Purpose: To determine the prevalence and prognostic value of mismatch repair (MMR) status and its relation to BRAF mutation (BRAF MT ) status in metastatic colorectal cancer (mCRC). Experimental Design: A pooled analysis of four phase III studies in first-line treatment of mCRC (CAIRO, CAIRO2, COIN, and FOCUS) was performed. Primary outcome parameter was the hazard ratio (HR) for median progression-free survival (PFS) and overall survival (OS) in relation to MMR and BRAF. For the pooled analysis, Cox regression analysis was performed on individual patient data.Results

Negative costimulation on T cells is exploited by both prostate cancer and melanoma to evade antitumor immunity. Blocking such mechanisms restores antitumor immunity as was demonstrated by the improved survival of patients with metastatic melanoma after treatment with an antibody blocking the CTLA-4 inhibitory receptor (ipilimumab). Enhanced expression of another inhibitory immunoreceptor, programmed death-1 (PD-1), and its ligand, PD-L1, was found to correlate with a poor prognosis in prostate cancer and melanoma. PD-1-blocking antibodies are being developed to modulate antitumor immune responses. To support preclinical and clinical development of anti-PD-1 therapy, we sought to develop biomarker assays that can detect the effect of PD-1-blocking agents in whole blood and peripheral blood mononuclear cells. In this study, we assessed the effect of PD-1 blockade in modulating super antigen (staphylococcus enterotoxin B)-induced and recall antigen (tetanus toxoid)-induced T-cell reactivity in vitro using whole blood and peripheral blood mononuclear cells from patients with advanced melanoma, prostate cancer, and healthy controls. PD-1 blockade was found to shift antigen-induced cellular reactivity toward a proinflammatory Th1/Th17 response, as evidenced by enhanced production of interferon γ, interleukin (IL)-2, tumor necrosis factor α, IL-6, and IL-17 and reduced production of the Th2 cytokines IL-5 and IL-13. It is interesting to note that suppression of Th2 responsivity was seen with whole blood cells only from patients with cancer. Taken together, we identified novel biomarker assays that might be used to determine the functional consequences of PD-1 blockade in peripheral blood cells from patients with cancer. How these assays translate to the local antitumor response remains to be established in a clinical setting.

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Postoperative radiotherapy and maxillary or mandibular tumor involvement are the highest contributing risk factors to decreasing MMO and the subsequent development of trismus after oral cancer treatment.

In this clinical 6-year follow-up study subjects with shortened dental arches (SDA, n = 55), characterized by the absence of molar support, are compared with subjects with complete dental arches (CDA, n = 52) with respect to items concerning craniomandibular dysfunction and oral comfort. In addition, a small group of subjects with SDA and removable partial dentures in the lower jaw (SDA + RPD, n = 19) is included in this study. Oral comfort is defined using the following criteria: (i) absence of pain and distress, meaning the absence of signs and symptoms of craniomandibular dysfunction: (ii) chewing ability; and (iii) appreciation of the appearance of the dentition in relation to absent posterior teeth. Additionally, complaints about the free-end RPD are described. It is concluded that: (i) a SDA (consisting of 3-5 occlusal units, OU) is not a risk factor for CMD and is able to provide long-term sufficient oral comfort; and (ii) free-end RPD (in the lower jaw) in SDA do not prevent CMD and do not improve oral function in terms of oral comfort.

Shortened dental arches consisting of anterior and premolar teeth have been shown to meet oral functional demands. However, the occlusal stability may be at risk as a result of tooth migration. The aim of this nine-year study was to investigate occlusal stability in shortened dental arches as a function over time. Occlusal stability indicators were: 'interdental spacing', 'occlusal contacts of anterior teeth in Intercuspal Position', 'overbite', 'occlusal tooth wear', and 'alveolar bone support'. Subjects with shortened dental arches (n = 74) were compared with subjects with complete dental arches (controls, n = 72). Repeated-measurement regression analyses were applied to assess age-dependent variables in the controls and to relate the occlusal changes to the period of time since the treatment that led to the shortened dental arches. Compared with complete dental arches, shortened dental arches had similar overbite and occlusal tooth wear. They showed more interdental spacing in the premolar regions, more anterior teeth in occlusal contact, and lower alveolar bone scores. Since the differences remained constant over time, we conclude that shortened dental arches can provide long-term occlusal stability. Occlusal changes were self-limiting, indicating a new occlusal equilibrium.

In this clinical 6-year follow-up study subjects with shortened dental arches (SDA, n = 55), characterized by the absence of molar support, are compared with subjects with complete dental arches (CDA, n = 52) with respect to occlusal stability. In addition, a small group of subjects with SDA and removable partial dentures in the lower jaw (SDA+RPD, n = 19) is included in this study. The aim of this study was to describe effects regarding occlusal stability in subjects with SDA during a 6-year period. The applied parameters for occlusal stability are: number of occlusal contacts in the anterior region, overbite, interdental spacing and alveolar bone support. The results of this study show that: (i) SDA do provide durable occlusal stability; (ii) free-end RPD do not contribute to occlusal stability in SDA; and (iii) SDA with periodontally involved teeth show continuing periodontal breakdown.

Background Hepcidin concentrations measured by various methods differ considerably, complicating interpretation. Here, a previously identified plasma-based candidate secondary reference material (csRM) was modified into a serum-based two-leveled sRM. We validated its functionality to increase the equivalence between methods for international standardization. Methods We applied technical procedures developed by the International Consortium for Harmonization of Clinical Laboratory Results. The sRM, consisting of lyophilized serum with cryolyoprotectant, appeared commutable among nine different measurement procedures using 16 native human serum samples in a first round robin (RR1). Harmonization potential of the sRM was simulated in RR1 and evaluated in practice in RR2 among 11 measurement procedures using three native human plasma samples. Comprehensive purity analysis of a candidate primary RM (cpRM) was performed by state of the art procedures. The sRM was value assigned with an isotope dilution mass spectrometry-based candidate reference method calibrated using the certified pRM. Results The inter-assay CV without harmonization was 42.1% and 52.8% in RR1 and RR2, respectively. In RR1, simulation of harmonization with sRM resulted in an inter-assay CV of 11.0%, whereas in RR2 calibration with the material resulted in an inter-assay CV of 19.1%. Both the sRM and pRM passed international homogeneity criteria and showed long-term stability. We assigned values to the low (0.95±0.11 nmol/L) and middle concentration (3.75±0.17 nmol/L) calibrators of the sRM. Conclusions Standardization of hepcidin is possible with our sRM, which value is assigned by a pRM. We propose the implementation of this material as an international calibrator for hepcidin.