Natural History of Malignant Bone Disease in Hepatocellular Carcinoma: Final Results of a Multicenter Bone Metastasis Survey

Background

Bone is an uncommon site of metastasis in patients with advanced hepatocellular carcinoma (HCC). Therefore, there are few studies concerning the natural history of bone metastasis in patients with HCC.

Patients and Methods

Data on clinicopathology, survival, skeletal-related events (SREs), and bone-directed therapies for 211 deceased HCC patients with evidence of bone metastasis were statistically analyzed.

Results

The median age was 70 years; 172 patients were male (81.5%). The median overall survival was 19 months. The median time to the onset of bone metastasis was 13 months (22.2% at HCC diagnosis); 64.9% patients had multiple bone metastases. Spine was the most common site of bone metastasis (59.7%). Most of these lesions were osteolytic (82.4%); 88.5% of them were treated with zoledronic acid. At multivariate analysis, only the Child Score was significantly correlated with a shorter time to diagnosis of bone metastases (p = 0.001, HR = 1.819). The median survival from bone metastasis was 7 months. At multivariate analysis, HCC etiology (p = 0.005), ECOG performance status (p = 0.002) and treatment with bisphosphonate (p = 0.024) were associated with shorter survival after bone disease occurrence. The site of bone metastasis but not the number of bone lesions was associated with the survival from first skeletal related event (SRE) (p = 0.021) and OS (p = 0.001).

Conclusions

This study provides a significant improvement in the understanding the natural history of skeletal disease in HCC patients. An early and appropriate management of these patients is dramatically needed in order to avoid subsequent worsening of their quality of life.     

Clinical Outcomes of Patients with Oral Cavity Squamous Cell Carcinoma and Retropharyngeal Lymph Node Metastasis Identified by FDG PET/CT

Purpose

Retropharyngeal lymph node (RPLN) metastasis is an uncommon finding in patients with oral cavity squamous carcinoma (OSCC). We sought to investigate the clinical outcomes, clinicopathological characteristics, and the priority of treatment with curative intent in OSCC patients with RPLN involvement.

Methods and Materials

Between January 2007 and January 2011, we identified 36 patients with primary RPLN metastases (n = 10) or RPLN relapse (n = 26). The follow-up continued until June 2013. Disease-specific survival (DSS), disease-free survival (DFS), and the potential benefits of salvage therapy served as the main outcome measures.

Results

The 2-year DSS and DFS rates of untreated patients with RPLN involvement were 20% and 24%, respectively. Level IV/V neck lymph node involvement was an adverse prognostic factor for DSS (P = 0.048) and DFS (P = 0.018). All of the patients presenting with neck lymph node involvement at level IV/V died within 6 months. Among patients who were treated for RPLN relapse, the 2-year DSS and DFS rates from the relapse day were 12.8% and 9.6%, respectively. Concomitant contralateral neck lymph node metastases (N2c) were associated with lower 2-year DSS (P = 0.005) and DFS (P = 0.011) rates. Moreover, five (55%) of the nine patients with recurrent disease in the contralateral RPLN had distant metastases within 6 months. Salvage therapy yielded the maximum survival benefit in patients without N2c disease and ipsilateral RPLN involvement alone (P = 0.005).

Conclusion

OSCC patients with RPLN involvement have poor outcomes. The risk factor for definitive treatment in OSCC patients with FDG PET/CT defined RPLN disease in primary disease was neck lymph node involvement at level IV/V and N2c and/or contralateral RPLN disease in recurrent disease. Treatment efforts with curative intent should be tailored according to individual risk factors.     

Analysis of Lymph Node Metastasis Correlation with Prognosis in Patients with T2 Gastric Cancer

Purpose

To investigate the correlated factors for lymph node metastasis and prognosis for patients with T2 gastric cancer.

Methods

A total of 442 patients with T2 gastric cancer who underwent gastrectomy from January 1996 to December 2009 were evaluated. The clinicopathological parameters were analyzed for lymph node metastasis and prognosis, including gender, age, tumor size, tumor location, histological type, depth of invasion, vascular tumor emboli, nervous invasion, resection type, and pathological stage.

Results

The rate of lymph node metastasis was 45.9%. Univariate analysis showed that depth of invasion, tumor size, and vascular tumor emboli were associated with lymph node metastasis. Logistic regression demonstrated that depth of invasion, tumor size, and vascular tumor emboli were independently predictive factors for lymph node metastasis. The 5-year survival rate was 64.0%. Multivariate analysis showed that tumor size, tumor location, resection type, and pathological stage were independent prognostic factors. Based on tumor size, there were significant differences of 5-year survival between small size tumor (<6 cm) and large size tumor (≥6 cm) according to stage IIA (P = 0.006). Based on tumor location, there were significant differences of 5-year survival among different tumor location according to stage IB. Based on resection type, there were significant differences of overall 5-year survival between curative surgery and palliative surgery according to stage IIB (P = 0.015) and IIIA (P = 0.001).

Conclusion

Depth of invasion, tumor size, and vascular tumor emboli were independently predictive factors for lymph node metastasis. Tumor size, tumor location, resection type, and pathological stage were independent prognostic factors.     

Lymph Node Ratio for Postoperative Staging of Laryngeal Squamous Cell Carcinoma with Lymph Node Metastasis

Background

Lymph node metastasis has a significant impact on laryngeal cancer prognosis. The role of lymph node ratio (LNR, ratio of metastatic to examined nodes) in the staging of laryngeal cancer was not reported.

Patients and Methods

Records of laryngeal cancer patients with lymph node involvement from Surveillance, Epidemiology, and End Results database (SEER, training set, N = 1963) and Fudan University Shanghai Cancer Center (FDSCC, validating set, N = 27) were analyzed for the prognostic value of LNR. Kaplan–Meier survival estimates, the Log-rank χ² test and Cox proportional hazards model were used for univariate and multivariate analysis. Optimal LNR cutoff points were identified by X-tile.

Results

Optimal LNR cutoff points classified patients into three risk groups R1 (≤0.09), R2 (0.09–0.20) and R3 (>0.20), corresponding to 5-year cause-specific survival and overall survival in SEER patients of 55.1%, 40.2%, 28.8% and 43.1%, 31.5%, 21.8%, 2-year disease free survival and disease specific survival in FDSCC patients of 74.1%, 62.5%, 50.0%, and 67.7%, 43.2%, 25.0%, respectively. R3 stratified more high risk patients than N3 with the same survival rate, and R classification clearly separated N2 patients to 3 risk groups and N1 patients to 2 risk groups (R1–2 and R3).

Conclusions

R classification is a significant prognostic factor of laryngeal cancer and should be used as a complementary staging system of N classification.     

Surgical Outcomes and Prognostic Factors of T4 Gastric Cancer Patients without Distant Metastasis

Objective

To evaluate surgical outcomes and prognostic factors for T4 gastric cancer treated with curative resection.

Methods

Between January 1994 and December 2008, 94 patients diagnosed with histological T4 gastric carcinoma and treated with curative resection were recruited. Patient characteristics, surgical complications, survival, and prognostic factors were analyzed.

Results

Postoperative morbidity and mortality were 18.1% and 2.1%, respectively. Multivariate analysis indicated lymph node metastasis (hazard ratio, 2.496; 95% confidence interval, 1.218–5.115; p = 0.012) was independent prognostic factor.

Conclusions

For patients with T4 gastric cancer, lymph node metastasis was associated with poorer survival. Neoadjuvant chemotherapy or aggressive adjuvant chemotherapy after radical resection was strongly recommended for these patients.     

The Expression of TMPRSS4 and Erk1 Correlates with Metastasis and Poor Prognosis in Chinese Patients with Gastric Cancer

Purpose

The present study investigated the clinical significance of transmembrane protease, serine 4(TMPRSS4) and extracellular signal-regulated kinases 1 (Erk1) in the development, progression and metastasis of gastric cancer.

Methods

Immunohistochemistry was employed to analyze TMPRSS4 and Erk1 expression in 436 gastric cancer cases and 92 non-cancerous human gastric tissues.

Results

Protein levels of TMPRSS4 and Erk1 were up-regulated in gastric cancer lesions compared with adjacent noncancerous tissues. High expression of TMPRSS4 correlated with age, size, Lauren’s classification, depth of invasion, lymph node and distant metastases, regional lymph node stage and TNM stage, and also with expression of Erk1. In stages I, II and III, the 5-year survival rate of patients with high TMPRSS4 expression was significantly lower than in patients with low expression. Further multivariate analysis suggests that up-regulation of TMPRSS4 and Erk1 were independent prognostic indicators for the disease, along with depth of invasion, lymph node and distant metastasis and TNM stage.

Conclusions

Expression of TMPRSS4 in gastric cancer is significantly associated with lymph node and distant metastasis, high Erk1 expression, and poor prognosis. TMPRSS4 and Erk1 proteins could be useful markers to predict tumor progression and prognosis of gastric cancer.     

Prognostic Factors of Melanoma Patients with Satellite or In-Transit Metastasis at the Time of Stage III Diagnosis

Background

Prognosis of patients with loco-regional skin metastases has not been analyzed in detail and the presence or absence of concurrent lymph node metastasis represents the only established prognostic factor thus far. Most studies were limited to patients already presenting with skin lesions at the time of initial diagnosis. We aimed to analyze the impact of a broad penal of prognostic factors in patients with skin metastases at the time of first metastatic spread, including patients with synchronous lesions already present at the time of initial diagnosis, stage I/II patients with loco-regional recurrence and patients initially presenting with skin metastasis but unknown primary melanoma.

Patients and Methods

We investigated disease-specific survival of 380 patients treated at our department between 1996 and 2010 using Kaplan Meier survival probabilities and Cox-proportional hazard analysis.

Results

Five-year survival probability was 60.1% for patients with skin metastases only and 36.3% for those with synchronous nodal metastases. The number of involved nodes and a tumor thickness of at least 3 mm had independent negative impact on prognosis. A strong relationship was identified between the risk of death and the number of involved nodes. Neither ulceration nor the timing of the first occurrence of metastases as either in stage I/II patients, at the time of excision of the primary melanoma or initially in patients with unknown primary tumor, had additional effects on survival.

Conclusion

Lymph node involvement was confirmed as the most important prognostic factor for melanoma patients with loco-regional skin metastasis including those with unknown primary tumor and stage I/II patients with skin recurrence. Consideration of the tumor thickness and of the number of involved lymph nodes instead of the exclusive differentiation into presence vs. absence of nodal disease may allow a more accurate prediction of prognosis for patients with satellite or in-transit metastases.     

FOXP3+ Lymphocyte Density in Pancreatic Cancer Correlates with Lymph Node Metastasis

Objective

To determine if the density of FOXP3⁺ lymphocytes in primary tumors and lymph nodes in pancreatic cancer correlates with the presence of lymph node metastases.

Methods

FOXP3⁺ lymphocyte density in primary pancreatic cancer tissue and draining lymph nodes was measured using immunohistochemistry. We analyzed the clinical and pathological aspects associated with the accumulation of FOXP3⁺ lymphocytes in pancreatic cancer. We also analyzed the correlation of density of FOXP3⁺ lymphocytes in lymph nodes with the nodal status and distance from the primary tumor.

Results

FOXP3⁺ lymphocyte density in pancreatic cancer was significantly higher than in paratumoral pancreatic tissue. The density of FOXP3⁺ lymphocytes in local tumor tissue correlated significantly with the histological grade and overall lymph node status. Furthermore, FOXP3⁺ lymphocyte density was significantly higher in positive lymph nodes than in negative ones, while it had no correlation with the distance of the lymph node from the primary tumor.

Conclusion

FOXP3⁺ lymphocyte density in primary tumor tissue in patients with pancreatic cancer correlates with lymph node metastasis. Lymph nodes containing metastases having higher FOXP3⁺ lymphocyte densities than do negative lymph nodes.     

Ratio between Negative and Positive Lymph Nodes Is Suitable for Evaluation the Prognosis of Gastric Cancer Patients with Positive Node Metastasis

Objective

To date, there is no consensus to evaluate the most appropriate category of the nodal metastasis for precise predication the prognosis of gastric cancer patients with positive node metastasis after curative surgery.

Methods

We retrospectively analyzed the clinicopathologic characteristics and overall survival (OS) of 299 gastric cancer patients with positive node metastasis after curative surgery for evaluation the optimal category of the nodal metastasis.

Results

With the univariate and multivariate survival analyses, the depth of primary tumor invasion was identified as the independent predicators with the OS of 299 gastric cancer patients with nodal metastasis postoperatively, as were the number of positive lymph nodes (PLNs), the number of negative lymph nodes (NLNs), and the ratio between negative and positive lymph nodes (RNPL). The RNPL was identified to be more suitable for predication the OS of gastric cancer patients with positive node metastasis than the ratio between positive and dissected lymph nodes (RPDL) by using the stratum procedure of survival analysis. Besides, we found both PLNs and NLNs were independently correlated with OS of gastric cancer patients with nodal metastasis when RNPL, instead of RPDL, was controlled in the partial correlation model.

Conclusions

RNPL, a new category of the nodal metastasis, was suitable for predication the OS of gastric cancer patients with nodal metastasis after curative resection, as were the PLNs, and NLNs.     

Natural History of Malignant Bone Disease in Renal Cancer: Final Results of an Italian Bone Metastasis Survey

Background

Bone metastasis represents an increasing clinical problem in advanced renal cell carcinoma (RCC) as disease-related survival improves. There are few data on the natural history of bone disease in RCC.

Patients and methods

Data on clinicopathology, survival, skeletal-related events (SREs), and bone-directed therapies for 398 deceased RCC patients (286 male, 112 female) with evidence of bone metastasis were statistically analyzed.

Results

Median time to bone metastasis was 25 months for patients without bone metastasis at diagnosis. Median time to diagnosis of bone metastasis by MSKCC risk was 24 months for good, 5 months for intermediate, and 0 months for poor risk. Median number of SREs/patient was one, and 71% of patients experienced at least one SRE. Median times to first, second, and third SRE were 2, 5, and 12 months, respectively. Median survival was 12 months after bone metastasis diagnosis and 10 months after first SRE. Among 181 patients who received zoledronic acid (ZOL), median time to first SRE was significantly prolonged versus control (n = 186) (3 months vs 1 month for control; P<0.05).

Conclusions

RCC patients with bone metastasis are at continuous risk of SREs, and in this survey ZOL effectively reduced this risk.     

Retrospective Analysis of 234 Nasopharyngeal Carcinoma Patients with Distant Metastasis at Initial Diagnosis: Therapeutic Approaches and Prognostic Factors

Purpose

The purpose of this retrospective study was to identify the independent prognostic factors and optimize the treatment for nasopharyngeal carcinoma (NPC) patients with distant metastasis at initial diagnosis.

Methods

A total of 234 patients referred between January 2001 and December 2010 were retrospectively analyzed. Among the 234 patients, 94 patients received chemotherapy alone (CT), and 140 patients received chemoradiotherapy (CRT). Clinical features, laboratory parameters and treatment modality were examined with univariate and multivariate analyses.

Results

The median overall survival (OS) time was 22 months (range, 2-125 months), and the 1-year, 2-year, 3-year overall survival rates were 82.2%, 51.3% and 34.1%. The overall response and disease control rates of metastatic lesions after chemotherapy were 56.0% and 89.8%. The factors associated with poor response were karnofsky performance score (KPS) <80, liver metastasis, lactate dehydrogenase (LDH)>245 IU/L, and number of chemotherapy cycles <4. The 3-year OS of patients receiving CRT was higher than those receiving CT alone (48.2% vs. 12.4%, p<0.001). Subgroup analysis showed that significantly improved survival was also achieved by radiotherapy of the primary tumor in patients who achieved complete remission (CR)/partial remission (PR) or stable disease (SD) of metastatic lesions after chemotherapy. Significant independent prognostic factors of OS were KPS, liver metastasis, levels of LDH, and multiple metastases. Treatment modality, response to chemotherapy and chemotherapy cycles were also associated with OS.

Conclusion

A combination of radiotherapy and chemotherapy seems to have survival benefits for selected patients with distant metastases at initial diagnosis. Clinical and laboratory characteristics can help to guide treatment selection. Prospective randomized studies are needed to confirm the result.     

Serum S100B,Lactate Dehydrogenase and Brain Metastasis Are Prognostic Factors in Patients with Distant Melanoma Metastasis and Systemic Therapy

Background

Prognostic factors of melanoma with distant metastasis and systemic treatment are only poorly established. This study aimed to analyse the impact of S100B, lactate dehydrogenase (LDH) and the type of treatment on survival in advanced patients receiving systemic treatment.

Patients and Methods

We analysed overall survival of 499 patients from the university department of dermatology in Tuebingen, Germany, with unresectable melanoma at the time point of initiation of first-line systemic therapy. Only patients who started treatment between the years 2000 and 2010 were included. Disease-specific survival was calculated by bivariate Kaplan Meier survival probabilities and multivariate Cox hazard regression analysis.

Results

In univariate analysis LDH, S100B, the site of distant metastasis (soft tissue vs. lung vs. other visceral), the presence of brain metastases and the type of treatment (monochemotherapy, polychemotherapy, immunotherapy or biochemotherapy) were associated with overall survival (all p<0.001). In multivariate analysis LDH (Hazard ratio [HR] 1.6 [1.3–2.1]; p<0.001), S100B (HR 1.6 [1.2–2.1]; p<0.001) and the presence of brain metastases (HR 1.5 [1.1–1.9]; p = 0.009), but not the type of treatment had significant independent impact. Among those factors normal S100B was the best indicator of long-term survival, which was 12.3% after 5 years for this subgroup.

Conclusion

Serum S100B is a prognostic marker predicting survival at the time of initiation of first-line treatment in unresectable melanoma patients. Compared to the other independent factors LDH and the presence of brain metastases it is most appropriate to predict long-term survival and requires further prospective investigation in patients treated with new and more potent drugs in metastatic melanoma.     

Reduced Expression of ZDHHC2 Is Associated with Lymph Node Metastasis and Poor Prognosis in Gastric Adenocarcinoma

Background

Zinc finger, DHHC-type containing 2 (ZDHHC2), originally named as reduced expression associated with metastasis protein (REAM), has been proposed as a putative tumor/metastasis suppressor gene and is often aberrantly decreased in human cancers. However ZDHHC2 expression pattern and its clinical significance have not yet been investigated in gastric adenocarcinoma.

Methodology/Principal Findings

Quantitative Real-Time PCR (qRT-PCR) and immunostaining were performed to detect ZDHHC2 expression in gastric adenocarcinoma, and then the correlation between ZDHHC2 expression and clinicpathologic parameters, and patient survival was analyzed. Compared to the adjacent normal tissues, ZDHHC2 expression was significantly reduced in gastric tumor tissues as shown by qRT-PCR and immunostaining. Low expression of ZDHHC2 was observed in 44.7% (211/472) of gastric adenocarcinoma patients, and was associated significantly with lymph node metastasis (p<0.001) and histological grade (p<0.001). Multivariate Cox regression analysis indicated that ZDHHC2 expression had a significant, independent predictive value for survival of gastric cancer patients (HR = 0.627, p = 0.001).

Conclusions/Significance

Our data suggest that reduced ZDHHC2 expression is associated with lymph node metastasis and independently predicts an unfavorable prognosis in gastric adenocarcinoma patients.     

Increased Expression of ATG10 in Colorectal Cancer Is Associated with Lymphovascular Invasion and Lymph Node Metastasis

Background

Autophagy has paradoxical and complex functions in cancer development, and autophagy-related genes (ATG) are key regulators in autophagy. Until now, more than 30 different ATG proteins have been identified in yeast, and their mammalian counterparts also have been reported. Although the roles of a few ATG proteins in cancer have been characterized, the role of ATG10 is almost completely unknown.

Methodology/Principal Findings

To investigate the clinicopathological role of ATG10 in colorectal cancer, we analyzed ATG10 expression in colorectal cancer tissues and cell lines. Protein expression analysis showed that ATG10 is highly increased in colorectal cancer (tissue - 18/37 cases, 48%; cell line –8/12 cell lines, 66%). Immunohistochemical analysis with clinicopathological features indicated a strong association of the up-regulation of ATG10 with tumor lymph node metastasis (p = 0.005) and invasion (p<0.001). Moreover, both 5-year disease free survival and overall survival rates of patients bearing tumors that did not express ATG10 were significantly higher than those of patients bearing ATG10-expressing tumors (p = 0.012).

Conclusion/Significance

Increased expression of ATG10 in colorectal cancer is associated with lymphovascular invasion and lymph node metastasis indicating that ATG10 may be a potential prognostic maker in colorectal cancer.     

Stromal Derived Factor-1 (SDF-1) and Its Receptors CXCR4 and CXCR7 in Endometrial Cancer Patients

Purpose

One of the most important function of stromal derived factor-1 (SDF-1) and its receptors, is regulating the process of metastasis formation. The aim of our study was to investigate the correlation between SDF-1, CXCR4 and CXCR7 protein levels measured by immunohistochemistry with the clinicopathological features and the survival of endometrial cancer patients.

Materials and Methods

92 patients aged 37–84 (mean 65.1±9.5) were enrolled to our study between January 2000 and December 2007. After the diagnosis of endometrial cancer, all women underwent total abdominal hysterectomy, with bilateral salpingoophorectomy and pelvic lymph node dissection. In all patients clinical stage (according to FIGO classification), histologic grade, myometrial invasion, lymph node and distant metastases were determined.Furthermore, the survival time was assessed. Immunohistochemical analyses of SDF-1, CXCR4 and CXCR7 were performed on archive formalin fixed paraffin embedded tissue sections.

Results

Statistically significant correlations (p<0.01) were reported between SDF-1 and the clinical stage of disease, lymph node metastases, distant metastases, deep myometrial invasion (≥50%), cervical involvement, involvement of adnexa. Statistically significant correlation (p<0.01) was found between SDF-1 expression and the risk of the recurrence. Higher SDF-1 expression was associated with ahigher risk of recurrence (p = 0.0001). The results of CXCR4and CXCR7 expression didn''t reveal any significant differences(p>0.05) between the proteins expression in the primary tumor cells and the clinicopathological features. Moreover, the Kaplan-Meier analyses demonstrated a stepwise impairment of cancer overall survival (OS) with increasing SDF-1 expression.

Conclusion

The important role of SDF-1 as a predictor of negative clinicopathological characteristics of atumor suggests that the expression of this stromal factor should be included in the panel of accessory pathomorphological tests and could be helpful in establishing a more accurate prognosis in endometrial cancer patients.     

Melanoma Patients with Unknown Primary Site or Nodal Recurrence after Initial Diagnosis Have a Favourable Survival Compared to Those with Synchronous Lymph Node Metastasis and Primary Tumour

Background

A direct comparison of prognosis between patients with regional lymph node metastases (LNM) detected synchronously with the primary melanoma (primary LNM), patients who developed their first LNM subsequently (secondary LNM) and those with initial LNM in melanoma with unknown primary site (MUP) is missing thus far.

Patients and Methods

Survival of 498 patients was calculated from the time point of the first macroscopic LNM using Kaplan Meier and multivariate Cox hazard regression analysis.

Results

Patients with secondary LNM (HR = 0.67; p = 0.009) and those with initial LNM in MUP (HR = 0.45; p = 0.008) had a better prognosis compared to patients with primary LNM (median survival time 52 and 65 vs. 24 months, respectively). A high number of involved nodes, the presence of in-transit/satellite metastases and male gender had an additional independent unfavourable effect.

Conclusions

Survival of patients with LNM in MUP and with secondary LNM is similar and considerably more favourable compared to those with primary LNM. This difference needs to be considered during patient counselling and for stratification purposes in clinical trials. The assumption of an immune privilege of patients with MUP which is responsible for rejection of the primary melanoma, and results in a favourable prognosis is not supported by our data.     

Lymphangiogenic Markers and Their Impact on Nodal Metastasis and Survival in Non-Small Cell Lung Cancer - A Structured Review with Meta-Analysis

Background

In non-small cell lung cancer (NSCLC), nodal metastasis is an adverse prognostic factor. Several mediating factors have been implied in the development of nodal metastases and investigated for predictive and prognostic properties in NSCLC. However, study results differ. In this structured review and meta-analysis we explore the published literature on commonly recognized pathways for molecular regulation of lymphatic metastasis in NSCLC.

Methods

A structured PubMed search was conducted for papers reporting on the expression of known markers of lymhangiogenesis in NSCLC patients. Papers of sufficient quality, presenting survival and/or correlation data were included.

Results

High levels of vascular endothelial growth factor C (VEGF-C, HR 1.57 95% CI 1.34–1.84) and high lymphatic vascular density (LVD, HR 1.84 95% CI 1.18–2.87) were significant prognostic markers of poor survival and high expression of VEGF-C, vascular endothelial growth factor receptor 3 (VEGFR3) and LVD was associated with lymph node metastasis in NSCLC.

Conclusion

Lymphangiogenic markers are prognosticators of survival and correlate with lymph node metastasis in NSCLC. Their exact role and clinical implications should be further elucidated.     

Sorafenib Combined with Transarterial Chemoembolization versus Transarterial Chemoembolization Alone for Advanced-Stage Hepatocellular Carcinoma: A Propensity Score Matching Study

Aims

The purpose of the present study was to compare the efficacies of transarterial chemoembolization (TACE) combined with sorafenib versus TACE monotherapy for treating patients with advanced hepatocellular carcinoma (HCC).

Methods

We enrolled 321 patients and selected 280 with advanced HCC (Barcelona Clinic Liver Cancer stage C) who underwent TACE therapy between February 2009 and February 2013. TACE alone (monotherapy group) was administered to 198 patients (70.7%), and the remaining 82 (29.3%) underwent repeat combined TACE and sorafenib therapy (combined group). To minimize selection bias, these latter 82 patients were matched using propensity-score matching at a 1∶2 ratio with 164 patients who received TACE monotherapy. The primary endpoints were overall survival (OS) and related subgroup analysis. The secondary endpoints were time to progression (TTP) and treatment-related adverse events.

Results

Of the respective patients in the combined and monotherapy groups, 64.6% and 49.2% had vascular invasion, 87.8% and 91.1% had extrahepatic metastasis, and 54.3% and 47.1% had both. In the propensity-score–matched cohort, the OS survival of the combined group was significantly higher compared with the monotherapy group (7.0 months vs. 4.9 months, respectively, P = 0.003). The TTP was significantly longer in the combined group (2.6 months vs. 1.9 months, respectively, P = 0.001). Subgroup analysis showed that the outcomes of patients with advanced HCC without main portal vein invasion who were treated with combined therapy were significantly better compared with those who received monotherapy (P<0.05). Univariate and subsequent multivariate analyses revealed that the addition of sorafenib was an independent predictor of favorable OS and TTP (adjusted hazard ratios, 0.63 and 0.62, respectively; P<0.05 for both).

Conclusion

Sorafenib plus TACE was more effective than TACE monotherapy for treating patients with advanced HCC without main portal vein invasion. Future trials with larger samples are required to validate these preliminary findings.     

Impact of Lymph Node Ratio on the Survival of Patients with Hypopharyngeal Squamous Cell Carcinoma: A Population-Based Analysis

Objective

To analyze the impact of the lymph node ratio (LNR, ratio of metastatic to examined nodes) on the prognosis of hypopharyngeal cancer patients.

Methods

SEER (Surveillance, Epidemiology and End Results)-registered hypopharyngeal cancer patients with lymph node metastasis were evaluated using multivariate Cox regression analysis to identify the prognostic role of the LNR. The categorical LNR was compared with the continuous LNR and pN classifications to predict cause-specific survival (CSS) and overall survival (OS) rates of hypopharyngeal cancer patients.

Results

Multivariate analysis of 916 pN+ hypopharyngeal cancer cases identified race, primary site, radiation sequence, T classification, N classification, M classification, the number of regional lymph nodes examined, the continuous LNR (Hazard ratio 2.415, 95% CI 1.707–3.416, P<0.001) and age as prognostic variables that were associated with CSS in hypopharyngeal cancer. The categorical LNR showed a higher C-index and lower Akaike information criterion (AIC) value than the continuous LNR. When patients (n = 1152) were classified into four risk groups according to LNR, R0 (LNR = 0), R1 (LNR ≤0.05), R2 (LNR 0.05–0.30) and R3 (LNR >0.30), the Cox regression model for CSS and OS using the R classification had a higher C-index value and lower AIC value than the model using the pN classification. Significant improvements in both CSS and OS were found for R2 and R3 patients with postoperative radiotherapy.

Conclusions

LNR is a significant prognostic factor for the survival of hypopharyngeal cancer patients. Using the cutoff points 0.05/0.30, the R classification was more accurate than the pN classification in predicting survival and can be used to select high risk patients for postoperative treatment.     

Identification of Biological Properties of Intralymphatic Tumor Related to the Development of Lymph Node Metastasis in Lung Adenocarcinoma

Background

Intralymphatic tumors in the extratumoral area are considered to represent the preceding phase of lymph node metastasis. The aim of this study was to clarify the biological properties of intralymphatic tumors susceptible to the development of lymph node metastasis, with special reference to the expression of cancer initiating/stem cell (CIC/CSC) related markers in cancer cells and the number of infiltrating stromal cells.

Material and Methods

Primary lung adenocarcinomas with lymphatic permeation in the extratumoral area were retrospectively examined (n = 107). We examined the expression levels of CIC/CSC related markers including ALDH1, OCT4, NANOG, SOX2 and Caveolin-1 in the intralymphatic cancer cells to evaluate their relationship to lymph node metastasis. Moreover, the number of infiltrating stromal cells expressing CD34, α-smooth muscle actin, and CD204 were also evaluated.

Results

Among the intralymphatic tissues, low ALDH1 expression in cancer cells, high SOX2 expression in cancer cells, and a high number of CD204(+) macrophages were independent predictive factors for lymph node metastasis (P = 0.004, P = 0.008, and P = 0.028, respectively). Among these factors, only low ALDH1 expression in cancer cells was significantly correlated with the farther spreading of lymph node metastasis (mediastinal lymph node, pathological N2) (P = 0.046) and the metastatic lymph node ratio (metastatic/resected) (P = 0.028). On the other hand, in the primary tumors, ALDH1 expression in the cancer cells was not associated with lymph node metastasis. Intralymphatic cancer cells expressing low ALDH1 levels exhibited lower E-cadherin expression levels than cancer cells with high levels of ALDH1 expression (P = 0.015).

Conclusions

Intralymphatic cancer cells expressing low levels of ALDH1 and infiltrating macrophages expressing CD204 have a critical impact on lymph node metastasis. Our study also highlighted the significance of evaluating the biological properties of intralymphatic tumors for tumor metastasis.