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Purpose: To analyze rates of expression of karyopherin alpha 2 (KPNA2) in different prostate tissues and to evaluate the prognostic properties for patients with primary prostate cancer.Experimental Design: Tissue microarrays (TMA) contained 798 formalin-fixed, paraffin-embedded prostate tissue cores from two different institutes of pathology. TMAs were stained immunohistochemically for KPNA2 and NBS1. SiRNA technologies were used to inhibit KPNA2 expression in vitro, and the effect of this inhibition on cellular viability was determined. Efficiency of knockdown experiments was determined by Western blot analysis.Results: KPNA2 expression was significantly upregulated in carcinomas of the prostate, especially in metastatic and castration-resistant prostate cancer samples. Positive nuclear KPNA2 immunoreactivity was identified as a novel predictor of biochemical recurrence after radical prostatectomy (n = 348), and was independent of the well-established predictive factors preoperative PSA value, Gleason score, tumor stage, and surgical margin status. These results were validated by analyzing a second and independent prostate cancer cohort (n = 330). Further, in vitro experiments showed that the cell proliferation and viability of PC3 cells was significantly reduced when KPNA2 expression was inhibited. KPNA2 knockdown did not induce PARP cleavage as marker for apoptosis. No significantly increased sub-G1 fraction could be found by FACS analysis.Conclusions: KPNA2 is a novel independent prognostic marker for disease progression after radical prostatectomy. This allows to identify patients who need more aggressive treatment. It can moreover be speculated that patients not suited for surveillance regimens might be identified at initial biopsy by a positive KPNA2 immunohistochemistry. Clin Cancer Res; 17(5); 1111–21. ©2011 AACR.

Supplementary Figures S1-S3; Supplementary Table S1.

The aim of this study was to investigate the accuracy of a previously described technique for guided biopsy of osseous pathologies of the jawbone in a clinical setting. The data sets of patients who had undergone guided biopsy procedures were retrospectively examined for accuracy. Digital planning of the biopsies and manufacturing of the tooth-supported drilling template were performed with superimposed cone beam computed tomography and intraoral scans using implant planning software. After a trephine biopsy was taken using the template, the postoperative low-dose cone beam computed tomography was analyzed for accuracy using the planning software with the corresponding (digitally-planned) biopsy cylinder. The mean angular deviation was 4.35 ± 2.5°. The mean depth deviation was -1.40 ± 1.41 mm. Guided biopsy seems to be an alternative to a conventional approach for minimally invasive and highly accurate jawbone biopsy.

This case study discusses the management of a disseminated Mycobacterium simiae and Mycobacterium avium infection causing an immune reconstitution inflammatory syndrome in a 52-year-old woman with HIV infection. Disseminated M. avium infections have extensively been described in HIV patients; however, reports of infections with M. simiae are rare. Treatment of M. simiae infections is challenging due to its high rates of natural drug resistances, and thus far, no standard treatment regimen exists.

Although the contribution of macrophages to metastasis is widely studied in primary tumors, the involvement of macrophages in tumor-draining lymph nodes (LNs) in this process is less clear. We find CD169+ macrophages as the predominant macrophage subtype in naive LNs, which undergo proliferative expansion in response to tumor stimuli. CD169+ LN macrophage depletion, using an anti-CSF-1R antibody or clodronate-loaded liposomes, leads to increased metastatic burden in two mouse breast cancer models. The expansion of CD169+ macrophages is tightly connected to B cell expansion in tumor-draining LNs, and B cell depletion abrogates the effect of CD169+ macrophage absence on metastasis, indicating that the CD169+ macrophage anti-metastatic effects require B cell presence. These results reveal a protective role of CD169+ LN macrophages in breast cancer metastasis and raise caution for the use of drugs aiming at the depletion of tumor-associated macrophages, which might simultaneously deplete macrophages in tumor-draining LNs., Cell Reports, 35 (2), ISSN:2666-3864, ISSN:2211-1247

BACKGROUND Epithelial-mesenchymal transition and cancer stem-like cells (CSC) have been linked to increased metastatic potential. We evaluated the prognostic impact of CD44, a CSC biomarker, on depth of invasion (DOI) and outcome in oral squamous cell carcinoma (OSCC). METHODS Using a multivariable logistic regression model, we evaluated in early OSCCs the relationship between CD44 expression at the invasive tumor front, DOI, sentinel lymph node biopsy, extension of nodal involvement, and survival. We also assessed whether CT and/or MRI could predict DOI preoperatively. RESULTS CD44 expression was associated with increased DOI (P = .018), worse disease-specific survival (P = .041) but not with positive sentinel lymph node biopsy (P > .05). Each millimeter increase in DOI was associated with a 31.1% higher risk for positive sentinel lymph node biopsy (95% CI: 5.8%-62.4%, P = .013) and with higher metastatic ratio (P = .015). Preoperative estimation of DOI by CT and/or MRI and histopathological DOI showed a strong correlation (P

BACKGROUND Chronic rhinosinusitis with nasal polyps (CRSwNP) is a type 2-dominated inflammatory disease of the upper air- ways. A subgroup of patients with CRSwNP suffer from intolerance to nonsteroidal anti-inflammatory drugs (NSAID) and develop NSAID-exacerbated respiratory disease (NERD). The aim of the study was to compare the cytokine based inflammatory endotype of nasal secretions of CRSwNP patients with and without NSAID intolerance. METHODS Nasal secretions were collected from twenty-six patients suffering from CRSwNP, thirteen with NERD and thirteen without NSAID intolerance. As control, nasal secretions were collected from fifteen healthy donors. Tryptase and ten human cyto- kines were analyzed: interleukin (IL)-4, IL-5, IL-6, IL-8, IL-12p70, IL-13, IL-17A, IL-23, IFN-g, and TNF-a by a cytokine multiple array on a Luminex 200 platform. RESULTS Grade of polyposis and frequency of polyp surgery was more severe in NERD- compared to non-NERD patients. IL-6 and IL-5 in CRSwNP was significantly increased compared to healthy participants. IL-5 and IL-13 were significantly increased in subjects suffering from NERD compared to CRSwNP patients without NERD. CONCLUSION We identified IL-13 as a possible specific biomarker in nasal secretions of patients with NERD, which allows us to differentiate between CRSwNP with vs. without NERD. The characterization of inflammatory endotypes in CRSwNP enables the introduction of the best available therapy in the context of precision medicine.

Background and purpose Preclinical data suggest that cetuximab should be continued after end of concurrent radiotherapy+cetuximab due to its efficacy against residual tumor cells in the irradiated tumor bed. Based on this concept the phase II add-on cetuximab (AOC) study was designed. Materials and methods Altogether 63 patients with advanced head and neck cancer were treated with radiochemotherapy (70 Gy, cisplatin 40 mg/m2 weekly) in combination with concurrent cetuximab (loading dose 400 mg/m2, then 250 mg/m2 weekly). Thereafter patients were randomized to cetuximab consolidation (500 mg/m2 biweekly × 6) or no further treatment. The primary endpoint was the 2-year locoregional control (LRC) rate. As translational research endpoints serum markers were analyzed before and during treatment and CT-based quantitative image analysis (radiomics) was performed. Results Median follow-up was 24 months. The 2-year LRC rates were 67.9% and 67.7% in the treatment arms with and without consolidation cetuximab, respectively. Higher than median levels of three serum markers were negatively associated with the 2-year LRC rate in the overall patient cohort: Osteopontin, IL8 and FasL2 (p ≤ 0.05). A radiomics model consisting of two radiomics features could be built showing that higher entropy and higher complexity of tumor Hounsfield unit distribution indicates worse LRC (concordance index 0.66). No correlation was found between biological and imaging markers. Conclusions There was no evidence that consolidation cetuximab would improve the 2-year LRC rate. Prognostic biological and imaging markers could be identified for the overall patient cohort. Studies with larger patient numbers are needed to correlate biological and imaging markers.

Although the contribution of macrophages to metastasis is widely studied in primary tumors, the involvement of macrophages in tumor-draining lymph nodes (LNs) in this process is less clear. We find CD169

Aberrant DNA methylation is an epigenetic hallmark of melanoma, but the expression of DNA methyltransferase (Dnmt)-1 in melanocytic tumors is unknown. Dnmt1 expression was analyzed in primary melanocytes, melanoma cell lines, and 83 melanocytic tumors, and its associations with proliferation, mutational status, and response to B-Raf and mitogen-activated protein kinase kinase (MEK) inhibition were explored. Dnmt1 expression was increased incrementally from nevi [mean fluorescence intensity (MFI), 48.1; interquartile range, 41.7 to 59.6] to primary melanomas (MFI, 68.8; interquartile range, 58.4 to 77.0) and metastatic melanomas (MFI, 87.5; interquartile range, 77.1 to 114.5) (P 0.001). Dnmt1 expression was correlated with Ki-67 expression (Spearman correlation, 0.483; P 0.001) and was independent of BRAF mutation status (P = 0.55). In BRAF-mutant melanoma, Dnmt1 was down-regulated during response to B-Raf and MEK inhibition and was again up-regulated on drug resistance in vitro and in vivo. Degradation of Dnmt1 by the histone deacetylase inhibitor suberoylanilide hydroxamic acid was associated with decreased cell viability in B-Raf inhibitor-sensitive and -resistant cell lines. This study demonstrates that Dnmt1 expression is correlated with proliferation in melanocytic tumors, is increased with melanoma progression, and is associated with response to B-Raf and MEK inhibition. Given its strong expression in metastatic melanoma, Dnmt1 may be a promising target for combined epigenetic and immunotherapy.

Background Aim was to analyse the role of PD-L1 in squamous cell carcinomas of the nasal vestibule. Advanced squamous cell carcinoma of the nasal vestibule is a highly aggressive tumour. The role of PD-L1 expression is unclear in this tumour type. Methodology Forty-six patients diagnosed between 1995 and 2014 were analyzed. Baseline characteristics and outcome were correlated to immunohistochemical staining of PD-L1. PD-L1 positivity of tumour cells and tumour infiltrating immune cells (TIIC) was defined by any staining of more than 1% of the tumour cells. Results PD-L1 expression was interpretable in 31 of 46 patients (67.4%). PD-L1 positivity was present in 14 (45.2%) patients tumour cells and 17 (54.8%) patients TIIC. PD-L1 positivity of tumour cells was associated with a favourable disease free survival (p=0.019). Conclusions Positivity for PD-L1 in tumour cells is a prognostic factor in squamous cell carcinoma of the nasal vestibule and might enable a patient-tailored treatment.

Tumor‐associated lymphangiogenesis and lymphatic invasion of tumor cells correlate with poor outcome in many tumor types, including breast cancer. Various explanations for this correlation have been suggested in the past, including the promotion of lymphatic metastasis and an immune‐inhibitory function of lymphatic endothelial cells (LECs). However, the molecular features of tumor‐associated lymphatic vessels and their implications for tumor progression have been poorly characterized. Here, we report the first transcriptional analysis of tumor‐associated LECs directly isolated from the primary tumor in an orthotopic mouse model of triple negative breast cancer (4T1). Gene expression analysis showed a strong upregulation of inflammation‐associated genes, including endothelial adhesion molecules such as VCAM‐1, in comparison to LECs derived from control tissue. In vitro experiments demonstrated that VCAM‐1 is not involved in the adhesion of tumor cells to LECs but unexpectedly promoted lymphatic permeability by weakening of lymphatic junctions, most likely through a mechanism triggered by interactions with integrin α4 which was also induced in tumor‐associated LECs. In line with this, in vivo blockade of VCAM‐1 reduced lymphatic invasion of 4T1 cells. Taken together, our findings suggest that disruption of lymphatic junctions and increased permeability via tumor‐induced lymphatic VCAM‐1 expression may represent a new target to block lymphatic invasion and metastasis., What's new? Tumor‐associated lymphatic vessels serve important roles in tumor progression and metastasis. Nonetheless, little is known about the molecular changes in these vessels that give rise to a tumor‐promoting phenotype. In this study, transcriptional analysis was performed on lymphatic endothelial cells (LECs) isolated from a mouse model of triple‐negative breast cancer. Endothelial adhesion molecules, including tumor‐induced VCAM‐1, were strongly upregulated in tumor‐associated LECs. Additional experiments showed that VCAM‐1 upregulation influences lymphatic permeability and that its inhibition attenuates lymphatic breast cancer cell invasion. The findings identify VCAM‐1 as a potential target for the blockade of lymphatic invasion of tumor cells.

Background Aim was to analyze the expression of different cancer testis antigens (CTA) and to assess its prognostic value in salivary gland carcinomas. Methods Patients with salivary gland carcinomas diagnosed 1994 to 2010 were included. Baseline characteristics, pathohistological, clinical, and outcome data were assessed. Tissue microarrays were constructed and immunohistochemistry for different CTA (NY-ESO1, NY-BR1, MAGE A1, MAGE A3, MAGE A4, MAGE C1/CT7, and MAGE C2/CT10) was performed. CTA expression was assessed and statistically correlated with pathological and outcome data. Results Expression rates of CTA in salivary gland tumors ranged from 0% to 40%. MAGE A4 expression was associated with a lower tumor grade tumor grading (P = .017), and a favorable recurrence-free (P = .003), disease-specific (P = .046) and overall survival (P = .028). Conclusions MAGE A4 is a highly significant prognostic marker in salivary gland carcinoma; its expression is associated with low-grade histology, a low rate of distant metastasis and a favorable survival. Level of evidence 4.

Background The purpose of this study was to analyze the role of p16INK4a and the prevalence of human papillomavirus (HPV) in squamous cell carcinoma (SCC) of the nasal vestibule. Methods Patients diagnosed from 1995 to 2014 were included in this study. Assessment of p16INK4a and HPV-DNA polymerase chain reaction (PCR) was performed and analyzed with respect to baseline, clinicopathological, and outcome parameters. The p16INK4a positivity was defined as unequivocal nuclear and cytoplasmic staining of ≥70% of the cells, whereas 50%-69% was considered to be a “borderline” result. Results There were 46 patients with SCCs of the nasal vestibule, of whom 31 (67.4%) were available for p16INK4a and 30 (65.2%) for analysis of HPV. Expression of p16INK4a was present in 19.4% and showed coincidence with high-risk HPV (P < .001). Neither p16INK4a nor HPV-DNA had significant impact on outcome. Conclusion Significant immunoreactivity for p16INK4a was present in about one-fifth of the samples and figured as a surrogate marker of high-risk HPV infection. There was no influence on outcome.

// Jutta Ernst 1, * , Kristian Ikenberg 2, * , Barbara Apel 2 , Desiree M. Schumann 1 , Gerhard Huber 3 , Gabriela Studer 4 , Tamara Rordorf 5 , Oliver Riesterer 4 , Matthias Rossle 6 , Dimitri Korol 7 , Marius G. Bredell 1 1 Department of Cranio-, Maxillofacial and Oral Surgery, University Hospital Zurich, Zurich, Switzerland 2 Department of Pathology, University Hospital Zurich, Zurich, Switzerland 3 Department of Otorhinolaryngology, University Hospital Zurich, Zurich, Switzerland 4 Department of Radiation Oncology, University Hospital Zurich, Zurich, Switzerland 5 Department of Oncology, University Hospital Zurich, Zurich, Switzerland 6 Department of Pathology, Cantonal Hospital Chur, Chur, Switzerland 7 Cancer Registry Zurich and Zug, University Hospital Zurich, Zurich, Switzerland * These authors have contributed equally to this work Correspondence to: Marius G. Bredell, email: marius.bredell@usz.ch Keywords: tongue cancer, cytokeratin 19 (CK19), Ki-67, head and neck cancer (HNC) Received: May 04, 2016 Accepted: September 12, 2016 Published: October 15, 2016 ABSTRACT Objectives: To explore the prognostic role of CK19 expression in squamous cell carcinomas within a well-defined cohort of oral tongue cancer patients. Methods: In our retrospective study, we investigated 129 patients with tongue cancer that had suitable material for inclusion in a tissue microarray (TMA). Where possible, samples were taken from central and peripheral regions of the tumor to generate a representative sample of the tumor. The expression level of CK19 was assessed by immunohistochemical staining. Results: Expression of CK19 in squamous cell carcinoma of the tongue was identified as a negative predictor for overall survival (OS; p

Objective was to analyze the role of PD-L1 and its relation to demographic, patho-clinical and outcome parameters in salivary gland carcinoma (SGC) patients. Patients treated for salivary gland carcinomas between 1994 and 2010 were included. A retrospective chart review for baseline characteristics, pathohistological, clinical and outcome data was performed. Immunohistochemistry for PD-L1 was performed using tissue microarrays. PD-L1 expression was assessed in tumor cells and tumor-infiltrating immune cells (TIIC) and statistical analysis with regard to baseline and outcome data was performed. Expression of PD-L1 (by means ≥1% of the cells with PD-L1 positivity) was present in the salivary gland carcinoma cells of 17%, in the TIIC of 20% and in both tumor cells and TIIC of 10% the patients. PD-L1 expression in tumor cells and both tumor cells and TIIC was related to tumor grading (p = 0.035 and p = 0.031, respectively). A trend towards higher grading was also seen for PD-L1 expression in TIICs (p = 0.058). Patients with salivary duct carcinomas and PD-L1 expressing TIICs showed a significantly worse DFS and OS (p = 0.022 and p = 0.003, respectively), those with both tumor cells and TIIC expressing PD-L1 a significantly worse DFS (p = 0.030). PD-L1 expression is present in 17% and 20% of salivary gland carcinoma cells and TIIC. Ten percent of the patient showed a PD-L1 positivity in both tumor cells and TIIC. This is related to high tumor grading and therefore might be a negative prognostic factor.

Podoplanin is a small transmembrane mucin-like glycoprotein that plays a crucial role in the development of the lung, heart and lymphatic vascular system. Its expression is upregulated in several types of human carcinomas and podoplanin levels in squamous cell carcinomas (SCCs) of the oral cavity and the lung correlate with cancer invasiveness, lymph node metastasis and shorter survival time of patients, indicating that podoplanin promotes tumor progression. However, its role during the early stages of carcinogenesis remain unclear. We generated mice with a specific deletion of podoplanin in epidermal keratinocytes (K5-Cre, Pdpnflox/flox mice) and subjected them to a multistep chemical skin carcinogenesis regimen. The rate of tumor initiation, the number, size and differentiation of tumors, and the malignant transformation rate were comparable in K5-Cre, Pdpnflox/flox mice and Pdpnflox/flox control mice. However, tumor cell invasion was reduced in K5-Cre, Pdpnflox/flox mice, in particular single cell invasion. Quantitative immunofluorescence analyses revealed that peritumoral lymphangiogenesis was reduced in K5-Cre, Pdpnflox/flox mice, whereas there were no major changes of tumor-associated immune cell subpopulations. Thus, keratinocyte-expressed podoplanin is dispensable for the early steps of skin carcinogenesis but contributes to the progression of established tumors.

Lymphatic vessels promote organ-to-organ metastasis in addition to mediating tumor cell dissemination from the primary site., Tumor lymphangiogenesis is accompanied by a higher incidence of sentinel lymph node metastasis and shorter overall survival in several types of cancer. We asked whether tumor lymphangiogenesis might also occur in distant organs with established metastases and whether it might promote further metastatic spread of those metastases to other organs. Using mouse metastasis models, we found that lymphangiogenesis occurred in distant lung metastases and that some metastatic tumor cells were located in lymphatic vessels and draining lymph nodes. In metastasis-bearing lungs of melanoma patients, a higher lymphatic density within and around metastases and lymphatic invasion correlated with poor outcome. Using a transgenic mouse model with inducible expression of vascular endothelial growth factor C (VEGF-C) in the lung, we found greater growth of lung metastases, with more abundant dissemination to other organs. Our findings reveal unexpected contributions of lymphatics in distant organs to the promotion of growth of metastases and their further spread to other organs, with potential clinical implications for adjuvant therapies in patients with metastatic cancer.

This paper examines the relationship between cost-effectiveness analysis and cost-benefit analysis. Provided that a cost-effectiveness analysis includes all the relevant societal costs, it is shown that a cost-effectiveness analysis can be interpreted as a cost-benefit analysis where the willingness to pay per effectiveness unit is assumed to be constant and the same for everyone. To relax this assumption the willingness to pay per effectiveness unit can be allowed to vary depending on for instance the size of the health effects and the target population. It is argued that cost-effectiveness analysis is best viewed as a subset of cost-benefit analysis, where the aim of the analysis is to estimate the cost function of producing health effects. It is also concluded that to interpret and use cost-effectiveness analysis as a tool to maximize the health effects for one specified real-world budget, will be inconsistent with a societal perspective and is likely to lead to major problems of suboptimization.

Objectives: Human papillomavirus (HPV) positive oropharyngeal cancer (oropharyngeal squamous cell carcinoma, OPSCC) is biologically and clinically different from HPV negative OPSCC. Here, we evaluate the use of a radiomic approach to identify the HPV status of OPSCC. Methods: Four independent cohorts, totaling 778 OPSCC patients with HPV determined by p16 were collected. We randomly assigned 80% of all data for model training (N = 628) and 20% for validation (N = 150). On the pre-treatment CT images, 902 radiomic features were calculated from the gross tumor volume. Multivariable modeling was performed using least absolute shrinkage and selection operator. To assess the impact of CT artifacts in predicting HPV (p16), a model was developed on all training data (M-all) and on the artifact-free subset of training data (M-no (art)), Models were validated on all validation data (V-all), and the subgroups with (V-art) and without (V-no (art)) artifacts. Kaplan-Meier survival analysis was performed to compare HPV status based on p16 and radiomic model predictions. Results: The area under the receiver operator curve for M-all and M-no (art) ranged between 0.70 and 0.80 and was not significantly different for all validation data sets. There was a consistent and significant split between survival curves with HPV status determined by p16 [p = 0.007; hazard ratio (HR): 0.46], M-all (p = 0.036; HR: 0.55) and M-no (art) (P = 0.027; HR: 0.49). Conclusion: This study provides proof of concept that molecular information can be derived from standard medical images and shows potential for radiomics as imaging biomarker of HPV status. Advances in knowledge: Radiomics has the potential to identify clinically relevant molecular phenotypes.

Objective Sinonasal undifferentiated carcinoma (SNUC) is an aggressive malignancy first described by Frierson et al. in 1986. As the tumor is very rare, current treatment recommendations are based on institutional case reports. We thus felt the need to perform a comprehensive systematic review and meta-analysis to investigate how treatment modalities are associated with survival. Design Case-series, systematic review and meta-analysis Methods We searched the OvidMedline, OvidEmbase, Web of Science, Biosis, Scopus and the Cochrane Library database libraries. We extracted aggregate and individual patient data for statistical analysis. To study the association between treatment modalities and survival, we used random-effects meta-regression for the aggregate- and cox mixed-effects models. Results 379 citations were found; 29 case series could be included in the final analysis, including a total number of 390 single patients (34.6% female). Median age at diagnosis was 52 years. 80.9% of patients presented with a T4 tumor and 16.0% with nodal metastasis at diagnosis. In individual patient data (IPD) meta-analysis, single modality (surgery alone or radiation alone) treatment was associated with reduced survival compared to double modality (surgery & radiation or chemoradiation) treatment (adjusted Hazard Ratio [aHR] 2.97, 95% ConfidenceInterval [1.41–6.27]) and compared to triple modality (surgery & radiation & chemotherapy) treatment (aHR 2.80 95%-CI 1.29–6.05 for triple vs. single modality). Triple modality treatment was not superior to double modality treatment. (aHR 1.06, 95%-CI 0.59–1.92). Conclusion Double and triple modality treatment are associated with improved survival over single modality but there is no evidence that triple modality is superior to double modality treatment.

Background Treatment of recurrent nasopharyngeal carcinoma is a challenging clinical problem. We report the case of a 46 year old male showing excellent response and signs of immunostimulation following re-re-irradiation for recurrent nasopharyngeal carcinoma under systemic treatment with pembrolizumab. Case presentation Patient was first diagnosed with locoregionally advanced, non-keratinizing nasopharyngeal carcinoma in 2010. After achieving complete remission following induction chemotherapy and concurrent curative chemoradiation, the patient subsequently developed distant and locoregionally recurrent disease. He received various treatments (neck dissection, radiotherapy to a bony metastasis, palliative chemotherapy, stereotactic re-irradiation of local recurrence) before initiation of anti- PD-1 immunotherapy with pembrolizumab in January of 2016. Following marked local progression 6 months thereafter, we performed re-re-irradiation of the recurrent tumor after careful evaluation and treatment planning. While treatment was well tolerated, the patient subsequently developed marked clinical and radiological signs of immunostimulation with mucosal irritation and swelling of lacrimal and salivary glands as described in the report. Immunotherapy with pembrolizumab was reinitiated, with re- staging showing excellent response with regression of all tumorous lesions. At the time of this report, following near complete recovery of inflammatory symptoms, the patient remains in excellent condition and free from recurrence under treatment with pembrolizumab. Conclusions To our knowledge, we report the first observation of a combined effect of immunotherapy and radiotherapy in a patient with recurrent nasopharyngeal carcinoma. Demonstrating distinct signs of immunostimulation as well as excellent tumor response in a heavily pretreated patient progressing under anti-PD-1 immunotherapy, the case adds to the rising paradigm of an immunostimulatory effect of radiotherapy in patients undergoing treatment with immune checkpoint inhibitors.

RAGE is a central driver of tumorigenesis by sustaining an inflammatory tumor microenvironment. This study links the soluble forms of RAGE (sRAGE and esRAGE) with clinical outcome of melanoma patients. Moreover, tissue expression of RAGE was analyzed using immunohistochemistry on two independent tissue microarrays (TMA) containing 35 or 257 primary melanomas, and 41 or 22 benign nevi, respectively. Serum concentrations of sRAGE and esRAGE were measured in 229 Stage III-IV patients using ELISA and plasma concentrations of sRAGE were analyzed in an independent second cohort with 173 samples of Stage I-IV patients. In this cohort, three well-described SNPs in the RAGE gene were analyzed. RAGE protein expression was highly upregulated in primary melanomas compared to benign nevi in the two TMA (p < 0.001 and p = 0.005) as well as in sun-exposed melanomas (p = 0.046). sRAGE and esRAGE were identified as prognostic markers for survival as diminished sRAGE (p = 0.034) and esRAGE (p = 0.012) serum levels correlated with poor overall survival (OS). Multivariate Cox regression analysis showed that diminished serum sRAGE was independently associated with poor survival (p = 0.009). Moreover, diminished sRAGE was strongly associated with impaired OS in the second cohort (p < 0.001). Multivariate Cox regression analysis including the investigated SNPs revealed an independent correlation of the two interacting promoter SNPs with impaired OS. In conclusion, the soluble forms of RAGE and variants in its genetic locus are prognostic markers for survival in melanoma patients with high risk for progression.

The aim of this study was to analyze the role of Ki-67, p53, and the "aberrant p53 pattern" in squamous cell carcinomas of the nasal vestibule. Patients between 1995 and 2014 were included. Baseline characteristics and outcome were analyzed with respect to immunohistochemical staining of Ki-67 and p53. "Aberrant p53 pattern" was represented by a moderate or strong staining of at least 60% of the tumor cells or a complete absence of immunoreactivity. Forty-six patients were included of whom 31 (67.4%) were available for Ki-67 and 32 (69.9%) for p53 immunohistochemistry. The "aberrant pattern" of p53 was present in 50% of the patients. While immunoreactivity for both Ki-67 and p53 was not related to each other or outcome, the "aberrant p53 pattern" was associated with a worse disease-free survival (p = 0.014). The "aberrant p53 pattern" is a negative prognostic factor in squamous cell carcinoma of the nasal vestibule and might enable a patient-tailored treatment.

Contains fulltext : 170562.pdf (Publisher’s version ) (Closed access) Cancer metastases arise from a multi-step process that requires metastasizing tumor cells to adapt to signaling input from varying tissue environments [1]. As an early metastatic event, cancer cell dissemination occurs through different migration programs, including multicellular, collective, and single-cell mesenchymal or amoeboid migration [2-4]. Migration modes can interconvert based on changes in cell adhesion, cytoskeletal mechanotransduction [5], and/or proteolysis [6], most likely under the control of transcriptional programs such as the epithelial-to-mesenchymal transition (EMT) [7, 8]. However, how plasticity of tumor cell migration and EMT is spatiotemporally controlled and connected upon challenge by the tumor microenvironment remains unclear. Using 3D cultures of collectively invading breast and head and neck cancer spheroids, here we identify hypoxia, a hallmark of solid tumors [9], as an inducer of the collective-to-amoeboid transition (CAT), promoting the dissemination of amoeboid-moving single cells from collective invasion strands. Hypoxia-induced amoeboid detachment was driven by hypoxia-inducible factor 1 (HIF-1), followed the downregulation of E-cadherin, and produced heterogeneous cell subsets whose phenotype and migration were dependent ( approximately 30%) or independent ( approximately 70%) of Twist-mediated EMT. EMT-like and EMT-independent amoeboid cell subsets showed stable amoeboid movement over hours as well as leukocyte-like traits, including rounded morphology, matrix metalloproteinase (MMP)-independent migration, and nuclear deformation. Cancer cells undergoing pharmacological stabilization of HIFs retained their constitutive ability for early metastatic seeding in an experimental model of lung metastasis, indicating that hypoxia-induced CAT enhances cell release rather than early organ colonization. Induced by metabolic challenge, amoeboid movement may thus constitute a common endpoint of both EMT-dependent and EMT-independent cancer dissemination programs. 9 p.

Recent studies identified unexpected expression and transcriptional complexity of the hemoprotein myoglobin (MB) in human breast cancer but its role in prostate cancer is still unclear. Expression of MB was immunohistochemically analyzed in three independent cohorts of radical prostatectomy specimens (n = 409, n = 625, and n = 237). MB expression data were correlated with clinicopathological parameters and molecular parameters of androgen and hypoxia signaling. Expression levels of novel tumor-associated MB transcript variants and the VEGF gene as a hypoxia marker were analyzed using qRT-PCR. Fifty-three percent of the prostate cancer cases were MB positive and significantly correlated with androgen receptor (AR) expression (p

Purpose This study aimed to predict local tumor control (LC) after radiochemotherapy of head and neck squamous cell carcinoma (HNSCC) and human papillomavirus (HPV) status using computed tomography (CT) radiomics. Methods and Materials HNSCC patients treated with definitive radiochemotherapy were included in the retrospective study approved by the local ethical commission (93 and 56 patients in the training and validation cohorts, respectively). Three hundred seventeen CT radiomic features, including those based on shape, intensity, texture, and wavelet transform, were calculated in the primary tumor region. Cox and logistic regression models were built to predict LC and HPV status, respectively. The best-performing features in the univariable analysis were included in the multivariable analysis after the exclusion of redundant features. The quality of the models was assessed using the concordance index (CI) for modeling of LC and receiver operating characteristics area under the curve (AUC) for HPV status prediction. The radiomics LC model was compared to a model incorporating clinical parameters (tumor stage, volume, and HPV status) and a mixed model. Results A radiomic signature comprising 3 features was significantly associated with LC (CI training = 0.75 and CI validation = 0.78), showing that tumors with a more heterogeneous CT density distribution are at risk for decreased LC. The addition of clinical parameters to the radiomics model slightly improved the model in the training cohort but not in the validation cohort. Another radiomic signature showed good performance in HPV status prediction (AUC training = 0.85 and AUC validation = 0.78) and indicated that HPV-positive tumors have a more homogenous CT density distribution. Conclusions Heterogeneity of HNSCC tumor density, quantified by CT radiomics, is associated with LC after radiochemotherapy and HPV status.

The purpose of this study was to analyze the role of p16Patients diagnosed from 1995 to 2014 were included in this study. Assessment of p16There were 46 patients with SCCs of the nasal vestibule, of whom 31 (67.4%) were available for p16Significant immunoreactivity for p16

Background: The mitotic rate was introduced as a major prognostic criterion for the staging of thin (≤1.0 mm) melanoma by the 2009 American Joint Committee on Cancer Staging and Classification (seventh edition). The detection of a single mitotic figure changes the tumor stage in thin melanoma. We sought to address the value of a dual staining to facilitate the determination of the mitotic rate and to assign the mitotic activity to melanocytes. Methods: The mitotic rate of melanoma cells was determined by dual phosphohistone-H3 (PHH3)/Melan-A immunohistochemistry. Results were compared with PHH3 staining alone and conventional hematoxylin and eosin (H&E)-stained slides of 15 melanomas with a tumor thickness

Importance The prognosis of advanced cutaneous T-cell lymphoma (CTCL), including Sezary syndrome and mycosis fungoides (MF), is poor. So far, no curative option apart from allogeneic stem cell transplantation is available. Large cell transformation often hallmarks cases with a more aggressive clinical course, and large tumor cells may express CD30. Recently, brentuximab vedotin, a conjugate of an anti-CD30 antibody and monomethylauristatin E, which inhibits the polymerization of microtubuli, has produced promising results in phase 2 trials in CD30 + Hodgkin lymphoma and anaplastic large cell lymphoma. Observations We describe 4 patients with advanced CTCL, 3 with MF and 1 with Sezary syndrome, who were treated with brentuximab. All patients had received multiple previous systemic therapies. In 2 cases of MF, a remission enabling subsequent allogeneic stem cell transplantation was achieved. Conclusions and Relevance Brentuximab is a well-tolerated, promising new treatment option for advanced CTCL that can be integrated in an allogeneic stem cell transplantation plan by selectively depleting malignant CD30 + cutaneous lymphoma cells.

RAGE is a central driver of tumorigenesis by sustaining an inflammatory tumor microenvironment. This study links the soluble forms of RAGE (sRAGE and esRAGE) with clinical outcome of melanoma patients. Moreover, tissue expression of RAGE was analyzed using immunohistochemistry on two independent tissue microarrays (TMA) containing 35 or 257 primary melanomas, and 41 or 22 benign nevi, respectively. Serum concentrations of sRAGE and esRAGE were measured in 229 Stage III-IV patients using ELISA and plasma concentrations of sRAGE were analyzed in an independent second cohort with 173 samples of Stage I-IV patients. In this cohort, three well-described SNPs in the RAGE gene were analyzed. RAGE protein expression was highly upregulated in primary melanomas compared to benign nevi in the two TMA (p0.001 and p = 0.005) as well as in sun-exposed melanomas (p = 0.046). sRAGE and esRAGE were identified as prognostic markers for survival as diminished sRAGE (p = 0.034) and esRAGE (p = 0.012) serum levels correlated with poor overall survival (OS). Multivariate Cox regression analysis showed that diminished serum sRAGE was independently associated with poor survival (p = 0.009). Moreover, diminished sRAGE was strongly associated with impaired OS in the second cohort (p0.001). Multivariate Cox regression analysis including the investigated SNPs revealed an independent correlation of the two interacting promoter SNPs with impaired OS. In conclusion, the soluble forms of RAGE and variants in its genetic locus are prognostic markers for survival in melanoma patients with high risk for progression.

A 53-year-old man presented with a recurrent left fourth nerve and acute left third nerve palsy (figure 1). Brain MRI showed leptomeningeal and oculomotor nerve contrast enhancement (figure 2). CSF examination indicated chronic lymphocytic meningitis with massively increased soluble interleukin (IL)-2 receptor and IL-6.1 Extensive infectious disease workup remained unremarkable. [18F]-Fluorodeoxyglucose (FDG)-PET/CT revealed active deep cervical lymph nodes containing noncaseating granulomas (figure 2). No pulmonary or other systemic manifestation was found, consistent with clinically isolated neurosarcoidosis.2 Upon immunosuppressive treatment,1,2 the oculomotor palsies rapidly remitted. Neurosarcoidosis is a rare condition lacking specific biomarkers.2 When suspected, FDG-PET/CT can guide diagnosis and prevent CNS biopsy.1 The authors thank the patient for consenting to the publication, the colleagues who were involved in treatment of the patient, and the photographers P. Bar and P. Breitschmid.