Variation in practice in endometrial cancer and potential for improved care and equity through molecular classification.

OBJECTIVES: We measured the variation in practice across all aspects of endometrial cancer (EC) management and assessed the potential impact of implementation of molecular classification. METHODS: Centers from across Canada provided representative tumor samples and clinical data, including preoperative workup, operative management, hereditary cancer program (HCP) referrals, adjuvant therapy, surveillance and outcomes, for all EC patients diagnosed in 2016. Tumors were classified into the four ProMisE molecular subtypes. RESULTS: A total of 1336 fully evaluable EC patients were identified from 10 tertiary cancer centers (TC; n = 1022) and 19 community centers (CC; n = 314). Variation of surgical practice across TCs was profound (14-100%) for lymphadenectomy (LND) (mean 57% Gr1/2, 82% Gr3) and omental sampling (20% Gr1/2, 79% Gr3). Preoperative CT scans were inconsistently obtained (mean 32% Gr1/2, 51% Gr3) and use of adjuvant chemo or chemoRT in high risk EC ranged from 0-55% and 64-100%, respectively. Molecular subtyping was performed retrospectively and identified 6% POLEmut, 28% MMRd, 48% NSMP and 18% p53abn ECs, and was significantly associated with survival. Within patients retrospectively diagnosed with MMRd EC only 22% had been referred to HCP. Of patients with p53abn EC, LND and omental sampling was not performed in 21% and 23% respectively, and 41% received no chemotherapy. Comparison of management in 2016 with current 2020 ESGO/ESTRO/ESP guidelines identified at least 26 and 95 patients that would have been directed to less or more adjuvant therapy, respectively (10% of cohort). CONCLUSION: Molecular classification has the potential to mitigate the profound variation in practice demonstrated in current EC care, enabling reproducible risk assessment, guiding treatment and reducing health care disparities.

Performance Characteristics of Endometrial Sampling in Diagnosis of Endometrial Carcinoma.

Outpatient endometrial biopsy can give false-negative results, with a 0.9% reported posttest probability for endometrial carcinoma (EC) after a negative result. Our objective was to determine if there has been any improvement in the performance characteristics of endometrial biopsy over the last 15 yr. All hysterectomy specimens with a diagnosis of EC or atypical hyperplasia (AH), reported between May 2011 and May 2015, were identified and cross-referenced for any negative endometrial sampling results during the 5 yr before hysterectomy. Negative endometrial samples were defined as either benign findings or insufficient/nondiagnostic, excluding those diagnosed as AH or EC and those for which follow-up sampling was recommended because of atypia. Of 1677 hysterectomy specimens showing AH or EC there were previous negative biopsies in 172: 116 benign and 56 insufficient/nondiagnostic. Over the same period 22,875 negative endometrial biopsy specimens were reported in our region. The posttest probability of having EC or AH in the hysterectomy specimen, given a negative endometrial biopsy result, was 0.74%. In a subset of 90 cases in which a negative biopsy was followed by a diagnosis of AH or EC in a hysterectomy specimen, the slides were independently reviewed. There were no cases where a diagnosis of carcinoma was missed. In 12 samples atypia or possible atypia was identified, and the level of agreement with the original diagnosis was excellent κ=0.83±0.05. In a prospective comparison of examination of 3 levels from each block versus a single slide in 319 cases, the routine preparation of additional slides did not yield clinically significant information. Although there has been evolution in the diagnostic criteria for AH and for recognition of morphologically subtle forms of AH or EC, our results demonstrate a significant lack of sensitivity of outpatient endometrial sampling in the diagnosis of endometrial malignancy/premalignancy. The sensitivity problems are mainly attributable to failure to sample abnormal endometrium. Independent review of slides or examination of additional levels did little to increase the diagnostic yield.

Carcinogenesis alters fatty acid profile in breast tissue.

Cancerogenesis is associated with cell membrane changes. The aim of this study was to investigate whether breast tissues with different degrees of cancer involvement have different fatty acid profiles. Fourteen breast cancer patients with a mean age of 61 years were recruited. Morphological features of the tumoral specimens were characterized. Approximately 60 % of patients had invasive ductal carcinoma, and 80 % were ER positive; 65 % were PR positive; and 65 % were HER2 negative. The segments with confirmed cancer had significantly less amounts of total lipids as compared with the corresponding grossly normal or interface tissues. The fatty acid profile in cancer tissue was significantly different from that in other tissues. Fatty acid composition of five classes of phospholipids revealed the variations between cancer tissue and the other two segments. A transition of changes in fatty acid composition in these fractions of phospholipids was observed. The interface tissue had intermediate amounts of several fatty acids including palmitic acid, stearic acid, and arachidonic acid. Interestingly, we observed significantly higher amounts of the n-3 fatty acid DHA in cancer tissue as compared to the other two tissues. Data from this study will provide evidence that biochemical changes particularly phospholipid composition may take place well in advance prior to morphological changes. Should this theory be confirmed by larger studies, deviation of phospholipid composition from normal values can be used as markers of susceptibility of tissue to cancer development.

Patterns of Error in Interpretive Pathology.

OBJECTIVES: To demonstrate how the educational presentation and targeted review of cases with discrepant interpretive findings between pathologists can raise awareness for specific diagnostic errors through identification of common overarching patterns of error in interpretive pathology. METHODS: We performed a review of 147 surgical pathology and cytopathology cases of discordances from 23 PowerPoint presentations presented between 2010 and 2017. Pathologists and pathology residents, blinded from the official interpretations, were presented each case and surveyed for their own diagnostic assessments. Survey results were compared with the final/correct interpretations of the signing pathologists. RESULTS: Of the 134 cases with available survey results, there were 87 (64.9%) for which most survey respondents proposed a diagnostic interpretation concordant with the final/correct diagnosis. There were 37 (27.6%) cases for which most survey responses were either wholly or partially discordant with the final/correct diagnosis. For 10 (7.5%) cases, there were equal numbers of concordant and discordant survey responses. CONCLUSIONS: Our analyses of the cases with frequent erroneous diagnoses reveal common patterns of error that are widely applicable and outline specific error-prone interpretive tendencies. Greater awareness for these tendencies, highlighted by presentation of discordant cases, can improve the quality of diagnostic pathology services.

A high-lipid diet potentiates left ventricular dysfunction in nitric oxide synthase 3-deficient mice after chronic pressure overload.

A high-lipid diet (HLD) may lead to adverse left ventricular (LV) remodeling and endothelial dysfunction in conditions of hemodynamic stress. Although congenital absence of nitric oxide synthase 3 (NOS3) leads to adverse LV remodeling after transverse aortic constriction (TAC), the effects of a HLD in this state remains unknown. Wild-type (WT) and NOS3 knockout mice (NOS3(-/-)) were randomized into the following 4 groups: 1) WT + low-lipid diet (LLD) (10% of energy); 2) WT + HLD (60% of energy); 3) NOS3(-/-) + LLD; and 4) NOS3(-/-) + HLD for a total of 12 wk. After 1 wk of randomization, TAC was performed on all groups. Serial echocardiography revealed a decrease in LV ejection fraction (LVEF) in WT and NOS3(-/-) mice fed the HLD compared with those fed the LLD diet at 12 wk post-TAC. Mice fed the NOS3(-/-) + HLD diet had a lower LVEF compared with mice in the other 3 groups (P < 0.05). There was greater myocyte hypertrophy, interstitial fibrosis, and percentage change in plasma cholesterol concentrations in the NOS3(-/-) + HLD group 12 wk post-TAC compared with the other 3 groups. Although high molecular weight fibroblast growth factor-2, a marker of cardiac hypertrophy, was more upregulated in the NOS3(-/-) + HLD group than in the other groups, markers of the renin-angiotensin system did not differ among them. A HLD potentiates LV dysfunction in NOS3(-/-) mice in a chronic pressure overload state.

Effects of long-term consumption of a high-fructose diet on conventional cardiovascular risk factors in Sprague-Dawley rats.

We investigated the effects of a high-fructose (HF) diet on cardiovascular risks in Sprague-Dawley rats. Twelve rats were randomly assigned to standard chow or HF diet for 20 weeks. Systolic blood pressure and circulating insulin, total cholesterol, and triacylglycerol levels were significantly higher in the HF group. Aortic sections appeared normal, but liver sections from the HF group showed lipid accretion, mild inflammation, and bile pigmentation. Liver samples from the HF group showed significantly higher total lipid levels and changes in fatty acid profile. Levels of 16:0, cis-9-18:2, cis-11-20:1, cis-13-20:1, cis-11-20:2 and 24:0 were significantly raised in the phospholipid fraction. Lower levels of cis-11-18:1, cis-9-18:2, and cis-11-20:1 and increased levels of 16:1, cis-9-18:1, and cis-13-20:1 were found in the non-esterified fatty acid fraction. HF-feeding resulted in significant reductions in plasma levels of certain inflammatory biomarkers. HF intake over time may negatively impact cardiovascular health and liver function in rats.

'Designer oils' low in n-6:n-3 fatty acid ratio beneficially modifies cardiovascular risks in mice.

Cardiovascular benefits of dietary n-3 fatty acids have been shown. However, benefits of n-3 fatty acids as part of a high fat, low n-6:n-3 fatty acid ratio diet has not been fully characterized. Aim of this study is to investigate cardiovascular and metabolic benefits of 'designer oils' containing a low ratio of n-6:n-3 fatty acids in C57BL/6 mice. Three groups of C57BL/6 mice were fed an atherogenic diet supplemented with either a fish oil- or flaxseed oil-based 'designer oil' with an approximate n-6:n-3 fatty acid ratio of 2:1 (treated groups, n = 6 each) or with a safflower oil-based formulation with a high ratio (25:1) of n-6:n-3 fatty acids (control group, n = 6) for 6 weeks. Food intake, body weight, and blood lipid levels were monitored regularly. Fatty acid profile of the heart tissues was assessed. Histological assessment of liver samples was conducted. At the end of the study body weight and food intake was significantly higher in the flax group compared to control. The levels of 20:5n-3 and 22:6n-3 was significantly increased in the heart phospholipids in both flax and fish groups compared to control; tissue 20:4n-6 was significantly reduced in the fish group compared to control. Significant liver pathology was observed in the control group only. Lowering dietary ratio of n-6:n-3 fatty acids may significantly reduce cardiovascular and metabolic risks in mice regardless of the source of n-3 fatty acids.

A rare case of coexistence of carcinoid tumor of appendix vermicularis and ileal endometriosis.

BACKGROUND: Carcinoid tumor is the most common tumor of appendix with overall good prognosis. Endometriosis is the implantation of endometrial glands and stroma outside the uterus. CASE REPORT: We here report the coexistence of carcinoid tumor of appendix and ileal endometriosis in a 37-year-old nulliparous woman who came to the emergency room with right lower abdominal pain mimicking acute appendicitis. The main clinical and laboratory findings included fever, leukocytosis and elevated ESR. With preoperative suspicion of acute appendicitis, laparatomy was performed and revealed apparently normal looking appendix, along with a nodule in the terminal ileum. Both the appendix and ileal nodule were removed. Histological examinations revealed carcinoid tumor of appendix and ileal endometriosis. The case was discharged 4 days after surgery with no pain and symptoms and remained symptom free for the 1 year period of follow up. CONCLUSION: Many cases of carcinoid tumor of the appendix and ileal endometriosis are diagnosed incidentally. Overall prognosis of these conditions is very good. Surgical treatment seems to be the best intervention for these disorders.

Hydatid disease of the spleen (report of 2 cases).

Hydatid disease is endemic in Middle East as well as other parts of the world including New Zealand and Australia [Altinors N, Senveli E, Donmez T, Bavbek M, Kars Z, Sanli M. Management of problematic intracranial hydatid cyst. Infection 1995;23:283-7]. Passing eggs from definite hosts--dogs and some wild carnivores--are ingested by intermediate hosts--humans and herbivores [Begg I, The radiology of hydatid disease. Am J Roentgenol 1985;145;639-48]. Larva penetrate the intestinal mucosa and reach the circulation, lodging and encysting in the body organs [Vahedian-Ardakani J. Hydatid cyst of the liver presenting as cutaneous abscesses. Ann Saudi Med 1997;17(2);235-7]. Liver and lungs account for more than 90% of organ involvements. Splenic involvement is rare occurrence of about 2.5%. [Franquet T, Montes M, Lecumberri FJ, Esparza J, Bescos JM. Hydatid disease of the spleen: imaging findings in nine patients. Am J Roentgenol 1990;154:525-8]. Here we report two cases of hydatid disease of the spleen in Izeh, a city in Khuzestan Province of Iran.

Atypical cells in a voided urine cytology specimen in a renal transplant recipient.

Voided urine is routinely collected from renal transplant patients to screen for polyomavirus. In rare cases, atypical lymphoid cells can be detected in voided urine and raise the suspicion of post-transplant lymphoproliferative disorder (PTLD). However, further immunohistochemistry of the cell block and flow cytometry is frequently limited by the low cellularity and poor preservation of voided urine. Therefore, PTLD of the renal allograft is usually diagnosed from tissue biopsy or nephrectomy specimens. Herein, we report a rare case of atypical cells in a voided urine cytology specimen from a kidney transplant recipient. Needle core biopsy of the renal allograft showed monomorphic PTLD. Diagn. Cytopathol. 2017;45:69-72. © 2016 Wiley Periodicals, Inc.

Pro-atherogenic effects of probucol in apo E-KO mice may be mediated through alterations in immune system: Parallel alterations in gene expression in the aorta and liver.

OBJECTIVE: To establish underlying molecular mechanisms of pro-atherogenic effects of probucol in apo E-KO mice. METHODS: Affymetrix Gene Chip System, GenMAPP/MAPPFinder software and real-time PCR techniques were used to identify alterations in gene expression and biological pathways in the liver and aorta of both male apo E-KO and male wild-type mice treated with or without probucol (1%, w/w) for 18 weeks. Plasma levels of lipids, cytokines, liver function test, and the extent of atherosclerosis and liver histology were examined. RESULTS AND CONCLUSIONS: Probucol treatment paradoxically reduced plasma cholesterol levels, increased plasma cytokine levels and atherogenesis in apo E-KO mice. Three hundred and sixty genes/transcripts and 110 biological processes were significantly differentially expressed in the liver of probucol-treated apo E-KO mice. The response to biotic stimulus, immune response and inflammatory response were the most prominent processes expressed in the liver. The expression of 60 of these genes involved in immune response including inflammatory responses, antigen presentation, humoral immune response, immune cell activation, innate immune response, and regulation of immune response was over-expressed. Many of these genes were also over-expressed in the aorta of probucol-treated apo E-KO mice. Such effects of probucol were not observed in the liver and aorta of wild-type mice. A significant interaction between apo E deficiency and probucol treatment was observed. Histological examinations showed a significant infiltration of inflammatory cells in the liver of probucol-treated apo E-KO mice, but not in C57BL/6 mice. These findings suggest that probucol-induced atherogenesis may be mediated through a pro-inflammatory state.

Lack of evidence for antiatherogenic effects of wheat bran or corn bran in apolipoprotein E-knockout mice.

Epidemiological studies have suggested that intake of whole grains is inversely associated with coronary artery disease. The mechanisms, however, are not completely clear. We tested the hypothesis that intake of wheat bran or corn bran would (1) increase the plasma concentration of phenolic antioxidants and (2) reduce atherosclerosis in apo E-knockout mice. Apo E-knockout (E-KO) mice were fed for 18 weeks with a 0.1% cholesterol-supplemented diet in the absence of grain brans or the presence of 1.7% yellow dent corn bran or 3.3% hard red spring wheat bran. The concentration of antioxidant ferulic acid in plasma and urine was measured by HPLC to monitor the bioavailability of grain phenolics. Plasma lipoprotein profiles were determined by a combination of HPLC and online enzymatic methods. Urinary 15-isoprostane F(2t), an in vivo LDL oxidation biomarker, and atherosclerotic lesions were analyzed by ELISA and histological methods, respectively. Dietary supplementation with corn or wheat bran resulted in a 4- and 24-fold increase, respectively, in urinary excretion of ferulic acid. The urinary recovery rate of ferulic acid from the two brans in apo E-KO mice was approximately 1.9-2.9%. Dietary corn bran but not wheat bran also significantly increased the concentration of total ferulic acid in plasma. Nevertheless, the supplementation with either bran product for 18 weeks did not significantly alter the urinary excretion of 15-isoprostane F(2t), change the lipoprotein profiles, nor reduce the atherosclerotic lesion development in this animal model. The results suggest that phenolic antioxidants from the two types of bran may not be sufficient to reduce atherosclerosis in this animal model.

A comparison of the effects of fish oil and flaxseed oil on cardiac allograft chronic rejection in rats.

Both fish and flaxseed oils are major sources of different n-3 fatty acids. Beneficial effects of fish oil on posttransplantation complications have been reported. The current study aimed to compare the effects of flaxseed and fish oils in a rat cardiac allograft model. Male Fischer and Lewis rats were used as donors and recipients, respectively, to generate a heterotopic cardiac allograft model. Animals were randomly assigned into three groups and fed a diet supplemented with 1) 5% (wt/wt) safflower oil (control, n = 7), 2) 5% (wt/wt) flaxseed oil (n = 8), or 3) 2% (wt/wt) fish oil (n = 7), and an intraperitoneal injection of cyclosporine A (CsA; 1.5 mg.kg(-1).day(-1)) over 12 wk. Body weight, blood pressure, plasma levels of lipids, CsA, select cytokines, as well as graft function and chronic rejection features were assessed. Body weight and blood CsA levels were similar among the groups. Relative to controls, both treated groups had lower systolic and diastolic blood pressure and plasma levels of macrophage chemotactic protein-1. Treatment with fish oil significantly (P < 0.05) lowered plasma levels of triglycerides, total cholesterol, and LDL-cholesterol. HDL-cholesterol concentrations were significantly higher (P < 0.05) in the flaxseed oil-treated group compared with the other two groups. Both flaxseed oil and fish oil may provide similar biochemical, hemodynamic, and inflammatory benefits after heart transplantation; however, neither of the oils was able to statistically significantly impact chronic rejection or histological evidence of apparent cyclosporine-induced nephrotoxicity in this model.