A 3-Year Survival Update from a Phase 2 Study of Paclitaxel Plus Cisplatin and 5-Fuorouracil Induction Chemotherapy for Locally Advanced Borderline-Resectable Esophageal Squamous Cell Carcinoma: The NEOCRTEC-1601 Clinical Trial.

BACKGROUND: This study updated 3-year analyses to further characterize the impact of docetaxel, cisplatin, and fluorouracil (TPF) chemotherapy followed by surgery. METHODS: This study was a single-center phase 2 clinical trial. Patients with a diagnosis of borderline resectable esophageal squamous cell carcinoma (BR-ESCC) because of the primary tumor or bulky lymph node that potentially invaded adjacent organs were eligible. The treatment started with TPF chemotherapy followed by surgery if the cancer was resectable, or by concurrent chemoradiation if it was unresectable. This updated report presents the 3-year overall survival (OS) and progression-free survival (PFS) rates. RESULTS: Surgery was performed for 27 patients (57.4%), and R0 resection was confirmed in 25 patients (53.2%). Pathologic complete response was confirmed in four patients (8.5%). The median follow-up time for the surviving patients was 44.8 months (range, 3.4-74.6 months). The median OS for all the patients was 41.9 months (95% confidence interval [CI], 18.6-65.3 months), with a median PFS of 38.7 months (95% CI, 23.5-53.9 months). The 3-year survival rate for all the patients was 54.4%. The 3-year survival rate for the R0 patients was 65.4%. CONCLUSION: Long-term follow-up evaluation confirmed that TPF followed by surgery is feasible and promising in terms of survival for BR-ESCC patients. Trial Registration ClinicalTrials.gov identifer: NCT02976909.

Pi-Pa-Run-Fei-Tang alleviates lung injury by modulating IL-6/JAK2/STAT3/IL-17 and PI3K/AKT/NF-κB signaling pathway and balancing Th17 and Treg in murine model of OVA-induced asthma.

ETHNOPHARMACOLOGICAL RELEVANCE: Pi-Pa-Run-Fei-Tang (PPRFT) is an empirical TCM prescription for treating asthma. However, the underlying mechanisms of PPRFT in asthma treatment have yet to be elucidated. Recent advances have revealed that some natural components could ameliorate asthma injury by affecting host metabolism. Untargeted metabolomics can be used to better understand the biological mechanisms underlying asthma development and identify early biomarkers that can help advance treatment. AIM OF THE STUDY: The aim of this study was to verification the efficacy of PPRFT in the treatment of asthma and to preliminarily explore its mechanism. MATERIALS AND METHODS: A mouse asthma model was built by OVA induction. Inflammatory cell in BALF was counted. The level of IL-6, IL-1ß, and TNF-α in BALF were measured. The levels of IgE in the serum and EPO, NO, SOD, GSH-Px, and MDA in the lung tissue were measured. Furthermore, pathological damage to the lung tissues was detected to evaluate the protective effects of PPRFT. The serum metabolomic profiles of PPRFT in asthmatic mice were determined by GC-MS. The regulatory effects on mechanism pathways of PPRFT in asthmatic mice were explored via immunohistochemical staining and western blotting analysis. RESULTS: PPRFT displayed lung-protective effects through decreasing oxidative stress, airway inflammation, and lung tissue damage in OVA-induced mice, which was demonstrated by decreasing inflammatory cell levels, IL-6, IL-1ß, and TNF-α levels in BALF, and IgE levels in serum, decreasing EPO, NO, and MDA levels in lung tissue, elevating SOD and GSH-Px levels in lung tissue and lung histopathological changes. In addition, PPRFT could regulate the imbalance in Th17/Treg cell ratios, suppress RORγt, and increase the expression of IL-10 and Foxp3 in the lung. Moreover, PPRFT treatment led to decreased expression of IL-6, p-JAK2/Jak2, p-STAT3/STAT3, IL-17, NF-κB, p-AKT/AKT, and p-PI3K/PI3K. Serum metabolomics analysis revealed that 35 metabolites were significantly different among different groups. Pathway enrichment analysis indicated that 31 pathways were involved. Moreover, correlation analysis and metabolic pathway analysis identified three key metabolic pathways: galactose metabolism; tricarboxylic acid cycle; and glycine, serine, and threonine metabolism. CONCLUSION: This research indicated that PPRFT treatment not only attenuates the clinical symptoms of asthma but is also involved in regulating serum metabolism. The anti-asthmatic activity of PPRFT may be associated with the regulatory effects of IL-6/JAK2/STAT3/IL-17 and PI3K/AKT/NF-κB mechanistic pathways.

Sacubitril/valsartan reduces susceptibility to atrial fibrillation by improving atrial remodeling in spontaneously hypertensive rats.

AIM: Sacubitril/valsartan (Sac/Val, LCZ696), the world's first angiotensin receptor-neprilysin inhibitor (ARNi), has been widely used in the treatment of heart failure. However, the use of Sac/Val in the treatment of atrial fibrillation (AF), especially AF with hypertension, has been less reported. We investigated the effect of Sac/Val on atrial remodeling and hypertension-related AF. METHODS: The AF induction rate and electrophysiological characteristics of spontaneously hypertensive rats (SHRs) treated with Sac/Val or Val were detected by rapid atrial pacing and electrical mapping/optical mapping. The whole-cell patch-clamp and Western blot were used to observe electrical/structural remodeling of atrial myocytes/tissue of rats and atrium-derived HL-1 cells cultured under 40 mmHg in vitro. RESULTS: Sac/Val was superior to Val in reducing blood pressure, myocardial hypertrophy and susceptibility of AF in SHRs. The shorten action potentials duration (APD), decreased L type calcium channel current (ICa,L) and Cav1.2, increased ultrarapid delayed rectified potassium current (Ikur) and Kv1.5 in atrial myocytes/tissue of SHRs could be better improved by Sac/Val, as well as the levels of atrial fibrosis. While the protein expression of angiotensin-converting enzyme-1 (ACE-1), angiotensin, angiotensin II type I AT1 receptor (AT1R) and neprilysin (NEP) were increased, which could be more effective ameliorated by Sac/Val than Val. Furthermore, Val + Sacubitrilat (LBQ657) (an active NEP inhibitor) was also superior to LBQ657 or Val in improving the electrical and structural remodeling of HL-1 cells through inhibiting NEP. CONCLUSION: Sac/Val can improve atrial structural and electrical remodeling induced by hypertension and reduce the AF susceptibility by inhibiting RAS and NEP. The above effects of Sac/Val were superior to Val alone.

Acetyltransferase p300 regulates atrial fibroblast senescence and age-related atrial fibrosis through p53/Smad3 axis.

Atrial fibrosis induced by aging is one of the main causes of atrial fibrillation (AF), but the potential molecular mechanism is not clear. Acetyltransferase p300 participates in the cellular senescence and fibrosis, which might be involved in the age-related atrial fibrosis. Four microarray datasets generated from atrial tissue of AF patients and sinus rhythm (SR) controls were analyzed to find the possible relationship of p300 (EP300) with senescence and fibrosis. And then, biochemical assays and in vivo electrophysiological examination were performed on older AF patients, aging mice, and senescent atrial fibroblasts. The results showed that (1) the left atrial tissues of older AF patients, aging mouse, and senescence human atrial fibroblasts had more severe atrial fibrosis and higher protein expression levels of p300, p53/acetylated p53 (ac-p53)/p21, Smad3/p-Smads, and fibrosis-related factors. (2) p300 inhibitor curcumin and p300 knockdown treated aging mouse and senescence human atrial fibroblasts reduced the senescence ratio of atrial fibroblasts, ameliorated the atrial fibrosis, and decreased the AF inducibility. In contrast, over-expression of p300 can lead to the senescence of atrial fibroblasts and atrial fibrosis. (3) p53 knockdown decreased the expression of aging and fibrosis-related proteins. (4) Co-immunoprecipitation and immunofluorescence showed that p53 forms a complex with smad3 and directly regulates the expression of smad3 in atrial fibroblasts. Our findings suggest that the mechanism of atrial fibrosis induced by aging is, at least, partially dependent on the regulation of p300, which provides new sights into the AF treatment, especially for the elderly.

Comparative Outcomes of Induction Chemotherapy Followed By Definitive Chemoradiotherapy versus Chemoradiotherapy Alone In Esophageal Squamous Cell Carcinoma.

Purpose: To compare the clinical outcomes of induction chemotherapy (IC) followed by chemoradiotherapy (CRT) versus chemoradiotherapy alone in patients with locally advanced esophageal squamous cell carcinoma (ESCC). Patients and methods: Between 2002 and 2015, 267 ESCC patients who received definitive CRT with docetaxel and cisplatin were enrolled in this study. Through a matched case-control study, 85 patients receiving IC before CRT were matched 1:1 to patients who received CRT alone, according to age, gender, performance status, tumor location, tumor length, and pretreatment TNM stage. Results: The median overall survival (OS) in the IC group was significantly better than that in the CRT group (26.0 vs. 22.0 months), with 3-year OS rates of 30.6% vs. 25.9%, respectively (P = 0.028). However, IC plus CRT was associated with a significantly higher rate of grade 3-4 leukopenia than CRT alone (P = 0.048). The overall clinical response rate was 50.6% after IC in the IC group. The IC responder group showed significantly more favorable OS (P=0.002) and progression-free survival (P=0.001) compared with the IC non-responder group and the CRT group. Multivariate analysis revealed that age ≥ 60 (P = 0.003) and the addition of IC (P=0.016) were independent prognostic factors that affected survival positively. Conclusions: The addition of IC before CRT yielded satisfactory clinical outcomes and manageable toxicities. The combination of IC with CRT might be a promising treatment strategy to further improve systemic control and survival in ESCC. Prospective randomized trials are required to confirm the role of IC.

PD-L1 Expression Is Associated with FOXP3+ Regulatory T-Cell Infiltration of Soft Tissue Sarcoma and Poor Patient Prognosis.

Background: Programmed death ligand-1(PD-L1) functions as a negative mediator of immune response through different pathways in anti-tumor immunity. Recent studies have reported that PD-L1 plays a pivotal role in the function of regulatory T-cells (Tregs). Although increases in FOXP3+ Tregs infiltration and PD-L1 expression have been revealed in several cancers, their correlation with soft tissue sarcoma remains unknown. Methods: We included 163 cases of soft tissue sarcoma who were diagnosed and underwent extensive and radical resection at the Sun Yat-sen University Cancer Center, Guangzhou, China, from 2000-2010. PD-L1 and FOXP3 expression was evaluated by immunohistochemistry. Correlation between their expressions and associations with clinicopathological features were studied. Results: Among 163 STS samples, 19 (11.7%) exhibited PD-L1 positivity, and 41 (25.2%) cases expressed high FOXP3+ Treg infiltration. Significant correlation between PD-L1 expression and FOXP3+Treg infiltration in STS was identified (r=0.450, p<0.001). In univariate analysis, PD-L1 expression was significantly associated with high tumor grade and the age of patients, while the presence of FOXP3+ in tumor infiltrating Tregs was significantly associated with the age of patients, high tumor stage, higher tumor grade and tumor depth. Multivariate analysis revealed PD-L1 and FOXP3 as independent prognostic indicators significantly associated with OS and DFS. Conclusions: Our study revealed that PD-L1 and FOXP3+Tregs may work synergistically in promoting immune evasion of the tumors in soft tissue sarcoma. A combined strategy to block PD-L1/PD-1 with simultaneous depletion of Tregs may show promise in enhancing the therapeutic efficacy of these patients.

Evaluation of interactions between RAW264.7 macrophages and small molecules by capillary electrophoresis.

In this study, the affinity interactions between RAW 264.7 macrophages and three small molecules including naringin, oleuropein and paeoniflorin were evaluated by affinity capillary electrophoresis (ACE), partial filling affinity capillary electrophoresis (PFACE) and frontal analysis capillary electrophoresis (FACE), respectively. The result indicated that ACE (varying concentrations of cell suspension were filled in the capillary as receptor) may not be suitable for the evaluation of interactions between cell and small molecules due to the high viscosity of cell suspension; PFACE can qualitatively evaluate the interaction, but the difference in viscosity between RAW264.7 suspension and buffer effects on the liner relationship between filling length and injection time, which makes the calculation of binding constant difficult. Furthermore, based on the PFACE results, naringin showed stronger interaction with macrophages than the other two molecules; taking advantage of the aggregation phenomenon of cell induced by electric field, FACE was successfully used to determine the stoichiometry (n = 5×109 ) and binding constant (Kb = 1×104 L/mol) of the interaction between RAW264.7 and naringin.

Concurrent cisplatin and 5-fluorouracil versus concurrent cisplatin and docetaxel with radiotherapy for esophageal squamous cell carcinoma: a propensity score-matched analysis.

The optimal concurrent chemotherapy regimen with radiotherapy for esophageal cancer is unknown. Here, we compared the survival outcomes and toxicity of definitive chemoradiotherapy with either cisplatin/5-fluorouracil (PF) or docetaxel/cisplatin (DP) in patients with unresectable esophageal squamous cell carcinoma (ESCC). In this study, we identified 317 patients with ESCC who received PF or DP concurrently with definitive radiotherapy. PF group patients received two cycles of cisplatin (60 mg/m2) and 5-fluorouracil (300 mg/m2) at 4-week intervals during radiotherapy. DP group patients received a concurrent three-weekly schedule of docetaxel (60 mg/m2) and cisplatin (80 mg/m2) or cisplatin (25 mg/m2) and docetaxel (25 mg/m2) weekly. The overall survival (OS) and progression-free survival (PFS) were compared using propensity score (-adjusted, -weighted, -stratified, and -matched) analyses. A sensitivity analysis was performed to examine the impact of unmeasured confounders. Inverse probability of treatment weighting for propensity score demonstrated an improvement in OS and PFS with DP group in comparison with PF group (hazard ratio, 0.700; 95% CI, 0.577-0.851) and similar results were achieved with propensity score matching and stratification. Grade 3-4 esophagitis was more common (16/102 vs. 4/102) and grade 3-4 thrombopenia and skin toxicity were less common (3/102 vs. 10/102; 7/102 vs. 19/102; respectively) in the PF group than the DP group. In conclusion, concurrent chemoradiotherapy with the DP regimen resulted in better OS and PFS compared to concurrent PF regimen with tolerable toxicities in ESCC patients. Prospective randomized trials are required to confirm the efficacy of the DP regimen.

Insulin-like growth factor binding protein-3 is a new predictor of radiosensitivity on esophageal squamous cell carcinoma.

Insulin-like growth factor binding protein-3 (IGFBP-3) plays an essential role in radiosensitivity of esophageal squamous cell carcinoma (ESCC). However, the underlying mechanism is not completely understood. Here, we observed that IGFBP-3 had favorable impact on the tumorigenicity of ESCC cells in nude mice by using an in vivo imaging system (IVIS) to monitor tumor growth treated with ionizing radiation (IR). Downregulation of IGFBP-3 expression enhanced tumor growth, inhibited anti-proliferative and apoptotic activity and result in IR resistance in vivo. Cell cycle antibody array suggested that silencing IGFBP-3 promoted transition from G0/G1 to S phase, perhaps though influencing Smad3 dephosphorylation and retinoblastoma protein (Rb) phosphorylation. Downregulation of P21 and P27, and upregulation of p-P27 (phospho-Thr187), cyclin-dependent kinase 2 (CDK2), and cyclin E1 might contribute to the G0/G1 to S phase transition promoted by IGFBP-3. Our results suggest that Smad3-P27/P21-cyclin E1/CDK2-phosphorylated retinoblastoma protein pathways might be involved in this IGFBP-3 mediated radiosensitivity transition in ESCC.

Association of insulin-like growth factor-binding protein-3 with radiotherapy response and prognosis of esophageal squamous cell carcinoma.

BACKGROUND: Insulin-like growth factor-binding protein-3 (IGFBP-3) is suggested to predict the radiosensitivity and/or prognosis of patients with esophageal squamous cell carcinoma (ESCC). The present study was designed to investigate the clinical and prognostic effects of IGFBP-3 on ESCC. METHODS: IGFBP-3 was detected by immunohistochemistry in paraffin-embedded tissues from 70 ESCC patients treated with radiotherapy alone and further examined by western blotting analysis in 10 pairs of fresh ESCC tissues and adjacent non-malignant esophageal specimens. Receiver operating characteristic (ROC) analysis was used to determine cut-off scores for tumor positivity and to evaluate patient survival status. The χ(2) test was performed to analyze the association of IGFBP-3 expression with clinical characteristics and radiotherapy response. Associations between prognostic outcomes and IGFBP-3 expression were investigated using Kaplan-Meier analysis and the Cox proportional hazards model. RESULTS: The threshold for IGFBP-3 positivity was set to greater than 65% [area under the ROC curve (AUC)=0.690, P<0.019]. Of the 70 ESCC patient tissues tested, 32 (45.7%) were defined as having high IGFBP-3 expression. The levels of IGFBP-3 protein expression were decreased in 70.0% (7 of 10) of ESCC tissues compared with adjacent non-malignant esophageal tissue. In addition, IGFBP-3 expression was associated with pathologic classification (P<0.05 for T, N, and M categories and clinical stage). Patients with elevated protein level of IGFBP-3 in the tumor had an improved radiotherapy response and prolonged overall survival (P<0.001). CONCLUSIONS: High level of IGFBP-3 expression in ESCC associates with early clinical stages and are predictive for favorable survival of the patients treated with radiotherapy.

Polymorphisms of insulin-like growth factor binding protein-3 as a predictor for risk and patient survival in esophageal squamous cell carcinoma.

BACKGROUND AND PURPOSE: Genetic single nucleotide polymorphisms (SNP) play a critical role in the development of esophageal squamous cell carcinoma (ESCC). The aim of this study is to investigate the associations between insulin-like growth factor binding protein-3 (IGFBP-3) gene polymorphisms and ESCC patients risk and survival after definitive chemoradiotherapy (CRT). MATERIALS AND METHODS: We undertook a case-control study to analyze two IGFBP-3 polymorphisms (rs2854744 A>C and rs2854746 G>C) in an Han Chinese population, by extraction of genomic DNA from the peripheral blood of 110 ESCC patients treated with CRT and 128 control participants, and performed IGFBP-3 genotyping using DNA sequencing. RESULTS: The obtained results indicated that overall, no statistically significant association was observed in rs2854746 G>C. However, rs2854744 A>C genotype was at increased risk of ESCCs (P=0.032; odds ratio (OR)=1.201, CI 95%:1.014-1.423). Moreover, rs2854744 A>C genotype ESCCs were more significantly common in patients with tumor size of >6cm than A allele ESCC and in cases of lower T stage. Furthermore, ESCC patients with rs2854744CC genotype have the poorer CRT response and shorter survival time than GG+GC genotype ESCC. CONCLUSIONS: In conclusion, polymorphism in IGFBP-3 rs2854744 A>C might be a potential predictor of ESCC risk and patient survival. Nevertheless, further investigation with a larger sample size is needed to support our results.

Concurrent radiotherapy and weekly chemotherapy of 5-fluorouracil and platinum agents for postoperative locoregional recurrence of oesophageal squamous cell carcinoma.

The most optimal management for postoperative locoregional recurrence of oesophageal squamous cell carcinoma is still controversial. Several studies have reported the feasibility and efficacy of concurrent chemoradiotherapy (CCRT), mostly with three-weekly or four-weekly schedule of chemotherapy. However, treatment compliance was not quite satisfactory, probably due to treatment-related toxicities. Since CCRT with weekly chemotherapy regimens have demonstrated a favorable toxicity profile as well as promising survival in certain types of cancer, we aimed to evaluate the efficacy and toxicity of radiotherapy concurrently with weekly chemotherapy with 5-fluorouracil (5-FU) and platinum agents for patients with postoperative locoregional recurrence of oesophageal squamous cell carcinoma in our center. Twenty-seven consecutive patients who were diagnosed with postoperative locoregional recurrence of oesophageal squamous cell carcinoma and received CCRT with weekly chemotherapy of 5-FU and platinum agents were retrospectively analyzed. Our data showed that the present protocol of radiotherapy combined concurrently with weekly chemotherapy of 5-FU and platinum agents was a safe and effective salvage treatment for postoperative locoregional recurrence of oesophageal squamous cell carcinoma.

Efficacy and prognostic analysis of chemoradiotherapy in patients with thoracic esophageal squamous carcinoma with cervical lymph nodal metastasis alone.

BACKGROUND: The prognostic factors of thoracic esophageal squamous carcinoma with cervical lymph nodal metastasis (CLNM) have not been specifically investigated. This study was performed to analyze the efficacy and prognostic factors of chemoradiotherapy for thoracic esophageal carcinoma with CLNM alone. METHODS: From 2002 to 2011, 139 patients with inoperable esophageal cancer who underwent chemoradiotherapy at the Sun Yat-Sen University were retrospectively analyzed. Median radiation doses were 60 Gy (range: 50-68 Gy). Univariate and multivariate analyses were performed to compare overall survival (OS) and progression-free survival (PFS). RESULTS: The 1- and 3-year OS rates were 68.2% and 27.9%, respectively. The 1- and 3-year PFS rates were 51.9% and 20.1%, respectively. The multivariate analysis demonstrated that response to treatment, T stage, pathological grade, and laterality of cervical lymph nodal metastases were independent prognostic factors for thoracic esophageal carcinoma with CLNM. CONCLUSIONS: Concurrent chemoradiotherapy is an important and hopeful treatment option for patients with esophageal cancer with CLNM alone. Our study has revealed that response to treatment, T stage, pathological grade and laterality of cervical lymph nodal metastases are significant prognostic factors for long-term survival.

The modified glasgow prognostic score is an independent prognostic factor in patients with inoperable thoracic esophageal squamous cell carcinoma undergoing chemoradiotherapy.

BACKGROUND AND PURPOSE: There is increasing evidence that the presence of an inflammation-based prognostic score (modified Glasgow prognostic score, mGPS) is associated with survival in patients with advanced cancer. This study aimed to assess whether the mGPS has prognostic value in patients with thoracic esophageal squamous cell carcinoma undergoing chemoradiotherapy. MATERIALS AND METHODS: A total of 212 patients undergoing chemoradiotherapy for newly-diagnosed esophageal squamous cell carcinoma between October, 2006 and December, 2011 were retrospectively analyzed. Serum C-reactive protein (CRP) and albumin were measured before initiation of treatment. The relationships between the mGPS and other relevant variables including white blood cell count, neutrophilic granulocyte count, platelet count, hemoglobin, bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) were analyzed. Overall survival (OS) and progression-free survival (PFS) were calculated. Significant prognostic factors were identified using univariate and multivariate analyses. RESULTS: Three-year OS for all patients was 24.6%; 3-year PFS was 21.3%. Patients with a mGPS of 0, 1 and 2 were 90, 78, 44, respectively. Higher mGPS was related to higher white blood cell, neutrophilic granulocyte and platelet counts, and lower total bilirubin. T stage, M stage and mGPS were independent prognostic indicators for OS; T stage, M stage, mGPS and platelet count were independent prognostic indicators for PFS. CONCLUSIONS: Pretreatment mGPS is an easily measurable significant prognostic factor and can be used in combination with conventional TNM staging to predict survival in patients with squamous cell carcinoma undergoing chemoradiotherapy.

Is there a benefit in receiving concurrent chemoradiotherapy for elderly patients with inoperable thoracic esophageal squamous cell carcinoma?

BACKGROUND AND PURPOSE: The benefit of concurrent chemoradiotherapy (CCRT) in elderly patients with inoperable esophageal squamous cell carcinoma (SCC) is controversial. This study aimed to assess the efficiency and safety of CCRT in elderly thoracic esophageal cancer patients. METHODS AND MATERIALS: Between January 2002 and December 2011, 128 patients aged 65 years or older treated with CCRT or radiotherapy (RT) alone for inoperable thoracic esophageal SCC were analyzed retrospectively (RT alone, n = 55; CCRT, n = 73). RESULTS: No treatment-related deaths occurred and no patients experienced any acute grade 4 non-hematologic toxicities. Patients treated with CCRT developed more severe acute toxicities than patients who received RT alone. The 3-year overall survival (OS) rate was 36.1% for CCRT compared with 28.5% following RT alone (p = 0.008). Multivariate analysis identified T stage and treatment modality as independent prognostic factors for survival. Further analysis revealed that survival was significantly better in the CCRT group than in the RT alone group for patients ≤ 72 years. Nevertheless, the CCRT group had a similar OS to the RT group for patients > 72 years. CONCLUSION: Our results suggest that elderly patients with inoperable thoracic esophageal SCC could benefit from CCRT, without major toxicities. However, for patients older than 72 years, CCRT is not superior to RT alone in terms of survival benefit.

Unilateral cervical nodal metastasis is an independent prognostic factor for esophageal squamous cell carcinoma patients undergoing chemoradiotherapy: a retrospective study.

PURPOSE: To determine the prognostic significance of unilateral cervical lymph nodal metastasis (CLNM) in patients with inoperable thoracic esophageal squamous cell carcinoma (SCC) and to identify significant prognostic factors in these patients. PATIENTS AND METHODS: This retrospective study involved 395 patients with inoperable esophageal SCC treated with concurrent chemoradiotherapy. The patients were classified into three groups according to their cervical lymph node status: group A, no evidence of CLNM; group B, unilateral CLNM; group C, other distant metastases. Overall survival (OS) and progression-free survival (PFS) were calculated. Significant prognostic factors were identified using univariate and multivariate analyses. RESULTS: The 3-year OS rates in groups A, B and C were 46.7%, 33.5% and 8.3%, respectively (p<0.001, log-rank test). The corresponding PFS rates were 40.7%, 26.4% and 4.7% (p<0.001, log-rank test). Group B had a similar prognosis to that of group A and better 3-year OS (p = 0.009) and PFS (p = 0.006) rates than those of group C. Multivariate analysis demonstrated that T stage, chemotherapy regimen and cervical lymph node involvement were independent prognostic factors affecting OS and PFS. CONCLUSIONS: Compared to other distant metastases, unilateral CLNM is associated with longer OS in esophageal SCC and should be regarded as a regional disease. Sex, T stage, concurrent chemotherapy modality and cervical lymph node involvement are independent predictors of survival in esophageal SCC.

Stereotactic ablative radiation therapy for centrally located early stage or isolated parenchymal recurrences of non-small cell lung cancer: how to fly in a "no fly zone".

PURPOSE: We extended our previous experience with stereotactic ablative radiation therapy (SABR; 50 Gy in 4 fractions) for centrally located non-small cell lung cancer (NSCLC); explored the use of 70 Gy in 10 fractions for cases in which dose-volume constraints could not be met with the previous regimen; and suggested modified dose-volume constraints. METHODS AND MATERIALS: Four-dimensional computed tomography (4DCT)-based volumetric image-guided SABR was used for 100 patients with biopsy-proven, central T1-T2N0M0 (n=81) or isolated parenchymal recurrence of NSCLC (n=19). All disease was staged with positron emission tomography/CT; all tumors were within 2 cm of the bronchial tree, trachea, major vessels, esophagus, heart, pericardium, brachial plexus, or vertebral body. Endpoints were toxicity, overall survival (OS), local and regional control, and distant metastasis. RESULTS: At a median follow-up time of 30.6 months, median OS time was 55.6 months, and the 3-year OS rate was 70.5%. Three-year cumulative actuarial local, regional, and distant control rates were 96.5%, 87.9%, and 77.2%, respectively. The most common toxicities were chest-wall pain (18% grade 1, 13% grade 2) and radiation pneumonitis (11% grade 2 and 1% grade 3). No patient experienced grade 4 or 5 toxicity. Among the 82 patients receiving 50 Gy in 4 fractions, multivariate analyses showed mean total lung dose >6 Gy, V20 >12%, or ipsilateral lung V30 >15% to independently predict radiation pneumonitis; and 3 of 9 patients with brachial plexus Dmax >35 Gy experienced brachial neuropathy versus none of 73 patients with brachial Dmax <35 Gy (P=.001). Other toxicities were analyzed and new dose-volume constraints are proposed. CONCLUSIONS: SABR for centrally located lesions produces clinical outcomes similar to those for peripheral lesions when normal tissue constraints are respected.

Effectiveness of stereotactic body radiotherapy for hepatocellular carcinoma with portal vein and/or inferior vena cava tumor thrombosis.

BACKGROUND: To report the feasibility, efficacy, and toxicity of stereotactic body radiotherapy (SBRT) for the treatment of portal vein tumor thrombosis (PVTT) and/or inferior vena cava tumor thrombosis (IVCTT) in patients with advanced hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Forty-one patients treated with SBRT using volumetric modulated arc therapy (VMAT) for HCC with PVTT/IVCTT between July 2010 and May 2012 were analyzed. Of these, 33 had PVTT and 8 had IVCTT. SBRT was designed to target the tumor thrombosis and deliver a median total dose of 36 Gy (range, 30-48 Gy) in six fractions during two weeks. RESULTS: The median follow-up was 10.0 months. At the time of analysis, 15 (36.6%) achieved complete response, 16 (39.0%) achieved partial response, 7 (17.1%) patients were stable, and three (7.3%) patients showed progressive disease. No treatment-related Grade 4/5 toxicity was seen within three months after SBRT. One patient had Grade 3 elevation of bilirubin. The one-year overall survival rate was 50.3%, with a median survival of 13.0 months. The only independent predictive factor associated with better survival was response to radiotherapy. CONCLUSIONS: VMAT-based SBRT is a safe and effective treatment option for PVTT/IVCTT in HCC. Prospective randomized controlled trials are warranted to validate the role of SBRT in these patients.

Assessing the role of volumetric-modulated arc therapy in hepatocellular carcinoma.

The role of volumetric-modulated arc therapy (VMAT) in hepatocellular carcinoma (HCC) remains controversial. The purpose of this study was to determine the potential clinical role of VMAT compared with three-dimensional conformal radiotherapy (3D CRT) for liver irradiation. Four-dimensional CT scans of 24patients with unresectable HCC were included and divided into two groups: (1) adjacent group (n = 11), with planning target volumes overlapping or within 1 cm adjacent to the alimentary tract; (2) nonadjacent group (n = 13), in which the normal liver itself was the dose-limiting structure. Target coverage, organs-at-risk (OARs) doses, delivery parameters, and treatment accuracy were evaluated. Superior target coverage, conformity, and homogeneity were achieved with VMAT compared with 3D CRT. In the adjacent group, VMAT provided superior sparing of serial functioning OARs including the stomach, small intestine, and spinal cord. In the nonadjacent group, VMAT provided inferior sparing of most OARs including the liver, stomach, and small intestine. For the whole group, the effective treatment time was 2.1 ± 0.3 min for 3D CRT and 3.1 ± 0.2 min for VMAT. For liver lesions adjacent to the alimentary tract, this study indicates that VMAT should be selected due to the plan quality, delivery efficiency, and superior sparing of stomach and small intestine. However, for liver lesions away from the alimentary tract, VMAT is not superior to 3D CRT for normal tissue protection.

Risk assessment of mouse gastric tissue cancer induced by dichlorvos and dimethoate.

Cancer hazards from pesticide residues in food have been much discussed in the past decade. In this study, we showed that dichlorvos and dimethoate affect hemoglobin content and hematocrit value, but had no effect on red blood cell counts and total plasma protein in mice. A 40-mg/kg/day dose of dichlorvos upregulated the expression of p16, Bcl-2 and c-myc genes in mouse gastric tissue. By contrast, expression of the p16, Bcl-2 and c-myc genes induced by low doses (5, 10 and 20 mg/kg/day) of dichlorvos demonstrated no change in the control check group (CK; 200 µl sterile saline perfused group; 0 mg/kg/day). Different doses of dimethoate all upregulated the expression of p16, Bcl-2 and c-myc genes in mouse gastric tissue. The results further demonstrated that mouse gastric tissue, exposed in the long-term to low doses of dichlorvos and dimethoate, has the potential to become cancerous.