The majority of patients with acute promyelocytic leukemia (APL) manifest the t(15;17)(q24.1;q21.2) translocation; however, a minor but significant proportion of patients with APL harbor complex, cryptic, or variant translocations, which typically involve RARA. With the exception of ZBTB16/RARA, these variants have similar morphologic and immunophenotypic features as classic APL. Study of the variant forms of APL not only gives insight into the pathogenesis of APL but also allows us to understand the mechanism of retinoid therapy. It is important to identify these cryptic and variant translocations because certain variants, including ZBTB16/RARA and STAT5B/RARA, are resistant to treatment with all-trans retinoic acid, arsenic trioxide, and anthracyclines. A cute promyelocytic leukemia (APL), comprising 5% to 8% of cases of acute myeloid leukemia (AML), is one of the best studied and understood hematopoietic malignancies. Unlike other forms of AML, APL is unique in that it can cause coagulopathy and death if not readily diagnosed.1,2 Morphologically classified as AML-M3 by the French-American-British (FAB) classification, APL is typically characterized by neoplastic proliferation of cells in the bone marrow with a promyelocytic phenotype and the balanced reciprocal translocation t(15;17) (q24.1;q21.2), which results in the expression of the promyelocytic leukemia (PML)-retinoic acid receptor-a (RARA) fusion protein.
Lymph node metastasis in patients with prostate cancer indicates a poorer prognosis compared with patients without lymph node metastasis; however, some patients with node-positive disease have long-term survival. Many studies have attempted to discern what characteristics of lymph node metastasis are prognostically significant. These characteristics include nodal tumor volume, number of positive lymph nodes, lymph node density, extranodal extension, lymphovascular invasion and tumor dedifferentiation. Favorable characteristics of regional lymph node involvement included a smaller tumor size and smaller tumor volume. However, the current staging system for prostate cancer does not provide different subclassifications for patients with node-positive prostate cancer. In recent years numerous advanced technologies for the detection of lymph node metastasis have been developed, including molecular imaging techniques and the CellSearch Circulating Tumor Cell System. With the increased detection of patients with prostate cancer, emergence of new technology to identify lymph node metastasis and the number of radical prostatectomies being performed on the rise, subclassifying patients with lymph node-positive disease is imperative. Subclassification would provide a better picture of patient prognosis and allow for a better understanding of targeted therapies to treat patients with lymph node metastasis.
Background: With the emergence of improved treatment strategies for patients with malignant lung tumors, it has become increasingly important to adequately diagnose and subclassify lung lesions. In our large retrospective study, we assessed the utility of fine-needle aspiration (FNA) in the diagnosis of primary and metastatic tumors to the lung. Methods: A computerized search of our laboratory informatics system was performed to identify cases from FNA of the lung and FNA of metastatic lung cancers to other sites. All of the corresponding surgical pathology reports were also reviewed. All of the cases were categorized as atypical (A), benign (B), malignant (M), nondiagnostic (ND), or suspicious (S) for data analysis purposes. Results: A total of 1,032 FNA cases were categorized as follows: 34 (3.3%) A, 142 (13.8%) B, 717 (69.5%) M, 121 (11.7%) ND, and 18 (1.7%) S. Of the 717 cases of malignant FNA, a specific tumor type was able to be rendered on cytomorphology alone or with the help of immunostains in 99% as follows: adenocarcinoma (296 cases, 41%), squamous cell carcinoma (158 cases, 22%), metastatic tumors (123 cases, 17%), small cell carcinoma (56 cases, 8%), non-small cell lung carcinoma (NSCLC) (58 cases, 8%), neuroendocrine carcinoma (15 cases, 2%), and poorly differentiated carcinoma (4 cases, 1%). Out of all NSCLC cases, 89% were able to be subclassified as either adenocarcinoma or squamous carcinoma. The most frequent origins of metastatic tumors to the lung were renal cell carcinoma (n = 22), melanoma (n = 17), colon (n = 15), breast (n = 14), and urothelial carcinoma (n = 10). There was also metastasis from 18 other organs with fewer than 5 cases each. There were 333 correlated histologic specimens including 191 small biopsies and 142 resection specimens. Diagnostic sensitivity and specificity for malignancy were 96 and 100%, respectively. Diagnostic accuracy was 97%. Sampling error resulted in 8 false-negative cases on FNA. Conclusions: FNA is both sensitive and specific in the diagnosis and subclassification of both primary and metastatic lung tumors. Eighty-nine percent of NSCLC cases were able to be further subclassified as adenocarcinoma or squamous cell carcinoma by FNA.
The tumor specificity of JAA-F11, a novel monoclonal antibody specific for the Thomsen-Friedenreich cancer antigen (TF-Ag-alpha linked), has been comprehensively studied by in vitro immunohistochemical (IHC) staining of human tumor and normal tissue microarrays and in vivo biodistribution and imaging by micro-positron emission tomography imaging in breast and lung tumor models in mice. The IHC analysis detailed herein is the comprehensive biological analysis of the tumor specificity of JAA-F11 antibody performed as JAA-F11 is progressing towards preclinical safety testing and clinical trials. Wide tumor reactivity of JAA-F11, relative to the matched mouse IgG3 (control), was observed in 85% of 1269 cases of breast, lung, prostate, colon, bladder, and ovarian cancer. Staining on tissues from breast cancer cases was similar regardless of hormonal or Her2 status, and this is particularly important in finding a target on the currently untargetable triple-negative breast cancer subtype. Humanization of JAA-F11 was recently carried out as explained in a companion paper “Humanization of JAA-F11, a Highly Specific Anti–Thomsen-Friedenreich Pancarcinoma Antibody and In Vitro Efficacy Analysis” (Neoplasia 19: 716-733, 2017), and it was confirmed that humanization did not affect chemical specificity. IHC studies with humanized JAA-F11 showed similar binding to human breast tumor tissues. In vivo imaging and biodistribution studies in a mouse syngeneic breast cancer model and in a mouse-human xenograft lung cancer model with humanized 124I- JAA-F11 construct confirmed in vitro tumor reactivity and specificity. In conclusion, the tumor reactivity of JAA-F11 supports the continued development of JAA-F11 as a targeted cancer therapeutic for multiple cancers, including those with unmet need.
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