Oncological outcome of unresectable lung metastases without extrapulmonary metastases in colorectal cancer

AIM: To explore the oncological outcomes of unresectable lung metastases without extrapulmonary metastases in colorectal cancer. METHODS: Patients with unresectable isolated lung metastases from colorectal cancer were prospectively collected in a single institution during a 5-year period. All patients received either the fluorouracil/leucovorin plus oxaliplatin, fluorouracil/leucovorin plus irinotecan or capecitabine plus oxaliplatin regimen as first-line treatment. The resectability after preoperative chemotherapy was evaluated. Patients' outcome and predictive factors for overall survival were also investigated by univariate and multivariate analysis.RESULTS: A total of 70 patients were included in the study. After standardized fi rst-line chemotherapy, only 4 patients (5.7%) were converted to resectable disease. The median overall survival time in all patients was 19 mo (95% CI: 12.6-25.4), with a 2-year overall survival rate of 38.8%. No survival difference was found among different fi rst-line chemotherapeutic regimens. Prognostic analysis demonstrated that only the fi rst response assessment for fi rst-line treatment was the independent factor for predicting overall survival. The median survival time in partial response, stable disease and progressive disease patients were 27 mo, 16 mo and 8 mo (P = 0.00001). CONCLUSION: Pulmonary metastasectomy can only be performed in a small part of unresectable lung metastases patients after chemotherapy. Patients' first response assessment is an important prognostic factor.

Combined use of chemotherapeutics and oncolytic adenovirus in treatment of AFP-expressing hepatocellular carcinoma

BACKGROUND:Hepatocellular carcinoma(HCC)which is always refractory to most chemotherapeutic agents may result in poor survival of patients with advanced HCC. Oncolytic adenovirus is a new form for cancer gene therapy via its ability to replicate and kill tumor cells in a tumor-specific manner.In order to eradicate tumors effectively, the combination of chemotherapeutic agents and oncolytic adenovirus has been considered.This study aimed to systematically analyze the possibility of synergistic cytotoxicity of oncolytic adenoviruses in combination with chemotherapeutic agents. METHODS:Several types of human HCC cell lines were used to determine the specificity and cytotoxicity of oncolytic adenovirus Ad5-HC and Ad5-AFP(IRES)by measuring cell viability in vitro and antitumor efficiency in vivo.The cytotoxicity of Ad5-HC and Ad5-AFP(IRES) combined with chemotherapeutic agents were also assessed by the methyl thiazolyl tetrazolium assay. RESULTS:Both Ad5-HC and Ad5-AFP(IRES)were significantly cytotoxic to HCC cells with great specificity in vitro and in vivo.The combination of oncolytic adenovirus with 5-FU,doxorubicin,and paclitaxel was synergistically effective for the killing of HCC cells. CONCLUSIONS:These data suggest that oncolytic adenovirus sensitize tumors to chemotherapy and the combination therapy of chemotherapeutic agents and oncolytic adenovirus has an enhanced antitumor effect on HCC cells.

Prognostic impact of metastatic lymph node ratio on gastric cancer after curative distal gastrectomy

AIM:To investigate the prognostic impact of metastatic lymph node ratio(rN) on gastric cancer after curative distal gastrectomy.METHODS:A total of 634 gastric cancer patients who underwent curative resection(R0) of lymph nodes at distal gastrectomy in 1995-2004.Correlations between positive nodes and retrieved nodes,between rN and retrieved nodes,and between rN and negative lymph node(LN) count were analyzed respectively.Prognostic factors were identif ied by univariate and multivariate analyses.Staging accuracy of the pN category(5th UICC/TNM system) and the rN category was compared according to the survival rates of patients.A linear regression model was used to identify the relation between rN and 5-year survival rate of the patients.RESULTS:The number of dissected LNs was related with metastatic LNs but not related with rN.Cox regression analysis showed that depth of invasion,pN and rN category were the independent predictors of survival(P < 0.05).There was a signif icant difference in survival between LN stages classif ied by the rN category or by the pN category(P < 0.05).However,no signif icant difference was found in survival rate between LN stages classif ied by the pN category or by the rN category(P > 0.05).Linear regression model showed a signif icant linear correlation between rN and the 5-year survival rate of gastric cancer patients(β = 0.862,P < 0.001).Pearson's correlation test revealed that negative LN count was negatively correlated with rN(P < 0.001).CONCLUSION:rN category is a better prognostic tool than the 5th UICC pN category for gastric cancer patients after curative distal gastrectomy.Increased negative LN count can reduce rN and improve the survival rate of gastric cancer patients.

Factors related to pleural effusion following hepatectomy for primary liver cancer

BACKGROUND: Pleural effusion frequently complicates hepatectomy and multiple factors contribute to its development following hepatectomy for primary liver cancer. The purpose of this study was to evaluate these factors. METHODS: From March 2003 to May 2005, 228 consecutive patients with primary liver cancer underwent hepatectomy in our department were evaluated retrospec- tively to identify factors related to postoperative pleural effusion. RESULTS: Among the 228 patients, postoperative pleural effusions arose in 58 (25.4%). Univariate analysis showed significant differences in postoperative ascites, subphrenic collection, Pringle manoeuvre length, drainage amount on postoperative day 1, albumin level on postoperative day 7, alanine aminotransferase (ALT) level on postoperative days 1 and 3, prealbumin level on postoperative days 3 and 7, and tumor size (P<0.05). Ordinal regression analysis revealed that subphrenic collection, drainage on postoperative day 1 and ALT plus prealbumin on postoperative days 1 and 3 were statistically significantly related to postoperative pleural effusion (P<0.05). CONCLUSION: Subphrenic collection and operative injury to the liver appeared to be significantly related to pleural effusion after hepatectomy for primary liver cancer.

APC gene mutations in Chinese familial adenomatous polyposis patients

AIM:To study the characteristics of APC(adenomatous polyposis coli)gene germline mutation in Chinese patients with familial adenomatous polyposis(FAP).METHODS:APC gene from 14 FAP families was amplified by polymerase chain reaction(PCR)and underwent direct sequencing to determine the micromutation type.For the samples without micromutation,the large fragment deletion of APC gene was examined by multiplex ligation-dependent probe amplification(MLPA).RESULTS:There were gene micromutations in 9 families with a micromutation detection rate of 64.3%(9/14),including 6 frameshift mutations(66.7%),1 nonsense mutation(11.1%)and 2 splicing mutations(22.2%).Large fragment deletions were detected by MLPA in 2 families.The total mutation detection rate of micromutations and large fragment deletions was 78.6%(11/14).CONCLUSION:The detection rate of APC gene germline mutation can be improved by direct sequencing combined with MLPA large fragment deletion detection.

Role of RECK methylation in gastric cancer and its clinical significance

AIM:To investigate the relation between RECK methylation and clinicopathological characteristics of gastric cancer patients and evaluate the role of RECK methylation in peritoneal metastasis of gastric cancer.METHODS:Methylation of RECK gene in 40 paired samples of gastric cancer and its corresponding adjacent normal mucosa,lymph nodes and peritoneal irrigation fluid was detected by methylation-specific polymerase chain reaction.RESULTS:Aberrant methylation of RECK gene was detected in 27.5%(11/40)of the adjacent normal mucosa samples,in 47.5%(19/40)of gastric cancer samples,in 57.1%(12/21)of the lymph node samples,and in 35%(14/40)of peritoneal irrigation fluid samples,respectively,with a significant difference between the adjacent normal mucosa and lymph node samples(P=0.023).Presence of RECK methylation in the primary tumor samples was significantly correlated with tumor invasion(P=0.023).The accuracy of RECK methylation in peritoneal lavage fluid samples for the diagnosis of peritoneal metastasis of gastric cancer was 72.5%(26/40),with a sensitivity of 66.7%(6/9) and a specificity of 74.2%(23/31).CONCLUSION:Aberrant methylation of RECK gene may provide useful information for the early diagnosis and treatment of peritoneal metastasis of gastric cancer.

Delayed hepatocarcinogenesis through antiangiogenic intervention in the nuclear factor-kappa B activation pathway in rats

BACKGROUND:The active form of nuclear factor-kappa B(NF- κB)is involved in the initiation,generation,and development of hepatocellular carcinoma(HCC),and is up-regulated in inflammation-associated malignancies.We investigated the dynamic expression of NF-κB and its influences on the occurrence of HCC through antiangiogenic(thalidomide) intervention in NF-κB activation. METHODS:Hepatoma models were induced with 2-fluorenyl- acetamide(2-FAA,0.05%)in male Sprague-Dawley rats,and thalidomide(100 mg/kg body weight)was administered intragastrically to intervene in NF-κB activation.The pathological changes in the liver of sacrificed rats were assessed after hematoxylin and eosin staining.NF-κB mRNA was amplified by RT-nested PCR.The alterations of NF-κB and vascular endothelial growth factor(VEGF)expression were analyzed by enzyme-linked immunosorbent assay,immunohistochemistry,and Western blotting. RESULTS:Rat hepatocytes showed denatured,precancerous,and cancerous stages in hepatocarcinogenesis,with an increasing tendency of hepatic NF-κB,NF-κB mRNA,and VEGF expression,and their values in the HCC group were higher than those in controls(P<0.001).In the thalidomide- treated group,the morphologic changes generated only punctiform denaturation and necrosis at the early or middle stages,and nodular hyperplasia or a little atypical hyperplasia at the final stages,with the expression of NF-κB (χ2=9.93,P<0.001)and VEGF(χ2=8.024,P<0.001)lower than that in the 2-FAA group. CONCLUSION:NF-κB is overexpressed in hepatocarcinogenesis and antiangiogenic treatment down-regulates the expression of NF-κB and VEGF,and delays the occurrence of HCC.

Melatonin and Doxorubicin synergistically induce cell apoptosis in human hepatoma cell lines

AIM:To investigate whether Melatonin has synergistic effects with Doxorubicin in the growth-inhibition and apoptosis-induction of human hepatoma cell lines HepG2 and Bel-7402.METHODS:The synergism of Melatonin and Doxorubicin inhibited the cell growth and induced cell apoptosis in human hepatoma cell lines HepG2 and Bel-7402.Cell viability was analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide(MTT)assay.Cell apoptosis was evaluated using TUNEL method and flow cytometry.Apoptosis-related protein Bax,Bcl-2 and caspase-3 expressions were measured by immunohistochemical staining.RESULTS:Treatment with Melatonin(10 -8 -10 -5 mol/L) alone had a dose-related inhibitory effect on cell proliferation but no cytotoxic effect on hepatoma cell lines HepG2 and Bel-7402.Interestingly,when combined with Doxorubicin,Melatonin significantly increased the effects of cell growth inhibition and cell apoptosis.Furthermore,TUNEL staining and flow cytometry revealed that cooperative apoptosis induction was associated with decreased expression of Bcl-2 as well as increased expression of Bax and Caspase3.CONCLUSION:The synergism of Melatonin and Doxorubicin inhibits hepatoma cell growth and induces cell apoptosis.

Role of BMP3 in progression of gastric carcinoma in Chinese people

AIM:To investigate the relation between gastric cancer and microsatellite instability(MSI),loss of heterozygosity(LOH)and promoter region methylation.METHODS:Fifty primary gastric carcinoma specimens were collected from patients with no family history of cancer.In addition,normal tissues were also collected from patients as controls.DNA was extracted by polymerase chain reaction for single-strand conformation polymorphism,bisulfite DNA sequencing,and methylation-specific band analysis.RESULTS:The positive rate for MSI and LOH in gastric carcinoma was 16%and 20%,respectively.According to the tumor,node and metastasis staging system,the LOH frequency was higher in gastric carcinoma at stages Ⅲ and Ⅳ than in gastric carcinoma at stagesⅠ and Ⅱ(P=0.01),which was also significantly correlated with lymph node metastasis and clinicopathological characteristics of gastric carcinoma.Methylation of bone morphogenetic protein 3(BMP3)gene promoter was detected in 64.44% of gastric carcinoma tissue samples.However,no statistical significance was observed between promoter region methylation and carcinoma differentiation.Interestingly,the BMP3 gene methylation rate was 71.05% and 28.58%,respectively,in MSI positive and negative cases(P=0.031),suggesting that BMP3 genetic instability and promoter methylation are initiated during gastric carcinogenesis.LOH was detected mostly in the late stages of gastric carcinoma,indicating that gastric carcinoma at late stages has a higher infiltration and a poorer prognosis.CONCLUSION:Promotor region methylation of the BMP3 gene may cause gastric carcinoma in Chinese people.

Pathologic research update of colorectal neuroendocrine tumors

Colorectal neuroendocrine tumors (NETs) originate from neuroendocrine cells in the intestinal tract, and represent a small area within oncology, but one which has provided increasing new data during the past years. Although the World Health Organization has determined clinical and histological features to predict prognosis for such tumors, they may not be valid on an individual basis. We aim to give an overview of the recent findings with regard to pathology, molecular genetics and diagnosis of NETs.

Role of ABC transporters in cancer chemotherapy

Multidrug resistance(MDR) in cancer cells can significantly attenuate the response to chemotherapy and increase the likelihood of mortality.The major mechanism involved in conferring MDR is the overexpression of ATP-binding cassette(ABC) transporters,which can increase efflux of drugs from cancer cells,thereby decreasing intracellular drug concentration.Modulators of ABC transporters have the potential to augment the efficacy of anticancer drugs.This editorial highlights some major findings related to ABC transporters and current strategies to overcome MDR.

Serum VEGFR-3 and survival of advanced gastric cancer patients treated with FOLFOX

AIM: To explore if vascular endothelial growth factor receptor-3 (VEGFR-3) and carcinoembryonic antigen (CEA) can predict overall survival in advanced gastric cancer.METHODS: VEGFR-3 level was assessed by enzymelinked immunosorbent assay,and CEA was assessed by chemiluminescence immunoassay in the sera of 81 advanced gastric cancer patients before treatment with oxaliplatin plus 5-fluorouracil and folinic acid.RESULTS: Median survival time in patients with a low serum VEGFR-3 level was significantly longer than in those with a higher VEGFR-3 level (15.4 mo vs 7.7 mo,P < 0.001).Patients with a low CEA level had a longer survival than those with a higher CEA level (15.8 mo vs 8.6 mo,P < 0.001).Thirty-nine patients with low VEGFR-3 and low CEA levels had a median survival of 19.7 mo (P = 0.0006).The hazard ratio for patients with a high VEGFR-3 level was 2.443 (P = 0.002).CONCLUSION: High serum VEGFR-3 level is correlated significantly with poor survival.In patients with a high serum level of VEGFR-3,alternative chemotherapy regimens should be considered.

Effects on the pouch of different digestive tract reconstruction modes assessed by radionuclide scintigraphy

AIM: To determine the effect of three digestive tract reconstruction procedures on pouch function, after radical surgery undertaken because of gastric cancer, as assessed by radionuclide dynamic imaging. METHODS: As a measure of the reservoir function, with a designed diet containing technetium-99m (99mTc), the emptying time of the gastric substitute was evaluated using a 99mTc-labeled solid test meal. Immediately after the meal, the patient was placed in front of a γ camera in a supine position and the radioactivity was measured over the whole abdomen every minute. A frame image was obtained. The emptying sequences were recorded by the microprocessor and then stored on a computer disk. According to a computer processing system, the half-emptying actual curve and the fitting curve of food containing isotope in the detected region were depicted, and the half-emptying actual curves of the three reconstruction procedures were directly compared. RESULTS: Of the three reconstruction procedures, the half-emptying time of food containing isotope in the Dual Braun type esophagojejunal anastomosis procedure (51.86±6.43 min) was far closer to normal, signif icantly better than that of the proximal gastrectomy orthotopic reconstruction (30.07±15.77 min, P=0.002) and P type esophagojejunal anastomosis (27.88±6.07 min, P=0.001) methods. The half-emptying actual curve and f itting curves for the Dual Braun type esophagojejunal anastomosis were fairly similar while those of the proximal gastrectomy orthotopic reconstruction and P type esophagojejunal anastomosis were obviously separated, which indicated bad food conservation in the reconstructed pouches. CONCLUSION: Dual Braun type esophagojejunal anastomosis is the most useful of the three procedures for improving food accommodation in patients with a pouch and can retard evacuation of solid food from the reconstructed pouch.

Retrospective analysis of perianal Paget's disease with underlying anorectal carcinoma

AIM:To analyze clinical and pathological characteristics of an aggressive subtype of perianal Paget's disease(PPD) and explore its rational treatment modalities.METHODS:PPD patients were retrospectively collected in the institutional colorectal database of the Fudan University Shanghai Cancer Center.Detailed patient histories of past medical condition,diagnosis,treatment,and pathological findings were reviewed.Surgical specimen from diagnosis and surgery were reviewed by two independent pathologists for confirmation of diagnoses.Follow up was accomplished by clinical interview by cellphone.RESULTS:In total,eight cases of PPD were analyzed.All patients had underlying anorectal adenocarcinoma,including seven with synchronous lesions and one with metachronous lesions.Moreover,all anorectal lesions had a mucin-producing component.The median age at diagnosis was 65(range 29-81 years),and the male/female ratio was 7:1.The Median follow-up time of all patients was 61.5 mo(range 10-204 mo).One patient treated with abdominoperineal resection(APR) died from lung metastases 10 mo after the APR operation.The other patients are still free of disease at the time of this analysis.CONCLUSION:PPD is a rare malignancy and is easily misdiagnosed.Underlying anorectal cancer was not unusual and was a significant prognostic factor.Rational treatment of both anorectal cancer and PPD lesion is essential for long-term survival.

Risk factors for early recurrence of small hepatocellular carcinoma after curative resection

BACKGROUND:Poorer prognosis is seen in patients with hepatocellular carcinoma (HCC) after curative hepatic resection with early recurrence (≤1 year) than in those with late recurrence (>1 year).This study aimed to identify risk factors for postoperative early recurrence of small HCC (≤3 cm in diameter).METHODS:The study population consisted of 158 patients who underwent curative resection for small HCC between January 2002 and July 2004.Risk factors for early recurrence were analyzed.RESULTS:Thirty-three (20.8%) patients developed early recurrence after surgery.Univariate analysis showed the following significant risk factors for early recurrence in small HCC:serum alpha-fetoprotein (AFP) level >100 ng/ml,lack of tumor capsule formation,microscopic vascular invasion,high Edmonson-Steiner grades,and cytokeratin-19 (CK-19) expression (P<0.05).Multivariate stepwise logistic regression analysis showed that serum AFP level >100 ng/ml (odds ratio 2.561,95% confidence interval 1.057 to 6.206,P=0.037) and microscopic vascular invasion (odds ratio 4.549,95% confidence interval 1.865 to 11.097,P=0.001) were independent factors.CONCLUSIONS:Postoperative early recurrence is related to serum AFP level >100 ng/ml and microscopic vascular invasion in patients with small HCC.Adjuvant therapy and careful follow-up are required for patients with these risk factors.

LOH analysis of genes around D4S2964 identifies ARD1B as a prognostic predictor of hepatocellular carcinoma

AIM:To investigate genes around the locus D4S2964 affected by loss of heterozygosity(LOH) and their clinical implications.METHODS:Four hundred and forty single nucleotide polymorphisms(SNPs) located at 49 genes around D4S2964 were selected from the National Center for Biotechnology Information website for the SNPs microarray fabrication.LOH of SNPs markers in 112 cases of hepatocellular carcinoma(HCC) tissues and paired adjacent liver tissues were investigated by the SNPs microarray.The correlation between allelic losses with clinicopathological features and overall survival was analyzed.RESULTS:A f ine map of LOH of SNPs in genes around D4S2964 was plotted.The average frequency of LOH in genes was 0.39.A correlation between cirrhosis and the FAL index(fractional allelic loss) was found(P = 0.0202).Larger tumor size was found to be signif icantly associated with LOH in genes ADP-ribosyltransferase 3(ART3),nucleoporin 54 kDa(NUP54),scavenger receptor class B,member 2(SCARB2) and coiled-coil domain containing 158(CCDC158)(P = 0.043,P = 0.019,P = 0.001,P = 0.037,respectively).Kaplan-Meier analysis showed that patients with LOH in ARD1 homolog B(ARD1B) and septin 11(SEPT11) had a significantly lower survival rate than those with retention(P = 0.021 and P = 0.004,respectively).A Cox regression model suggested that LOH in ARD1B and SEPT11,respectively,were predictors of the overall survival in HCC(P = 0.006 and P = 0.026,respectively).CONCLUSION:LOH in genes around D4S2964 may play an important role in HCC development and progression.LOH in ARD1B and SEPT11 could serve as novel prognostic predictors in HCC patients.