Final report of a prospective randomized study on thoracic radiotherapy target volume for limited-stage small cell lung cancer with radiation dosimetric analyses.

BACKGROUND: The thoracic radiotherapy (TRT) target volume for limited-stage small-cell lung cancer (SCLC) has been controversial for decades. In this report, the final results of a prospective randomized trial on the TRT target volume before and after induction chemotherapy are presented. METHODS: After 2 cycles of etoposide and cisplatin, patients arm were randomized to receive TRT to the postchemotherapy or prechemotherapy tumor volume in a study arm and a control arm. Involved-field radiotherapy was received in both arms. TRT consisted of 1.5 grays (Gy) twice daily in 30 fractions to up to a total dose of 45 Gy. Lymph node regions were contoured, and intentional and incidental radiation doses were recorded. RESULTS: The study was halted early because of slow accrual. Between 2002 and 2017, 159 and 150 patients were randomized to the study arm or the control arm, respectively; and 21.4% and 19.1% of patients, respectively, were staged using positron emission tomography/computed tomography (P = .31). With a median follow-up of 54.1 months (range, 19.9-165.0 months) in survivors, the 3-year local/regional progression-free probability was 58.2% and 65.5% in the study and control arms, respectively (P = .44), and the absolute difference was -7.3% (95% CI, -18.2%, 3.7%). In the study and control arms, the median overall survival was 21.9 months and 26.6 months, respectively, and the 5-year overall survival rate was 22.8% and 28.1%, respectively (P = .26). Grade 3 esophagitis was observed in 5.9% of patients in the study arm versus 15.5% of those in the control arm (P = .01). The isolated out-of-field failure rate was 2.6% in the study arm versus 4.1% in the control arm (P = .46), and all such failures were located in the supraclavicular fossa or contralateral hilum. The regions 7, 3P, 4L, 6, 4R, 5, and 2L received incidental radiation doses >30 Gy. CONCLUSIONS: TRT could be limited to the postchemotherapy tumor volume, and involved-field radiotherapy could be routinely applied for limited-stage SCLC.

Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study.

BACKGROUND: Cisplatin-based adjuvant chemotherapy is the standard of care for patients with resected stage II-IIIA non-small-cell lung cancer (NSCLC). RADIANT and SELECT trial data suggest patients with EGFR-mutant stage IB-IIIA resected NSCLC could benefit from adjuvant EGFR tyrosine kinase inhibitor treatment. We aimed to compare the efficacy of adjuvant gefitinib versus vinorelbine plus cisplatin in patients with completely resected EGFR-mutant stage II-IIIA (N1-N2) NSCLC. METHODS: We did a randomised, open-label, phase 3 trial at 27 centres in China. We enrolled patients aged 18-75 years with completely resected (R0), stage II-IIIA (N1-N2), EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg) NSCLC. Patients were stratified by N stage and EGFR mutation status and randomised (1:1) by Pocock and Simon minimisation with a random element to either gefitinib (250 mg once daily) for 24 months or intravenous vinorelbine (25 mg/m2 on days 1 and 8) plus intravenous cisplatin (75 mg/m2 on day 1) every 3 weeks for four cycles. The primary endpoint was disease-free survival in the intention-to-treat population, which comprised all randomised patients; the safety population included all randomised patients who received at least one dose of study medication. Enrolment to the study is closed but survival follow-up is ongoing. The study is registered with ClinicalTrials.gov, number NCT01405079. FINDINGS: Between Sept 19, 2011, and April 24, 2014, 483 patients were screened and 222 patients were randomised, 111 to gefitinib and 111 to vinorelbine plus cisplatin. Median follow-up was 36·5 months (IQR 23·8-44·8). Median disease-free survival was significantly longer with gefitinib (28·7 months [95% CI 24·9-32·5]) than with vinorelbine plus cisplatin (18·0 months [13·6-22·3]; hazard ratio [HR] 0·60, 95% CI 0·42-0·87; p=0·0054). In the safety population, the most commonly reported grade 3 or worse adverse events in the gefitinib group (n=106) were raised alanine aminotransferase and asparate aminotransferase (two [2%] patients with each event vs none with vinorelbine plus cisplatin). In the vinorelbine plus cisplatin group (n=87), the most frequently reported grade 3 or worse adverse events were neutropenia (30 [34%] patients vs none with gefitinib), leucopenia (14 [16%] vs none), and vomiting (eight [9%] vs none). Serious adverse events were reported for seven (7%) patients who received gefitinib and 20 (23%) patients who received vinorelbine plus cisplatin. No interstitial lung disease was noted with gefitinib. No deaths were treatment related. INTERPRETATION: Adjuvant gefitinib led to significantly longer disease-free survival compared with that for vinorelbine plus cisplatin in patients with completely resected stage II-IIIA (N1-N2) EGFR-mutant NSCLC. Based on the superior disease-free survival, reduced toxicity, and improved quality of life, adjuvant gefitinib could be a potential treatment option compared with adjuvant chemotherapy in these patients. However, the duration of benefit with gefitinib after 24 months might be limited and overall survival data are not yet mature. FUNDING: Guangdong Provincial Key Laboratory of Lung Cancer Translational Medicine; National Health and Family Planning Commission of People's Republic of China; Guangzhou Science and Technology Bureau; AstraZeneca China.

Long non-coding RNAs (LncRNA) regulated by transforming growth factor (TGF) ß: LncRNA-hit-mediated TGFß-induced epithelial to mesenchymal transition in mammary epithelia.

Long noncoding RNAs (lncRNAs) are emerging as key regulators in various biological processes. Epithelial-to-mesenchymal transition (EMT) is a developmental process hijacked by tumor cells to depart from the primary tumor site, invade surrounding tissue, and establish distant metastases. Transforming growth factor ß (TGFß) signaling has been shown to be a major inducer of EMT and to facilitate breast cancer metastasis. However, the role of lncRNAs in this process remains largely unknown. Here we report a genome-wide lncRNA profile in mouse mammary epithelial NMuMG cells upon TGFß induction of EMT. Among 10,802 lncRNAs profiled, over 600 were up-regulated and down-regulated during the EMT, respectively. Furthermore, we identify that lncRNA-HIT (HOXA transcript induced by TGFß) mediates TGFß function, i.e. depletion of lncRNA-HIT inhibits TGFß-induced migration, invasion, and EMT in NMuMG. LncRNA-HIT is also significantly elevated in the highly metastatic 4T1 cells. Knockdown of lncRNA-HIT in 4T1 results in decrease of cell migration, invasion, tumor growth, and metastasis. E-cadherin was identified as a major target of lncRNA-HIT. Moreover, lncRNA-HIT is conserved in humans and elevated expression associates with more invasive human primary breast carcinoma. Collectively, these data suggest that a subset of lncRNAs such as lncRNA-HIT play a significant role in regulation of EMT and breast cancer invasion and metastasis, and could be potential therapeutic targets in breast cancers.

Cell-Free RNA Content in Peripheral Blood as Potential Biomarkers for Detecting Circulating Tumor Cells in Non-Small Cell Lung Carcinoma.

Circulating tumor cells (CTCs) have been implicated in tumor progression and prognosis. Techniques detecting CTCs in the peripheral blood of patients with non-small cell lung carcinoma (NSCLC) may help to identify individuals likely to benefit from early systemic treatment. However, the detection of CTCs with a single marker is challenging, owing to low specificity and sensitivity and due to the heterogeneity and rareness of CTCs. Herein, the probability of cell-free RNA content in the peripheral blood as a potential biomarker for detecting CTCs in cancer patients was investigated. An immunomagnetic enrichment of real-time reverse-transcription PCR (RT-PCR) technology for analysis of CTCs in NSCLC patients was also developed. The mRNA levels of four candidate genes, cytokeratin 7 (CK7), E74-like factor 3 (ELF3), epidermal growth factor receptor (EGFR), and erythropoietin-producing hepatocellular carcinoma receptor B4 (EphB4) that were significantly elevated in tumor tissues and peripheral blood mononuclear cells (PBMCs) were determined. The expression of CK7 and ELF3 in tumor tissues and EGFR in PBMCs was associated with lymph node metastasis (all p < 0.05). The expression of CK7 in PBMCs was correlated with age and EphB4 in PBMCs correlated with histopathological type, respectively (all p < 0.05). The expression of all four genes in tumor tissues and PBMCs was significantly correlated with the clinical stage (all p < 0.01). Survival analysis showed that the patients with enhanced expression of CK7, ELF3, EGFR, and EphB4 mRNA in PBMCs had poorer disease-free survival (DFS) and overall survival (OS) than those without (all p < 0.0001). The present study showed that this alteration of cell-free RNA content in peripheral blood might have clinical ramifications in the diagnosis and treatment of NSCLC patients.

The impact of cyclin D1 overexpression on the prognosis of ER-positive breast cancers: a meta-analysis.

Cyclin D1 (CCND1), a key regulator of cell cycle progression, is overexpressed in many human cancers, including breast cancer. However, the impact of CCND1 overexpression in these cancers remains unclear and controversial. We conducted a systematic literature search in PubMed and EMBASE with the search terms "cyclin D1", "CCND1", "breast cancer", "prognosis", and potential studies for analysis were selected. Studies with survival data, including progression-free survival (PFS), overall survival (OS) or metastasis-free survival (MFS), were included in this meta-analysis. A total of 33 studies containing 8,537 cases were included. The combined hazard risk (HR) and its 95 % confidence interval (CI) of OS, PFS and MFS were 1.13 (95 % CI 0.87-1.47; P = 0.35), 1.25 (95 % CI 0.95-1.64; P = 0.12), and 1.04 (95 % CI 0.80-1.36; P = 0.76), respectively, for primary breast cancer patients with tumors exhibiting CCND1 overexpression. Interestingly, the impact of CCND1 expression on OS was a 1.67-fold (95 % CI 1.38-2.02; P = 0.00) increased risk for ER-positive breast cancer patients. However, CCND1 overexpression exhibited no association with the PFS or OS of patients who received epirubicin-based neoadjuvant chemotherapy, for which the P values were 0.63 and 0.47, respectively. In summary, CCND1 overexpression impacts the prognosis of ER-positive breast cancer patients, but not patients with unselected primary breast cancer or patients treated with neoadjuvant chemotherapy.

Down-regulation of PTEN expression modulated by dysregulated miR-21 contributes to the progression of esophageal cancer.

BACKGROUND AND AIM: miR-21, a putative tumor oncomiR, is a frequently overexpressed miRNA in a variety of tumors. Because it targets tumor-suppressor genes it has been linked to tumor progression. In this study we investigated the role of miR-21 in esophageal squamous cell carcinoma (ESCC), and its possible mechanism. METHODS: Expression of miR-21 was detected by stem-loop RT-PCR in tissue from 76 invasive ESCC at stage I-IV and in their corresponding para-cancerous histological normal tissues (PCHNT). Thirty endoscopic esophageal mucosal biopsy specimens from non-tumor patients were used as controls. Expression of PTEN in 76 paired ESCC and PCHNT was investigated by real-time RT-PCR and an immunohistochemical method, respectively. Paired tumor and PCHNT specimens of 20 ESCC cases were randomly selected for western blot analysis. The effect of miR-21 on PTEN expression was assessed in the ESCC cell line with an miR-21 inhibitor to reduce miR-21 expression. Furthermore, the roles of miR-21 in cell biology were analyzed by use of miR-21 inhibitor-transfected cells. RESULTS: Stem-loop RT-PCR revealed miR-21 was significantly overexpressed in ESCC tissues and cell lines. Overexpression of miR-21 correlated with tumor status, lymph node metastasis, and clinical stage. We demonstrated that knockdown of miR-21 significantly increased expression of PTEN protein. Consequent PTEN expression reduced cell proliferation, invasion, and migration. CONCLUSIONS: Our findings suggest that miR-21 could be a potential oncomiR, probably by regulation of PTEN, and a novel prognostic factor for ESCC patients.

[Effect of miRNA-106a expression on the prognosis of patients with esophageal squamous cell carcinoma].

OBJECTIVE: To study the expression of miRNA-106a gene in esophageal squamous cell carcinoma (ESCC) and its association with clinicopathological features and prognosis of ESCC patients. METHODS: Real-time fluorescence quantitative polymerase chain reaction (PCR) assay was used to determine the expression of miRNA-106a gene in esophageal cancer tissue and corresponding normal mucosa of 81 cases. Immunohistochemical technique was applied to detect the expression of p53, human epidermal growth factor receptor 2 (HER-2), DNA topoisomerase II (Topo II) and multidrug resistance-associated protein (MRP). The association of miRNA-106a expression with clinicopathological features, expression of related proteins, and prognosis of the patients was analyzed. RESULTS: Among the 81 cases, under-expression of miRNA-106a gene was found in 48 cases (59.3%), normal expression in 22 cases (27.2%), and overexpression in 11 cases (13.6%). The expression of miRNA-106 gene was significantly associated with lymph node metastasis, pathological stage, and nerve invasion (all P < 0.05), significantly associated with expression of p53 (P = 0.006), and not significantly associated with expressions of HER-2, Topo II and MRP proteins (all P > 0.05). The expression of miRNA-106a gene was also significantly associated with progression-free survival (PFS, P = 0.032), but not significantly with overall survival (OS, P = 0.486). The results of Cox multivariate regression analysis showed that the PFS of ESCC patients was significantly correlated with lymph node metastasis (P = 0.029), but not correlated with the age, gender, tumor length, T stage, degree of differentiation, nerve invasion, and miRNA-106a expression (all P > 0.05). CONCLUSIONS: In esophageal squamous cell carcinomas, the miRNA-106a gene is under-expressed, with tumor suppressor function, and may be regarded as a biological marker to assess the prognosis in patients with esophageal squamous cell carcinoma.

[Incidence and mortality of cancer in Zhejiang province in 2009].

OBJECTIVE: To investigate the incidence and mortality of cancer registered in Zhejiang province in 2009. METHODS: The statistics of incidence and mortality of cancer were collected from 6 population-based cancer registries in Zhejiang province, including 30 613 new incidence cases and 16 920 death cases reported in 2009. The 6 cancer registries covered population at 9 560 699 in all. The crude rate, age-standardized rate, cumulative rate (0-74 years old), cut rate (35-64 years old), age-specific rate of incidence/mortality as well as the constitution of top 10 common cancers were then calculated and analyzed. The age-standardized rate was calculated and adjusted by the Chinese standard population in 1982 as well as the Segi's world standard population. RESULTS: The crude incidence of cancer was 320.20/100 000. Age-standardized incidence by Chinese standard population and by world standard population were separately 161.99/100 000 and 207.92/100 000, the cumulative rate was 23.83% and the cut rate was 346.87/100 000. Meanwhile, the crude mortality rate was 176.97/100 000, and the age-standardized mortality by Chinese standard population and by world standard population were 79.17/100 000, 107.02/100 000, respectively; and the cumulative mortality rate was 12.23% and cut rate was 139.75/100 000. Age-specific incidence among 0-34 years old population remained low; however, the incidence among 35-39 age group increased obviously (116.46/100 000, 954 cases). The incidence among 45-49 age group elevated even more sharply (272.97/100 000, 2388 cases) and finally reached the peak among 80-84 age group (1564.36/100 000, 2272 cases). Age-specific mortality arose among 40-44 age group (48.06/100 000, 424 cases) and reached its peak among 80-84 age group (1392.23/100 000, 2022 cases) as well. The most common types of cancer were lung cancer, gastric cancer, colorectal cancer, liver cancer, breast cancer, esophageal cancer, thyroid cancer, pancreatic cancer, cervical cancer and lymphoma, which accounted for 74.37% (22 763/30 613) of all new cancer cases.Lung cancer, liver cancer, gastric cancer, colorectal cancer, esophageal cancer, pancreatic cancer, leukemia, lymphoma, brain tumors and breast cancer accounted for 87.75% (14 848/16 920) of all cancer deaths. CONCLUSION: The incidence and mortality of cancer both increased in 2009 according to the statistics from cancer registry in Zhejiang province.Lung cancer, malignant tumor in digestive system and breast cancer were still the key challenges in cancer prevention and control. Meanwhile, the increased incidence of thyroid cancer should also be noticed.

Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of stage IIIA-N2 EGFR-mutant non-small-cell lung cancer: final overall survival analysis of the EMERGING-CTONG 1103 randomised phase II trial.

EMERGING-CTONG 1103 showed improved progression-free survival (PFS) with neoadjuvant erlotinib vs. chemotherapy for patients harbouring EGFR sensibility mutations and R0 resected stage IIIA-N2 non-small cell lung cancer (NSCLC) (NCT01407822). Herein, we report the final results. Recruited patients were randomly allocated 1:1 to the erlotinib group (150 mg/day orally; neoadjuvant phase for 42 days and adjuvant phase to 12 months) or to the GC group (gemcitabine 1250 mg/m2 plus cisplatin 75 mg/m2 intravenously; 2 cycles in neoadjuvant phase and 2 cycles in adjuvant phase). Objective response rate (ORR), complete pathologic response (pCR), PFS, and overall survival (OS) were assessed along with safety. Post hoc analysis was performed for subsequent treatments after disease recurrence. Among investigated 72 patients (erlotinib, n = 37; GC, n = 35), the median follow-up was 62.5 months. The median OS was 42.2 months (erlotinib) and 36.9 months (GC) (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.47-1.47; p = 0.513). The 3- and 5-year OS rates were 58.6% and 40.8% with erlotinib and 55.9% and 27.6% with GC (p3-y = 0.819, p5-y = 0.252). Subsequent treatment was administered in 71.9% and 81.8% of patients receiving erlotinib and GC, respectively; targeted therapy contributed mostly to OS (HR, 0.35; 95% CI, 0.18-0.70). After disease progression, the ORR was 53.3%, and the median PFS was 10.9 months during the EGFR-TKI rechallenge. During postoperative therapy, grade 3 or 4 adverse events (AEs) were 13.5% in the erlotinib group and 29.4% in the GC group. No serious adverse events were observed. Erlotinib exhibited clinical feasibility for resectable IIIA-N2 NSCLC over chemotherapy in the neoadjuvant setting.

Heterogeneity of chemosensitivity in esophageal cancer using ATP-tumor chemosensitivity assay.

AIM: Current chemotherapy for esophageal cancer is conducted on the basis of empirical information from clinical trials, which fails to take into account the known heterogeneity of chemosensitivity between patients. This study was aimed to demonstrate the degree of heterogeneity of chemosensitivity in esophageal cancers. METHODS: A total of 42 esophageal cancer specimens were collected. The heterogeneity of chemosensitivity in esophageal cancer specimens was examined using an ex vivo ATP-tumor chemosensitivity assay (ATP-TCA). RESULTS: Thirty eight specimens produced evaluable results (90.5%). The most active single agent tested was nedaplatin, to which 28.9% of samples were sensitive. Combinations of chemotherapy agents exhibited much higher sensitivity: cisplatin + paclitaxel was sensitive in 16 of 38 (42.1%) of samples, while nedaplatin+paclitaxel was more effective, which was sensitive in 20 of 38 cases (52.6%). CONCLUSION: There was a marked heterogeneity of chemosensitivity in esophageal cancer. Chemosensitivity testing may provide a practical method for testing new regimens before clinical trials in esophageal cancer patients.

[DNA methylation status of RARß2 and p16(INK4α) in peripheral blood and tumor tissue in patients with esophageal squamous cell carcinoma].

OBJECTIVE: To study the methylation status of retinoic acid receptor ß2 (RARß2) and p16(INK4α) genes in peripheral blood and tumor tissues and the perioperative dynamic changes of free RARß2 and p16(INK4α) in the peripheral blood, and to investigate the relationship between RARß2 and p16(INK4α) methylation in peripheral blood and clinicopathological characteristics of esophageal squamous cell carcinoma (ESCC) and their value in evaluating the completeness of surgical resection. METHODS: Real-time methylation specific polymerase chain reaction (real-time MSP) technique was used to detect the methylation status of RARß2 and p16(INK4α) in tumor tissue, adjacent normal tissue and peripheral blood perioperatively in 76 cases of ESCC. Sixty age-matched healthy volunteers were randomly selected as a control. RESULTS: RARß2 and p16(INK4α) hypermethylation presented in both tumor tissue [72.4% (55/76) and 86.8% (66/76)] and peripheral blood [63.2% (48/76) and 71.1% (54/76)] in the ESCC patients, showing a good agreement between them. RARß2 and p16(INK4α) hypermethylation was significantly related with pathological stage, lymph node metastasis, and invasion of nerves and vessels (P < 0.05). The DNA methylation rate in peripheral blood was increasing first and then decreasing in the preoperative, intraoperative and postoperative periods. Moreover, the RARß2 methylation in peripheral blood was shown to be significantly associated with family history of cancer (P = 0.023). CONCLUSION: RARß2 and p16(INK4α) methylation in the peripheral blood in ESCC patients may reflect the tumor-bearing status in the body, and may serve as a valuable marker in assessment of the degree of completeness of surgical resection in ESCC patients.

[Clinicopathological features and prognostic analysis of esophageal sarcomatoid carcinoma].

OBJECTIVE: To analyze the clinicopathological characteristics and prognosis of a rare histological type of esophageal cancer-sarcomatoid carcinoma. METHODS: Clinicopathological data of 31 patients with esophageal sarcomatoid carcinoma who underwent surgery in the Department of Thoracic Surgery of Zhejiang Cancer Hospital from Jan 2000 to Dec 2009 were collected and analyzed. The survival analysis was performed using Kaplan-Meier method. RESULTS: All the patients underwent surgery. Of the 31 patients, one received preoperative chemoradiotherapy and postoperative chemotherapy, and 8 received postoperative chemotherapy. All the tumors were located in the middle or lower esophagus. Microscopically, the tumors were composed of both carcinomatous and sarcomatous components, and there was a transition between the two components, but no obvious heterogenous elements such as osteosarcoma, chondrosarcoma or rhabdomyosarcoma were found. In the carcinomatous components, positive expression of CK and EMA was found in all the 31 cases, and positive expression of vimentin in 5 of the 31 cases. In the sarcomatous components, positive expression of CK, EMA and vimentin was found in 29, 28 and 23 cases, respectively. The 1-, 3-, and 5-year survival rates were 80.6%, 55.9% and 33.4%, respectively, and the median survival time was 40 months. CONCLUSIONS: Esophageal sarcomatoid carcinoma is a particular type of esophageal malignancy with unique clinicopathological features. The diversity and complexity of the carcinomatous and sarcomatous components and their potential of transformation and differentiation lead to different prognosis from each other.

[A multi-centered randomized controlled study of neo-adjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of esophagus: an interim analysis].

OBJECTIVE: To evaluate the safety and validity of neo-adjuvant chemoradiotherapy followed by surgery for locally advanced esophageal carcinoma. METHODS: Patients with IIB, III staged squamous cell carcinoma of thoracic esophagus were randomly allocated to either preoperative chemoradiotherapy followed by surgery (arm A) or surgery alone (arm B). In arm A, chemotherapy and radiotherapy were performed concurrently. Patients received two cycles of vinorelbine and cisplatin. Vinorelbine at 25 mg/m(2) per day was administered as a bolus infusion at d1, d8, d22 and d29. Cisplatin at 75 mg/m(2) was administered by an intravenous infusion at d1 and d22 (or 25 mg/m(2) days 1 - 4 and 22 - 25). A total radiotherapeutic dose of 40 Gy was delivered in 20 daily fractions of 2.0 Gy each (5 d/wk for 4 weeks). Three-incisioned esophagectomy was performed at Weeks 4 - 6 after chemoradiotherapy. Primary outcome was overall survival time. An interim analysis was performed in June 2011. RESULTS: From July 2007 to June 2011, 123 eligible patients were randomly assigned at 7 cooperative cancer centers (54 cases in arm A vs 69 cases in arm B). In arm A, the clinical response rate of chemoradiotherapy was 90.7%. All patients finished the preoperative chemoradiotherapy. Forty-nine cases continued to receive esophagectomy. The pathological complete response rate was 29.6%. The rate of R0 resection in arm A was significant higher than that in arm B(96.0% vs 85.5%, P = 0.015). The most common grade 3/4 toxicity of chemoradiotherapy was leukopenia occurring in 33 cases (61.1%). Vomiting and esophagitis were usually of Grade 1/2. No patient died or abandoned surgery because of chemoradiation toxicity. Between arms A and B, operative duration, blood loss, duration of chest tube drainage and length of postsurgical hospital stay were similar. The incidences of postoperative heart failure (2.0% vs 1.4%, P = 1.000), anastomotic leakage (8.2% vs 11.6%, P = 0.759) and hoarseness (6.1% vs 4.3%, P = 0.691) were not significantly different. The incidence of pulmonary infection in arm A was slightly higher than that in arm B (8.2% vs 1.4%, P = 0.094). No perioperative deaths occurred in either group. There were no significant differences in overall survivals at 1, 2 years between arms A and B (85.6%/75.5% vs 79.1%/66.1%, P = 0.207). The disease-free survivals at 1, 2 years in arm A were slightly higher than in arm B (86.6%/83.2% vs 70.9%/61.8%, P = 0.075). CONCLUSION: Neo-adjuvant chemoradiation followed by surgery may achieve a high clinical response rate and pathologic complete tumor regression rate. It significantly increases the R0 resection rate and down stage the esophageal cancer patients. But its ultimate efficacy awaits further follow-up studies.

microRNA-1321 and microRNA-7515 contribute to the progression of non-small cell lung cancer by targeting CDC20.

Cell division cycle 20 (CDC20) and microRNAs (miRNAs) are differentially expressed in non-small cell lung cancer (NSCLC). The current study aimed to investigate the role of miR-1321 and miR-7515 regulation in CDC20 during NSCLC development. CDC20 expression in paracancerous and tumor tissues was assessed using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The relationship between CDC20 expression and prognosis of patients was analyzed using the TCGA database. The expression profile of CDC20 in healthy lung cells and NSCLC cells was detected using qRT-PCR and western blotting. After the knockdown of CDC20 in NSCLC cells, the cell proliferation, apoptosis, migration, invasion, and cell cycle changes were investigated by CCK8, EdU, flow cytometry, wound healing, and Transwell assays. The miRNAs targeting CDC20 were predicted using two bioinformatics websites and validated using dual-luciferase assays. CDC20 was enhanced in NSCLC tissues and cells, thus predicting the poor prognosis in NSCLC patients. After CDC20 inhibition, the malignant phenotype of NSCLC cells was reverted. miR-1321 and miR-7515 targeted CDC20 and exhibited the same anti-tumor effects as CDC20 silencing. Functional rescue experiments showed that CDC20 overexpression averted the anti-tumor effects of miR-1321 and miR-7515 on NSCLC cells. miR-1321 and miR-7515 inhibited NSCLC development by targeting CDC20. Thus, the current study has implications in NSCLC treatment and provides novel insights into NSCLC management.

Efficacy and safety of esophagectomy via left thoracic approach versus via right thoracic approach for middle and lower thoracic esophageal cancer: a multicenter randomized clinical trial (NST1501).

Background: Left thoracic approach (LTA) has been a favorable selection in surgical treatment for esophageal cancer (EC) patients in China before minimally invasive esophagectomy (MIE) is popular. This study aimed to demonstrate whether right thoracic approach (RTA) is superior to LTA in the surgical treatment of middle and lower thoracic esophageal squamous cell carcinoma (TESCC). Methods: Superiority clinical trial design was used for this multicenter randomized controlled two-parallel group study. Between April 2015 and December 2018, cT1b-3N0-1M0 TESCC patients from 14 centers were recruited and randomized by a central stratified block randomization program into LTA or RTA groups. All enrolled patients were followed up every three months after surgery. The software SPSS 20.0 and R 3.6.2. were used for statistical analysis. Efficacy and safety outcomes, 3-year overall survival (OS) and disease-free survival (DFS) were calculated and compared using the Kaplan-Meier method and the log-rank test. Results: A total of 861 patients without suspected upper mediastinal lymph nodes (umLN) were finally enrolled in the study after 95 ineligible patients were excluded. 833 cases (98.7%) were successfully followed up until June 1, 2020. Esophagectomies were performed via LTA in 453 cases, and via RTA in 408 cases. Compared with the LTA group, the RTA group required longer operating time (274.48±78.92 vs. 205.34±51.47 min, P<0.001); had more complications (33.8% vs. 26.3% P=0.016); harvested more lymph nodes (LNs) (23.61±10.09 vs. 21.92±10.26, P=0.015); achieved a significantly improved OS in stage IIIa patients (67.8% vs. 51.8%, P=0.022). The 3-year OS and DFS were 68.7% and 64.3% in LTA arm versus 71.3% and 63.7% in RTA arm (P=0.20; P=0.96). Conclusions: Esophagectomies via both LTA and RTA can achieve similar outcomes in middle or lower TESCC patients without suspected umLN. RTA is superior to LTA and recommended for the surgical treatment of more advanced stage TESCC due to more complete lymphadenectomy. Trial Registration: ClinicalTrials.gov NCT02448979.

Novel statistical framework to identify differentially expressed genes allowing transcriptomic background differences.

MOTIVATION: Tests of differentially expressed genes (DEGs) from microarray experiments are based on the null hypothesis that genes that are irrelevant to the phenotype/stimulus are expressed equally in the target and control samples. However, this strict hypothesis is not always true, as there can be several transcriptomic background differences between target and control samples, including different cell/tissue types, different cell cycle stages and different biological donors. These differences lead to increased false positives, which have little biological/medical significance. RESULT: In this article, we propose a statistical framework to identify DEGs between target and control samples from expression microarray data allowing transcriptomic background differences between these samples by introducing a modified null hypothesis that the gene expression background difference is normally distributed. We use an iterative procedure to perform robust estimation of the null hypothesis and identify DEGs as outliers. We evaluated our method using our own triplicate microarray experiment, followed by validations with reverse transcription-polymerase chain reaction (RT-PCR) and on the MicroArray Quality Control dataset. The evaluations suggest that our technique (i) results in less false positive and false negative results, as measured by the degree of agreement with RT-PCR of the same samples, (ii) can be applied to different microarray platforms and results in better reproducibility as measured by the degree of DEG identification concordance both intra- and inter-platforms and (iii) can be applied efficiently with only a few microarray replicates. Based on these evaluations, we propose that this method not only identifies more reliable and biologically/medically significant DEG, but also reduces the power-cost tradeoff problem in the microarray field. AVAILABILITY: Source code and binaries freely available for download at http://comonca.org.cn/fdca/resources/softwares/deg.zip.

Aberrant methylation of different DNA repair genes demonstrates distinct prognostic value for esophageal cancer.

BACKGROUND: DNA mismatch repair (MMR) deficiency results in a strong mutator phenotype and high-frequency microsatellite instability (MSI-H), which are the hallmarks of many tumors. AIM: The objective of this study is to investigate the promoter CpG island methylation status of mismatch repair genes human mutL homolog 1 (hMLH1), human mutS homolog 2 (hMSH2), and O(6)-methylguanine-DNA methyltransferase (MGMT) in esophageal squamous cell carcinoma (ESCC) and its roles in alkylating agents chemotherapy. METHODS: Real-time methylation-specific polymerase chain reaction (PCR) (real-time MSP) was employed to detect promoter CpG island methylation of the hMLH1, hMSH2, as well as MGMT genes in 235 surgical tumor tissue samples from ESCC patients and their corresponding normal tissue samples. RESULTS: Promoter CpG island methylation of hMLH1, hMSH2, and MGMT were detectable in 43.4, 28.9, and 40.4% of ESCC tumor DNA, respectively, and the loss rates of hMLH1, hMSH2, and MGMT protein expression were 48.6, 34.5, and 40.9% in tumor tissues, respectively. For the entire population of 235 ESCC patients who were enrolled in operating treatment combined with radiotherapy and chemotherapy with alkylating agents, there was a significant difference in the overall survival between patients with methylated MGMT promoter and those with an unmethylated MGMT promoter (P < 0.05). CONCLUSION: Promoter CpG island methylation may be a frequent event in ESCC carcinogenesis. Detection of the methylated sequences of hMLH1, hMSH2, and MGMT appears to be promising as a predictive factor in primary ESCC.

[Analysis of prognostic factors in patients with locoregional recurrence of esophageal carcinoma after curative treatment].

OBJECTIVE: The aim of this paper was to evaluate the treatment outcome of multimodal treatment for 196 patients with locoregional recurrent esophageal cancer after curative treatment and to determine the prognostic factors of recurrence. METHODS: One hundred and ninety six patients with locoregional recurrent esophageal cancer curatively treated in our hospital were included in this study. Kaplan-Meier method was used to analyze the survival rate. Log rank test was used to evaluate the difference between the groups. Multivariate survival analysis was conducted using a Cox proportional hazard regression model with a backward stepwise procedure. RESULTS: The overall 1-, 2- and 3-year survival rates were 29.8%, 5.9% and 4.0%, respectively, with a median survival time of 8.0 months. The univariate analysis showed that ECOG PS, the interval between initial treatment and recurrence, the regimens of initial treatment and retreatment were independent prognostic factors. The multivariate analysis showed that the regimens of initial treatment and retreatment were independent prognostic factors. Retreatment methods significantly influenced the survival. The median survival time of chemoradiotherapy, radiation therapy alone, chemotherapy alone, EGFR-TKI and best supportive care were 13.0, 7.0, 6.0, 4.0 and 3.0 months, respectively (P = 0.000). CONCLUSIONS: The prognosis of patients with locoregional recurrent esophageal cancer after curative treatment is poor. The main prognostic factors are the regimens of initial treatment and retreatment. Multimodal treatment including radiotherapy and chemotherapy may improve the long-term survival of the patients.

Incidence and mortality trend of cervical cancer in 11 cancer registries of china.

OBJECTIVE: In many countries, the cervical cancer prevalence has declined but less information about the changes is available in China. This study aims to understand the epidemiological characteristics and trend of cervical cancer in China. METHODS: Cervical cancer data of 11 cancer registries during 1988-2002 in China were analyzed. The age and urban/rural differences and trend of cervical cancer incidence and mortality were described and discussed. RESULTS: During 1988-2002, a total of 6007 incidence cases and 3749 mortality cases of cervical cancer were reported in the 11 cancer registries. The incidence crude rate of cervical cancer was 3.80/100,000 and the world age adjusted rate was 2.78/100,000. In the same period, the mortality crude rate was 2.37/100,000 and the world age adjusted rate was 1.66/100,000. Declined incidence and mortality trends were observed during this period in urban as well as in rural areas. When calculating the rates by age group, we found that the declining trends were only for older women and increasing trends for younger women, especially for women in the rural areas. CONCLUSION: The incidence and mortality rates declined during the period of 1988-2002 in China for older women. The younger women showed an increasing trend during the same period, especially for women in rural area.