Upregulated expression of DDX5 predicts recurrence and poor prognosis in breast cancer.

DEAD-box helicase 5 (DDX5) has been shown to promote tumorigenesis and cancer progression. However, the relationship between DDX5 and recurrence in breast cancer (BC) patients remains unknown. The objective of the present study was to evaluate the correlation of DDX5 with recurrence-free survival (RFS) and breast cancer-specific survival (BCSS) in patients with BC. The expression of DDX5 was examined by immunohistochemical analysis. RFS was calculated by Kaplan-Meier survival analysis. Univariate and multivariable associations were assessed by Cox proportional hazards models. In the present study, a total of 868 BC patients were analysed, and we found that DDX5 protein was significantly overexpressed in BC tissues compared to adjacent normal tissues. Elevated DDX5 was associated with an aggressive phenotype in BC patients. Moreover, DDX5 protein was upregulated in recurrent patients compared with nonrecurrent patients, and DDX5 protein levels were positively associated with worse RFS and BCSS in BC patients. High DDX5 expressing BC patients with age more than 50 year, advanced clinical stage or histological grade had a significantly increased risk of recurrence and shorter survival. Our findings highlight the significance of DDX5 in the recurrence and clinical outcome of BC patients and suggest that DDX5 may be a potential predictive biomarker for patients with BC.

« HER2-faible ¼, un nouveau concept dans la prise en charge des cancers du sein: HER2-low breast cancer: a new concept in breast cancer treatment strategy.

HER2, a human epidermal growth factor, being activated by amplification, is a negative prognostic factor in breast cancer. HER2 is the target of anti-HER2 antibodies (Trastuzumab, Pertuzumab…). For more than 10 years, breast cancers have been classified into HER2 positive and HER2 negative. However, the advent of new cytotoxic drugs combined with anti-HER2 antibodies, such as TDM1 or trastuzumab déruxtécan, have shown very promising therapeutic activity in patients with low HER2 expression breast cancer. These new therapeutic perspectives encourage a better identification of low HER2 tumours in order to identify patients who could benefit from them. Thus, the classification of breast tumours evolves to individualize HER2-negative tumours (score 0), HER2-positive tumours (score 3+ and 2+ amplified) and HER2-low tumours (scores 1+ and 2+ not-amplified). HER2-low tumours are common and represent more than half of all breast cancers. To identify these HER2-low tumours, pathology laboratories should not change their usual technique calibrated according to ASCO/CAP and GEFPICS recommendations. Until more clinical data about response to these new treatment strategies are available, GEFPICS does not require pathologists to identify this HER2-low category. Nevertheless, this designation will allow clinicians to identify patients whose tumours fall into this category in the very short term and offer them new treatment options.

A phase 2 study of anastrozole in patients with oestrogen receptor and/progesterone receptor positive recurrent/metastatic granulosa cell tumours/sex-cord stromal tumours of the ovary: The PARAGON/ANZGOG 0903 trial.

BACKGROUND: Hormonal therapies are commonly prescribed to patients with metastatic granulosa cell tumours (GCT), based on high response rates in small retrospective studies. Aromatase inhibitors (AIs) are reported to have high response rates and an accepted treatment option. We report the results of a phase 2 trial of an AI in recurrent/metastatic GCTs. METHODS: 41 patients with recurrent ER/PR + ve GCT received anastrozole 1 mg daily until progression or unacceptable toxicity. The primary endpoint was clinical benefit rate (CBR) at 12 weeks, evaluated by RECIST1.1 criteria. Secondary endpoints included progression-free survival (PFS), CBR duration, quality of life and toxicity. RESULTS: The CBR at 12 weeks in 38 evaluable patients was 78.9%, which included one (2.6%; 95% CI: 0.5-13.5%) partial response and 76.3% stable disease. Two additional patients without measurable disease were stable, based on inhibin. Median PFS was 8.6 m (95% CI 5.5-13.5 m). There were delayed responses observed after 12 weeks with a total of 4 pts. (10.5%; 95% CI 4.2%-24.1%) with a RECIST partial response; 23 (59%) patients were progression-free at 6 months. The adverse effects were predominantly low grade. CONCLUSIONS: This is the first prospective trial of hormonal therapy in GCTs. Although there was a high CBR, the objective response rate to anastrozole was much lower than the pooled response rates of >70% to AIs reported in most retrospective series and case reports. PARAGON demonstrates the importance of prospective trials in rare cancers and the need to reconsider the role of AIs as single agents in GCTs.

Trastuzumab tolerability in the treatment of advanced (stage III-IV) or recurrent uterine serous carcinomas that overexpress HER2/neu.

OBJECTIVE: Due to previously reported trastuzumab safety concerns and the scant data available in endometrial cancer patients, we sought to assess the safety, tolerability and toxicity profile of trastuzumab in patients with advanced/recurrent uterine serous carcinoma (USC) that overexpress HER2/neu in our multicenter randomized phase II trial. METHODS: Patients were randomized 1:1 to receive carboplatin/paclitaxel (C/P) for 6 cycles ± trastuzumab (T) with the experimental arm continuing to receive single agent trastuzumab maintenance treatment until disease progression/toxicity. Progression-free-survival was the primary endpoint; overall-survival and toxicity were secondary endpoints. Adverse events (AEs) were compared between treatment arms. RESULTS: There were 28 patients in the C/P arm and 32 patients in the experimental (C/P + T) arm. Fifty-eight patients (97%) experienced 977 treatment-related AEs of which 875 (89.6%) were low-grade (grade 1-2) and 102 (10.4%) were high-grade (grade 3-5). The mean ± standard deviation of AEs per patient was 15.5 ± 16.3 in the C/P arm and 17.0 ± 16.0 in the C/P + T arm. Gastrointestinal AEs were the most common in both arms (n = 155, 15.7%) of which 94.2% were low-grade (n = 146). Importantly, no significant difference between treatment arms was detected in any system-organ class of AE including cardiac AE. Five (17%) of 29 patients who received prolonged trastuzumab maintenance therapy had no sign of cumulative toxicity after an average (range) of 5.1 (4.2-6.3) years. CONCLUSIONS: Trastuzumab appears to be safe and has a manageable toxicity profile both when used in combination with chemotherapy and when used for single agent maintenance in patients with HER2/neu positive USC. This safety profile is reassuring given the proven efficacy of trastuzumab in advanced/recurrent HER2/neu positive USC.

[Expression of CD44 in Tumor Tissue and Serum of Small Cell Lung Cancer and Its Clinical Prognostic Significance].

BACKGROUND: Small cell lung cancer (SCLC) is a highly aggressive malignancy characterized by rapid growth, early metastasis and acquired therapeutic resistance, and the prognosis is extremely poor. Studies have proved that the stem cell marker CD44 is correlated with tumor recurrence and treatment resistance, however, there are limited reports yet concerning on the CD44 expression and its clinical prognostic significance in SCLC patients. The purpose of this study is to investigate the expression of CD44 in tumor tissues as well as serum of SCLC patients and explore its correlation with the clinical characteristics, therapeutic effect and prognosis. METHODS: The tumor tissues and serum samples of 47 newly diagnosed SCLC patients were collected. Immunohistochemistry and enzyme-linked immunosorbent assay were applied to detect CD44. The relationship between CD44 level and the clinical characteristics as well as prognosis of the patients was analyzed. RESULTS: The stem cell marker CD44 was detectable both in serum sample and tumor tissue of SCLC patients. The positive rate of CD44 in tumor tissue was significantly higher in patients with performance status (PS) 2 than that of patients with PS 0-1 (85.71% vs 30%, P=0.017). Patients were divided in to different groups according to the treatment efficacy. The CD44 immunohistochemical score and serum level in the disease progression group were significantly higher than those in the disease control group, and the differences were statistically significant (P=0.006, P=0.034), Univariate analysis depicted that the progression-free survival (PFS) of CD44 positive patients was significantly shorter than that of CD44 negative patients (5.23 mon vs 9.03 mon, P=0.036). CONCLUSIONS: The positive expression of CD44 in tumor tissues of pre-treatment SCLC patients is correlated with poor PFS. The clinical significance of CD44 is worthy to be further studied.

New insights into patterns of first metastatic sites influencing survival of patients with hormone receptor-positive, HER2-negative breast cancer: a multicenter study of 271 patients.

BACKGROUND: The initial therapeutic strategy for hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer is based on the first metastatic site; however, little evidence is available regarding the influence of metastatic distribution patterns of first metastatic sites on prognosis. In this study, we aimed to identify the metastatic distribution patterns of first metastatic sites that significantly correlate with survival after recurrence. METHODS: We performed a retrospective review of records from 271 patients with recurrent metastatic HR+/HER2- breast cancer diagnosed between January 2000 and December 2015. We assessed survival after recurrence according to the metastatic distribution patterns of the first metastatic sites and identified significant prognostic factors among patients with single and multiple metastases. RESULTS: Prognosis was significantly better in patients with a single metastasis than in those with multiple metastases (median overall survival after recurrence: 5.86 years vs. 2.50 years, respectively, p < 0.001). No metastatic organ site with single metastasis was significantly associated with prognostic outcome, although single metastasis with diffuse lesions was an independent risk factor for worse prognosis (HR: 3.641; 95% CI: 1.856-7.141) and more easily progressing to multiple metastases (p = 0.002). Multiple metastases, including liver metastasis (HR: 3.145; 95% CI: 1.802-5.495) or brain metastasis (HR: 3.289; 95% CI: 1.355-7.937), were regarded as significant independent poor prognostic factors; however, multiple metastases not involving liver or brain metastasis were not significantly related to prognosis after recurrence. CONCLUSIONS: Single metastases with diffuse lesions could more easily disseminate systemically and progress to multiple metastases, leading to a poor prognosis similar to multiple metastases. Our findings indicate that the reconsideration of the determinant factors of therapeutic strategies for first recurrence in HR+/HER2- breast cancer may be needed.

Outcomes of Hormone-Receptor Positive, HER2-Negative Breast Cancers by Race and Tumor Biological Features.

Background: Black women have higher hormone receptor positive (HR+) breast cancer mortality than White women. Early recurrence rates differ by race, but little is known about genomic predictors of early recurrence among HR+ women. Methods: Using data from the Carolina Breast Cancer Study (phase III, 2008-2013), we estimated associations between race and recurrence among nonmetastatic HR+/HER2-negative tumors, overall and by PAM50 Risk of Recurrence score, PAM50 intrinsic subtype, and tumor grade using survival curves and Cox models standardized for age and stage. Relative frequency differences (RFD) were estimated using multivariable linear regression. To assess intervention opportunities, we evaluated treatment patterns by race among patients with high-risk disease. Results: Black women had higher recurrence risk relative to White women (crude hazard ratio = 1.81, 95% confidence interval [CI] = 1.34 to 2.46), which remained elevated after standardizing for clinical covariates (hazard ratio = 1.42, 95% CI = 1.05 to 1.93). Racial disparities were most pronounced among those with high PAM50 Risk of Recurrence score (5-year standardized recurrence risk = 18.9%, 95% CI = 8.6% to 29.1% in Black women vs 12.5%, 95% CI = 2.0% to 23.0% in White women) and high grade (5-year standardized recurrence risk = 16.6%, 95% CI = 11.7% to 21.5% in Black women vs 12.0%, 95% CI = 7.3% to 16.7% in White women). However, Black women with high-grade tumors were statistically significantly less likely to initiate endocrine therapy (RFD = -8.3%, 95% CI = -15.9% to -0.6%) and experienced treatment delay more often than White women (RFD = +9.0%, 95% CI = 0.3% to 17.8%). Conclusions: Differences in recurrence by race appear greatest among women with aggressive tumors and may be influenced by treatment differences. Efforts to identify causes of variation in cancer treatment are critical to reducing outcome disparities.

The Spectroscopic Similarity between Breast Cancer Tissues and Lymph Nodes Obtained from Patients with and without Recurrence: A Preliminary Study.

Lymph nodes (LNs) play a very important role in the spread of cancer cells. Moreover, it was noticed that the morphology and chemical composition of the LNs change in the course of cancer development. Therefore, finding and monitoring similarities between these characteristics of the LNs and tumor tissues are essential to improve diagnostics and therapy of this dreadful disease. In the present study, we used Raman and Fourier transform infrared (FTIR) spectroscopies to compare the chemical composition of the breast cancer tissues and LNs collected from women without (I group-4 patients) and with (II group-4 patients) recurrence. It was shown that the similarity of the chemical composition of the breast tissues and LNs is typical for the II group of the patients. The average Raman spectrum of the breast cancer tissues from the I group was not characterized by vibrations in the 800-1000 cm-1 region originating from collagen and carbohydrates, which are typical for tumor-affected breast tissues. At the same time, this spectrum contains peaks at 1029 cm-1, corresponding to PO2- from DNA, RNA and phospholipids, and 1520 cm-1, which have been observed in normal breast tissues before. It was shown that Raman bands of the average LN spectrum of the II group associated with proteins and carbohydrates are more intensive than those of the breast tissues spectrum. The intensity of the Raman spectra collected from the samples of the II group is almost three times higher compared to the I group. The vibrations of carbohydrates and amide III are much more intensive in the II group's case. The Raman spectra of the breast cancer tissues and LNs of the II group's samples do not contain bands (e.g., 1520 cm-1) found in the Raman spectra of the normal breast tissues elsewhere. FTIR spectra of the LNs of the I group's women showed a lower level of vibrations corresponding to functional group building nucleic acid, collagen, carbohydrates, and proteins in comparison with the breast cancer tissues. Pearson's correlation test showed positive and more significant interplay between the nature of the breast tissues and LN spectra obtained for the II group of patients than that in the I group's spectra. Moreover, principal component analysis (PCA) showed that it is possible to distinguish Raman and FTIR spectra of the breast cancer tissues and LNs collected from women without recurrence of the disease.

Clinical utility of tumour marker velocity of cancer antigen 15-3 (CA 15-3) and carcinoembryonic antigen (CEA) in breast cancer surveillance.

BACKGROUND: Serum tumour markers, cancer antigen 15-3 (CA 15-3) and carcinoembryonic antigen (CEA) are not routinely recommended for detecting breast cancer recurrence and monitoring treatment. In this study, we aim to evaluate the diagnostic accuracy of absolute CA 15-3 and CEA levels and report on the clinical utility of tumour marker velocity in breast cancer surveillance. METHODS: 67 consecutive patients over a 15-year period (1998-2012) with available serial serum CA 15-3 and CEA measurements at recurrence were matched to a control group of patients. Tumour marker velocity was derived from the average change in consecutive tumour marker values over time, expressed in unit/year. Logistic regression analysis was performed to investigate the association between tumour characteristics, tumour marker velocity and disease recurrence. RESULTS: Using the Youden index values, the optimal cut-off values for absolute CA 15-3 and CEA corresponded to the normal assay reference range while tumour marker velocity values were derived to be 2.5U/mL/year and 1.2ng/mL/year respectively. CA 15-3 velocity > 2.5U/mL/year had the highest AUROC value of 0.85 than CEA velocity alone. When either tumour marker velocity exceeded threshold values, the sensitivity, specificity, negative predictive value and positive predictive value were 94.0%, 73.1%, 92.5%, and 77.8% respectively. In the multivariate logistic regression analysis, having both CA 15-3 and CEA velocity exceeding the cut-off values was shown to be a significant predictor for disease recurrence (p = 0.01). CONCLUSION: These findings highlighted the clinical utility of serial tumour markers measurements and its velocity in breast cancer surveillance.

Absence of high-risk human papilloma virus in p16 positive inverted sinonasal papilloma.

OBJECTIVES: Sinonasal inverted papilloma (SIP) is a relatively rare disease, and its etiology is not understood. It is characterized by locally aggressive growth and a strong tendency to recur despite its benign histology. AIMS: The aim of this study was to identify the presence of human papilloma virus (HPV) and its surrogate marker p16 in SIP tissue samples from a regional cohort. MATERIAL AND METHODS: Subjects were identified from our regional center cohort of 88 SIP patients treated between 1984-2014. From these subjects, 54 were included in this study. Of these, 53 biopsies were analyzed with PCR, and 54 samples were immunohistochemically stained for p16. DNA was extracted from histopathologically verified SIP. Genotype screening for 13 high risk-, 5 oncogenic and 6 low risk HPV types was performed using the PapilloCheck® HPV-screening test. RESULTS: HPV analysis was successful for 38 of 53 samples. Of the 38 successfully analyzed samples, only 2 samples were positive for HPV 11. Notably, p16 was present in the epithelia in all samples, and in the papilloma lesions in 37 samples. CONCLUSION: Since only 2 out of 38 SIPs were positive for HPV (type 11), and at the same time p16 was positive in epithelia in all samples and in 37 of 38 papilloma lesions of the samples, it is concluded that p16 cannot be used as a surrogate marker for high-risk HPV-infection in SIP. We are currently planning a prospective, multicenter study in order to increase the study power and in order to be able to better evaluate the clinical implications of HPV-and p16 in SIP.

HER2 assessment by bright-field dual in situ hybridization in cell blocks of recurrent and metastatic breast carcinoma.

BACKGROUND: Breast cancer recurrences or metastases often are diagnosed using cytology material. Cell blocks (CBs) with adequate cellularity are crucial for the determination of accurate hormonal and human epidermal growth factor receptor 2 (HER2) status and to guide treatment. In the current study, the authors evaluated the concordance of HER2 status between bright-field dual in situ hybridization (DISH), fluorescence in situ hybridization (FISH), and HER2 immunohistochemistry (IHC) performed on formalin-fixed CBs of recurrent and metastatic breast cancers. METHODS: The authors searched for patients who had breast carcinoma recurrences or metastases diagnosed between 2010 and 2018 by fine-needle aspiration or by the drainage of body cavity fluids with HER2 IHC and/or FISH performed on formalin-fixed CBs. Cases with adequate tumor cellularity (>50 cells) were selected. HER2 DISH was performed on all CBs. HER2 status of the primary breast carcinoma was recorded. RESULTS: Formalin-fixed CBs were identified from 30 patients with breast cancer recurrences and metastases in axillary lymph nodes (LNs) (5 patients), mediastinal LNs (8 patients), internal mammary LNs (1 patient), supraclavicular LNs (2 patients), portocaval LNs (1 patient), chest wall (3 patients), pleural fluid (3 patients), bone (4 patients), liver (2 patients), and lung (1 patient). All cases had HER2 IHC performed at the study institution and were scored by breast pathologists according to the American Society of Clinical Oncology/College of American Pathologists guidelines. The HER2 DISH results demonstrated 100% concordance (30 of 30 cases) with the concurrent IHC and/or FISH. CONCLUSIONS: All methods of HER2 evaluation were found to accurately identify the amplification status. DISH can be used in tandem with IHC as a reflex assay instead of FISH and is an efficient and reliable method with which to determine HER2 amplification in formalin-fixed CBs.

Distribution of Locoregional Breast Cancer Recurrence in Relation to Postoperative Radiation Fields and Biological Subtypes.

PURPOSE: To investigate incidence and location of locoregional recurrence (LRR) in patients who have received postoperative locoregional radiation therapy (LRRT) for primary breast cancer. LRR-position in relation to applied radiotherapy and the primary tumor biological subtype were analyzed with the aim of evaluating current target guidelines and radiation therapy techniques in relation to tumor biology. METHODS AND MATERIALS: Medical records were reviewed for all patients who received postoperative LRRT for primary breast cancer in southwestern Sweden from 2004 to 2008 (N = 923). Patients with LRR as a first event were identified (n = 57; distant failure and death were considered competing risks). Computed tomographic images identifying LRR were used to compare LRR locations with postoperative LRRT fields. LRR risk and distribution were then related to the primary breast cancer biologic subtype and to current target guidelines. RESULTS: Cumulative LRR incidence after 10 years was 7.1% (95% confidence interval [CI], 5.5-9.1). Fifty-seven of the 923 patients in the cohort developed LRR (30 local recurrences and 30 regional recurrences, of which 3 cases were simultaneous local and regional recurrence). Most cases of LRR developed fully (56%) or partially (26%) within postoperatively irradiated areas. The most common location for out-of-field regional recurrence was cranial to radiation therapy fields in the supraclavicular fossa. Patients with an estrogen receptor negative (ER-) (hazard ratio [HR], 4.6; P < .001; 95% CI, 2.5-8.4) or HER2+ (HR, 2.4; P = .007; 95% CI, 1.3-4.7) primary breast cancer presented higher risks of LRR compared with those with ER+ tumors. ER-/HER2+ tumors more frequently recurred in-field (68%) rather than marginally or out-of-field (32%). In addition, 75% of in-field recurrences derived from an ER- or HER+ tumor, compared with 45% of marginal or out-of-field recurrences. A complete pathologic response in the axilla after neoadjuvant treatment was associated with a lower degree of LRR risk (P = .022). CONCLUSIONS: Incidence and location of LRR seem to be related to the primary breast cancer biologic subtype. Individualized LRRT according to tumor biology may be applied to improve outcomes.

Immune Microenvironment of Primary and Recurrent Craniopharyngiomas: A Study of the Differences and Clinical Significance.

OBJECTIVE: This study explored the differences between the immune microenvironments of primary and recurrent craniopharyngiomas (CPs). In addition, we investigated the relationship between the immune microenvironment and clinical characteristics of CP. METHODS: We collected 52 specimens from 26 patients with CPs. For each patient, specimens for both primary and recurrent CPs were obtained. We performed an immunohistochemical analysis of these specimens to determine the distributions of M2 macrophages, CD8+ T cells, programmed cell death 1 ligand 1 (PD-L1), and Ki67. RESULTS: In recurrent CP specimens, the distributions of M2 macrophages, Ki67, and PD-L1 increased compared with primary CP specimens (P = 0.019, P = 0.0084, and P = 0.0319, respectively). Moreover, the distributions of M2 macrophages, CD8+ T cells, and PD-L1 in papillary CPs were higher than those observed in adamantinomatous craniopharyngiomas (ACPs) (P = 0.0317, P = 0.0359, and P < 0.0001, respectively). In the adult ACP group, M2 macrophages, CD8+ T cells, and PD-L1 were more abundant/expressed than in the child ACP group (P = 0.0159, P = 0.0215, and P < 0.0088, respectively). A positive correlation was found between M2 macrophages and CD8+ T cells (r = 0.4079; P = 0.0027). Correspondingly, M2 macrophages and CD8+ T cells were both positively correlated with PD-L1 (r = 0.4564; P = 0.0007 and r = 0.3987; P = 0.0034, respectively). The observed high expression of M2 macrophages in primary CPs suggests a shortened time for tumor recurrence (P = 0.0131). CONCLUSIONS: The microenvironment of recurrent CP varies from that of primary CP. The abundance of M2 macrophages in primary CP may indicate a risk of early recurrence. Therefore, it is recommended to increase the frequency of follow-up examinations in these patients.

Correlation of radiological and immunochemical parameters with clinical outcome in patients with recurrent glioblastoma treated with Bevacizumab.

BACKGROUND: Some phase 2 trials had reported encouraging progression-free survival with Bevacizumab in monotherapy or combined with chemotherapy in glioblastoma. However, phase 3 trials showed a significant improvement in progression free survival without a benefit in overall survival. To date, there are no predictive biomarker of response for Bevacizumab in glioblastoma. METHODS: We used Immunochemical analysis on tumor samples and pretreatment and post-treatment perfusion-MRI to try to identify possible predictive angiogenesis-related biomarkers of response and survival in patients with glioblastoma treated with bevacizumab in the first recurrence. We analyzed histological parameters: vascular proliferation, mitotic number and Ki-67 index; molecular factors: MGMT promoter methylation, EGFR amplification and EGFR variant III; immunohistochemical: MET, Midkine, HIF1, VEGFA, VEGF-R2, CD44, Olig2, microvascular area and microvascular density; and radiological: rCBV. RESULTS: In the statistical analysis, no significant correlation of any histological, molecular, microvascular or radiological parameters could be demonstrated with the response rate, PFS or OS with bevacizumab treatment. CONCLUSION: Unfortunately, in this histopathological, molecular, immunohistochemical and neuroradiological study we did not find any predictive biomarker of response or survival benefit for Bevacizumab in glioblastoma.

High expression of survivin independently correlates with tumor progression and mortality in patients with skull base chordomas.

OBJECTIVE: The object of this study was to clarify the expression characteristics and prognostic value of survivin in skull base chordomas. METHODS: In this retrospective study, the authors measured the expression of survivin at the mRNA level in 81 samples from 71 patients diagnosed with skull base chordomas at their hospital in the period from July 2005 to January 2015. Clinical data collection, follow-up, and survival analyses were performed, and correlations were analyzed. RESULTS: Of the 71 patients, 50 had primary chordomas with a mean survivin expression level of 1.09; the other 21 patients had recurrent chordomas with a mean survivin expression level of 2.57, which was 2.36 times higher than the level in the primary chordoma patients (p < 0.001, Mann-Whitney U-test). In addition, an analysis of 18 paired samples derived from 9 patients showed that the expression level of survivin was 2.62 times higher in recurrent tumors than in primary tumors (p = 0.002, paired t-test). The Spearman rank correlation coefficient method showed that the expression level of survivin was positively correlated with the mean ratio of tumor signal intensity to the signal intensity of surrounding brainstem on T1-weighted sequences (RT1; rs = 0.274, p = 0.021) and was negatively correlated with the mean ratio of tumor signal intensity to the signal intensity of surrounding brainstem on T2-weighted sequences (RT2; rs = -0.389, p = 0.001). A multivariate Cox proportional-hazards model suggested that pathology (p = 0.041), survivin expression level (p = 0.018), preoperative Karnofsky Performance Status (KPS; p = 0.012), and treatment history (p = 0.009) were independent prognostic factors for tumor progression. Survivin expression level (p = 0.008), preoperative KPS (p = 0.019), tumor diameter (p = 0.027), and intraoperative blood loss (p = 0.015) were independent prognostic factors for death. CONCLUSIONS: Survivin expression level and preoperative KPS were independent significant prognostic factors for tumor progression and death in skull base chordoma patients. Recurrent skull base chordomas and chordomas with high RT1 and low RT2 were likely to have high survivin expression. Other independent risk factors related to tumor progression included conventional pathology and treatment history, whereas additional mortality-related risk factors included larger tumor diameter and greater intraoperative blood loss.

Pancreatic cancer arising in the remnant pancreas is not always a relapse of the preceding primary.

This study aimed to understand the biology of pancreatic ductal adenocarcinoma that arises in the remnant pancreas after surgical resection of a primary pancreatic ductal adenocarcinoma, using integrated histological and molecular analysis. Patients who underwent a completion pancreatectomy for local recurrence following resection of a primary pancreatic ductal adenocarcinoma were studied with histological analysis and next-generation sequencing of the primary and the recurrent cancer. Of six patients that met the inclusion criteria, three cases were classified as "true" recurrences, i.e., the primary and the cancer in the remnant pancreas shared both morphological features and molecular alterations. Two cases were identified as having independent cancers that exhibited different histological and molecular profiles. In the remaining case, the relationship could not be determined. Pancreatic ductal adenocarcinoma that arises in the remnant pancreas can be either a second primary or a "true" relapse of the preceding primary. The differentiation of second primaries from local recurrences may have important implications for patient management.

MUC1 expression in colorectal carcinoma: Clinicopathological correlation and prognostic significance.

INTRODUCTION: MUC1 overexpression has been linked to cancer development and has been associated with a higher stage at diagnosis and presence of lymph node or distant metastases. However, its prognostic significance is still unclear. We aimed to evaluate the relationship between MUC1 expression and prognosis of colorectal carcinoma. MATERIALS AND METHODS: Immunohistochemical expression of MUC1 in 96 colorectal carcinomas with analysis of potential prognostic influence. RESULTS: 55.2% of patients were women and the mean age was 65.9 years. Tumors were more frequently located in rectum or sigmoid colon (60.4% and 21.9%). Most tumors were T3 (60.3%). 36.9% of patients showed lymph node metastases and 30.2% showed distant metastasis at the time of diagnosis. MUC1 was intensely positive in 46% and negative in 37.9% of tumors. Overall, 61% of patients recurred and 40.4% died during follow-up. 58.5% of tumors of surviving patients were intensely positive for MUC1 and 29.5% were negative, as compared with 28.5% (intense positivity) and 51.4% (negativity) in the group of patients who died (p=0.022). 65% of tumors of patients without recurrences showed intense positivity for MUC1 and 23% of them were negative as compared with 33.9% (intense positivity) and 47% (negativity) in the group of patients who recurred (p=0.019). CONCLUSIONS: Loss of MUC1 expression was more frequent in cases with disease recurrence or death, as compared with patients with stable disease, in whom intense positivity was more frequently seen. These findings disagree with the majority of previous studies, indicating the need for further investigation.

Collagen Features of Dermatofibrosarcoma Protuberans Skin Base on Multiphoton Microscopy.

Dermatofibrosarcoma protuberans is a rare, low-grade skin fibroblastic tumor which tends to recur locally due to its high misdiagnosis. Dermatofibrosarcoma protuberans usually spreads through the intracutaneous and subcutaneous layers into the deep dermis layer in which the main component is collagen. Therefore, alterations in collagen shape and content are important for accurate diagnosis of dermatofibrosarcoma protuberans. In this study, multiphoton microscopy was employed to observe normal human skin and dermatofibrosarcoma protuberans skin. Then, a centerline based on an algorithm that skeletonizes a binary image of fibers was applied to analyze collagen shapes in 2 types of skin. Then, collagen content, including intensity and density, was quantitatively obtained to demonstrate differences between the 2 skin types. Results indicate that collagen shape and density can be considered as auxiliary diagnostic parameters to improve the accuracy of dermatofibrosarcoma protuberans diagnosis.

Expression of urokinase-type plasminogen activator and its receptor in squamous cell carcinoma of the oral tongue.

Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) act in the proteolysis of basement membrane and extracellular matrix structures, facilitating tumor invasion. The purpose of this study was to evaluate the relationship between these proteins and clinicopathological parameters in squamous cell carcinoma of the oral tongue (SCCOT). Sixty cases of SCCOT were submitted to immunohistochemistry and analyzed semiquantitatively at the invasion front and in the tumor core. The results were associated with lymph node metastasis, clinical stage, locoregional recurrence, clinical outcome and histological grade of malignancy. A higher expression of uPA was observed in cases of tumors of high-grade versus low-grade malignancy (p = 0.010). Moreover, the cases with the worst pattern of invasion presented an overexpression of uPA (p = 0.011). The presence of locoregional recurrence was associated with uPAR (p = 0.039), and the expression of both biomarkers was much higher at the invasion front than in the tumor core (p < 0.001). The results suggest uPA and uPAR are involved in the progression and aggressiveness of SCCOT, mainly at the tumor-host interface.