Novel NCOA2/3-rearranged low-grade fibroblastic spindle cell tumors: A report of five cases.

Spindle cell mesenchymal neoplasms are a diverse and often challenging diagnostic group. While morphological impression is sufficient for some diagnoses, increasingly immunohistochemical and even molecular data is required to render an accurate diagnosis, which can lead to the characterization of new entities. We describe five cases of novel mesenchymal neoplasms with rearrangements in the NCOA2 and NCOA3 genes partnered with either CTCF or CRTC1. Three tumors occurred in the head and neck (palate, auditory canal), while the other two were in visceral organs (lung, urinary bladder). All cases occurred in adults (range 33-86) with a median age of 42 and fairly even sex distribution = (male-to-female = 3:2). Morphologically, they had similar features consisting of monotonous, bland spindle to ovoid cells with fascicular and reticular arrangements in a myxohyaline to collagenous stroma. However, immunophenotypically they had essentially a null phenotype, with only two tumors staining partially for CD34 and smooth muscle actin. Targeted RNA sequencing detected in-frame CTCF::NCOA2 (one case), CRTC1::NCOA2 (two cases), and CTCF::NCOA3 (two cases) fusions. Treatment was surgical resection in all cases. Local recurrence and/or distant metastases were not observed in any case (median follow-up, 7.5 months; range, 2-19 months). Given their morphologic, immunohistochemical, and molecular similarities, we believe that these cases may represent an emerging family of low-grade NCOA2/3-rearranged fibroblastic spindle cell neoplasms.

Novel CRTC1::MRTFB(MKL2) Gene Fusion Detected in Myxoid Mesenchymal Neoplasms With Myogenic Differentiation Involving Bone and Soft Tissues.

Appropriate classification of fusion-driven bone and soft tissue neoplasms continues to evolve, often relying on the careful integration of morphologic findings with immunohistochemical, molecular, and clinical data. Herein, we present 3 cases of a morphologically distinct myxoid mesenchymal neoplasm with myogenic differentiation and novel CRTC1::MRTFB (formerly MKL2) gene fusion. Three tumors occurred in 1 male and 2 female patients with a median age of 72 years (range: 28-78). Tumors involved the left iliac bone, the right thigh, and the left perianal region with a median size of 4.0 cm (4.0-7.6 cm). Although 1 tumor presented as an incidental finding, the other 2 tumors were noted, given their persistent growth. At the time of the last follow-up, 1 patient was alive with unresected disease at 6 months, 1 patient was alive without evidence of disease at 12 months after surgery, and 1 patient died of disease 24 months after diagnosis. On histologic sections, the tumors showed multinodular growth and were composed of variably cellular spindle to round-shaped cells with distinct brightly eosinophilic cytoplasm embedded within a myxoid stroma. One tumor showed overt smooth muscle differentiation. Cytologic atypia and mitotic activity ranged from minimal (2 cases) to high (1 case). By immunohistochemistry, the neoplastic cells expressed focal smooth muscle actin, h-caldesmon, and desmin in all tested cases. Skeletal muscle markers were negative. Next-generation sequencing detected nearly identical CRTC1::MRTFB gene fusions in all cases. We suggest that myxoid mesenchymal tumors with myogenic differentiation harboring a CRTC1::MRTFB fusion may represent a previously unrecognized, distinctive entity that involves soft tissue and bone. Continued identification of these novel myxoid neoplasms with myogenic differentiation will be important in determining appropriate classification, understanding biologic potential, and creating treatment paradigms.

Novel EWSR1::GFI1B gene fusion in angiofibroma of soft tissue.

AIMS: Angiofibroma of soft tissue is a benign soft tissue tumour characterised by bland spindle cells and a distinct branching vascular network. The majority of soft tissue angiofibromas harbour AHRR::NCOA2 gene fusions. Here we present three cases of EWSR1::GFI1B-fused soft tissue tumours that are morphologically most reminiscent of soft tissue angiofibroma. METHODS AND RESULTS: All three cases presented in male patients with an age range of 35-78 years (median = 54 years). Two cases presented as subcutaneous nodules on the trunk (posterior neck and chest wall); one was an intramuscular foot mass. The tumours were unencapsulated nodules with infiltrative margins ranging from 2.2 to 3.4 cm in greatest dimension. Histologically, the tumours contained uniformly bland fibroblastic spindle cells with ovoid to fusiform nuclei and delicate cytoplasmic processes embedded in a myxoid to myxocollagenous stroma. All three cases were characterised by a thin-walled, branching vascular network evenly distributed throughout the tumour. Overt cytological atypia or conspicuous mitotic activity was absent. The spindle cells had an essentially null immunophenotype. By targeted RNA sequencing, an in-frame gene fusion between EWSR1 exons 1-7 and GFI1B exons 6-11 or 7-11 was detected in all three cases. The tumours were marginally excised. For all three cases, there were no documented local recurrence or distant metastases during a limited follow-up period of 6-10 months. CONCLUSIONS: We propose that EWSR1::GFI1B may represent a novel fusion variant of soft tissue angiofibroma.

TRPS1, a New Promising Marker for Assessment of Distant Metastatic Breast Cancer.

This article reviewed the identification of breast cancer in the distant metastatic setting through traditional immunohistochemical markers, such as mammaglobin and GATA3, compared with the novel immunohistochemical stain, Trichorhinophalangeal syndrome-1 (TRPS1). We review previous studies evaluating TRPS1 staining, which were conducted using cytology specimens, as well as our recently conducted study evaluating this stain using surgical tissue samples, both from primary and distant metastatic invasive breast carcinoma. In summary, although no immunohistochemical stain is 100% specific or sensitive, in the metastatic setting where tissue available for ancillary studies is limited, TRPS1 was a reliable and even a standalone marker for breast origin, particularly in cases of triple-negative breast cancer.

Socio-ecological influences on adolescent dietary typologies.

Background: Dietary behaviours of adolescence are concerning, and this may impact long-term well-being. Aim: This study examined the socio-ecological determinants of dietary behaviours in a national prospective cohort study of English adolescents. Methods: Latent class analysis was used to identify the typologies of eight dietary behaviours: fruit, vegetable, breakfast, sugar-sweetened beverages, artificial-sweetened beverages, fast-food, bread, and milk from 7402 adolescents aged 13-15 years (mean 13.8 ± 0.45 years) (50.3% female and 71.3% white ethnicity) participating in the U.K. Millennium Cohort Study (sixth survey). Multinomial logistic regression and path analysis predicted associations between personal characteristics, individual, influential others, social environment and physical environment determinants and three distinct diet typologies: (1) healthy, (2) less-healthy and (3) mixed, (reference category = mixed). Results: Within Path analysis, the magnitudes of coefficients were small to moderate suggesting a relatively weak relationship between the variables. Model 1 reported adolescents within the less-healthy compared to mixed typology had lower levels of physical activity (ß = 0.074, 95% CI = -0.115, -0.033), and have siblings (ß = 0.246, 95% CI = 0.105, 0.387). Model 2 reported adolescents within the healthy compared to mixed typology had lower screen time (ß = 0.104, 95% CI = 0.067, 0.141), and lower social media usage (ß = 0.035, 95% CI = 0.024, 0.046). Conclusion: This study highlights the importance of considering multiple dietary determinants. These findings are likely to be useful in supporting the development of multi-faceted interventions. They emphasise the need to move away from investigating silo behaviours on individual diet components and a step towards more systems thinking to improve adolescent eating behaviours.

Amyloid in the breast: retrospective review with clinicopathological and radiological correlation of 32 cases from a single institution.

AIMS: Mammary amyloid is an uncommon and easily overlooked pathological diagnosis with ambivalent presentation. Herein, we delineate the clinicopathological and radiographic characteristics of mammary amyloid. METHODS AND RESULTS: The Department of Pathology database was searched from 1993 to 2019 for keywords 'breast' and 'amyloid', yielding 32 cases from 23 patients, including consultation cases. All patients were female, age range = 52-81 (mean = 67.4 years). The left breast was involved more than the right (43 versus 33%, respectively); bilateral amyloid involvement was also present (24%). Amyloid was most often associated with a benign histopathological diagnosis (57%), lymphoma in 39% [all B cell lymphomas; five of nine were mucosa-associated lymphoid tissue (MALT) lymphoma] and rarely with a concurrent epithelial malignancy (invasive lobular carcinoma, 4%). Of the 14 patients with available clinical history, amyloid presented as a mass clinically or radiographically (six patients, 43%), as microcalcifications (five patients, 36%), and only occasionally as an asymmetry (14%) or fibroglandular density (7%). Microscopic examination detected microcalcifications in an additional nine cases (total 14 patients; 44% of the cohort). Interestingly, one patient had concurrent epithelial and haematological malignancy and amyloid within an axillary lymph node. Co-morbidities included autoimmune diseases and multiple myeloma. CONCLUSION: The majority of mammary amyloid cases are associated with benign histopathological findings, while imaging most frequently noted microcalcifications or mass lesions. To avoid overlooking amyloid as simply fat necrosis or fibroelastotic stromal change, a low threshold for performing ancillary stains should be considered in elderly women with benign core needle findings performed for mass lesions or microcalcifications.

The effects of hypoxia on hunger perceptions, appetite-related hormone concentrations and energy intake: A systematic review and meta-analysis.

Exposure to hypoxia appears to depress appetite and energy intake, however the mechanisms are not fully understood. The aim of this review was to determine the magnitude of changes in hunger and energy intake in hypoxic compared with normoxic environments, and establish any alterations in appetite-related hormone concentrations. PubMed and The Cochrane Library as well as MEDLINE, SPORTDiscus, PsycINFO and CINAHL, via EBSCOhost, were searched through 1st April 2017 for studies that evaluated hunger, energy intake and/or appetite-related hormones in normoxia and during hypoxic exposure in a within-measures design. A total of 28 studies (comprising 54 fasted and 22 postprandial comparisons) were included. A random-effects meta-analysis was performed to establish standardised mean difference (SMD) with 95% confidence intervals. Hypoxic exposure resulted in a trivial but significant decrease in postprandial hunger scores (SMD: -0.15, 95% CI: -0.29 to -0.01; n = 14; p = 0.043) and a moderate decrease in energy intake (SMD: -0.50, 95% CI: -0.85 to -0.15; n = 8; p = 0.006). Hypoxic exposure resulted in a decrease (albeit trivial) in postprandial acylated ghrelin concentrations (SMD: -0.16, 95% CI: -0.25 to -0.08; n = 7; p < 0.0005), and a moderate increase in fasted insulin concentrations (SMD: 0.41, 95% CI: 0.17 to 0.65; n = 34; p = 0.001). Meta-regression revealed a decrease in postprandial acylated ghrelin concentrations (p = 0.010) and an increase in fasted insulin concentrations (p = 0.020) as hypoxic severity increased. Hypoxic exposure reduces hunger and energy intake, which may be mediated by decreased circulating concentrations of acylated ghrelin and elevated insulin concentrations. PROSPERO registration number: CRD42015017231.

Changes in appetite, energy intake, body composition, and circulating ghrelin constituents during an incremental trekking ascent to high altitude.

PURPOSE: Circulating acylated ghrelin concentrations are associated with altitude-induced anorexia in laboratory environments, but have never been measured at terrestrial altitude. This study examined time course changes in appetite, energy intake, body composition, and ghrelin constituents during a high-altitude trek. METHODS: Twelve participants [age: 28(4) years, BMI 23.0(2.1) kg m-2] completed a 14-day trek in the Himalayas. Energy intake, appetite perceptions, body composition, and circulating acylated, des-acylated, and total ghrelin concentrations were assessed at baseline (113 m, 12 days prior to departure) and at three fixed research camps during the trek (3619 m, day 7; 4600 m, day 10; 5140 m, day 12). RESULTS: Relative to baseline, energy intake was lower at 3619 m (P = 0.038) and 5140 m (P = 0.016) and tended to be lower at 4600 m (P = 0.056). Appetite perceptions were lower at 5140 m (P = 0.027) compared with baseline. Acylated ghrelin concentrations were lower at 3619 m (P = 0.046) and 4600 m (P = 0.038), and tended to be lower at 5140 m (P = 0.070), compared with baseline. Des-acylated ghrelin concentrations did not significantly change during the trek (P = 0.177). Total ghrelin concentrations decreased from baseline to 4600 m (P = 0.045). Skinfold thickness was lower at all points during the trek compared with baseline (P ≤ 0.001) and calf girth decreased incrementally during the trek (P = 0.010). CONCLUSIONS: Changes in plasma acylated and total ghrelin concentrations may contribute to the suppression of appetite and energy intake at altitude, but differences in the time course of these responses suggest that additional factors are also involved. Interventions are required to maintain appetite and energy balance during trekking at terrestrial altitudes.

Dietary nitrate supplementation enhances short but not longer duration running time-trial performance.

PURPOSE: This study evaluated the effects of dietary nitrate (NO3-) supplementation on physiological functioning and exercise performance in trained runners/triathletes conducting short and longer-distance treadmill running time-trials (TT). METHOD: Eight trained male runners or triathletes completed four exercise performance tests comprising a 10 min warm up followed by either a 1500 or 10,000 m treadmill TT. Exercise performance tests were preceded 3 h before the exercise by supplementation with either 140 ml concentrated nitrate-rich (~12.5 mmol nitrate) (BRJ) or nitrate-deplete (~0.01 mmol nitrate) (PLA) beetroot juice. RESULTS: BRJ supplementation significantly elevated plasma [NO2-] (P < 0.05). Resting blood pressure and exercise [Formula: see text] were not significantly different between BRJ and PLA (P > 0.05). However, post-exercise blood [lactate] was significantly greater in BRJ following the 1500 m TT (6.6 ± 1.2 vs. 6.1 ± 1.5 mM; P < 0.05), but not significantly different between conditions in the 10,000 m TT (P > 0.05). Performance in the 1500 m TT was significantly faster in BRJ vs. PLA (319.6 ± 36.2 vs. 325.7 ± 38.8 s; P < 0.05). Conversely, there was no significant difference in 10,000 m TT performance between conditions (2643.1 ± 324. 1 vs. 2649.9 ± 319.8 s, P > 0.05). CONCLUSION: Acute BRJ supplementation significantly enhanced 1500 m, but not 10,000 m TT performance. These findings suggest that BRJ might be ergogenic during shorter distance TTs which allow for a high work rate, but not during longer distance TTs, completed at a lower work rate.

The effect of moderate versus severe simulated altitude on appetite, gut hormones, energy intake and substrate oxidation in men.

Acute exposure to high altitude (>3500 m) is associated with marked changes in appetite regulation and substrate oxidation but the effects of lower altitudes are unclear. This study examined appetite, gut hormone, energy intake and substrate oxidation responses to breakfast ingestion and exercise at simulated moderate and severe altitudes compared with sea-level. Twelve healthy males (mean ± SD; age 30 ± 9years, body mass index 24.4 ± 2.7 kg·m-2) completed in a randomised crossover order three, 305 min experimental trials at a simulated altitude of 0 m, 2150 m (∼15.8% O2) and 4300 m (∼11.7% O2) in a normobaric chamber. Participants entered the chamber at 8am following a 12 h fast. A standardised breakfast was consumed inside the chamber at 1 h. One hour after breakfast, participants performed a 60 min treadmill walk at 50% of relative V˙O2max. An ad-libitum buffet meal was consumed 1.5 h after exercise. Blood samples were collected prior to altitude exposure and at 60, 135, 195, 240 and 285 min. No trial based differences were observed in any appetite related measure before exercise. Post-exercise area under the curve values for acylated ghrelin, pancreatic polypeptide and composite appetite score were lower (all P < 0.05) at 4300 m compared with sea-level and 2150 m. There were no differences in glucagon-like peptide-1 between conditions (P = 0.895). Mean energy intake was lower at 4300 m (3728 ± 3179 kJ) compared with sea-level (7358 ± 1789 kJ; P = 0.007) and 2150 m (7390 ± 1226 kJ; P = 0.004). Proportional reliance on carbohydrate as a fuel was higher (P = 0.01) before breakfast but lower during (P = 0.02) and after exercise (P = 0.01) at 4300 m compared with sea-level. This study suggests that altitude-induced anorexia and a subsequent reduction in energy intake occurs after exercise during exposure to severe but not moderate simulated altitude. Acylated ghrelin concentrations may contribute to this effect.

Dietary nitrate supplementation enhances high-intensity running performance in moderate normobaric hypoxia, independent of aerobic fitness.

Nitrate-rich beetroot juice (BRJ) increases plasma nitrite concentrations, lowers the oxygen cost (V⋅O2) of steady-state exercise and improves exercise performance in sedentary and moderately-trained, but rarely in well-trained individuals exercising at sea-level. BRJ supplementation may be more effective in a hypoxic environment, where the reduction of nitrite into nitric oxide (NO) is potentiated, such that well-trained and less well-trained individuals may derive a similar ergogenic effect. We conducted a randomised, counterbalanced, double-blind placebo controlled trial to determine the effects of BRJ on treadmill running performance in moderate normobaric hypoxia (equivalent to 2500 m altitude) in participants with a range of aerobic fitness levels. Twelve healthy males (V⋅O2max ranging from 47.1 to 76.8 ml kg(-1) min(-1)) ingested 138 ml concentrated BRJ (∼15.2 mmol nitrate) or a nitrate-deplete placebo (PLA) (∼0.2 mmol nitrate). Three hours later, participants completed steady-state moderate intensity running, and a 1500 m time-trial (TT) in a normobaric hypoxic chamber (FIO2 âˆ¼ 15%). Plasma nitrite concentration was significantly greater following BRJ versus PLA 1 h post supplementation, and remained higher in BRJ throughout the testing session (p < 0.01). Average V⋅O2 was significantly lower (BRJ: 18.4 ± 2.0, PLA: 20.4 ± 12.6 ml kg(-1) min(-1); p = 0.002), whilst arterial oxygen saturation (SpO2) was significantly greater (BRJ: 88.4 ± 2.7, PLA: 86.5 ± 3.3%; p < 0.001) following BRJ. BRJ improved TT performance in all 12 participants by an average of 3.2% (BRJ: 331.1 ± 45.3 vs. PL: 341.9 ± 46.1 s; p < 0.001). There was no apparent relationship between aerobic fitness and the improvement in performance following BRJ (r(2) = 0.05, p > 0.05). These findings suggests that a high nitrate dose in the form of a BRJ supplement may improve running performance in individuals with a range of aerobic fitness levels conducting moderate and high-intensity exercise in a normobaric hypoxic environment.

Effect of Galactose Ingestion Before and During Exercise on Substrate Oxidation, Postexercise Satiety, and Subsequent Energy Intake in Females.

OBJECTIVE: To examine the effects of consuming a galactose carbohydrate (CHO) drink on substrate oxidation, postexercise satiety, and subsequent energy intake. METHODS: Nine recreationally active eumenorrheic females undertook 3 trials, each consisting of running for 60 minutes at 65% VO(2peak) followed immediately by a 90-minute rest period. Prior to (300 ml) and at 15-minute intervals during exercise (150 ml), participants consumed either a glucose (GLU: GI 89) or galactose (GAL: GI 20) drink, each of which contained 45 g of CHO, or an artificially sweetened placebo (PLA). Following the rest period, participants were provided with an ad libitum test lunch and asked to record food intake for the remainder of the day. RESULTS: Plasma glucose was significantly greater throughout exercise and rest following the GLU trial compared with the GAL and PLA trials (P < 0.05); however there were no differences in CHO oxidation. Hunger was significantly lower (P < 0.05) throughout the GAL compared to the GLU and PLA trials. There were no significant differences between trials for energy intake during the postexercise meal. Overall net energy balance for the 24 hours was negative in both the GAL (-162 ± 115 kcal; P < 0.05 vs GLU) and PLA trials (-49 ± 160 kcal). CONCLUSIONS: Results demonstrate that ingesting a solution containing GAL before and during exercise can positively impact postexercise satiety and energy balance throughout the day, compared to a more readily available and widely consumed form of CHO. Despite this, there appears to be no apparent benefit in consuming a CHO beverage on fuel utilization for this moderate exercise intensity and duration.

Dietary Intakes of Elite 14- to 19-Year-Old English Academy Rugby Players During a Pre-Season Training Period.

Good nutrition is essential for the physical development of adolescent athletes, however data on dietary intakes of adolescent rugby players are lacking. This study quantified and evaluated dietary intake in 87 elite male English academy rugby league (RL) and rugby union (RU) players by age (under 16 (U16) and under 19 (U19) years old) and code (RL and RU). Relationships of intakes with body mass and composition (sum of 8 skinfolds) were also investigated. Using 4-day diet and physical activity diaries, dietary intake was compared with adolescent sports nutrition recommendations and the UK national food guide. Dietary intake did not differ by code, whereas U19s consumed greater energy (3366 ± 658 vs. 2995 ± 774 kcal·day-1), protein (207 ± 49 vs. 150 ± 53 g·day-1) and fluid (4221 ± 1323 vs. 3137 ± 1015 ml·day-1) than U16s. U19s consumed a better quality diet than U16s (greater intakes of fruit and vegetables; 4.4 ± 1.9 vs. 2.8 ± 1.5 servings·day-1; nondairy proteins; 3.9 ± 1.1 vs. 2.9 ± 1.1 servings·day-1) and less fats and sugars (2.0 ± 1. vs. 3.6 ± 2.1 servings·day-1). Protein intake vs. body mass was moderate (r = .46, p < .001), and other relationships were weak. The findings of this study suggest adolescent rugby players consume adequate dietary intakes in relation to current guidelines for energy, macronutrient and fluid intake. Players should improve the quality of their diet by replacing intakes from the fats and sugars food group with healthier choices, while maintaining current energy, and macronutrient intakes.

Mouth Rinsing With Carbohydrate Solutions at the Postprandial State Fail to Improve Performance During Simulated Cycling Time Trials.

Mouth rinsing with carbohydrate (CHO) solutions during cycling time trials results in performance enhancements; however, most studies have used approximately 6% CHO solutions. Therefore, the purpose of this study was to compare the effectiveness of mouth rinsing with 4, 6, and 8% CHO solutions on 1-hour simulated cycling time trial performance. On 4 occasions, 7 trained male cyclists completed at the postprandial period, a set amount of work as fast as possible in a randomized counterbalanced order. The subjects rinsed their mouth for 5 seconds, on completion of each 12.5% of the trial, with 25 ml of a non-CHO placebo and 4, 6, and 8% CHO solutions. No additional fluids were consumed during the time trial. Heart rate (HR), ratings of perceived exertion (RPE), thirst (TH), and subjective feelings (SF) were recorded after each rinse. Furthermore, blood samples were drawn every 25% of the trial to measure blood glucose and blood lactate concentrations, whereas whole-body CHO oxidation was monitored continuously. Time to completion was not significant between conditions with the placebo, 4, 6, and 8% conditions completing the trials in 62.0 ± 3.0, 62.8 ± 4.0, 63.4 ± 3.4, and 63 ± 4.0 minutes, respectively. There were no significant differences between conditions in any of the variables mentioned above; however, significant time effects were observed for HR, RPE, TH, and SF. Post hoc analysis showed that TH and SF of subjects in the CHO conditions but not in the placebo were significantly increased by completion of the time trial. In conclusion, mouth rinsing with CHO solutions did not impact 1-hour cycling performance in the postprandial period and in the absence of fluid intake. Our findings suggest that there is scope for further research to explore the activation regions of the brain and whether they are receptive to CHO dose, before specific recommendations for athletic populations are established. Consequently, mouth rinsing as a practical strategy for coaches and athletes is questionable under specific conditions and should be carefully considered before its inclusion. Emphasis should be focused on appropriate dietary and fluid strategies during training and competition.

Is PAS Stain Necessary to Exclude Whipple Disease in Duodenal Biopsies?

Objective. Whipple disease, caused by Tropheryma whipplei, is a rare infectious condition primarily presenting with malabsorptive diarrhea. Small bowel biopsies typically reveal foamy macrophages containing periodic acid-Schiff-positive/diastase (PAS/D) resistant T. whipplei bacilli, and PAS(D) staining is occasionally requested by clinicians in duodenal biopsies, which are often histologically unremarkable. The yield of PAS(D) staining in such biopsies has never been reported to our knowledge. Methods. The anatomic pathology database was searched for all specimens of duodenal biopsies stained with PAS(D) from 1993 to 2021. Specimens were categorized by the following histomorphologic features: unremarkable, nonspecific changes, or expansion of the lamina propria by aggregates of foamy histiocytes. Follow-up information was collected, including microbiologic confirmatory testing. Results. There was a total of 193 specimens of duodenal biopsies stained with PAS(D). Biopsies lacking foamy histiocytes on H&E (n = 158) were never PAS-positive. Thirteen biopsies contained PAS-positive histiocytes; 9 out of the 13 PAS-positive specimens were subsequently confirmed to be T. whipplei. Of the 193 specimens, 124 specimens had a clinical request for PAS(D) staining. Only 3 of the 124 (2.4%) specimens showed foamy histiocytes containing PAS-positive granules, all of which were confirmed positive for T. whipplei. Conclusion. PAS(D) staining is unnecessary to exclude Whipple disease in duodenal biopsies without foamy macrophage aggregates, regardless of clinical suspicion. Clinical suspicion-driven biopsies often yield negative results for Whipple disease.

Spatial Transcriptomics Suggests That Alterations Occur in the Preneoplastic Breast Microenvironment of BRCA1/2 Mutation Carriers.

Breast cancer is the most common cancer in females, affecting one in every eight women and accounting for the majority of cancer-related deaths in women worldwide. Germline mutations in the BRCA1 and BRCA2 genes are significant risk factors for specific subtypes of breast cancer. BRCA1 mutations are associated with basal-like breast cancers, whereas BRCA2 mutations are associated with luminal-like disease. Defects in mammary epithelial cell differentiation have been previously recognized in germline BRCA1/2 mutation carriers even before cancer incidence. However, the underlying mechanism is largely unknown. Here, we employ spatial transcriptomics to investigate defects in mammary epithelial cell differentiation accompanied by distinct microenvironmental alterations in preneoplastic breast tissues from BRCA1/2 mutation carriers and normal breast tissues from noncarrier controls. We uncovered spatially defined receptor-ligand interactions in these tissues for the investigation of autocrine and paracrine signaling. We discovered that ß1-integrin-mediated autocrine signaling in BRCA2-deficient mammary epithelial cells may differ from BRCA1-deficient mammary epithelial cells. In addition, we found that the epithelial-to-stromal paracrine signaling in the breast tissues of BRCA1/2 mutation carriers is greater than in control tissues. More integrin-ligand pairs were differentially correlated in BRCA1/2-mutant breast tissues than noncarrier breast tissues with more integrin receptor-expressing stromal cells. IMPLICATIONS: These results suggest alterations in the communication between mammary epithelial cells and the microenvironment in BRCA1 and BRCA2 mutation carriers, laying the foundation for designing innovative breast cancer chemo-prevention strategies for high-risk patients.

The effect of discretionary snack consumption on overall energy intake, weight status, and diet quality: A systematic review.

The consumption frequency and portion size of discretionary snacks are thought to contribute to a greater food intake and risk of overweight or obesity in the developed world but evidence from epidemiological studies is inconclusive. To investigate this, we systematically evaluated evidence on the effects of discretionary snack consumption on weight status, energy intake, and diet quality. Articles involving discretionary snacks reported against the outcome measures of any primary, peer-reviewed study using human participants from free-living conditions for all age groups were included. A total of 14,780 titles were identified and 40 eligible publications were identified. Three key outcomes were reported: weight status (n = 35), energy intake (n = 11), and diet quality (n = 3). Increased discretionary snack consumption may contribute modestly to energy intake, however, there is a lack of consistent associations with increased weight/BMI. Although cross-sectional analyses offered conflicting findings, longitudinal studies in adults showed a consistent positive relationship between discretionary snack intake and increasing weight or body mass index. Given that experimental findings suggest reducing the size of discretionary snacks could lead to decreased consumption and subsequent energy intake, food policy makers and manufacturers may find it valuable to consider altering the portion and/or packaging size of discretionary snacks.

Validation Study of the Newly Proposed Refined Diagnostic Criteria for Malignant Phyllodes Tumor With 136 Borderline and Malignant Phyllodes Tumor Cases.

The World Health Organization (WHO) diagnostic criteria for malignant phyllodes tumor (MPT) may miss a significant number of MPTs with metastatic potential. New refined diagnostic criteria (Refined Criteria) for MPT were recently proposed. The aim of this study is to validate the Refined Criteria. This validation study included 136 borderline (borderline phyllodes tumor [BoPT]) and MPT cases that were not included in the initial study. We evaluated tumor classifications based on both the Refined Criteria and the WHO criteria. The Refined Criteria defines MPT when these criteria are met (1) stromal overgrowth with ≥ 1 feature(s) of marked stromal cellularity, marked stromal cytologic atypia, or ≥10 mitoses per 10 high-power fields (10 mitoses/10 HPFs) or (2) marked stromal cellularity with ≥1 feature(s) of marked stromal cytologic atypia, ≥10 mitoses/10 HPFs or permeative border. The WHO criteria require all 5 morphologic features (stromal overgrowth, permeative border, marked stromal cellularity, marked stromal cytologic atypia, and ≥10 mitoses/10 HPFs) for an MPT diagnosis. Using the Refined Criteria, none of the 61 BoPTs developed metastasis and 40.0% of the 75 MPTs developed metastases; local recurrence was seen in 11.5% BoPTs and 25.3% MPTs. Using the WHO criteria, 9.6% of the 94 BoPTs developed metastases and 50.0% of the 42 MPTs developed metastases; 14.9% of the BoPTs had local recurrence and 28.6% of the MPTs had local recurrence. Nine (30.0%) of the 30 tumors that developed distant metastases were diagnosed as BoPTs by the WHO criteria. When we combined the 75 MPTs from this validation cohort with the 65 MPT cases from the published data using the Refined Criteria, 50 (35.7%) of the 140 MPTs developed metastases, whereas 8 cases with metastases were <5 cm. In the univariate analysis with log-rank test, stromal overgrowth, marked stromal cellularity, marked stromal cytologic atypia, ≥10 mitoses/10 HPFs, presence of heterologous components other than liposarcomatous component, and presence of stromal necrosis were significantly associated with the risk of metastasis (all with P < 0.05). In multivariate analysis with Cox proportional hazard regression, stromal overgrowth and marked stromal cellularity were significantly associated with metastasis (both with P < 0.001). The Refined Criteria are superior to the WHO criteria in predicting the clinical outcomes of BoPTs and MPTs. Using the Refined Criteria, 35.7% of 140 patients with MPT developed metastases, whereas none (0%) of the patients with BoPT developed metastases. Patients with MPT have a high metastatic rate; these patients may benefit from systemic chemotherapy or targeted therapies. In contrast, patients with BoPT may be managed with complete local excision alone without chemotherapy.

The effect of galactose ingestion on affect and perceived exertion in recreationally active females.

The beneficial effects of acute carbohydrate (CHO) supplementation on exercise performance have been well described. Also reported is the attenuation of perceived exertion and enhancement of affect during prolonged exercise following CHO ingestion. However, no studies to date have assessed the impact of the type of CHO ingested on affective responses during moderate intensity exercise, lasting 60 min or less. Therefore, the aim of the present study was to investigate the effects of consuming a galactose (GAL) CHO drink versus a glucose (GLU) CHO or placebo (PLA) drink before and during exercise on affect and perceived exertion. Nine recreationally active females undertook three trials, each consisting of running for 60 min at 65% VO2max followed immediately by a 90 min rest period. Prior to (300 ml) and at every 15 min during exercise (150 ml), participants consumed either a GLU or GAL drink each containing 45 g of CHO, or an artificially-sweetened PLA drink. Ratings of pleasure-displeasure and perceived activation were measured throughout exercise and the rest period and measures of perceived exertion were measured during exercise. Plasma glucose and serum insulin were significantly greater throughout exercise and rest following the GLU trial compared with the GAL and PLA trials (P<0.05). Measures of perceived activation and pleasure-displeasure were not enhanced nor RPE reduced as a result of ingestion of a CHO solution. In conclusion, the GAL beverage elicited a more favourable metabolic profile in the exercising females but this did not translate into an enhanced affective profile. Indeed, CHO ingestion had no noticeable effect on the assessed psychological indices during 60 min of moderate-intensity exercise in females. It is suggested that the maintenance of a positive affective profile may be explained more by the level of hydration as opposed to fuel availability. Therefore, those seeking to use beverages containing CHO to enhance their exercise experience may take note of these findings as this practise appears unjustified.

Re-Classification with Outcome Correlation of Previously Diagnosed Malignant Phyllodes Tumors Applying the 2016 Consensus Guidelines.

Background. Classification of phyllodes tumors is challenging due unclear diagnostic criteria, recently addressed by consensus review criteria. Herein, we reviewed all malignant phyllodes tumor resections and reclassified them based on the consensus guidelines, correlating with outcome. We hypothesize that application of criteria would result in a significant proportion being "down-graded" to either borderline or benign phyllodes tumor. Methods. Primary resections of malignant phyllodes tumor were reviewed by four AP board-certified, breast fellowship-trained pathologists. Morphologic variables delineated in consensus guidelines (ie stromal cellularity, cellular atypia, tumor border, presence of heterologous elements, presence of stromal overgrowth) were evaluated. Following review, cases were reclassified as benign, borderline, or malignant. Results. Upon reclassification, 20% (5/20) cases were "down-graded" to borderline phyllodes tumor while 80% (15/20) remained malignant phyllodes tumor. Two morphologic features were statistically significant including broadly infiltrating tumor border in 80% (12/15) of malignant phyllodes tumors compared to none in borderline phyllodes tumor (0/5) (p = 0.004) and stromal overgrowth in 67% (10/15) of malignant phyllodes tumor compared to none in borderline phyllodes tumors (0/5) (p = 0.03). Upon review of the pathology reports, 30% (6/20) contained all 5 histomorphologic variables delineated in the consensus review criteria. Malignant phyllodes tumor resulted in five cases with recurrence (33.3%, 5/15) and three cases with metastases (20.0%, 3/15) and borderline phyllodes tumor resulted in one case with recurrence (20.0%, 1/5) and no metastases (0/5). Conclusion. The consensus guidelines for phyllodes tumor are useful for subclassification. We hypothesize that standardize reporting of the histomorphologic variables may lead to better consensus.