No significant histological or ultrastructural tendinosis changes in the hamstring tendon in patients with mild to moderate osteoarthritis of the knee?

PURPOSE: To investigate the periarticular degenerative changes of the knee joint in association with osteoarthritis (OA). More tendinosis was expected to be found in the semitendinosus tendon in patients with knee OA than in patients without knee OA. METHODS: Samples from 41 patients were included between January 2016 and October 2017. Twenty-one patients median age 53 (33-63) years with mild to moderate OA underwent high tibial osteotomy (HTO) and 20 patients median age 38 (31-57) years without OA underwent anterior cruciate ligament reconstruction (ACLR). Biopsies from the semitendinosus tendon were obtained at the time of surgery and examined histologically, morphologically and ultrastructurally using light and electron microscope. RESULTS: The histological evaluation of the semitendinosus tendon revealed the presence of more hemosiderin in the ACLR group. No significant morphological or ultrastructural differences were shown between patients in the HTO and ACLR group. CONCLUSION: Patients with mild and moderate medial compartment knee OA displayed no more degenerative changes in their semitendinosus tendon than patients without OA, as seen in both the light and the electron microscope. LEVEL OF EVIDENCE: III.

Grading of oral squamous cell carcinomas - Intra and interrater agreeability: Simpler is better?

BACKGROUND: Numerous studies have been presented on histological grading of oral squamous cell carcinomas (OSCC) for predicting survival, but uncertainty of their usefulness rises due to discordances of results. A scoring system should be robust and well validated, and intra- and interrater agreement can be used as a tool to visualize the strength of reproducibility. METHODS: Here, we present an intra- and inter-observer study on evaluation of OSCC using some of the most common histopathological parameters. The observers were from different Norwegian university hospitals, and calibration to ensure accuracy was first performed. Percentage of the agreement was calculated for the score made by the individual observer at different times, as well as between pairs of observers. RESULTS: The evaluation made by the same observer at two different time points (intrarater) correlated better than observations made by different participants (interrater). In an attempt to increase the rate of agreement, many of the parameters were either dichotomized into simply low- and high grade, or to a three-tier system when more than three options in the original design. This increased the concurrence with 15.4% for the intrarater and with 23% for the interrater comparisons. CONCLUSION: High agreement for histopathological parameters can be difficult to obtain on hematoxylin and eosin staining in scoring systems with many options. A simpler system might be more advantageous to achieve higher degree of reproducibility.

The effects of terlipressin and direct portacaval shunting on liver hemodynamics following 80% hepatectomy in the pig.

Liver failure is the major cause of death following liver resection. Post-resection portal venous pressure (PVP) predicts liver failure, is implicated in its pathogenesis, and when PVP is reduced, rates of liver dysfunction decrease. The aim of the present study was to characterize the hemodynamic, biochemical, and histological changes induced by 80% hepatectomy in non-cirrhotic pigs and determine if terlipressin or direct portacaval shunting can modulate these effects. Pigs were randomized (n=8/group) to undergo 80% hepatectomy alone (control); terlipressin (2 mg bolus + 0.5-1 mg/h) + 80% hepatectomy; or portacaval shunt (PCS) + 80% hepatectomy, and were maintained under terminal anesthesia for 8 h. The primary outcome was changed in PVP. Secondary outcomes included portal venous flow (PVF), hepatic arterial flow (HAF), and biochemical and histological markers of liver injury. Hepatectomy increased PVP (9.3 ± 0.4 mmHg pre-hepatectomy compared with 13.0 ± 0.8 mmHg post-hepatectomy, P<0.0001) and PVF/g liver (1.2 ± 0.2 compared with 6.0 ± 0.6 ml/min/g, P<0.0001) and decreased HAF (70.8 ± 5.0 compared with 41.8 ± 5.7 ml/min, P=0.002). Terlipressin and PCS reduced PVP (terlipressin = 10.4 ± 0.8 mmHg, P=0.046 and PCS = 8.3 ± 1.2 mmHg, P=0.025) and PVF (control = 869.0 ± 36.1 ml/min compared with terlipressin = 565.6 ± 25.7 ml/min, P<0.0001 and PCS = 488.4 ± 106.4 ml/min, P=0.002) compared with control. Treatment with terlipressin increased HAF (73.2 ± 11.3 ml/min) compared with control (40.3 ± 6.3 ml/min, P=0.026). The results of the present study suggest that terlipressin and PCS may have a role in the prevention and treatment of post-resection liver failure.

Correction to: More tendon degeneration in patients with shoulder osteoarthritis.

Unfortunately, the given name and the family name of the authors were incorrectly identified in the original article. The author names are corrected here by this correction paper. The original article has been corrected.

More tendon degeneration in patients with shoulder osteoarthritis.

PURPOSE: Tendon disorders are a major problem in the general population. It is known that rotator cuff tendinopathy contributes to osteoarthritis (OA) of the shoulder. The aim of the study was to analyse the presence of tendinopathy in patients with shoulder OA and an intact rotator cuff, using a multimodal approach. METHODS: Thirteen consecutive patients median age 67 (52-84) years, with OA of the shoulder, and 13 consecutive control patients, with a fracture of the proximal humerus, median age 70 (51-84) years, underwent an open biopsy procedure from the biceps and subscapularis tendon in conjunction with shoulder arthroplasty. In addition to a macroscopic evaluation, the samples underwent histologic, morphologic and ultrastructural analyses in light and transmission electron microscopy. RESULTS: Macroscopic degeneration was found in 15 of 26 specimen in the OA group but in seven of 25 in the control group (p = 0.048). The histologic analysis revealed a non-significant difference for the total degeneration score (TDS) between the study groups. The morphologic evaluation of the samples revealed that the OA group had significantly more samples with non-homogeneous extracellular matrix (ECM), (p = 0.048). Ultrastructurally, the OA group revealed a significantly larger fibril diameter in the biceps tendon (p < 0.0001) but not in the subscapularis tendon compared with the control group. CONCLUSION: A significantly worse macroscopic appearance and significantly more morphologically inhomogeneous ECM, indicating more tendon degeneration, were found in the OA group compared with the control group. This indicates that it could be beneficial to treat the tendinosis in an early stage to decrease symptoms from the OA. STUDY DESIGN: Level of evidence, III.

Presence of high-endothelial venules correlates with a favorable immune microenvironment in oral squamous cell carcinoma.

Oral squamous cell carcinomas are associated with a poor prognosis, which may be partly due to functional impairment of the immune response. Lymphocyte recruitment to the tumor site is facilitated by high-endothelial venules, whereas expression of programmed-death ligand 1 (PD-L1) can impair T-cell function. Thus, we hypothesize that these factors are important in shaping the immune response in oral squamous cell carcinoma. In the present study, we characterized the immune infiltrate in formalin-fixed, paraffin-embedded tumor samples from 75 oral squamous cell carcinoma patients. We used immunohistochemistry to determine the distribution of immune cell subsets, high-endothelial venules, and PD-L1, as well as quantitative real-time polymerase chain reaction to assess the expression of inflammatory cytokines and chemokines associated with lymphocyte trafficking. Finally, we calculated correlations between the presence of immune cell subsets, the gene expression patterns, high-endothelial venules, PD-L1, and the clinicopathological parameters, including patient survival. The presence of high-endothelial venules correlated with increased number of CD3+ T cells and CD20+ B cells, higher levels of the chemokines CXCL12 and CCL21, and lower levels of CCL20, irrespective of the tumors' T stage. In univariate analysis, high levels of CD20+ B cells and CD68+ macrophages, positive high-endothelial venule status, and low T and N stages predicted longer patient survival. However, only the presence of high-endothelial venules and a low T stage were independent positive prognosticators. This indicates that high-endothelial venules are important mediators and a convenient marker of an antitumor immune response in oral squamous cell carcinoma. Our findings suggest that these vessels are a potential immunomodulatory target in this type of cancer. PD-L1 staining in tumor cells correlated with lower T stage, increased infiltration of CD4+ cells, and higher expression of several inflammation-related cytokines. Thus, oral squamous cell carcinomas rich in CD4+ cells may preferentially respond to PD-1/PD-L1 blockade therapy.

Presence of tumour high-endothelial venules is an independent positive prognostic factor and stratifies patients with advanced-stage oral squamous cell carcinoma.

Staging of oral squamous cell carcinoma is based on the tumour-node-metastasis (TNM) system, which has been deemed insufficient for prognostic purposes. Hence, better prognostic tools are needed to reflect the biological diversity of these cancers. Previously, high numbers of specialized blood vessels called high-endothelial venules have been reported to be associated with prolonged survival in patients with breast cancer. In this study, we analysed the prognostic value and morphological characteristics of tumour-associated high-endothelial venules in oral cancer. The presence of tumour-associated high-endothelial venules was evaluated by immunohistochemistry in 75 patients with oral squamous cell carcinoma and analysed with correlation to clinicopathological parameters, patients' survival and vessel morphology. Ten of the samples were analysed at multiple levels to evaluate intratumoural heterogeneity. The presence of tumour-associated high-endothelial venules was found to be associated with lower disease-specific death in multivariate regression analyses (P = 0.002). High-endothelial venules were present in all (n = 53) T1-T2 tumours, but only in two thirds (n = 14) of the T3-T4 tumours. The morphology of high-endothelial venules was heterogeneous and correlated with lymphocyte density. High-endothelial venules were found to be distributed homogeneously within the tumours. We found the presence of tumour-associated high-endothelial venules to be an easy-to-use, robust, and independent positive prognostic factor for patients with oral cancer. Absence of these vessels in advanced-stage tumours might identify patients with more aggressive disease. Evaluating the presence of tumour-associated high-endothelial venules might help to tailor the treatment of oral cancer patients to their individual needs.

Increased lymph node retrieval decreases adjuvant chemotherapy rate for stage II colon cancer.

OBJECTIVE: Investigation of lymph nodes in colorectal specimens after surgery due to cancer is important for staging the cancer. There has to be an adequate number of lymph nodes to conclude a node-negative status. Our aim was to investigate if change in fixative could give increased lymph node yield, and if this could result in a potential decrease of adjuvant treatment for stage II patients. In addition, we wanted to evaluate if the change in fixative could potentially affect subsequent molecular testing. MATERIAL AND METHODS: All resection specimens from one hospital were from 2011 fixed in GEWF while resection specimens from two other hospitals were fixed in conventional buffered formalin. Number of lymph nodes harvested were compared from two periods; 2009/2010 and 2012/2013. In addition, tumors fixed in GEWF and tumors fixed in formalin were tested separately with immunohistochemical staining and molecular testing. RESULTS: There was a significant increase in lymph node retrieval in specimens fixed in GEWF compared to number of lymph nodes found before the implementation of this fixative (p < 0.001). For hospitals using only formalin, the number of nodes did not increase significantly. Number of positive lymph nodes did not increase. Immunohistochemical staining can be a problem with tumors fixed in GEWF, but DNA quality seems not affected by the changes. CONCLUSIONS: GEWF enhances lymph node detection in colorectal cancer specimens, leading to fewer patients being falsely defined as high-risk stage II. The loss of stability when staining for MMR-proteins can be overcome by molecular analysis when needed.

Nationwide improvement of rectal cancer treatment outcomes in Norway, 1993-2010.

BACKGROUND: The Norwegian Rectal Cancer Project was initated in 1993 with the aims of improving surgery, decreasing local recurrence rates, improving survival, and establishing a national rectal cancer registry. Here we present results from the Norwegian Colorectal Cancer Registry (NCCR) from 1993 to 2010. MATERIAL AND METHODS: A total of 15 193 patients were diagnosed with rectal cancer in Norway 1993-2010, and were registered with clinical data regarding diagnosis, treatment, locoregional recurrences and distant metastases. Of these, 10 796 with non-metastatic disease underwent tumour resection. The results were stratified into five time periods, and the treatment outcomes were compared. Recurrence rates are presented for the 9785 patients who underwent curative major resection (R0/R1). RESULTS: Among all 15 193 patients, relative five-year survival increased from 54.1% in 1993-1997 to 63.4% in 2007-2010 (p < 0.001). Among the 10 796 patients with stage I-III disease who underwent tumour resection, from 1993-1997 to 2007-2010, relative five-year survival improved from 71.2% to 80.6% (p < 0.001). An increasing proportion of these patients underwent surgery at large-volume hospitals; and 30- and 100-day mortality rates, respectively, decreased from 3.0% to 1.4% (p < 0.001) and from 5.1% to 3.0% (p < 0.011). Use of preoperative chemoradiotherapy increased from 6.5% in 1993 to 39.0% in 2010 (p < 0.001). Estimated local recurrence rate after major resection (R0/R1) decreased from 14.5% in 1993-1997 to 5.0% in 2007-2009 (p < 0.001), and distant recurrence rate decreased from 26.0% to 20.2% (p < 0.001). CONCLUSION: Long-term outcomes from a national population-based rectal cancer registry are presented. Improvements in rectal cancer treatment have led to decreased recurrence rates of 5% and increased survival on a national level.

Plectin as a prognostic marker in non-metastatic oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is associated with a poor 5-year survival rate. In general, patients diagnosed with small tumors have a fairly good prognosis, but some small tumors have an aggressive behavior leading to early death. There are at present no reliable prognostic biomarkers for oral cancers. Thus, to optimize treatment for the individual patient, there is a need for biomarkers that can predict tumor behavior. METHOD: In the present study the potential prognostic value of plectin was evaluated by a tissue microarray (TMA) based immunohistochemical analysis of primary tumor tissue obtained from a North Norwegian cohort of 115 patients diagnosed with OSCC. The expression of plectin was compared with clinicopathological variables and 5 year survival. RESULTS: The statistical analysis revealed that low expression of plectin in the tumor cells predicted a favorable outcome for patients with non-metastatic disease (p = 0.008). Furthermore, the expression of plectin was found to correlate (p = 0.01) with the expression of uPAR, which we have previously found to be a potential prognostic marker for T1N0 tumors. CONCLUSIONS: Our results indicate that low expression of plectin predicts a favorable outcome for patients with non-metastatic OSCC and the expression level of plectin may therefore be used in the treatment stratification for patients with early stage disease.

Clinical use of optical coherence tomography to identify angiographic silent stent thrombosis.

OBJECTIVES: Patients previously treated with coronary stents may suffer an acute coronary syndrome (ACS) without any evidence of thrombus formation on coronary angiography (CAG). This may be due to partial, nonocclusive stent thrombosis with microembolization. In this paper, we illustrate possible mechanisms both with optical coherence tomography (OCT) and histology. DESIGN: We present two cases with ACS from very late stent thrombosis who have been previously treated with first-generation drug-eluting stents (DES). RESULTS: The first patient had ACS 15 months after DES implantation. The angiogram (CAG) was near normal with slight peri-stent contrast staining. OCT revealed abnormalities including thrombus not visible on CAG. These are findings that may explain the ACS. The second patient had subclinical episodes with chest pain after DES implantation. The patient died from stent thrombosis in a DES. Postmortem histological examination of the coronary arteries revealed stent struts with little or no neointimal coverage, persistent peri-strut fibrin deposition, inflammatory cells, malapposition, and small luminal platelet-rich thrombi. Old spotty myocardial infarctions were found in the supplied territory possibly caused by earlier episodes of embolizing thrombus. CONCLUSIONS: In patients with previous implanted DES presenting with ACS, OCT may detect abnormalities and thrombus formation not visible on CAG. Such findings may impact the treatment strategy in these patients.

Characterisation and prognostic value of tertiary lymphoid structures in oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinomas are often heavily infiltrated by immune cells. The organization of B-cells, follicular dendritic cells, T-cells and high-endothelial venules into structures termed tertiary lymphoid structures have been detected in various types of cancer, where their presence is found to predict favourable outcome. The purpose of the present study was to evaluate the incidence of tertiary lymphoid structures in oral squamous cell carcinomas, and if present, analyse whether they were associated with clinical outcome. METHODS: Tumour samples from 80 patients with oral squamous cell carcinoma were immunohistochemically stained for B-cells, follicular dendritic cells, T-cells, germinal centre B-cells and high-endothelial venules. Some samples were sectioned at multiple levels to assess whether the presence of tertiary lymphoid structures varied within the tumour. RESULTS: Tumour-associated tertiary lymphoid structures were detected in 21 % of the tumours and were associated with lower disease-specific death. The presence of tertiary lymphoid structures varied within different levels of a tissue block. CONCLUSIONS: Tertiary lymphoid structure formation was found to be a positive prognostic factor for patients with oral squamous cell carcinoma. Increased knowledge about tertiary lymphoid structure formation in oral squamous cell carcinoma might help to develop and guide immune-modulatory cancer treatments.

Clinicopathological characteristics of oral squamous cell carcinoma in Northern Norway: a retrospective study.

BACKGROUND: The main aim of the study was to evaluate if patients with oral squamous carcinomas in Northern Norway differ from patients in other countries with regard to clinicopathological characteristics and also study the influence of risk factors. Such a comparison is of demographical interest, and also important for the interpretation of result from studies on prognostic biomarkers. METHODS: We describe clinicopathological characteristics of 133 North Norwegian patients diagnosed with squamous cell carcinoma of the oral cavity in the period 1986-2002, and evaluate the significance of different risk factors. RESULTS: The cohort consisted of 69 men and 64 women, giving male/female ratio of 1.1. Forty-seven of the 133 patients (35%) died of the disease within 5 years from diagnosis. There was no significant difference between the genders concerning time to disease specific death, even though men both smoked and drank more alcohol than women. As expected, the strongest predictors for disease specific death were tumour size and the presence of regional lymph node metastasis. We also found that heavy smokers and drinkers presented with more advanced disease, more often localized to the floor of mouth compared to non-smoking and abstinent patients, who more often presented with tumours of the mobile tongue. CONCLUSIONS: Our results correlate well with previously published clinicopathological data on comparable cohorts, which is important when considering the applicability of results from biomarker studies performed on this material compared to other cohorts, and vice versa.

ROR2 is a novel prognostic biomarker and a potential therapeutic target in leiomyosarcoma and gastrointestinal stromal tumour.

Soft-tissue sarcomas are a group of malignant tumours whose clinical management is complicated by morphological heterogeneity, inadequate molecular markers and limited therapeutic options. Receptor tyrosine kinases (RTKs) have been shown to play important roles in cancer, both as therapeutic targets and as prognostic biomarkers. An initial screen of gene expression data for 48 RTKs in 148 sarcomas showed that ROR2 was expressed in a subset of leiomyosarcoma (LMS), gastrointestinal stromal tumour (GIST) and desmoid-type fibromatosis (DTF). This was further confirmed by immunohistochemistry (IHC) on 573 tissue samples from 59 sarcoma tumour types. Here we provide evidence that ROR2 expression plays a role in the invasive abilities of LMS and GIST cells in vitro. We also show that knockdown of ROR2 significantly reduces tumour mass in vivo using a xenotransplantation model of LMS. Lastly, we show that ROR2 expression, as measured by IHC, predicts poor clinical outcome in patients with LMS and GIST, although it was not independent of other clinico-pathological features in a multivariate analysis, and that ROR2 expression is maintained between primary tumours and their metastases. Together, these results show that ROR2 is a useful prognostic indicator in the clinical management of these soft-tissue sarcomas and may represent a novel therapeutic target.

Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts.

BACKGROUND: The risk of recurrence of gastrointestinal stromal tumour (GIST) after surgery needs to be estimated when considering adjuvant systemic therapy. We assessed prognostic factors of patients with operable GIST, to compare widely used risk-stratification schemes and to develop a new method for risk estimation. METHODS: Population-based cohorts of patients diagnosed with operable GIST, who were not given adjuvant therapy, were identified from the literature. Data from ten series and 2560 patients were pooled. Risk of tumour recurrence was stratified using the National Institute of Health (NIH) consensus criteria, the modified consensus criteria, and the Armed Forces Institute of Pathology (AFIP) criteria. Prognostic factors were examined using proportional hazards and non-linear models. The results were validated in an independent centre-based cohort consisting of 920 patients with GIST. FINDINGS: Estimated 15-year recurrence-free survival (RFS) after surgery was 59·9% (95% CI 56·2-63·6); few recurrences occurred after the first 10 years of follow-up. Large tumour size, high mitosis count, non-gastric location, presence of rupture, and male sex were independent adverse prognostic factors. In receiver operating characteristics curve analysis of 10-year RFS, the NIH consensus criteria, modified consensus criteria, and AFIP criteria resulted in an area under the curve (AUC) of 0·79 (95% CI 0·76-0·81), 0·78 (0·75-0·80), and 0·82 (0·80-0·85), respectively. The modified consensus criteria identified a single high-risk group. Since tumour size and mitosis count had a non-linear association with the risk of GIST recurrence, novel prognostic contour maps were generated using non-linear modelling of tumour size and mitosis count, and taking into account tumour site and rupture. The non-linear model accurately predicted the risk of recurrence (AUC 0·88, 0·86-0·90). INTERPRETATION: The risk-stratification schemes assessed identify patients who are likely to be cured by surgery alone. Although the modified NIH classification is the best criteria to identify a single high-risk group for consideration of adjuvant therapy, the prognostic contour maps resulting from non-linear modelling are appropriate for estimation of individualised outcomes. FUNDING: Academy of Finland, Cancer Society of Finland, Sigrid Juselius Foundation and Helsinki University Research Funds.

Deep learning-based image analysis reveals significant differences in the number and distribution of mucosal CD3 and γδ T cells between Crohn's disease and ulcerative colitis.

Colon mucosae of ulcerative colitis (UC) and Crohn's disease (CD) display differences in the number and distribution of immune cells that are difficult to assess by eye. Deep learning-based analysis on whole slide images (WSIs) allows extraction of complex quantitative data that can be used to uncover different inflammatory patterns. We aimed to explore the distribution of CD3 and γδ T cells in colon mucosal compartments in histologically inactive and active inflammatory bowel disease. By deep learning-based segmentation and cell detection on WSIs from a well-defined cohort of CD (n = 37), UC (n = 58), and healthy controls (HCs, n = 33), we quantified CD3 and γδ T cells within and beneath the epithelium and in lamina propria in proximal and distal colon mucosa, defined by the Nancy histological index. We found that inactive CD had significantly fewer intraepithelial γδ T cells than inactive UC, but higher total number of CD3 cells in all compartments than UC and HCs. Disease activity was associated with a massive loss of intraepithelial γδ T cells in UC, but not in CD. The total intraepithelial number of CD3 cells remained constant regardless of disease activity in both CD and UC. There were more mucosal CD3 and γδ T cells in proximal versus distal colon. Oral corticosteroids had an impact on γδ T cell numbers, while age, gender, and disease duration did not. Relative abundance of γδ T cells in mucosa and blood did not correlate. This study reveals significant differences in the total number of CD3 and γδ T cells in particularly the epithelial area between CD, UC, and HCs, and demonstrates useful application of deep segmentation to quantify cells in mucosal compartments.

S100A4 expression in xenograft tumors of human carcinoma cell lines is induced by the tumor microenvironment.

Increased expression of the invasion- and metastasis-associated protein S100A4 is found in many types of cancer, but the regulation of S100A4 expression is poorly understood. The microenvironment surrounding tumors has a significant effect on tumor progression, and in the present study, we investigated the role of the microenvironment in the expression of S100A4. Tumors of three different human carcinoma cell lines were established in the tongue or skin of mice, and S100A4 expression was assessed by quantitative RT-PCR, Western blotting, and immunohistochemical analysis in tumors and stromal tissue and in cancer cells grown in vitro. Tongue tumors of the oral squamous cell carcinoma cell line HSC-4 showed a pronounced increase in S100A4 expression during tumor growth, whereas only a minor increase was detected in skin tumors of the same cell line. The S100A4 expression correlated with the methylation status of cytosine-guanine sites in the first intron of the gene. For all cell lines, S100A4 expression in the tumor stroma was related to the presence of inflammatory cells rather than to the level of S100A4 in the tumor cells.

Validation of Selected Head and Neck Cancer Prognostic Markers from the Pathology Atlas in an Oral Tongue Cancer Cohort.

The Pathology Atlas is an open-access database that reports the prognostic value of protein-coding transcripts in 17 cancers, including head and neck cancer. However, cancers of the various head and neck anatomical sites are specific biological entities. Thus, the aim of the present study was to validate promising prognostic markers for head and neck cancer reported in the Pathology Atlas in oral tongue squamous cell carcinoma (OTSCC). We selected three promising markers from the Pathology Atlas (CALML5, CD59, LIMA1), and analyzed their prognostic value in a Norwegian OTSCC cohort comprising 121 patients. We correlated target protein and mRNA expression in formalin-fixed, paraffin-embedded cancer tissue to five-year disease-specific survival (DSS) in univariate and multivariate analyses. Protein expression of CALML5 and LIMA1 were significantly associated with five-year DSS in the OTSCC cohort in univariate analyses (p = 0.016 and p = 0.043, respectively). In multivariate analyses, lymph node metastases, tumor differentiation, and CALML5 were independent prognosticators. The prognostic role of the other selected markers for head and neck cancer patients identified through unbiased approaches could not be validated in our OTSCC cohort. This underlines the need for subsite-specific analyses for head and neck cancer.

Tumor-associated macrophages and macrophage-related immune checkpoint expression in sarcomas.

Early trials for immune checkpoint inhibitors in sarcomas have delivered mixed results, and efforts to improve outcomes now look to combinatorial strategies with novel immunotherapeutics, including some that target macrophages. To enhance our understanding of the sarcoma immune landscape, we quantified and characterized tumor-associated macrophage infiltration and expression of the targetable macrophage-related immune checkpoint CD47/SIRPα across sarcoma types. We surveyed immunohistochemical expression of CD68, CD163, CD47, and SIRPα in tissue microarrays of 1242 sarcoma specimens (spanning 24 types). Non-translocation sarcomas, particularly undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma, had significantly higher counts of both CD68+ and CD163+ macrophages than translocation-associated sarcomas. Across nearly all sarcoma types, macrophages outnumbered tumor-infiltrating lymphocytes and CD163+ (M2-like) macrophages outnumbered CD68+ (M1-like) macrophages. These findings were supported by data from The Cancer Genome Atlas, which showed a correlation between increasing macrophage contributions to immune infiltration and several measures of DNA damage. CD47 expression was bimodal, with most cases showing either 0% or >90% tumor cell staining, and the highest CD47 scores were observed in chordoma, angiosarcoma, and pleomorphic liposarcoma. SIRPα scores correlated well with CD47 expression. Given the predominance of macrophage infiltrates over tumor-infiltrating lymphocytes, the bias toward M2-like (immunosuppressive) macrophage polarization, and the generally high scores for CD47 and SIRPα, macrophage-focused immunomodulatory agents, such as CD47 or IDO-1 inhibitors, may be particularly worthwhile to pursue in sarcoma patients, alone or in combination with lymphocyte-focused agents.

Characteristics and prognosis of primary treatment-naïve oral cavity squamous cell carcinoma in Norway, a descriptive retrospective study.

OBJECTIVES: Incidence of oral cavity squamous cell carcinomas is rising worldwide, and population characterization is important to follow for future trends. The aim of this retrospective study was to present a large cohort of primary oral cavity squamous cell carcinoma from all four health regions of Norway, with descriptive clinicopathological characteristics and five-year survival outcomes. MATERIALS AND METHODS: Patients diagnosed with primary treatment-naïve oral cavity squamous cell carcinomas at all four university hospitals in Norway between 2005-2009 were retrospectively included in this study. Clinicopathological data from the electronic health records were compared to survival data. RESULTS: A total of 535 patients with primary treatment-naïve oral cavity squamous cell carcinomas were identified. The median survival follow-up time was 48 months (range 0-125 months) after treatment. The median five-year overall survival was found to be 47%. Median five-year disease-specific survival was 52%, ranging from 80% for stage I to 33% for stage IV patients. For patients given treatment with curative intent, the overall survival was found to be 56% and disease-specific survival 62%. Median age at diagnosis was 67 years (range 24-101 years), 64 years for men and 72 years for women. The male: female ratio was 1.2. No gender difference was found in neither tumor status (p = 0.180) nor node status (p = 0.266), but both factors influenced significantly on survival (p<0.001 for both). CONCLUSIONS: We present a large cohort of primary treatment-naïve oral cavity squamous cell carcinomas in Norway. Five-year disease-specific survival was 52%, and patients eligible for curative treatment had a five-year disease-specific survival up to 62%.