). All subtypes were associated with a lower risk of bone-only localization. Central nervous system (CNS) involvement was more common in HER2 positive BC (OR 6.3, 95% CI 1.08-36.66). Liver, lung and CNS involvement influenced negatively OS (HR 1.64, 95% CI 1.29-2.07; HR 1.49, 95% CI 1.18-1.90; HR 2.891, 95% CI 1.85-4.51, respectively) and PFS (HR 1.39, 95% CI 1.13-1.71; HR 1.26, 95% CI 1.02-1.55; HR 1.75, 95% CI 1.12-2.71, respectively). Multivariate analysis confirmed liver involvement as independent predictor of worse OS (HR 1.64, 95% CI 1.15-2.34). Stratification by metastatic pattern showed significant differences in terms of PPS but not in terms of PFS. The study suggests that BS may be characterized by typical patterns of metastatic spread and have different impact on clinical outcome.

Portal vein-circulating tumor cells predict liver metastases in patients with resectable pancreatic cancer.

Pancreatic cancer patients underwent surgical resection often present distant metastases early after surgery. Detection of circulating tumor cells (CTCs) has been correlated to a worse oncological outcome in patients with advanced pancreatic cancer. The objective of this pilot study is to investigate the possible prognostic role of CTCs in patients undergoing surgery for pancreatic cancer. In 20 patients undergoing pancreatic resection, 10 mL blood sample was collected intraoperatively from both systemic circulation (SC) and portal vein (PV). Blood sample was analyzed for CTCs with CellSearch® system. All patients underwent an oncologic follow-up for at least 3 years, quarterly. CTCs were detected in nine (45%) patients: five patients had CTCs in PV only, three patients in both SC and PV, and one patient in SC only. CTC-positive and CTC-negative patients were similar for demographics and cancer stage pattern. No significant differences were found in both overall and disease-free survival between CTC-positive and CTC-negative patients. At 3-year follow-up, portal vein CTC-positive patients presented a higher rate of liver metastases than CTC-negative patients (53 vs. 8%, p = 0.038). CTCs were found in 45% of the patients. No correlation between CTCs and survival was found. The presence of CTCs in portal vein has been associated to higher rate of liver metastases after surgery.

Clinical characteristics and prognosis of hepatoid adenocarcinoma of the stomach

Hepatoid adenocarcinoma of the stomach (HAS) is a special type of gastric cancer characterized with hepatoid differentiation and the production of large amounts of α-fetoprotein (AFP). The pathogenesis of HAS is still not clear. Most of the relative studies are single case reports, and studies with large sample are absent. The prognosis of HAS is poor. HAS has a high rate of liver metastasis. The biology behaviors of HAS differ from common gastric cancers. Radical resection of the gastric cancer is considered to be the main treatment when no liver metastasis is found, while the treatment regimens of the metastasis lesions are still in debate. The serum AFP test is important for the early detection and diagnosis of HAS, and it is crucial for monitoring the therapeutic effect and the relapse and metastasis of the tumor.

MiRNA27a Is a Biomarker for Predicting Chemosensitivity and Prognosis in Metastatic or Recurrent Gastric Cancer

We previously identified five miRNAs (miR-1, miR-20a, miR-27a, miR-34a, and miR-423-5p) that are up-regulated in gastric cancer. The goal of this study was to investigate the value of these miRNAs as potential biomarkers for predicting chemosensitivity and prognosis in metastatic or recurrent gastric cancer patients who received first-line chemotherapy. A total of 82 patients with metastatic or recurrent GC receiving first-line chemotherapy were included in our study. The expression levels of the five miRNAs were evaluated using hydrolysis probe-based stem-loop quantitative reverse transcription polymerase chain reaction (qRT-PCR) in individual samples before first-line chemotherapy. Patients receiving first-line chemotherapy with fluoropyrimidine combined with oxaliplatin or paclitaxel were chosen for the chemosensitivity analysis. The relationships between expression of the five-miRNAs and clinicopathological parameters, response to chemotherapy and prognosis were analyzed statistically. Patients with higher miRNA1 expression levels tended to have a higher rate of liver metastasis, and higher miRNA34a expression levels occurred more frequently in males (P = 0.022). The expression of the remaining three miRNAs showed no obvious relationship to any of the clinicopathological features. The partial response rates of the patients with high miRNA1 expression and low miRNA1 expression were 11.1% and 23.1%, respectively (P = 0.048). Similar results were observed for miRNA27a (the partial response rate was 7.7% vs. 25.9%, P = 0.018). Patients with up-regulated miRNA27a expression had a significantly worse overall survival (OS) than patients with lower miRNA27a expression (P = 0.024). In patients with MRGC, miRNA27a is a potential biomarker for predicting resistance to fluoropyrimidine-based chemotherapy and a novel prognostic marker for gastric cancer.

Immunohistochemical Loss of Succinate Dehydrogenase Subunit A (SDHA) in Gastrointestinal Stromal Tumors (GISTs) Signals SDHA Germline Mutation

A subset (7% to 10%) of gastric gastrointestinal stromal tumors (GISTs) is notable for the immunohistochemical loss of succinate dehydrogenase (SDH) subunit B (SDHB), which signals the loss of function of the SDH complex consisting of mitochondrial inner membrane proteins. These SDH-deficient GISTs are known to be KIT/PDGFRA wild type, and most patients affected by this subset of GISTs are young. Some of these patients have germline mutations of SDH subunit genes SDHB, SDHC, or SDHD, known as Carney-Stratakis syndrome when combined with paraganglioma. More recently, germline mutations in SDH subunit A gene (SDHA) have also been reported in few patients with KIT/PDGFRA wild-type GISTs. In this study we immunohistochemically examined 127 SDHB-negative and 556 SDHB-positive gastric GISTs and 261 SDHB-positive intestinal GISTs for SDHA expression using a mouse monoclonal antibody 2E3 (Abcam). Cases with available DNA were tested for SDHA, SDHB, SDHC, and SDHD gene mutations using a hybridization-based custom capture next-generation sequencing assay. A total of 36 SDHA-negative GISTs (28%) were found among 127 SDHB-negative gastric GISTs. No SDHB-positive GIST was SDHA negative. Among 7 SDHA-negative tumors analyzed, there were 7 SDHA mutants, most germline. A second hit indicating biallelic inactivation of SDHA was present in 6 of those cases. These patients had no other SDH subunit gene mutations. Among the 25 SDHA-positive, SDHB-negative GISTs analyzed, we identified 3 SDHA mutations (1 germline), and 11 SDHB, SDHC, or SDHD mutations (mostly germline), and 11 patients with no SDH mutations. Compared with patients with SDHA-positive GISTs, those with SDHA-negative GISTs had an older median age (34 vs. 21 y), lower female to male ratio (1.8 vs. 3.1) but similar mitotic counts and median tumor sizes, with a slow course of disease in most cases, despite a slightly higher rate of liver metastases. SDHA-negative GISTs comprise approximately 30% of SDHB-negative/SDH-deficient GISTs, and SDHA loss generally correlates with SDHA mutations.

Liver-directed chemotherapy of cetuximab and bevacizumab in combination with oxaliplatin is more effective to inhibit tumor growth of CC531 colorectal rat liver metastases than systemic chemotherapy

Colorectal carcinoma is, through to its high rate of liver metastasis (mCRC), the second most cause of cancer death worldwide. Tumor resection represents the only potential cure. In cases of unresectable disease systemic chemotherapy (sCHT) remains the therapy of choice. Modern sCHT regimens including biological agents can induce tumor response that leads to curative surgery of initially unresectable mCRC. However, liver-directed therapy via hepatic arterial infusion (HAI) may produce higher response rates than sCHT. Herein we studied whether a HAI of cetuximab (CE) plus bevacizumab (BE) with or without oxaliplatin (OX) can inhibit tumor growth in a rat model. WAG/Rij rats underwent subcapsular hepatic tumor implantation. After 10 days animals received either HAI or sCHT of CE plus BE, OX or all three drugs. Saline-treated animals served as controls. Tumor growth was estimated at day 10 and 13. On day 13 liver and tumor tissue was studied histologically and immunohistochemically. In controls the tumors grew about 50 %. OX alone was not capable of inhibiting tumor growth. In contrast, CE plus BE given as HAI significantly reduced tumor growth compared to sCHT (p < 0.05). HAI of CE plus BE combined with OX yielded an even more pronounced inhibition of tumor growth. Immunohistochemistry revealed a decreased tumor cell proliferation and tumor vascularization. The present study demonstrates that HAI of CE plus BE is effective to inhibit tumor growth. This effect is even more pronounced in combination with OX. Systemic application of these agents cannot achieve comparable effects.

Stem cell gene Girdin: a potential early liver metastasis predictor of colorectal cancer

The objective of this study is to investigate the liver's metastasis-related genes and the relationship between Girdin protein expression and clinical and pathological characteristics and prognosis in colorectal cancer. The differential expression of genes between tumor cells from cases with liver metastasis and those from cases without liver metastasis were detected using an RT(2) Profiler™ PCR Array. The expression of the stem cell gene Girdin was analyzed using immunohistochemistry staining. Subsequently, the relationship between Girdin and clinicopathological parameters of colorectal cancer was determined. The Girdin protein was verified as a gene related to liver metastasis and was expressed positively in 161 (37.01 %) of the 435 cases examined. The expression of Girdin protein was related to histological grade and distant metastasis (P = 0.007 and 0.007, respectively). After analyzing survival rates, cases with highly expressed Girdin protein were shown to attain a significantly higher rate of liver metastasis and poorer postoperative, disease-specific survival than those with no or low expressed Girdin protein (P = 0.001). In the Cox regression test, the depth of tumor invasion, histological grade, duke's stage, distant metastasis, and the Girdin protein were detected as an independent prognostic factor (0.020, 0.032, 0.001, 0.001, and 0.010, respectively). The Girdin protein may be a potential new early liver metastasis biomarker of colorectal cancer.

Nodal involvement as an indicator of postoperative liver metastasis in carcinoma of the papilla of Vater

Although lymph node metastatic involvement is one of the most important prognostic factors for carcinoma of the papilla of Vater, a detailed analysis of this factor in relation to prognosis has not been conducted. From 1985 to 2003, 29 patients with carcinoma of the papilla of Vater underwent pancreaticoduodenectomy and dissection of regional lymph nodes at Yamagata University Hospital. We analyzed clinicopathologic variables in relation to prognosis and precisely evaluated nodal involvement in each patient to determine lymphatic flow. Furthermore, the relationship between recurrent site and nodal involvement was investigated. The overall survival rate was 55% at 5 years. The significant prognostic factors were morphological ulcer formation (P = 0.04), histological type (P = 0.03), nodal involvement (P = 0.002), and lymphatic invasion (P = 0.03). Multivariate analysis indicated no independent factor, but nodal involvement may be the strongest prognostic factor. The overall rate of nodal involvement was 41.4% (12 of 29 patients). The metastatic rates in the superior posterior pancreaticoduodenal lymph nodes, the inferior posterior pancreaticoduodenal lymph nodes, the superior mesenteric lymph nodes, and paraaortic lymph nodes were high (31.0%, 20.7%, 17.2%, and 13.8%, respectively). Patients with nodal involvement had a significantly higher rate of liver metastasis after surgery than those without it (P = 0.02). Ulcer formation and histological type were significantly correlated with nodal involvement (P = 0.05 and P = 0.002, respectively). Nodal involvement is the most important prognostic factor in patients with carcinoma of the papilla of Vater. Patients with nodal involvement are at high risk of liver metastasis; therefore, adjuvant therapy may be necessary for the control of liver metastasis. Preoperative ulcer formation and histological type in the biopsy specimen are good indicators for extended lymph node dissection and adjuvant therapy, because these variables are correlated with nodal involvement. However, our data revealed only the sites of the positive nodes, without addressing the effect of extended lymph node dissection and adjuvant chemotherapy. To date, there has been reporting of extended lymph node dissection and adjuvant chemotherapy in patients with carcinoma of the papilla of Vater. Further studies will be necessary to resolve these problems.

Clinicopathologic Features of Gastric Cancers Producing Alpha-Fetoprotein

Background: Patients with gastric cancers producing alpha-fetoprotein (AFP) were reported to have a poor prognosis with high rates of liver metastasis. The purpose of the present study was to clarify the clinicopathological features of AFP-producing gastric cancers, in particular characteristics of liver metastasis, and to evaluate treatment of these cancers. Methods: In 27 of the 29 cases with elevated preoperative serum AFP levels among a total of 974 primary gastric cancers, AFP production was confirmed in gastric cancer cells by immunohistochemistry. These cases were included in the AFP-positive gastric cancer group (AFP(+), 2.7%). The remaining 945 cases with normal serum AFP levels were designated the AFP-negative gastric cancer group (AFP(–)). Results: There was a higher incidence of lymph node metastasis, a deeper invasion of the gastric wall, a higher frequency of advanced stage, a more marked lymphatic invasion and a higher rate of liver metastasis in the AFP(+) group than in the AFP(–) group. The patients received curative resection in AFP(+) group had a significantly worse survival rates in comparison to that in AFP(–) group. With respect to liver metastasis (n = 17) in AFP(+) group, of 3 cases who received curative hepatic resection, 1 patient survived more than 3 years, while the remaining 2 died in less than 3 years due to multiple liver recurrence. The patients (n = 5) who received palliative resection for liver metastasis followed by transarterial continuous infusion chemotherapy all died in less than 1 year. Conclusion: AFP-producing gastric cancers had aggressive behavior and their clinical or biological features were quite different from the common AFP-negative gastric cancers. Surgical resection of liver metastasis from AFP-producing gastric cancers was unsatisfactory. The development of a novel multimodal therapy against AFP-producing gastric cancers is needed.

Prognostic significance of lymph node involvement in middle and distal bile duct cancer

Background. Although lymph node involvement is considered an important prognostic factor, a detailed analysis has not been conducted in middle (Bm) and distal (Bi) bile duct cancer. Methods. The histopathology of resections taken from 59 patients with Bm and Bi disease (Bm, 33 patients; Bi, 26 patients) was examined. The prevalence of lymph node involvement and its relationship to recurrence and prognosis were investigated. Survival rates were investigated according to the number of metastatic lymph nodes found, the TNM nodal stages, and the nodal stage classifications of The General Rules of the Japanese Society of Biliary Surgery. Results. The frequency of nodal involvement in Bm and Bi was 45.5% and 30.8%, respectively. A significant correlation existed between a patient's prognosis and his TNM nodal stage, Japanese Society of Biliary Surgery nodal stage, and the number of metastatic lymph nodes found (P <.0001, respectively). Among 8 sites of postoperative recurrence, metastasis occurred most frequently in the liver (16/23). Patients with nodal involvement had a significantly higher rate of liver metastasis (10/23) than those without it (6/36) (P =.024). Conclusions. The number of metastatic lymph nodes found in patients with Bm or Bi cancer, and the nodal stage of their nodes, are significant prognostic indicators. Patients with nodal involvement are at high risk for liver metastasis in Bm and Bi disease.(Surgery 2001;129:677-83.)