Explore the vast range of titles available.

Smad4 or DPC4 belongs to a family of signal transduction proteins that are phosphorylated and activated by transmembrane serine-threonine receptor kinases in response to transforming growth factor beta (TGF-β) signaling via several pathways. The gene acts as a tumour suppressor gene and inactivation of smad4/DPC4 is best recognised in pancreatic cancer. However, smad4/DPC4 is also mutated in other conditions and cancers such as juvenile polyposis syndrome with and without hereditary haemorrhagic telangiectasia, colorectal and prostate cancers.Immunohistochemistry for smad4/DPC4 protein is most useful in separating benign/reactive conditions from pancreatic cancer in needle/core biopsies. In normal and reactive states, the protein is localised to the cytoplasm and nucleus, while the protein is lost in high-grade pancreatic intraepithelial neoplasia/carcinoma in situ and pancreatic cancer.

This is a review of the morphological spectrum of fatty tumours containing a component of spindle cells, highlighting the immunohistochemical and cytogenetic workup that is now mandatory for accurate diagnosis, with the goal of providing a practical approach for practising surgical pathologists. There have been significant advances in recent years in classifying and understanding the pathogenesis of fatty tumours with spindle cells, based on the correlation of histological, immunohistochemical and cytogenetic/molecular findings. In spite of this, morphological diagnosis and accurate classification of fatty tumours with spindle cells can be challenging to diagnostic pathologists. A group of three lesions: spindle cell lipoma, mammary-type myofibroblastoma and cellular angiofibroma share morphological features and are united by retinoblastoma protein (pRb) loss. Closely allied to these lesions, especially spindle cell lipoma is the newly designated atypical spindle cell lipomatous tumour, which shares morphological, immunohistochemical and cytogenetic features with the trio of tumours lacking nuclear pRb. All of these lesions lack MDM2 and CDK4 amplification as well and separation is based on clinical features, principally location. Atypical lipomatous tumour or well-differentiated liposarcoma shows retention of pRb but overexpression and amplification of MDM2. Fatty tumours with spindle cells need to be extensively sampled, with careful attention paid to cellular atypia and location, and they need to have immunohistochemical workup with pRb, MDM2, desmin, CD34 and p16. In addition, cytogenetic analysis for MDM2 and CDK4 amplification has become crucial for the proper identification of these lesions.

Eosinophilic gastrointestinal diseases (EGIDs), including eosinophilic gastroenteritis and eosinophilic colitis, have been increasing in prevalence in Western countries in recent years. Eosinophils are normally scanty in the gastrointestinal tract, and increased numbers of eosinophils can denote pathology. Normal values for tissue eosinophils vary widely between different segments of the colon, thus location of the biopsy is critically important for the interpretation of findings. However, no standard diagnostic criteria have been proposed for the diagnosis of eosinophilic gastroenteritis or eosinophilic colitis. Gut eosinophilia encompasses entitites that are predominantly immunoglobulin E (IgE)-mediated, the primary EGIDs and those that are secondary and not IgE-mediated. A final diagnosis of eosinophilic gastrointestinal diseases requires careful pathological assessment, clinical correlation and exclusion of several differential diagnoses.

Neoadjuvant chemoradiation (NACR) is now standard of care in stage II and III rectal cancer. The advent of this modality of treatment has impacted on the way the pathological evaluation of resection specimens that have been subjected to preoperative chemoradiation is conducted. The gross description, sectioning and microscopic examination have had to be adapted to accommodate the changes induced by NACR. Attempts at introducing a uniform approach to the gross triaging and reporting of these specimens have been met with muted response. There still exists much variation in approach. The purpose of this overview is to highlight some of the newer developments and issues around NACR-treated rectal cancers from a pathological point of view. The NACR-treated resection specimens should be handled in a consistent manner, at least within individual institutions, if not universally. There should be generous sampling with multiple sections taken as tumour is often sequestered deep in the bowel wall. Microscopic examination should be extra vigilant as residual cancer can be present as single cells or small clusters, often deep in the muscularis propria or serosa. Acellular pools of mucin or non-viable tumour cells in mucin within the bowel wall or lymph nodes are not regarded as positive and do not upstage the tumour. The issue of grading of regression has been the subject of much debate, and several approaches have been published. It is recommended that a system that has clinical meaning and use to oncologists be used. Lymph node counts will be reduced after NACR, but reasonable attempts to accrue 12 nodes should be made.

Immunohistochemistry (IHC) for mismatch repair (MMR) proteins is used to identify MMR status: being diffusely positive (intact/retained nuclear staining) or showing loss of nuclear tumour staining (MMR protein deficient). Four colonic adenocarcinomas and a gastric adenocarcinoma with associated dysplasia that displayed heterogenous IHC staining patterns in at least one of the four MMR proteins were characterised by next‐generation sequencing (NGS). In order to examine a potential molecular mechanism for these staining patterns, the respective areas were macrodissected, analysed for microsatellite instability (MSI) and investigated by NGS and multiplex ligation‐dependent probe amplification (MLPA) analysis of MLH1, MSH2, MSH6 and PMS2 genes, including MLH1 methylation analysis. One colonic adenocarcinoma showed heterogenous MSH6 IHC staining and molecular analysis demonstrated increasing allelic burden of two MSH6 frameshift variants (c.3261delC and c.3261dupC) in areas with MSH6 protein loss compared to areas where MSH6 was retained. Two colonic adenocarcinomas with heterogenous MLH1 staining showed no differences in sequence variants. In one of these cases, however, MLH1 was hypermethylated in the area of MLH1 loss. Another colon carcinoma with heterogenous PMS2 staining (but with retained MSH6) showed both MSH6 c.3261dupC and 3260_3261dupCC where PMS2 protein was lost and only c.3261dupC where PMS2 was retained. The gastric carcinoma showed complete loss of MSH6 in dysplastic foci, while the underlying invasive carcinoma showed retention of MSH6. Both these areas, however, were MSI‐high and showed the same MSH6 variant: c.3261delC. The gastric dysplasia additionally showed MSH6 c.3261dupC. In four of the five cases where MMR protein was lost, these areas were MSI‐high. Heterogenous MMR IHC (focal and/or zonal within the same tumour or between invasive and dysplastic preinvasive areas) is not always due to artefact and is invariably related to MSI‐high status in the areas of loss. An interesting aspect to this study is the presence of MSH6 somatic mutations irrespective of whether MSH6 IHC staining was intact or lost.

Amino acid bioavailability is critical for muscle protein synthesis (MPS) and preservation of skeletal muscle mass (SMM). Ageing is associated with reduced responsiveness of MPS to essential amino acids (EAA). Further, the older adult population experiences anabolic resistance, leading to increased frailty, functional decline and depleted muscle mass preservation, which facilitates the need for increased protein intake to increase their SMM. This review focuses on the role of proteins in muscle mass preservation and examines the contribution of EAA and protein intake patterns to MPS. Leucine is the most widely studied amino acid for its role as a potent stimulator of MPS, though due to inadequate data little is yet known about the role of other EAA. Reaching a conclusion on the best pattern of protein intake has proven difficult due to conflicting studies. A mixture of animal and plant proteins can contribute to increased MPS and potentially attenuate muscle wasting conditions; however, there is limited research on the biological impact of protein blends in older adults. While there is some evidence to suggest that liquid protein foods with higher than the RDA of protein may be the best strategy for achieving high MPS rates in older adults, clinical trials are warranted to confirm an association between food form and SMM preservation. Further research is warranted before adequate recommendations and strategies for optimising SMM in the elderly population can be proposed.

The aim of the study was to identify dietary patterns (DP) and examine differences in anthropometric measures, blood pressure (BP), cardiorespiratory fitness and nutritional knowledge of 6- and 10-year-old children at baseline and following a nutrition and physical activity intervention, with respect to DP and treatment group. This is a longitudinal study. Food diary, nutritional knowledge questionnaire and 550-m walk/run test measured dietary intake, nutritional knowledge and cardiorespiratory fitness, respectively. BP, weight, height and waist circumference were also measured and BMI and waist-to-height ratio (WHtR) were derived. All measurements were performed at baseline and following intervention. Two primary schools (one intervention, one control) in Cork, Ireland, were selected. Participants were 6- (n 39, age 5·9 (sd 0·6) years) and 10- (n 49, age 9·8 (sd 0·5) years)-year-olds. Two DP were identified, using k-means cluster analysis, for both 6- (unhealthy and nutrient-dense) and 10-year-olds (processed and Western diet) at baseline. DP derived post-intervention were (1) plant-based and (2) processed foods for 6-year-olds and (1) nutrient-dense and (2) unhealthy for 10-year-olds. There was no statistically significant difference in DP for 6- and 10-year-olds at baseline and post-intervention (P > 0·05). Following the intervention, a multivariate ANOVA showed there were no statistically significant differences in nutritional knowledge, BMI, WHtR, cardiorespiratory fitness and BP based on DP and intervention/control group for both age groups (P > 0·05). Three out of four dietary patterns identified for 6- and 10-year-olds were unfavourable. While no statistically significant evidence of intervention impact was found on DP, a positive trend was emerging among 10-year-olds.

Brewers’ spent grain (BSG) is a low-value co-product of the brewing industry produced in large quantities annually. This paper reviews the existing evidence regarding the phenolic component of BSG, focusing on composition, extraction and biofunctions such as antioxidant, anti-atherogenic, anti-inflammatory and anti-carcinogenic activities. Furthermore, the incorporation of BSG in foodstuffs will be discussed, including the use of BSG as an animal feed supplement and the potential of BSG to be incorporated into foods for human consumption. BSG contains hydroxycinnamic acids including ferulic acid, p-coumaric acid and caffeic acid; which have shown bioactivity in the pure form (antioxidant, anti-inflammatory, anti-atherogenic and anti-cancer). Phenolic extracts from BSG have also shown antioxidant potential, by protecting against oxidant-induced DNA damage, possibly by Fe chelation. Studies show that BSG has many benefits when used as a supplement in animal feed, such as increasing milk yield, milkfat content and in providing essential dietary amino acids. The incorporation of BSG in human foods such as cookies and ready-to-eat snacks has resulted in increased protein and fibre contents of the products, where the changes in organoleptic properties are controllable. It can be concluded that the phenolic component of BSG has potential bioactive effects, which are worth pursuing given that the inclusion of BSG into human foodstuffs is viable and beneficial.

ObjectiveTo provide an overview of the pathology and molecular pathogenesis of traditional serrated adenomas (TSA).DesignDescribe the morphology and molecules that play a role in their pathogenesis.ResultsThese exuberant polypoid lesions are typified by tall cells with deeply eosinophilic cytoplasm, elongated nuclei bearing delicate chromatin, ectopic crypt foci, deep clefting of the lining mucosa and an overall resemblance to small bowel mucosa.Broadly, TSAs arise via three mechanisms. They may be BRAF mutated and CpG island methylator phenotype (CIMP)-high: right sided, mediated through a microvesicular hyperplastic polyp or a sessile serrated adenoma, may also have RNF43 mutations and result in microsatellite stable (MSS) colorectal cancers (CRC). The second pathway that is mutually exclusive of the first is mediated through KRAS mutation with CIMP-low TSAs. These are left-sided TSAs, are not associated with another serrated polyp and result in MSS CRC. These TSAs also have RSPO3, RNF43 and p53 mutations together with aberrant nuclear localisation of β-catenin. Third, there is a smaller group of TSAs that are BRAF and KRAS wild type and arise by as yet unknown molecular events. All TSAs show retention of mismatch repair proteins.ConclusionThese are characteristic unusual polyps with a complex molecular landscape.

Leiomyomas of deep soft tissue are extremely rare and should only be diagnosed following adherence to stringent histological criteria, namely, the absence of nuclear atypia and of coagulative tumor necrosis. Whether extremely low counts of, or even any, mitotic activity are acceptable when making a diagnosis of leiomyoma in deep soft tissue sites is controversial. The morphology and immunophenotype of smooth muscle tumors in deep soft tissue are similar to their counterparts irrespective of topography. It is interesting to note that leiomyomas of deep soft tissue (extremity and retroperitoneum) are often hyalinized/sclerosed and calcified. However, the prediction of their behavior and correct codification is dependent on thorough, meticulous search for mitoses and necrosis. Leiomyomas of deep soft tissue in the extremity should be devoid of mitoses and “significant” cytological atypia. An occasional larger, slightly pleomorphic cell in the midst of bland spindle cells, can be regarded as insignificant atypia. If any mitotic activity and several atypical cells are encountered in smooth muscle tumors of deep soft tissue of the extremity, it would be prudent to invoke the appellation of smooth muscle tumor of uncertain malignant potential and advocate wide local excision and follow-up.