Local recurrence of soft tissue sarcoma: A radiomic analysis

Background To perform a radiomics analysis in local recurrence (LR) surveillance of limb soft tissue sarcoma (STS) Patients and methods This is a sub-study of a prospective multicenter study with Institutional Review Board approval supported by ESSR (European Society of Musculoskeletal Radiology). radiomics analysis was done on fast spin echo axial T1w, T2w fat saturated and post-contrast T1w (T1wGd) 1.5T MRI images of consecutively recruited patients between March 2016 and September 2018. Results N = 11 adult patients (6 men and 5 women; mean age 57.8 \ub1 17.8) underwent MRI to exclude STS LR: a total of 33 follow-up events were evaluated. A total of 198 data-sets per patients of both pathological and normal tissue were analyzed. Four radiomics features were significantly correlated to tumor size (p < 0.02) and four radiomics features were correlated with grading (p < 0.05). ROC analysis showed an AUC between 0.71 (95%CI: 0.55-0.87) for T1w and 0.96 (95%CI: 0.87-1.00) for post-contrast T1w. Conclusions radiomics features allow to differentiate normal tissue from pathological tissue in MRI surveillance of local recurrence of STS. radiomics in STS evaluation is useful not only for detection purposes but also for lesion characterization

Una procedura per la valutazione dei limiti di utilizzo di O-Ring sottoposti ad intensi fasci di neutroni

Si presenta una procedura per la previsione della durata di utilizzo di O-ring in materiale polimerico impiegati nei bersagli per la produzione di fasci di ioni radioattivi. Si sono dapprima condotte prove di tenuta a vuoto e analisi a elementi finiti di un O-ring di riferimento operante con diversi livelli di interferenza con la cava, identificando la precompressione limite per la tenuta e la corrispondente pressione di contatto con la cava. Si sono poi effettuate prove di trazione e di Compression Set su campioni di O-ring in EPDM, preventivamente sottoposti a diversi livelli di irraggiamento in campi misti di neutroni e gamma, analizzando l’effetto della dose assorbita sul comportamento meccanico del materiale e sulle corrispondenti proprietà resistenziali, e definendo opportune leggi costitutive. Si sono infine simulate le progressive modifiche di comportamento della guarnizione indotte dall’irraggiamento, prevedendone la durata in esercizio in termini di tenuta e di resistenza strutturale

Induction of tumor-specific cytotoxicity in tumor infiltrating lymphocytes by HPV16 and HPV18 E7-pulsed autologous dendritic cells in patients with cancer of the uterine cervix.

OBJECTIVE: To evaluate the potential of autologous dendritic cells (DC) pulsed with HPV16 and HPV18 E7 oncoprotein in restoring tumor-specific cytotoxicity in populations of tumor infiltrating lymphocytes (TIL) for adoptive immunotherapy of cervical cancer patients. METHODS: Full-length E7-pulsed DC-stimulated CD8(+) T cells derived from peripheral blood (PBL) and from tumor tissues (TIL) were tested and compared for their ability to induce a HLA class-I-restricted cytotoxic T lymphocyte (CTL) response against autologous tumor cells. In addition, in order to correlate cytotoxic activity by CTL with a particular lymphoid subset, analysis of surface antigens and intracellular CD3 zeta chain and two-color flow cytometric analysis of intracellular cytokine expression (IFN-gamma vs IL-4) at the single cell level were performed. RESULTS: DC stimulation induced powerful cytotoxicity against autologous tumor target cells by TIL-derived CD8(+) T cells from all three cervical cancer patients, while autologous Epstein-Barr virus-transformed lymphoblastoid cell lines were not lysed. Killing of autologous tumor cells was higher by CD8(+) T cells from TIL compared to PBL (P > 0.01) and was more strongly inhibited by anti-HLA class I MAb (P > 0.05). Phenotypically, all CTL populations were CD3(+)/CD8(+), with higher levels of CD56 expression by TIL-derived CTL. Finally, although a marked Type 1 cytokine bias (i.e., IFN-gamma(high)/IL-4(low)) was observable in both PBL- and TIL-derived DC-stimulated CD8(+) T cell populations, TIL-derived CD8(+) T cells showed a higher percentage of IFN-gamma-positive cells compared to PBL. CONCLUSIONS: Full-length E7-pulsed DC can consistently restore strong CD8(+) CTL responses against autologous HPV16- and HPV18-infected cervical cancer cells. DC-stimulated TIL may represent a superior source of tumor-specific CTL compared to PBL for adoptive T cell immunotherapy of patients harboring metastatic or recurrent cervical cancer refractory to standard treatment modalities

Breast cancer Ki-67 expression prediction by digital breast tomosynthesis radiomics features

The aim of this paper was to investigate whether quantitative radiomic features extracted from digital breast tomosynthesis (DBT) are associated with Ki-67 expression of breast cancer. This was a prospective ethically approved study of 70 women diagnosed with invasive breast cancer in 2018, including 40 low Ki-67 expression (Ki-67 proliferation index <14%) cases and 30 high Ki-67 expression (Ki-67 proliferation index ≥ 14%) cases. A set of 106 quantitative radiomic features, including morphological, grey/scale statistics, and texture features, were extracted from DBT images. After applying least absolute shrinkage and selection operator (LASSO) method to select the most predictive features set for the classifiers, low versus high Ki-67 expression was evaluated by the area under the curve (AUC) at receiver operating characteristic analysis. Correlation coefficient was calculated for the most significant features

Restoration of tumor specific human leukocyte antigens class I-restricted cytotoxicity by dendritic cell stimulation of tumor infiltrating lymphocytes in patients with advanced ovarian cancer

Despite the large number of potentially cytotoxic tumor-infiltrating (TIL) and tumor-associated (TAL) lymphocytes accumulated in the peritoneal cavity ascitic fluid and tumor tissue, advanced ovarian cancer is a progressive disease, suggesting that TIL and TAL populations eventually become functionally suppressed in vivo. Dendritic cells (DC) are the most powerful professional antigen presenting cells known in humans and recently, ovarian tumor antigen pulsed DC have been shown to elicit tumor specific human leukocyte antigens (HLA)-class I-restricted cytotoxicity from the peripheral blood of advanced ovarian cancer patients. In this study, we have evaluated the potential of tumor antigen-pulsed fully mature DC stimulation in restoring tumor-specific cytotoxicity in anergic TIL populations from advanced ovarian cancer patients. In addition, we have compared tumor-specific T-cell responses induced by tumor antigen-loaded DC in TIL to those induced in TAL and peripheral blood lymphocytes (PBL). DC stimulation induced powerful cytotoxicity against autologous tumor target cells in TIL-derived CD8+ T-cells from all patients tested, while autologous Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCL) were not lysed. Killing of autologous tumor cells was higher by CD8+ T-cells from TIL compared to PBL and TAL (P < 0.01) and was more strongly inhibited by anti-HLA class I MAb (P < 0.05 compared to PBL and TAL). Phenotypically, all cytotoxic T lymphocyte (CTL) populations were CD3+/CD8+, with variable levels of CD56 expression. Finally, although a marked Type 1 cytokine bias [ie, interferon-gamma/interleukin-4 (IFN-gammahigh/IL-4low)] was observable in all DC-stimulated CD8+ T-cell populations, TIL derived CD8+ T-cells showed a higher percentage of IFN-gamma positive cells compared to TAL and PBL. Taken together, these data show that tumor lysate-pulsed DC can consistently restore strong CD8+ CTL responses from TIL against autologous ovarian cancer cells. DC-stimulated TIL may represent a superior source of tumor-specific CTL for adoptive T-cell immunotherapy for advanced ovarian cancer

The serine protease stratum corneum chymotryptic enzyme (kallikrein 7) is highly overexpressed in squamous cervical cancer cells.

OBJECTIVE: To determine whether the Stratum Corneum Chymotryptic Enzyme (SCCE), a novel serine protease known to contribute to the cell shedding process by catalyzing the degradation of intercellular cohesive structures at the skin surface, is overexpressed in human cervical tumors. METHODS: SCCE expression was evaluated in 18 cervical cancer cell lines (i.e., 10 primary and 8 established cell lines) as well as in 8 normal cervical keratinocyte cultures by RT-PCR. In addition, SCCE expression was evaluated by immunohistochemistry on paraffin-embedded tumor tissue. RESULTS: Normal cervical keratinocytes did not express SCCE. In contrast, 50% of the primary and 50% of the established cervical cancer cell lines expressed SCCE by RT-PCR. Eighty percent (i.e., four of five) of primary squamous cervical tumors and 20% (i.e., one of five) of primary adenocarcinomas expressed SCCE. Five out of five (100%) of the patients harboring SCCE-positive tumors were found to have metastatic involvement of the pelvic tumor draining lymph nodes. Immunohistochemistry staining of paraffin-embedded cervical cancer specimens confirmed SCCE expression in tumor cells and its absence on normal cervical epithelial cells. CONCLUSION: Squamous cervical cancer expressed high levels of SCCE, suggesting that this protease may play an important role in invasion and metastasis. Because SCCE appears only in abundance in tumor tissue and contains a secretion signal sequence, suggesting that SCCE is secreted, it may prove to be a useful diagnostic/prognostic tool for the detection of metastatic or recurrent disease or as a novel molecular target for cervical cancer therapy

The novel serine protease tumor-associated differentially expressed gene-15 (matriptase/MT-SP1) is highly overexpressed in cervical carcinoma.

BACKGROUND: Tumor-associated differentially expressed gene-15 (TADG-15/matriptase/MT-SP1) is a novel transmembrane serine protease involved in numerous biologic processes, including activation of growth and angiogenic factors and degradation of extracellular matrix components. To assess the value of TADG-15 as a possible marker for tumor detection and/or as a target for therapeutic intervention, the authors investigated the frequency of expression of TADG-15 in human cervical tumors. METHODS: TADG-15 expression was evaluated in 19 cervical carcinoma cell lines (i.e., 11 primary tumor cell lines and 8 established cell lines) and in 8 normal cervical keratinocyte control cultures using reverse transcriptase-polymerase chain reaction (RT-PCR). In addition, to validate gene expression data at the protein level, TADG-15 expression was evaluated by immunohistochemistry on paraffin embedded tissue from which all 11 primary tumor cell lines were established. RESULTS: TADG-15 was expressed at high levels in 8 of 11 (73%) primary cervical carcinoma cell lines and in 6 of 8 (75%) established cervical carcinoma cell lines by RT-PCR. Expression of TADG-15 was found in 6 of 6 (100%) primary squamous cell cervical carcinomas, whereas 2 of 5 (40%) primary adenocarcinomas expressed TADG-15. In contrast, none of the normal cervical keratinocyte control cultures (n = 4) or flash-frozen normal cervical biopsy specimens (n = 4) expressed TADG-15. Immunohistochemistry staining of paraffin embedded cervical carcinoma specimens confirmed TADG-15 expression in tumor cells and its absence on normal cervical epithelial cells. CONCLUSIONS: Cervical carcinoma cells expressed high levels of TADG-15, suggesting that this protease may play an important role in invasion and metastasis. Because TADG-15 appears only in abundance in squamous tumor tissue and contains a proteolytic cleavage site, suggesting that the TADG-15 protease domain is released, it may prove to be a useful diagnostic tool for the early detection of recurrent/persistent cervical carcinoma after standard treatment or as a novel molecular target for therapy in patients with cervical carcinoma

Diagnostic and prognostic impact of serum HE4 detection in endometrial carcinoma patients

Background:To date, no good marker for screening or disease monitoring of endometrial cancer (EC) is available. The aims of this study were to investigate HE4 gene, protein expression and serum HE4 (sHE4) levels in a panel of ECs and normal endometria (NEs) and to correlate sHE4 with patient clinicopathological characteristics and prognosis.Methods:Using quantitative real-time PCR we tested 46 ECs and 20 NEs for HE4 gene expression. Protein expression was analysed by immunohistochemistry on tissue microarrays in 153 ECs and 33 NEs. Pre-operative serum samples from 138 EC and 76 NE patients were analysed with HE4-EIA assay. Association between sHE4 and patient clinicopathological characteristics or outcome was evaluated.Results:Protein and HE4 gene were significantly upregulated in EC tissues and sera, compared with controls. High sHE4 levels were significantly associated with worse EC clinical characteristics. By univariate survival analysis, high sHE4 levels significantly correlated with decreased overall survival, progression-free survival and disease-free survival, retaining their independent prognostic value on the poorly differentiated EC cohort.Conclusion:We demonstrate, for the first time, that high sHE4 levels correlates with an aggressive EC phenotype and may constitute an independent prognostic factor for poorly differentiated-ECs. Determination of sHE4 could be clinically useful in identifying high-risk EC patients for a more aggressive adjuvant therapy.British Journal of Cancer advance online publication, 5 April 2011; doi:10.1038/bjc.2011.109 www.bjcancer.com

The novel serine protease tumor-associated differentially expressed gene-14 (KLK8/Neuropsin/Ovasin) is highly overexpressed in cervical cancer.

OBJECTIVE: Serine proteases are redundant enzymes implicated in the extracellular modulation required for tumor growth and invasion. Tumor-associated differentially expressed gene-14 (TADG-14) is a novel transmembrane serine protease recently reported by our group to be highly overexpressed in ovarian carcinomas. The goal of this study was to investigate the frequency of expression of the TADG-14 gene in human cervical tumors. STUDY DESIGN: TADG-14 expression was evaluated in 19 cervical cancer cell lines (11 primary and 8 established cell lines) as well as in 8 normal cervical keratinocyte cultures by reverse transcriptase polymerase chain reaction. In addition, to validate gene expression data at the protein level, TADG-14 expression was evaluated by immunohistochemistry on paraffin-embedded tissue from which all 11 primary tumor cell lines were established. RESULTS: TADG-14 was found to be highly expressed in 82% (9/11) primary cervical cancer cell lines and in 87% (7/8) established cervical cancer cell lines by reverse transcriptase-polymerase chain reaction. Expression of TADG-14 by primary squamous cervical tumors was 100% (6/6), whereas 60% (3/5) of primary adenocarcinomas expressed TADG-14. In contrast, none of the normal cervical keratinocyte control cultures (n=4) or flash frozen normal cervical biopsy specimens (n=4) expressed TADG-14. Immunohistochemistry staining of paraffin-embedded cervical cancer specimens confirmed TADG-14 expression in tumor cells and its absence on normal cervical epithelial cells. CONCLUSION: Cervical cancer expressed a high level of TADG-14, suggesting that this protease may play an important role in invasion and metastasis. Because TADG-14 appears only in abundance in tumor tissue and contains a secretion signal sequence, suggesting that TADG-14 is secreted, it may prove to be a useful diagnostic tool for the early detection of recurrent/persistent cervical cancer after standard treatment or as a novel molecular target for cervical cancer therapy

Restoration of tumor-specific HLA class I restricted cytotoxicity in tumor infiltrating lymphocytes of advanced breast cancer patients by in vitro stimulation with tumor antigen-pulsed autologous dendritic cells.

Breast tumor infiltrating lymphocytes (TIL) are enriched in tumor-specific cytotoxic T lymphocytes (CTL), and may represent a superior source of CTL compare to peripheral blood lymphocytes (PBL), for adoptive T cell immunotherapy of breast cancer. However, the immunocompetence of TIL and the possibility to consistently restore their tumor-specific lytic activity in vitro remains an open issue. In this study we evaluated the potential of tumor antigen-pulsed fully mature dendritic cell (DC) stimulation in restoring tumor-specific cytotoxicity in anergic TIL populations from advanced breast cancer patients. In addition we have compared tumor-specific T cell responses induced by tumor antigen-loaded DC stimulation of TIL to responses induced from PBL. Although TIL were consistently non-cytotoxic after isolation or culture in the presence of interleukin-2 (IL-2), in matched experiments from three consecutive patients, tumor-lysate-pulsed DC-stimulated CD8+ T cell derived from TIL were found to be significantly more cytotoxic than PBL (p < 0.05). In addition, cytotoxicity against autologous tumor cells was more significantly inhibited by an anti-HLA class I (W6/32) MAb in TIL compared to PBL (p < 0.05). CTL populations derived from TIL and PBL did not lyse autologous EBV-transformed lymphoblastoid cell lines, and showed negligible cytotoxicity against the NK-sensitive cell line K562. Furthermore, in both CD8+ T cell populations the majority of the tumor-specific CTL exhibited a Th1 cytokine bias (IFN-gamma(high)/IL-4(low)). Taken together, these data show that tumor lysate-pulsed mature DC can consistently restore tumor-specific lytic activity in non-cytotoxic breast cancer TIL. These results may have important implications for the treatment of chemotherapy resistant breast cancer with active or adoptive immunotherap