Multicentric Recurrence Research Articles

MicroRNA Profile Predicts Recurrence after Resection in Patients with Hepatocellular Carcinoma within the Milan Criteria

ObjectiveHepatocellular 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.MethodsWe 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).ResultsThe 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<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<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’.ConclusionmicroRNA profiling can predict HCC recurrence in Milan criteria cases.

Molecular signatures of noncancerous liver tissue can predict the risk for late recurrence of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is an aggressive malignancy mainly due to tumor metastases or recurrence even after undergoing potentially curative treatment. There are two types of HCC recurrence. The early and late tumor recurrences appear in distinct biological contexts, and their clinical courses are quite different. Therefore, it is important to precisely and distinctly discriminate the risk of each type of HCC recurrence. Many researchers have used DNA microarray technology to reclassify HCC with respect to its malignant potential. Some of these studies successfully identified specific gene-expression signatures derived from the cancerous tissues of HCC for predicting the early recurrence due to intrahepatic metastasis. However, there are no well-defined predictors for late recurrence. Recently, a few studies have focused on the nontumorous portion of liver tissues to predict late recurrence, possibly due to de novo hepatocarcinogenesis based on the idea of "field cancerization." This study reviewed the possible value of a gene-expression analysis of noncancerous liver tissue to clarify the risk for multicentric late recurrence of HCC. These findings may have important implications for chemopreventive strategies and tailored surveillance programs. Furthermore, this approach may also be applicable to other multifocal tumors, such as head and neck carcinoma.

Differentiating Early and Late Recurrences After Resection of HCC in Cirrhotic Patients: Implications on Surveillance, Prevention, and Treatment Strategies

Hepatocellular carcinoma (HCC) is one of the most common human malignancies. The majority of HCCs occur in a background of cirrhosis related to hepatitis B virus, hepatitis C virus, or alcoholism. The presence of cirrhosis has significant impact on the management of the cancer. The impairment of liver function as a result of cirrhosis restricts the treatment options, and cirrhosis is also known to predispose to multicentric hepatocarcinogenesis and increase the risk of recurrence after resection of HCC. The advent of liver transplantation and radiofrequency ablation have provided better chances of curative treatment for patients with small HCC detected by screening in recent years; however, hepatic resection remains the mainstay of curative treatment for HCC associated with Child-Pugh class A cirrhosis. While the perioperative safety and long-term survival of liver resection in cirrhotic liver have improved in recent years, the rate of postoperative recurrence of HCC remains high. In more than 80% of the cases of postoperative recurrence after resection of HCC, the recurrent tumors occur in the liver remnant. The mechanisms of intrahepatic recurrence can be either intrahepatic metastasis from the initial tumor or a de novo multicentric tumor. Differentiation of the two has potential implications on surveillance, prevention, and management strategies for recurrence. Clinically, it is impossible to distinguish the two based on imaging appearances. The only definitive way of differentiation is by genetic or molecular studies of the clonal origin of the tumors, which are technically complicated and cannot be used in clinical practice. Hence, several groups of authors have attempted to differentiate intrahepatic metastasis and multicentric recurrence based on the interval of development of recurrence from the time of resection and risk factors associated with the recurrence. These studies have consistently demonstrated that early recurrence within the first 2 years after resection of HCC is likely to be associated with aggressive tumor pathological factors such as high tumor grade, microvascular invasion, and microsatellite lesions, whereas late recurrence is more likely related to underlying liver conditions such as the presence of cirrhosis and hepatitis activity. Such results suggested that early recurrence is most likely the consequence of occult metastasis from the initial tumor, whereas late recurrence more likely represents multicentric tumors. Cucchetti et al. conducted a study on the risk factors associated with early and late recurrence in 204 patients with cirrhosis who had undergone resection of HCC. The authors identified high alpha-fetoprotein level, poorly differentiated tumor, and microvascular invasion as the risk factors for early recurrence within 2 years after resection, and male gender, older age, high transaminase levels, multiple primary tumors, and high alpha-fetoprotein level as risk factors for late recurrence beyond 2 years. These findings are generally in line with those of previous studies. To demonstrate that late recurrence is most likely related to new multicentric tumor development in the cirrhotic liver, the authors further compared the incidence and risk factors of late recurrence in resected patients with the those of development of HCC in a cohort of 150 cirrhotic patients undergoing regular surveillance of HCC. Such data are not available in previous studies and provide a better insight into the risk of late recurrence after resection of HCC in cirrhotic patients. The authors showed that the risk factors for development of HCC in a group of cirrhotic patients undergoing surveillance were similar to the risk Society of Surgical Oncology 2009

Modified functional end‐to‐end stapled intestinal anastomosis: technique and clinical results in 15 dogs

To evaluate the use of a gastrointestinal anastomosis (GIA) stapling device to perform small intestinal anastomosis in the dog. A retrospective study to evaluate the use of a GIA stapling device to perform small intestinal anastomosis in 15 dogs. Reasons for intervention included dehiscence of a previous enterotomy (four of 15), intestinal neoplasia (five of 15), vascular compromise (three of 15), intussusception (two of 15) and foreign body (one of 15). The mean time taken to perform the anastomosis was 7.7 minutes (range five to 12 minutes). No operative complications were recorded and all dogs recovered from the surgery. Major (two dogs) and minor (six dogs) short-term complications of pyrexia and anorexia were recorded in six dogs. In five of these, the cause was considered to be related to a pre-existing peritonitis. One dog was euthanased five months postoperatively for a multi-centric recurrence of intestinal lymphoma. Six month follow-up confirmed an unremarkable and complete recovery in all remaining dogs. No major or minor long-term complications were recorded in any individual. A modified stapled functional end-to-end intestinal anastomosis holds merit and should be considered a viable alternative to other stapled and sutured anastomosis techniques.

Clinicopathologic features of re-resected cases of intraductal papillary mucinous neoplasms (IPMNs)

We analyzed the clinical characteristics and patterns of recurrence of intraductal papillary mucinous neoplasms (IPMNs) from 100 consecutive surgical cases. The average age was 62 +/- 12 years. The tumor was located in the head in 65 patients, body in 25 patients, and tail in 10 patients. Sixty-seven patients had benign IPMNs, and 33 patients had malignant IPMNs. Malignant IPMNs were observed more frequently in the head (42%) as compared with the body (20%) or tail (10%) (P < .05). During the follow-up period, 5 patients recurred and underwent second operation. In the first operation, 1 patient underwent pancreatoduodenectomy for the head tumor and the other 4 patients underwent distal pancreatectomy for the body and/or tail tumor. Although histopathologic findings in the first operation were adenoma in 2 and carcinoma in 3 patients, all patients developed carcinoma by the time of the second operation. No hyperplasia developed recurrence. The overall recurrence rate for the head tumors was 1.5% (1 out of 65), whereas that for the body and tail tumors was 11.4% (4 out of 35) (P < .05). Metachronous multicentric recurrence was suspected in 4 cases. These results indicate that adenomatous or carcinomatous IPMNs, especially originated from the body or tail, should be carefully observed even with a histologically negative surgical margin.

Improved Long‐term Survival after Liver Resection for Hepatocellular Carcinoma in the Modern Era: Retrospective Study from HCV‐endemic Areas

It remains unclear whether recent progress in perioperative management and treatment for recurrent hepatocellular carcinoma (HCC) has improved patient outcomes in hepatitis C virus-endemic areas. The clinicopathologic and follow-up data of 218 consecutive HCC patients who underwent curative resection between 1982 and 2003 were analyzed. Patients were assigned to one of two groups: before 1992 (early group; n=82) and 1992 and later (late group; n=136). Factors influencing survival rates were investigated by multivariate analysis. The effects of the period during which the hepatic resection was done on the patients' outcome were examined with respect to tumor size. The 5-year cancer-related and disease-free survival rates were 51.4% and 20.4%, respectively. The late group showed better 5-year cancer-related survival than the early group (64.1% vs. 33.8%), but disease-free survival did not differ significantly between the groups. On multivariate analysis, the period of the hepatic resection was identified as an independent prognostic factor for cancer-related survival (relative risk 0.70, P<0.01) but not disease-free survival. There were no differences in the cancer-related and disease-free survival rates between the two groups for patients with tumors<or=25 mm. In patients with HCCs>50 mm, both cancer-related and disease-free survival rates were better in patients in the late group. During the past two decades, improvements in the treatment of recurrent HCC tumors have contributed to controlling large HCCs but not to controlling the multicentric development of HCCs. It may be important to control multicentric recurrence of HCC to improve patient survival in areas where the hepatitis C virus is endemic.

Specific Gene-Expression Profiles of Noncancerous Liver Tissue Predict the Risk for Multicentric Occurrence of Hepatocellular Carcinoma in Hepatitis C Virus–Positive Patients

Hepatitis C virus (HCV) infection produces chronic hepatitis, cirrhosis, and, ultimately, hepatocellular carcinoma (HCC). A molecular analysis of the damaged liver tissues infected with HCV may identify specific gene-expression profiles associated with a risk for liver carcinogenesis. Forty patients with HCV-positive HCC were classified into two groups: single nodular HCC group (n = 28) and multicentric HCC group (n = 12). Using a complementary DNA microarray, we compared the gene-expression patterns of the noncancerous liver tissue specimens between the two groups. We also identified the differentially expressed genes related to multicentric recurrence in the liver remnant. We then evaluated whether a specific gene-expression profile can accurately estimate the risk for multicentric hepatocarcinogenesis. We selected the 230 differentially expressed genes in the multicentric HCC group. A hierarchical clustering analysis identified a cluster that might be closely associated with the multicentric occurrence of HCC. On the basis of the gene-expression profiling of the 36 genes commonly associated with both multicentric HCC and multicentric recurrence, we created a scoring system to estimate the risk for multicentric hepatocarcinogenesis. The prediction score of patients in the multicentric HCC group with multicentric recurrence (19.9 +/- 9.2) was significantly higher (P < .05) than that in the single nodular HCC group without multicentric recurrence (-1.8 +/- 12.7). Specific gene-expression signatures in noncancerous liver tissue may help to accurately predict the risk for developing HCC.

Angiosarcoma with Sacral Origin Metastasizing to the Lung

A 73-year-old man with fever, lumbago and hemosputum showed ground-glass opacity around multiple lung nodules on chest computed tomography. Examination of the man revealed anemia. Specimens obtained by video-assisted thoracic surgery revealed angiosarcoma, but the primary site of angiosarcoma could not be detected before autopsy. Angiosarcoma is a rare malignant neoplasm with rapid proliferation and they can arise at any region of the body. It can originate in the skin, soft tissue, liver or heart. Their multicentric and local recurrence easily leads us to misdiagnosis, and we have struggled to reach diagnosis and its origin. Angiosarcoma should be included in the different diagnosis of diffuse pulmonary hemorrhage with multiple lung nodules.

Prognostic Significance of Simultaneous Measurement of Three Tumor Markers in Patients With Hepatocellular Carcinoma

We conducted a prospective study to evaluate the significance of simultaneous measurement of 3 currently used tumor markers in the evaluation of tumor progression and prognosis of patients with hepatocellular carcinoma (HCC). Three tumor markers for HCC, alpha-fetoprotein (AFP), Lens culinaris agglutinin A-reactive fraction of AFP (AFP-L3), and des-gamma-carboxy prothrombin (DCP), were measured in the same serum samples obtained from 685 patients at the time of initial diagnosis of HCC. Positivity for AFP >20 ng/dL, AFP-L3 >10% of total AFP, and/or DCP >40 mAU/mL was determined. In addition, tumor markers were measured after treatment of HCC. Of the 685 patients, 337 (55.8%) were positive for AFP, 206 (34.1%) were positive for AFP-L3, and 371 (54.2%) were positive for DCP. In a comparison of patients positive for only 1 tumor marker, patients positive for AFP-L3 alone had a greater number of tumors, whereas patients positive for DCP alone had larger tumors and a higher prevalence of portal vein invasion. When patients were compared according to the number of tumor markers present, the number of markers present clearly reflected the extent of HCC and patient outcomes. The number of markers present significantly decreased after treatment. Tumor markers AFP-L3 and DCP appear to represent different features of tumor progression in patients with HCC. The number of tumor markers present could be useful for the evaluation of tumor progression, prediction of patient outcome, and treatment efficacy.

A Multicentric Development Of Intraductal Papillary Mucinous Neoplasm Treated By Repeated Pancreatectomy

There are few reports of multicentric recurrence after resection of lesions of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. We report a case of repeated pancreatectomy for recurrent IPMN showing multicentric development in the pancreatic remnant after resection of the initial lesion. In February 1999 a 70-year-old man underwent distal pancreatectomy for a cystic neoplasm in the pancreatic tail. Histological examination revealed invasive intraductal papillary mucinous adenocarcinoma (IPMC) with lymph node metastasis. Forty-seven months later, a cystic mass with an intracystic nodule was detected during surveillance by computed tomography. The patient underwent completion pancreatectomy. Histological examination demonstrated IPMC with neural invasion. In immunohistochemical staining, the initial specimen was positive for proteinase-activated receptor 2, but the second specimen was not. The present case helps elucidate the multicentric development of IPMN of the pancreas. We recommend careful surveillance for the recurrence of IPMN in the pancreatic remnant after resection.

Prognostic value of thymidine phosphorylase activity in liver tissue adjacent to hepatocellular carcinoma

Measurement of thymidine phosphorylase (TP) activity in normal liver tissue adjacent to hepatocellular carcinoma (HCC) may predict multicentric recurrence a long time after an operation. The authors investigated this activity in 92 patients with HCC who had a single HCC equal to or less than 5 cm. Fresh samples (tumors with adjacent normal tissues) were collected from 92 patients with HCC who underwent curative hepatic resection. The levels of TP activity in nonfixed, fresh, and frozen HCC specimens with adjacent noncancerous liver tissue were biochemically measured by using an enzyme-linked immunosorbent assay method. Patients who had a high TP level in normal liver tissue had significantly earlier recurrence (median disease-free survival, 819 days; 95% confidence interval [95% CI], 478-1044 days) compared with patients who had a low TP level (median disease-free survival, 1376 days; lower limit of 95% CI, 921 days; P = 0.0171). Multivariate analysis showed that patients who had a low TP level in adjacent liver tissue had a 0.387-fold higher risk of postoperative recurrence compared with patients who had a high TP level (P = 0.0067). TP activity in normal liver tissue adjacent to HCC is related to tumor occurrence and may predict postoperative tumor recurrence.

Partial-breast treatment for early breast cancer: emergence of a new paradigm

Although hailed as a paradigm shift, the breast conservative treatment that emerged in the 1980s was in fact an extension of the Halstedian concept, wherein whole-breast irradiation (WBI) compensated for the limited surgery. Observations that 80-90% of breast recurrences after breast conservative surgery and WBI occur in the tumor bed questions the need for protracted elective WBI, and provides the rationale for accelerated-partial-breast irradiation (APBI) of small cancers without adverse features predisposing to multicentric recurrence. APBI can be given over a week with various external beam, intraoperative or brachytherapy (interstitial or MammoSite) techniques. Since the approval of MammoSite by the US FDA in May 2002, a surge of interest has been evident, with 4,000 cases treated using this technique in the past 2 years. Several phase II APBI brachytherapy studies show that 4 to 7-year breast control rates (95%), survival and cosmetic outcome obtained from more than 600 appropriately selected women are comparable to matched or historic controls receiving WBI. The 2 to 3-year interim results of two ongoing randomized trials do not show any early detriment with APBI. If mature results of randomized trials confirm equivalence of APBI to conventional WBI in selected women, it would mark a paradigm shift and a major advance in treatment. This would allow many more women to opt for breast conservation, resolve the dilemmas regarding chemotherapy and radiotherapy sequencing and perhaps would be more cost effective.

Significance of multicentric cancer recurrence after potentially curative ablation of hepatocellular carcinoma: a longterm cohort study of 892 patients with viral cirrhosis.

Tumor recurrence is common after potentially curative ablation of hepatocellular carcinoma; therefore, the incidence of intrahepatic metastasis and multicentric carcinogenesis was evaluated. A cohort of 892 patients with cirrhosis caused by either hepatitis B virus (n=246) or hepatitis C virus (n=646) was followed up without interferon administration. Hepatocellular carcinogenesis rates were 28.0% at the end of the fifth year, 49.2% at the tenth year, and 61.3% at the fifteenth year. Sex, hepatitis virus, alpha-fetoprotein, platelet count, age, and indocyanine green retention test value significantly affected the carcinogenesis rate. Of 372 patients with tumor development, 162 (43.5%) received surgical or radical locoregional therapy. On the assumption that a second carcinogenesis after sufficient ablation of well-differentiated cancer was attributable to multicentric carcinogenesis, recurrence rates after curative therapy in all the 162 patients, and the recurrence rates in 39 patients with solitary, small, and well-differentiated histology were analyzed: the rates were 58.2% and 30.9% at the third year, 75.9% and 53.4% at the fifth year, and 89.6% and 79.9% at the tenth year, respectively. The estimated incidence of multicentric recurrence was, therefore, 31% or higher at the third year and 53% or higher at the fifth year. The actual second carcinogenesis rates (multicentric recurrence) were approximately 1.6 times as high as those of the virtual second carcinogenesis rates calculated from statistical simulation. A longterm cohort study disclosed that multicentric carcinogenesis was the principal mechanism of recurrence after curative ablation of hepatocellular carcinoma and that the concept of "carcinogenic stage" should be introduced to improve the understanding of carcinogenic events in viral cirrhosis.

Preventive treatments for recurrence after curative resection of hepatocellular carcinoma--a literature review of randomized control trials.

To review the inhibitory effect of preventive approaches on recurrence after operation in patients with hepatocellular carcinoma (HCC), we summarized all available publications reporting randomized control trial indexed in PubMed. The treatment approaches presented above included pre-operative transcatheter arterial chemoembolization (TACE), post-operative TACE, systemic or locoregional chemotherapy, immunotherapy, Interferons and acyclic retinoic acid. Although no standard treatment has been established, several approaches presented promising results, which were both effective and tolerable in post-operative patients. Pre-operative TACE was not effective on prolonging survivals, while post-operative TACE was shown with both disease-free survival and overall survival benefits in some papers, however, it was also questioned by others. Systemic chemotherapy was generally not effective on prolonging survival but also poorly tolerated for its significant toxicities. Adoptive immunotherapy using LAK cells was proved to be beneficial to patients' survival in a recent paper. Interferon alpha and Interferon beta can inhibit recurrence in HCC patients with HCV infection background, though the mechanism is not fully understood. Acyclic retinoic acid was shown to decrease multi-centric recurrence after operation, which was reported by only one group. In conclusion, several adjuvant approaches have been studied for their efficacy on recurrence in HCC patients in randomized control trials; however, multi-centric randomized control trial is still needed for further evaluation on their efficacy and systemic or local toxicities; in addition, new adjuvant treatment should be investigated to provide more effective and tolerable methods for the patients with HCC after operation.

Left atrial myxoma with multicentric recurrence and evidence of metastases

Left atrial myxoma with multicentric recurrence and evidence of metastases