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Objective To assess the concordance of tumour grade in specimens obtained from diagnostic cystoscopic biopsy and transurethral resection of bladder tumour (TURBT) and explore the risk factors of upgrading. Methods The medical records of 205 outpatients who underwent diagnostic cystoscopic biopsy before initial TURBT were retrospectively reviewed. Comparative analysis of the tumour grade of biopsy and operation specimens was performed. Tumour grade changing from low-grade (LG) to high-grade (HG) with or without variant histology was defined as upgrading. Univariate and multivariate logistic regression analyses were performed to identify the risk factors of upgrading. Results For the 205 patients, the concordance of tumour grade between biopsy and operation was 0.639. The concordance for patients who were preoperatively diagnosed with LG and HG was 0.504 and 0.912, respectively. Univariate and multivariate logistic regression analyses showed that older age, tumour multifocality, high neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and low lymphocyte-to-monocyte ratio (LMR) were significantly associated with upgrading (odds ratio [OR] ranging from 0.412 to 4.364). The area under the curve of the different multivariate models was improved from 0.752 to 0.821, and decision curve analysis demonstrated a high net benefit when NLR, LMR, and PLR were added. Moreover, the nomogram was well calibrated. Conclusions Diagnostic cystoscopic biopsy may not accurately represent the true grade of new bladder cancer, especially for outpatients with LG. Moreover, older age, tumour multifocality, high NLR, PLR, and low LMR are risk factors of upgrading, and systemic inflammatory markers improve the predictive ability.

Objectives: Most patients with gallbladder cancer (GBC) present with advanced-stage disease and have a poor prognosis. Radical resection remains the only therapeutic option to improve survival in patients with GBC. This study aimed to analyze the prognostic factors in patients with stage ⅣGBC and to identify a subgroup of patients who might benefit from R0 resection. Methods: A total of 285 patients with stage ⅣGBC were retrospectively analyzed at our institution from January 2008 to December 2012. Factors potentially influencing the prognosis of GBC after surgery were analyzed by univariate and multivariate analyses. Results: The 1-, 3-, and 5-year overall survival rates were 6.6% (15/229), 0.9% (2/229), and 0 (0/229), respectively. Ascites (relative risk [RR] ＝ 1.631, 95% confidence interval [CI]: 1.221-2.180, P ＝ 0.001), pathological grade (RR ＝ 1.337, 95% CI: 1.050-1.702, P ＝0.018), T stage (RR ＝1.421, 95% CI: 1.099-1.837, P ＝0.000), M stage (RR ＝1.896, 95% CI: 1.409-2.552, P ＝ 0.000), and surgery (RR ＝ 1.542, 95% CI: 1.022-2.327, P ＝ 0.039) were identified as independent risk factors influencing prognosis. The median survival time (MST) was significantly higher in patients undergoing R0 resection than in those undergoing R1/R2 resection (6.0 vs. 2.7 months; P < 0.001). In subgroup analyses, stage IVA patients benefited from R0 resection (MST for R0 vs. R1/R2, 11.0 vs. 4.0 months; P ＝ 0.003), while R0 resection had a significant survival benefit than R1/R2 resection in patient with stage IVB GBC without distant metastasis (MST for R0 vs. R1/R2, 6.0 vs. 3.0 months; P ＝ 0.007). Conclusion: Ascites, pathological grade, T stage, M stage, and surgery were independent risk factors influencing prognosis in patients with stage ⅣGBC. N2 lymph node metastasis did not preclude curative resection, and radical resection should be considered in patients with stage ⅣGBC without distant metastasis once R0 margin was achieved. Key words: Gallbladder cancer; Surgery; Prognosis; Tumor-node-metastasis (TNM) stage

Background: The clinicopathological impacts of c-Met overexpression in bladder cancer have been investigated in several studies with conflicting results. We performed this systematic review and meta-analysis to assess the pathologic and prognostic roles of c-Met status in bladder cancer patients. Methods: Eligible studies were searched and identified from the PubMed and China National Knowledge Infrastructure (CNKI) databases (up until October 4, 2018). The DerSimonian-Laird random-effects model was used to calculate the pooled risk estimates. Results: Eight studies including 1,336 bladder cancer cases were eventually included in this meta-analysis. We detected a significantly increased risk of poor overall survival (OS) associated with the high expression of c-Met (HR=2.42, 95% CI 1.36-4.32). There was no association between c-Met status and nuclear grade (OR=0.82, 95% CI 0.29-2.31) or tumor stage (OR=1.42, 95% CI 0.41-4.89). Conclusion: This study shows that the overexpression of c-Met in primary cancer tissues is associated with a worse OS in human bladder cancer. However, larger studies using standardized methods and criteria are warranted to verify these findings.

Objective To analyze the clinical profile and prognosis of primary Fallopian tube cancer (PFTC) in order to improve earlier diagnosis. Methods In this retrospective study, 57 women with PFTC were assessed from 2006 to 2016. Pathology, clinical index, recurrence, and survival were analyzed. Results Mean age was 57.35 ± 9.01 years, and 73% (19/26) of the patients with early-stage PFTC (I/II) were aged less than 60 years. Of patients who presented with abnormal vaginal bleeding, 75% (9/12) were at an early stage and their condition was often misdiagnosed as endometrial carcinoma preoperatively. In patients with Stages I/II and Stages III/IV PFTC, 59.09% (13/22) and 96.43% (27/28), respectively, had adnexal masses on color Doppler ultrasonography. The 5-year overall survival (OS) and disease-free survival rates were 69.23% and 44.23%, respectively, and univariate analysis showed that tumor stage and residual tumor size significantly affected the two survival rates. Conclusion Primary Fallopian tube cancer is more likely to be misdiagnosed in patients aged less than 60 years or those presenting with vaginal bleeding at the premenopausal stage. Magnetic resonance imaging, cervical smear, and endometrial brush may be helpful for early PFTC diagnosis. Satisfactory cytoreductive surgery is critical because tumor stage and residual tumor size are significantly associated with the OS rate.

PURPOSE The purpose of this study was to evaluate the prognostic value of Immunoscore in patients with stage III colon cancer (CC) and to analyze its association with the effect of chemotherapy on time to recurrence (TTR). METHODS An international study led by the Society for Immunotherapy of Cancer evaluated the predefined consensus Immunoscore in 763 patients with American Joint Committee on Cancer/Union for International Cancer Control TNM stage III CC from cohort 1 (Canada/United States) and cohort 2 (Europe/Asia). CD3+ and cytotoxic CD8+ T lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The primary end point was TTR. Secondary end points were overall survival (OS), disease-free survival (DFS), prognosis in microsatellite stable (MSS) status, and predictive value of efficacy of chemotherapy. RESULTS Patients with a high Immunoscore presented with the lowest risk of recurrence, in both cohorts. Recurrence-free rates at 3 years were 56.9% (95% CI, 50.3% to 64.4%), 65.9% (95% CI, 60.8% to 71.4%), and 76.4% (95% CI, 69.3% to 84.3%) in patients with low, intermediate, and high immunoscores, respectively (hazard ratio [HR; high v low], 0.48; 95% CI, 0.32 to 0.71; P = .0003). Patients with high Immunoscore showed significant association with prolonged TTR, OS, and DFS (all P < .001). In Cox multivariable analysis stratified by participating center, Immunoscore association with TTR was independent (HR [high v low], 0.41; 95% CI, 0.25 to 0.67; P = .0003) of patient’s sex, T stage, N stage, sidedness, and microsatellite instability status. Significant association of a high Immunoscore with prolonged TTR was also found among MSS patients (HR [high v low], 0.36; 95% CI, 0.21 to 0.62; P = .0003). Immunoscore had the strongest contribution χ2 proportion for influencing survival (TTR and OS). Chemotherapy was significantly associated with survival in the high-Immunoscore group for both low-risk (HR [chemotherapy v no chemotherapy], 0.42; 95% CI, 0.25 to 0.71; P = .0011) and high-risk (HR [chemotherapy v no chemotherapy], 0.5; 95% CI, 0.33 to 0.77; P = .0015) patients, in contrast to the low-Immunoscore group ( P > .12). CONCLUSION This study shows that a high Immunoscore significantly associated with prolonged survival in stage III CC. Our findings suggest that patients with a high Immunoscore will benefit the most from chemotherapy in terms of recurrence risk.

The objective of this research was to study the physiological performance of young novice male drivers after they were administered different doses of alcohol. The physiological performance...

Background: Patients harboring co-mutations of epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangements may have difficulty in choosing appropriate tyrosine kinase inhibitor (TKI) therapy. Herein, a real-word cohort with more than 20,000 NSCLC patients was retrospectively established. Characteristics of co-mutations were analyzed extensively. Method: Formalin fixation and paraffin embedded (FFPE) tumor samples of non-small lung cancer cases from 12 clinical centers were enrolled. A multi-gene PCR panel (Amoy multi-gene PCR kit v.1), which includes EGFR, ALK, ROS1, RET, KRAS, NRAS, BRAF, HER2, and PIK3CA was applied to analyze driver gene mutation status. The cycle threshold (CT) values of positive mutation were recorded. CT ranking score (CTS) of a specific mutation type in a certain sample is calculated as 1-Rx (Rx: The quantile of the CT value of sample x, taking the CT value of the unique mutation sample in this study as a reference). Results: Co-mutations of EGFR/ALK were observed in 41 patients,including EGFR 19del/EML4-ALK (n=19) and EGFR L858R/EML4-ALK (n=10). Median CT values (25.51, n=19) of EGFR 19del in EGFR/ALK co-mutation samples were significantly higher than EGFR 19del mono-mutation (23.01, n=3973, p < 0.01). Higher median CT values of ALK-fusion in EGFR/ALK co-mutated samples were also observed when compared with mono-ALK fusion (26.1 vs 18.5). Median CTS of EGFR 19del, L858R and ALK fusion were 15.5% (n=19), 30.5% (n=10), and 3.2% (n=29) respectively. When defined CTS > 33.3% as positive cut-off of value, 41% (n=12) of EGFR/ALK co-mutation samples were EGFR CTS positive, 17.2% (n=5) were ALK CTS positive. No EGFR/ALK CTS co-positive samples was observed. Compared with L858R, 19del has a higher CTS positive rate of ALK when co-mutated with ALK (26.3% vs 0%, p < 0.01). Conclusion: Compared with EGFR or ALK mono-mutation, abundance of dominant clone comprising either mutated EGFR or ALK-fusion in co-mutation samples is lower, which was proved by the reported poor TKI efficacy in co-mutated patients. CTS can evaluate dominant clone for NSCLC with co-mutated driver genes. Indicated by CTS, tumor with EGFR/ALK co-mutation tends to form a single dominant clone. L858R is more likely to be the dominant subclone than 19del. Therefore, CTS algorism is a promising tool providing clone estimation. And it should be further validated in future perspective clinical trials. Citation Format: Yang Liu, Xianghong Yang, Yu Li, Yongchun Zhou, Yihua Chen, Peng Cheng, Renya Zhang, Xiaowei Qi, Lihua Yang, Guanjun Zhang, Lijuan Qu, Yanfeng Xi, Guanshan Zhu, Yuchen Han. A novel algorism evaluating dominant clonality in Chinese NSCLC patients with concomitant EGFR and ALK variation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3136.

// Bo Xie 1, * , Guanjun Zhang 2, * , Xiao Wang 3 and Xin Xu 3 1 Department of Urology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012, China 2 Department of Urology, Hospital of Traditional Chinese Medicine of Shangyu, Shangyu 312300, Zhejiang, China 3 Department of Urology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China * These authors contributed equally to this work Correspondence to: Bo Xie, email: drxiebo2012@163.com Xin Xu, email: drxuxin@zju.edu.cn Keywords: body mass index, prostate cancer, meta-analysis, dose-response, cohort Received: May 30, 2017 Accepted: August 26, 2017 Published: September 15, 2017 ABSTRACT The relationship between body mass index (BMI) and incidence of prostate cancer is still inconclusive. We performed a dose-response meta-analysis of eligible cohort studies to evaluate potential association of BMI with prostate cancer risk by subtype of prostate cancer (nonaggressive and aggressive). A comprehensive literature search was performed in PubMed and Web of Science databases through March 22, 2017. Linear and non-linear dose-response meta-analyses were carried out to evaluate the effects of BMI on incidence of prostate cancer. A total of 21 cohort or nested case-control studies (17 for nonaggressive and 21 for aggressive prostate cancer) were included in this meta-analysis. For nonaggressive prostate cancer, the pooled relative risk (RR) per 5 kg/m 2 increment of BMI with 95% confidence interval (CI) was 0.96 (95% CI 0.92–1.00). Sensitivity analysis indicated that this result was not robust and steady. For aggressive prostate cancer, a significant linear direct relationship with BMI (RR, 1.07; 95% CI 1.03–1.12) for every 5 kg/m2 increase was observed. Statistically significant heterogeneity was detected for nonaggressive prostate cancer ( P = 0.020, I 2 = 46.1%) but not for aggressive prostate cancer ( P = 0.174, I 2 = 22.4%). In conclusion, BMI level may be positively associated with aggressive prostate cancer risk. Further large prospective cohort studies are warranted to confirm the findings from our study.

Although a secondary mutation and the epithelial-to-mesenchymal transition (EMT) are encountered very often in patients received the EGFR-TKI targeted treatment. The entire detrimental morphological change of the cancer entity was rare reported. Herein we report a case that acquired resistance to EGFR-TKI with T790M mutation and complete EMT morphological change of the tumor tissue. The primary lung tumor from a 52-year-old woman was diagnosed with moderate differentiated adenocarcinoma, with intensively positiveTTF-1 and E-cadherin in differentiated glandular structure but not the budding cancer cell cluster which with an intensive Vimentin staining. Molecular analysis revealed an EGFR exon 19 deletion and with an excellent response to Gefitinib treatment. Microscopic examination of recurred tumor specimens revealed a diffuse poorer differentiated proliferation of atypical cells. Immunostaining showed intensive Vimentin but almost completely negative for E-cadherin and TTF-1. Genetic analyses revealed T790M mutation. It is worth noting that rare clinical studies have been reported that acquired EGFR-TKI resistant lung adenocarcinoma underwent T790M mutation and almost complete EMT together. More significantly, the similarity of poorly differentiated cancer cell cluster in the primary lesions to recurred tumor lesions, which may pre-harbor drug resistance mutation should not be neglected underneath the predominant morphologic patterns.

Objective: To analyze the clinical epidemiological characteristics of patients with gallbladder carcinoma recruited from 17 hospitals in five northwestern provinces of China (Shaanxi Province, Gansu Province, Qinghai Province, Ningxia Hui Autonomous Region, and Xinjiang Uygur Autonomous Region) from 2009 to 2013, and to summarize the clinical diagnosis and treatment data of gallbladder carcinoma. Methods: Clinical information of 2379 patients with gallbladder carcinoma from 17 hospitals in five northwestern provinces of China was retrospectively collected and analyzed using the âQuestionnaire for Gallbladder Carcinoma Patients in Northwestern Area of China.â All information was verified with EpiData software and analyzed with SPSS 13.0 software. Results: (1) Gallbladder carcinoma accounted for 2.7% (2379/86,609) of all biliary tract diseases during the study period, which was significantly higher than that from 1986 to 1998 (PÂ

Information in histology slides are usually visualized by different staining techniques, each of them unveils specific chemical and biological substances within tissue samples. Correlations between different stains can be useful to predict how certain tissue slides may look like if they were stained by other staining techniques. This work investigates two stains including hematoxylin and eosin (H&E) and immunohistochemistry (IHC) in digital pathological slides. Four cases of surgical biopsies were used in this work. The specimens were subjected to two consecutive stains with a decoloring process based on ethanol and potassium permanganate in between. After each stain, slides were digitized and archived as results. Comparing the effects of the two staining pipelines, IHC slides after decoloring of H&E showed that the cell structure was clear, the positive IHC staining was accurate, the background of the slide was clean, there was no DAB residue, and tissue fragments were intact. However, the other pipeline where IHC was stained before H&E showed that the nuclear border was blurred. Eosin is lightly colored resulting in low contrast visualization of nucleoplasm, DAB is not completely decolored, and parts of tissue were fragmented. We conclude that, from the proposed staining and decoloring technique, tissue slides could be stained with IHC more effectively on decolored H&E slides than those stained with H&E after IHC. Utilizing digital section scanning technology, we can obtain pairs of tissue images stained differently while preserving the exact same tissue structure.

The aim of this study is to examine the immunocytochemical expression of p53, Ki-67, and CA125 in endometrial brush samples for endometrial cancer. Forty-four patients were recruited with liquid-based cytology preparations during a 5-month period. Both the histological and cytological samples were assessed by histology based on hematoxylin and eosin (H&E), and the expression of p53, CA125, and Ki-67 in endometrial cells was examined by immunocytochemistry. The percentage and intensity of endometrial cells were scored on a scale of 0–3. The final score was calculated by the addition of all partial scores, and then Probit model was used to predict the possibility for malignant lesions. The mean immunoreactivity score of the three immunocytochemical biomarkers (p53, CA125, and Ki-67) in the positive group (including atypical hyperplastic cells and malignant cells) was significantly higher than in the negative group (benign cells and non-atypical hyperplastic cells). The possibility value of the positive group was also significantly higher than the negative group (P < 0.05). The cutoff value of the possibility value was 0.754, the sensitivity and specificity of which were 86.4 and 95.5%. The assessment of p53, CA125, and Ki-67 combined with the prediction model is valuable for the detection of endometrial cancer and atypical hyperplasia in endometrial cytology.

Recently, the research on early detection of precancerous change and endometrial carcinoma has been focusing on minimally invasive procedures for screening. On this basis, we aim to verify the feasibility of endometrial samplers for screening endometrial cancer using Li Brush. We recruited patients undergoing hysterectomy for different diseases from the Inpatient Department of the Department of Obstetrics and Gynecology. Before surgery, endometrial cells were collected by Li Brush. The cytopathologic diagnosis from Li Brush and the histopathologic diagnosis from hysterectomy in the same patient were compared to calculate sensitivity (Se), specificity (Sp), false-negative rate (FNR), false-positive rate (FPR), positive predictive value (PV+) %, and negative predictive value (PV-). The research enrolled 293 women into this self-controlled trial. According to the hypothesis test of paired four lattices, we obtained the following indicators: Se 92.73, Sp 98.15, FNR 7.27, FPR 1.85, PV+92.73, and PV−98.15%. The endometrial sampler Li Brush is an efficacious instrument for screening endometrial cancer.

Contains fulltext : 193579.pdf (Publisher’s version ) (Closed access) BACKGROUND: The estimation of risk of recurrence for patients with colon carcinoma must be improved. A robust immune score quantification is needed to introduce immune parameters into cancer classification. The aim of the study was to assess the prognostic value of total tumour-infiltrating T-cell counts and cytotoxic tumour-infiltrating T-cells counts with the consensus Immunoscore assay in patients with stage I-III colon cancer. METHODS: An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I-III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology. An Immunoscore for each patient was derived from the mean of four density percentiles. The primary endpoint was to evaluate the prognostic value of the Immunoscore for time to recurrence, defined as time from surgery to disease recurrence. Stratified multivariable Cox models were used to assess the associations between Immunoscore and outcomes, adjusting for potential confounders. Harrell's C-statistics was used to assess model performance. FINDINGS: Tissue samples from 3539 patients were processed, and samples from 2681 patients were included in the analyses after quality controls (700 patients in the training set, 636 patients in the internal validation set, and 1345 patients in the external validation set). The Immunoscore assay showed a high level of reproducibility between observers and centres (r=0.97 for colon tumour; r=0.97 for invasive margin; p

Objectives To explore clinicopathological features and effects of surgical treatment of squamous/adenosquamous carcinoma of the gallbladder. Methods We enrolled 411 patients who were surgically treated for gallbladder cancer in our hospital, including 10 with squamous cell carcinoma (SCC), 24 with adenosquamous carcinoma (ASC), and 377 with adenocarcinoma (AC). The ASC–SCC group was compared with the AC group for clinicopathological features and surgical outcomes. Results The patients' average age was 61.4 years. Abdominal pain was the most common presenting symptom, and 67.6% of patients had gallstones. All patients had advanced-stage (T3/T4) carcinomas. The ASC–SCC group had significantly higher percentages of T4 disease (61.8%) and N1 nodal involvement (58.8%) than did the AC group (T4 disease: 34.0%, P = 0.001; N1 involvement: 39.0%, P = 0.02). Patients in the ASC–SCC group who underwent R0 resections had significantly better 1-year survival (30%) than those who underwent R1 or R2 resections (0%; P = 0.025), but lower 1-year survival rates than similar-staged patients in the AC group (69.3%; P = 0.016). Conclusions Patients with gallbladder ASC–SCC were similar to those with AC in clinical characteristics, but tended to have more infiltration of multiple adjacent organs and lymphatic metastasis. Curative resection could give these patients better outcomes. J. Surg. Oncol. 2015;112:677–680. © 2015 Wiley Periodicals, Inc.

Cortactin, the cytoplasmic substrate of HDAC6, is known to play an actin cytoskeletal regulatory role which is implicated in the motility of cancer cells, and thus in cancer progression. Its activity is found to be regulated by HDAC6. However, the significance of cortactin and HDAC6 remains unclear in uncommon histologic variant human prostatic foamy gland carcinoma (PfCa). In this study, we aimed to identify the expression and potential role of cortactin and HDAC6 in PfCa. Therefore, 16 PfCa specimens containing 48 foci with distinctive lesions were collected to identify the status of cortactin and HDAC6 by immunohistochemistry. Their correlation between clinicopathological characteristics and prognostic values were further analysed. The effect of cortactin and HDAC6 on prostate cancer cell migration and invasion was then evaluated in IA8 cells. The results showed that expression of cortactin and HDAC6 was significantly higher in PfCa foci, compared to that of high-grade prostatic intraepithelial neoplasia (HGPIN) foci and benign foci (P < 0.05). Cortactin and HDAC6 were associated with poor prognosis of patients with PfCa (P < 0.05). Multivariable Cox regression analysis showed HDAC6 level was a significant prognostic factor for survival of patients with PfCa (β = 1.200, Wald value = 7.282, P = 0.007, 95% CI = 1.389–7.941, P < 0.01, β > 0). Both knocking down cortactin and inhibition of HDAC6 activity with tubacin reduced in vitro migration and invasion ability of IA8 cells substantially. Furthermore, HDAC6 has prognostic value for patients with PfCa. Dysregulation of cortactin and HDAC6 is implicated in the invasiveness and migration of prostate cancer cells.

A number of reports have identified HPV DNA in breast cancer specimens and HPV type 16, 18, 31, 33, 45, and 51 were more prevalent. HPV 58 was frequently detected in cervical cancer in Shaanxi China. The aim of the present study was to investigate whether HPV 58 present in breast cancer. 169 cases of breast cancer samples and 83 benign breast lesions were analyzed. Type specific primers and oligonucliotide probe were used for the detection of HPV 58 by conventional PCR and in situ hybridization techniques. The HPV 58 viral load were measured by qPCR. p16 protein expression were evaluated by immunohistochemistry. HPV 58 E7 DNA was detected in 25 out of 169 formalin fixed paraffin embedded breast cancer tissues (14.79%) by PCR, only 1 out of 83 non-malignant breast lesions showed positive (1.20%). The results of ISH showed that 17 out of 169 (10.06%) malignant samples were positive for HPV 58 E7, and only 1 out of 83 non-malignant lesions was positive. Positive p16 immunostaining was observed in all the HPV 58 E7 ISH positive cases, but 16 out of 98 cases with HPV negative were p16 positive. The presence of HPV 58 in both normal duct epithelial cells and carcinoma in situ along with its presence in the cancer cells of the same specimen indicated the possible causal role of HPV 58 in breast cancer. The findings provide a solid morphological evidence of the involvement of HPV 58 in breast cancer development.

O1 Combinatorial CD8+ and PD-L1+ cell densities correlate with response and improved survival in non-small cell lung cancer (NSCLC) patients treated with durvalumab #### Sonja Althammer1, Keith Steele2, Marlon Rebelatto2, Tze Heng Tan1, Tobias Wiestler1, Guenter Schmidt1, Brandon Higgs2, Xia

Background Radical resection is an effective therapeutic method to increase the survival rate of patients with gallbladder cancer (GBC). In addition to the surgical approach, the relationships between various clinicopathologic factors and the outcome of patients with GBC remain controversial. Methods Clinical and laboratory examination characteristics, pathological and surgical data, and post-operative survival time of 338 patients with advanced GBC who received treatment at the First Affiliated Hospital of Xi'an Jiaotong University, China from January 2008 to December 2012 were analyzed retrospectively. Factors influencing the prognosis of GBC after surgery were analyzed by univariate and multivariate analysis. Results The overall survival rates for curative resection patients were significantly greater than those for non-curative resection patients (1-,3-,5-year survival rate and mean-survival time: 59.0%, 47.3%, 44.3% and 22.0 months vs. 12.7%, 8.3%, 7.7% and 3.0 months) (P < 0.001). For the curative resection patients, positive margin, lymph node metastasis, poorly pathological differentiation and the presence of ascites were all independent risk factors for poor prognosis. For patients with T3 stage, neither segmentectomy of IVb and V nor common bile duct resection improved the prognosis (P = 0.867 and P = 0.948). For patients with T4 stage, aggressive curative resection improved the prognosis (P = 0.007). Conclusions An advanced T stage does not preclude curative resection. Positive margin, lymph node metastasis, poorly pathological differentiation and the presence of ascites are all independent risk factors for poor prognosis in the curative intent resection patients. The range of liver resection and whether common bile duct resection is performed do not influence the prognosis as long as R0 resection is achieved.

Objective The significance of isolated high-grade prostatic intraepithelial neoplasia in initial biopsy as an predictor for prostate cancer has been extensively research, and the true relationship remnant is no clear till now. The aim of this study is to evaluate prediction value of cancer on repeat biopsy in patients with high-grade prostatic intraepithelial neoplasia, using multivariate analysis.

Interdigitating dendritic cell sarcoma is an extremely rare neoplasm derived from professional antigen presenting cells. We report an unusual case of such a tumor occurring in a 61-year-old woman who had undergone orthotopic liver transplantation for stage IVA2 primary hepatocellular carcinoma with a raised preoperative α-fetoprotein level, followed by tacrolimus-based immunosuppressive therapy. During her subsequent management, the tacrolimus blood levels ranged from 7.9 ng/mL to 16.1 ng/mL. Physical examination revealed bilateral neck and left axillary lymphadenopathy. No evidence of either chronic hepatitis B virus or Epstein-Barr virus could be detected in serum. An excisional biopsy of a right neck lymph node was performed. Microscopically, the normal architecture was diffusely effaced by a proliferation of spindled to ovoid cells arrayed in a fascicular, ill-defined whorled pattern and small lymphocytes were admixed in varying numbers with the tumor cells. Immunohistochemical studies showed that the tumor cells were positive for S100 protein, vimentin and CD68. Based on these findings, the case was diagnosed as an interdigitating dendritic cell sarcoma. The patient unfortunately had no response to 2 cycles of CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone), and died of wide spread disease 6 months after the original biopsy. We propose that tacrolimus-based immunosuppression was associated with the development of interdigitating dendritic cell sarcoma after liver transplantation in this case.

The −137 G/C and −607 C/A polymorphisms in interleukin-18 (IL-18) gene have been reported to be associated with Alzheimer’s disease (AD) risk, but the results are inconclusive. Considering a single study may lack the power to provide reliable conclusion, we performed a meta-analysis to investigate the association between the IL-18 −137 G/C and −607 C/A polymorphisms and AD susceptibility. A comprehensive literature search of PubMed, Embase, China National Knowledge Infrastructure (CNKI) and Wanfang databases were conducted before September 1, 2015. The pooled odds ratio (OR) with 95 % confidence intervals (CIs) were calculated. Five eligible studies with a total of 1536 subjects were finally included in this meta-analysis. For the IL-18 −137 G/C polymorphism, a significantly decreased risk was detected in patients carrying the C allele of −137 G/C in all study subjects in allele model (C vs. G: OR = 0.816, 95 % CI = 0.680–0.980, p = 0.029). Moreover, stratification by ethnicity indicated markedly association between the −137 G/C C allele and AD risk in Asians. For the IL-18 −607 C/A polymorphism, a significantly decreased risk was found in patients carrying the A allele of −607 C/A in all study subjects in dominant model (AA + CA vs. CC: OR = 0.696, 95 % CI = 0.529–0.915, p = 0.010). However, the results suggested no significant association between the −607 C/A polymorphism and AD susceptibility when stratified by ethnicity. Our present meta-analysis suggests that the C allele carrier of IL-18 −137 G/C was associated with decreased risk for AD in Asians. Further well-designed case–control studies with larger sample size and more ethnic groups are needed to confirm these conclusions.

This study aimed to determine the prognostic value of perineural invasion (PNI) in patients with colorectal cancer (CRC), particularly patients with TNM stage II and stage III.A total of 159 CRC patients who had undergone radical resection were retrospectively analyzed. Histopathological evaluation of tissue samples was conducted on hematoxylin and eosin-stained sections. PNI was considered positive when cancer cells were observed inside the nerve sheath, or when at least 33% of the nerve periphery was surrounded by cancer cells. A 3-tier grading system (PNI0, PNI1, PNI2) based on the depth of PNI was used to assess the localization of PNI in the bowel. PNI and other prognostic factors were evaluated by survival analysis.PNI status in CRC significantly affected postoperative overall survival (P0.001). The five-year survival rates for PNI-negative and PNI-positive patients were 77% and 32%, respectively. PNI was closely correlated with tumor gross type, tumor grade, depth of invasion, lymph node metastasis, clinical stage, vessel invasion, tumor budding grade, and tumor growth pattern. Multivariate analysis revealed that PNI was an independent prognostic factor (HR=2.223, P=0.003). The survival of PNI-positive patients was significantly poorer than that of PNI-negative patients in stages II and III (P=0.003 and P=0.008, respectively). The overall survival of colorectal patients was in the descending order of PNI-negative at stage II, PNI-positive at stage II/PNI-negative at stage III, and PNI-positive at stage III (P0.001). When the PNI status and T stage were considered together, overall survival curves of the PNI2 patients were significantly worse than those of PNI1 patients in pT4 stage (P=0.019).PNI is a poor independent prognostic factor for CRC. It could complement classic TNM staging classification in stratifying CRC patients in stages II and III. Assessment of the site-specific distribution of PNI may further enhance the impact of PNI contribution to the prognosis of CRC.

Sofosbuvir, a hepatitis C virus (HCV) NS5B polymerase inhibitor, is a new direct-acting antiviral for chronic HCV infection. This systematic review and proportional meta-analysis examined the efficacy and safety of sofosbuvir-based therapy for chronic HCV infection in treatment-naive and -experienced patients. Medline, Cochrane Database of Systematic Reviews, EMBASE and Web of Science databases were searched. Clinical trials examining sofosbuvir plus ribavirin (RBV) and pegylated interferon-α (peg-IFN) or sofosbuvir plus RBV among adults with chronic HCV infection were included. Data were extracted on virological responses including sustained virological response at post-treatment Week 12 (SVR12), relapse, treatment discontinuation due to an adverse event (AE), virological breakthrough during treatment, and AEs. One trial and 13 treatment arms/cohorts from seven studies met the criteria for analysis in treatment-naive patients who were treated with sofosbuvir, RBV and peg-IFN; the SVR12 was 89% (95% CI 85-92%), relapse was 5% and the serious adverse event (SAE) rate was 4%. Six treatment arms/cohorts met the criteria for analysis in treatment-naive patients who were treated with sofosbuvir and RBV; the SVR12 was 72% (95% CI 60-81%), relapse was 27% and the SAE rate was 3%. Three treatment arms/cohorts met the criteria for analysis in treatment-experienced patients who were treated with sofosbuvir and RBV; the SVR12 was 51% (95% CI 27-75%), relapse was 46% and the SAE rate was 4%. In conclusion, sofosbuvir-based treatment is effective and safe in treating chronic HCV infection, although the SVR12 of its combination with RBV, especially in treatment-experienced patients, requires improvement.

Carcinoma showing thymus-like elements (CASTLE) is a rare malignant tumor of the thyroid or adjacent neck soft tissues, whose histogenesis is still debated. It may resemble other primary or metastatic poorly differentiated tumors histologically and the differential diagnosis is crucial for CASTLE has a better prognosis. However, CASTLE as a second primary tumor has not been reported in the literature. We report three cases of thyroid CASTLE, including a unique tumor following breast-conserving surgery for early-stage breast invasive carcinoma. There were two female and one male. All three tumors were located in the right lobe of the thyroid, and one tumor showed extension into the surrounding soft tissue. Histologically, all tumors showed expansive growth and consisted of cords, nests or sheets of epithelial cells divided into irregularly shaped lobules by fibrous connective tissue with lymphoplasmacytic infiltration. Focal squamous differentiation resembling Hassall's corpuscles were observed. All cases stained positively for CD5, CD117, high molecular weight cytokeratin, cytokeratin, P63, carcinoembryonic antigen and epithelial membrane antigen. Positive staining for Bcl-2 in two cases and chromogranin A in one case was noted. Ki-67 expression ranged from 15 to 25%. Thyroid transcription factor and CD3 were negative. There was no evidence of recurrent or metastatic disease at following surgery. These features demonstrated CASTLE may arise from branchial pouch remnants, the thyroid solid cell nests. CASTLE is a rare entity, awareness of its occurrence as a second primary tumor is important to avoid overtreatment because it is associated with a favorable prognosis.

We investigated the prognostic value of tumor budding in 160 cases of operable invasive ductal carcinoma, not otherwise specified (IDC-NOS). The number of buds was counted in H&E slides with a maximal invasive margin in a 0.950mm(2) field of vision (200×). According to a cut-off score selected by ROC analysis, the cohort was dichotomized into a low (0-7 budding foci, 107 cases, 66.9%) and a high-grade budding group (8 or more budding foci, 53 cases, 33.1%). The inter-observer test showed a good reproducibility with 0.717 as the К value. High-grade budding was significantly associated with the presence of lymphovascular invasion (LVI) (P=0.001), larger tumor size (P=0.014), and worse clinical outcome (P

Objective Cortactin acts as a prominent substrate of histone deacetylases (HDACs) and plays important roles in tumour progression in several human cancers. However, the clinical significance of its expression in human prostate cancer (PCa) has not been determined. We aimed to identify the potential role of cortactin expression in tumour progression and prognosis in PCa and the association with HDACs. Methods 256 foci with distinctive lesions in 110 prostate specimens were collected to identify the status of among cortactin, SIRT2, histone deacetylase 6 (HDAC6) by immunohistochemistry and its relationship with clinicopathological and follow-up data were analysed. Results The results showed that cortactin expression was significantly higher (79.1%), and SIRT2 expression was lower (37.3%) in PCa foci, when it was compared with high-grade prostatic intraepithelial neoplasia foci and benign foci, respectively. HDAC6 expression was low and had no statistical significance in PCa. High intensity of cortactin staining was significantly and independently associated with a high prostate-specific antigen (PSA) level, high Gleason score, clinical stage progression and shortened survival time in patients with PCa. High intensity of SIRT2 staining was significantly and independently associated with a high PSA level, old age, high Gleason score and clinical stage progression. Multivariable Cox regression analysis showed cortactin expression was a significant prognostic factor for survival of patients with PCa (β, 0.736; 95% CI 1.371 to 3.181; p=0.001). Conclusions The results suggested that cortactin seems to be a satisfactory marker to predict tumour progression and survival in cases of PCa. And it may be SIRT2 rather than HADAC6 is responsible for tumour occurrence and the progression of PCa.

We present a case of adenomyoepithlioma (AME) arising from the tonsil. AME is an uncommon tumor that typically arises in breast, but rarely found in salivary glands, lung, and skin. Its biological features have not been thoroughly characterized. Here we describe a primary AME originating from the tonsil. The pathologic changes were characterized by hypercellularity, the dominance of both epithelial and myoepithelial cells. Malignancy was evidenced by the presence of a high mitotic rate and invasive growth. The epithelial cells express high levels of cytokeratin and epithelial membrane antigen (EMA). The myoepithelial cells show positive staining for calponin, p63, vimentin, and S-100. A thorough review of the literature indicates that this is likely the first reported case of AME from the tonsil. Following descriptions of the diagnosis, treatment, and prognosis of this specific case, pathologic and clinical characteristics of AME from other tissues are also compiled and discussed.

Epithelioid hemangioendotheliomas are unique vascular tumors characterized by epithelioid or histiocytoid endothelial cells that mainly affect adults. This low-grade malignant vascular tumor was described as a distinctive condition in 1982 by Weiss and Enzinger. Although the tumor is classified in between an angiolymphoid hyperplasia with eosinophilia and an epithelioid angiosarcoma, it sometimes takes a clinical course resembling that of angiosarcoma. We describe that case of a 12-year-old boy who presented with an approximately 6-month history of a spontaneous chronic lesion in his right armpit and became a painful ulceration in the prior 2-month period. The histopathologic examination revealed small nests and cords of spindling epithelioid endothelial cells, intracytoplasmic lumina containing erythrocytes, pinocytotic vesicles and a necrotic area. Immunohistochemical staining was positive for the endothelial markers CD31, CD34, CK(+), and vim(+). On the basis of these findings the diagnosis of EHE was made. After surgery, pathologic examination revealed metastasis in the lymph nodes. So polychemotherapy was started. As our case report shows, it is possibility that cutaneous ulceration of a malignant tumor such as EHE should be considered, even in children.

Basement membrane degradation and blood-brain barrier damage appear after cerebral infarction, severely impacting neuronal and brain functioning; however, the underlying pathogenetic mechanisms remain poorly understood. In this study, we induced cerebral infarction in stroke-prone spontaneously hypertensive rats by intragastric administration of high-sodium water (1.3% NaCl) for 7 consecutive weeks. Immunohistochemical and immunofluorescence assays demonstrated that, compared with the non-infarcted contralateral hemisphere, stroke-prone spontaneously hypertensive rats on normal sodium intake and Wistar-Kyoto rats, matrix metalloproteinase-9 expression, the number of blood vessels with discontinuous collagen IV expression and microvessel density were significantly higher, and the number of continuous collagen IV-positive blood vessels was lower in the infarct border zones of stroke-prone spontaneously hypertensive rats given high-sodium water. Linear correlation analysis showed matrix metalloproteinase-9 expression was positively correlated with the number of discontinuously collagen IV-labeled blood vessels and microvessel density in cerebral infarcts of stroke-prone spontaneously hypertensive rats. These results suggest that matrix metalloproteinase-9 upregulation is associated with increased regional angiogenesis and degradation of collagen IV, the major component of the basal lamina, in stroke-prone spontaneously hypertensive rats with high-sodium water-induced focal cerebral infarction.

Purpose: We evaluated the feasibility of Raman spectroscopy (RS) in diagnosis and prognosis of castra- tion-resistant prostate cancer (CRPC) in patients with prostate cancer (PC). Materials and methods: Raman spectra are detected from PC cell lines (LNCaP and C4-2) and tissues using a Labram HR 800 RS. Then, principal com- ponent analysis (PCA) and support vector machine (SVM) are applied for prediction. A leave-one-out cross-val- idation is used to train and test the SVM. Results: There are 50 qualified patients, including 33 with androgen- dependent prostate cancer (ADPC) and 17 with CRPC. The spectral changes at 1126, 1170, 1315 to 1338, and 1447 cm −1 between CRPC and ADPC are detected in both cells and tissues models, which are assigned to specific amino acids and DNA. PCA/SVM algorithm provided a sensitivity of 88.2% and a specificity of 87.9% for diagnosing CRPC tissues. Furthermore, 14 patients with ADPC progressed to CRPC within 12 months. These patients are separated into two groups depending on whether their cancers progressed to CRPC within 12 months. PCA/SVM could differentiate these two groups with a sensitivity of 85.7% and a specificity of 88.9%. Conclusions: RS has the potential in diagnosis and prognosis of CRPC in clinical practice. © The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution

The primary osteosarcoma in soft tissue is very rare. Three cases were admitted to our hospital since 1956.

Background Change of mitochondrial DNA (mtDNA) copy number is widely reported in various human cancers, including gastric cancer, and is considered to be an important hallmark of cancers. However, there is remarkably little consensus on the value of variable mtDNA content in the prognostic evaluation of this cancer. Methods Using real-time quantitative PCR approach, we examined mtDNA copy number in a cohort of gastric cancers and normal gastric tissues, and explored the association of variable mtDNA content with clinical outcomes of gastric cancer patients. Results Our data showed that the majority of gastric cancer patients had low mtDNA content as compared to control subjects although the relative mean mtDNA content was higher in the former than the latter. Moreover, we found that variable mtDNA content was strongly associated with lymph node metastasis and cancer-related death of the patients with late-stage tumors. Notably, variable mtDNA content did not affect overall survival of gastric cancer patients, however, we found that increased mtDNA content was associated with poor survival in the patients with late-stage tumors. Conclusion In this study, we demonstrated that variable mtDNA content markedly increased the risk of lymph node metastasis and high mortality of the patients with late-stage tumors. Additionally, we found a strong link between increased mtDNA content and worse survival of the patients with late-stage tumors. Taken together, variable mtDNA content may be a valuable poor prognostic factor for advanced gastric cancer patients. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1344721463103353.