Multicentric Recurrence Research Articles

Imaging Classification of Exophytic HCC and Our Experience with Microwave Ablation of Type 2 Lesions

Abstract Purpose The purpose of this article is to classify hepatocellular carcinoma (HCC) based on imaging and to evaluate the role of ultrasound-guided microwave ablation (MWA) in the management of type 2 exophytic HCC. Materials and Methods A retrospective study was performed at our institution after approval by the Institutional Review Board. The study was undertaken from January 2017 to May 2022. Based on the location, HCC was classified and categorized on cross-sectional imaging into four types. All MWA procedures were performed using ultrasound guidance. Patients were followed up every 3 months with cross-sectional imaging. Results During the study period, 225 lesions were reviewed. MWA was performed in 13 type 2 exophytic HCC patients. Segment 3 (38%) was the most common site when categorized as per Couinaud classification and segment 6 was the next common site. Technical success of complete ablation, evaluated by postprocedure contrast-enhanced computed tomography scan, was 100%. The median follow-up period was 24 months (range: 9–24 months). One patient presented with a residual lesion on the first follow-up at 30 days. Two other patients followed up to 9 months were free of HCC. Ten patients followed up at 1 year showed no recurrence, while 7 of them were followed up for 24 months, and 1 of whom showed multicentric recurrence which was treated by selective intra-arterial radiation therapy. Conclusion A classification system for exophytic lesions can allow for better patient selection, planning, and reporting of ablative outcomes. MWA has performed well when ablating these technically challenging lesions with a certain degree of planning.

What is the optimal surgical treatment for hepatocellular carcinoma beyond the debate between anatomical versus non-anatomical resection?

The optimal type of hepatectomy for hepatocellular carcinoma (HCC)-anatomical or non-anatomical resection-remains controversial despite numerous comparative studies. There are common fundamental issues in published studies comparing anatomical resection with non-anatomical resection: (1) confounding by indication, (2) setting primary outcomes, and (3) a lack of a clear definition of non-anatomical resection. This degrades the quality of the comparison of the two types of surgery. To measure the therapeutic effect of hepatectomy, it is essential to understand the accumulated knowledge underlying these issues, such as the mechanism of hepatocellular carcinoma spread, tumor blood flow drainage theory, and the three patterns of hepatocellular carcinoma recurrence: (1) local intrahepatic metastasis, (2) systemic metastasis, and (3) multicentric carcinogenesis recurrence. Based on evidence that the incidence of local intrahepatic metastasis was so low it was almost negligible, the therapeutic effect of anatomical resection on the oncological survival was determined to be similar to that of non-anatomical resection. Recent research progress demonstrating the clinical impact of subclinical dissemination of HCC after surgery may stimulate new debate on the optimal surgical treatment for HCC beyond the comparison of anatomical and non-anatomical resection.

Four gene intrahepatic metastasis–risk signature predicts hepatocellular carcinoma malignant potential and early recurrence from intrahepatic metastasis

BackgroundHepatocellular carcinoma has a high recurrence rate even after curative surgery, and hepatocellular carcinoma risk–predictive biomarkers will enable identification of patients who most need close monitoring and cancer-preventive intervention. Hepatocellular carcinoma has 2 different recurrence patterns—a multicentric recurrence and an intrahepatic metastasis. We have reported that the molecular gene signature from the gene expression of adjacent liver can be used to predict multicentric recurrence of hepatocellular carcinoma, but the signature to predict recurrence from intrahepatic metastasis has not been established. We aimed to identify the recurrence from intrahepatic metastasis gene signature from the gene expression of tumor to predict recurrence from intrahepatic metastasis. MethodsThe intrahepatic metastasis-risk signature was created based on the exhaustive analysis using a microarray transcriptome database of hepatocellular carcinoma. The intrahepatic metastasis-risk signature was measured in a cohort of 80 hepatocellular carcinoma patients, and the correlation with hepatocellular carcinoma recurrence and overall survival and each gene signature were analyzed and validated. ResultsThe gene signature assay classified the patients into high- (n = 20), intermediate- (n = 40), and low-risk (n = 20) groups. The high-risk prediction was independently associated with higher early hepatocellular carcinoma recurrence (hazard ratio = 3.7, P = .03) in multivariable modeling adjusted by tumor size, tumor number, and microvascular invasion. Gene set enrichment analysis demonstrates that the gene sets associated with “cell cycle” or “histone modulation” are highly enriched in the high intrahepatic metastasis gene signature group ConclusionThe intrahepatic metastasis gene signature predicts early recurrence and is associated with malignant potential related to the promoted cell cycle.

The landscape of postsurgical recurrence patterns in diffuse low-grade gliomas.

Early and maximal safe surgical resection optionally followed by adjuvant treatment is currently recommended in diffuse low-grade glioma (DLGG). Although this management delays malignant transformation (MT), recurrence will most often occur. Because this relapse usually arises locally, reoperation can be considered, with possible further chemotherapy/radiotherapy. However, due to a prolonged overall survival, a large spectrum of unusual recurrence patterns begins to emerge during long-term follow-up, beyond the classical slow and local tumor re-growth. We review various atypical patterns of DLGG relapse, we discuss their pathophysiological mechanisms and how to adapt the treatment(s). Those patterns include very diffuse, ipsi- or bilateral gliomatosis-like progression, multicentric recurrence with emergence of remote low-grade or high-grade glioma, leptomeningeal dissemination, acute (early or delayed) local MT or bulky relapse into the operating cavity. This landscape of recurrence patterns may allow physicians to elaborate new tailored therapeutic strategies and scientists to develop original hypotheses for basic research.

Baseline multicentric tumors, distant recurrences and leptomeningeal dissemination predict poor survival in patients with recurrent glioblastomas receiving bevacizumab.

There are no widely accepted MRI markers that predict treatment outcomes of bevacizumab among patients with recurrent glioblastoma (GB). We aimed to determine if conventional MRI features of recurrent GB predict survival of patients receiving bevacizumab. Patients with recurrent GB were retrospectively included if they received bevacizumab monotherapy between 2008 and 2017 after failure of standard treatment. Their MRI studies obtained at baseline and tumor recurrence, prior to bevacizumab treatment, were evaluated for multiple MRI features including measurable tumor, baseline multicentric tumors, distant recurrence, non-contrast-enhancing tumor, deep white matter invasion, multiple parenchymal tumors, bilateral cerebral involvement, ependymal extension and leptomeningeal dissemination. Predictive values of MRI features and patient characteristics on patient survival were statistically analyzed. A total of 103 patients were included. Baseline multicentric tumors (OR = 4.07; P = 0.042) and distant recurrence (OR = 28.5; P < 0.001) were two significant predictors of 3-month progression-free survival (PFS) rate. Distant recurrence (HR = 3.94; P < 0.001) was the only independent predictor of PFS. Baseline multicentric tumors (HR = 1.97; P = 0.028), distant recurrence (HR = 4.73; P < 0.001) and leptomeningeal dissemination (HR = 2.28; P = 0.044) were three independent predictors of overall survival. Baseline multicentric tumors, distant recurrence and leptomeningeal dissemination predicted poor survival among patients receiving bevacizumab for recurrent GB. Conventional MRI may help selecting patients with recurrent GB for bevacizumab treatment.

Muscle-invasive bladder and urethral cancer recurrence after surgical management of upper tract urothelial carcinoma: A review of 305 patients.

Bladder cancer recurrence after management of upper tract urothelial carcinoma (UTUC) is a common disease. Although the incidence and risk factors for the development of noninvasive bladder tumor have been reported in many series, rare studies have reported on muscle invasive bladder cancer (MIBC) and its urethral recurrence. We aimed to report the incidence, risk factors and survival rate for the development of MIBC and urethral tumors after surgical management of UTUC. We retrospectively reviewed patients who were surgically treated for UTUC from 1983 to 2013. The tumor was categorized according to the 1997 TNM staging and the 3-tiered WHO grading systems. The primary endpoint of this study was the occurrence of any post-treatment MIBC and its urethral recurrences. We studied the possible risk factors that may contribute to the development of such pathology as well as the prognosis of this pathology. A total of 297 patients were eligible for analysis. Intravesical tumor recurrence was observed in 139 (46.8%) patients and radical cystectomy was warranted for 36 patients (MIBC or multicentric bladder recurrence). Twenty-seven patients were fit for surgery with ileal loop conduit was the urinary diversion for the majority, and others received radiotherapy. Ureteral tumor was the only statistically significant risk factor (p=0.001) and the incidence increased as the ureteral tumors became more distal (p=0.01). Occurrence of invasive or multicenteric bladder recurrence was a predictor for local, urethral recurrence and distant metastasis (p=0.016, 0.0001 and 0.01 respectively). Seven patients had urethral urothelial carcinoma; 5 were diagnosed at the time of cystectomy and 2 were discovered later (1 and 3 years after cystectomy). MIBC is a relatively uncommon (6%) post UTUC, and ureteral tumors, especially distal in location, are the independent risk factor. Extended surveillance for those patients is needed. Urethral cancer recurrence is rare (2%); most cases are localized in the posterior urethra, they are noninvasive, and may develop even after cystectomy.

MiR-223 and Stathmin-1 Expression in Non-tumor Liver Tissue of Patients with Hepatocellular Carcinoma.

Overexpression of stathmin (STMN1) has been reported for several tumor entities. STMN1 expression correlated with the detection of mutant p53, also suggesting loss-of-function-dependent mechanisms for its accumulation in hepatocellular carcinoma (HCC) cells. On the other hand, miR-223 has been identified as one of the most down-regulated miRNAs in HCC, and its expression was shown to be negatively correlated with STMN1 expression. The aim of this study was to investigate the clinical significance of STMN1 and miRNA-223 expression. Fifty-six consecutive patients with HCC who underwent curative hepatectomy as initial treatment were enrolled. They were divided into two groups based on the STMN1 expression level: high (n=36) and low (n=20) gene-expression groups. We compared the clinicopathological factors between the groups with high and low expression in non-tumor tissues. Thirty out of 56 patients were also divided into groups with high (n=15) and low (n=15) miR-223 expression and compared the clinicopathological factors between the two groups. There were no significant differences in patient background between high and low STMN1 expression groups. The incidence of multicentric (MC) recurrence in the high-expression group was significantly higher than in the low-expression group and high STMN1 expression was shown to be an independent risk factor for MC recurrence. There were also no significant differences in patient background between high and low miR-223 expression groups; however, the disease-free survival rate in the group with low expression was significantly worse. Furthermore, MC-related miRNAs identified by miRNA microarray clearly clustered patients into MC recurrence and non-recurrence groups. Both gene and miRNA expression profiles in non-tumor liver tissues could predict the risk for MC recurrence. Such molecular information may be useful in enabling better decision making for patients with HCC.

Outcomes after resection of occupational cholangiocarcinoma.

Cholangiocarcinoma caused by exposure to 1,2-dichloropropane and/or dichloromethane is recognized as occupational cholangiocarcinoma. The aim of this study was to investigate the outcomes after resection of occupational cholangiocarcinoma to establish a treatment strategy for this disease. Clinicopathological findings and outcomes after surgical intervention in 20 patients with occupational cholangiocarcinoma were investigated. Of 20 the patients, curative resection was performed in 16 patients. Three patients underwent radiation at the stump of the bile ducts. Adjuvant chemotherapy was performed in 12 patients. Biliary intraepithelial neoplasia, intraductal papillary neoplasm of the bile duct, and/or chronic bile duct injury was detected in most subjects. Intraabdominal infection developed after surgery in nine patients. Cholangiocarcinoma recurred in 12 of the 20 patients. The recurrent tumors in five patients developed at a different part of the bile duct from the primary tumor and a second resection was performed in four of these five patients. The incidence of postoperative complications including intraabdominal infection was high in patients with occupational cholangiocarcinoma. Multicentric recurrence occurred not infrequently after surgery because the bile ducts had a high potential for the development of carcinoma. The aggressive treatment including second resection for the multicentric recurrence appeared to be effective.

From radical to nipple sparing mastectomy: Techniques, indications and safety

The role of surgery in the management of breast cancer has continuously evolved over the last 100 years. William Halsted pioneered in breast cancer management by establishing that the primary goal of surgery was to treat the disease and prolong survival by containing the loco-regional spread with radical resections; his radical mastectomy was widely used for almost 100 years. Thanks to the results of well-designed randomized control trials that began in the 1970s, the treatment goal for the management of breast cancer shifted in a different direction, and the role of surgery altered dramatically. As a result, the extreme “one size fits all” radical mastectomies were gradually replaced by a more “tailor-made” less invasive modified technique, but without compromising the prognosis and survival. Eventually, the correct and timely resection of the tumour in a way that minimized morbidity, without causing unnecessary harm and burden to the patient, became the basic goal of breast surgery. Conservation of the breast and acceptable cosmesis became the main purpose of breast surgery and the gold standard for early stage breast cancer. Notwithstanding, approximately 20-30% of women with breast cancer undergo mastectomy. Nevertheless, the face of mastectomy has altered during the last three decades and what used to be a simple, and unfortunately often mutilating removal of the cancerous breast lesion, has become a sophisticated, often technically demanding, and definitely quality-of-lifeoriented part of the multidisciplinary process. In this review, we present the historical evolution of mastectomy while analyzing the indications, technical points and safety of each approach. In the “Halsted” radical mastectomy, the breast was removed along with the overlying skin and both pectoralis muscles, together with complete en bloc resection of the regional lymph nodes. In the 1940s, a less radical procedure was proposed by Patey: a modification of the radical mastectomy where the pectoralis major was preserved, followed a few years later by a less radical approach that preserved both pectoral muscles. This modified technique subsequently became the gold standard procedure in the USA in the 1970s and remains, to date, the current conventional form of mastectomy. In the 1950s, silicone implants were introduced to breast surgery. Given the prolonged survival for many patients, breast reconstruction became a reality. In 1991, Toth and Lambert described a new form of mastectomy (the skin sparing mastectomy) where the breast was removed from well-planned incisions in a way that most of the skin, particularly the inframammary fold, was preserved in order to allow immediate reconstruction and better cosmetic results. Eventually, a new form of SSM where the nipple areola complex (NAC) was also preserved emerged as a surgical option in order to further improve the cosmetic outcome of mastectomy in selected patients. In conclusion, mastectomy still remains necessary for a high percentage of breast cancer patients, though radical mastectomy is rarely used nowadays. The main indications for mastectomy are extensive or multicentric disease, contraindication, failure or recurrence after breast conserving surgery (BCS), locally advanced and inflammatory cancer, risk reduction, and if the patient so chooses. Skin-sparing mastectomy is a safe option offering better cosmetic results for patients with an indication for mastectomy and immediate reconstruction, provided that the skin is not involved and there is no inflammatory cancer. Nipple-sparing mastectomy can be applied safely in carefully selected patients, providing them with even better cosmetic results. Riskreducing mastectomy should be performed when indicated in a way that provides the patient optimal quality of life.

The incidence of multicentric recurrence after liver resection for hepatocellular carcinoma: a matched case-controlled study of hepatocellular carcinoma arising from normal liver and diseased liver

The incidence of multicentric recurrence after liver resection for hepatocellular carcinoma: a matched case-controlled study of hepatocellular carcinoma arising from normal liver and diseased liver

Identification of aberrant DNA methylation profiles in non-tumor liver tissues of patients with non-B, non-C hepatocellular carcinoma.

249 Background: Percentage of patients with non-B non-C (NBNC) hepatocellular carcinoma (HCC) is rapidly increasing in Japan. We have previously shown that miRNA expression profiles in non-tumor liver tissues of patients with NBNC-HCC are different from those of patients with HBV-HCC and HCV-HCC. Moreover, we have recently reported that specific miRNA expression profiles in non-tumor liver tissues can predict a risk of multicentric recurrence after hepatectomy for HCC (Hepatol Res, 2013). In this study, we performed the genome-wide analysis of aberrant DNA methylation in non-tumor liver tissues of patients with NBNC-HCC. Methods: We divided the 23 patients, who underwent hepatectomy, into 3 groups; NBNC (HBcAb-, n=7), NBNC (HBcAb+, n=8), and normal control (NC, n=8). We analyzed DNA methylation status in fresh-frozen non-tumor liver tissues using Infinium Human Methylation 450 Bead Chip (illumina). Gene-expression levels of several identified genes were analyzed by quantitative RT-PCR to validate the correlation between DNA methylation status and gene-expressions. Results: We identified 87 differentially methylated genes in HBcAb- liver tissues, and 603 genes in HBcAb+ liver tissues in comparison to NC liver tissues (Beta value&gt;0.2, P&lt;0.05). Thirty CpG sites were commonly hyper- or hypo-methylated in both HBcAb- and HBcAb+ livers. High percentages of aberrant DNA methylation were observed in gene body. One hypermethylated gene (Lrig1, an intestinal stem cell marker that functions as a tumor suppressor) was confirmed to be down-regulated in its gene-expression level by quantitative RT-PCR. One hypomethylated gene (LEF1, a molecule enhancing hepatocarcinogenesis though Wnt/beta-catenin signaling) was also confirmed to be up-regulated. Ingenuity Pathway Analysisrevealed the association of Wnt/beta-catenin signaling with aberrant DNA methylation status. Conclusions: Genome-wide analysis of aberrant DNA methylation in non-tumor liver tissues may provide not only molecular mechanisms of epigenetic modulation during hepatocarcinogenesis but also early molecular diagnosis in patients with NBNC-HCC.

Differential response of idiopathic sporadic tumoral calcinosis to bisphosphonates.

Context:Tumoral calcinosis is a disorder of phosphate metabolism characterized by ectopic calcification around major joints. Surgery is the current treatment of choice, but a suboptimal choice in recurrent and multicentric lesions.Aims:To evaluate the efficacy of bisphosphonates for the management of tumoral calcinosis on optimized medical treatment.Settings and Design:The study was done in the endocrine department of a tertiary care hospital in South India. We prospectively studied two patients with recurrent tumoral calcinosis who had failed therapy with phosphate lowering measures.Materials and Methods:After informed consent, we treated both patients with standard age adjusted doses of bisphosphonates for 18 months. The response was assessed by X ray and whole body 99mTc-methylene diphosphonate bone scan at the beginning of therapy and at the end of 1 year. We also estimated serum phosphate levels and urinary phosphate to document serial changes.Results:Two patients (aged 19 and 5 years) with recurrent idiopathic hyperphosphatemic tumoral calcinosis, following surgery were studied. Both patients had failed therapy with conventional medical management − low phosphate diet and phosphate binders. They had restriction of joint mobility. Both were given standard doses of oral alendronate and parenteral pamidronate respectively for more than a year, along with phosphate lowering measures. At the end of 1 year, one of the patients had more than 95% and 90% reduction in the size of the lesions in right and left shoulder joints respectively with total improvement in range of motion. In contrast, the other patient (5-year-old) had shown no improvement, despite continuing to maintain normophosphatemia following treatment.Conclusions:Bisphosphonate therapy in tumoral calcinosis is associated with lesion resolution and may be used as a viable alternative to surgery, especially in cases with multicentric recurrence or treatment failure to other drugs.

CD34 Expression in Noncancerous Liver Tissue Predicts Multicentric Recurrence of Hepatocellular Carcinoma

Background: Metachronous multicentric recurrence of hepatocellular carcinoma (HCC) is a common cause of morbidity and mortality following curative surgical resection. Clinical and laboratory predictors of these processes can markedly aid in managing these patients. Capillarization of hepatic sinusoids is also a well-known phenomenon in many liver diseases, especially in neoplastic liver diseases. Here, we investigated the clinical features, fibrosis scores and distribution of CD34 in noncancerous hepatic tissues of postresection patients with and without multicentric recurrence. Methods: Eighteen patients with multicentric recurrence of HCC diagnosed by histological examination of repeated hepatectomy specimens and 72 HCC patients with more than 5-year disease-free survival postresection participated in the study. We compared the clinicopathological features of these two groups. We examined noncancerous hepatic tissues for iron deposition by Prussian blue staining and computed the CD34-labeling index (LI) through immunohistochemistry using anti-CD34 antibody. Results: CD34-LI was significantly higher in the multicentric recurrence group (p < 0.001) and staging scores of fibrosis were also significantly higher in the recurrence group (p = 0.035). A high histological activity grade (p = 0.057) and a high alanine aminotransferase level (p = 0.060) were also associated with recurrence. There were no significant differences between the two groups in age, sex, hepatitis B virus surface antigen and anti-hepatitis C virus antibody levels, or grade of iron deposition. On multivariate analysis, high CD34-LI was the only independent risk factor (p = 0.001) for metachronous multicentric recurrence. Conclusion: CD34 expression in the capillaries and sinusoids of noncancerous hepatic tissue is a risk factor for multicentric recurrence of HCC. Histologic assessment of hepatic tissue with CD34 immunohistochemistry might be useful for the prognostic evaluation of HCC patients after surgery.

Specific miRNA expression profiles of non‐tumor liver tissue predict a risk for recurrence of hepatocellular carcinoma

It is reasonable to investigate non-tumor liver tissues to predict a risk for development of hepatocellular carcinoma (HCC). A molecular analysis of chronically damaged liver tissues may identify specific miRNA expression profiles associated with a risk for multicentric (MC) HCC. Twenty HCC patients, who underwent a curative hepatectomy were classified into two groups: a non-MC group (no MC recurrence in more than 3 years, n = 10) and an MC group (MC recurrence within 3 years after hepatectomy, n = 10). An miRNA microarray (955 probes) was used to compare the miRNA expression patterns of the non-cancerous liver tissues between the two groups. This study identified the differentially expressed miRNA related to MC recurrence in the liver remnant. No differences were observed between the two groups in the liver function tests and pathological variables including both tumor factors and non-tumor liver tissues. The investigation selected 20 differentially expressed miRNA related to MC recurrence. Eighteen miRNA were downregulated, while two miRNA were upregulated in the MC group. A hierarchical clustering analysis identified a cluster that may be associated with risk of the MC recurrence of HCC. The MC recurrence-related miRNA included let-7d*, miR-328 and miR18a*, which potentially regulate K-ras gene expression. A significant inverse correlation between the miR-18a* expression and the K-ras mRNA expression was confirmed by quantitative reverse transcription polymerase chain reaction. Specific miRNA expression signatures in non-cancerous liver tissue may help to predict the risk for de novo development of HCC.

Subependymal spread of recurrent glioblastoma detected with the intraoperative use of 5-aminolevulinic acid

Recurrent glioblastoma (GBM) can occur locally or at distant sites within the brain. Though MRI is the standard imaging modality for primary and recurrent GBM, the full extent of diffuse lesions may not be appreciated on MRI alone. Glioblastomas with ependymal and/or subependymal spread are examples of diffuse infiltrative tumors that are incompletely seen on MRI. Some other adjuvant visualization technique such as intraoperative fluorescence-assisted 5-aminolevulinic acid (5-ALA) could be used to assist the surgeon in localizing the infiltrating tumor. The authors report on a 56-year-old man who presented 7 years after initial resection of an occipital lobe GBM with imaging consistent with distant discrete foci of tumor recurrence. Because these foci were distant from the original resection cavity, there was concern for diffuse, infiltrative tumor elsewhere throughout the brain versus a distant multicentric recurrence. Therefore, the patient was given 5-ALA prior to surgery to aid in tumor detection intraoperatively. Using fluorescent visualization of the resection cavity, it was confirmed that there was subependymal and ependymal spread of the recurrent tumor along the lateral ventricle connecting the recurrence to the previous tumor site. Magnetic resonance imaging may not completely detect the presence of diffuse tumor infiltrating the ependymal or subependymal spaces. Therefore, adjunct intraoperative use of fluorescence-assisted visualization with 5-ALA may be helpful in highlighting and detecting infiltrative tumor to accurately detect tumor burden and distinguish it from a separate multicentric recurrence.

Non-hypervascular hypointense nodules detected by Gd-EOB-DTPA-enhanced MRI are a risk factor for recurrence of HCC after hepatectomy

The gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) often depicts non-hypervascular hypointense hepatic nodules during the hepatobiliary phase in patients with hepatocellular carcinoma (HCC). It is unclear whether the presence of these nodules is associated with HCC recurrence after hepatectomy. We conducted a prospective observational study to investigate the impact of the presence of non-hypervascular hypointense hepatic nodules on the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI on the recurrence of HCC after hepatectomy. A total of 77 patients who underwent hepatectomy for primary, non-recurrent, hypervascular HCC were prospectively followed up after hepatectomy. Post-operative recurrence rates were compared according to the presence of non-hypervascular hypointense nodules on preoperative Gd-EOB-DTPA-enhanced MRI. Recurrence rates after hepatectomy were higher in patients with non-hypervascular hypointense nodules (risk ratio 1.9396 [1.3615-2.7222]) and the presence of non-hypervascular hypointense nodules was an independent factor associated with postoperative recurrence (risk ratio 2.1767 [1.5089-3.1105]) along with HCC differentiation and portal vein invasion. While no differences were found in the rate of intrahepatic metastasis recurrence based on the preoperative presence of non-hypervascular hypointense hepatic nodules, the rate of multicentric recurrence was significantly higher in patients with preoperative non-hypervascular hypointense hepatic nodules. Patients with preoperative non-hypervascular hypointense hepatic nodules detected during the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI are at higher risk of HCC recurrence after hepatectomy, mainly due to multicentric recurrence.

Strategy for improving survival and reducing recurrence of HCV-related hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related death in the world. With advances in imaging diagnostics, accompanied by better understanding of high-risk patients, HCC is now frequently detected at an early stage; however, the prognosis remains poor. The recurrence rate after treatment of HCC is higher than that associated with cancers of other organs. This may be because of the high incidence of intrahepatic distant recurrence and multicentric recurrence, especially with hepatitis C virus (HCV)-related hepatocellular carcinoma. The Barcelona Clinic Liver Cancer (BCLC) classification has recently emerged as the standard classification system for the clinical management of patients with HCC. According to the BCLC staging system, curative therapies (resection, transplantation, transcatheter arterial chemoembolization, percutaneous ethanol injection therapy, percutaneous microwave coagulation therapy and percutaneous radiofrequency ablation) can improve survival in HCC patients diagnosed at an early stage and offer a potential long-term cure. However, treatment strategies for recurrent disease are not mentioned in the BCLC classification. The strategy for recurrence may differ according to the recurrence pattern, i.e., intrahepatic distant recurrence vs multicentric recurrence. In this article, we review recurrent HCC and the therapeutic strategies for reducing recurrent HCC, especially HCV-related HCC.

Abstract 4425: Specific miRNA expression profiles of non-tumor liver tissues predict the risk for multicentric occurrence of hepatocellular carcinoma

Abstract Background: It is reasonable to investigate the non-tumor liver tissues to predict a risk for development of hepatocellular carcinoma (HCC). We have previously reported that specific gene-expression profiles of non-tumor liver tissues (up-regulation of STMN1, down-regulation of CYP1A2, etc.) can predict the risk for multicentric (MC) occurrence of HCC. In this study, we thus examined whether specific miRNA expression patterns of non-tumor liver tissues could also predict the risk for MC occurrence of HCC. In addition, characteristics of miRNAs associated with the development of HCC were investigated. Methods: 1. We divided the 35 HCC patients, who underwent hepatectomy, into 3 groups based on the etiological factors of HCC; hepatitis B virus (HBV, n=10), hepatitis C virus (HCV, n=7), and non-B non-C (NBNC, n=18). Non-tumor liver tissues from 3 patients with metastatic liver tumors served as normal control (NC). We analyzed miRNA expressions in non-tumor liver tissues using a miRNA microarray (Agilent Technologies, 866 probes), and compared between each HCC group and the NC group. 2. We divided the 20 HCC patients, who underwent hepatectomy, into 2 groups; non-MC group (no MC recurrence more than 3 years, n=10) and MC group (MC recurrence within 3 years after hepatectomy, n=10). We identified specific miRNA expression patterns associated with MC recurrence. Results: 1. A hierarchical clustering analysis clearly divided each HCC group and the NC group. Compared to the NC group, 25 miRNA, such as let-7 family, miR-451/144 family, miR-10b, miR-16, miR-26b, miR-223, miR-326, and miR-328 were significantly down-regulated in the NBNC group. Interestingly, most of these miRNAs were associated with the expressions of caner stem cell markers, such as CD44, CD133, AVCC1, ABCG2, and MDR1. In addition, miR-494, which reduces the PTEN expression, was up-regulated in both the HCV and NBNC group compared to the NC group. The expression of miR-328, which reduces the ABCG2 (BCRP1) expression, was validated using RT-PCR. 2. A hierarchical clustering analysis divided the non-MC group and the MC group. The MC recurrence-related miRNA included let-7, miR-328, and miR18a*, which regulates K-ras gene expression. Conclusions: The risk for MC recurrence of HCC may possibly be predicted by not only the specific gene-expression profiles but also the specific miRNA expression profiles of non-tumor liver tissues in HCC patients. Moreover, the down-regulation of specific miRNAs, which inhibit the expressions of caner stem cell markers, may be associated with the MC occurrence of HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4425. doi:1538-7445.AM2012-4425

Colon Carcinoma Presenting with a Synchronous Oesophageal Carcinoma and Basal Cell Carcinoma of the Skin

With advances in diagnostic techniques and treatment modalities, the number of patients identified with colorectal carcinoma who develop multiple primary malignancies during long-term followup has been increasing. We report a patient who developed three histologically distinct malignancies. Primary colon carcinoma treated radically followed by an 8-year disease-free period. The patient then presented with progressive dysphagia and was investigated and diagnosed to have a synchronous multicentric squamous cell carcinoma of the oesophagus and basal cell carcinoma of the skin. There was a simultaneous multicentric recurrence in the colon. This case is worth mentioning because the clustering of three primary malignancies (synchronous and metachronous) is of rare occurrence in a single patient, and, to our knowledge, this is the first report of this combination occurring in the same individual. In addition, the report emphasizes the importance of evaluating patients with known colonic primary neoplasms for synchronous colonic and extracolonic tumors.

Abstract 4961: MicroRNA profile predicts recurrence after resection in patients with hepatocellular carcinoma within the Milan criteria

Abstract Objective: Hepatocellular carcinoma (HCC) is difficult to manage due to the high frequency of post-surgical recurrence. Early detection of the HCC recurrence after liver resection is important in making further therapeutic options, such as salvage liver transplantation. In this study, we utilized microRNA expression profiling to assess the risk of HCC recurrence after liver resection. Methods: We examined microRNA expression profiling in paired tumor and non-tumor liver tissues from 73 HCC patients who satisfied the Milan Criteria. We constructed prediction models of recurrence-free survival using the Cox proportional hazard model and principal component analysis. The prediction efficiency was assessed by the leave-one-out cross-validation method, and the time-averaged area under the ROC curve (ta-AUROC). Results: The univariate Cox analysis identified 13 and 56 recurrence-related microRNAs in the tumor and non-tumor tissues, such as miR-96. The number of recurrence-related microRNAs was significantly larger in the non-tumor-derived microRNAs (N-miRs) than in the tumor-derived microRNAs (T-miRs, P&amp;lt;0.0001). The best ta-AUROC using the whole dataset, T-miRs, N-miRs, and clinicopathological dataset were 0.8281, 0.7530, 0.7152, and 0.6835, respectively. The recurrence-free survival curve of the low-risk group stratified by the best model was significantly better than that of the high-risk group (Log-rank: P=0.00029). The T-miRs tend to predict early recurrence better than late recurrence, whereas N-miRs tend to predict late recurrence better (P&amp;lt;0.0001). This finding supports the concept of early recurrence by the dissemination of primary tumor cells. and multicentric late recurrence by the ‘field effect’. Conclusion: microRNA profiling can predict HCC recurrence in Milan criteria cases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4961. doi:10.1158/1538-7445.AM2011-4961