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.

Pathologic responses and surgical outcomes after neoadjuvant immunochemotherapy versus neoadjuvant chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma.

Background: Currently, the role of immunotherapy in neoadjuvant setting for patients with locally advanced esophageal squamous cell carcinoma (ESCC) is gradually attracting attention. Few studies compared the efficacy of neoadjuvant immunochemotherapy (NICT) and neoadjuvant chemoradiotherapy (NCRT). Our study aimed to compare treatment response and postoperative complications after NICT followed by surgery with that after conventional NCRT in patients with locally advanced ESCC. Methods: Of 468 patients with locally advanced ESCC, 154 received conventional NCRT, whereas 314 received NICT. Treatment response, postoperative complications and mortality between two groups were compared. Pathological response of primary tumor was evaluated using the Mandard tumor regression grade (TRG) scoring system. Pathological complete response (pCR) of metastatic lymph nodes (LNs) was defined as no viable tumor cell within all resected metastatic LNs. According to regression directionality, tumor regression pattern was summarized into four categories: type I, regression toward the lumen; type II, regression toward the invasive front; type III, concentric regression; and type IV, scattered regression. Inverse probability propensity score weighting was performed to minimize the influence of confounding factors. Results: After adjusting for baseline characteristics, the R0 resection rates (90.9% vs. 89.0%, P=0.302) and pCR (ypT0N0) rates (29.8% vs. 34.0%, P=0.167) were comparable between two groups. Patients receiving NCRT showed lower TRG score (P<0.001) and higher major pathological response (MPR) rate (64.7% vs. 53.6%, P=0.001) compared to those receiving NICT. However, NICT brought a higher pCR rate of metastatic LNs than conventional NCRT (53.9% vs. 37.1%, P<0.001). The rates of type I/II/III/IV regression patterns were 44.6%, 6.8%, 11.4% and 37.1% in the NICT group, 16.9%, 8.2%, 18.3% and 56.6% in the NCRT group, indicating a significant difference (P<0.001). Moreover, there were no significant differences in the incidence of total postoperative complications (35.8% vs. 39.9%, P=0.189) and 30-d mortality (0.0% vs. 1.1%, P=0.062). Conclusion: For patients with locally advanced ESCC, NICT showed a R0 resection rate and pCR (ypT0N0) rate comparable to conventional NCRT, without increased incidence of postoperative complications and mortality. Notablely, NICT followed by surgery might bring a promising treatment response of metastatic LNs.

Genome-scale CRISPR activation screening identifies a role of ELAVL2-CDKN1A axis in paclitaxel resistance in esophageal squamous cell carcinoma.

Neoadjuvant chemotherapy (NAC) may provide survival benefits for patients with advanced esophageal squamous cell carcinoma. However, tumor cells can display primary or secondary resistance to paclitaxel (PTX), a primary component of induction chemotherapy regimen. To identify genes capable of conveying PTX resistance, we performed a genome-wide CRISPR transcriptional activation library in human KYSE-180 cells. High throughput next generation sequencing was further applied to establish the phenotype-to-genotype relationship. Our highest-ranking hits are CDKN1A, TSPAN4, ELAVL2, JUNB and PAAF1. We generated evidence that esophageal tumors with high CDKN1A, ELAVL2 and TSPAN4 levels, quantified using qRT-PCR and Western blot assays, showed poorer chemotherapy response. Higher expression levels of TSPAN4 and ELAVL2 protein are independent risk factors for poor chemotherapy response in ESCC patients. We then found that overexpression of CDKN1A, ELAVL2 or TSPAN4 in ESCC cell lines significantly promoted the resistance to PTX by inhibiting cell apoptosis. Interestingly, ESCC cells overexpressed CDKN1A, ELAVL2 or TSPAN4 also acquired resistance to cisplatin (DDP). This phenomenon may be explained by cross-resistance of chemotherapy. We additionally found an association between ELAVL2 and CDKN1A, which may be regarded as the upstream and downstream factors that synergistically involved in the regulation of chemo-resistance in ESCC. Therefore, our study demonstrated that the genome-wide CRISPR activation library is a powerful strategy for the discovery of chemo-resistant genes critical for ESCC and we reported the first evidence that the ELAVL2-CDKN1A axis may be an important mechanism involved in chemo-resistance in ESCC.

The identification of the ATR inhibitor VE-822 as a therapeutic strategy for enhancing cisplatin chemosensitivity in esophageal squamous cell carcinoma.

Inducing DNA damage is known to be one of the mechanisms of cytotoxic chemotherapy agents for cancer such as cisplatin. The endogenous DNA damage response confers chemoresistance to these agents by repairing DNA damage. The initiation and transduction of the DNA damage response (DDR) signaling pathway, which is dependent on the activation of ATM (ataxia-telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3-related), is essential for DNA damage repair, the maintenance of genomic stability and cell survival. Therefore, ATM or ATR inhibition is considered as a promising strategy for sensitizing cancer cells to chemotherapy. This study is aimed to explore the effect of ATR inhibitor on sensitizing ESCC (esophageal squamous cell carcinoma) cells to cisplatin, and whether ATM deficiency could impact the sensitization. We found that 21.5% of ESCC cases had ATM deficiency and that patients with ATR activation after neoadjuvant chemotherapy had worse chemotherapy response and poorer overall survival than that without ATR activation (32 mons vs. >140mons). Then, it was shown that VE-822 inhibited ATR-CHK1 pathway activation, leading to the accumulation of cisplatin-modified DNA. And it inhibited cell proliferation, induced cell cycle arrest in G1 phase and enhanced cell apoptosis. Moreover, VE-822 significantly sensitized ESCC cells to cisplatin, and these two drugs had synergistic effects, especially in ATM-deficient cells, in vitro and in vivo. Our results suggest that ATR inhibition combining with cisplatin is a new strategy for managing patients with ESCC, especially those with ATM-deficiency. However, this is an idea that requires further validation.

P21, COX-2, and E-cadherin are potential prognostic factors for esophageal squamous cell carcinoma.

Much research effort has been devoted to identifying prognostic factors for esophageal squamous cell carcinoma (ESCC) by immunohistochemistry; however, no conclusive findings have been reached thus far. We hypothesized that certain molecules identified in previous studies might serve as useful prognostic markers for ESCC. Therefore, the aim of the current study was to validate the most relevant markers showing potential for ESCC prognosis in our prospective esophageal cancer database. A literature search was performed using the PubMed database for papers published between 1980 and 2015 using the following key words: 'esophageal cancer,' 'prognosis,' and 'immunohistochemistry.' Literature selection criteria were established to identify the most widely studied markers, and we further validated the selected markers in a cohort from our single-surgeon team, including 153 esophageal cancer patients treated from 2000 to 2010. A total of 1799 articles were identified, 82 of which met the selection criteria. Twelve markers were found to be the most widely studied, and the validation results indicated that only P21, COX-2, and E-cadherin were independent prognostic factors for ESCC patients in this series. The systemic review and cohort validation suggest that P21, COX-2, and E-cadherin are potential prognostic factors for ESCC, paving the way for more targeted prospective validation in the future.

The equivalent efficacy of multiple operations for multiple primary lung cancer and a single operation for single primary lung cancer.

BACKGROUND: The incidence of synchronous and metachronous multiple primary lung cancers (MPLCs) has been increasing recently. The new multidisciplinary classification of lung adenocarcinoma and TNM Classification of Lung Cancer (7(th) edition, 2009), have improved the understanding of MPLC. Most researchers recommend that surgical therapy should be actively pursued if the patient's physical condition and lung function permit it and if a complete cure can be achieved. However, few studies have reported the long-term efficacy of surgical treatment for MPLC, which we explored in this study. METHODS: A total of 1,290 Lung cancer patients from a prospectively maintained database, treated by a single surgeon group between January 2000 and July 2013, at Beijing Cancer Hospital, Peking University, were reviewed. We retrospectively analyzed the clinical data of 31 patients diagnosed with MPLC out of 1290 lung cancer patients, focusing on long-term survival. RESULTS: MPLC patients accounted for 2.4% (31/1,290) of the patient cohort: 27 had synchronous MPLC (87.1%) and 4 had metachronous MPLC (12.9%). The 1-, 3- and 5-year postoperative survival rates were 100%, 75.8% and 75.8%. On stratification according to TNM stage, the 1-, 3- and 5-year of patients with stage I cancer (20 patients) were 100%, 77.2% and 77.2%, not statistically significant with those for the entire cohort (1,290 patients; 95.4%, 80.5% and 66.2%, P=0.455). CONCLUSIONS: When the patient's physical condition and tumor-related factors permit it, surgery should be the first choice of treatment for MPLC; it is associated with an equivalent efficacy to that of surgery for single primary lung cancer.

Deregulated HOXB7 Expression Predicts Poor Prognosis of Patients with Esophageal Squamous Cell Carcinoma and Regulates Cancer Cell Proliferation In Vitro and In Vivo.

BACKGROUND: We observed abnormal HOXB7 expression in esophageal squamous cell carcinoma (ESCC) previously. This study was to evaluate the prognostic significance of HOXB7 and reveal the potential mechanism. METHODS: Immunohistochemistry was used to confirm the abnormal expression of HOXB7 in ESCC. The prognostic significance of HOXB7 expression was analyzed in two independent cohorts. RNAi was used to establish two stable HOXB7-knockdown cell strains. CCK8 assay, cell growth curve assay, colony formation assay, flow cycle analysis and tumorigenicity assay in nude mice were employed to investigate the effect of HOXB7 on proliferation in vitro and in vivo. RESULTS: Immunohistochemistry confirmed the abnormal expression of HOXB7 in ESCC compared with paracancerous mucosa (18/23 vs. 9/23, p=0.039). HOXB7 expression was positively correlated with the T stage, lymph node metastasis and TNM stage. The median survival of patients with high HOXB7 expression was significantly shorter than that with low expression (45 months vs. 137 months, p = 0.007 for cohort 1; 19 months vs. 34 months, p = 0.001 for cohort 2). Multivariate survival analysis showed that HOXB7 expression was another independent prognostic factor (HR [95% CI] = 0.573 [0.341-0.963], p = 0.036 for cohort 1; HR [95%CI] = 0.543 [0.350-0.844], p = 0.024 for cohort 2). Experiments in vitro and in vivo showed that after knockdown of HOXB7, the proliferation rate dropped, growth rate descended, colony-formation ability reduced, G1-phase arrest occurred and the tumorigenicity reduced remarkably. CONCLUSIONS: HOXB7 could promote cancer cell proliferation and might be an independent prognostic factor for patients with ESCC.

The survival predictive significance of HOXC6 and HOXC8 in esophageal squamous cell carcinoma.

BACKGROUND & AIM: Esophageal squamous cell carcinoma (ESCC), a common disease in China, is mainly treated surgically. We established a prospective database of patients with esophageal cancer between January 2000 and December 2010, including 486 subjects with ESCC who underwent surgical treatment. In this study, we explored the prognostic significance of the expressions of HOXC6 and HOXC8, responsible for embryonic development, by studying the specimens collected from clinical subjects during strict follow-up periods. MATERIALS & METHODS: Immunohistochemistry was used to detect the expressions of HOXC6 and HOXC8 in 274 ESCC subjects including 138 ESCC subjects treated with surgery alone and 136 ESCC subjects treated with neoadjuvant chemotherapy. Survival analysis was performed from the day of surgery to August 2013. RESULTS: The 5-y survival rate of the 274 ESCC subjects was 44.2%, with a median survival time of 44.12 mo. For the 274 ESCC subjects involved in the investigation of HOXC6 and HOXC8 expressions, the median survival time of subjects with high-level expressions of HOXC6 and HOXC8 was shorter than that for subjects with low-level expressions (P = 0.001, P < 0.001, respectively). Similar results were obtained from the analysis of the prognostic value of HOXC6 and HOXC8 in the group treated with surgery alone and the group treated with neoadjuvant chemotherapy. Multivariate analysis demonstrated that HOXC6 and HOXC8 expressions were independent prognostic factors in patients with ESCC. CONCLUSIONS: The HOXC6 and HOXC8 genes can be used as prognostic markers in patients with ESCC, but prospective studies are still needed to confirm.

[Impact of early enteral nutrition on the intestinal motility of patients after esophagectomy].

OBJECTIVE: To assess the impact of early enteral nutrition (EN) on the intestinal motility of patients after esophagectomy. METHODS: Thirty-five consecutive patients undergoing esophagectomy for esophageal cancer by a single surgical team from the Peking University Cancer Hospital from June 2011 to July 2011 were enrolled. Patients were randomly divided into EN group (n=20) and parenteral nutrition group (control group, n=15) within 24 h after esophagectomy procedure. Bowel sound recovery time was monitored by auscultation, and the gastrointestinal tract symptoms were recorded. RESULTS: Bowel sound recovery time was (45.1±20.3) h in the EN group, and was (56.7±17.0) h in the control group (P=0.082). Gastrointestinal symptoms such as nausea, abdominal distension, diarrhea occurred in 4 patients in EN group and 3 patients in control group and were alleviated by lowering infusion speed and more off-bed ambulation, and no significant difference was seen between the two groups (P=1.000). CONCLUSIONS: Early enteral nutrition in the patients after esophagectomy is safe and feasible. Early enteral nutrition does not delayed bowel function recovery or increase gastrointestinal symptoms.

[Efficacy analysis of comprehensive treatment in small cell esophageal carcinoma following resection].

OBJECTIVE: To summarize the surgical outcome of patients with small cell esophageal carcinoma(SCEC). METHODS: Clinical data of patients with esophageal carcinoma were retrospectively collected from March 2000 to March 2011 at the Thoracic Surgery Department of the Peking University Cancer Hospital. Data included tumor characteristics, staging, treatment, response, short-term outcome, and long-term survival. RESULTS: A total of 546 patients with esophageal carcinoma were identified, among whom there were 15 patients with SCEC(2.7%). Fourteen cases received multimodality treatment based on operation and one underwent operation alone. Four patients had preoperative chemotherapy and 10 had postoperative chemotherapy. Four patients had postoperative radiation. After excluding one case of postoperative death within 3 months, the median overall survival was 14.3 months(range, 4 to 99 months), significantly worse than those with non-SCEC(42.2 months, P<0.05). CONCLUSION: SCEC is rare and the outcomes are poor. It should be considered as a systematic disease.

[Disability and common treatment strategies associated with knee pain in a rural Chinese population].

OBJECTIVE: To estimate the burden of disability and health services use by people with knee pain, with or without radiographic evidence of osteoarthritis (OA), in rural northern China. METHODS: A population-based cross-sectional survey was conducted among 1030 residents of Wuchuan County, Inner Mongolia, aged 50 years old and over. The participants completed an interviewer-based questionnaire and obtained bilateral weight-bearing posterior-anterior semi-flexed knee radiographs. RESULTS: Of 1027 participants with knee radiographs, 513 (50%) participants reported knee pain in most days of at least a month over the past 12 months. Of those with knee pain, 109 (21%) had radiographic OA (Kellgren Lawrence grade > or =2) in symptomatic knees. Adjusting for age, gender, BMI, education and back pain, the presence of knee pain was associated with a significantly greater difficulty in walking, climbing 10 steps, stooping, performing cleaning chores and preparing meals. Among 513 subjects with knee pain, the presence of radiographic disease was significantly associated with the presence of unbearable pain (36% vs. 59%), restricted activity (39% vs. 64%), use of NSAIDs (78% vs. 88%) and consulting a doctor over the last 12 months (33% vs. 59%). CONCLUSION: Knee pain is associated with significant physical disability in rural China The prevalent use of NSAIDs for knee pain and a low use of knee surgery should be of particular concerns. These findings will be useful to guide the distribution of future health care resources and preventive strategies.

[Long-term efficacy of transhiatal esophagectomy for esophageal carcinoma and esophagogastric junction cancer].

OBJECTIVE: To evaluate the long-term efficacy of transhiatal esophagectomy (THE) for esophageal carcinoma or esophagogastric junction cancer. METHODS: Between March 2000 and December 2009, a total of 544 patients with either esophageal carcinoma or esophagogastric junction cancer underwent esophagectomy via THE (n=63) or other approaches (n=481) in Beijing cancer hospital institution. Procedures were performed by a single surgeon team. Long-term survival was compared between two groups. RESULTS: The 1-year, 3-year, 5-year, and 8-year accumulative survival rates in THE group were 91.0%, 60.5%, 44.6%, and 44.6%, respectively, while those in non-THE group were 84.5%, 49.2%, 37.2%, and 28.7%, respectively. The THE group showed better long-term survival than the non-THE group, however the difference was not statistically significant. CONCLUSION: THE is a safe alternative for esophageal carcinoma and esophagogastric junction cancer.

[Involvement of amygdala in the emotional processing of pain].

This review will discuss the recent studies about the role of amygdala in pain processing. Pain has a strong emotional component, and the amygdala plays a major role in emotional behaviours. An increasing number of evidences implicated the amygdala in the process of pain encoding and modulation. Amygdala may integrate the nociceptive information from the spinal cord and the trigeminal nucleus with information of other sensory modalities from thalamic and cortical areas, and generate the emotional reactions and the behavioral responses of pain. On the other hand, amygdala may also be involved in pain modulation through connections with periaquiductal gray (PAG) , rostral ventromedial medulla (RVM), and other brain stem areas.