HtrA3 stromal expression is correlated with tumor budding in stage II colorectal cancer.

Tumor budding is a well-established adverse prognostic factor in colorectal carcinoma (CRC). It may represent a form of epithelial-to-mesenchymal transition (EMT), although the underlying mechanisms remain unclear. High-temperature requirement A3 (HtrA3) is an inhibitor of the bone morphogenetic protein pathway, the suppression of which has been linked to EMT. Since HtrA3 is highly expressed in the desmoplastic stroma at the CRC invasive front, we sought to evaluate the relationship between tumor budding and HtrA3 expression in 172 stage II CRC resection specimens. All tumors were evaluated for tumor budding, with the highest budding slide selected for pan-keratin (CK) and HtrA3 immunohistochemistry. Representative areas of tumor core and invasive front, including budding and non-budding areas, were marked on CK stained slides, and then evaluated on HtrA3 stained slides. HtrA3 expression in tumor cells (tHtrA3) and peritumoral stroma (sHtrA3) was assessed for staining percentage and intensity (the product yielding a final score). Tumors with high-grade tumor budding (HGTB) showed increased expression of sHtrA3 in budding areas compared to non-budding areas at the invasive front (P<0.001). In addition, sHtrA3 expression at the invasive front was significantly higher in HGTB tumors compared to minimally budding tumors (P<0.05). tHtrA3 expression at the invasive front was significantly associated with high histological grade (P<0.05). Higher sHtrA3 expression in the tumor core (but not invasive front) was significantly associated with decreased 5-year overall survival on univariate analysis (P<0.05), but not multivariate analysis. HtrA3 expression in the peritumoral stroma of patients with stage II CRC is associated with HGTB and may be a novel marker of poor outcome.

Menacalc, a quantitative method of metastasis assessment, as a prognostic marker for axillary node-negative breast cancer.

BACKGROUND: Menacalc is an immunofluorescence-based, quantitative method in which expression of the non-invasive Mena protein isoform (Mena11a) is subtracted from total Mena protein expression. Previous work has found a significant positive association between Menacalc and risk of death from breast cancer. Our goal was to determine if Menacalc could be used as an independent prognostic marker for axillary node-negative (ANN) breast cancer. METHODS: Analysis of the association of Menacalc with overall survival (death from any cause) was performed for 403 ANN tumors using Kaplan Meier survival curves and the univariate Cox proportional hazards (PH) model with the log-rank or the likelihood ratio test. Cox PH models were used to estimate hazard ratios (HRs) for the association of Menacalc with risk of death after adjustment for HER2 status and clinicopathological tumor features. RESULTS: High Menacalc was associated with increased risk of death from any cause (P=0.0199, HR (CI)=2.18 (1.19, 4.00)). A similarly elevated risk of death was found in the subset of the Menacalc cohort which did not receive hormone or chemotherapy (n=142) (P=0.0052, HR (CI)=3.80 (1.58, 9.97)). There was a trend toward increased risk of death with relatively high Menacalc in the HER2, basal and luminal molecular subtypes. CONCLUSIONS: Menacalc may serve as an independent prognostic biomarker for the ANN breast cancer patient population.

Elevated expression of podocalyxin is associated with lymphatic invasion, basal-like phenotype, and clinical outcome in axillary lymph node-negative breast cancer.

Lymphatic invasion (LVI) is associated with disease recurrence in axillary node-negative (ANN) breast cancer. Using gene expression profiling of 105 ANN tumors, we found that podocalyxin (PODXL) was more highly expressed in tumors with LVI (LVI+) than in those without LVI (LVI-). Differences in PODXL expression were validated using real-time polymerase chain reaction as well as by immunohistochemistry in an independent set of 652 tumors on tissue microarrays. Disease-free survival (DFS) analyses were conducted for association of high PODXL protein expression with risk of distant recurrence overall and within breast cancer subtypes using both Cox and cure-rate models. High PODXL expression was associated with poor prognosis features including large tumor size, high histological grade, estrogen and progesterone receptor negativity, and with clinical alterations characteristic of the basal-like breast cancer phenotype. Surprisingly, despite having other poor prognosis characteristics, women with high PODXL expressing tumors had better long-term DFS in multivariate analysis with traditional clinicopathologic factors including LVI and HER2 status (P = 0.001). PODXL has the potential to be a useful biomarker for identifying good prognosis patients in characteristically poor prognosis breast cancer groups and may impact treatment of women with this disease.

Negative Impact of COVID-19 Associated Health System Shutdown on Patients Diagnosed With Colorectal Cancer: A Retrospective Study From a Large Tertiary Center in Ontario, Canada.

Background: In March 2020, a directive to halt all elective and non-urgent procedures was issued in Ontario, Canada because of COVID-19. The directive caused a temporary slowdown of screening programs including surveillance colonoscopies for colorectal cancer (CRC). Our goal was to determine if there was a difference in patient and tumour characteristics between CRC patients treated surgically prior to the COVID-19 directive compared to CRC patients treated after the slowdown. Methods: CRC resections collected within the Champlain catchment area of eastern Ontario in the 6 months prior to COVID-19 (August 1, 2019-January 31, 2020) were compared to CRC resections collected in the 6 months post-COVID-19 slowdown (August 1, 2020-January 31, 2021). Clinical (e.g., gender, patient age, tumour site, and clinical presentation) and pathological (tumour size, tumour stage, nodal stage, and lymphovascular invasion) features were evaluated using chi-square tests, T-tests, and Mann-Whitney tests where appropriate. Results: Three hundred and thirty-eight CRC specimens were identified (173 pre-COVID-19, 165 post-COVID-19 slowdown). CRC patients treated surgically post-COVID-19 slowdown had larger tumours (44 mm vs. 35 mm; P = 0.0048) and were more likely to have presented emergently (24% vs. 10%; P < 0.001). Although there was a trend towards higher tumour stage, nodal stage, and clinical stage, these differences did not reach statistical significance. Other demographic and pathologic variables including patient gender, age, and tumour site were similar between the two cohorts. Interpretation: The COVID-19 slowdown resulted in a shift in the severity of disease experienced by CRC patients in Ontario. Pandemic planning in the future should consider the long-term consequences to cancer diagnosis and management.

Diagnostic and surgical dilemma of cholecystitis that mimics cancer - A case report of xanthogranulomatous cholecystitis.

INTRODUCTION: Xanthogranulomatous cholecystitis (XGC) is a rare and benign chronic inflammatory disease of the gallbladder that can mimic carcinoma on presentation, imaging, and gross pathology. The aim of this case report is to describe the considerations involved in navigating the diagnostic and surgical dilemma of managing XGC in a patient with findings equivocal to gallbladder cancer. PRESENTATION OF CASE: A 64-year-old female patient presented with an incidental, suspicious gallbladder mass on imaging. Due to her asymptomatic presentation and high risk features for carcinoma on imaging, an oncologic, en-bloc resection of the mass involving the gallbladder, liver, wall of duodenum, and hepatic flexure of the colon was performed. On pathological examination, the gallbladder specimen showed marked lymphohistiocytic inflammatory infiltrate of XGC that extended into adjacent structures without dysplasia. The patient had an uncomplicated postoperative course. DISCUSSION: Considerations around management of XGC must include the potential consequences associated with overtreating a benign entity or undertreating a potentially curable malignancy. Imaging findings that may be more suggestive of XGC include continuous mucosal lines and the presence of pericholecystic infiltration or fat stranding. Pitfalls of biopsy include potential tumour spillage and false negative results, especially when both XGC and cancer are present. Intraoperatively, macroscopic examination of the mass can also be misleading. CONCLUSION: Surgeons must ensure that preoperative counselling includes the possibility of both XGC and gallbladder carcinoma, especially when findings are uncharacteristic. XGC must be managed with careful consideration of all findings and multidisciplinary input from a team of surgeons, radiologists, and pathologists.

Concurrent Adult-Onset Diffuse ß-Cell Nesidioblastosis and Pancreatic Neuroendocrine Tumor: A Case Report and Review of the Literature.

Nesidioblastosis is an uncommon cause of organic persistent hyperinsulinemic hypoglycemia in adults. We report a case of adult-onset diffuse ß-cell nesidioblastosis in a 49-year-old woman who was status-post Roux-en-Y gastric bypass and distal pancreatectomy for a well-differentiated pancreatic neuroendocrine tumor. While the neuroendocrine tumor was suspected to be an insulinoma, persistent hypoglycemia postoperatively suggested either incomplete resection or a second pancreatic neoplasm. Completion pancreatectomy revealed islet ß-cell hyperplasia and nuclear pleomorphism consistent with ß-cell nesidioblastosis. The patient's blood glucose levels normalized after completion pancreatectomy. While ß-cell nesidioblastosis and insulinomas can coexist in the same patient, pathologists should be aware of ß-cell nesidioblastosis as a potential cause for hyperinsulinemic hypoglycemia and should exclude it in patients who have not shown definitive clinical response after surgical excision of a pancreatic neuroendocrine tumor.

Fresh Cut Versus Stored Cut Paraffin-embedded Tissue: Effect on Immunohistochemical Staining for Common Breast Cancer Markers.

The proper handling of unstained paraffin slides for immunohistochemistry has been a matter of debate, with several studies demonstrating loss of antigenicity with prolonged storage at room temperature, 4°C and -20°C. The purpose of this study was to determine whether long-term storage of unstained slides at -80°C would impact the staining intensity and expression distribution of markers used to molecularly subtype breast cancer specimens [estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), cytokeratin 5 (CK5), epidermal growth factor receptor (EGFR), and Ki67]. The staining pattern of previously unstained breast tumor slides (n=39 to 64) stored at -80°C for a minimum of 9.93 years (avg., 12.8 y) was compared with the staining pattern of fresh cut slides from the same tumors. The Allred scoring method was used to score ER (0 to 2, negative; 3 to 8, positive), CK5 (≥4, positive), and EGFR (≥4, positive). ASCO/CAP guidelines were used to assess HER2 (0/1+, 2+, or 3+). Ki67 scores were determined based on the proportion of cells stained of any intensity, with 20% staining used as a cut-off. Agreement was assessed using concordance rates and chance-corrected agreement statistics. The chance-corrected agreements were as follows: 0.94 (38/39) for ER, 0.92 (53/55) for CK5, 0.87 (61/64) for EGFR, 0.86 (37/39) for HER2, and 0.67 (46/54) for Ki67. Long-term storage of cut unstained slides at -80°C does not significantly impact the scoring interpretation of ER, CK5, EGFR, and HER2.

Rice body formation without rheumatic disease or tuberculosis infection: a case report and literature review.

Rice body formation is an uncommon inflammatory disorder associated with systemic disorders such as rheumatoid arthritis and tuberculosis infection. The pathophysiology of rice bodies is poorly understood. We describe a case of rice body formation in a 51-year-old male who presented with pain and swelling of the left wrist. The patient had no previous history of rheumatic disease, joint trauma, or infectious disease. He underwent a radical tenosynovectomy and had immediate improvement of symptoms. Despite extensive evaluation, the etiology of the rice bodies could not be identified. An increasing number of case reports have described rice body formation without a known cause suggesting an alternative, unidentified method of pathogenesis. We describe a unique case of rice body formation and a review of the literature with emphasis on theories of pathogenesis, diagnostic methods, and treatment.

The essential role of insulin-like growth factor-1 in the intestinal tropic effects of glucagon-like peptide-2 in mice.

BACKGROUND & AIMS: Glucagon-like peptide-2 (GLP-2) is an intestinal hormone that acts through unknown pathways to induce intestinal growth. We investigated the role of the insulin-like growth factors (IGF-1 and IGF-2) as mediators of GLP-2-enhanced growth in the murine intestine. METHODS: IGF-1 expression and secretion were determined in GLP-2-responsive primary intestinal cultures treated with GLP-2. Parameters of intestinal growth were assessed in wild-type (CD1, Igf1(+/+) and Igf2+), heterozygous (Igf1(+/-)), and null (Igf1(-/-) and Igf2(-P)) mice treated chronically with saline, GLP-2, IGF-1, or R-Spondin1. RESULTS: GLP-2 increased IGF-1 messenger RNA expression and IGF-1 secretion in intestinal cultures and increased expression of IGF-1 messenger RNA in mouse small intestine in vivo. Igf1(+/+) and Igf2+ mice responded to .1 microg/g(-1) per day(-1) GLP-2 with increased intestinal weights, morphometric parameters, and proliferative indices. In contrast, Igf1(-/-) mice were unresponsive to the same dose of GLP-2, failing to demonstrate changes in intestinal weight, morphometry, or proliferation. However, a significant effect of 1 microg/g(-1) per day(-1) GLP-2 was observed in Igf1(-/-) mice, but only in terms of small intestinal weight when normalized for body weight. Furthermore, Igf2(-P) mice demonstrated a partially impaired response in terms of small intestinal growth. Both Igf1(-/-) and Igf2(-P) mice exhibited normal-enhanced intestinal growth in response to IGF-1 and/or R-Spondin1. CONCLUSIONS: GLP-2 enhances intestinal IGF-1 expression and secretion, and IGF-1 is required for small and large intestinal growth in response to GLP-2. These findings identify IGF-1 as an essential mediator of the intestinotropic actions of GLP-2.