Randomized Trial of First-Line Tyrosine Kinase Inhibitor With or Without Radiotherapy for Synchronous Oligometastatic EGFR-Mutated Non-Small Cell Lung Cancer.

BACKGROUND: Adding radiotherapy (RT) to systemic therapy improves progression-free survival (PFS) and overall survival (OS) in oligometastatic non-small cell lung cancer (NSCLC). Whether these findings translate to epidermal growth factor receptor (EGFR)-mutated NSCLC remains unknown. The SINDAS trial (NCT02893332) evaluated first-line tyrosine kinase inhibitor (TKI) therapy for EGFR-mutated synchronous oligometastatic NSCLC and randomized to upfront RT vs no RT; we now report the prespecified interim analysis at 68% accrual. METHODS: Inclusion criteria were biopsy-proven EGFR-mutated adenocarcinoma (per amplification refractory mutation system or next generation sequencing), with synchronous (newly diagnosed, treatment naïve) oligometastatic (≤5 metastases; ≤2 lesions in any one organ) NSCLC without brain metastases. All patients received a first-generation TKI (gefitinib, erlotinib, or icotinib), and randomization was between no RT vs RT (25-40 Gy in 5 fractions depending on tumor size and location) to all metastases and the primary tumor/involved regional lymphatics. The primary endpoint (intention to treat) was PFS. Secondary endpoints included OS and toxicities. All statistical tests were 2-sided. RESULTS: A total of 133 patients (n = 65 TKI only, n = 68 TKI with RT) were enrolled (2016-2019). The median follow-up was 23.6 months. The respective median PFS was 12.5 months vs 20.2 months (P < .001), and the median OS was 17.4 months vs 25.5 months (P < .001) for TKI only vs TKI with RT. Treatment yielded no grade 5 events and a 6% rate of symptomatic grade 3-4 pneumonitis in the TKI with RT arm. Based on the efficacy results of this prespecified interim analysis, the ethics committee recommended premature cessation of this trial. CONCLUSIONS: As compared with a first-line TKI alone, addition of upfront local therapy using RT statistically significantly improved PFS and OS for EGFR-mutated NSCLC.

LncRNA PVT1 facilitates DLBCL development via miR-34b-5p/Foxp1 pathway.

Diffuse large B-cell lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkin lymphoma and is a very aggressive malignancy with tumor growing rapidly in organs like lymph nodes. The pathogenesis of DLBCL is not clear and the prognosis of DLBCL requires improvement. Here, we investigated the mechanisms of DLBCL, with the focus on lncRNA PVT1/miR-34b-5p/Foxp1 axis. Human DLBCL tissues from diagnosed DLBCL patients and four human DLBCL cell lines, one normal human B lymphoblastoid cell line were used. qRT-PCR and western blotting were employed to measure expression levels of lncRNA PVT1, Foxp1, miR-34b-5p, ß-catenin, and proliferation-related proteins. MTT assay and colony formation assay were performed to determine cell proliferation. Flow cytometry was used to examine cell apoptosis. ChIP and Dual-luciferase assay were utilized to validate interactions of Foxp1/promoters, PVT1/miR-34b-5p and miR-34b-5p/Foxp1. Mouse tumor xenograft model was used to determine the effect of sh-PVT1 on tumor growth in vivo. In this study, we found PVT1 and Foxp1 were elevated in DLBCL tissues and cells while miR-34b-5p was decreased. Knockdown of PVT1, overexpression of miR-34b-5p, or Foxp1 knockdown repressed DLBCL cell proliferation but enhanced cell apoptosis. PVT1 directly bound miR-34b-5p to disinhibit Foxp1/ß-catenin signaling. Foxp1 regulated CDK4, CyclinD1, and p53 expression via binding with their promoters. Knockdown of Foxp1 partially reversed the effects of miR-34b-5p inhibitor on DLBCL cell proliferation and apoptosis. Inhibition of PVT1 through shRNA suppressed DLBCL tumor growth in vivo. All in all, lncRNA PVT1 promotes DLBCL progression via acting as a miR-34b-5p sponge to disinhibit Foxp1/ß-catenin signaling.

Association between variant alleles of major histocompatibility complex class II regulatory genes and nasopharyngeal carcinoma susceptibility.

Major histocompatibility complex (MHC) class II regulatory genes play a paramount role in immune response that can exert a predominant influence on clinical outcome of Epstein-Barr virus infection consistently assumed as the main pathogenetic factor for nasopharyngeal carcinoma. To elucidate the relationship between allelic variants of MHC class II regulatory genes and susceptibility to nasopharyngeal carcinoma, a total of 28 polymorphic loci at MHC class II regulatory genes, involving CIITA, CREB1, RFX family genes (RFX5, RFXAP, and RFXANK), and NFY family genes (NFYA, NFYB, and NFYC), were genotyped by multiplex SNaPshot minisequencing in 137 patients with nasopharyngeal carcinoma and 107 healthy controls from the southern Chinese population. Allelic analysis disclosed that rs7404873, rs6498121, rs6498126, and rs56074043 shared correlations with nasopharyngeal carcinoma (Ptrend < 0.05). Further, rs6498126 on CIITA was independently associated with the risk of developing nasopharyngeal carcinoma (CC vs. GG, odds ratio: 7.386, 95% confidence interval: 1.934-28.207, Ptrend < 0.01). Conversely, rs7404873 on CIITA and rs56074043 on NFYB manifested epistatic interaction to decreased susceptibility of nasopharyngeal carcinoma (rs7404873, TT vs. GG, odds ratio: 0.256, 95% confidence interval: 0.088-0.740, Ptrend < 0.05; rs56074043, AA vs. AG, odds ratio: 0.341, 95% confidence interval: 0.129-0.900, Ptrend < 0.05). Additionally, bioinformatics analysis revealed that the three variants were transcriptional regulatory in function and might impact the expression of nearby genes. The findings suggested genetic variants on MHC class II regulatory genes contributed to nasopharyngeal carcinoma susceptibility and might provide new insights for screening high-risk population.

A retrospective study comparing D1 limited lymph node dissection and D2 extended lymph node dissection for N3 gastric cancer.

BACKGROUND: In countries in East Asia, the typical treatment for curable gastric cancer is gastrectomy with D2 lymphadenectomy. However, whether D2 lymphadenectomy is beneficial for high-risk N3 node disease remains controversial. We conducted a multi-institution retrospective study on patients with high-risk, locally advanced gastric cancer. To compare the rates of disease-free survival (DFS) and overall survival (OS) between radical D2-type gastric resection and lymphadenectomy and the more limited D1 type resection and lymphadenectomy. METHODS: From July 2010 to June 2015, 74 patients out of 949 who underwent curative-intent R0 surgery were selected in pairs to compare the survival outcomes between those who underwent radical D2 type (n=37) vs. the more limited D1 type (n=37) gastric resection and lymphadenectomy. RESULTS: The median DFS was 9.72 and 7.81 months for the D2 and D1 types, respectively (P=0.746), and the OS was 16.39 and 15.85 months for the D2 and D1 types, respectively (P=0.937). CONCLUSIONS: No statistically significant differences in DFS and OS were noted between D1 and D2 procedures for those with N3 disease. Our results support the hypothesis that a novel multidisciplinary approach rather than a surgical approach alone is needed to improve the survival outcomes of high-risk patients with N3 gastric cancer.

Clinical efficacy of metronomic chemotherapy after cool-tip radiofrequency ablation in the treatment of hepatocellular carcinoma.

PURPOSE: Anti-angiogenic agents have shown promise for treating advanced hepatocellular carcinoma (HCC), and the primary mechanism of low-dose metronomic chemotherapy using traditional cytotoxic drugs is anti-angiogenic. This study evaluated the efficacy of metronomic capecitabine and thalidomide after cool-tip radiofrequency ablation (RFA), relative to RFA alone, for treating patients with HCC. METHODS AND MATERIALS: Patients with HCC were randomly apportioned to a test group (n = 22) receiving metronomic chemotherapy with capecitabine and thalidomide after RFA, or a control group (n = 28) receiving RFA only. Serum circulating endothelial cells (CECs) and vascular endothelial growth factor (VEGF) were measured in all patients before and 1 month after RFA treatment. Enhanced computed tomography or ultrasound imaging was performed to evaluate efficacy during 12 months of follow-up. The treatment groups were further stratified as HCC within or outside the Milan criteria for transplantation. RESULTS: One month post-treatment, the tumour response rate (TRR), including complete response and partial response rate, of the test and control groups was statistically similar. At 12 months, the TRR of the test group (68.2%) was significantly higher than that of the control group (35.7%). In the test group, the TRR of patients whose tumour burdens were outside the Milan criteria was significantly higher than that of the control group. One month post-treatment, CECs and VEGF levels of the test group were significantly lower than baseline, while those of the control group were significantly higher. At the end of the 12-month follow-up, there was a progression-free survival (PFS) benefit of 2 months in the test group. CONCLUSION: Metronomic capecitabine and thalidomide after RFA significantly reduced recurrence of HCC and extended PFS, especially for HCC outside the Milan criteria, perhaps via reduction of serum CECs and VEGF levels and inhibition of tumour angiogenesis.

A prognostic model to predict survival in stage III colon cancer patients based on histological grade, preoperative carcinoembryonic antigen level and the neutrophil lymphocyte ratio.

BACKGROUND: Stage III colon cancer patients demonstrate diverse clinical outcomes. The aim of this study was to develop a prognostic model in order to better predict their survival. MATERIALS AND METHODS: From 2004 to 2010, 548 patients were retrospectively analyzed, among whom 328 were defined as the study group and the remaining 220 served as a validation group. Clinico-pathologic features, including age, gender, histological grade, T stage, number of positive lymph nodes, number of harvest lymph nodes, pretreatment carcinoembryonic antigen (CEA) levels and pretreatment neutrophil lymphocyte ratio (NLR), were collected. Kaplan-Meier survival curves were used to detect prognostic factors and multivariate analysis was applied to identify independent examples on which to develop a prognostic model. Finally, the model was further validated with the validation group. RESULTS: Histological grade (p=0.002), T stage (p=0.011), number of positive lymph nodes (p=0.003), number of harvested lymph nodes (p=0.020), CEA (p=0.005), and NLR (p<0.001) were found as prognostic factors while histological grade [RR(relative risk):0.632, 95%CI (Confidence interval) 0.405~0.985, p=0.043], CEA (RR:0.644, 95%CI:0.431~0.964, p=0.033) and NLR (RR:0.384, 95%CI:0.255~0.580, p<0.001) levels were independent. The prognostic model based on these three factors was able to classify patients into high risk, intermediate and low risk groups (p<0.001), both in study and validation groups. CONCLUSIONS: Histological grade, pretreatment CEA and NLR levels are independent prognostic factors in stage III colon cancer patients. A prognostic model based on these factors merits attention in future clinical practice.

Toxicarioside A inhibits SGC-7901 proliferation, migration and invasion via NF-κB/bFGF signaling.

AIM: To investigate the inhibitory role of toxicarioside A on the gastric cancer cell line human gastric cancer cell line (SGC-7901) and determine the underlying molecular mechanism. METHODS: After SGC-7901 cells were treated with toxicarioside A at various concentrations (0.5, 1.5, 4.5, 9.0 µg/mL) for 24 h or 48 h, cell viability was determined by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay, and the motility and invasion of tumor cells were assessed by the Transwell chamber assay. Immunofluorescence staining, reverse transcription polymerase chain reaction and Western blotting were performed to detect the expression of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor-1 (FGFR1), and nuclear factor-kappa B (NF-κB) activation was examined by electrophoretic mobility shift assay. RESULTS: The results showed that toxicarioside A was capable of reducing cell viability, inhibiting cell growth, and suppressing cell migration and invasion activities in a time- and dose-dependent manner in SGC-7901 cells. Further analysis revealed that not only the expression of bFGF and its high-affinity receptor FGFR1 but also the NF-κB-DNA binding activity were effectively blocked by toxicarioside A in a dose-dependent manner compared with the control group (P < 0.05 or P < 0.01). Interestingly, application of the NF-κB specific inhibitor, pyrrolidinedithiocarbamate (PDTC), to SGC-7901 cells significantly potentized the toxicarioside A-induced down-regulation of bFGF compared with the control group (P < 0.05). CONCLUSION: These findings suggest that toxicarioside A has an anti-gastric cancer activity and this effect may be achieved partly through down-regulation of NF-κB and bFGF/FGFR1 signaling.

[Inducing specific antitumor effects on osteosarcoma by fused vaccine of rat dendritic cells].

BACKGROUND & OBJECTIVE: Dendritic cells (DCs) are the strongest antigen presenting cells (APCs). But immune therapy based on DCs for osteosarcoma has seldom been reported. This study was designed to investigate the immunologic potency and antitumor effects of fused vaccine of rat DCs on osteosarcoma. METHODS: Mononuclear cells in rat bone marrow were propagated in vitro under the condition of recombinant granulocytemacrophage colony-stimulating factor (rGM-CSF), recombinant interleukin-4 (rIL-4), and recombinant tumor necrosing factor-alpha (rTNF-alpha) to obtain DCs. DCs were purified by monoclonal antibody OX62 and magnetic beads, and confirmed by morphologic observation, phenotype determine, and functional experiments. Osteosarcoma cell line UMR-106 was fused with allogeneic or syngeneic DCs by electrofusion to produce the tumor vaccine. Each kind of tumor vaccine was injected subcutaneously into 10 rats to observe its specific antitumor effects. RESULTS: Survival rate of rats after injection of 1x10(7) UMR-106 cells was 70% in allogeneic tumor vaccine group, and 50% in syngeneic tumor vaccine group. The survival rats stood up to the second challenge of 1x10(7) UMR-106 cells 7 weeks after injection. After immunization of 2x10(6) UMR106-DCs, tumors in 60% of the rats bearing pre-established tumor cells diminished or vanished. CONCLUSION: Fused tumor vaccine of UMR-106 cells and allogeneic DCs might induce specific anti-tumor effects on osteosarcoma.

[Clinical significance of RT-PCR in detection of axillary lymph node micrometastases from breast cancer].

BACKGROUND & OBJECTIVE: Recently, it has been reported that reverse transcription polymerase chain reaction(RT-PCR) for the detection of related tumor marker genes expression in lymph nodes can be used to evaluate tumor metastasis and results in higher sensitivity. The objective of this study was to investigate the clinical significance of RT-PCR for detecting axillary lymph node metastases of breast cancer. METHODS: RT-PCR was used to examine the mRNA of MUC1 and keratin19 in axillary lymph nodes. The lymph node metastases was assessed referring to the results of both RT-PCR and hematoxylin-eosin(HE) staining. All 37 patients with negative HE staining had been followed up for at least three years. RESULTS: Both MUC1 and keratin19 expression were detected in all 86 breast cancer specimens, while it was undetectable in all lymph nodes from patients with benign diseases. Among 37 patients with negative HE staining in lymph nodes, 11 were positive for keratin19 expression (29.7%), whose 3-year recurrence rate was 45.5% (5/11), while the patients with negative keratin19 expression was just 12.5% (2/26, P< 0.01). CONCLUSION: The expression of MUC1 and keratin19 in lymph nodes detected by RT-PCR can be regarded as a sign of breast cancer micrometastasis, which can be used to evaluate prognosis in patients as well as to choose the postoperative treatment protocols.

Bone tumors of the extremities or pelvis treated by microwave-induced hyperthermia.

From July 1992 through March 1999, 213 patients with malignant bone tumors of the extremities (176 patients) and pelvis (37 patients) were treated by microwave-induced hyperthermia. Osteosarcoma and chondrosarcoma were the most common diagnoses. The limb-salvage procedure was done as follows: After separating the tumor-bearing bone and the extraosseous mass from surrounding normal tissues with a proper margin, microwave energy was delivered into the tumor while the healthy tissues were protected carefully from overheating. Restrengthening of the devitalized bone was necessary in many cases. The eschar resulting from the heat necrosis was curettaged. Most patients can walk early with a partial weightbearing brace for support. The survival rate was 73.9%. Fracture, local recurrence, and infection were the main complications although the majority of complications occurred early in the study. Thermotherapy is a novel and effective way to treat bone tumors in selected patients.

[Apoptosis antagonizing transcription factor is a gene highly expressed in highly metastatic human osteosarcoma cell lines].

BACKGROUND & OBJECTIVE: Osteosarcoma is the most common malignant bone tumor in adolescents and yound adults. It is characterized by a high propensity for pulmonary metastasis. In spite of successful control of the primary tumor, death from pulmonary metastases occurs in > 30% of patients within 5 years. A better understanding of the molecular mechanisms that regulate the process of metastasis can provide a biological foundation for the design of more effective therapy. We established a metastatic model in nude mice with the method of orthotopically transplanting human osteosarcoma cell line SOSP-9607 and selected and isolated SOSP-M with highly metastatic potential. This study is to clone genes associated with osteosarcoma metastasis and to investigate the molecular mechanism of osteosarcoma metastasis by comparing the levels of gene expression between the two cells lines. METHODS: Using suppression subtractive hybridization, the substracted cDNA library of highly metastatic human osteosarcoma cell line SOSP-M was constructed. Positive clones were screened by differential screen technique. Partial positive clones were sequenced. The interested upexpressed clones in SOSP-M cells were analyzed through Northern blot and RT-PCR for the low metastatic cell lines SOSP-9607 and OS-9901, highly metastatic cell line SOSP-M and three pulmonic metastatic nodules. RESULTS: Two positive cDNA clones from highly metastatic cell line SOSP-M subtracted cDNA library were identical(99% homology) to apoptosis antagonizing transcription factor. Northern blot and RT-PCR analysis demonstrated that apoptosis antagonizing transcription factor expressed highly in high metastatic cell line SOSP-M and three pulmonic metastatic nodules, but not in low metastatic cell line SOSP-9607 and OS-9901. CONCLUSION: Apoptosis antagonizing transcription factor may play an important role in promoting metastasis of osteosarcoma.