Establishment and validation of a multigene model to predict the risk of relapse in hormone receptor-positive early-stage Chinese breast cancer patients / 中华医学杂志(英文版)

BACKGROUND@#Breast cancer patients who are positive for hormone receptor typically exhibit a favorable prognosis. It is controversial whether chemotherapy is necessary for them after surgery. Our study aimed to establish a multigene model to predict the relapse of hormone receptor-positive early-stage Chinese breast cancer after surgery and direct individualized application of chemotherapy in breast cancer patients after surgery.@*METHODS@#In this study, differentially expressed genes (DEGs) were identified between relapse and nonrelapse breast cancer groups based on RNA sequencing. Gene set enrichment analysis (GSEA) was performed to identify potential relapse-relevant pathways. CIBERSORT and Microenvironment Cell Populations-counter algorithms were used to analyze immune infiltration. The least absolute shrinkage and selection operator (LASSO) regression, log-rank tests, and multiple Cox regression were performed to identify prognostic signatures. A predictive model was developed and validated based on Kaplan-Meier analysis, receiver operating characteristic curve (ROC).@*RESULTS@#A total of 234 out of 487 patients were enrolled in this study, and 1588 DEGs were identified between the relapse and nonrelapse groups. GSEA results showed that immune-related pathways were enriched in the nonrelapse group, whereas cell cycle- and metabolism-relevant pathways were enriched in the relapse group. A predictive model was developed using three genes ( CKMT1B , SMR3B , and OR11M1P ) generated from the LASSO regression. The model stratified breast cancer patients into high- and low-risk subgroups with significantly different prognostic statuses, and our model was independent of other clinical factors. Time-dependent ROC showed high predictive performance of the model.@*CONCLUSIONS@#A multigene model was established from RNA-sequencing data to direct risk classification and predict relapse of hormone receptor-positive breast cancer in Chinese patients. Utilization of the model could provide individualized evaluation of chemotherapy after surgery for breast cancer patients.

Potential unreliability of ALK variant allele frequency in the efficacy prediction of targeted therapy in NSCLC / 医学前沿

Anaplastic lymphoma kinase (ALK) is the most common fusion gene involved in non-small cell lung cancer (NSCLC), and remarkable response has been achieved with the use of ALK tyrosine kinase inhibitors (ALK-TKIs). However, the clinical efficacy is highly variable. Pre-existing intratumoral heterogeneity (ITH) has been proven to contribute to the poor treatment response and the resistance to targeted therapies. In this work, we investigated whether the variant allele frequencies (VAFs) of ALK fusions can help assess ITH and predict targeted therapy efficacy. Through the application of next-generation sequencing (NGS), 7.2% (326/4548) of patients were detected to be ALK positive. On the basis of the adjusted VAF (adjVAF, VAF normalization for tumor purity) of four different threshold values (adjVAF < 50%, 40%, 30%, or 20%), the association of ALK subclonality with crizotinib efficacy was assessed. Nonetheless, no statistical association was observed between median progression-free survival (PFS) and ALK subclonality assessed by adjVAF, and a poor correlation of adjVAF with PFS was found among the 85 patients who received first-line crizotinib. Results suggest that the ALK VAF determined by hybrid capture-based NGS is probably unreliable for ITH assessment and targeted therapy efficacy prediction in NSCLC.

The role played by human epidermal growth factor receptor 2 amplification/overexpression in gallbladder cancer and its association with clinico-pathology and prognosis / 中华肝胆外科杂志

Objective:To study the amplification / overexpression of human epidermal growth factor receptor 2 (HER2) in patients with gallbladder cancer, and to analyze the correlation between amplification/overexpression of HER2 with clinicopathological features and survival in patients after R 0 resection. Methods:There were 14 males and 26 females, aged (60.3±8.7) years old and treated at the Cancer Hospital of Chinese Academy of Medical Sciences from January 2011 to December 2016 who met the inclusion criteria of the study. Immunohistochemistry and fluorescence in situ hybridization were used to detect amplification / expression of HER2 in resected tumor tissues. Patients were divided into two groups according to the HER2 gene expression: the HER2-negative group ( n=40) and the HER2-positive group ( n=10). The Chi-square test was used to analyze the relationship between amplification/expression of HER2 and clinicopathological parameters. Patients were followed up by telephone for prognosis. The Kaplan-Meier method was used for survival analysis. The Cox proportional hazard model was used to explore factors affecting prognosis of gallbladder cancer patients. Results:HER2 amplification/overexpression was found in 10 patients with gallbladder cancer, with a positive rate of HER2 being 20.0% (10/50). There was a significant difference in the proportion of patients with vascular tumor thrombus between the HER2 negative group and the HER2 positive group [7.5%(3/40) vs. 30.0%(3/10), P<0.05]. On follow-up, data of 46 patients was available. There were 36 patients in the HER2-negative group and 10 patients in the HER2-positive group. Compared with the HER2-negative group, the median recurrence-free survival (10.10 vs. 75.07 months) and the median overall survival (16.77 vs. 83.07 months) of the HER2-positive group were both significantly lower (both P<0.05) than the HER2-negative group. Univariate analysis showed HER2 positivity to be a risk factor for recurrence-free and overall survival in patients with gallbladder cancer after radical resection. Cox multivariable analysis revealed that lymph node metastasis was an independent risk factor for both recurrence-free ( HR=4.31, 95% CI: 1.92-9.68, P<0.001) and overall survival ( HR=3.44, 95% CI: 1.08-11.00, P=0.037). Conclusion:Amplification / overexpression of HER2 was associated with venous invasion and worse prognosis in patients with gallbladder cancer.

Analysis on the causes of estrogen receptor-negative and progesterone receptor-positive breast cancer / 中华内分泌外科杂志

The pathological subtypes of breast cancer can be further divided into different molecular subtypes based on their immunohistochemical staining, such as estrogen receptor (ER) , progesterone receptor (PR) , human epidermal growth factor receptor2 (HER2) and Ki67 expression, including luminal subtype, HER2 overexpression subtype and triple negative subtype. The luminal subtype is defined as ER and/or PR positive. In molecular mechanism, the expression activity of ER can regulate the expression of PR, so the expression of ER and PR is usually consistent. However, in the process of detection, some breast cancers with inconsistent ER/PR expression often appear, especially those with ER (-) /PR (+) . There is still controversy about whether such cases are true. Patients with this type of breast cancer should be subjected to ER and PR immunohistochemical staining again, and then reclassified according to HER2 status. The expression of ER/PR is closely related to the efficacy of endocrine therapy for breast cancer, so its test results will directly affect the treatment options of clinician. This article will review and discuss the research progress of the causes and mechanisms of ER (-) /PR (+) breast cancer.

The analysis of genetic and clinicopathologic characteristics in patients with follicular thyroid neoplasm / 中华肿瘤杂志

Objective@#To explore the molecular characteristics of follicular variant papillary thyroid carcinoma (FVPTC), follicular thyroid adenoma (FTA) and follicular thyroid carcinoma (FTC), and investigate their role in tumorigenesis, differential diagnosis and prognosis evaluation in patients with follicular thyroid neoplasm.@*Methods@#We retrospectively analyzed 50 surgical resection samples of follicular thyroid neoplasm. DNA was obtained from formalin-fixed, paraffin-embedded tissue, and subjected to next-generation sequencing (NGS) to analyze 50 hotspots for mutation in genes.@*Results@#47 samples passed quality control, including 29 FVPTCs, 8 FTAs and 10 FTCs. 75.9% of FVPTCs harbored mutated genes: BRAF V600E (31.0%, 9/29) was the most frequent, followed by TP53 (27.6%, 8/29), and N/KRAS (20.7%, 6/29). In contrast, 37.5% (3/8) FTAs carried NRAS Q61R mutation with 12.5% (1/8) FTA carrying mutated BRAF G466E. 20% (2/10) FTCs harbored NRAS Q61R mutation, and 20% (2/10) FTCs with TP53 mutations. BRAF V600E gene mutation only appeared in FVPTC, and was associated with age of onset and lymph node metastasis. There was no significant correlation between N/KRAS mutations and clinical pathologic features. Patients with lymph node metastasis group seems to have more TP53 mutation.@*Conclusions@#BRAF V600E gene mutation can be used to identity FVPTC from FTA/FTC. N/KRAS mutations cannot be used as the exclusive indicator of benign and malignant in thyroid follicular tumor. TP53 mutations play an important role in the process of follicular thyroid neoplasm, indicating more aggressive behavior and poor prognosis.

Clinicopathological characteristics and differential diagnosis of interdigitating dendritic cell sarcoma / 中华肿瘤杂志

Objective@#To analyze the clinicopathological features and differential diagnosis of interdigitating dendritic cell sarcoma (IDCS).@*Methods@#The clinical pathological features of 7 IDCS were analyzed. Among them, the follow-up results of 6 cases were available.@*Results@#Among the 7 IDCS patients, 4 cases were male and 3 were female. The age of the patients ranged from 26 to 69 years.Three cases were originated from lymph nodes and 4 cases were originated from skin, stomach, adrenal gland and mesentery, respectively. Microscopically, the tumor cells presented as fascicular and storiform proliferation and infiltrated by lymphocytes. The tumor cells were short-spindle or ovoid, with indistinct border of cytoplasm. The immunohistochemistry results showed that tumor cells were S-100, Vim, CD68 and CD163 positive, and AE1/AE3, EMA, CD117, CD34, Desmin, SMA, CD1α, CD21, CD23, CD35, HMB45, Melan-A, MelanPan and ALK negative.The BRAF mutation and clonal rearrangement of T and B cells were not detected. Among the follow-up period of 7 IDCS patients, 3 occurred disease progressions.@*Conclusions@#IDCS is extremely rare with unique pathological features, and its lesion is not limited to the lymph node. The IDCS patients with extensive lesions may have worse prognose. The differential diagnosis of IDCS includes other histiocytic and dendritic cell neoplasms, malignant melanoma and soft tissue neoplasms.

Consistency of ALK Ventana-D5F3 immunohistochemistry interpretation in lung adenocarcinoma among Chinese histopathologists / 中华病理学杂志

Objective@#To understand the consistency of ALK Ventana-D5F3 immunohistochemistry (IHC) interpretation in Chinese lung adenocarcinoma among histopathologists from different hospitals, and to recommend solution for the problems found during the interpretation of ALK IHC in real world, with the aim of the precise selection of patients who can benefit from ALK targeted therapy.@*Methods@#This was a multicenter and retrospective study. A total of 109 lung adenocarcinoma cases with ALK Ventana-D5F3 IHC staining were collected from 31 lung cancer centers in RATICAL research group from January to June in 2018. All cases were scanned into digital imaging with Ventana iSCANcoreo Digital Slide Scanning System and scored by 31 histopathologists from different centers according to ALK binary (positive or negative) interpretation based on its manufacturer′s protocol. The cases with high inconsistency rate were further analyzed using FISH/RT-PCR/NGS.@*Results@#There were 49 ALK positive cases and 60 ALK negative cases, confirmed by re-evaluation by the specialist panel. Two cases (No. 2302 and No.2701) scored as positive by local hospitals were rescored as negative, and were confirmed to be negative by RT-PCR/FISH/NGS. The false interpretation rate of these two cases was 58.1% (18/31) and 48.4% (15/31), respectively. Six out of 31 (19.4%) pathologists got 100% accuracy. The minimum consistency between every two pathologists was 75.8%.At least one pathologist gave negative judgement (false negative) or positive judgement (false positive) in the 49 positive or 60 negative cases, accounted for 26.5% (13/49), 41.7% (25/60), respectively, with at least one uncertainty interpretation accounted for 31.2% (34/109).@*Conclusion@#There are certain heterogeneities and misclassifications in the real world interpretation of ALK-D5F3 IHC test, which need to be guided by the oncoming expert consensus based on the real world data.

Combination of environmental friendly reagent and ultrasonic assisted rapid processing for protein and molecular detection in tumor biopsy specimens / 中华病理学杂志

Objective@#To investigate the impact of ultrasonic assisted rapid processing technique combined with the environment friendly reagent (which can be utilized in fixing,dehydrating and clearing) on processing tumor biopsy specimens and the subsequent target detection.@*Methods@#Postoperative tissue samples of 56 cases of breast cancer, colorectal cancer, lung cancer, stomach cancer, liver mass, bladder mass, uterus mass were obtained at the National Cancer Center, Cancer Hospital, Chinese Academy of Medical Sciences from February to April, 2017. Three specimens ranging in size from 1 to 3 mm were collected from each sample, and were separated into control group (traditional tissue-processing method); experiment group 1 (3.7% neutral buffered formaldehyde fixation, composite environment friendly reagent and ultrasonic assisted rapid processing) and experimental group 2 (composite environment friendly reagent direct fixation, higher temperature and longer time for tissue processing). Two pathologists blinded to the experimental groups scored totally the nuclear, cytoplasmic, and membrane staining of 43 cases of immunohistochemistry (IHC), four HER2 fluorescence in situ hybridization (FISH), 20 extracted DNA quality and four EGFR gene mutation detection in lung adenocarcinoma; the results were compared with the control group.@*Results@#There was no difference in the IHC staining, HER2 FISH, the DNA quality, and EGFR genetic results between experimental group 1 and control group. For experiment group 2, comparing results of IHC staining, HER2 FISH and the quality of DNA, there was no obvious difference from control group and experiment group 1, but might show an increase in the background of IHC staining. The difference between the treatment temperature and time in the experimental group 2 did not affect the results of the gene mutation detection.@*Conclusions@#Environment freindly reagent and ultrasonic assisted rapid processing equipment could be used for rapid processing and diagnosis for tumor biopsies. Using complex environment-friendly reagents supplement fixation, higher treatment temperature and longer treatment time do not significantly affect the IHC, FISH and molecular detection accuracy.

The clinical and pathological features, biomarker characteristics and prognosis analysis of lung adenosquamous carcinoma / 中华肿瘤杂志

Objective@#Adenosquamous carcinoma of lung is an uncommon subtype with more aggressive behavior and poor prognosis than adenocarcinoma and squamous cell carcinoma. This study was aimed to investigate the clinicopathological characteristics and prognostic factors of lung adenosquamous carcinoma.@*Methods@#The pathological features and follow-up data of 133 patients were collected and the prognostic factors of these patients were retrospectively analyzed.@*Results@#Among the 133 patients, 81 cases (60.9%) smoked. Among the 62 patients whose percentage of histological components were identified, 45 cases had >50% adenocarcinoma components, and 17 cases had >50% squamous cell carcinoma components. 55 patients had lymph node metastasis at the first visit. All patients accepted at least one test of tumor driven gene mutation, and the results showed that the mutation rate of EGFR was 50.8% (67/132), the mutation rate of K-ras was 8.6% (11/128), the ALK-positive rate was 4.2% (2/48). The gender, smoking status, and the proportion of pathological components were the main influence factors of EGFR mutation status. The median overall survival was 28 months, the rates of 1-year, 3-year, and 5-year survival were 72.9%, 23.3%, and 9.0%, respectively. EGFR tyrosine kinase inhibitors (TKIs) treatment was an independent risk factor for prognose of these patients (P=0.024).@*Conclusions@#Lung adenosquamous carcinoma is a rare subtype with high malignancy and poor prognosis. Early diagnosis and driven-mutation-based individualized therapy may improve the survival of patients with lung adenosquamous carcinoma.

Review on Treatment Modalities for Resectable IIIa/N2 Non-small Cell Lung Cancer / 中国肺癌杂志

Standard treatment for resectable IIIa/N2 non-small-cell lung cancer (NSCLC) is still under debate. Optional treatments include chemotherapy, radiotherapy and surgery, other options include target therapy and immunotherapy. Multidisciplinary treatment has therefore been emphasized by various clinical trials, including bimodality strategy which has been defined as chemotherapy plus surgery or chemotherapy plus radiotherapy, and trimodality treatment which refers to chemotherapy plus surgery and radiotherapy. However, there is still no consensus on the optimal strategy on treating resectable IIIa/N2 NSCLC. Therefore, we reviewed a series of phase II and III clinical trials as well as some meta-analyses and case reports to compare the efficacy of different strategies on survival of cN2 NSCLC, and concluded that for resectable IIIa/N2 NSCLC surgery is recommended, and that strategy of chemotherapy plus surgery may not achieve better survival than that of chemotherapy plus radiotherapy. Size of tumor as well as lymph nodes should be taken into account when choosing optimal therapy, so that promising individualized strategy could be given to patients with resectable stage IIIa/N2 NSCLC.
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Detection of circulating tumor DNA in epidermal growth factor receptor-TKI relapsed non-small cell lung cancer patients using next-generation sequencing and an analysis of the resistant mechanisms / 中华病理学杂志

Objective@#Next-generation sequencing (NGS) was performed on circulating tumor DNA (ctDNA) samples from tyrosine kinase inhibitor (TKI)-naïve non-small cell lung cancers (NSCLC) and TKI-relapsed NSCLC to investigate the clinical value.@*Methods@#A total of 381 plasma samples from patients who were diagnosed with lung cancer in Cancer Hospital Chinese Academy of Medical Sciences from March 2017 to May 2018 were enrolled in the study. NGS was performed using a custom-designed panel that covers 10 lung cancer-related driven genes. Paired plasma-tissue samples from 39 patients were collected to analyses the sensitivity and specificity of detecting driver gene mutations using ctDNA. NGS was also performed on plasma samples from TKI-relapsed patients to identify TKI resistance mechanisms.@*Results@#Thirty-nine plasma samples collected from 39 NSCLC patients (including 21 female and 18 male) with corresponding tissue biopsies were analyzed for the sensitivity and specificity. The average age was 56 years (range 29 to 82 years). A high concordance of 84.62% (33/39) was observed between ctDNA and tissue biopsies. Compared with tissue biopsies, NGS sensitivity for ctDNA was 82.14% and specificity was 90.91%.Among these 39 patients, 34 were advanced stage patients (III-IV stage). The concordance, sensitivity, and specificity for ctDNA among the advanced stage patients were 88.24% (30/34), 86.36% (29/34) and 91.67% (31/34), respectively. Among the 381 plasma samples [including 231 TKI-naïve patients and 150 epithelial growth factor receptor(EGFR)-TKI relapsed patients], EGFR mutation was the most common driver gene among the 221 TKI-naïve lung adenocarcinoma patients (32.58%, 72/221). For 133 patients who progressed after first-generation EGFR-TKI, T790M was found to be the most frequent resistant mechanism (39.10%, 52/133), as well as bypass activation (3.01%, 4/133; such as MET amplification and ERBB2 amplification). Among those first-generation EGFR-TKI relapsed patients with EGFR sensitive mutations, T790M was detected in 53.06% (52/98). For the 17 patients who progressed after third-generation EGFR-TKI, C797S was found to be the most common resistant mechanism (4/17).@*Conclusions@#The concordance, sensitivity and specificity between ctDNA and tissue biopsies are acceptable. ctDNA analysis provides valuable information for lung cancer patients′ targeted treatment, especially for patients not fitted for biopsies.

Consistency of PD-L1 immunohistochemical detection platforms in biopsy samples with advanced lung adenocarcinoma: a multicenter study / 中华病理学杂志

Objective@#To analyze the expression of programmed death ligand 1 (PD-L1) in patients with advanced lung adenocarcinoma and the consistency of four PD-L1 immunohistochemical detection platforms, with an aim of establishing baseline information to predict and select patients for programmed death 1 (PD-1)/PD-L1 immune inhibitor therapy. @*Methods@#This was a multi-center retrospective study, collecting totally 57 advanced lung adenocarcinoma biopsy specimens from four centers from August 2017 to December 2017.The mean age of 57 patients was 59 (range 34-81) years, and 29 cases were male, 28 cases were female. Four PD-L1 immunohistochemical stains were done for each case, including 22C3 (Dako), 28-8 (Abcam), SP263 (Ventana), and SP142 (Ventana). Among them, 22C3 staining was done using Dako autostainer, and for the other three antibodies, Ventana Ultraview detection system and autostainer was used. The immunohistochemical slides were read by two trained histopathologists in a double-blinded way, and the percentage of PD-L1 positive tumor cells was assessed as <1%, 1%-24%, 25%-49% and more than 50%. @*Results@#The Dako 22C3 was used as the standard. There were eight cases in which the PD-L1 staining was more than 50% (14.0%, 8/57). The staining consistency of tumor cells was higher in 22C3, 28-8 and SP263 (ρ=0.729-0.809). The two scoring doctors had a high degree of concordance in PD-L1 positive tumor cells (ρ=0.707-0.896), and this was most noticeable in 22C3 and SP263. @*Conclusions@#22C3, 28-8 and SP263 show high consistency in tumor cell staining. The study can provide an effective basis for screening for potential patient population that may benefit from immunotherapy.

The application of conventional smears and liquid-based cytologic slides of lymphatic metastasis specimens of lung adenocarcinoma acquired by fine needle aspiration to detect the expression of anaplastic lymphoma kinase protein / 中华肿瘤杂志

Objective@#To explore the feasibility of conventional smears and liquid-based cytologic slides of lymphatic metastasis specimens of lung adenocarcinoma acquired by fine needle aspiration cytology (FNAC) to detect the expression of anaplastic lymphoma kinase (ALK/D5F3) by immunocytochemistry (ICC) analysis.@*Methods@#The lymphatic metastasis specimens of 147 lung adenocarcinoma, including 100 liquid-based cytologic slides and 47 conventional smears, were collected in this study. ALK fusion protein was detected by Roche Ventana ICC technology, which was compared with the ALK fusion gene assessed by fluorescence in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction (RT-PCR).@*Results@#The positive rate of ALK (D5F3) fusion protein in advanced lung adenocarcinoma acquired by FNAC was 11.6% (17/147), and 10.6% (5/47) and 12.0% (12/100) were reached in conventional smears and liquid-based cytologic slides, respectively.Among 147 cases, 57 cases including 17 positive cases and 40 negative cases were verified by RT-PCR and FISH. The whole coincidence rate reached 96.5% (55/57). The sensitivity and specificity of ALK (D5F3) fusion protein detected in lung adenocarcinoma acquired by FNAC were 94.1% (16/17) and 97.5% (39/40), respectively. The sensitivity and specificity were both 100% (5/5 of sensitivity and 10/10 of specificity) in conventional smears, while 91.7% (11/12) and 96.7% (29/30) in liquid-based cytologic slides.@*Conclusion@#Conventional smears and liquid-based cytologic slides of FNAC samples can be used to perform ICC analysis of ALK (D5F3) expression in advanced lung adenocarcinoma, especially for patients who have no opportunity for surgery or whose resected samples are difficult to form cell block.

A systematic review of international simulation models on the natural history of breast cancer:current understanding and challenges for Chinese-population-specific model development / 中华流行病学杂志

Objective To systematically review the worldwide simulation model studies on the natural history of breast cancer and to summarize related parameters.Methods A structured literature search was conducted in PubMed and the Cochrane Library to identify articles during 1980-2015.Articles were screened independently by two researchers.Health states in the natural history and relevant parameters were extracted.Results A total of 36 studies were included for analysis,within the earliest one was published in 1990.Most studies were from Europe and America countries,and 2 studies from China.Markov model was mostly applied to evaluating breast cancer screening programs (n=32).Reported health status included “healthy” (n=36),ductal carcinoma in situ (DCIS,n=17),invasive breast cancer (IBC,n=36),and death (n=27).There were two definite classifications for IBC,tumor size (n=9) and TNM staging (n=9,3 studies reported transition rates).The median (range) of annual transition rates from DCIS to stage-I IBC,I to Ⅱ,Ⅱ to Ⅲ,Ⅲ to Ⅳ were 0.279 (0.259-0.299),0.150 (0.069-0.430),0.100 (0.060-0.128) and 0.210 (0.010-0.625),respectively.A total of 15 studies reported the mean duration from predinical to clinical stage for IBC was 1.95-4.70 years,which gradually increased with age,and 7 studies reported that for DCIS.Conclusions Despite closer attention was paid to breast cancer natural history models,in recent years atypical hyperplasia has been neglected.Data on the mean duration of DCIS requires reasonable conversion.Various classifications for IBC exist whereas transition rates are limited.Current findings would be valuable references but challenging for the Chinese-population specific natural history model,development.

A systematic review of international simulation models on the natural history of breast cancer:current understanding and challenges for Chinese-population-specific model development / 中华流行病学杂志

Objective To systematically review the worldwide simulation model studies on the natural history of breast cancer and to summarize related parameters.Methods A structured literature search was conducted in PubMed and the Cochrane Library to identify articles during 1980-2015.Articles were screened independently by two researchers.Health states in the natural history and relevant parameters were extracted.Results A total of 36 studies were included for analysis,within the earliest one was published in 1990.Most studies were from Europe and America countries,and 2 studies from China.Markov model was mostly applied to evaluating breast cancer screening programs (n=32).Reported health status included “healthy” (n=36),ductal carcinoma in situ (DCIS,n=17),invasive breast cancer (IBC,n=36),and death (n=27).There were two definite classifications for IBC,tumor size (n=9) and TNM staging (n=9,3 studies reported transition rates).The median (range) of annual transition rates from DCIS to stage-I IBC,I to Ⅱ,Ⅱ to Ⅲ,Ⅲ to Ⅳ were 0.279 (0.259-0.299),0.150 (0.069-0.430),0.100 (0.060-0.128) and 0.210 (0.010-0.625),respectively.A total of 15 studies reported the mean duration from predinical to clinical stage for IBC was 1.95-4.70 years,which gradually increased with age,and 7 studies reported that for DCIS.Conclusions Despite closer attention was paid to breast cancer natural history models,in recent years atypical hyperplasia has been neglected.Data on the mean duration of DCIS requires reasonable conversion.Various classifications for IBC exist whereas transition rates are limited.Current findings would be valuable references but challenging for the Chinese-population specific natural history model,development.

Analysis of the relationship of DNA mismatch repair with clinicopathologic features and prognosis of colon cancer / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To explore the relationship between DNA mismatch repair (MMR) and clinicopathologic features and prognosis in patients with stages II and III colon cancers.</p><p><b>METHODS</b>The clinical and pathological data of 440 patients with stage II/III colon cancer after radical resection were retrospectively reviewed and analyzed. Immunohistochemical staining was used to assess the expression of MMR proteins (MLH1, MSH2, MSH6 and PMS2), and the correlation between DNA MMR and clinicopathological features and prognosis of colon cancers was analyzed.</p><p><b>RESULTS</b>Of the 440 tumor samples tested for DNA mismatch repair status, 90 (20.5%) demonstrated defective DNA mismatch repair and 350 (79.5%) had proficient DNA mismatch repair. Defective DNA mismatch repair (dMMR) was associated with young patients (≤ 60), proximal colon cancer, stage II, poorly differentiated adenocarcinoma and mucinous adenocarcinoma (P<0.05 for all). Among the 440 patients, 126 (28.6%) cases had recurrence or metastasis and 93 (21.1%) died during the median follow-up of 61.0 months. The five-year disease-free survival (DFS) rate was 82.2% among the patients with tumor exhibiting dMMR, significantly higher than that in patients with tumors exhibiting pMMR (68.9%, P=0.02). The univariate and mutlivariate analyses showed that the MMR status is an independent factor affecting 5-year disease-free survival and overall survival (OS) in colon cancer patients (P<0.05 for both).</p><p><b>CONCLUSIONS</b>Defective DNA mismatch repair (dMMR) is associated with patients with proximal colon cancer, stage II and poorly defferentiated adenocarcinoma and mucinous adenocarcinoma. The prognosis for patients with dMMR is better than those with pMMR. dMMR may be a useful biomarker for the prognosis of colon cancer.</p>

Comparison of real-time PCR method with Sanger sequencing for detection of BRAF muta-tion in papillary thyroid carcinoma / 临床与实验病理学杂志

Purpose To investigate the positive rate and concordance rate of BRAF mutation in papillary thyroid carcinoma detected by real-time PCR method and Sanger sequencing. Methods 312 papillary thyroid carcinomas patients were enrolled in this study. Real-time PCR method and Sanger sequencing were performed to detect BRAF gene mutations. The frequency of BRAF mutation and the concordance of two methods were analyzed. Results BRAF mutation was detected in 65. 4% (204/312) and 63. 8% (199/312) of 312 papillary thyroid carcinoma samples by using real-time PCR method and Sanger sequencing, respectively. There was no significant correlation between BRAF gene mutations and patients’ gender. There was significant correlation between BRAF gene mutations and patients’ age. The overall concordance between real-time PCR method and Sanger sequencing for BRAF mutation detection was 98. 4%. Conclusion Real-time PCR method provides an effective method in BRAF gene mutation detection.

Relationship between EGFR and KRAS mutations and clinicopathologic features of non-small cell lung cancers / 临床与实验病理学杂志

Purpose To explore the relationship between the mutations of epidermal growth factor receptor ( EGFR) and KRAS genes and clinicopathological characteristics in patients with non-small cell lung cancers (NSCLC). Methods Clinical samples from 431 NSCLC patients were obtained for EGFR and KRAS gene analysis. PCR based direct DNA sequencing was used to investigate mutations in exon 18-21 of EGFR gene and codon 12 and 13 of exon 2 of KRAS gene. Results The overall EGFR mutation rate of primary NSCLC was 53. 6% (231/431) in this study cohort and eight cases showed double EGFR mutations. Mutation rates in female and male were 65. 2% (122/187) and 46. 9% (98/209), respectively. The mutation rate was higher in patients with non-smokers and adeno-carcinoma and adenosquamous carcinoma subtypes than in their counterparts (PT, G>A, G>C) , and three patients had codon 13 mutations ( G>A, G>T) . Most of these mutations were G to T transversion (64. 5%, 20/31). Conclusion Polymerase chain reaction-direct sequencing is a reliable and effective method for the detection of the EGFR and KRAS gene mutation in NSCLC patients. The mutation rate of EGFR is higher in Chinese patients, especial-ly in non-smoking female patients with adenocarcinoma.

Detection and significance of epidermal growth factor receptor mutation in esophageal, esophagogastric junction and gastric cancers / 中华肿瘤杂志

<p><b>OBJECTIVE</b>Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) have been reported to be effective in the treatment of esophageal and esophagogastric junction cancers. The aim of this study was to detect the frequency of EGFR mutation and expression in Chinese patients with esophageal, esophagogastric junction and gastric cancers, and to clarify the value of EGFR mutation and expression in predicting the efficacy of TKI in the treatment of these tumors.</p><p><b>METHODS</b>In this study, 180 tumor samples with histologically confirmed esophageal cancer (39 cases), cancer of the esophagogastric junction (92 cases) and gastric cancer (49 cases) were collected. Twenty-nine different EGFR mutations in exons 18-21 were assessed by real-time PCR-optimized oligonucleotide probe method. EGFR protein expression was evaluated by immunohistochemistry (IHC) in 89 tumor samples.</p><p><b>RESULTS</b>The mutation analysis for EGFR (exons 18-21) showed no mutations in any of the hotspots of the gene in the 180 tumor samples analyzed. EGFR expression was negative in 12 tumor samples, 1+ in 31 tumor samples, 2+ in 24 tumor samples, and 3+ in 22 tumor samples. EGFR expression was 2+ or 3+ in 12 (92.3%) of the 13 esophageal squamous cell carcinomas, 29 (47.5%) of the 61 esophagogastric junction cancers, and 5 (33.3%) of the 15 gastric adenocarcinomas.</p><p><b>CONCLUSIONS</b>Our results indicate that EGFR mutation in exons 18-21 is absent in the examined samples of esophageal, esophagogastric junction and gastric cancers. More studies are warranted to explore the predictive biological markers for the therapeutic response to EGFR TKI.</p>

Correlation between BRAF V600E mutation and clinicopathologic features of papillary thyroid carcinoma / 中华病理学杂志

<p><b>OBJECTIVE</b>To study the prevalence of the BRAF V600E mutation in papillary thyroid carcinoma (PTC) and its association with clinicopathologic features.</p><p><b>METHODS</b>Two hundred and ninety-two patients with primary PTC encountered during the period from December 2010 to December 2012 and underwent surgery in Cancer Hospital, Chinese Academy of Medical Science were enrolled into the study. Polymerase chain reaction was used to amplify exon 15 of the BRAF gene from paraffin-embedded thyroid tumor specimens, followed by direct sequencing to detect the BRAF V600E mutation. Statistical analysis was performed with SPSS 16.0 for Windows. Association between BRAF mutation and clinicopathologic parameters was tested with the χ(2) test or Fisher exact test as appropriate.</p><p><b>RESULTS</b>There were 87 males and 205 females in the cohort. The age of patients ranged from 13 to 84 years (mean = 43.1 years). BRAF V600E mutation was found in 190 cases (65.1%). The presence of BRAF V600E mutation correlated with age at diagnosis (older than 45 years), tumor volume (larger than 1 cm), extrathyroidal extension, classic type/tall-cell variant and advanced disease stage (P < 0.05). BRAF V600E mutation did not correlate significantly with gender, multicentricity, lymph node metastasis or anatomic location (P > 0.05).</p><p><b>CONCLUSION</b>BRAF V600E mutation is associated with high-risk clinicopathologic characteristics in patients with PTC. The BRAF V600E mutation may be a potential prognostic factor in PTC patients.</p>