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.

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.

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.

Tumor budding score predicts lymph node status in oral tongue squamous cell carcinoma and should be included in the pathology report.

BACKGROUND: The majority of oral cavity cancers arise in the oral tongue. The aim of this study was to evaluate the prognostic value of tumor budding in oral tongue squamous cell carcinoma, both as a separate variable and in combination with depth of invasion. We also assessed the prognostic impact of the 8th edition of the American Joint Committee on Cancer's TNM classification (TNM8), where depth of invasion (DOI) supplements diameter in the tumor size (T) categorization. METHODS: Patients diagnosed with primary oral tongue squamous cell carcinoma were evaluated retrospectively. Spearman bivariate correlation analyses with bootstrapping were used to identify correlation between variables. Prognostic value of clinical and histopathological variables was assessed by Log rank and Cox regression analyses with bootstrapping using 5-year disease specific survival as outcome. The significance level for the hypothesis test was 0.05. RESULTS: One-hundred and fifty patients had available material for microscopic evaluation on Hematoxylin and Eosin-stained slides and were included in the analyses. Reclassification of tumors according to TNM8 caused a shift towards a higher T status compared to the previous classification. The tumor budding score was associated with lymph node metastases where 23% of the patients with low-budding tumors had lymph node metastases, compared with 43% of those with high-budding tumors. T-status, lymph node status, tumor budding, depth of invasion, and the combined tumor budding/depth of invasion score were all significantly associated with survival in univariate analyses. In multivariate analyses only N-status was an independent prognosticator of survival. CONCLUSION: Reclassification according to TNM8 shifted many tumors to a higher T-status, and also increased the prognostic value of the T-status. This supports the implementation of depth of invasion to the T-categorization in TNM8. Tumor budding correlated with lymph node metastases and survival. Therefore, information on tumor budding can aid clinicians in treatment planning and should be included in pathology reports of oral tongue squamous cell carcinomas.

A combined histo-score based on tumor differentiation and lymphocytic infiltrate is a robust prognostic marker for mobile tongue cancer.

We wanted to evaluate the prognostic value of common histopathological variables in a large cohort of patients with cancer in the mobile tongue as such information can be important for treatment stratification of the individual patient, especially for patients with low-stage disease. In addition, we wanted to investigate whether an alternative scoring model with fewer options would compromise the prognostic value. One hundred fifty patients with oral tongue squamous cell carcinomas that were treated in curative intent and with available HE-stained tumor sections were included. We reclassified all tumors and performed univariate and multivariate survival analyses of histopathological and clinical variables. For the complete cohort, lymph node status, grade of differentiation, perineural infiltration, and lymphocytic infiltration were independent prognosticators. In the low-stage disease group, independent prognostic factors were tumor size, grade of differentiation, and lymphocytic infiltrate. For patients with low-stage disease, a histo-score combining the scores for tumor differentiation and lymphocytic infiltrate identified a group of patients with particularly low survival, as patients with moderately or poorly differentiated tumors and little lymphocytic infiltrate had a less favorable 5-year survival outcome than patients in the high-stage disease group. This study shows that a histo-score combining tumor differentiation and lymphocytic infiltration should be given special consideration in treatment planning. Our results also illustrate that many variables can be scored with fewer options than previously suggested to increase their reproducibility, and still maintain their prognostic value.

Nephronectin promotes breast cancer brain metastatic colonization via its integrin-binding domains.

This study demonstrates a role for the extracellular matrix protein nephronectin (NPNT) in promoting experimental breast cancer brain metastasis, possibly through enhanced binding to- and migration through brain endothelial cells. With the introduction of more targeted breast cancer treatments, a prolonged survival has resulted during the last decade. Consequently, an increased number of patients develop metastasis in the brain, a challenging organ to treat. We recently reported that NPNT was highly expressed in primary breast cancer and associated with unfavourable prognosis. The current study addresses our hypothesis that NPNT promotes brain metastases through its integrin-binding motifs. SAGE-sequencing revealed that NPNT was significantly up-regulated in human breast cancer tissue compared to pair-matched normal breast tissue. Human brain metastatic breast cancers expressed both NPNT and its receptor, integrin α8ß1. Using an open access repository; BreastMark, we found a correlation between high NPNT mRNA levels and poor prognosis for patients with the luminal B subtype. The 66cl4 mouse cell line was used for expression of wild-type and mutant NPNT, which is unable to bind α8ß1. Using an in vivo model of brain metastatic colonization, 66cl4-NPNT cells showed an increased ability to form metastatic lesions compared to cells with mutant NPNT, possibly through reduced endothelial adhesion and transmigration.

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%.

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.

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.

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.

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.

APC mosaicism in a young woman with desmoid type fibromatosis and familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is usually caused by germline mutations in the adenomatous polyposis coli (APC) gene. The classic form is characterized by hundreds to thousands of adenomas in the colorectum and early onset colorectal cancer (CRC) if left untreated. FAP is also associated with multiple extra-colonic manifestations such as gastroduodenal polyps, osteomas, epidermoid cysts, fibromas and desmoids. Most desmoid tumours in FAP patients occur intra-abdominally. Approximately 15-20% of the APC mutations are de novo mutations. Somatic mosaicism has been reported in some sporadic cases of polyposis but is probably an underestimated cause of the disease. This case report presents the detection of a mosaic APC mutation in a 26-year-old woman who as a child had been diagnosed with desmoid type fibromatosis. FAP was suggested when she presented with extensive extra abdominal fibromatosis. Our findings indicate that APC mutations may be suspected in patients presenting with a desmoid regardless of its location. If there is clinical evidence that the patient has FAP, adenomas and colonic mucosa in addition to leukocyte DNA should be included in the screening, preferably using methods that are more sensitive than Sanger sequencing.

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.

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.

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.

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.

KIT and PDGFRA mutations and the risk of GI stromal tumor recurrence.

PURPOSE: Mutated KIT and platelet-derived growth factor alpha gene (PDGFRA) drive GI stromal tumor (GIST) oncogenesis, but the clinical significance of their single mutations is known incompletely. PATIENTS AND METHODS: We identified 11 population-based series of patients with GIST through a literature search and pooled individual data from 3,067 patients treated with macroscopically complete tumor excision. Mutation analysis was done from 1,505 tumors. We analyzed associations between KIT and PDGFRA mutations and recurrence-free survival (RFS) in the subsets in which patients were treated with surgery alone. RESULTS: We identified 301 different single mutations in KIT and 33 in PDGFRA. Patients with PDGFRA mutations had more favorable RFS than those with KIT mutations (hazard ratio, 0.34; P = .004). Only one of the 35 GISTs with KIT exon 11 duplication mutations recurred. Patients with deletions of only one codon of KIT exon 11 had better RFS than those with another deletion type, and some KIT exon 11 substitution mutations (Trp557Arg, Val559Ala, and Leu576Pro) were also associated with favorable RFS. Patients with an identical mutation had greatly variable outcomes depending on the standard prognostic factors, notably, mitotic count. Commonly used risk stratification schemes tended to overestimate the risk for recurrence in subgroups with prognostically favorable mutations. CONCLUSION: GISTs with an identical KIT or PDGFRA mutation may have widely varying risks for recurrence. Most of the patients with PDGFRA mutations and those with KIT exon 11 duplication mutation or deletion of one codon have favorable RFS with surgery alone and are usually not candidates for adjuvant therapy.

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.