Impact of the updated 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines on Human Epidermal Growth Factor Receptor 2 (HER2) gene testing in invasive breast cancers: A single center study

The study aimed to evaluate the impact of the updated 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines on Human Epidermal Growth Factor Receptor 2 (HER2) testing in invasive breast cancer compared with previous 2013 guidelines. Between Jan 2014 and May 2020, 3364 consecutive invasive breast carcinomas with concurrent HER2 immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) results were retrospectively reviewed for HER2 status. Both 2013 and 2018 testing criteria were applied to establish the HER2 status. The testing algorithms involved testing of invasive breast carcinomas by IHC, with equivocal results being reflexed to FISH assays. Concordance rate improved from 92.7% to 94.1% in the non-equivocal IHC cases with the 2018 guidelines. Comparing 2013 versus 2018 criteria, HER2 non-amplified cases increased significantly from 73.7% (n = 2478) to 76.8% (n = 2585), HER2 amplified cases remained similar from 23.4% (n = 789) to 23.2% (n = 779) while equivocal cases decreased from 2.9% (n = 97) to 0% with the new guidelines. Thus, 107 cases (3.2%) were reclassified from HER2 equivocal (n = 97) and amplified (n = 10) to non-amplified with the updated 2018 guidelines. Under the 2018 criteria, a total of 259 cases (7.7%) belonged to the uncommon categories (groups 2 to 4), with group 3 being the most frequent (4.6%), followed by group 4 (2.9%) and group 2 (0.2%). Implementation of 2018 guidelines resulted in a significant increase in HER2 non-amplified cases, mainly due to the abolishment of the equivocal FISH group. This has helped resolve the clinical practice dilemma by providing a more definitive HER2 gene status.     

Increased LDL electronegativity in chronic kidney disease disrupts calcium homeostasis resulting in cardiac dysfunction

Chronic kidney disease (CKD), an independent risk factor for cardiovascular disease, is associated with abnormal lipoprotein metabolism. We examined whether electronegative low-density lipoprotein (LDL) is mechanistically linked to cardiac dysfunction in patients with early CKD. We compared echocardiographic parameters between patients with stage 2 CKD (n = 88) and normal controls (n = 89) and found that impaired relaxation was more common in CKD patients. Reduction in estimated glomerular filtration rate was an independent predictor of left ventricular relaxation dysfunction. We then examined cardiac function in a rat model of early CKD induced by unilateral nephrectomy (UNx) by analyzing pressure–volume loop data. The time constant of isovolumic pressure decay was longer and the maximal velocity of pressure fall was slower in UNx rats than in controls. When we investigated the mechanisms underlying relaxation dysfunction, we found that LDL from CKD patients and UNx rats was more electronegative than LDL from their respective controls and that LDL from UNx rats induced intracellular calcium overload in H9c2 cardiomyocytes in vitro. Furthermore, chronic administration of electronegative LDL, which signals through lectin-like oxidized LDL receptor-1 (LOX-1), induced relaxation dysfunction in wild-type but not LOX-1^−/− mice. In in vitro and in vivo experiments, impaired cardiac relaxation was associated with increased calcium transient resulting from nitric oxide (NO)-dependent nitrosylation of SERCA2a due to increases in inducible NO synthase expression and endothelial NO synthase uncoupling. In conclusion, LDL becomes more electronegative in early CKD. This change disrupts SERCA2a-regulated calcium homeostasis, which may be the mechanism underlying cardiorenal syndrome.     

Renal Dysfunction is the Strongest Prognostic Factor After Carotid Artery Stenting According to Real-World Data

PurposeThrough the progression of devices, the adaptation of carotid artery stenting (CAS) has been expanded according to the non-inferiority of CAS for carotid endarterectomy reported by several randomized control trials. To maintain favorable outcomes, identifying prognostic factors is essential for optimizing treatment indications and periprocedural management. This study focused on the prognostic factors of CAS using real-world data.MethodsThis retrospective multicenter cohort study aimed to identify the prognostic factors after CAS using real-world data from the stroke registry of Yokohama (STrOke Registry of Yokohama; STORY) from January 1, 2018 to May 31, 2021. Patient characteristics, procedural factors, complications, and prognoses were collected using medical records.ResultsData from 107 patients were enrolled in this study after excluding those with insufficient data (2 cases). The mean participant age was 74.9±8.2 years, and 66 patients (61.7%) were symptomatic. Symptomatic lesions were a significant prognostic factor in the overall analysis (p=0.003). A multivariate analysis showed that the estimated glomerular filtration rate (eGFR) (odds ratio: 1.11, p=0.003) and staged CAS (odds ratio: 38.9, p=0.04) were independent prognostic factors. The odds ratio and relative risk of mRS deterioration when eGFR was under 49 mL/min/1.73 m² compared with when eGFR was above 49 mL/min/1.73 m² were 5.2 and 3.74, respectively.ConclusionsIn this real-world multicenter study, we established independent prognostic factors for CAS using high totality data. For patients with symptomatic lesions and low eGFR (≤49 mL/min/1.73 m²), indication for treatment should be considered strictly.     

Clinicopathological aspects of therapy-related acute myeloid leukemia and myelodysplastic syndrome

Therapy-related myeloid neoplasm (t-MN) is a rare but devastating consequence of chemotherapy and/or radiotherapy used for the treatment of solid cancers and various hematologic malignancies. Our current understanding of the etiology is that hematopoietic clones that are contemporaneous with the primary cancer and resistant to the cytotoxic exposure have the potential to undergo selective expansion and transformation to t-MN. Consequently, a large proportion of cases are associated with adverse risk factors, resulting in limited effective treatment options. Despite the emergence of some therapies with promising activity in t-MN, most effects are short-lived and allogeneic stem cell transplantation remains the only curative option for eligible patients. This review summarizes the current literature on t-AML and t-MDS, with the aim of providing practical recommendations on the clinical evaluation and management of these conditions.     

From the archives of MD Anderson Cancer Center: Intravascular large B-cell lymphoma with numerous circulating lymphoma cells

Intravascular large B-cell lymphoma (IVLBCL) is a rare, clinically aggressive form of large B-cell lymphoma that is preferentially located within blood vessel lumina. Despite its intravascular location, a leukemic phase of disease seems to be uncommon. After encountering a patient with IVLBCL with numerous circulating lymphoma cells, we reviewed the literature and identified 6 patients with IVLBCL who had numerous circulating lymphoma cells (defined by ≥10% lymphoma cells in peripheral blood). The percentage of circulating lymphoma cells in this patient cohort was variable, with a median of 36% (range, 14% - 87%), Bone marrow was involved in all 5 patients assessed. Elevation of liver transaminases preferentially affecting aspartate aminotransferase (AST, 3/3, 100%), hepatosplenomegaly (4/5, 80%), thrombocytopenia (100%), CD5 positivity (100%) and monotypic lambda light chain predominance (3/4, 75%) were common features. Conventional cytogenetic analysis performed in 4 patients revealed a complex karyotype with multiple abnormalities particularly deletions and copy number aberrations involving chromosomes 6q and 18. The clinical courses of these patients were highly variable, but overall there was a high mortality rate of 75% with 18-months of follow-up. Due to the rarity of IVLBCL, along with its variable clinical manifestations and subtle pathologic changes, the diagnosis is often delayed which may contribute to the poor outcome of IVLBCL patients. Recognition that this disease can present rarely with a leukemic phase further expands our knowledge of the clinicopathologic spectrum of IVLBC.     

A DNA vaccine expressing an optimized secreted FAPα induces enhanced anti-tumor activity by altering the tumor microenvironment in a murine model of breast cancer

Cancer-associated fibroblasts (CAFs), major components of the tumor microenvironment (TME), promote tumor growth and metastasis and inhibit the anti-tumor immune response. We previously constructed a DNA vaccine expressing human FAPα, which is highly expressed by CAFs, to target these cells in the TME, and observed limited anti-tumor effects in the 4T1 breast cancer model. When the treatment time was delayed until tumor nodes formed, the anti-tumor effect of the vaccine completely disappeared. In this study, to improve the safety and efficacy, we constructed a new FAPα-targeted vaccine containing only the extracellular domain of human FAPα with a tissue plasminogen activator signal sequence for enhanced antigen secretion and immunogenicity. The number of CAFs was more effectively reduced by CD8⁺ T cells induced by the new vaccine. This resulted in decreases in CCL2 and CXCL12 expression, leading to a significant decrease in the ratio of myeloid-derived suppressor cells in the TME. Moreover, when mice were treated after the establishment of tumors, the vaccine could still delay tumor growth. To facilitate the future application of the vaccine in clinical trials, we further optimized the gene codons and reduced the homology between the vaccine and the original sequence, which may be convenient for evaluating the vaccine distribution in the human body. These results indicated that the new FAPα-targeted vaccine expressing an optimized secreted human FAPα induced enhanced anti-tumor activity by reducing the number of FAPα⁺ CAFs and enhancing the recruitment of effector T cells in the 4T1 tumor model mice.