Neoadjuvant PD-1 inhibitor (Sintilimab) in NSCLC.

INTRODUCTION: Programmed death receptor-1 (PD-1) inhibitors have shown efficacy in first-line treatment of NSCLC; however, evidence of PD-1 inhibitor as neoadjuvant treatment is limited. This is a phase 1b study to evaluate the safety and outcome of PD-1 inhibitor in neoadjuvant setting. METHODS: Treatment-naive patients with resectable NSCLC (stage IA-IIIB) received two cycles of sintilimab (200 mg, intravenously, day 1 out of 22). Operation was performed between day 29 and 43. Positron emission tomography-computed tomography scans were obtained at baseline and before the operation. The primary end point was safety. Efficacy end points included rate of major pathologic response (MPR) and objective response rate. Expression of programmed cell death ligand 1 was also evaluated (registration number: ChiCTR-OIC-17013726). RESULTS: A total of 40 patients enrolled, all of whom received two doses of sintilimab and 37 underwent radical resection. A total of 21 patients (52.5%) experienced neoadjuvant treatment-related adverse events (TRAEs). Four patients (10.0%) experienced grade 3 or higher neoadjuvant TRAEs, and one patient had grade 5 TRAE. Eight patients achieved radiological partial response, resulting in an objective response rate of 20.0%. Among 37 patients, 15 (40.5%) achieved MPR, including six (16.2%) with a pathologic complete response in primary tumor and three (8.1%) in lymph nodes as well. Squamous cell NSCLC exhibited superior response compared with adenocarcinoma (MPR: 48.4% versus 0%). Decrease of maximum standardized uptake values after sintilimab treatment correlated with pathologic remission (p < 0.00001). Baseline programmed cell death ligand 1 expression of stromal cells instead of tumor cells was correlated with pathologic regression (p = 0.0471). CONCLUSIONS: Neoadjuvant sintilimab was tolerable for patients with NSCLC, and 40.5% MPR rate is encouraging. The decrease of maximum standardized uptake values after sintilimab might predict pathologic response.

Clinical characteristics and medical service utilization of lung cancer in China, 2005-2014: Overall design and results from a multicenter retrospective epidemiologic survey.

OBJECTIVES: This study aimed to explore the clinical profile and its trajectory of lung cancer on clinicopathological characteristics and medical service utilization in China. METHODS: Patients diagnosed with primary lung cancer in tertiary hospitals during 2005-14 were selected from seven geographic regions of China. Data on clinical characteristics and medical service utilization was extracted from medical record, and the ten-year trends were explored. RESULTS: A total of 7184 patients were included, the mean age was 58.3 years and the male-to-female-ratio was 2.7. From 2005 to 2014, the proportion of ≥60 year-old patients increased from 41.2% to 56.2% (p < 0.001). The smoking rate decreased from 62.9% to 51.1% (p < 0.001) and the proportion of females increased from 23.5% to 31.9% (p < 0.001). The proportion of advanced stage increased from 41.9% to 47.4% (p < 0.001). Adenocarcinoma's proportion increased from 36.4% to 53.5% (p < 0.001) while that of squamous carcinoma decreased from 45.4% to 34.4% (p < 0.001). The application of chest X-ray dropped from 50.2% to 31.0% (p < 0.001) but that of chest CT increased from 65.8% to 81.4% (p < 0.001). As two main treatment options, chemotherapy (p = 0.290) and surgery (p = 0.497) remained stable. The medical expenditure per patient increased from 40,508 to 66,020 Chinese Yuan (p < 0.001). CONCLUSIONS: The sustaining high smoking exposure, increasing proportion of female patients, advancing clinical stage, shifting of predominant pathology and increasing medical expenditure demonstrate potential challenges and directions on lung cancer prevention and control in China. Despite substantial changes of clinical characteristics, main treatment options remained unchanged, which needs further investigation.

[Pattern of lymphatic metastasis and risk factor of esophageal carcinoma that invades less than adventitia].

OBJECTIVE: To explore the pattern of lymphatic metastasis and risk factors of esophageal carcinoma that invades less than adventitia. METHODS: Clinical data of 484 patients receiving esophagectomy from January 2011 to August 2014 were reviewed, whose carcinoma invaded less than adventitia. The lymph node metastasis pattern of the primary tumor and corresponding influence factor were analyzed. RESULTS: Total lymph node metastatic rate was 32.0% (155/484). Sixteen of 61 upper thoracic esophageal carcinoma patients (26.2%) had lymphatic metastasis. Fifty-five of 201 middle thoracic esophageal carcinoma patients (27.4%) had lymphatic metastasis. Eighty-four of 222 lower thoracic esophageal carcinoma patients(37.8%) had lymphatic metastasis. The deeper tumor invaded, the easier lymph node metastasis occurred, as well as the lower of the tumor differentiation and the larger of the tumor diameter. Multivariate analysis revealed lesion diameter (P=0.005), differentiation degree (P=0.007) and invasion depth (P=0.001) were independent risk factors of lymphatic metastasis in esophageal cancer that invaded less than adventitia. CONCLUSION: Depth of tumor invasion, diameter of tumor and tumor differentiation are risk factors of lymph node metastasis of esophageal carcinoma that invades less than adventitia.

Application of video-assisted thoracic surgery in the standard operation for thoracic tumors.

OBJECTIVE: To evaluate the short-term outcomes of video-assisted thoracic surgery (VATS) for thoracic tumors. METHODS: The data of 1,790 consecutive patients were retrospectively reviewed. These patients underwent VATS pulmonary resections, VATS esophagectomies, and VATS resections of mediastinal tumors or biopsies at the Cancer Institute & Hospital, Chinese Academy of Medical Sciences between January 2009 and January 2012. RESULTS: There were 33 patients converted to open thoracotomy (OT, 1.84%). The overall morbidity and mortality rate was 2.79% (50/1790) and 0.28% (5/1790), respectively. The overall hospitalization and chest tube duration were shorter in the VATS lobectomy group (n=949) than in the open thoracotomy (OT) lobectomy group (n=753). There were no significant differences in morbidity rate, mortality rate and operation time between the two groups. In the esophageal cancer patients, no significant difference was found in the number of nodal dissection, chest tube duration, morbidity rate, mortality rate, and hospital length of stay between the VATS esophagectomy group (n=81) and open esophagectomy group (n=81). However, the operation time was longer in the VATS esophagectomy group. In the thymoma patients, there was no significant difference in the chest tube duration, morbidity rate, mortality rate, and hospital length of stay between the VATS thymectomy group (n=41) and open thymectomy group (n=41). However, the operation time was longer in the VATS group. The median tumor size in the VATS thymectomy group was comparable with that in the OT group. CONCLUSIONS: In early-stage (I/II) non-small cell lung cancer patients who underwent lobectomies, VATS is comparable with the OT approach with similar short-term outcomes. In patients with resectable esophageal cancer, VATS esophagectomy is comparable with OT esophagectomy with similar morbidity and mortality. VATS thymectomy for Masaoka stage I and II thymoma is feasible and safe, and tumor size is not contraindicated. Longer follow-ups are needed to determine the oncologic equivalency of VATS lobectomy, esophagectomy, and thymectomy for thymoma vs. OT.

[Surgical treatment of sternal tumors: resection of the tumors and reconstruction of the chest wall defects].

OBJECTIVE: To investigate the efficacy of surgical treatment of sternal tumors and repairing methods of the chest wall defects. METHODS: Fifteen patients with sternal tumors were diagnosed and underwent resection of the sternal tumors according to the en-bolck principle and repair of the chest wall defects using various materials from January 1968 to December 2010 in our hospital. RESULTS: Of 6 patients with sternal manubrim tumors, one patient had reconstruction only with steel wire, other 5 patients healed completely after repair with soft materials. Of 7 patients with sternal body tumors, one patient recovered quickly without reconstruction because he had only partial resection; four patients had chest wall repair with soft materials, but they breathed hardly; and two patients had chest wall reconstruction with rigid materials. One patient had ventilatory support, another patient recovered quickly. Ventilatory support was needed in two patients treated by subtotal sternectomy because they had chest wall repair with soft materials. CONCLUSIONS: In surgical treatment of sternal tumors by manubrim sternetomy, the chest wall defects can be constructed with soft materials. After resection of sternal body tumors and subtotal sternectomy, the thoracic wall defects need to be reconstructed with rigid materials.

[Application of video assisted thoracic surgery for chest tumors: experience of 144 cases in a single institution].

OBJECTIVE: To evaluate the indication and safety of video assisted thoracic surgery (VATS) for chest tumors. METHODS: Data of 144 consecutive patients receiving VATS between January and November 2009 in Cancer hospital Chinese Academy of Medical Sciences were retrospectively reviewed. RESULTS: There was no conversion to open thoracotomy. Overall morbidity rate was 2.08% (3/144) and mortality rate was 0.69% (1/144). There were no significant differences for operative time, number of nodal dissection, morbidity rate, mortality rate, overall hospitalization and postoperative length of stay between VATS lobectomy group and open thoracotomy (OT) lobectomy group. Chest tube duration was shorter in the VATS lobectomy group than OT lobectomy group and more early-stage lung cancer patients were found in VATS group. There were no significant differences for number of nodal dissection, chest tube duration, morbidity rate, mortality rate, and postoperative length of stay between VATS lung wedge resection group and OT lung wedge resection group. Operative time and overall hospitalization were shorter in the VATS wedge resection group than OT wedge resection group. CONCLUSION: Morbidity and mortality rate of VATS were acceptable. VATS lobectomy can be used as an alternative surgical technique for early-stage lung cancer. For lung wedge resection, VATS was superior than OT.

[Identification and Functional Analysis of A Novel Candidate Oncogene RAP2B in Lung Cancer.].

BACKGROUND: RAP2B is one of the 50 novel candidate genes cloned from the differential expression cDNA libraries constructed in lung cancer cells. Though RAP2B contains conserved domain and belongs to Ras superfamily, the function of RAP2B in carcinogenesis is still poorly understood. The aim of this study is to explore the roles of RAP2B gene in carcinogenesis. METHODS: RT-PCR was applied to examine transcriptional status of RAP2B in the tumor and corresponding adjacent tissues collected from 27 patients with lung squamous cell carcinoma. RAP2B expression plasmid was constructed and transfected into Rat1 cells to evaluate the in vitro transformation ability through colony formation assay. Reporter gene assay was performed to reveal the relationship between RAP2B gene and NF-kappaB pathway. RESULTS: About 67% (18/27) of tumor tissues show higher mRNA expression than that in the corresponding adjacent normal tissues. Typical transforming focus formation was observed in Rat1 cells which were transfected with RAP2B gene. The reporter gene assay data showed that RAP2B activated NF-kappaB pathway more than 3 folds compared with the mock vector. CONCLUSIONS: RAP2B may be a novel candidate oncogene that plays important roles in carcinogenesis through activation of NF-kappaB pathway.

Characteristics and prognosis of primary malignant melanoma of the esophagus.

Primary malignant melanoma of the esophagus is an extremely rare but highly aggressive tumor. The preoperative diagnosis is complicated for the lack of specificity. Unfortunately, the prognosis of primary malignant melanoma of the esophagus remains dismal from most literatures. To better understand this special condition, we reviewed the medical records of patients with primary malignant melanoma of the esophagus in our center, retrospectively. Seven cases were seen at Cancer Hospital (Institute) of Chinese Academy of Medical Sciences from 1975 through 2006. Six patients had complete clinical data. Of the six patients, two were females and four were males. The patients mean age was 51 years, ranging from 41 to 60 years. Similar to esophageal carcinoma, dysphagia was the most common symptom. Only one patient, however, was pathologically diagnosed as primary malignant melanoma of the esophagus preoperatively. Surgical procedures were performed to all patients. Among the six patients one accepted radiotherapy perioperatively. Four patients accepted biochemotherapy postoperatively. The most common reason for death was metastasis. Four of the six patients had metastasis to the liver, adrenal gland, heart and lymph nodes, respectively. The survival varied from 5 months to 17 years and the median survival was 8 months. Our data show that primary malignant melanoma of the esophagus is a highly aggressive disease with poor prognosis. Surgery remains the first selected therapy. The role of radiotherapy and chemotherapy in the treatment of primary malignant melanoma of the esophagus is still uncertain.

Identification of genes differentially expressed in human primary lung squamous cell carcinoma.

To identify differentially expressed genes in lung squamous cell carcinomas (SCCs), the suppression subtractive hybridization method (SSH) was performed comparing six lung tumour tissues and 10 morphologically normal bronchial epithelial tissues. A cDNA library consisting of 220 upregulated genes in tumour tissue was established and named as LSCC (lung squamous cell carcinoma). Of them, six were tested using semi-quantitative reverse transcription-PCR on 27 pairs of tumour tissue and normal lung tissue. Differential expression was confirmed in five of these six genes, including IGFBP5, SQLE, RAP2B, CLDN1, and TBL1XR1. The elevated mRNA expression of RAP2B, CLDN1 and TBL1XR1, three genes located on chromosome 3q, were further validated in 64.3% (18/28), 82.1% (23/28), and 75.0% (21/28) of lung SCC tumour tissues, respectively, by quantitative real-time reverse transcription-PCR analysis. Moreover, western blot analysis showed that the protein expression of TBL1XR1 was also upregulated in 53.3% (8/15) of lung SCC tumour samples, as well as in five lung cancer cell lines and in one human immortalized bronchial epithelial cell line. All the initial characteristics of these genes were first reported in the lung SCCs. The differentially expressed genes reported in this study will provide a valuable resource for understanding the pathogenesis of lung SCCs and for discovery of novel diagnostic or therapeutic targets.

Mediastinal lymphangiohemangioma communicating with the left innominate vein.

The CT manifestation of lymphangiohemangioma in a 17-year-old boy is reported. A mass composed of the central malformed, dilated venous channels and peripheral unenhanced soft tissue was revealed in the anterior mediastinum. The venous feeding enhancement of the mass is very characteristic. The diagnosis of lymphangiohemangioma was made by pathologic study of the surgical specimen.

[Comparison of clinical and surgico-pathological TNM stage of 2007 lung cancer patients].

OBJECTIVE: An accurate clinical TNM staging of lung cancer is essential for the precise determination of the extent of the disease in order that an optimal therapeutic strategy can be planned. This is especially true in patients with marginally resectable tumors. Clinical over-staging of the disease may deny a patient the benefit of surgery, whereas under-staging may oblige a patient to accept a fruitless or even harmful surgery. We aimed to analyze preoperative clinical (c-TNM) and postoperative surgico-pathologic staging (p-TNM) of lung cancer patients in order to evaluate the accuracy of our clinical staging and its implications on the surgical strategy for lung cancer. METHODS: We did a retrospective comparison of c-TNM and p-TNM staging of 2007 patients with lung cancer surgically treated from January 1999 to May 2003. Preoperative evaluation and c-TNM staging of all patients were based on physical examination, laboratory studies, routine chest X-ray and CT scan of the chest and upper abdomen. Other examinations included sputum cytology, bronchoscopy, abdominal ultrasonography, bone scintiscan, brain CT/MRI, and mediastinoscopy whenever indicated. RESULTS: In the present study the comparison of c-TNM and p-TNM staging of 2007 patients with lung cancer revealed an overall concurrence rate of only 39.0%. In the entire series the extent of disease was clinically underestimated in 45.2% and overestimated in 15.8% of the patients. Among all c-TNM stages the c-IA/B stage of 1105 patients gave the highest rate (55.2%) of underestimating the extent of disease. Clinical staging of T subsets was relatively easy with an overall accuracy rate of 72.9%, while that of N subsets was relatively more difficult with an overall accuracy rate of 53.5%. Analysis also showed that c-IV stage may not be an absolute contraindication to surgery, because in half of the patients, c-M1 turned out to be p-M0, providing the possibility of resectional surgery depending on the status of T and N. CONCLUSION: For reasons to be further determined, the present preoperative clinical TNM staging of lung cancer remains a crude evaluation. Further efforts to improve its accuracy are needed.

[Screening of hypermethylated DNA fragments in tumor tissue derived from patients with lung cancer].

The investigations on the role of DNA methylation in carcinogenesis have been mainly focused on promoter hypermethylation of tumor suppressor genes. As a number of genes associated with cancer development may be influenced by DNA methylation, identification of these genes is of great importance for understanding the epigenetic alteration in carcinogenesis. In this study, hypermethylated regions of genomic DNA from Chinese lung cancer patients were identified by a modified methylation-sensitive arbitrarily primed PCR (MS-AP-PCR). Eight hypermethylated DNA fragments (HMDF) were separated from a PCR product region between 300 and 500bp in size. After cloning, sequencing and searching with Blast and NewCpGseek programs,the result showed that all of them were typical CpG island sequences, four fragments had 99% approximately 100% homology to regions on human chromosome 2, 7, 9 and 10, respectively,but only one revealed to be known gene. Neural Network Promoter Prediction, TSSG and TSSW programs were run to analyze possible functions of the rest 7 fragments, of which 4 were identified as candidate promoter regions, indicating that they might belong to new genes. The hypermethylated DNA fragments identified in this study might be specific epigenetic alterations in the Chinese lung cancer.

Identification of differentially expressed genes in human lung squamous cell carcinoma using suppression subtractive hybridization.

Lung cancer is one of the major causes of cancer-related deaths. Over the past decade, much has been known about the molecular changes associated with lung carcinogenesis; however, our understanding to lung tumorigenesis is still incomplete. To identify genes that are differentially expressed in squamous cell carcinoma (SCC) of the lung, we compared the expression profiles between primarily cultured SCC tumor cells and bronchial epithelial cells derived from morphologically normal bronchial epithelium of the same patient. Using suppression subtractive hybridization (SSH), two cDNA libraries containing up- and down-regulated genes in the tumor cells were constructed, named as LCTP and LCBP. The two libraries comprise 258 known genes and 133 unknown genes in total. The known up-regulated genes in the library LCTP represented a variety of functional groups; including metabolism-, cell adhesion and migration-, signal transduction-, and anti-apoptosis-related genes. Using semi-quantitative reverse transcription-polymerase chain reaction, seven genes chosen randomly from the LCTP were analyzed in the tumor tissue paired with its corresponding adjacent normal lung tissue derived from 16 cases of the SCC. Among them, the IQGAP1, RAP1GDS1, PAICS, MLF1, and MARK1 genes showed a consistent expression pattern with that of the SSH analysis. Identification and further characterization of these genes may allow a better understanding of lung carcinogenesis.

[Detection of hypermethylation of p16 gene in plasma DNA from lung cancer patients].

OBJECTIVE: To detect hyper methylation of p16 gene in plasma DNA from patients with lung cancer, and to assess its potential as a malignant marker. METHODS: Using a modified semi-nested methylation-specific PCR (MSP), the status of methylation of the p16 was investigated in plasma DNA from 137 lung cancer patients and 112 matched tumor tissues. RESULTS: Hypermethylation of the p16 was present in 75.2% (103/137) of the plasma samples and 80.4% (90/112) of the tumor tissues. Hypermethylation of the p16 in the plasma was detected in 77.9% squamous-cell carcinoma, 65.1% adenocarcionma, 75.1% adeno-squamous-cell carcinoma, and 91.7% small-cell lung cancer. Only in those patients whose tumor tissues had hypermethylation of p16 gene, similar changes could be detected in their plasma samples. Hypermethylation of the p16 in plasma and the corresponding tumor tissues was not significantly correlated with the clinical stage and pathological type of the tumor. CONCLUSION: The result indicates that hypermethylation of the p16 may be a useful marker in the auxiliary diagnosis of lung cancer.

[Hypermethylation of p16 gene in clinical specimens of patients with lung cancer].

OBJECTIVE: To evaluate aberrant methylation of the p16 promoter as a useful biomarker of lung cancer. METHODS: A modified methylation-specific semi-nested PCR was performed to detect p16 hypermethylation in the matched samples of tumor tissue, blood plasma and sputum derived from 51 cases of lung cancer patients. RESULTS: Hypermethylation of p16 promoter was demonstrated in 84.3% of the tumor tissues, 70.6% of the blood plasma and 76.5% of the sputum specimens, respectively. Only the patients whose tumor tissues had p16 hypermethylation exhibited aberrant methylation in their plasma and/or sputum specimens. Combining with cytological examination, 92.2% of the patients with lung cancer could be detected by p16 hypermethylation assay in both sputum and plasma samples. CONCLUSION: The results indicate that p16 hypermethylation in plasma and sputum identified by semi-nested PCR is a biomarker of lung cancer which can be useful as an auxillary diagnostic parameter.