Estrogen/Progesterone Receptor Loss, CTNNB1 and KRAS Mutations Are Associated With Local Recurrence or Distant Metastasis in Low-Grade Endometrial Endometrioid Carcinoma.

A subset of endometrial endometrioid carcinomas (EECs) with low-grade histology recur with poor outcomes. Published evidence suggests that poor outcomes may be associated with loss of expression of ER-alpha (ER-α) as well as with ß-Catenin-1 ( CTNNB1 ) and Kirsten rat sarcoma viral oncogene homolog ( KRAS ) mutations. This study reports on institutional experience with the incidence of recurrence in low-grade EEC and their association with CTNNB1 and KRAS mutations as well as estrogen/progesterone receptor (ER/PR) expression. Forty-eight (8.5%) out of 568 cases of low-grade EEC with biopsy-proven recurrence were identified; and were analyzed by immunohistochemistry for ER, PR, p53, MMR protein, and mutation analysis for exon 3 of the CTNNB1 and exon 2 of KRAS in relation to recurrence type, local or distant metastasis/recurrence. Twenty-three patients (4%) developed local, and 25 patients (4.4%) developed distant metastases/recurrence. Decreased expression or loss of ER/PR was found in 17/44 (38.6%) patients with recurrence. Eighty-four percent of patients with low-grade EEC and local recurrence had CTNNB1 mutations. Seventy-three percent of patients with distant metastasis/recurrence had KRAS mutations. The association of these mutations with the type of recurrence was statistically significant for both. Five cases with the morphology of low-grade EEC were reclassified as mesonephric-like carcinoma and were universally characterized by distant metastasis/recurrence, loss of ER/PR expression, large tumor size, absence of CTNNB1 mutations, and the presence of KRAS mutations. In low-grade EEC, CTNNB1 and KRAS mutations are associated with local recurrence and distant metastasis/recurrence, respectively, suggesting that these 2 different progression types may be conditioned by tumor genotype. ER/PR immunohistochemistry may be helpful in identifying poor performers in low-grade EEC. Furthermore, identification of the decreased expression or loss of ER/PR in tumors with low-grade histology should prompt consideration of mesonephric-like carcinoma, which is a more aggressive tumor than the low-grade EEC. KRAS mutations were associated with distant metastasis/recurrence in tumors with and without mesonephric-like phenotype.

Outcomes of Patients with Small Intestine Adenocarcinoma in a Canadian Province: A Retrospective Multi-Center Population-Based Cohort Study.

Background: Small intestine adenocarcinoma is a rare cancer. The current study aims to determine the outcomes of patients with small intestine adenocarcinoma in a Canadian province. Methods: This retrospective population-based cohort study assessed patients with small intestine adenocarcinoma who were diagnosed from 2008 to 2017 in Saskatchewan. A Cox proportional multivariate regression analysis was performed to determine the correlation between survival and exploratory factors. Results: 112 eligible patients with a median age of 73 years and M:F of 47:53 were identified. Overall, 75% had a comorbid illness, and 45% had a WHO performance status >1. Of the 112 patients, 51 (46%) had early-stage disease and 61 (54%) had advanced-stage disease. The median overall survival (mOS) was as follows: stage one, 59 months; stage two, 30 months; stage three, 20 months; and stage four, 3 months (p < 0.001). The median disease-free survival of patients with stage three disease who received adjuvant chemotherapy was 26 months (95% CI:23.1−28.9) vs. 4 months (0.0−9.1) with observation (p = 0.04). Patients who received chemotherapy for advanced disease had a mOS of 10 months (3.5−16.5) vs. 2 months (0.45−3.6) without chemotherapy (p < 0.001). In the multivariate analysis, stage four disease, hazard ratio (HR), 3.20 (1.84−5.40); WHO performance status >1, HR, 2.22 (1.42−3.45); lack of surgery, HR, 2.10 (1.25−3.50); and a neutrophil:lymphocyte ratio of >4.5, HR, 1.72 (1.10−2.71) were significantly correlated with inferior survival. Conclusions: Most patients with small intestine adenocarcinoma were diagnosed with advanced-stage disease. Advanced-stage disease, poor performance status, lack of surgery and a baseline neutrophil:lymphocyte ratio >4.5 were correlated with inferior survival.

Retinoid receptors are expressed in mouse and human lungs.

Retinoid receptors are members of nuclear receptor superfamily consisting of two distinct families: RARs (retinoic acid receptors) and RXRs (retinoid X receptors). Each family contains three receptor subtypes α, ß, and γ. Retinoids transduce their effects through binding to retinoid receptors and inhibit transcription factors such as activator protein-1 and nuclear factor-κB (NF-κB) both of which regulate the transcription of several inflammatory genes. Considering the role of retinoid receptors in lung physiology, we need a precise understanding of their expression in normal and inflamed lungs. We used light and electron microscopic immunohistochemistry and Western blot to determine the expression of retinoid receptors in a murine model of endotoxin-induced (E. coli; 055:B5, 80 µg intranasal) acute lung inflammation and normal human lungs. Western blot showed expression of all six retinoid receptor subtypes in normal and inflamed mouse lungs. Immunohistology localized differential expression of retinoid receptors in airway epithelium, alveolar/septal macrophages, vascular endothelium, and alveolar septum in mouse lungs. Intranasal LPS challenge in mice resulted in increased expression of RXRα in airway epithelium compared to control animals. All six retinoid receptor subtypes were expressed in normal human lungs. Immunoelectron microscopy further confirmed the localization of all the receptors in various lung cells including the nucleus of these cells. The basal and altered expression of retinoid receptors in normal and inflamed lungs, respectively, may suggest their roles in lung pathophysiology.

Recovery of borderline oxacillin-resistant Staphylococcus pseudintermedius (BORSP) from bone and soft tissue of a rheumatoid arthritis patient with severe osteoporosis: transmission from the family dog.

We report a case of borderline oxacillin-resistant S. pseudintermedius (BORSP) in a rheumatoid arthritis patient with severe osteoporosis. The organism is also resistant to erythromycin and clindamycin. We also present clear evidence on transmission from the family dog.

Mixed epithelial endocrine neoplasms of the colon and rectum - An evolution over time: A systematic review.

BACKGROUND: Mixed tumors of the colon and rectum, composed of a combination of epithelial and endocrine elements of benign and malignant potential are rare neoplasms. These can occur anywhere in the gastrointestinal tract and are often diagnosed incidentally. Though they have been a well-documented entity in the pancreas, where the exocrine-endocrine mixed tumors have been known for a while, recognition and accurate diagnosis of these tumors in the colon and rectum, to date, remains a challenge. This is further compounded by the different terminologies that have been attributed to these lesions over the years adding to increased confusion and misclassification. Therefore, dedicated literature reviews of these lesions in the colon and rectum are inconsistent and are predominantly limited to case reports and case series of limited case numbers. Though, most of these tumors are high grade and of advanced stage, intermediate and low grade lesions of these mixed tumors are also increasingly been reported. There are no established independent consensus based guidelines for the therapeutic patient management of these unique lesions. AIM: To provide a comprehensive targeted literature review of these complex mixed tumors in the colon and rectum that chronicles the evolution over time with summarization of historical perspectives of terminology and to further our understanding regarding their pathogenesis including genomic landscape, clinicoradiological features, pathology, treatment, prognosis, the current status of the management of the primary lesions, their recurrences and metastases. METHODS: A comprehensive review of the published English literature was conducted using the search engines PubMed, MEDLINE and GOOGLE scholar. The following search terms ["mixed tumors colon" OR mixed endocrine/neuroendocrine tumor/neoplasm/lesion colon OR adenocarcinoma and endocrine/neuroendocrine tumor colon OR mixed adenocarcinoma and endocrine/neuroendocrine carcinoma colon OR Amphicrine tumors OR Collision tumors] were used. Eligibility criteria were defined and all potential relevant items, including full articles and/or abstracts were independently reviewed, assessed and agreed upon items were selected for in-depth analysis. RESULTS: In total 237 full articles/abstracts documents were considered for eligibility of which 45 articles were illegible resulting in a total of 192 articles that were assessed for eligibility of which 139 have been selected for reference in this current review. This seminal manuscript is a one stop article that provides a detailed outlook on the evolution over time with summarization of historical perspectives, nomenclature, clinicoradiological features, pathology, treatment, prognosis and the current status of the management of both the primary lesions, their recurrences and metastases. Gaps in knowledge have also been identified and discussed. An important outcome of this manuscript is the justified proposal for a new, simple, clinically relevant, non-ambiguous terminology for these lesions to be referred to as mixed epithelial endocrine neoplasms (MEENs). CONCLUSION: MEEN of the colon and rectum are poorly understood rare entities that encompass an extensive range of heterogeneous tumors with a wide variety of combinations leading to tumors of high, intermediate or low grade malignant potential. This proposed new revised terminology of MEEN will solve the biggest hurdle of confusion and misclassification that plagues these rare unique colorectal neoplasms thus facilitating the future design of multi institutional prospective randomized controlled clinical trials to develop and evaluate newer therapeutic strategies that are recommended for continued improved understanding and personal optimization of clinical management of these unique colorectal neoplasms.

Bacteremia with Staphylococcus pseudintermedius in a 4 month old pediatric oncology patient.

Staphylococcus pseudintermedius colonizes and is a pathogen of dogs and is being increasingly recognized from specimens from humans with various infections. We describe a case of S. pseudintermedius bacteremia in a 4 month old pediatric oncology patient with clear evidence of transmission from the family pet.

Multiple colonic and ileal perforations due to unsuspected intestinal amoebiasis-Case report and review.

Amoebiasis, caused by the intestinal protozoan Entamoeba histolytica, though a relatively common parasitic disease in the tropical and subtropical regions, is uncommon in the developed countries. In these countries, as amoebic colitis shares similar clinical symptoms and endoscopic features with inflammatory bowel disease (IBD), these cases can be easily unrecognized and misdiagnosed. In this case report, we discuss the case of an adult patient with invasive intestinal amoebiasis, who was initially managed as Crohn's disease on corticosteroid treatment and subsequently rapidly deteriorated and developed multiple perforations in the colon and ileum. Despite total colectomy followed by resection of the small bowel, he died of multiple organ failure and sepsis within two months of his initial clinical presentation of diarrhea with abdominal pain. The learning point of this case is that invasive intestinal amoebiasis should be considered as a differential diagnosis at the first clinical adult presentation of IBD-like symptoms despite suggestive endoscopic findings of Crohn's like ulcers. Regardless of negative endoscopic biopsies, due to the low sensitivity of microscopic examination, serology test for antibody and molecular test for Entamoeba DNA are recommended for accurate detection and identification of Entamoeba species, especially in the high risk populations with recent travel to endemic zones and for patients with immunosuppression and comorbidities such as diabetes mellitus, tuberculosis, alcoholism, HIV/AIDS and in pregnant women. Amoebiasis should be completely ruled out prior to corticosteroid administration, to avoid severe complications such as fulminant intestinal amoebiasis which is associated with an inherently high mortality.

Extrapelvic Metastases in Endometrial Stromal Sarcomas: A Clinicopathological Review With Immunohistochemical and Molecular Characterization.

Endometrial stromal sarcoma is a rare uterine tumor associated with favorable outcomes despite its ability to recur and metastasize to distant sites. Most recurrences are local, being limited to the abdomen/pelvis, but distant metastases can occur. Metastatic endometrial stromal sarcoma can occur many months to years after the original diagnosis or may present prior to the primary, potentially creating a diagnostic challenge. We report a bi-institutional review of 10 cases of endometrial stromal sarcoma with extrapelvic metastases without a prior history of endometriosis. The histologic, immunophenotypic, and molecular characteristics of these tumors are analyzed in the context of a relevant literature review.

Stanniocalcin 2 expression is associated with a favourable outcome in male breast cancer.

Breast cancer can occur in either gender; however, it is rare in men, accounting for <1% of diagnosed cases. In a previous transcriptomic screen of male breast cancer (MBC) and female breast cancer (FBC) occurrences, we observed that Stanniocalcin 2 (STC2) was overexpressed in the former. The aim of this study was to confirm the expression of STC2 in MBC and to investigate whether this had an impact on patient prognosis. Following an earlier transcriptomic screen, STC2 gene expression was confirmed by RT-qPCR in matched MBC and FBC samples as well as in tumour-associated fibroblasts derived from each gender. Subsequently, STC2 protein expression was examined immunohistochemically in tissue microarrays containing 477 MBC cases. Cumulative survival probabilities were calculated using the Kaplan-Meier method and multivariate survival analysis was performed using the Cox hazard model. Gender-specific STC2 gene expression showed a 5.6-fold upregulation of STC2 transcripts in MBC, also supported by data deposited in Oncomine™. STC2 protein expression was a positive prognostic factor for disease-free survival (DFS; Log-rank; total p = 0.035, HR = 0.49; tumour cells p = 0.017, HR = 0.44; stroma p = 0.030, HR = 0.48) but had no significant impact on overall survival (Log-rank; total p = 0.23, HR = 0.71; tumour cells p = 0.069, HR = 0.59; stroma p = 0.650, HR = 0.87). Importantly, multivariate analysis adjusted for patient age at diagnosis, node staging, tumour size, ER, and PR status revealed that total STC2 expression as well as expression in tumour cells was an independent prognostic factor for DFS (Cox regression; p = 0.018, HR = 0.983; p = 0.015, HR = 0.984, respectively). In conclusion, STC2 expression is abundant in MBC where it is an independent prognostic factor for DFS.

Hepatic endometrial stromal sarcoma.

Endometrial stromal sarcomas are rare tumors that may recur or metastasize many years after their initial presentation. Though most recurrences are within the pelvis, distant metastases can occur, and are most common to the lungs. Metastases to the liver are extremely rare. Herein we report two cases of endometrial stromal sarcoma with metastases to the liver without a prior history of endometriosis, accompanied by their histology, immunohistochemistry, and molecular analysis in the context of a relevant literature review.

Invasive lobular carcinoma of the male breast - a systematic review with an illustrative case study.

Male breast cancer is rare, comprising only 1% of all mammary cancers; invasive ductal carcinoma is by far the commonest subtype in both men and women. Though lobular breast cancer is the second most common subtype seen in women, such cancers are extremely uncommon in men, and this is likely related to the lack of lobular development in the male breast. Thus, due to the rarity of this subtype among breast cancers, compounded by the overall rarity of breast cancer in men, current understanding of the pathogenesis of this disease and its management is largely derived from case series and extrapolation of information from the larger cohort of female patients. This paper provides a systematic review on invasive lobular carcinoma of the male breast in the context of an illustrative case study. A comprehensive analysis of the National Cancer Institute's Surveillance, Epidemiology, and End Results Data 1973-2013 leading to an exploration of the pathogenesis, epidemiology, clinical presentation, diagnosis, tumor characteristics, and management of lobular breast carcinoma in men is also discussed. Lobular subtype of breast cancer remains an enigmatic elusive disease that needs additional research to unravel its overall pathogenesis and molecular profile to provide insight for improved therapeutic management options.

Characterisation of male breast cancer: a descriptive biomarker study from a large patient series.

Male breast cancer (MBC) is rare. We assembled 446 MBCs on tissue microarrays and assessed clinicopathological information, together with data from 15 published studies, totalling 1984 cases. By immunohistochemistry we investigated 14 biomarkers (ERα, ERß1, ERß2, ERß5, PR, AR, Bcl-2, HER2, p53, E-cadherin, Ki67, survivin, prolactin, FOXA1) for survival impact. The main histological subtype in our cohort and combined analyses was ductal (81%, 83%), grade 2; (40%, 44%), respectively. Cases were predominantly ERα (84%, 82%) and PR positive (74%, 71%), respectively, with HER2 expression being infrequent (2%, 10%), respectively. In our cohort, advanced age (>67) was the strongest predictor of overall (OS) and disease free survival (DFS) (p = 0.00001; p = 0.01, respectively). Node positivity negatively impacted DFS (p = 0.04). FOXA1 p = 0.005) and AR p = 0.009) were both positively prognostic for DFS, remaining upon multivariate analysis. Network analysis showed ERα, AR and FOXA1 significantly correlated. In summary, the principle phenotype of MBC was luminal A, ductal, grade 2. In ERα+ MBC, only AR had prognostic significance, suggesting AR blockade could be employed therapeutically.

A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer.

Purpose: Breast cancer affects both genders, but is understudied in men. Although still rare, male breast cancer (MBC) is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar.Experimental Design: A transcriptomic investigation of male and female breast cancer was performed, confirming transcriptomic data in silico Biomarkers were immunohistochemically assessed in 697 MBCs (n = 477, training; n = 220, validation set) and quantified in pre- and posttreatment samples from an MBC patient receiving everolimus and PI3K/mTOR inhibitor.Results: Gender-specific gene expression patterns were identified. eIF transcripts were upregulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (log-rank P = 0.013; HR = 1.77, 1.12-2.8 and P = 0.035; HR = 1.68, 1.03-2.74, respectively), or when coexpressed (P = 0.01; HR = 2.66, 1.26-5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis [eIF4E P = 0.016; HR = 2.38 (1.18-4.8), eIF5 P = 0.022; HR = 2.55 (1.14-5.7); coexpression P = 0.001; HR = 7.04 (2.22-22.26)]. Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/everolimus, with extended survival.Conclusions: Translational initiation pathway inhibition could be of clinical utility in MBC patients overexpressing eIF4E and eIF5. With mTOR inhibitors that target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required. Clin Cancer Res; 23(10); 2575-83. ©2016 AACR.

Primary pulmonary/pleural melanoma in a 13 year-old presenting as pleural effusion.

Melanoma in children, adolescents, and young adults is uncommon and reported almost exclusively as cutaneous melanoma. Melanoma presenting as a pleural effusion is very rare in adults and not reported in the pediatric population. Additionally, primary pulmonary melanoma is overall very rare and undocumented in pediatric patients. Furthermore, the distinction between a primary pulmonary/pleural melanoma versus a regressed cutaneous melanoma with pulmonary/pleural metastases remains extremely challenging. We discuss a case of a previously healthy 13-year-old girl that presented with a left-sided pleural effusion. Investigations revealed a large mediastinal mass, left-sided pleural and pulmonary nodules, a sacral mass, and bone marrow infiltration. The neoplasm was subsequently diagnosed by morphology and immunocytochemistry with histological correlation as malignant melanoma. As no mucosal, eye, or cutaneous lesions were identified, we deliberate the likelihood of a regressed cutaneous melanoma with metastases versus primary pulmonary/pleural melanoma with pleural effusion and discuss its diagnostic approach.

Gastric biomarkers: a global review.

BACKGROUND: Gastric cancer is an aggressive disease with a poor 5-year survival and large global burden of disease. The disease is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Despite the many prognostic, predictive, and therapeutic biomarkers investigated to date, gastric cancer continues to be detected at an advanced stage with resultant poor clinical outcomes. MAIN BODY: This is a global review of gastric biomarkers with an emphasis on HER2, E-cadherin, fibroblast growth factor receptor, mammalian target of rapamycin, and hepatocyte growth factor receptor as well as sections on microRNAs, long noncoding RNAs, matrix metalloproteinases, PD-L1, TP53, and microsatellite instability. CONCLUSION: A deeper understanding of the pathogenesis and biological features of gastric cancer, including the identification and characterization of diagnostic, prognostic, predictive, and therapeutic biomarkers, hopefully will provide improved clinical outcomes.

Cytomegalovirus Colitis: An Uncommon Mimicker of Common Colitides.

Cytomegalovirus latency, though ubiquitous in the human population, is known to cause colitis in both immunocompromised and immunocompetent hosts. Furthermore, the clinical, endoscopic, and histologic appearance of cytomegalovirus colitis can mimic that of inflammatory bowel disease, an extremely well-documented disease. In this context, though many reports have looked at inflammatory bowel disease with superimposed cytomegalovirus infection, less attention has been paid to cytomegalovirus as a primary cause of isolated colitis. Owing to the rarity of this phenomenon, it is important to consider this diagnosis and implement proper testing to avoid misdiagnosis and mismanagement.

Targeting synthetic lethality between the SRC kinase and the EPHB6 receptor may benefit cancer treatment.

Application of tumor genome sequencing has identified numerous loss-of-function alterations in cancer cells. While these alterations are difficult to target using direct interventions, they may be attacked with the help of the synthetic lethality (SL) approach. In this approach, inhibition of one gene causes lethality only when another gene is also completely or partially inactivated. The EPHB6 receptor tyrosine kinase has been shown to have anti-malignant properties and to be downregulated in multiple cancers, which makes it a very attractive target for SL applications. In our work, we used a genome-wide SL screen combined with expression and interaction network analyses, and identified the SRC kinase as a SL partner of EPHB6 in triple-negative breast cancer (TNBC) cells. Our experiments also reveal that this SL interaction can be targeted by small molecule SRC inhibitors, SU6656 and KX2-391, and can be used to improve elimination of human TNBC tumors in a xenograft model. Our observations are of potential practical importance, since TNBC is an aggressive heterogeneous malignancy with a very high rate of patient mortality due to the lack of targeted therapies, and our work indicates that FDA-approved SRC inhibitors may potentially be used in a personalized manner for treating patients with EPHB6-deficient TNBC. Our findings are also of a general interest, as EPHB6 is downregulated in multiple malignancies and our data serve as a proof of principle that EPHB6 deficiency may be targeted by small molecule inhibitors in the SL approach.

Paget's disease of the male breast in the 21st century: A systematic review.

Paget's disease of the breast is characterized by eczematous changes of the nipple-areolar complex and is associated with an underlying in situ or invasive breast carcinoma in most cases. Histologically, Paget's disease is identified by epithelial cells with abundant basophilic or amphophilic, finely granular cytoplasm with a large, centrally situated nucleus, most abundant in the lower epidermal layers. Due to the rarity of the condition among breast cancers, compounded by the rarity of breast cancer in men, understanding of the disease's presentation, course, and optimal treatment in men is largely derived from case reports and extrapolation of findings from studies in female patients. Paget's disease must be differentiated from other conditions including eczema, Bowen's disease, squamous cell carcinoma, and melanoma. Recognition of Paget's disease clinically and pathologically is critical as the superficial lesion may be the only sign of an underlying ductal carcinoma and its presence may be of prognostic significance. This article provides an update on cases of Paget's disease of the breast in men reported in the published literature together with a comprehensive analysis of the National Cancer Institute's Surveillance, Epidemiology, and End Results Data, 1973-2012. Current understanding and management of the disease in the context of male patients is reviewed. However, additional research is required to further understand the overall pathogenesis and molecular profile of Paget's disease to provide improved insight for personalized, precision-based therapeutic options.