Histological Vascular Invasion Research Articles

Evolution of suppressing TSH therapy at diagnosis and in the long-term follow-up in a cohort of differentiated thyroid cancer

IntroductionTo evaluate the adequacy of TSH suppression therapy (TSHst) at the first disease assessment and the last follow-up visit. MethodsRetrospective observational study of those patients under follow-up of DTC in a reference hospital. Results216 patients (79.2% women) were evaluated, with a mean age 59.0 ± 13.1 years-old and a mean follow-up of 6.9 ± 4.3 years. 88.4% were papillary carcinomas.At diagnosis, 69.2% had a low risk of recurrence (RR) compared to 13.6% with a high RR. Dynamic risk stratification (DRS) classified patients at first disease assessment and the last visit as excellent response (ER) in 60.0% and 70.7%, respectively.Those patients with ER in the first and last follow-up control maintained TSHst in 30.7% and 16.3% of the cases, respectively (p < 0.001).The factors associated with maintaining TSHst at the last control were younger age, higher RR at diagnosis, DRE at follow-up, presence of multifocality and histological vascular invasion (p < 0.05).In a logistic regression analysis adopting tsTSH at follow-up as the dependent variable, exclusively age (β = −0.062; p < 0.001), RR at diagnosis (β = 1.074; p < 0.05) and EDR during follow-up (β = 1.237; p < 0.05) maintained statistical significance. ConclusionsDespite the current recommendations, 30.7% of patients with low RR and initial ER are under TSHst. This percentage reduced to 16.3% in those patients with ER after a mean follow-up of 6.9 years. Age, baseline RR, and DRE during follow-up were associated to maintaining tsTSH.

Papillary thyroid carcinoma: the impact of histologic vascular invasion.

The American Thyroid Association (ATA) recurrence risk prediction system considers vascular invasion (VI) as a relative indicator for adjuvant radioactive iodine (RAI) treatment, nevertheless VI final role in PTC management is yet to be defined. This study aims to assess the impact of histologic VI in papillary thyroid carcinoma (PTC). A retrospective study with PTC patients admitted in our Thyroid Cancer Unit, between January 1960 and December 2016 was performed. We reviewed 905 patient records with 275 having full information about VI on their pathological reports. Demographic and clinical variables were obtained, and univariate/multivariate analysis was performed in order to obtain potential predictive prognostic factors. Fifty-one out 275 patients presented VI (18.5%; 95% CI 14.4-23.6%), these individuals had larger tumors (median 19 mm vs. 12 mm, P<0.001) with more frequent extraglandular invasion (54.0% vs. 17.1%, P<0.001), regional lymph nodes involvement (29.8% vs. 12.6%, P=0.003)and distant metastasis (10.9% vs. 1.9%, P=0.003) at diagnosis. VI was an independent predictor for regional lymph node and/or distant metastasis at diagnosis (OR 2.93 [IC 95% 1.16-7.41, P=0.008]). After a median follow-up time was 68.5 months patients with VI presented higher rates of local recurrence and lymph node metastasis recurrence. In this study, the presence of VI in PTC is associated to higher rate of lymph node and distant metastasis at diagnosis. Its presence should be probably considered an adverse prognostic factor in PTC, perhaps justifying more aggressive therapeutic and follow-up approaches in such cases.

Evolución del tratamiento supresor de la TSH al diagnóstico y en el seguimiento en una cohorte de carcinoma diferenciado de tiroides

IntroductionTo evaluate the adequacy of TSH suppression therapy (TSHst) at the first disease assessment and the last follow-up visit. MethodsRetrospective observational study of those patients under follow-up of DTC in a reference hospital. Results216 patients (79.2% women) were evaluated, with a mean age 59.0±13.1 years-old and a mean follow-up of 6.9±4.3 years. 88.4% were papillary carcinomas.At diagnosis, 69.2% had a low risk of recurrence (RR) compared to 13.6% with a high RR. Dynamic risk stratification (DRS) classified patients at first disease assessment and the last visit as excellent response (ER) in 60.0% and 70.7%, respectively.Those patients with ER in the first and last follow-up control maintained TSHst in 30.7% and 16.3% of the cases, respectively (p < 0.001).The factors associated with maintaining TSHst at the last control were younger age, higher RR at diagnosis, DRE at follow-up, presence of multifocality and histological vascular invasion (p < 0.05).In a logistic regression analysis adopting tsTSH at follow-up as the dependent variable, exclusively age (β = -0.062; p < 0.001), RR at diagnosis (β = 1 074; p < 0.05) and EDR during follow-up (β =1 237; p < 0.05) maintained statistical significance. ConclusionsDespite the current recommendations, 30.7% of patients with low RR and initial ER are under TSHst. This percentage reduced to 16.3% in those patients with ER after a mean follow-up of 6.9 years. Age, baseline RR, and DRE during follow-up were associated to maintaining tsTSH.

Assessment of TSPAN Expression Profile and Their Role in the VSCC Prognosis.

The role and prognostic value of tetraspanins (TSPANs) in vulvar squamous cell carcinoma (VSCC) remain poorly understood. We sought to primarily determine, at both the molecular and tissue level, the expression profile of the TSPANs CD9, CD63, CD81, and CD82 in archived VSCC samples (n = 117) and further investigate their clinical relevance as prognostic markers. Our studies led us to identify CD63 as the most highly expressed TSPAN, at the gene and protein levels. Multicomparison studies also revealed that the expression of CD9 was associated with tumor size, whereas CD63 upregulation was associated with histological diagnosis and vascular invasion. Moreover, low expression of CD81 and CD82 was associated with worse prognosis. To determine the role of TSPANs in VSCC at the cellular level, we assessed the mRNA levels of CD63 and CD82 in established metastatic (SW962) and non-metastatic (SW954) VSCC human cell lines. CD82 was found to be downregulated in SW962 cells, thus supporting its metastasis suppressor role. However, CD63 was significantly upregulated in both cell lines. Silencing of CD63 by siRNA led to a significant decrease in proliferation of both SW954 and SW962. Furthermore, in SW962 particularly, CD63-siRNA also remarkably inhibited cell migration. Altogether, our data suggest that the differential expression of TSPANs represents an important feature for prognosis of VSCC patients and indicates that CD63 and CD82 are likely potential therapeutic targets in VSCC.

Expression of UTX Indicates Poor Prognosis in Patients With Luminal Breast Cancer and is Associated With MMP-11 Expression.

Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX) is involved in the epigenetic regulation. A previous mouse xenograft study revealed that UTX knockdown is associated with downregulated expression of matrix metalloproteinase-11 (MMP-11). The authors investigated 224 cases of breast cancer from Kangbuk Samsung Medical Center between 2000 and 2005. Nuclear UTX and cytoplasmic MMP-11 expressions were assessed using immunohistochemistry of tumor tissue microarray specimens. The relationships between the expression of UTX, MMP-11, and patients' outcomes were analyzed. UTX expression was significantly associated with high histologic grade, lymphatic invasion, vascular invasion, and tumoral expression of MMP-11. Survival analysis revealed that patients with UTX expression had a poorer overall survival rate (P=0.010) as well as diminished disease-free survival rate (P=0.001). The prognostic power of UTX expression was significant in patients with luminal-type breast cancer (P=0.027, overall survival; P=0.008, disease-free survival). Validation of UTX can provide further prognostic information beyond traditional indicators and represents a potential therapeutic target for breast cancer.

Autologous falciform ligament graft as A substitute for mesentericoportal vein reconstruction in pancreaticoduodenectomy

ObjectiveTo evaluate the falciform ligament as an autologous substitute for mesentericoportal vein reconstruction during pancreaticoduodenectomy. BackgroundMesentericoportal vein reconstruction was needed in some certain cases during pancreaticoduodenectomy, and a rapidly available substitute was required. MethodsThe falciform ligament was used as an autologous substitute during pancreaticoduodenectomy in 6 patients between June 2016 and May 2017. Anticoagulation was not performed at any stage and venous patency was estimated by Color-Doppler ultrasonography and contrast-enhanced computed tomography. Results6 patients underwent vascular resection during pancreaticoduodenectomy for malignant tumors. The falciform ligament graft, with a mean length of 26 mm (10–40), was immediately harvested and used as a lateral patch for reconstruction of the mesentericoportal vein (n = 6). Severe morbidity included Clavien grade-III complications occurred in 1(16.7%) patients but there was no graft-related complications. Histological vascular invasion was present in all the patients (n = 6, 100%), and all had an R0 resection (100%). All venous reconstructions were patent (100%) after a mean follow-up of 12 (6–16) months. ConclusionsAn autologous falciform ligament graft can be safely used as a lateral substitute for mesentericoportal vein reconstruction during pancreaticoduodenectomy; this could help improve the radical resection rate of malignant tumors when oncologically required.

Analysis of the Infiltrative Features of Chordoma: The Relationship Between Micro-Skip Metastasis and Postoperative Outcomes.

Chordomas are very rare primary malignant bone tumors that arise commonly from the sacrum (50-60%) and clivus (25-35%). Chordomas have a high rate of recurrence. The authors confirmed a unique histologic infiltration pattern of chordomas that resembles a skip-metastatic lesion in normal tissue around tumor, which they named "micro-skip metastasis." This study aimed to examine the correlations between the clinicopathologic features of chordomas, including micro-skip metastasis, and the clinical outcomes, including overall survival, local recurrence-free survival, and distant metastasis-free survival. The study analyzed histopathologic and clinical data from patients with sacral chordomas who underwent en bloc resection from July 1991 through July 2014. Cases with a minimum follow-up period shorter than 20months after resection were excluded. Kaplan-Meier survival analyses with log-rank tests were performed for overall survival, metastasis-free survival, and recurrence-free survival. The study retrospectively reviewed 40 patients. The mean follow-up period was 98.2months (range 22-297months). The local recurrence rate was 41.3%. Micro-skip metastases, observed in 17 patients (42.5%), were associated with a significantly increased risk of local recurrence (p=0.023) but not with overall survival or distant metastasis-free survival. Poorer overall survival was associated with histologic vascular invasion (p=0.030) and a greater maximum tumor diameter (p=0.050). The presence of micro-skip metastasis was associated with a higher rate of local recurrence. The maximum tumor diameter and the presence of histologic vascular invasion were associated with poorer overall survival.

Histological vascular invasion is a novel prognostic indicator in extranodal natural killer/T-cell lymphoma, nasal type.

Extranodal natural killer (NK)/T-cell lymphoma, (ENKTL), nasal type, is an aggressive lymphoma with no validated prognostic parameters, to date. In the present study, vascular invasion by this tumor was retrospectively analyzed in 214 patients with untreated ENKTL to evaluate its association with clinical features, treatment response and prognosis. Histological vascular invasion by the tumor was confirmed in 32.7% of patients with ENKTL. The presence of vascular invasion significantly correlated with poor performance status, B symptoms, extranodal involved sites, advanced stage, elevated serum lactate dehydrogenase, D-dimer and cluster of differentiation 68+ tumor-associated macrophages. Upon treatment termination, the complete remission (CR) rate and overall response rate were significantly lower for the vascular invasion group compared with the non-vascular invasion group. Furthermore, vascular invasion resulted in significantly reduced 5-year progression-free survival (PFS; 21.8 vs. 60.1%) and overall survival (OS; 36.8 vs. 77.0%) rates. Using the multivariate Cox regression model, vascular invasion, stage III/IV and CR after chemotherapy were independent prognostic factors for OS and PFS. Thus, histological vascular invasion by the tumor affected the response to treatment, and was also an independent prognostic factor for OS and PFS in ENKTL, nasal type, suggesting a role for vascular invasion in disease progression.

The association of intravascular stromal cells with prognosis in high-grade neuroendocrine carcinoma of the lung.

Histological vascular invasion (VI) is major predictor of recurrence after surgery for several cancer types. We previously reported that VI with abundant stromal cell infiltrates was a negative prognostic factor in lung adenocarcinoma. This study examined whether stromal cell infiltrates within VI are associated with prognosis in high-grade neuroendocrine carcinoma (HGNEC) of the lung. We investigated the relationship between the frequency and density of VI and recurrence-free survival (RFS) of 60 resected HGNEC patients without adjuvant chemotherapy. We examined prognostic effects of CD204 (+) macrophages, CD34 (+) microvessels and α-smooth muscle actin (+) myofibroblasts within VI. Correlation between expressions of stem cell-related molecules (ALDH-1, Notch 1, CD44) and epithelial-mesenchymal transition-related molecules (E-cadherin, S100A4) in cancer cells within VI and RFS was also analyzed. Among 60 cases, 51 cases showed VI. Although the presence of VI was a significant predictor for worse RFS (P = 0.04), the frequency and density of VI were not correlated with RFS. The number of CD204 (+) macrophage, CD34 (+) microvessels and α-smooth muscle actin (+) myofibroblasts within VI did not influence on the RFS. On the contrary, cases with higher Notch 1 expression in cancer cells in the VI displayed significantly shorter RFS than lower expression group (7.6 vs. 29.4 months, P = 0.02). The current study revealed the presence of stromal cells within VI was not significant predictor for recurrence in HGNEC. This suggests that in HGNEC, unlike adenocarcinoma, intravascular stromal cells are not major contributors to metastasis.

Unique intravascular tumor microenvironment predicting recurrence of lung squamous cell carcinoma.

Histological vascular invasion (VI) by tumors is a risk factor for recurrence after surgical resection. However, VI features vary histologically. The aim of this study was to identify characteristic VI features that are associated with recurrence in squamous cell carcinoma (SCC) of the lung. We enrolled 149 patients with pathological stage I primary lung SCC in this study and examined whether the presence, frequency, and size of VI were associated with recurrence. We also evaluated immunophenotypes of carcinoma cells and stromal cells within VI areas. Of the 149 patients, 58 had tumors with VI. The presence of VI was significantly correlated with shorter recurrence-free survival (RFS) (P = 0.018). Although VI frequency was not associated with RFS, larger VI size (>425 µm) was significantly correlated with shorter RFS (P = 0.003). Carcinoma cells within larger VI areas expressed significantly higher levels of podoplanin, cancer stem cell marker (P = 0.039); higher numbers of CD34(+) microvessels (P = 0.009), CD204(+) macrophages (P = 0.026), and α-SMA(+) myofibroblasts (P = 0.056) were present within larger VI areas than within smaller VI ones. Our results indicate that larger VI areas are a predictor for recurrence in lung SCC; also, within the larger blood vessel, cancer stem cells and abundant stromal cells can create a more favorable microenvironment for tumor metastasis.

Parietal Peritoneum as an Autologous Substitute for Venous Reconstruction in Hepatopancreatobiliary Surgery.

To evaluate the parietal peritoneum (PP) as an autologous substitute for venous reconstruction during hepatopancreatobiliary (HPB) surgery. Venous resection during liver or pancreatic resection may require a rapidly available substitute especially when the need for venous resection is unforeseen. The PP was used as an autologous substitute during complex liver and pancreatic resections. Postoperative anticoagulation was standard and venous patency was assessed by routine computed tomographic scans. Thirty patients underwent vascular resection during pancreatic (n = 18) or liver (n = 12) resection, mainly for malignant tumors (n = 29). Venous resection was an emergency procedure in 4 patients due to prolonged vascular occlusion. The PP, with a mean length of 22 mm (15-70), was quickly harvested and used as a lateral (n = 28) or a tubular (n = 2) substitute for reconstruction of the mesentericoportal vein (n = 24), vena cava (n = 3), or hepatic vein (n = 3). Severe morbidity included Clavien grade-III complications in 4 (13%) patients but there was no PP-related or hemorrhagic complications. Histological vascular invasion was present in 18 (62%) patients, and all had an R0 resection (100%). After a mean follow-up of 14 (7-33) months, all venous reconstructions were patent except for 1 tubular graft (97%). A PP can be safely used as a lateral patch for venous reconstruction during HPB surgery; this could help reduce reluctance to perform vascular resection when oncologically required. Clinical trials identification: NCT02121886.

Prognostic Impact of Des-γ-carboxyl Prothrombin in Living-Donor Liver Transplantation for Recurrent Hepatocellular Carcinoma

BackgroundAlthough the Milan criteria are widely accepted for liver transplantation (LT) in patients for hepatocellular carcinoma (HCC), they have not been fully evaluated for salvage LT in patients with recurrent HCC. We have previously reported outcomes of living-donor LT (LDLT) for HCC and identified 2 risk factors affecting recurrence-free survival (RFS): tumor size >5 cm and des-γ-carboxyl prothrombin (DCP) concentration >300 mAU/mL (Kyushu University criteria). This study was designed to clarify risk factors for tumor recurrence after LDLT in patients with recurrent HCC. MethodsOutcomes in 114 patients who underwent LDLT for recurrent HCC were analyzed retrospectively. RFS rates after LDLT were calculated, and risk factors for tumor recurrence were identified. ResultsThe 1-, 3-, and 5-year RFS rates after LDLT were 90.6%, 80.4%, and 78.8%, respectively. Univariate analysis showed that tumor recurrence was associated with alpha-fetoprotein concentration ≥300 ng/mL, DCP concentration ≥300 mAU/mL, tumor number ≥4, tumor size ≥5 cm, transarterial chemotherapy before LDLT, duration of last treatment of HCC to LDLT <3 months, bilobar distribution, exceeding Milan criteria, exceeding Kyushu University criteria, poor differentiation, and histologic vascular invasion. Multivariate analysis showed that DCP ≥300 mAU/mL (P = .03) and duration from last treatment to LDLT <3 months (P = .01) were independent predictors of RFS. ConclusionsDCP concentration and time between last treatment and LDLT are prognostic of RFS in patients undergoing LDLT for HCC.

Clinical, pathologic, and immunohistochemical prognostic factors in dogs with thyroid carcinoma.

BackgroundPrognostic markers for dogs with thyroid tumors are limited.Hypothesis/ObjectivesTo identify clinical, pathologic, and immunohistochemical prognostic factors for dogs with thyroid tumors.AnimalsSeventy dogs with thyroid neoplasia.MethodsRetrospective study. Dogs with thyroid neoplasia were included when follow‐up information and formalin‐fixed paraffin‐embedded tumor samples were available. Immunohistochemistry (IHC) was performed for thyroglobulin, calcitonin, Ki‐67, and E‐cadherin. Correlation of tumor variables (diameter, volume, localization, scintigraphic uptake, thyroid function, IHC) with local invasiveness and metastatic disease was performed on all tumor samples. Forty‐four dogs treated by thyroidectomy were included in a survival analysis.ResultsFifty dogs (71%) had differentiated follicular cell thyroid carcinoma (dFTC) and 20 (29%) had medullary thyroid carcinoma (MTC). At diagnosis, tumor diameter (P = .007; P = .038), tumor volume (P = .020), tumor fixation (P = .002), ectopic location (P = .002), follicular cell origin (P = .044), and Ki‐67 (P = .038) were positively associated with local invasiveness; tumor diameter (P = .002), tumor volume (P = .023), and bilateral location (P = .012) were positively associated with presence of distant metastases. Forty‐four dogs (28 dFTC, 16 MTC; stage I–III) underwent thyroidectomy. Outcome was comparable between dogs with dFTC and MTC. Macroscopic (P = .007) and histologic (P = .046) vascular invasion were independent negative predictors for disease‐free survival. Although time to presentation, histologic vascular invasion and Ki‐67 were negatively associated with time to metastases, and time to presentation was negatively associated with time to recurrence, no independent predictors were found. E‐cadherin expression was not associated with outcome.Conclusions and Clinical ImportancePrognostic factors have been identified that provide relevant information for owners and clinicians.

P0093 AMACR overexpression is associated with clinical and biological aggressiveness in urothelial carcinomas of the upper urinary tract and urinary bladder

Background Alpha-methylacyl CoA racemase (AMACR) is essential for catabolism of branched-chain fatty acids, allowing their subsequent β -oxidation to generate energy. However, its significance has not been assessed in urothelial carcinoma. We therefore analysed the clinicopathological and biological significance of AMACR expression in urothelial carcinoma. Methods Laser capture microdissection coupled with real-time qRT-PCR was used to detect AMACR transcript level in 22 urothelial carcinomas of the urinary bladder. Immunohistochemistry evaluated by using H-score was used to determine AMACR protein expression in 295 urothelial carcinomas of the urinary bladder and 340 urothelial carcinomas of the upper urinary tract. mRNA and protein expression were correlated with clinicopathological features. AMACR protein expression was further evaluated for associations with disease-specific survival (DSS) and metastasis-free survival (MeFS). In vitro, AMACR overexpressing urothelial carcinoma cell lines (BFTC905 and RTCC-1) were evaluated for its biological function using RNA interference. Findings Increments of AMACR transcript level was associated with higher pT status ( p = 0.017). AMACR protein overexpression was significantly associated with advanced pT status (both p p ⩽ 0.001), high histological grade (both p ⩽ 0.001), vascular invasion (urothelial carcinomas of the upper urinary tract, p p = 0.003), frequent mitoses (urothelial carcinomas of the upper urinary tract, p = 0.007; urothelial carcinomas of the urinary bladder, p p = 0.025; urothelial carcinomas of the urinary bladder, p = 0.001) and MeFS (urothelial carcinomas of the upper urinary tract, p = 0.028; urothelial carcinomas of the urinary bladder, p = 0.019) in multivariate analysis. In both urothelial carcinoma cell lines, stable AMACR knockdown resulted in impaired cell proliferation, as well as migration/invasion capabilities. Interpretation AMACR overexpression is associated with advanced clinical features for patients with urothelial carcinoma and may serve as a potential prognostic biomarker and a novel therapeutic target.

Clinical outcomes and prognostic factors of adjuvant treatment in resectable biliary tract cancer.

370 Background: The survival outcomes and prognostic factors of adjuvant treatment after resection for biliary tract cancer (BTC) has not been clearly established. We analyzed the clinical outcomes and prognostic factors of patients with resected BTCs between adjuvant treatment and non-adjuvant treatment group. Methods: A total 189 patients of BTC were treated with surgery followed by adjuvant chemotherapy or concurrent chemoradiotherapy between Jan. 2008 and Jan. 2013. We retrospectively analyzed the clinical characteristics and recurrence and survival outcomes with following variables: histologic grade, resected margin status, lymphatic/vascular/perineural invasion, T and N stage, treatment modality. Results: Median age at diagnosis was 64 years (range: 32-85). Of the total 189 patients, R0 resection was done in 152 patients (80.4%). Among the 73 patients with adjuvant treatment, forty-one patients (21.6%) were treated with adjuvant 5-FU based systemic chemotherapy and 31 patients with chemoradiotherapy (16.5%). Recurrence rate were 39.7%. Median disease free survival (DFS) time was 58.1 months (95% CI, 38.9-77.3) and median overall survival (OS) time was 87.8 months (95% CI, 79.5-96.0). Adjuvant treatment showed the tendency to improve DFS with 39.0 months (95% CI, 8.9-69.1) in the adjuvant group compared with 57.0 months (95% CI, 39.5-74.5) in the non-adjuvant group, however, without statistical significance (p=0.113). Between the recurrent and non-recurrent group, perineural invasion, lymphatic invasion and poorly differentiated histology showed statistical significant difference, respectively (65.3% vs 35% ; p &lt;.001, 28% vs 14.9% ; p = .028, and 8.1% vs 7.1% ; p = .011). Presence of perineural invasion showed association with RFS (HR= 1.543; 95% CI 1.133-2.102, p=.006). There was no other significant correlation in R1 resection, poor histologic grade, lymphatic and vascular invasion, chemotherapy regimen, and treatment modality with survival outcome. Conclusions: Perineural invasion could be a potential prognostic factor for recurrence. Further prospective study should be warranted to confirm this data.

Prognostic Factors Affecting Survival at Recurrence of Hepatocellular Carcinoma After Living-Donor Liver Transplantation

In living-donor liver transplantation (LDLT) for hepatocellular carcinoma (HCC), it is important to predict not only who may be susceptible to recurrence but also who may survive longer. The neutrophil/lymphocyte ratio (NLR) is useful to properly assess the patient without decreasing the long-term survival after LDLT. In this study, we investigated the relationship between NLR and prognosis of patients with recurrent HCC after LDLT. In total, 167 LDLTs for HCC were enrolled in this study. Clinicopathologic factors for HCC recurrence after LDLT were investigated and prognostic factors were examined with respect to survival. The following factors were found to be significant in patients with HCC recurrence compared with the controls: α-fetoprotein ≧300 ng/mL, des-γ-carboxyprothrombin ≧300 mAU/mL, NLR ≧4, tumor number >3, tumor size ≧5 cm, duration of last treatment of HCC to LDLT <3 months, Milan criteria exceeded, histologic tumor number ≧10, histologic tumor size >5 cm, poor differentiation, presence of histologic vascular invasion, adjuvant chemotherapy, and interferon therapy against patients with hepatitis C virus. Male sex, interferon therapy against patients with hepatitis C virus, α-fetoprotein ≧300 ng/mL at recurrence, NLR ≧4 at recurrence, and nonsurgical resection for recurrent HCC were significantly related to poor prognosis. The 3-year survival rate after recurrence was 0% in patients with NLR ≧4 and 43.6% in patients with NLR <4. NLR was reelevated after LDLT in patients who later died; however, NLR gradually decreased in surviving patients. NLR at recurrence is a prognostic factor affecting survival after recurrence in LDLT for HCC.

Identification of intravascular tumor microenvironment features predicting the recurrence of pathological stage I lung adenocarcinoma

Histological vascular invasion (VI) by tumors is reportedly a risk factor influencing recurrence or survival after surgical treatment; however, few studies have evaluated which VI features affect recurrence or survival. The objective of this study was to evaluate how VI features affect recurrence in lung adenocarcinoma patients. We selected 106 patients with pathological stage I lung adenocarcinoma who showed VI and examined the properties of intravascular tumors associated with recurrence. First we investigated the relationship between the frequency of VI in a histological cross-section and the incidence of recurrence; however, a significant impact was not observed. Microscopic examination revealed the intravascular tumors were composed of not only cancer cells but also non-cancerous cells. To examine whether the characteristics of intravascular cancer cells and/or non-cancerous cells have prognostic value, we examined the expression levels of epithelial-mesenchymal transition-related markers in cancer cells and the numbers of infiltrating non-cancerous cells, including macrophages, endothelial cells, and fibroblasts. High levels of E-cadherin expression in the intravascular cancer cells were significant predictors of recurrence (P = 0.004), whereas the expressions of CD44, CD44 variant 6, and vimentin were not. Large numbers of intravascular CD204(+) macrophages (P = 0.016), CD34(+) microvessels (P = 0.007), and α-smooth muscle actin (+) fibroblasts (P = 0.033) were also significant predictors of recurrence. Our results indicated VI with abundant stromal cell infiltrates might be a predictor of recurrence and suggested the tumor microenvironment created by cancer cells and stromal cells within the blood vessel may play an important role during the metastatic process.

Abstract 1055: Enhancer of Zeste Homologue 2 (EZH2) may relate to progression of intra and extrahepatic cholangiocarcinoma

Abstract [Background and Aims]Enhancer of Zeste Homolog 2 (EZH2) is one of the polycomb proteins and involved in the progress of several solid tumors by methylating histone3 Lysin27 (H3K27) and silencing various genes. However, the role of EZH2 in cholangiocarcinoma has not been clarified. In this study, we investigated the significance of EZH2 expression in intrahepatic and extrahepatic cholangiocarcinoma progression.[Patients and Methods]Fourty-seven intrahepatic cholangiocarcinoma (ICC) patients and 45 extrahepatic cholangiocarcinoma (ECC) patients treated with curative resection from 1993 to 2010 were enrolled. We examined the EZH2 expression by immunohistochemistry, and relationship between EZH2 expression and clinicopathological factors, such as gender, age, CA19-9, tumor diameter, tumor number, histological vascular invasion, differentiation, lymph node metastasis and prognosis. To assess whether EZH2 relates to angiogenesis and tumor growth, Ki67 expression and microvessel density (MVD) using CD34 were also examined by immunohistochemistry. EZH2 expression was investigated eight cholangiocarcinoma cell lines. Using small interfering RNA against EZH2, the influence of EZH2 knock-down on cholangiocarcinoma cell proliferation and invasion was studied in vitro. [Results]In ICC, 24 patients (51.0%) shows a high expression of EZH2 when the cutoff value was determined to be 10%. The EZH2 high expression is significantly correlated with tumor diameter &amp;gt; 3.5cm (P=0.0113) and MVD score (P=0.039). The high EZH2 expression group showed significantly worse overall survival (p=0.045). In ECC, 19 patients(42.2%) showed a high EZH2 expression. The EZH2 high expression is significantly correlated with positive lymph node metastasis (p=0.0469), high Ki67 expression (P=0.0017). The high EZH2 expression group showed significantly worse overall survival (P=0.0261). All of the eight cholangiocarcinoma cell lines expressed EZH2 in a various level. When we knock down the expression of EZH2 in RBE cells, the expression of H3K27 was reduced and cell growth decreased. However, EZH2 down-regulation didn't affect cell invasion.[Conclusion]EZH2 may relate to the progression of intra and extrahepatic cholangiocarcinoma. 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 1055. doi:1538-7445.AM2012-1055

Investigation of Histological Vascular Invasion From Preoperative Evaluation in Patients with Hepatocellular Carcinoma Who Underwent Living Donor Liver Transplantation

Tumor vascular invasion is one of the worst factors of metastasis and/or recurrence in hepatocellular carcinoma (HCC) patients after living donor liver transplantation (LDLT), leading to poor outcomes. We investigated the relevance between preoperative parameters and histological vascular invasion among HCC patients who underwent LDLT. We enrolled 27 HCC patients who underwent LDLT from September 2003 to February 2011 in our hospital. Their primary diseases were hepatitis C (n = 16) hepatitis B (n = 9), primary biliary cirrhosis (n = 1), and cryptogenic liver cirrhosis (n = 1). The 2 groups were positive (N = 7) versus negative (N = 20) histological vascular invasion. We compared the greatest size and numbers of tumors from preoperative enhanced computerized axial tomography (CAT) scans, preoperative serum levels of alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II), as well as preoperative anticancer therapy. The preoperative greatest average diameter and numbers of tumor were 2.99 cm and 2.43, respectively, among positive patients, and 1.93 cm and 1.3, respectively, among patients with negative vascular invasion. The mean values of AFP and PIVKA-II were 3568.7 ng/mL and 2511.7 mAU/mL, respectively, among positive patients, and 812.8 ng/mL and 134.8 mAU/mL, respectively, among patients with negative vascular invasion. Five positive and 11 negative patients received preoperative anticancer therapy. Even if the tumor was within Milan criteria, namely, maximum size 3 cm and number of tumors 3, preoperative treatment may be a preoperative predictive factor for positive histological vascular invasion.

Clinicopathologic significance and function of S-phase kinase-associated protein 2 overexpression in hepatocellular carcinoma

The F-box protein S-phase kinase-associated protein 2 is frequently overexpressed in human cancers. Herein, we aimed to investigate the expression pattern, clinical significance, and biological function of S-phase kinase-associated protein 2 in hepatocellular carcinoma. Analysis by reverse transcriptase polymerase chain reaction, Western blot, and immunohistochemistry revealed that S-phase kinase-associated protein 2 was aberrantly overexpressed in hepatocellular carcinomas relative to adjacent nontumor liver tissues. This overexpression was significantly associated with advanced tumor stage, increased histologic grade, vascular invasion, and intrahepatic metastasis, as well as worse overall survival and higher early recurrence rate. Knockdown of the endogenous S-phase kinase-associated protein 2 expression in 1 hepatocellular carcinoma cell line, Huh7, by RNA interference reduced cell proliferation, blocked the cell cycle at G1 phase, and increased apoptosis. S-phase kinase-associated protein 2 silencing resulted in a deregulation of multiple cell-cycle regulatory proteins in Huh7 cells, as detected by quantitative real-time polymerase chain reaction arrays. Furthermore, high S-phase kinase-associated protein 2 immunoreactivity was found to be significantly correlated with reduced expression of P27, P21, and cell-cycle checkpoint kinase 2, as well as with increased expression of transcription factors Dp-1, cyclin D2, and cyclin D1 in hepatocellular carcinoma tissues. These data demonstrate that S-phase kinase-associated protein 2 expression is closely linked to tumor progression and represents an independent predictor of poor prognosis in hepatocellular carcinoma. S-phase kinase-associated protein 2 is involved in hepatocellular carcinoma cell proliferation through regulating numerous genes involved in cell-cycle progression, thereby providing a potential therapeutic target for this malignancy.