Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers

Background: Reported prevalence, penetrance and expression of deleterious mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2, may reflect differences in the clinical criteria used to select families for DNA testing. The authors have previously reported that clinical criteria are not sensitive enough to identify MMR mutation carriers among incident colorectal cancer cases. Objective: To describe the sensitivity of the criteria when applied to families with a demonstrated MMR mutation. Methods: Families with an aggregation of colorectal cancers were examined for deleterious MMR mutations according to the Mallorca guidelines. All families with a detected MMR mutation as of November 2009 were reclassified according to the Amsterdam and Bethesda criteria. Results: Sixty-nine different DNA variants were identified in a total of 129 families. The original Amsterdam clinical criteria were met by 38%, 12%, 78% and 25% of families with mutations in MSH2, MSH6, MLH1 and PMS2, respectively. Corresponding numbers for the revised Amsterdam criteria were 62%, 48%, 87% and 38%. Similarly, each of the four clinical Bethesda criteria had low sensitivity for identifying MSH6 or PMS2 mutations. Conclusion: Amsterdam criteria and each of the Bethesda criteria were inadequate for identifying MSH6 mutation-carrying kindreds. MSH6 mutations may be more common than currently assumed, and the penetrance/expression of MSH6 mutations, as derived from families meeting current clinical criteria, may be misleading. To increase detection rate of MMR mutation carriers, all cancers in the Lynch syndrome tumour spectrum should be subjected to immunohistochemical analysis and/or analysis for microsatellite instability

Cements for tunnel grouting – Rheology and flow properties tested at different temperatures

This paper presents work being carried out in Work Package 3 of TIGHT (True Improvement in Grouting High pressure Technology for tunnelling) project. The objective is to investigate flow and mechanical properties of three cements (A, B and C) at actual tunnel- and room –temperatures using various laboratory methods. The cements were first characterized in terms of grain size distribution and specific surface area. Then the grouts made from the three cements were tested for flow properties and mechanical strength. Cement grouts were prepared at two different temperatures of 8 °C and 20 °C to represent the actual tunnelling temperature of projects in Scandinavia and the room temperature, respectively. The experimental program comprised of a total of 590 tests, including the tests presented in this paper and elsewhere. The experiments include grain size distribution, specific surface area, viscosity, bleeding, hydration temperature, setting time and strength of cured grout specimens. Four different water to cement (w/c) ratios of 0.6, 0.8, 1.0 and 1.2 were used for most of the tests. Results showed that the grouts prepared from the three cements had quite different behaviour in terms of rheology, flow and mechanical properties. Viscosity of various types of cement grouts is very different at low w/c ratios but the difference decreases with increasing w/c ratio. All three cements fulfil the requirements described by ASTM for bleeding at w/c ratios up to 1.0, but only cement A qualifies for w/c ratios of greater than 1.0. Also cement A sets much faster than cement B and C, as proved by the Vicat needle test and heat of hydration. Temperature evolvement and heat of hydration, during initial stages of setting, is both higher and faster for cement A than cements B and C. Results show that there is a negative correlation between the heat of hydration and the uniaxial compressive strength of cement grout specimens. It is also illustrated that fast temperature increase in a cement grout leads to a lower strength of the cured grout specimen

Symptomatic Primary (AL) Amyloidosis of the Stomach and Duodenum

Primary (AL) amyloidosis of the gastrointestinal tract is relatively rare, and symptomatic amyloidosis of the stomach is even more seldom. We present the case of a patient who was referred to upper endoscopy because of weight loss, nausea, and vomiting. Large areas of intramucosal hemorrhages were seen, and biopsies resulted in profuse bleeding stopped with endoscopic clips. The biopsies showed amyloid depositions and further workup revealed that the patient also had cardiac and neuropathic involvements. The patient started treatment with dexamethasone, melphalan and bortezomib. After treatment was started the nausea and epigastric discomfort improved, and a reduction in the biochemical markers troponin T, NT-proBNP, and M-component was observed. Gastric amyloidosis is rarely seen at upper endoscopy in patients without a previously established diagnosis, but the unusual endoscopic findings and bleeding tendency after biopsy should be kept in mind by gastroenterologists

Cements for tunnel grouting – Rheology and flow properties tested at different temperatures

This paper presents work being carried out in Work Package 3 of TIGHT (True Improvement in Grouting High pressure Technology for tunnelling) project. The objective is to investigate flow and mechanical properties of three cements (A, B and C) at actual tunnel- and room –temperatures using various laboratory methods. The cements were first characterized in terms of grain size distribution and specific surface area. Then the grouts made from the three cements were tested for flow properties and mechanical strength. Cement grouts were prepared at two different temperatures of 8 °C and 20 °C to represent the actual tunnelling temperature of projects in Scandinavia and the room temperature, respectively. The experimental program comprised of a total of 590 tests, including the tests presented in this paper and elsewhere. The experiments include grain size distribution, specific surface area, viscosity, bleeding, hydration temperature, setting time and strength of cured grout specimens. Four different water to cement (w/c) ratios of 0.6, 0.8, 1.0 and 1.2 were used for most of the tests. Results showed that the grouts prepared from the three cements had quite different behaviour in terms of rheology, flow and mechanical properties. Viscosity of various types of cement grouts is very different at low w/c ratios but the difference decreases with increasing w/c ratio. All three cements fulfil the requirements described by ASTM for bleeding at w/c ratios up to 1.0, but only cement A qualifies for w/c ratios of greater than 1.0. Also cement A sets much faster than cement B and C, as proved by the Vicat needle test and heat of hydration. Temperature evolvement and heat of hydration, during initial stages of setting, is both higher and faster for cement A than cements B and C. Results show that there is a negative correlation between the heat of hydration and the uniaxial compressive strength of cement grout specimens. It is also illustrated that fast temperature increase in a cement grout leads to a lower strength of the cured grout specimen

BRAF V600E mutation in early-stage multiple myeloma: good response to broad acting drugs and no relation to prognosis

In this study, we analyzed the prevalence and clone size of BRAF V600E mutation in 209 patients with multiple myeloma and related the results to clinical phenotype, response and survival. Biopsies were screened for BRAF V600E by allele-specific real-time PCR (AS-PCR). Positive results were confirmed by immunohistochemistry, Sanger sequencing and, in three patients from whom we had stored purified myeloma cells, whole-exome sequencing. Eleven patients (5.3%) were BRAF V600E mutation positive by AS-PCR and at least one other method. The fraction of mutated cells varied from 4 to 100%. BRAF V600E-positive patients had no characteristic clinical phenotype except for significantly higher levels of serum creatinine (125 versus 86 μmol/l) Seven of eleven patients responded with at least very good partial response to alkylators, immunomodulatory agents or proteasome inhibitors. Progression-free and overall survival were similar in patients with and without the mutation. By this integrated approach, we found that patients with BRAF V600E mutation responded very well to broad acting drugs and there was no relation to prognosis in early-stage myeloma. In particular, a large mutated cell fraction did not correlate with aggressive disease

The Norwegian PMS2 founder mutation c.989-1G>T shows high penetrance of microsatellite instable cancers with normal immunohistochemistry

Background Using immunohistochemistry (IHC) to select cases for mismatch repair (MMR) genetic testing, we failed to identify a large kindred with the deleterious PMS2 mutation c.989-1G > T. The purpose of the study was to examine the sensitivity of IHC and microsatellite instability-analysis (MSI) to identify carriers of the mutation, and to estimate its penetrance and expressions. Methods All carriers and obligate carriers of the mutation were identified. All cancer diagnoses were confirmed. IHC and MSI-analysis were performed on available tumours. Penetrances of cancers included in the Amsterdam and the Bethesda Criteria, for MSI-high tumours and MSI-high and low tumours were calculated by the Kaplan-Meier algorithm. Results Probability for co-segregation of the mutation and cancers by chance was 0.000004. Fifty-six carriers or obligate carriers were identified. There was normal staining for PMS2 in 15/18 (83.3%) of tumours included in the AMS1/AMS2/Bethesda criteria. MSI-analysis showed that 15/21 (71.4%) of tumours were MSI-high and 4/21 (19.0%) were MSI-low. Penetrance at 70 years was 30.6% for AMS1 cancers (colorectal cancers), 42.8% for AMS2 cancers, 47.2% for Bethesda cancers, 55.6% for MSI-high and MSI-low cancers and 52.2% for MSI-high cancers. Conclusions The mutation met class 5 criteria for pathogenicity. IHC was insensitive in detecting tumours caused by the mutation. Penetrance of cancers that displayed MSI was 56% at 70 years. Besides colorectal cancers, the most frequent expressions were carcinoma of the endometrium and breast in females and stomach and prostate in males

Runaway Train: A Leaky Radiosensitive SCID with Skin Lesions and Multiple Lymphomas

The nuclease Artemis is essential for the development of T-cell and B-cell receptors and repair of DNA double-strand breaks, and a loss of expression or function will lead to a radiosensitive severe combined immunodeficiency with no functional T-cells or B-cells (T-B-SCID). Hypomorphic mutations in the Artemis gene can lead to a functional, but reduced, T-cell and B-cell repertoire with a more indolent clinical course called “leaky” SCID. Here, we present the case of a young man who had increasingly aggressive lymphoproliferative skin lesions from 2 years of age which developed into multiple EBV+ B-cell lymphomas, where a hypomorphic mutation in the Artemis gene was found in a diagnostic race against time using whole exome sequencing. The patient was given a haploidentical stem cell transplant while in remission for his lymphomas and although the initial course was successful, he succumbed to a serious Pneumocystis jirovecii pneumonia 5 months after the transplant. The case underscores the importance of next-generation sequencing in the diagnosis of patients with suspected severe immunodeficiency