Anticancer drug-loaded multifunctional nanoparticles to enhance the chemotherapeutic efficacy in lung cancer metastasis.

BACKGROUND: Inhalation of chemotherapeutic drugs directly into the lungs augments the drug exposure to lung cancers. The inhalation of free drugs however results in over exposure and causes severe adverse effect to normal cells. In the present study, epidermal growth factor (EGF)-modified gelatin nanoparticles (EGNP) was developed to administer doxorubicin (DOX) to lung cancers. RESULTS: The EGNP released DOX in a sustained manner and effectively internalized in EGFR overexpressing A549 and H226 lung cancer cells via a receptor-mediated endocytosis. In vitro cytotoxicity assay showed that EGNP effectively inhibited the growth of A549 and H226 cells in a dose-dependent manner. In vivo biocompatibility study showed that both GNP and EGNP did not activate the inflammatory response and had a low propensity to cause immune response. Additionally, EGNP maintained a high therapeutic concentration in lungs throughout up to 24 h comparing to that of free drug and GNP, implying the effect of ligand-targeted tumor delivery. Mice treated with EGNP remarkably suppressed the tumor growth (~90% tumor inhibition) with 100% mice survival rate. Furthermore, inhalation of EGNP resulted in elevated levels of cleaved caspase-3 (apoptotic marker), while MMP-9 level significantly reduced comparing to that of control group. CONCLUSIONS: Overall, results suggest that EGF surface-modified nanocarriers could be delivered to lungs via inhalation and controlled delivery of drugs in the lungs will greatly improve the therapeutic options in lung cancer therapy. This ligand-targeted nanoparticulate system could be promising for the lung cancer treatment.

Liposome-based co-delivery of siRNA and docetaxel for the synergistic treatment of lung cancer.

Combination of more than one therapeutic strategy is the standard treatment in clinics. Co-delivery of chemotherapeutic drug and small interfering RNA (siRNA) within a nanoparticulate system will suppress the tumor growth. In the present study, docetaxel (DTX) and BCL-2 siRNA was incorporated in a PEGylated liposome to systemically deliver in a lung cancer model (A549). The resulting nanoparticle (lipo-DTX/siRNA) was stable and exhibited a sustained release profile. The co-delivery of therapeutic moieties inhibited the cell proliferation (A549 and H226) in a time-dependent manner. Moreover, the co-delivery system of DTX and siRNA exhibited a remarkable apoptosis of cancer cells with elevated levels of caspase 3/7 activity (apoptosis markers). Cell cycle analysis further showed remarkable increase in sub-G0/G1 phase, indicating increasing hypodiploids or apoptotic cells. Pharmacokinetic study showed a long circulating profile for DTX from lipo-DTX/siRNA system facilitating the passive tumor targeting. In vivo antitumor study on A549 cell bearing xenograft tumor model exhibited a remarkable tumor regression profile for lipo-DTX/siRNA with 100% survival rate. The favorable tumor inhibition response was attributed to the synergistic effect of DTX potency and MDR reversing ability of BCL-2 siRNA in the tumor mass. Overall, experimental results suggest that co-delivery of DTX and siRNA could be promising approach in the treatment of lung cancers.

Prognostic value of tumor volume for patients with nasopharyngeal carcinoma treated with concurrent chemotherapy and intensity-modulated radiotherapy.

PURPOSE: We aimed to analyze prognostic factors in patients with nasopharyngeal carcinoma (NPC) treated with concurrent chemotherapy and intensity-modulated radiotherapy (IMRT); in addition, we aimed to elucidate the value of primary gross tumor volume (GTVp) in predicting prognosis of patients. METHODS: Between February 2001 and December 2008, 321 patients with NPC treated with concurrent chemotherapy and IMRT were analyzed retrospectively. GTVp was calculated from treatment planning computed tomography scans. A receiver operating characteristics (ROC) curve was used to determine the best cutoff point of GTVp. RESULTS: The 5-year local failure-free survival (LFFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) for NPC patients were 93.8, 80.1, 73.0, and 83.7 %, respectively. Univariate and multivariate analyses indicated that GTVp had exhibited a statistically significant correlation with LFFS, DMFS, DFS, and OS (P < 0.05, all), whereas T classification was not an independent prognostic factor. According to ROC curve analysis, 49 and 19 mL were determined as the cutoff points of GTVp for local control and distant metastasis, respectively. Based on this, 321 patients were divided into three volume subgroups. LFFS, DMFS, DFS, and OS demonstrated significant differences among patients in different volume subgroups (P < 0.001, all) and were superior to T classification for predicting prognosis of NPC patients. CONCLUSIONS: Primary gross tumor volume is an independent prognostic factor in local control, distant metastasis, disease-free survival, and overall survival in NPC. An adjusted TNM staging system that includes GTVp as a quantitative indicator to evaluate prognosis is warranted.

Using CT or MRI to assess locoregional spread to determine the radiotherapy target of hypopharyngeal carcinoma.

AIM: To identify the locoregional extension of hypopharyngeal carcinoma (HPC), particularly the invasion of the nasopharynx and skull base, and metastasis of level VI and retropharyngeal lymph node (RPLN) by investigating computed tomography (CT) and magnetic resonance (MR) images; together with the radiotherapy target of HPC. METHODS: CT and MR images of 186 patients with pathologically confirmed HPC between Aug 2000 and Dec 2010 were analyzed retrospectively. We used the χ(2) test and logistic regression to analyze local invasion and regional spread and to determine their relationships. RESULTS: Of the 186 patients, there was only one case of invasion of the nasopharynx without skull base involvement. The rate of regional node metastasis was 79%. There was no significant relationship between T stage and lymph node metastasis (P = 0.1). Level IV metastasis (P = 0.001), RPLN metastasis (P = 0.041) and esophageal invasion (P = 0.003) were significantly correlated with level VI metastasis. Primary tumor subsite (P = 0.024), bilateral cervical node metastasis (P < 0.001) and size of cervical nodes (P = 0.01) significantly contributed to the occurrence of RPLN metastasis. CONCLUSION: The locoregional spread of HPC occurs via certain routes. It is potentially unnecessary to routinely and prophylactically irradiate the nasopharynx and skull base. Patients with early stage HPC should receive bilateral cervical prophylactic irradiation. The decision regarding the administration of prophylactic irradiation to the level VI and RPLN areas should be according to the relative risk factors.

XPC gene polymorphisms contribute to bladder cancer susceptibility: a meta-analysis.

Numerous studies have investigated the association between three polymorphisms (Lys939Gln, Ala499Val and PAT-/+) of Xeroderma pigmentosum group C (XPC) gene and bladder cancer susceptibility; however, the findings are inconclusive. In order to acquire a more precise estimation of the relationship, we performed a meta-analysis based on 10 studies including 3,934 cases and 4,269 controls for Lys939Gln, five studies including 2,113 cases and 2,249 controls for Ala499Val, and seven studies including 2,834 cases and 3,048 controls for PAT-/+ polymorphism. We searched publications from EMBASE, MEDLINE, and Chinese Biomedical. We calculated pooled odds ratio (OR) and 95% confidence interval (CI) by using either fixed-effects or random-effects model according to the between-study heterogeneity. We found that all studied polymorphisms were individually associated with increased overall cancer risks, as shown by ORs (95% CIs) below: the Lys939Gln (Gln/Gln vs. Lys/Lys: OR = 1.39, 95% CI = 1.08-1.79; recessive model: OR = 1.42, 95% CI = 1.11-1.83; and allele comparing: OR = 1.12, 95% CI = 1.003-1.24), the Ala499Val (Val/Val vs. Ala/Ala: OR = 1.82, 95% CI = 1.19-2.79; recessive model: OR = 1.70, 95% CI = 1.18-2.46; and allele comparing: OR = 1.23, 95% CI = 1.01-1.50), and the PAT-/+ (+/+ vs. -/-: OR = 1.36, 95% CI = 1.03-1.79 and recessive model: OR = 1.34, 95% CI = 1.06-1.70). Furthermore, stratification analyses demonstrated an increased risk for Asian populations as to the Lys939Gln and PAT-/+ whereas for Caucasian populations as to the Ala499Val polymorphism in the homozygous and recessive models. Despite some limitations, this meta-analysis suggests that XPC polymorphisms are associated with bladder cancer risk, but this association warrants further validation in well-designed studies with large sample sizes.

Poly (AT) deletion/insertion polymorphism of the XPC gene contributes to urinary system cancer susceptibility: a meta-analysis.

Numerous studies have investigated the association between xeroderma pigmentosum complementation group C (XPC) poly (AT) deletion/insertion (PAT -/+) polymorphism and cancer susceptibility; however, the findings are inconsistent. Therefore, we performed a meta-analysis based on 32 publications including 10,214 cases and 11,302 controls to acquire a more robust estimation of the relationship. We searched publications from MEDLINE, EMBASE and CBM which assessed the associations between XPC PAT -/+ polymorphism and cancer risk. We calculated pooled odds ratio (OR) and 95% confidence interval (CI) by using either fixed-effects or random-effects model. We found that individuals carrying the PAT +/+ genotype have significantly increased cancer risk (PAT +/+ vs. PAT -/-: OR=1.18, 95% CI=1.03-1.35 and recessive model: OR=1.19, 95% CI=1.06-1.33). Further stratification analysis showed a significantly increased risk for prostate cancer (PAT +/+ vs. PAT -/-: OR=2.20, 95% CI=1.39-3.48, recessive model: OR=2.07, 95% CI=1.33-3.23 and PAT + vs. PAT -: OR=1.39, 95% CI=1.12-1.71), bladder cancer (recessive model: OR=1.33, 95% CI=1.03-1.72), Caucasian ethnicity (recessive model: OR=1.21, 95% CI=1.02-1.43), population-based studies (recessive model: OR=1.23, 95% CI=1.05-1.43) and studies with relatively large sample size (PAT +/+ vs. PAT -/-: OR=1.18, 95% CI=1.04-1.35 and recessive model: OR=1.20, 95% CI=1.08-1.33). Despite some limitations, this meta-analysis established solid statistical evidence for the association between the XPC PAT +/+ genotype and cancer risk, especially for urinary system cancer, but this association warrants further validation in single large studies.

Nasopharyngeal tuberculosis: CT and MRI findings in thirty-six patients.

PURPOSE: Tuberculosis is uncommon in the nasopharynx. The purpose of this study was to investigate the CT and MRI features of 36 cases of tuberculosis in this area. MATERIALS AND METHODS: CT (n=15) and MRI (n=21) scans from 36 patients with histologically proved tuberculosis of the nasopharynx were reviewed by two experienced radiologists, paying particular attention to the lesions' distribution, location, extent, size, internal architecture, pattern, and degree of enhancement, and cervical lymphadenopathy. RESULTS: Twenty-nine patients exhibited a polypoid mass pattern and seven had diffuse mucosal thickening. The roof of the nasopharynx was involved in all cases. The mean size of the lesions was 11.4mm. Striped pattern was detected in 19 cases. Adjacent muscle invasion or bone destruction was not detected. Heterogeneous enhancement was detected in all patients, and necrosis in the nasopharyngeal lesions was detected in 16 cases. Poor, moderate, and marked enhancement was detected in one, 27, and eight cases, respectively. Thirty-four patients had involvement of the cervical lymph nodes. Twenty-two and 28 cases were associated with bilateral lymphadenopathy or necrosis, respectively. The retropharyngeal lymph node was the most commonly involved site (94.1%). CONCLUSION: The presence of necrosis and striped pattern in nasopharyngeal lesions, site predilection, no invasion of regional structures, and central necrosis with peripheral rim enhancement of cervical lymphadenopathy may suggest the diagnosis of nasopharyngeal tuberculosis.

Correlation between nasopharyngeal carcinoma tumor volume and the 2002 International Union Against Cancer tumor classification system.

BACKGROUND: The correlation between primary tumor volume and nasopharyngeal carcinoma (NPC) UICC 2002 T classification, N classification and distant metastasis after radiation therapy was discussed to provide further evidence for the inclusion of tumor volume into the TNM classification staging system. METHODS: Between February 2001 and December 2008, 666 patients with NPC treated with intensity-modulated radiation therapy (IMRT) were analyzed retrospectively. Primary gross tumor volume was calculated from treatment planning computed tomography scans. The Kruskal-Wallis and Mann-Whitney tests were used for comparison of continuous variables and the chi-square test was used for categorical variables. A logistic regression model was used for multivariate analysis. RESULTS: Median primary tumor volume of the 666 patients was 20.35 ml (range, 0.44 - 192.63 ml), and it gradually increased with T classification. Statistically significant differences in tumor volume were observed between patients with different T classifications (p < 0.001). The cervical lymph node metastasis rate was 64.7% (430/666); the differences in primary tumor volume between patients with or without lymph node metastasis were statistically significant (p < 0.001). Posttreatment distant metastasis occurred in 100 NPC patients, and the five-year distant metastasis-free survival was 84.2%. Univariate and multivariate analyses showed that N classification (p < 0.001) and tumor volume (p = 0.007) were the main factors influencing distant metastasis. CONCLUSION: Tumor volume was correlated with T classification, cervical lymph node mestastasis and distant metastasis after radiation therapy in nasopharyngeal carcinoma, suggesting that tumor volume should be included into the TNM staging system.

Analysis of risk factors for retropharyngeal lymph node metastasis in carcinoma of the hypopharynx.

BACKGROUND: The purpose of this study was to investigate the incidence of retropharyngeal lymph node (RPLN) metastasis and to explore the associated risk factors using CT and MRI, to direct clinical radiotherapy in hypopharyngeal carcinoma (HPC). METHODS: The CT and MRI images of 218 patients with pathologically confirmed HPC were analyzed retrospectively. The chi-square test and logistic regression were used for statistical analysis. RESULTS: The incidence of RPLN metastasis in HPC was 17.0%, and the highest rate of 36.4% was found in pharyngeal wall carcinoma. None of the patients with N0 classification exhibited RPLN metastasis. Univariate and multivariate analyses demonstrated that primary tumor subsites, bilateral cervical lymph node metastasis, the number and size of cervical lymph nodes, and level V metastasis were significantly associated with RPLN metastasis. CONCLUSIONS: Our findings demonstrated that primary carcinoma subsites and multiple metastatic cervical lymph nodes are the principal risk factors for RPLN metastasis.

Prognostic significance of tumor volume in patients with nasopharyngeal carcinoma undergoing intensity-modulated radiation therapy.

BACKGROUND: This study was undertaken to analyze the correlation between primary gross tumor volume (GTVp) and prognosis in patients with nasopharyngeal carcinoma (NPC) undergoing intensity-modulated radiation therapy (IMRT). METHODS: Between February 2001 and December 2006, 305 patients with NPC treated with IMRT were analyzed retrospectively. GTVp was calculated from treatment planning CT scans. RESULTS: Univariate and multivariate analyses indicated that GTVp had a statistically significant correlation to local control, distant metastasis, and overall survival in patients with NPC, whereas T classification was not an independent prognostic factor. Among patients classified with N0-1 and N2-3, there were significant differences in the rates of distant metastasis between those with GTVp smaller and larger than 25 mL (p < .001 and p = .002, respectively). CONCLUSIONS: GTVp is highly significant in evaluating local control, distant metastasis, and overall survival of patients with NPC treated with IMRT. Therefore, it is recommended that GTVp be included in the new TNM classification system.

CT-guided needle biopsy through mandibular area for the diagnosis of nasopharyngeal carcinoma in the parapharyngeal space.

BACKGROUND AND OBJECTIVE: The primary submucous type of nasopharyngeal carcinoma (NPC) or the recurrent NPC in the parapharyngeal space is difficult to be diagnosed histologically by conventional biopsy because of the obstruction of the surrounding structures. This study was performed to evaluate the needle biopsy approach through the madibular area into the parapharyngeal space under the guidance of computed tomography (CT) for NPC. METHODS: Between July 6, 2005 and October 23, 2009, a total of 6 patients were enrolled into the study. Two patients with cervical lymph node metastasis were clinically suspicious of NPC according to their clinical manifestations. However, no cancer cell could be found by repeated nasopharyngeal biopsies followed by histologic examinations. The other 4 patients were diagnosed with recurrent NPCs by magnetic resonance imaging (MRI) or/and positron emission tomography (PET)-CT scan, showing tumors in the parapharyngeal spaces in 3 patients and enlarged retropharyngeal lymph node in 1 patient. The CT-guided puncture was performed through the mandibular skin and the cutting needle biopsy was taken at the parapharyngeal space focus. RESULTS: All the cutting needle biopsies of projected locations have been performed safely. Finally, all the 7 specimens met the requirement of pathologic diagnosis and the cases were all confirmed histologically to be NPCs. The main complication was mild ache at the puncture point. No blood vessel or nerve was injured and no patient needed special treatment. CONCLUSIONS: The CT-guided puncture biopsy of the parapharyngeal space through the mandibular area is simple and feasible. It can be an additional option for routine nasopharyngeal biopsy.

Analysis of cervical and retropharyngeal lymph node metastases in the patients with hypopharyngeal carcinoma with computed tomography and magnetic resonance imaging.

BACKGROUND AND OBJECTIVE: Hypopharyngeal carcinoma has a high risk for early regional lymphatic dissemination. However, reports about regional lymph node metastases, especially retropharyngeal lymph node metastases, are rare. This research explored the spread of hypopharyngeal carcinoma, especially metastases of the retropharyngeal lymph nodes by studying computed tomography (CT) and magnetic resonance imaging (MRI) images. METHODS: The CT/MRI images of 88 patients with pathologically confirmed hypopharyngeal carcinomas that were performed at our hospital between August 2000 and March 2009 were analyzed retrospectively. The interrelations among local stage and lymph nodes in various regions were analyzed by Chi2 test and multivariate logistical regression. RESULTS: The rate of regional lymph node metastasis for all patients was 73.9%, and the highest rates of positive lymph nodes were at levels IIa (61.4%), IIb (44.3%), and III (37.5%). Metastases to levels I, IV, V, and VI were rare, as were retropharyngeal lymph-node metastases, which were always combined with metastases at levels II and III. Univariate analysis showed that level-IV metastases correlated to metastases at levels Ib and III; retropharyngeal lymph node metastases were correlated to level IIb and bilateral cervical lymph node metastases. Multivariate analysis showed that level-VI metastases correlated to level IV and that retropharyngeal lymph-node metastases correlated to bilateral cervical lymph node metastases. CONCLUSIONS: Regional lymph node metastases in patients with hypopharyngeal carcinoma follow some regulations, and skip metastasis is rare. The highest rates of positive lymph nodes are at levels II and III. Bilateral lymph node metastases may be a risk factor for retropharyngeal lymph node metastases.