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Reflex mismatch repair immunohistochemistry (MMR IHC) testing for MLH1, PMS2, MSH2 and MSH6 is used to screen for Lynch syndrome. Recently MMR-deficiency (MMRd) has been approved as a pan-cancer predictive biomarker for checkpoint inhibitor therapy, leading to a vast increase in the use of MMR IHC in clinical practice. We explored whether immunohistochemical staining with PMS2 and MSH6 can be used as a reliable substitute. This two-antibody testing algorithm has the benefit of saving tissue, cutting costs and saving time. PubMed, Embase and Cochrane library were systematically searched for articles reporting on MMR IHC. The weighed percentage of cases with isolated MLH1 or MSH2 loss or combined MLH1/MSH2 loss alone was analyzed using a random effects model meta-analysis in R. The search yielded 1704 unique citations, of which 131 studies were included, describing 9014 patients. A weighed percentage of 1.1% (95% CI 0.53–18.87, I = 87%) of cases with isolated MLH1 or MSH2 loss or combined MLH1/MSH2 loss alone was observed. In the six articles with the main aim of investigating the two-antibody testing algorithm all MMRd cases were detected with the two-antibody testing algorithm, there were no cases with isolated MLH1 or MSH2 loss or combined MLH1/MSH2 loss alone. This high detection rate of MMRd of the two-antibody testing algorithm supports its use in clinical practice by specialized pathologists. Staining of all four antibodies should remain the standard in cases with equivocal results of the two-antibody testing algorithm. Finally, educational sessions in which staining pattern pitfalls are discussed will continue to be important.

To develop guidelines for more effective news literacy interventions, we conducted focus groups with early adolescents (12-15 years old) on what these interventions should be like. Participants (N= 55) discussed that motivating early adolescents is a challenge, but did provide more insight into their preferences and needs. Future interventions should be easy to find and use, make news literate behaviors more accessible, should be interactive, and should tailor the content toward the target group. Developing interventions based on these guidelines could positively influence various predictors of news literate behaviors in early adolescents, and, in turn, lead to more news literate behaviors.

Standard molecular classification of endometrial cancers (EC) is now endorsed by the WHO and identifies p53-abnormal (p53abn) EC as the subgroup with the poorest prognosis and the most likely to benefit from adjuvant chemo(radio)therapy. P53abn EC are POLEwildtype, mismatch repair proficient and show abnormal immunohistochemical (IHC) staining for p53. Correct interpretation of routinely performed p53 IHC has therefore become of paramount importance. We aimed to comprehensively investigate abnormal p53 IHC patterns and their relation to clinicopathological and molecular features. Tumor material of 411 molecularly classified high-risk EC from consenting patients from the PORTEC-3 clinical trial were collected. p53 IHC was successful in 408 EC and was considered abnormal when the tumor showed a mutant expression pattern (including subclonal): overexpression, null or cytoplasmic. The presence of pathogenic mutations was determined by next generation sequencing (NGS). Abnormal p53 expression was observed in 131/408 (32%) tumors. The most common abnormal p53 IHC pattern was overexpression (n= 89, 68%), followed by null (n= 12, 9%) and cytoplasmic (n= 3, 2%). Subclonal abnormal p53 staining was observed in 27 cases (21%), which was frequently but not exclusively, associated with POLEmutations and/or MMRd (n= 22/27; p< 0.001). Agreement between p53 IHC and TP53NGS was observed in 90.7%, resulting in a sensitivity and specificity of 83.6% and 94.3%, respectively. Excluding POLEmut and MMRd EC, as per the WHO-endorsed algorithm, increased the accuracy to 94.5% with sensitivity and specificity of 95.0% and 94.1%, respectively. Our data shows that awareness of the abnormal p53 IHC patterns are prerequisites for correct EC molecular classification. Subclonal abnormal p53 expression is a strong indicator for POLEmut and/or MMRd EC. No significant differences in clinical outcomes were observed among the abnormal p53 IHC patterns. Our data support use of the WHO-endorsed algorithm and combining the different abnormal p53 IHC patterns into one diagnostic entity (p53abn EC).

In the first part of this paper (Afrika Matematika 1–24, 2011) we introduced a method for computing the value of a polyconvex envelope at a given feed $$A_0 \in \mathbb{R }^{m \times n}$$ A0∈Rm×n . The method generalizes an approach for computing convex envelopes proposed by Michelsen (Fluid Phase Equilibria 9:1–19 1982; Fluid Phase Equilibria 9:21–40 1982), and later implemented by McKinnon and Mongeau (J Optim Glob 12(4):325–351, 1998). While alternating between a local and a global optimization phase, Lagrange multipliers from the former are passed on to the latter. Here we address the possibility that the Lagrange multipliers may not be well defined because the linear independence constraint qualifications are not satisfied. By computing the multipliers via linear programming duality we obtain a modified method that is guaranteed to converge under assumptions similar to the ones given by McKinnon and Mongeau (J Optim Glob 12(4):325–351, 1998) for the convex envelop. At the end we will present several numerical results obtained with this new approach.