Percutaneous transhepatic cholangial drainage or antibiotic therapy worsens response to immunotherapy in advanced cholangiocarcinoma.

BACKGROUND: Bile duct obstruction is a common issue for patients with advanced cholangiocarcinoma (CCA). Percutaneous transhepatic cholangial drainage (PTCD) is often required to relieve the obstruction. However, PTCD may alter the intestinal microbiota, which can affect the efficacy of immunotherapy. Antibiotics (ATB) can also have significant immunomodulatory effects by perturbing the gut microbiota. Therefore, this study aimed to investigate whether PTCD or ATB therapy is associated with overall survival (OS) or progression-free survival (PFS) in patients with advanced CCA receiving first-line chemotherapy plus immune checkpoint blockade (ICB) in clinical practice. We also explored whether the gut microbiota changes after receiving PTCD. METHODS: We conducted a single-center retrospective analysis of PTCD and ATB therapy in patients with advanced CCA. PTCD was performed before ICB initiation, and ATB was administered within 1 month before and 6 weeks after ICB initiation. Our primary outcomes were PFS and OS. Moreover, we used 16s rRNA sequencing to analyze fecal and bile samples obtained from patients who underwent PTCD. RESULTS: In total, 107 patients with CCA were included. Among patients who did not undergo PTCD, ICB plus chemotherapy significantly improved OS vs. chemotherapy alone (hazard ratio [HR] 0.21, 95% confidence interval [CI] 0.09-0.45, p < 0.0001). PFS was also significantly improved in patients who received ICB plus chemotherapy compared with chemotherapy alone (HR 0.36, 95% CI 0.16-0.80, p = 0.0024). However, ICB plus chemotherapy did not improve survival compared with chemotherapy alone among patients who received PTCD. Overall changes in the fecal microbiota of patients after PTCD involved significant reductions in which Escherichia - Shigella. CONCLUSIONS: The use of ATB or PTCD in patients with CCA receiving ICB was associated with worse OS compared with chemotherapy alone, and PTCD affects the gut microbiota. Escherichia - Shigella was significantly reduced in feces of patients after PTCD.

Tuftsin-tailored fusion protein inhibits the growth of circulating gastric tumor cells associated with macrophage phagocytosis.

Circulating tumor cells (CTCs) are a major cause of tumor metastasis and resistance to anticancer therapies. To date, no effective low-toxicity chemotherapeutic agents or antibodies have exhibited significant clinical activity against CTCs. Macrophages are important mediators of antitumor immunity. Tuftsin (TF), a tetrapeptide located at residues 289-292 of the CH2 domain of the Fc region of the IgG heavy chain, binds to Nrp-1, a receptor on the surface of macrophages that promotes phagocytosis and induces nonspecific activation of the immune system against tumors. Lidamycin (LDM) is an antitumor chemotherapy agent that is strongly cytotoxic to tumors and can dissociate into an apoprotein (LDP) and active enediyne (AE) in vitro. We previously constructed the fusion protein LDP-TF through genetic engineering and inserted the chromophore AE to produce LDM-TF, which can target macrophages to promote their phagocytic and cytotoxic activity against tumor cells. Preliminary experiments confirmed the anti-tumor activity of LDM-TFs. In this study, we found that LDM-TF effectively inhibited the growth of CTCs of gastric cancer origin and enhanced macrophage phagocytosis both in vivo and in vitro. Tumor cell expression of CD47, which helps to evade phagocytosis by macrophages, was substantially downregulated by LDM-TF. Notably, our in vitro experiments demonstrated that the combination of LDM-TF and anti-CD47 antibodies promoted phagocytosis more than either component alone. Our findings demonstrate the significant inhibitory effect of LDM-TF on the growth of CTCs of gastric cancer origin and suggest that the combination of LDM-TF and anti-CD47 antibodies may exhibit synergistic effects, thereby providing a new option for the clinical treatment of patients with advanced tumors that have metastasized.

Effect of thoracic radiotherapy dose on the prognosis of advanced lung adenocarcinoma harboring EGFR mutations.

BACKGROUND: The aim of this study was to investigate the effects of different thoracic radiotherapy doses on OS and incidence of radiation pneumonia which may provide some basis for optimizing the comprehensive treatment scheme of these patients with advanced EGFR mutant lung adenocarcinoma. METHODS: Data from 111 patients with EGFR-mutant lung adenocarcinoma who received thoracic radiotherapy were included in this retrospective study. Overall survival (OS) was the primary endpoints of the study. Kaplan-Meier method was used for the comparison of OS. The Cox proportional-hazard model was used for the multivariate and univariate analyses to determine the prognostic factors related to the disease. RESULTS: The mOS rates of the patients, who received radiotherapy dose scheme of less than 50 Gy, 50-60 Gy (including 50 Gy), and 60 Gy or more were 29.1 months, 34.4 months, and 51.0 months, respectively (log-rank P = 0.011). Although trend suggested a higher levels of pneumonia cases with increasing radiation doses, these lack statistical significance (χ2 = 1.331; P = 0.514). The multivariate analysis showed that the thoracic radiotherapy dose schemes were independently associated with the improved OS of patients (adjusted hazard ratio [HR], 0.606; 95% CI, 0.382 to 0.961; P = 0.033). CONCLUSIONS: For the patients with advanced EGFR-mutant lung adenocarcinoma, the radical thoracic radiotherapy dose scheme (≥ 60 Gy) could significantly prolong the OS of patients during the whole course management.

Survival prediction models for patients with anal carcinoma receiving definitive chemoradiation: A population-based study.

The present study aimed to develop two nomograms in order to predict cancer-specific survival (CSS) and overall survival (OS) of patients with anal carcinoma receiving definitive chemoradiotherapy. Data from studies including patients with anal carcinoma, who were determined to be positive histologically and diagnosed between 2004 and 2010, were obtained from the Surveillance, Epidemiology, and End Results database. Significant prognostic factors for CSS and OS of patients were screened to develop nomograms through univariate and multivariate analyses. Nomograms were validated using internal and external data. The predictive abilities of the generated models were evaluated by concordance index (C-index) and calibration curves. Risk stratification was performed for patients with the same TNM stage. A total of 1,473 patients and six independent prognostic factors for CSS and OS, namely age, sex, ethnicity, marital status at diagnosis, T stage and N stage, were included in the nomogram calculations. Calibration curves demonstrated that nomogram prediction was in high accordance with actual observation. The C-indices of nomograms were greater than those of models based on the sixth edition of the American Joint Committee on Cancer TNM staging system for CSS prediction (training cohort, 0.72 vs. 0.70; validation cohort, 0.68 vs. 0.62) and OS (training cohort, 0.70 vs. 0.66; validation cohort, 0.68 vs. 0.62). Survival curves demonstrated significant survival differences among the different risk groups. Nomograms were more accurate than the conventional TNM staging system in prognosis prediction. In addition, survival performances of patients with the same TNM stage could be further distinguished by risk stratification, which provided individualized prediction for patients. These survival prediction methods may aid clinicians in patient counseling and in selecting more individualized therapeutic strategies.

Enediyne-activated, EGFR-targeted human ß-defensin 1 has therapeutic efficacy against non-small cell lung carcinoma.

Human ß-defensins contain an oncolytic motif that binds to tumor cell membranes and mediate permeabilization, rapid induction of cytolysis, and apoptosis. Previous studies have indicated that a fragment of the mature human ß-defensin-1 (HBD1) peptide (DF) has antitumor properties. While targeted drug treatments using fusion proteins have been shown to increase drug efficacy, this phenomenon has not been studied for this defensin. Thus, in this study, we designed and prepared a fusion protein containing this HBD1 fragment and an epidermal growth factor receptor (EGFR)-targeting oligopeptide (Ec) as well as lidamycin (LDM), an extremely potent cytotoxic antitumor antibiotic, which consists of an apoprotein (LDP) and a highly active enediyne (AE). The fusion protein (Ec-LDP-DF) and its enediyne-integrated fusion protein (Ec-LDP(AE)-DF) were then purified and used to treat lung carcinoma cells in culture as well as lung carcinoma xenograft mouse models. The multifunctional fusion protein Ec-LDP-DF was shown to effectively bind to EGFR-expressing tumor cells. Furthermore, the enediyne-energized Ec-LDP(AE)-DF analog exhibited extremely potent cytotoxicity in NSCLC cell lines and an IC50 less than 10-10 mol/L. Ec-LDP(AE)-DF also significantly inhibited the growth of human carcinoma A549 and H460 xenografts in athymic mice at well-tolerated doses. Treatment resulted in cell cycle arrest and apoptosis in a dose-dependent manner. EGF-stimulated EGFR phosphorylation was also abolished by Ec-LDP(AE)-DF. In summary, our understanding of the role of defensins in cancer development and progression is continually expanding, and Ec-LDP(AE)-DF is a promising cancer cell-targeting agent for NSCLC.

Thoracic radiation therapy could give survival benefit to elderly patients with extensive-stage small-cell lung cancer.

AIM: To evaluate the effect of thoracic radiation therapy (TRT) in elderly patients (aged ≥65 years) with extensive-stage small-cell lung cancer (ES-SCLC). PATIENTS & METHODS: This study reviewed the records of 118 elderly patients with ES-SCLC (all with distant metastasis) through January 2006-December 2013. The patients were divided into either a chemotherapy (ChT)/TRT-combination group or a ChT-alone group. RESULTS: The median survival time and 3-year overall survival rates in the ChT/TRT group were significantly higher than those in the ChT-alone group (17.0 vs 11.7 months; 18.1 vs 14.9%; p = 0.014). The 3-year overall survival rates in patients who received prophylactic cranial irradiation were also higher than the rates in patients who did not receive prophylactic cranial irradiation (18.1 vs 5.1%; p = 0.708). CONCLUSION: TRT combined with ChT could provide a survival benefit to elderly patients with ES-SCLC.

Minimum absolute lymphocyte counts during radiation are associated with a worse prognosis in patients with unresectable hepatocellular carcinoma.

BACKGROUND: Peripheral blood lymphocytes play an important role in antitumour immunity. We examined the relationship between the minimum absolute lymphocyte counts (Min ALCs) during radiotherapy (RT) and clinical outcomes in patients with hepatocellular carcinoma (HCC). METHODS: Data from a total of 69 HCC patients who had received RT were retrospectively analysed. Peripheral blood lymphocytes were measured before RT, weekly during RT and after RT. Regression and mixed-effect models were used to assess the relationships with and potential predictors of overall survival (OS). Receiver-operating characteristic (ROC) curve analysis was used to define optimal cut-off points of continuous variables for outcomes. RESULTS: The median follow up was 30 months (range, 4-68 months). The median survival time (MST), 1-year OS rate and 2-year OS rate of the whole group were 25 months, 51% and 39%, respectively. The average circulating lymphocyte counts declined during RT (1493.19 versus 503.48 cells/µl, p < 0.001). A lower Min ALC was associated with worse OS (p = 0.001), with a cut-off value of 450 cells/µl (sensitivity and specificity, 50% and 70.6%, respectively). The MSTs, 1-year OS rates and 2-year OS rates were 15 months versus 47 months, 27% versus 78% and 4% versus 71% for patients with relatively lower (⩽450 cells/µl) and higher Min ALCs (>450 cells/µl), respectively (p < 0.001). After adjusting for potential confounders, multivariate Cox regression analysis demonstrated that Min ALC independently predicted patients' OS (HR, 0.32; 95% CI, 0.15-0.69). CONCLUSIONS: Lower Min ALCs during RT may act as a worse prognostic factor for HCC after RT.

Comparison of intra-arterial chemoembolization with and without radiotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis: a meta-analysis.

PURPOSE: Numerous studies have tried to combine transarterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC) with radiotherapy (RT) for the treatment of hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT). However, the efficacy of TACE or HAIC combined with RT versus TACE or HAIC alone remains controversial. Thus, we performed a meta-analysis to compare the efficacy and safety of intra-arterial chemoembolization combined with RT versus intra-arterial chemoembolization alone for the treatment of HCC patients with PVTT. METHODS: PubMed, Embase, and Cochrane Library databases were systematically searched for eligible studies. Two authors independently reviewed the abstracts, extracted relevant data and rated the quality of studies. The major end points were objective response rate (ORR), overall survival (OS), and adverse events. RESULTS: Eight studies with a total of 1,760 patients were included in this meta-analysis. The pooled results showed that intra-arterial chemoembolization combined with RT significantly improved ORR of PVTT (OR, 4.22; 95% CI, 3.07-5.80; P<0.001) and OS (HR, 0.69; 95% CI, 0.57-0.83; P=0.001), but did not affect ORR of primary liver tumor (OR, 1.37; 95% CI, 0.67-2.79; P=0.390). The incidence of grade 3 or 4 leukopenia (OR, 5.80; 95% CI, 2.478-13.56; P<0.001) and thrombocytopenia (OR, 3.77; 95% CI, 1.06-13.43; P=0.041) was higher in the intra-arterial chemoembolization plus RT group than in the intra-arterial chemoembolization group. CONCLUSION: Combination therapy of intra-arterial chemoembolization and RT for HCC patients with PVTT could bring higher ORR of PVTT and better survival benefits. This combination therapy was also associated with a significantly increased risk of adverse events. However, they were mostly mild to moderate and successfully treated with conservative treatment.

GOLPH3 overexpression correlates with poor response to neoadjuvant therapy and prognosis in locally advanced rectal cancer.

Neoadjuvant chemoradiotherapy (nCRT) combined with surgery is a standard therapy for locally advanced rectal cancer (LARC). The aim of this study was to assess the expression of GOLPH3 (Golgi phosphoprotein 3), a newly found oncogene, in LARC as well as its relationship with nCRT sensitivity and prognosis. We retrospectively analyzed 148 LARC cases receiving nCRT and total mesorectal excision (TME). Immunohistochemistry was used to assess GOLPH3 and mTOR (mammalian target of rapamycin) in tumor tissues. Then, the associations of GOLPH3 with pathological characteristics and prognosis of rectal cancer were assessed. The 148 cases included 77 with high GOLPH3 expression (52.03%), which was associated with tumor invasive depth and lymphatic metastasis. Cases with high GOLPH3 expression had 2.58 and 2.71 fold higher local relapse and distant metastasis rates compared with the low expression group. Correlation analyses showed that GOLPH3 was an independent indicator for judging tumor down-staging and postoperative TRG (tumor regression grade), indicating it could predict nCRT sensitivity. In addition, GOLPH3 expression was associated with mTOR levels. Multiple-factor analysis indicated that GOLPH3 was an independent prognosis indicator for 5 year-DFS (disease free survival) and OS (overall survival) in LARC. These results reveal that GOLPH3 is an independent predictive factor for nCRT sensitivity and prognosis in LARC, with a mechanism related to mTOR.

Superiority of helical tomotherapy on liver sparing and dose escalation in hepatocellular carcinoma: a comparison study of three-dimensional conformal radiotherapy and intensity-modulated radiotherapy.

BACKGROUND AND PURPOSE: To compare the difference of liver sparing and dose escalation between three-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), and helical tomotherapy (HT) for hepatocellular carcinoma. PATIENTS AND METHODS: Sixteen unresectable HCC patients were enrolled in this study. First, some evaluation factors of 3DCRT, IMRT, and HT plans were calculated with prescription dose at 50 Gy/25 fractions. Then, the doses were increased using HT or IMRT independently until either the plans reached 70 Gy or any normal tissue reached the dose limit according to quantitative analysis of normal tissue effects in the clinic criteria. RESULTS: The conformal index of 3DCRT was lower than that of IMRT (P<0.001) or HT (P<0.001), and the homogeneity index of 3DCRT was higher than that of IMRT (P<0.001) or HT (P<0.001). HT took the longest treatment time (P<0.001). For V 50% (fraction of normal liver treated to at least 50% of the isocenter dose) of the normal liver, there was a significant difference: 3DCRT > IMRT > HT (P<0.001). HT had a lower D mean (mean dose) and V 20 (V n, the percentage of organ volume receiving ≥n Gy) of liver compared with 3DCRT (P=0.005 and P=0.005, respectively) or IMRT (P=0.508 and P=0.007, respectively). D mean of nontarget normal liver and V 30 of liver were higher for 3DCRT than IMRT (P=0.005 and P=0.005, respectively) or HT (P=0.005 and P=0.005, respectively). Seven patients in IMRT (43.75%) and nine patients in HT (56.25%) reached the isodose 70 Gy, meeting the dose limit of the organs at risk. CONCLUSION: HT may provide significantly better liver sparing and allow more patients to achieve higher prescription dose in HCC radiotherapy.

The prognostic role of TCF4 expression in locally advanced rectal cancer patients treated with neoadjuvant chemoradiotherapy.

BACKGROUND: At present no useful factors to predict the sensitivity to neoadjuvant chemoradiotherapy (nCRT) have been established in patients with locally advanced rectal cancer (LARC). OBJECTIVE: The objective of this study was to explore the prognostic role of T cell factor 4 (TCF4) expression in predicting tumor response to nCRT and tumor outcomes for patients with LARC. METHODS: The study enrolled 96 patients who underwent nCRT followed by total mesorectal excision (TME). The TCF4 expression of all patients' biopsies before nCRT was evaluated by Immunohistochemical staining method. RESULTS: After completion of nCRT, 5 cases (5.2%) achieved clinical complete response (cCR) thus the remaining 91 patients underwent a standardized total mesorectal excision (TME) procedure. There were 44 patients (45.8%) achieved good tumor response (including TRG 3-4 and 5 cCR patients) while poor response (TRG 0-2) was achieved in 52 patients (54.2%). Our results demonstrated that patients with low expression of TCF4 were more sensitive to nCRT than those with high TCF4 expression (P=0.031). Low TCF4 expression before nCRT and good response were significantly associated with improved 5-year disease-free survival and 5-year overall survival (P<0.05). Multivariate analysis confirmed that the pretreatment TCF4 expression was an independent prognostic factor. CONCLUSIONS: Our data revealed that low TCF4 protein expression was a useful predictive factor of good tumor response to nCRT and good outcomes in patients with LARC.

Prophylactic cranial irradiation improved the overall survival of patients with surgically resected small cell lung cancer, but not for stage I disease.

OBJECTIVES: We conducted a retrospective study to evaluate the role of prophylactic cranial irradiation (PCI) on patients with surgically resected small cell lung cancer (SCLC). PATIENTS AND METHODS: Between January 2003 and December 2009, the records of completely resected patients who were diagnosed with SCLC and definitive pTNM stage on the basis of histological proof were reviewed. According to the therapy modality, patients were allocated to PCI group and non-PCI group. RESULTS: A total of 193 patients were finally included, 67 patients in PCI group and 126 in non-PCI group. The OS rates at 2-year and 5-year in PCI group were 92.5%, and 54.9%, respectively, and those of non-PCI were 63.2% and 47.8%, respectively (p=0.005). The BMFS rate at 2-year and 5-year in PCI group was significantly better than those of non-PCI group (96.8%, 76.6% and 79.4%, 75.5%, respectively, p = 0.014). But PCI could not confer survival benefit in the patients with p-stage I. Multivariate analysis revealed that PCI (HR = 2.339; p = 0.001) was an independent prognostic factor of the overall survival. CONCLUSIONS: PCI could improve the OS of patients with surgically resected SCLC, but not for p-stage I patients.

Prognostic value of serum γ-glutamyl transferase in unresectable hepatocellular carcinoma patients treated with transcatheter arterial chemoembolization combined with conformal radiotherapy.

The detection of γ-glutamyl transferase (GGT) has previously been reported to be useful in the diagnosis in hepatocellular carcinoma (HCC). The aim of the present study was to investigate the baseline serum GGT levels in patients with intermediate HCC (Barcelona Clinic Liver Cancer stage B) following treatment with transcatheter arterial chemoembolization (TACE) combined with three-dimensional conformal radiotherapy (3DCRT). A total of 154 intermediate HCC patients with Child-Pugh grade A were retrospectively investigated. Receiver operating characteristic (ROC) analysis was used to determine the optimal threshold for the GGT serum levels, and univariate and multivariate analyses were used to establish the prognostic factors. The median overall survival (OS) time was 24.3 months. The optimal threshold for GGT was 85 U/L (sensitivity, 75.13%; specificity, 69.81%; and area under the ROC curve, 0.763). The one-, three- and five-year OS rates were 79.9, 49.7 and 17.2%, respectively, for patients with low GGT levels (≤85 U/l) and 52.3, 22.1 and 8.5%, respectively, for patients with high GGT levels (>85 U/l) (P=0.007). The results indicated that the serum GGT level was an independent prognostic factor (hazard ratio=2.32; P=0.007) for OS. Furthermore, in subgroups stratified according to serum α-fetoprotein, gross tumor volume and radiation dose, serum GGT was also found to correlate with OS (P<0.05). Therefore, the baseline GGT level may be a significant prognostic factor for intermediate HCC patients with Child-Pugh grade A following TACE combined with 3DCRT.

The prognostic role of EZH2 expression in rectal cancer patients treated with neoadjuvant chemoradiotherapy.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) combined with surgery has been implemented as a standard treatment strategy in locally advanced rectal cancer (LARC). However, there is a wide spectrum of response to nCRT. The aim of this study was to determine whether enhancer of zeste homologue 2 (EZH2 ) expression could predict response to nCRT and outcomes for patients in LARC. METHOD: The study examined the EZH2 expression in 112 biopsies by immohistochemistry. The associations between EZH2 and clinical characters were analyzed. RESULTS: EZH2 expression in biopsy tissue was significantly related to increased tumor cell proliferation, as assessed by Ki-67 expression with a cutoff value of 37% (p <0.001). High EZH2 expression was correlated closely with low differentiation (p = 0.029), high CEA level (p = 0.041), T4 status (p = 0.011) and node metastasis (p =0.045). By univariate and multivariate analysis, we observed low EZH2 expression could reliably and independently predict the good response to nCRT ( p = 0.026 and p = 0.023) and down-staging ( p = 0.021 and p = 0.027). In univariate analysis, high EZH2 expression was significantly associated with poor 5-year disease-free survival (p = 0.025) and 5-year overall survival (p = 0.032). In multivariate analysis, EZH2 was a prognostic factor for 5-year DFS (HR = 2.287; 95% CI 1.137-4.602, p = 0.020) but not for 5-year OS (HR = 2.182; 95% CI 0.940-5.364, p = 0.069). CONCLUSION: Our study revealed that low EZH2 expression in biopsy tissue might be a useful predictive factor of good tumor response to nCRT and longer 5-year DFS in patients with LARC. However this is a relatively small retrospective study, to further validate the role of EZH2 in rectal cancer, large consistent cohort studies are needed.

Mutations of KRAS and PIK3CA as independent predictors of distant metastases in colorectal cancer.

The objective was to evaluate DNA mutations of KRAS, BRAF, and PIK3CA and their clinicopathological correlations with colorectal cancer (CRC) and to identify their contribution to distant metastases in CRC. A total of 148 tumor samples were obtained from patients with CRC in the Shandong Tumor Hospital and Institute between January 2008 and December 2009. DNA was extracted for polymerase chain reaction amplification and pyrosequencing to evaluate mutations of KRAS, BRAF, and PIK3CA, and clinicopathological correlations of these mutations with CRC [including age, gender, tumor location, pathological type, tumor-node-metastasis (TNM) classification, and distant metastatic status] were analyzed. KRAS, BRAF, and PIK3CA mutation rates were identified in 46 (31.1 %), 11 (7.4 %), and 14 (9.5 %) of the total 148 CRC tumor samples, respectively. Neither mutation had significant correlation with age, gender, size and location of the tumor, and pathological type. KRAS, BRAF, and PIK3CA mutations were found in 14 (66.7 %), 3 (14.3 %), and 8 (38.1 %) of the 21 distant metastatic colorectal tumor samples, respectively. The relative risks of distant metastasis for KRAS, BRAF, and PIK3CA mutations were 30.4 versus 6.8 % (P = 0.001), 27.3 versus 13.1 % (P = 0.191), and 57.1 versus 9.7 % (P < 0.001) (5-year risks), respectively. Patients with either KRAS or PIK3CA mutations are more susceptible to distant metastasis. Thus, these two mutations might be used as independent predictors of distant metastatic CRC.

Human epidermal growth factor receptor-2 expression in locally advanced rectal cancer: association with response to neoadjuvant therapy and prognosis.

The aim of this study was to determine whether pretreatment status of human epidermal growth factor receptor-2 (HER-2) could predict pathologic response to neoadjuvant chemoradiotherapy (nCRT) and outcomes for patients with locally advanced rectal cancer (LARC). A total of 119 patients diagnosed with LARC received standardized multimodal treatment. Their HER-2 status was determined in pretreatment biopsies by immunohistochemistry (IHC) and FISH. Tumor response was assessed in resected regimens using the tumor regression grade system and TNM staging system. Twenty-two cases in 119 patients assessed as IHC3+ or IHC2+ plus gene-amplified were determined as HER-2 positive. Positive HER-2 status was not associated with any pretreatment clinicopathologic parameters (P > 0.05). HER-2 status could not predict pathologic response to nCRT based on downstaging (P = 0.210) and tumor regression grade (P = 0.085) but it provides us with a trend that HER-2-positive tumors may be resistant to nCRT. Positive HER-2 status was significantly associated with poor 5-year disease-free survival (P = 0.015) and 5-year overall survival (P = 0.026). It can act as a worse prognostic factor for LARC patients.

PDCD4 as a predictor of sensitivity to neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients.

OBJECTIVE: The purpose of this study was to examine the role of programmed cell death 4 (PDCD4) expression in predicting tumor response to neoadjuvant chemoradiotherapy and outcomes for patients with locally advanced rectal cancer. METHODS: Clinicopathological factors and expression of PDCD4 were evaluated in 92 patients with LARC treated with nCRT. After the completion of therapy, 4 cases achieved clinical complete response (cCR), and thus the remaining 88 patients underwent a standardized total mesorectal excision procedure. There were 38 patients (41.3%) with a good response (TRG 3-4) and 54 (58.7%) with a poor one (TRG 0-2). RESULTS: Immunohistochemical staining analyses showed that patients with high expression of PDCD4 were more sensitive to nCRT than those with low PDCD4 expression (P=0.02). High PDCD4 expression before nCRT and good response (TRG3-4) were significantly associated with improved 5-year disease-free survival and 5-year overall survival (P<0.05). Multivariate analysis demonstrated that the pretreatment PDCD4 expression was an independent prognostic factor. CONCLUSION: Our study demonstrated that high expression of PDCD4 protein is a useful predictive factor for good tumor response to nCRT and good outcomes in patients with LARC.

A comparison of liver protection among 3-D conformal radiotherapy, intensity-modulated radiotherapy and RapidArc for hepatocellular carcinoma.

PURPOSE: The analysis was designed to compare dosimetric parameters among 3-D conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT) and RapidArc (RA) to identify which can achieve the lowest risk of radiation-induced liver disease (RILD) for hepatocellular carcinoma (HCC). METHODS: Twenty patients with HCC were enrolled in this study. Dosimetric values for 3DCRT, IMRT, and RA were calculated for total dose of 50 Gy/25 f. The percentage of the normal liver volume receiving >40, >30, >20, >10, and >5 Gy (V(40), V(30), V(20), V(10) and V(5)) were evaluated to determine liver toxicity. V5, V(10), V(20), V(30) and D(mean) of liver were compared as predicting parameters for RILD. Other parameters included the conformal index (CI), homogeneity index (HI), and hot spot (V(110%)) for the planned target volume (PTV) as well as the monitor units (MUs) for plan efficiency, the mean dose (D(mean)) for the organs at risk (OARs) and the maximal dose at 1% volume (D1%) for the spinal cord. RESULTS: The D(mean) of IMRT was higher than 3DCRT (p = 0.045). For V5, there was a significant difference: RA > IMRT >3DCRT (p <0.05). 3DCRT had a lower V(10) and higher V(20), V(30) values for liver than RA (p <0.05). RA and IMRT achieved significantly better CI and lower V(110%) values than 3DCRT (p <0.05). RA had better HI, lower MUs and shorter delivery time than 3DCRT or IMRT (p <0.05). CONCLUSION: For right lobe tumors, RapidArc may have the lowest risk of RILD with the lowest V(20) and V(30) compared with 3DCRT or IMRT. For diameters of tumors >8 cm in our study, the value of Dmean for 3DCRT was lower than IMRT or RapidArc. This may indicate that 3DCRT is more suitable for larger tumors.

NSE can predict the sensitivity to definitive chemoradiotherapy of small cell carcinoma of esophagus.

Patients with esophageal small cell carcinoma undergoing definitive chemoradiotherapy (CRT) seem to have disparity in tumor response. The identification of CRT sensitivity-related tumor markers would be helpful for selecting patients most likely to benefit from CRT. The aim of this study was to examine the predictive value of biological markers in small cell carcinoma of the esophagus (SCEC) patients treated with definitive CRT. Pretreatment serum levels of neurone-specific enolase (NSE), cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), and carcinoembryonic antigen (CEA) were measured by immunoradiometric assays, while the tumor responses were evaluated according to the World Health Organization response criteria. The relationships between pretreatment expression of NSE, CYFRA21-1, CEA, and the tumor response to CRT were analyzed. The effective rates (complete response + partial response) in NSE high and low groups were 10.80 % (9/82) and 37.98 % (31/82), respectively (P = 0.003).The results from statistical analysis indicated that the effectiveness of CRT was significantly associated with the serum levels of NSE before treatment (P = 0.002). The overall survival (OS) of the patients with high NSE levels was worse than that of those with low NSE levels (P = 0.004). In multivariate analysis, low level of NSE was the most significant independent predictor of good OS (P = 0.003). The result showed a promising predictive value of NSE regarding to the sensitivity of tumors to CRT. NSE may be a reliable surrogate marker of CRT efficacy in patients with SCEC.

Circulating lymphocytes as predictors of sensitivity to preoperative chemoradiotherapy in rectal cancer cases.

OBJECTIVE: The objective of this study was to identify clinical predictive factors for tumor response after neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC). METHODS: All factors were evaluated in 88 patients with LARC treated with nCRT. After a long period of 4-8 weeks of chemoradiotherapy, 3 patients achieved clinical complete response (cCR) and thus aggressive surgery was avoided, and the remaining 85 patients underwent a curative-intent operation. The response to nCRT was evaluated by tumor regression grade (TRG) system. RESULTS: There were 32 patients (36.4%) with good tumor regression (TRG 3-4) and 56 (63.6%) with poor tumor regression (TRG 0-2). Lymphocyte counts and ratios were higher in good response cases (P=0.01, 0.03, respectively) while neutrophil ratios and N/L ratios were higher in poor response cases (P=0.04, 0.02, respectively). High lymphocyte ratios before nCRT and good tumor regression (TRG3-4) were significantly associated with improved 5-year disease-free survival (P<0.05). Pretreatment nodal status was also significantly associated with 5-year disease-free survival and 5-year overall survival (P<0.05). Multivariate analysis confirmed that the pretreatment lymphocyte ratio and lymph nodal status were independent prognostic factors. CONCLUSION: Our study suggested that LARC patients with high lymphocyte ratios before nCRT would have good tumor response and high 5-year DFS and OS.