Spontaneous Regression of Primary Cutaneous Diffuse Large B-Cell Lymphoma on Sequential FDG PET.

ABSTRACT: Primary cutaneous diffuse large B-cell lymphoma, leg type is a rare, aggressive lymphoma characterized by skin involvement predominantly in the lower extremities. We present a case of an elderly woman with pathology diagnosis of primary cutaneous diffuse large B-cell lymphoma, leg type with spontaneous regression without systematic therapy documented by sequential FDG PET scans and clinical follow-up.

SOCS1 Deficiency Promotes Hepatocellular Carcinoma via SOCS3-Dependent CDKN1A Induction and NRF2 Activation.

SOCS1 deficiency, which increases susceptibility to hepatocellular carcinoma (HCC), promotes CDKN1A expression in the liver. High CDKN1A expression correlates with disease severity in many cancers. Here, we demonstrate a crucial pathogenic role of CDKN1A in diethyl nitrosamine (DEN)-induced HCC in SOCS1-deficient mice. Mechanistic studies on DEN-induced genotoxic response revealed that SOCS1-deficient hepatocytes upregulate SOCS3 expression, SOCS3 promotes p53 activation, and Cdkn1a induction that were abolished by deleting either Socs3 or Tp53. Previous reports implicate CDKN1A in promoting oxidative stress response mediated by NRF2, which is required for DEN-induced hepatocarcinogenesis. We show increased induction of NRF2 and its target genes in SOCS1-deficient livers following DEN treatment that was abrogated by the deletion of either Cdkn1a or Socs3. Loss of SOCS3 in SOCS1-deficient mice reduced the growth of DEN-induced HCC without affecting tumor incidence. In the TCGA-LIHC dataset, the SOCS1-low/SOCS3-high subgroup displayed increased CDKN1A expression, enrichment of NRF2 transcriptional signature, faster disease progression, and poor prognosis. Overall, our findings show that SOCS1 deficiency in hepatocytes promotes compensatory SOCS3 expression, p53 activation, CDKN1A induction, and NRF2 activation, which can facilitate cellular adaptation to oxidative stress and promote neoplastic growth. Thus, the NRF2 pathway represents a potential therapeutic target in SOCS1-low/SOCS3-high HCC cases.

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.

Impact of Reflex Testing for BRAF Mutational Status in Advanced Melanoma.

CONTEXT.­: The use of targeted therapy in patients with advanced, BRAF-mutated melanomas has necessitated timely access to BRAF mutational status in order for clinicians to proceed with treatment decisions. OBJECTIVE.­: To assess the impact of pathologist-initiated reflex BRAF testing in patients with advanced melanoma on laboratory turnaround time and time to systemic treatment. DESIGN.­: At our tertiary care center and 3 affiliated community hospitals, we implemented a guideline for pathologist-initiated reflex testing for BRAF mutational status in patients diagnosed with melanoma and positive lymph nodes or new diagnosis of a metastatic site. Retrospective review was performed for 65 cases of advanced melanoma for which BRAF testing was ordered, during a period inclusive of 6 months before and after guideline implementation. RESULTS.­: Implementation of reflex testing guidelines did not significantly affect the overall number of BRAF tests ordered for patients with melanoma. In cases with reflex testing compared to routine testing, total turnaround time was reduced by from 52.5 ± 5.6 to 18.6 ± 1.0 days (P < .001). In patients who received systemic therapy, without intentional delay by interval completion lymph node dissection (CLND), the use of reflex BRAF testing reduced time to systematic treatment from 71.7 ± 11.4 to 37.7 ± 4.6 days (P = .02). Time to systematic treatment was unchanged in those who underwent interval CLND (118.9 ± 10.9 versus 110.5 ± 22.5; P = .75). CONCLUSIONS.­: These data support a recommendation for pathologist-initiated reflex testing of BRAF mutational status in advanced melanoma as a standard practice in pathology laboratories.

Hypergammaglobulinemic purpura of Waldenström-Unusual and impressive case in a patient with myeloma: A case report.

Background: Hypergammaglobulinemic purpura of Waldenström is an uncommon disease, which presents mostly in women on the lower extremities. It is sometimes associated with underlying immune dysregulation. Sjögren syndrome is the most common association; however, rare occurrences of the self-resolving syndrome with lymphoma or myeloma have been reported. Case Summary: We describe an unusual and impressive presentation of hypergammaglobulinemic purpura of Waldenström in an elderly female patient with myeloma. Notably, the patient did not have any concurrent connective tissue diseases. Despite her florid presentation, her hypergammaglobulinemic purpura of Waldenström spontaneously resolved within a few days. Conclusion: Hypergammaglobulinemic purpura of Waldenström is a self-resolving but recurrent syndrome, which may be associated with autoimmune disorders or rarely myeloma. Early diagnosis of the syndrome may avoid unnecessary treatment interventions and should prompt screening for underlying diseases.

Selecting Patients for Oncotype DX Testing Using Standard Clinicopathologic Information.

INTRODUCTION: Indiscriminate ordering of Oncotype DX (ODX) is expensive and of poor value to patients, physicians, and health care providers. The 3 Magee equations, Gage Algorithm, and University of Tennessee predictive algorithm all use standard clinicopathologic data to provide surrogate ODX scores. In this hypothesis-generating study, we evaluated whether these prognostic scores could be used to identify patients unlikely to benefit from additional ODX testing. PATIENTS AND METHODS: Retrospective data was collected from 302 patients with invasive ductal breast cancer and available ODX scores. Additional data was available for: Magee equations 1 (212 patients), 2 (299 patients), 3 (212 patients), Gage Algorithm (299 patients), and University of Tennessee predictive algorithm (286 patients). ODX scores were banded according to the TAILORx results. RESULTS: Correlation with ODX scores was between 0.7 and 0.8 (Gage), 0.8 and 0.9 (Magee 2, University of Tennessee predictive algorithm), and > 0.9 (Magee 1 and 3). Magee 3 was the most robust and is proposed as a screening tool: for patients aged ≤ 50 years, ODX testing would be not required if the Magee 3 score was < 14 or ≥ 20; for those aged > 50 years, ODX would not be required if the Magee 3 score was < 18 or ≥ 26. Using these cut-offs, 110 (51.9%) of 212 patients would be deemed as not requiring ODX testing, and 109 (99.1%) of110 patients would be appropriately managed. CONCLUSIONS: Use of all formulae, and the Magee 3 equation in particular, are proposed as possible screening tools for ODX testing, resulting in significantly reduced frequency of ODX testing. This requires validation in other populations.

Met induces mammary tumors with diverse histologies and is associated with poor outcome and human basal breast cancer.

Elevated MET receptor tyrosine kinase correlates with poor outcome in breast cancer, yet the reasons for this are poorly understood. We thus generated a transgenic mouse model targeting expression of an oncogenic Met receptor (Met(mt)) to the mammary epithelium. We show that Met(mt) induces mammary tumors with multiple phenotypes. These reflect tumor subtypes with gene expression and immunostaining profiles sharing similarities to human basal and luminal breast cancers. Within the basal subtype, Met(mt) induces tumors with signatures of WNT and epithelial to mesenchymal transition (EMT). Among human breast cancers, MET is primarily elevated in basal and ERBB2-positive subtypes with poor prognosis, and we show that MET, together with EMT marker, SNAIL, are highly predictive of poor prognosis in lymph node-negative patients. By generating a unique mouse model in which the Met receptor tyrosine kinase is expressed in the mammary epithelium, along with the examination of MET expression in human breast cancer, we have established a specific link between MET and basal breast cancer. This work identifies basal breast cancers and, additionally, poor-outcome breast cancers, as those that may benefit from anti-MET receptor therapies.

HGF converts ErbB2/Neu epithelial morphogenesis to cell invasion.

Activation of the hepatocyte growth factor receptor Met induces a morphogenic response and stimulates the formation of branching tubules by Madin-Darby canine kidney (MDCK) epithelial cells in three-dimensional cultures. A constitutively activated ErbB2/Neu receptor, NeuNT, promotes a similar invasive morphogenic program in MDCK cells. Because both receptors are expressed in breast epithelia, are associated with poor prognosis, and hepatocyte growth factor (HGF) is expressed in stroma, we examined the consequence of cooperation between these signals. We show that HGF disrupts NeuNT-induced epithelial morphogenesis, stimulating the breakdown of cell-cell junctions, dispersal, and invasion of single cells. This correlates with a decrease in junctional proteins claudin-1 and E-cadherin, in addition to the internalization of the tight junction protein ZO-1. HGF-induced invasion of NT-expressing cells is abrogated by pretreatment with a pharmacological inhibitor of the mitogen-activated protein kinase kinase (MEK) pathway, which restores E-cadherin and ZO-1 at cell-cell junctions, establishing the involvement of MEK-dependent pathways in this process. These results demonstrate that physiological signals downstream from the HGF/Met receptor synergize with ErbB2/Neu to enhance the malignant phenotype, promoting the breakdown of cell-cell junctions and enhanced cell invasion. This is particularly important for cancers where ErbB2/Neu is overexpressed and HGF is a physiological growth factor found in the stroma.