Emilian Racila

CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy.

The CD19 antigen plays an important role in clinical oncology. In normal cells, it is the most ubiquitously expressed protein in the B lymphocyte lineage. CD19 expression is induced at the point of B lineage commitment during the differentiation of the hematopoietic stem cell, and its expression continues through preB and mature B cell differentiation until it is finally down-regulated during terminal differentiation into plasma cells. CD19 expression is maintained in B-lineage cells that have undergone neoplastic transformation, and therefore CD19 is useful in diagnosis of leukemias and lymphomas using monoclonal antibodies (mAbs) and flow cytometry. Interestingly, CD19 is also expressed in a subset of acute myelogenous leukemias (AMLs) indicating the close relationship between the lymphoid and myeloid lineages. Because B lineage leukemias and lymphomas rarely lose CD19 expression, and because it is not expressed in the pluripotent stem cell, it has become the target for a variety of immunotherapeutic agents, including immunotoxins. Treatment of non-Hodgkins lymphoma (NHL) and acute lymphocytic leukemia (ALL) with anti-CD19 mAbs coupled to biological toxins has proven to be effective in vitro and in animal models, and has shown some promising results in Phase I clinical trials. Recently, the analysis of anti-CD19 effects on lymphoma cell growth has highlighted a novel mechanism of immunotherapy. Engagement of cell surface receptors like CD19 by mAbs can have anti-tumor effects by the activation of signal transduction pathways which control cell cycle progression and programmed cell death (apoptosis).

A polymorphism in the complement component C1qA correlates with prolonged response following rituximab therapy of follicular lymphoma.

Purpose: Complement may play a role in the clinical response to rituximab and other monoclonal antibody–based therapies of cancer. The purpose of this study was to explore the relationship between the C1qA[276] polymorphism and the clinical response to rituximab in patients with follicular lymphoma. Experimental Design: Genotyping for C1qA[276A/G] was done in 133 subjects with follicular lymphoma treated with single-agent rituximab, and correlation with clinical response was done using Cox regression analysis. Results: Prolonged remission was observed among subjects that responded clinically to rituximab therapy and were carriers of the A allele compared with homozygous G subjects. Homozygous G subjects had a time to progression of 282 days, whereas A-allele carriers had a time to progression of 708 days [hazard ratio, (HR), 2.5; 95% confidence interval (95% CI), 2.0-3.1; P = 0.02]. Among subjects who achieved complete remission, homozygous G subjects had a time to progression of 250 days, whereas A-allele carriers had a time to progression of 1,118 days (HR, 4.5; 95% CI, 4.1-4.8, P = 0.04). The difference persisted after controlling for CD32 and CD16 polymorphisms. In patients who responded to rituximab used as first-line agent, a linear trend was observed among the C1qA[276] genotypes, with homozygous A subjects achieving complete response at a higher rate compared with heterozygous or homozygous G subjects. Conclusions: Our findings indicate that polymorphisms in the C1qA gene may affect the clinical response and duration of response to rituximab therapy of follicular lymphoma. These results could have direct implications on designing antibodies with improved efficiency and enhance our understanding of the role of complement in monoclonal antibody therapy.

Depletion of the C3 component of complement enhances the ability of rituximab-coated target cells to activate human NK cells and improves the efficacy of monoclonal antibody therapy in an in vivo model

Growing evidence indicates antibody-dependent cellular cytotoxicity (ADCC) contributes to the clinical response to monoclonal antibody (mAb) therapy of lymphoma. Recent in vitro analysis suggests C3b can inhibit mAb-induced natural killer (NK)-cell activation and ADCC. Further studies were conducted to assess the effect of C3 depletion on mAb-induced NK activation and therapy of lymphoma. Normal human serum inhibited the ability of rituximab-coated lymphoma cells to activate NK cells as previously reported. Serum did not inhibit NK-cell activation when it was preincubated with cobra venom factor (CVF) to deplete C3. Similar results were found when transudative pleural fluid or nonmalignant ascites was used as surrogates for extravascular fluid, suggesting the inhibitory effect of complement may be present in the extravascular compartment, in which many malignant lymphocytes reside. In vivo, C3 was depleted before mAb treatment in a syngeneic murine model of lymphoma. Survival of lymphoma-bearing mice after treatment with CVF plus mAb and with a human C3 derivative with CVF-like functions (HC3-1496) plus mAb was both superior to that of mAb alone. These studies show that complement depletion enhances NK-cell activation induced by rituximab-coated target cells and improves the efficacy of mAb therapy in a murine lymphoma model.

Homozygous single nucleotide polymorphism of the complement C1QA gene is associated with decreased levels of C1q in patients with subacute cutaneous lupus erythematosus

We report an association between a non-familial form of photosensitive Lupus-specific skin disease, subacute cutaneous lupus erythematosus (SCLE), and a new single nucleotide polymorphism (SNP) in the C1QA gene. We also describe an association between this SNP and lower levels of serum C1q. This SNP consists of adenine replacing the third guanine in the codon for amino acid residue Gly70 (position excludes the 22 amino acid leading peptide) that is located in the second exon of the C1QA gene. We have designated this SNP C1qA - Gly70GGA (the GenBank sequence at this location is C1qA - Gly70GGG). A survey of 19 SCLE patients showed that 11 (58%) were homozygous for C1qA - Gly70GGA SNP, seven (37%) were heterozygous, and only one patient (5%) was homozygous for the GenBank sequence. In contrast, only 13 of 62 (21%) normal controls were homozygous for the C1qA - Gly70GGA SNP, 41 (66%) controls were heterozygous and eight (13%) controls were homozygous for the GenBank sequence. Thus, the C1qA - Gly70GGA SNP is strongly associated with SCLE (P-value = 0.005 by chi-square analysis with Yates correction). This SNP would traditionally be classified as clinically silent as it does not encode a different amino acid. However, our studies have suggested that this SNP appears to be associated with a functional abnormality of C1q expression since its presence correlates inversely with serum levels of C1q antigenic protein in both SCLE patients and normal controls. The mechanism by which this phenotypic change is associated with the translationally silent (synonymous) C1qA - Gly70GGA genetic variation is currently unknown.

The pattern of clinical breast cancer metastasis correlates with a single nucleotide polymorphism in the C1qA component of complement

Complement is one of primary defense mechanisms against intravascular microorganisms and could play a role in the immune response to malignancy and hence its clinical behavior. We evaluated if the sole coding polymorphism of C1qA associates with outcome in patients with breast carcinoma. Genotyping for C1qA[276A/G] was performed in 63 breast cancer subjects with localized tumor and compared with that in 38 breast cancer subjects with metastasis. Established risk factors for clinical outcome were considered and evaluated in multivariable analysis. Breast cancer subjects with heterozygous or homozygous C1qA[276G] genotype had a higher rate of metastasis than subjects with the homozygous C1qA[276A] genotype [hazard ratio (HR) 2.4, 95% confidence interval (CI) 1.1–4.1]. This association was stronger when only metastatic sites associated with hematogenous spread, i.e., to the bone, liver, and brain, were considered (HR 3.5, 95% CI 1.4–5.6) and remained statistically significant after adjustment for the number of positive lymph nodes, estrogen receptor status, and progesterone receptor status. There was no statistical difference in the C1qA[276A/G] allelic distribution between all subjects with breast cancer and controls. These results suggest there could be an association of a single nucleotide polymorphism at position 276 of the C1qA component of complement with breast cancer metastasis to sites linked to hematogenous spread of disease. The C1qA polymorphism associated with decreased distant metastasis has also been correlated with an increased incidence of subcutaneous systemic lupus and C1q deficiencies, suggesting that an altered immune response may play a role in the observed association.

Calcium-binding protein S100A4 confers mesenchymal progenitor cell fibrogenicity in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a prevalence of 1 million persons worldwide. The fibrosis spreads from affected alveoli into contiguous alveoli and leads to death by asphyxiation. We previously discovered that the IPF lung harbors fibrogenic mesenchymal progenitor cells (MPCs) that serve as a cell of origin for disease-mediating myofibroblasts. In a prior genomewide transcriptional analysis, we found that IPF MPCs displayed increased expression of S100 calcium-binding A4 (S100A4), a protein linked to cancer cell proliferation and invasiveness. Here, we have examined whether S100A4 mediates MPC fibrogenicity. Ex vivo analysis revealed that IPF MPCs had increased levels of nuclear S100A4, which interacts with L-isoaspartyl methyltransferase to promote p53 degradation and MPC self-renewal. In vivo, injection of human IPF MPCs converted a self-limited bleomycin-induced mouse model of lung fibrosis to a model of persistent fibrosis in an S100A4-dependent manner. S100A4 gain of function was sufficient to confer fibrotic properties to non-IPF MPCs. In IPF tissue, fibroblastic foci contained cells expressing Ki67 and the MPC markers SSEA4 and S100A4. The expression colocalized in an interface region between myofibroblasts in the focus core and normal alveolar structures, defining this region as an active fibrotic front. Our findings indicate that IPF MPCs are intrinsically fibrogenic and that S100A4 confers MPCs with fibrogenicity.

Donor-acquired fat embolism syndrome after lung transplantation

OBJECTIVES Fat embolism is a known complication of severe trauma and closed chest cardiac resuscitation both of which are more common in the lung transplant donor population and can lead to donor-acquired fat embolism syndrome (DAFES). The objective was to review the diagnosis and management of DAFES in the lung transplantation literature and at our centre. METHODS We performed a literature review on DAFES using the Medline database. We then reviewed the transplant record of Brigham and Womens Hospital, a large academic hospital with an active lung transplant programme, for cases of DAFES. RESULTS We identified 2 cases of DAFES in our centre, one of which required extracorporeal membrane oxygenation (ECMO) for successful management. In contrast to the broader literature on DAFES, which emphasizes unsuccessfully treated cases, both patients survived. CONCLUSION DAFES is a rare but likely underappreciated early complication of lung transplant as it can mimic primary graft dysfunction. Aggressive interventions, including ECMO, may be necessary to achieve a good clinical outcome following DAFES.

Mapping electrical properties heterogeneity of tumor using boundary informed electrical properties tomography (BIEPT) at 7T: Magnetic Resonance in Medicine

To develop and evaluate a boundary informed electrical properties tomography (BIEPT) technique for high‐resolution imaging of tumor electrical properties (EPs) heterogeneity on a rodent tumor xenograft model.

Metastatic medullary thyroid carcinoma or calcitonin-secreting carcinoid tumor of lung? A diagnostic dilemma in a patient with lung mass and thyroid nodule

Calcitonin‐secreting neuroendocrine tumors are rare and have been reported in literature as case reports or case series in various organs including lung, pancreas, larynx, bladder, and ovary. These tumors have similar cytologic features and immunohistochemical profile to medullary thyroid carcinoma and thus it is difficult to distinguish them, especially when calcitonin‐secreting neuroendocrine tumors are intermediate or higher grade and there is a mass lesion in the thyroid gland. Here, we report a rare case of calcitonin secreting atypical carcinoid tumor of the lung in a patient with thyroid nodule. However, after extensive ancillary studies on the thyroid gland, no tumor was detected and subsequent resection specimen revealed a pulmonary atypical carcinoid tumor with metastasis to level 11 lymph node. Being aware of this entity has significant clinical, diagnostic, and therapeutic implications and can prevent unnecessary thyroidectomies with subsequent possible morbidities.

Case Report: Combined Small Cell Lung Cancer in a Lung Transplant Recipient

Lung transplantation confers an increased risk of lung cancer, especially for single lung transplant recipients, due to both the epidemiologic risk factors associated with the patient population and the posttransplantation immunosuppression required. We report what we believe to be the first case of combined small cell lung carcinoma identified in the native lung of a single lung transplant recipient. Combined small cell lung cancer is an increasingly recognized subtype of small cell carcinoma, and its possible presence is an important consideration in the interpretation of fine-needle aspiration biopsies. In our case, initial fine-needle aspiration suggested squamous cell carcinoma, and it was only after lobectomy that the diagnosis of small cell carcinoma was made. The case highlights the increased risk of malignancy in lung transplant recipients and suggests a role for adaptation of lung cancer screening guidelines to address this high-risk population.