Clinical characteristics, medical service utilization, and expenditure for colorectal cancer in China, 2005 to 2014: Overall design and results from a multicenter retrospective epidemiologic survey.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer in China, however, publicly available, descriptive information on the clinical epidemiology of CRC is limited. METHODS: Patients diagnosed with primary CRC during 2005 through 2014 were sampled from 13 tertiary hospitals in 9 provinces across China. Data related to sociodemographic characteristics, the use of diagnostic technology, treatment adoption, and expenditure were extracted from individual medical records. RESULTS: In the full cohort of 8465 patients, the mean ± SD age at diagnosis was 59.3 ± 12.8 years, 57.2% were men, and 58.7% had rectal cancer. On average, 14.4% of patients were diagnosed with stage IV disease, and this proportion increased from 13.5% in 2005 to 20.5% in 2014 (P value for trend < .05). For diagnostic techniques, along with less use of x-rays (average, 81.6%; decreased from 90.0% to 65.7%), there were increases in the use of computed tomography (average, 70.4%; increased from 4.5% to 90.5%) and magnetic resonance imaging (average, 8.8%; increased from 0.1% to 20.4%) over the study period from 2005 to 2014. With regard to treatment, surgery alone was the most common (average, 50.1%), but its use decreased from 51.3% to 39.8% during 2005 through 2014; and the use of other treatments increased simultaneously, such as chemotherapy alone (average, 4.1%; increased from 4.1% to 11.9%). The average medical expenditure per patient was 66,291 Chinese Yuan (2014 value) and increased from 47,259 to 86,709 Chinese Yuan. CONCLUSIONS: The increasing proportion of late-stage diagnoses presents a challenge for CRC control in China. Changes in diagnostic and treatment options and increased expenditures are clearly illustrated in this study. Coupled with the recent introduction of screening initiatives, these data provide an understanding of changes over time and may form a benchmark for future related evaluations of CRC interventions in China.

Submucosal Enhancing Stripe as a Contrast Material-enhanced MRI-based Imaging Feature for the Differentiation of Stage T0-T1 from Early T2 Rectal Cancers.

Background Accurate differentiation of stage T0-T1 rectal tumors from stage T2 rectal tumors facilitates the selection of appropriate surgical treatment. MRI is a recommended technique for local staging, but its ability to distinguish T1 from T2 tumors is poor. Purpose To explore the value of a submucosal enhancing stripe (SES), an uninterrupted enhancing band between the rectal tumor and the muscular layer on contrast material-enhanced T1-weighted images, as a potential imaging feature to differentiate T0-T1 from T2 rectal tumors. Materials and Methods This retrospective study included patients with pT0-T1 and pT2 rectal tumors who underwent pretreatment MRI and rectal tumor resection between January 2012 and November 2019. Two radiologists independently evaluated tumor characteristics (SES; status of muscularis propria [SMP]; and tumor shape, location, and size) at MRI. The associations of clinical and imaging characteristics with stage T0-T1 or T2 tumors were assessed, ß values were calculated, and predictive models were built. The diagnostic accuracies for the differentiation of T0-T1 tumors from T2 tumors with SES and SMP were compared. Results Data from 431 patients (mean age, 60 years ± 10 [standard deviation]; 261 men) were evaluated. SES (ß = 3.9; 95% CI: 3.1, 4.7; P < .001), SMP (ß = 1.3; 95% CI: 0.7, 1.9; P < .001), and carpetlike shape (ß = 1.6; 95% CI: 0.5, 2.8; P = .01) were independent factors distinguishing T0-T1 tumors from T2 tumors. The diagnostic accuracy was 87% (95% CI: 84, 90; 376 of 431) for SES and 67% (95% CI: 63, 72; 290 of 431) for SMP (P < .001). Conclusion Submucosal enhancing stripe (SES) at contrasted-enhanced MRI, status of muscularis propria (SMP) on T2-weighted images, and tumor shape can serve as independent imaging features to differentiate stage T0-T1 rectal tumors from stage T2 rectal tumors. Moreover, SES is a more accurate feature than is SMP. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Turkbey in this issue.

B7-H3 immune checkpoint expression is a poor prognostic factor in colorectal carcinoma.

Although PD-1/PD-L1 immunotherapy has been used successfully in treating many cancers, metastatic colorectal cancer (CRC) patients are not as responsive. B7-H3 is a promising target for immunotherapy and we found it to have the highest expression among B7-CD28 family members in CRC. Thus, the aim of the present study was to investigate B7-H3 expression in a large CRC cohort. B7-H3, B7-H4, and PD-L1 protein levels and differential lymphocyte infiltration were evaluated in tissue microarrays from 805 primary tumors and matched metastases. The relationships between immune markers, patient characteristics, and survival outcomes were determined. B7-H3 (50.9%) was detected in more primary tumors than B7-H4 (29.1%) or PD-L1 (29.2%), and elevated B7-H3 expression was associated with advanced overall stage. Co-expression of B7-H3 only with B7-H4 or PD-L1 was infrequent in primary tumors (6.3%, 5.7%, respectively). Moreover, B7-H3 in primary tumors was positively correlated with their respective expression at metastatic sites (ρ = 0.631; p < 0.001). No significant relationships between B7-H4 and PD-L1 and survival were observed; however, B7-H3 overexpression in primary tumors was significantly related to decreased disease-free survival. A positive relationship between B7-H3 expression and high density CD45RO T cell was observed in primary tumors, whereas B7-H4 and PD-L1 overexpression were related to CD3 T-cell infiltration. In conclusion, compared with B7-H4 and PD-L1, B7-H3 expression exhibited a higher prevalence and was significantly related to aggressiveness, worse prognosis and CD45RO T-cell infiltration in primary tumors. Further exploration of this potential target of immunotherapy in CRC patients is warranted.

[Prognostic and Predictive Value of a Modified Diagnostic Biopsy-Adapted Immunoscore in Patients with Rectal Cancer After Neoadjuvant Treatment- a translational study from the STELLAR trial].

BACKGROUND: The purpose of this study was to assess the prognostic significance of the modified diagnostic biopsy-adapted immunoscore (mISb) in determining the outcomes for patients with locally advanced rectal cancer (LARC) in a neoadjuvant setting. METHODS: We included 181 LARC patients from a single subcenter of a prospective study comparing total neoadjuvant therapy (TNT) based on short-course radiotherapy with long-term chemoradiotherapy (CRT). Tumor biopsies at baseline were stained for CD8+ and CD3+ T-cell densities. The mISb was developed using mean percentile of CD8+ T-cell density and CD8/CD3 ratios. Patients were classified into low (0%-25%), intermediate (>25%-70%), and high (>70%-100%) in both groups. The relativity among different lymphocytes and their correlation with survival were illustrated. Survival analyses and Cox regression models were used to compare the prognostic value of mISb and ISb for survival outcomes, and to assess the role of mISb in TNT and CRT subgroups respectively. RESULTS: In this study, 151 (83.4%) patients received surgery and 30 (16.6%) followed a watch and wait strategy. A strong correlation was found between CD8+ and CD3+ T-cell densities (R=0.86, P<0.001), while a weak correlation witnessed between CD8+ and CD8/CD3 ratio (R=0.45). The 3-year disease-free survival (DFS) for the entire cohort was 69.9%, with 57.2%, 68.6%, and 85.5% for the low, intermediate, and high mISb groups respectively (P=0.01), while ISb failed to distinguish survival outcomes. Multivariate analysis revealed mISb to be an independent prognostic factor for DFS in surgically treated patients (P=0.01). Specifically, patients with high mISb score showed longer PFS than other subgroups in the TNT cohort (P=0.049), but no significant difference was found in the CRT population. CONCLUSIONS: In this study, mISb demonstrates significant prognostic value in LARC patients receiving preoperative therapies, especially in the TNT subgroup. These findings may help tailor the intensity of neoadjuvant therapy for patients.

[Relationship between HPV-DNA status and p16 protein expression in oropharyngeal squamous cell carcinoma and their clinical significance].

OBJECTIVE: To investigate the relationship between HPV-DNA status and p16 protein expression in oropharyngeal squamous cell carcinoma (OSCC) and their clinical significance. METHODS: Sixty-six patients with oropharyngeal squamous cell carcinomas treated in the Cancer Hospital of Chinese Academy of Medical Sciences from Jan. 1999 to Dec. 2009 were included in this study. Their formalin-fixed and paraffin-embedded tumor tissue blocks met the eligibility criteria and were used in this study. A "sandwich" technique was used to prepare paraffin sections for HPV-DNA analysis. HPV-DNA was detected using the SPF10 LiPA25 version 1 assay. The expression of p16 protein was detected by immunohistochemistry. The survival rates of patients with different HPV-DNA and p16 protein status were analyzed. RESULTS: HPV-DNA was detected in 11 (16.7%) of all specimens. Expression of p16 protein was detected in 9 of the 11 patients with HPV-positive tumors, and in 12 patients of 55 HPV-negative tumors. The expression of p16 protein was highly correlated with the presence of HPV-DNA (P < 0.001). The tumors were classified into three groups based on the p16 protein expression and HPV-DNA status: group A (9 patients): HPV(+) and p16 protein(+); group B (14 patients): HPV-DNA(+)/p16 protein(-) or HPV-DNA(-)/p16 protein(+); and group C (43 patients): HPV-DNA(-)/p16 protein(-). The 3-year OS rates of these 3 groups were 100%, 77.8% and 42.0% (P = 0.001), and their DSS rates were 100%, 77.8% and 46.4%, respectively(P = 0.004). CONCLUSIONS: In oropharyngeal squamous cell carcinomas, p16 protein expression is highly correlated with the presence of HPV-DNA, and might be a surrogate marker for HPV-positive OSCC. Combination of p16 protein and HPV-DNA status detection may help to more accurately stratify oropharyngeal carcinomas and predict their prognosis.

Efficacy of peripheral blood stem cell transplantation versus conventional chemotherapy on anaplastic large-cell lymphoma:a retrospective study of 64 patients from a single center.

Anaplastic large-cell lymphoma (ALCL) is characterized by frequently presenting adverse factors at diagnosis. Many groups believed aggressive treatment strategies such as autologous stem cell transplantation brought survival benefit for ALCL patients. However, few compared these approaches with conventional chemotherapy to validate their superiority. Here, we report a study comparing the efficacy of peripheral blood stem cell transplantation (PBSCT) and conventional chemotherapy on ALCL. A total of 64 patients with primary systemic ALCL were studied retrospectively. The median follow-up period was 51 months (range, 1-167 months). For 48 patients undergoing conventional chemotherapy only, the 4-year event-free survival (EFS) and overall survival (OS) rates were 70.7% and 88.3%, respectively. Altogether, 16 patients underwent PBSCT, including 11 at first remission (CR1/PR1), 3 at second remission, and 2 with disease progression during first-line chemotherapy. The 4-year EFS and OS rates for patients underwent PBSCT at first remission were 81.8% and 90.9%, respectively. Compared with conventional chemotherapy, PBSCT did not show superiority either in EFS (P = 0.240) or in OS (P = 0.580) when applied at first remission. Univariate analysis showed that patients with B symptoms (P = 0.001), stage III/IV disease (P = 0.008), bulky disease (P = 0.075), negative anaplastic lymphoma kinase (ALK) expression (P = 0.059), and age ≤ 60 years (P = 0.054) had lower EFS. Furthermore, PBSCT significantly improved EFS in patients with B symptoms (100% vs. 50.8%, P = 0.027) or bulky disease (100% vs. 52.8%, P = 0.045) when applied as an up-front strategy. Based on these results, we conclude that, for patients with specific adverse factors such as B symptoms and bulky disease, PBSCT was superior to conventional chemotherapy in terms of EFS.

R-CHOP regimen can significantly decrease the risk of disease relapse and progression in patients with non-germinal center B-cell subtype diffuse large B-cell lymphoma.

To further explore the role of rituximab when added to the CHOP-like regimen in the treatment of immunohistochemically defined non-germinal center B-cell subtype (non-GCB) diffuse large B-cell lymphoma(DLBCL), 159 newly diagnosed DLBCL patients were studied retrospectively based on the immunohistochemical evaluation of CD10, Bcl-6, MUM-1, and Bcl-2. Altogether, 110 patients underwent the CHOP-like regimen, and rituximab was added for the other 49 patients. Cox regression analysis showed that compared with the CHOP-like regimen, the rituximab-based regimen(R-CHOP regimen) significantly decreased the risk of disease relapse and progression in CD10-negative patients (P=0.001), Bcl-6-negative patients (P=0.01), and MUM-1-positive patients (P=0.003). The risk of disease relapse in patients with non-GCB subtype (P=0.002) also decreased. In contrast, patients with the opposite immunohistochemical marker expression profile and GCB subtype did not benefit from treatment with the R-CHOP regimen. In addition, non-GCB subtype patients had a significantly higher expression rate of Bcl-2 than GCB subtype patients (P=0.042). Although univariate analysis found that both Bcl-2-positive and -negative patients had significantly higher event-free survival rates with the R-CHOP regimen, only Bcl-2 positivity (P=0.004) maintained significance in the Cox regression analysis. We conclude that the addition of rituximab can significantly improve the prognosis of patients with non-GCB subtype DLBCL, which is closely related to the expression of CD10, Bcl-6, MUM-1, and Bcl-2.

[Detection of human papillomavirus in oropharyngeal squamous cell carcinoma].

OBJECTIVE: To investigate the infection rate and subtypes of human papilloma virus(HPV) in patients with oropharyngeal squamous cell carcinoma (OSCC) and analyze the clinicopathologic features of patients with or without HPV infection. METHODS: A total of 66 biopsy or surgical specimens of OSCC archived in the Pathology Department of Chinese Academy of Medical Sciences were analyzed by polymerase chain reaction (PCR), and the generic amplification products were detected by DNA enzyme immunoassay (DEIA) and typed by reverse hybridization line probe assay. RESULTS: HPV-DNA was detected in 11 (16.7%) of all specimens. Among them, 7 were infected with HPV-16,and the remaining 4 patients were infected with HPV-16/11, HPV-35, HPV-58/52, and HPV-33/52/54, respectively. HPV-16 was detected in 72.7% of all positive specimens. There were more females in HPV-positive group than HPV-negative group (36.4% vs. 1.8%,P=0.002). Patients with HPV-positive tumors were more likely to be non-smokers (36.4% vs. 0,p=0.001) and non-drinkers (45.5% vs. 1.8%,p=0.001) than those with HPV-negative tumors. The proportion of moderately or poorly differentiated tumors was higher in HPV-positive patients than HPV-negative patients (81.8% vs. 63.7%), although without statistical significance (p=0.409). No difference was observed in T classification, N classification, and overall tumor stage. CONCLUSIONS: HPV infection rate was 16.7% in this cohort. HPV-positive OSCC has its unique etiologic and clinicopathological characteristics.

Multicenter, Randomized, Phase III Trial of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer (STELLAR).

PURPOSE: To ascertain if preoperative short-term radiotherapy followed by chemotherapy is not inferior to a standard schedule of long-term chemoradiotherapy in patients with locally advanced rectal cancer. MATERIALS AND METHODS: Patients with distal or middle-third, clinical primary tumor stage 3-4 and/or regional lymph node-positive rectal cancer were randomly assigned (1:1) to short-term radiotherapy (25 Gy in five fractions over 1 week) followed by four cycles of chemotherapy (total neoadjuvant therapy [TNT]) or chemoradiotherapy (50 Gy in 25 fractions over 5 weeks, concurrently with capecitabine [chemoradiotherapy; CRT]). Total mesorectal excision was undertaken 6-8 weeks after preoperative treatment, with two additional cycles of CAPOX (intravenous oxaliplatin [130 mg/m2, once a day] on day 1 and capecitabine [1,000 mg/m2, twice a day] from days 1 to 14) in the TNT group and six cycles of CAPOX in the CRT group. The primary end point was 3-year disease-free survival (DFS). RESULTS: Between August 2015 and August 2018, a total of 599 patients were randomly assigned to receive TNT (n = 302) or CRT (n = 297). At a median follow-up of 35.0 months, 3-year DFS was 64.5% and 62.3% in TNT and CRT groups, respectively (hazard ratio, 0.883; one-sided 95% CI, not applicable to 1.11; P < .001 for noninferiority). There was no significant difference in metastasis-free survival or locoregional recurrence, but the TNT group had better 3-year overall survival than the CRT group (86.5% v 75.1%; P = .033). Treatment effects on DFS and overall survival were similar regardless of prognostic factors. The prevalence of acute grade III-V toxicities during preoperative treatment was 26.5% in the TNT group versus 12.6% in the CRT group (P < .001). CONCLUSION: Short-term radiotherapy with preoperative chemotherapy followed by surgery was efficacious with acceptable toxicity and could be used as an alternative to CRT for locally advanced rectal cancer.

Preoperative Concurrent Chemoradiotherapy Versus Neoadjuvant Chemotherapy for Locally Advanced Gastric Cancer: Phase II Randomized Study.

Objective: We evaluated and compared the efficacy and safety of neoadjuvant chemoradiotherapy (NACRT) versus neoadjuvant chemotherapy (NACT) for locally advanced gastric cancer (LAGC) in a single-center randomized phase II trial. Methods: Patients with LAGC were enrolled and received either NACT or NACRT, followed by gastrectomy and adjuvant chemotherapy. The primary endpoint was an R0 resection rate. Results: We enrolled 75 patients: 75.7% (NACT, 28/37 patients) and 76.3% (NACRT, 29/38 patients) underwent surgery; R0 resection rates were 73.0% (27/37) and 73.7% (28/38), respectively. The NACRT group had significantly better major pathological response than the NACT group (37.9% vs 17.9%, p = 0.019). Between-group postoperative complications were not significantly different. The median follow-up was 59.6 months; 5-year overall survival (OS) rate was 50.1% (NACT) and 61.9% (NACRT); neither group reached the median OS; median progression-free survival was 37.3 and 63.4 months, respectively. Conclusions: S-1-based NACRT did not improve the R0 resection rate, although it presented better tumor regression with similar safety to NACT. Trial registration: ClinicalTrial.gov NCT02301481.

Expressions of the γ2 chain of laminin-5 and secreted protein acidic and rich in cysteine in esophageal squamous cell carcinoma and their relation to prognosis.

Previous studies have shown that the expressions of the γ2 chain of laminin-5 and secreted protein acidic and rich in cysteine (SPARC) play important roles in oncogenesis and the development of carcinoma. To assess the expressions of laminin-5 γ2 chain and SPARC in esophageal squamous cell carcinoma (SCC), and to clarify the prognostic significance of the expressions of laminin-5 γ2 chain and SPARC in esophageal SCC, we detected the expressions of laminin-5 γ2 chain and SPARC in cancer tissue and corresponding normal mucosa from 116 patients with advanced (stages II-IV) esophageal SCC using the tissue microarray-based immunohistochemistry and analyzed the correlation of the expressions with clinicopathologic characteristics and survival. We found that in normal esophageal tissues, laminin-5 γ2 chain was expressed in the basement membrane, whereas in esophageal SCC tissues, laminin-5 γ2 chain was expressed in the cytoplasm of carcinoma cells, with a positive rate of 72.4%. SPARC was not detected in normal esophageal mucosa, but was expressed in stromal fibroblasts in 84.6% of esophageal SCC cases and in cancer cells in 7.8% of esophageal SCC cases. There was a significant correlation between laminin-5 γ2 chain and stromal SPARC expression in esophageal SCC (Spearman's rho=0.423, P<0.001). The expressions of both laminin-5 γ2 chain and stromal SPARC were correlated with survival (P=0.032 and P=0.034, respectively). In stage-II esophageal SCC, the expression of laminin-5 γ2 chain was significantly correlated with survival (P=0.023), while the expression of SPARC was not significantly correlated with survival (P=0.154). Patients with elevated levels of laminin-5 γ2 chain and SPARC expressions had a poorer prognosis than did those lacking elevated levels of laminin-5 γ2 chain expression and/or elevated levels of SPARC expression (P=0.001). In stage-II esophageal SCC, patients with elevated levels of laminin-5 γ2 chain and SPARC expressions had a poorer prognosis (P<0.001). These results suggest that laminin-5 γ2 chain and SPARC may play roles in the progression of esophageal SCC and their simultaneous expression is correlated with poorer prognosis, especially in patients with stage-II SCC.

[Primary superficial small cell neuroendocrine carcinoma of esophagus: clinicopathologic and immunohistochemical analysis of 15 cases].

OBJECTIVE: To study the clinicopathologic and immunohistochemical features of primary superficial esophageal small cell neuroendocrine carcinoma (ESCNC). METHODS: The clinical, pathologic and immunohistochemical features were retrospectively analyzed in 15 cases of superficial ESCNC. An immunohistochemical study for chromogranin A, neuron-specific enolase, synaptophysin, CD56, TTF-1, 34ßE12, AE1/AE3, and CK10/13 was performed. RESULTS: Superficial ESCNC accounted for 4.8%(15/312) of all cases of superficial carcinoma of the esophagus encountered during the same period. The median survival time was 19 months and the mean survival time was 23.7 months after diagnosis. The one, two and five-year survival rates were 10/15, 5/15 and 1/15, respectively. The immunophenotypic profile was as follows: neuron-specific enolase (15/15), synaptophysin (15/15), AE1/AE3 (15/15), CD56 (14/15), TTF-1 (9/15), chromogranin A (8/15), 34ßE12 (1/15) and CK10/13 (0/15). CONCLUSIONS: Superficial ESCNC is a rare and aggressive malignant tumor with poor prognosis. Surgical resection coupled with post-operative chemoradiotherapy is the mainstay of treatment. The immunohistochemical study is valuable in pathologic diagnosis and differential diagnosis.

[Comparison of histopathologic changes and expression of biomarkers in breast carcinoma before and after neoadjuvant chemotherapy].

OBJECTIVE: To investigate the relationship between the pathologic responses and histologic type, grade, the expression of ER, PR and HER2 and their changes in breast carcinoma before and after neoadjuvant chemotherapy (NAC). METHODS: Two-hundred and nine cases of breast cancer with NAC were analyzed and clinical, pathologic data were evaluated based on the Miller and Payne ( MP) grading system. The expression of ER, PR and HER2 in the cancers before and after NAC were detected by immunohistochemistry (MaxVision method). SPSS 15.0 software was used to conduct statistical analysis. RESULTS: (1) Pathologic responses to the NAC were graded as MP1 (14 cases), MP2 (35 cases), MP3 (106 cases), MP4 (36 cases) and MP5 (18 cases); (2) The expression of ER in core needle biopsy had related negatively to the pathologic response (chi2 = 33.083, P = 0.001). However, the histologic type, grade, ER and PR status, and HER2 expression in surgically-removed specimens had not related to the pathologic response (P>0.05); (3) After NAC, the pathologic type and grade changed in 6. 8% (9/132) and 34.9% (30/86) of the cases, and the rates of changes in the expression of ER, PR and HER2 were 42.4% (75/177), 55.4% (98/177) and 26.6% (46/173) , respectively. Only the expression of HER2 had significant difference between before and after neoadjuvant chemotherapy (P = 0.049). The changes in other data had no relationship with the pathologic response (P>0.05). CONCLUSIONS: Analysis of core needle biopsy can provide important information to predict the pathologic responses to the NAC. The pathologic appearance, grade, ER, PR and HER2 in breast carcinoma may change after NAC. It is necessary to examine the histologic type, grade and the expression of ER, PR and HER2 after NAC once more.

The role of cytology in endobronchial ultrasound-guided transbronchial needle aspiration: A study of 813 cases focusing on diagnostic yield, an analysis of misdiagnosed cases and diagnostic accordance rate of cytological subtyping.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive technique for cytological and histological diagnosis. The objective of this study was to explore the role of cytological diagnosis in EBUS-TBNAs. METHODS: Eight hundred and thirteen consecutive cases performed EBUS-TBNA with both cytological and histological diagnoses were retrospectively reviewed. All patients were followed up for clinical data. RESULTS: Before immunohistochemical examination, the cytological sensitivity, specificity, and diagnostic accuracy of EBUS-TBNAs were 92.9% (421/453), 98.9% (348/352), 95.5% (769/805), respectively. After immunohistochemical examination, the sensitivity, specificity, and diagnostic accuracy were 93.0% (423/455), 99.4% (348/350), 95.8% (771/805), respectively. The majority of false-negative were cases whose cytological diagnosis was "atypical" or the cytological diagnosis suggested "inadequate." "Neoplastic" were also prone to false-negative cytology. The diagnostic accordance rate of cytological subtyping was 90.3% for squamous-cell carcinoma, 99.2% for adenocarcinoma, and 98.1% for small-cell carcinoma before immunohistochemical examination, and became 85.9%, 98.5%, and 98.2% after immunohistochemical examination, respectively. CONCLUSION: Cytological diagnosis in EBUS-TBNAs had a good sensitivity and high specificity. The sensitivity and specificity of cytological diagnosis were proved to be higher after the immunohistochemical examination. At the same time, cytology had high accordance rate in subtype diagnosis. False-negative results occurred more commonly in cases whose cytological diagnosis was "atypical" or the cytological diagnosis suggested "inadequate" or the corresponding histological diagnosis was "Neoplastic."

Classification and genetic counselling for a novel splicing mutation of the MLH1 intron associated with Lynch syndrome in colorectal cancer.

BACKGROUND: Lynch-syndrome-associated cancer is caused by germline pathogenic mutations in mismatch repair genes. The major challenge to Lynch-syndrome screening is the interpretation of variants found by diagnostic testing. This study aimed to classify the MLH1 c.1989 + 5G>A mutation, which was previously reported as a variant of uncertain significance, to describe its clinical phenotypes and characteristics, to enable detailed genetic counselling. METHODS: We reviewed the database of patients with Lynch-syndrome gene detection in our hospital. A novel variant of MLH1 c.1989 + 5G>A identified by next-generation sequencing was further investigated in this study. Immunohistochemical staining was carried out to assess the expression of MLH1 and PMS2 protein in tumour tissue. In silico analysis by Alamut software was used to predict the MLH1 c.1989 + 5G>A variant function. Reverse transcription-polymerase chain reaction and sequencing of RNA from whole blood were used to analyse the functional significance of this mutation. RESULTS: Among affected family members in the suspected Lynch-syndrome pedigree, the patient suffered from late-stage colorectal cancer but had a good prognosis. We found the MLH1 c.1989 + 5G>A variant, which led to aberrant splicing and loss of MLH1 and PMS2 protein in the nuclei of tumour cells. An aberrant transcript was detectable and skipping of MLH1 exon 17 in carriers of MLH1 c.1989 + 5G>A was confirmed. CONCLUSIONS: MLH1 c.1989 + 5G>A was detected in a cancer family pedigree and identified as a pathological variant in patients with Lynch syndrome. The mutation spectrum of Lynch syndrome was enriched through enhanced genetic testing and close surveillance might help future patients who are suspected of having Lynch syndrome to obtain a definitive early diagnosis.

[Expression of fascin and CK14 in different histological types of cancer and its differential diagnostic significance].

OBJECTIVE: To investigate and analyze the expression of fascin and CK14 in multiple histological types of cancer and to explore the potential value of the two proteins as markers in diagnosis and differential diagnosis of various cancer types. METHODS: Tissue microarray containing esophageal squamous cell carcinoma (SCC), lung SCC, larynx SCC, uterine cervical SCC, SCC of external genital organs, lung adenocarcinoma, gastric adenocarcinoma, colorectal adenocarcinoma, heptocellular carcinoma, pancreatic ductal adenocarcinoma, breast infiltrating ductal carcinoma, thyroid papillary carcinoma, uterine endometrioid adenocarcinoma, ovarian serous adenocarcinoma and renal clear cell carcinoma, 30 cases each, as well as corresponding normal controls was constructed. The expression of fascin and CK14 among different types of carcinoma and corresponding normal controls was detected by immunohistochemistry. RESULTS: In normal esophagus, bronchus, larynx, uterine cervix and skin, fascin was mainly expressed in the basal cells or reserve cells, but the expression was diffuse in esophageal SCC, lung SCC, larynx SCC, uterine cervical SCC and SCC of external genital organs, with a positive rate of 90.0%, 90.0%, 96.7%, 78.6% and 89.7%, respectively. In the normal tissue of other organs, except breast and uterine endometrium, fascin was negative. In lung adenocarcinoma, gastric adenocarcinoma, colorectal adenocarcinoma, hepatocellular carcinoma, pancreatic ductal adenocarcinoma, breast infiltrating dutal adenocarcinoma, thyroid papillary carcinoma, uterine endometrioid adenocarcinoma, ovarian serous adenocarcinoma and renal clear cell carcinoma, the positive rates were 38.0%, 23.3%, 14.3%, 10.3%, 73.3%, 13.3%, 6.7%, 60.0%, 66.7% and 10.0%, respectively. The difference between fascin expression in SCC and in other histological types was statistically significant (P < 0.001). CK14 was mainly expressed in the basal cells, reserve cells or myoepithelia of normal tissues. The positive rates of CK14 were 76.7%, 36.7%, 83.3%, 60.7% and 96.3% in esophageal SCC, lung SCC, larynx SCC, uterine cervical SCC and SCC of external genital organs, respectively. It was weak and focal in lung adenocarcinoma, gastric adenocarcinoma, colorectal adenocarcinoma, hepatocellular carcinoma, pancreatic ductal adenocarcinoma, breast infiltrating dutal adenocarcinoma, thyroid papillary carcinoma, uterine endometrioid adenocarcinoma, ovarian serous adenocarcinoma, and renal clear cell carcinoma, with a positive rate of 13.3%, 13.3%, 20.7%, 41.4%, 46.7%, 6.7%, 40.0%, 13.3%, 20.0% and 6.7%, respectively. The difference between CK14 expression in SCC and in other histological types was statistically significant (P < 0.001). The difference between co-expression of fascin/CK14 in SCC and in other histological types was also statistically significant (P < 0.001). CONCLUSION: Fascin and CK14 are highly expressed in SCC, compared with other histological types of carcinoma. Combination of fascin and CK14 should be a valuable marker in diagnosis and differential diagnosis of carcinoma.

[Differences between clinical response and pathologic response of breast cancer after neoadjuvant chemotherapy].

OBJECTIVE: to investigate the pathologic basis of the difference between clinical response and pathologic response of breast carcinoma after neoadjuvant chemotherapy. METHODS: two hundred and nine cases of breast cancer with neoadjuvant therapy were analyzed and clinical data were collected from June, 2005 to December, 2007. All patients had core needle biopsy taken before neoadjuvant chemotherapy and were operated within 4 weeks after neoadjuvant chemotherapy. Clinical examination, X-ray of breast and/or B ultrasonography of primary breast focus were taken before and after neoadjuvant chemotherapy. Clinical responses of breast primary focus were evaluated according to RECIST (response evaluation criteria in solid tumors) version 1.1.Pathologic responses of breast primary focus were evaluated according to Miller and Payne (MP) grading system. SPSS 15.0 software was used to statistical analysis. RESULTS: (1) Clinical responses basing on clinical examination showed complete response, partial response, stable disease and progressive response, in 33, 124, 41 and 11 cases respectively. (2) Eighty-seven cases had X-ray of breast taken before and after neoadjuvant chemotherapy. Clinical response basing on X-ray, showed complete response, partial response and stable disease in 8, 42 and 37 cases respectively. (3) Pathologic responses of breast primary focus were as MP1 (14 cases), MP2 (35 cases), MP3 (106 cases), MP4 (36 cases) and MP5 (18 cases). (4) The clinical response basing on clinical examination were related to the pathologic response (χ(2) = 33.668, P = 0.001); and the clinical response basing on X-ray of breast were also related to the pathologic response (χ(2) = 22.404, P = 0.004). (5) The pathologic basis of the difference between the pathologic response and the clinical response basing on X-ray of breast were: embolism of carcinoma, mucinous carcinoma, intraductal carcinoma with ossifying-type calcification, nodular fibrosis and others. CONCLUSIONS: the clinical response may be related to the pathologic response. The difference between the two may be caused by pathologic changes. Some benign and malignant pathologic changes may contribute to the under-estimation of clinical response over pathologic response; whereas embolism of carcinoma may contribute to the over-estimation of clinical response over pathologic response.

[DNA microarrays-based microRNA expression profiles derived from formalin-fixed paraffin-embedded tissue blocks of squammous cell carcinoma of larynx].

OBJECTIVE: To establish DNA microarrays-based microRNA (miRNA) expression profiles of squamous cell carcinoma of larynx, using archived formalin-fixed paraffin-embedded tissue blocks, and to screen out and identify the differentially expressed miRNAs associated with the biological characteristics of this malignant disease. METHODS: Total RNA was prepared from the formalin-fixed paraffin-embedded tissue blocks. After quality identification and fluorescent labeling, the RNA samples were hybridized with the Agilent human miRNA microarrays which contains 723 probes for human miRNAs. The data was processed with the softwares GeneSpring GX and R-Project. RESULTS: From the formalin-fixed paraffin-embedded tumor blocks collected, 24 RNA samples were obtained with the quality accorded to the requirement of miRNA microarray analysis, and both the hybridization and consequent data processing were accomplished. A total of 319 miRNAs were identified and among them 96 were detected in all the 24 formalin-fixed paraffin-embedded blocks of laryngeal carcinoma; and 5 differentially expressed miRNAs (false discovery rate < 0.05) were found to be associated significantly with the lymphatic metastasis of laryngeal squamous cell carcinoma (P < 0.05), including miR-23a(*), miR-28-5p, miR-15a, miR-16 and miR-425. CONCLUSIONS: Histopathological archives of well-annotated formalin-fixed paraffin-embedded tissue specimens are the valuable resources for miRNA study including to collect RNA samples for miRNA microarray analysis. A panel of differentially expressed miRNAs (miR-23a(*), miR-28-5p, miR-15a, miR-16 and miR-425) derived from the miRNA expression profile may serve as the potential molecular biomarkers for the prediction of metastasis development in laryngeal squamous cell carcinoma.

Evaluation of clinical significance of claudin 7 and construction of prognostic grading system for stage II colorectal cancer.

BACKGROUND: Claudin 7 is often abnormally expressed in cancers and promotes the progression of some malignancies. However, the role of claudin 7 in stage II colorectal cancer (CRC) has not been studied. AIM: To assess the expression and prognostic value of claudin 7 in stage II CRC. METHODS: We retrospectively studied 231 stage II CRC patients who underwent radical surgery at our hospital from 2013 to 2014. The protein expression level of claudin 7 was assessed and its relationship with clinicopathological features and prognosis was statistically analyzed. The independent prognostic factors were identified by Cox proportional hazards models. A prognostic grading system was constructed to stratify the survival of CRC patients. RESULTS: The expression of claudin 7 was significantly reduced in cancer tissues compared with normal tissues (P < 0.001), and its low expression was closely related to recurrence of the disease (P = 0.017). Multivariate analysis confirmed that claudin 7 low expression (claudin 7-low) (P = 0.028) and perineural invasion positivity (PNI+) (P = 0.026) were independent predictors of poor disease-free survival (DFS). A prognostic grading system based on the status of claudin 7 and PNI classified the patients into three prognostic grades: grade A (claudin 7-high and PNI-), grade B (claudin 7-low and PNI-, claudin 7-high and PNI+), and grade C (claudin 7-low and PNI+). The DFS was significantly different among the three grades (grade B vs grade A, P = 0.032; grade C vs grade A, P < 0.001; grade C vs grade B, P = 0.040). CONCLUSION: Claudin 7 can be used as a new prognostic marker to predict the DFS of patients with stage II CRC. The prognostic grading system with the addition of claudin 7 can further improve prognosis stratification of patients.

[Diagnostic value of transbronchial needle aspiration combined with transesophageal endoscopic ultrasound-guided fine needle aspiration in mediastinal and pulmonary hilar lesions].

OBJECTIVE: To evaluate the value of transbronchial needle aspiration (TBNA) combined with transesophageal endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in the diagnosis of mediastinal and pulmonary hilar lesions as well as in the lymph node staging (N staging) of lung cancer. METHODS: 129 patients with mediastinal and pulmonary hilar lesions underwent either TBNA or EUS-FNA with cytological needle aspiration. The samples obtained from TBNA or EUS-FNA were examined by both cytologiy and histopathology. RESULTS: Of the 129 patients, 59 underwent TBNA and 70 EUS-FNA. The diagnostic rate were 84.7% (50/59) by TBNA and 94.3% (66/70) by EUS-FNA, resepectively. The diagnosis of 116 (89.9%) patients were confirmed by either TBNA or EUS-FNA. The pathological and cytological diagnostic rates were 92.2% (107/116) and 88.0% (102/116), resepectively. The diagnostic rate was elevated by 8.4% (9/107) through pathological examination. The histological classification rates by cytological and pathological examination were 73.8% (76/116) and 89.3% (92/103), respectively. The diagnostic rate of histological classification was elevated by 35.5% (27/76) through pathological examination. CONCLUSION: The combination of TBNA and EUS-FNA can improve the diagnostic rate for wider mediastinal and pulmlonary hilar lesions. Pathological examination of the samples obtained from the TBNA and EUS-FNA can elevate not only the rate of diagnosis but also the rate of histological classification.