Brett Mahon

Development and validation of a plasma biomarker panel for discerning clinical significance of indeterminate pulmonary nodules.

Introduction: The recent findings of the National Lung Screening Trial showed 24.2% of individuals at high risk for lung cancer having one or more indeterminate nodules detected by low-dose computed tomography–based screening, 96.4% of which were eventually confirmed as false positives. These positive scans necessitate additional diagnostic procedures to establish a definitive diagnosis that adds cost and risk to the paradigm. A plasma test able to assign benign versus malignant pathology in high-risk patients would be an invaluable tool to complement low-dose computed tomography–based screening and promote its rapid implementation. Methods: We evaluated 17 biomarkers, previously shown to have value in detecting lung cancer, against a discovery cohort, comprising benign (n = 67) cases and lung cancer (n = 69) cases. A Random Forest method based analysis was used to identify the optimal biomarker panel for assigning disease status, which was then validated against a cohort from the Mayo Clinic, comprising patients with benign (n = 61) or malignant (n = 20) indeterminate lung nodules. Results: Our discovery efforts produced a seven-analyte plasma biomarker panel consisting of interleukin 6 (IL-6), IL-10, IL-1ra, sIL-2R&agr;, stromal cell-derived factor-1&agr;+&bgr;, tumor necrosis factor &agr;, and macrophage inflammatory protein 1 &agr;. The sensitivity and specificity of our panel in our validation cohort is 95.0% and 23.3%, respectively. The validated negative predictive value of our panel was 93.8%. Conclusion: We developed a seven-analyte plasma biomarker panel able to identify benign nodules, otherwise deemed indeterminate, with a high degree of accuracy. This panel may have clinical utility in risk-stratifying screen-detected lung nodules, decrease unnecessary follow-up imaging or invasive procedures, and potentially avoid unnecessary morbidity, mortality, and health care costs.

Biomarkers of the insulin-like growth factor pathway predict progression and outcome in lung cancer.

BACKGROUND Insulin-like growth factor 1 (IGF-I), IGF binding proteins (IGFBP) 1 to 7, and C-peptide have been postulated to predict survival in non-small cell lung cancer (NSCLC). Studying serum levels in NSCLC patients treated with surgical resection may provide information on the aggressiveness of tumors and be predictive of disease recurrence. METHODS Immunobead assays were used to measure pretreatment serum levels of IGF-I, IGFBP1 to IGFBP7, and C-peptide in 100 NSCLC patients. Of these, 59 had no metastatic progression (T1 to T4 N0 M0), whereas 41 had positive lymph nodes (T1 to T4 N1 to N3 M0). Data were analyzed using the Mann-Whitney two-sided rank sum test or Kaplan-Meier curves. RESULTS Low serum IGFBP5 levels correlated strongly with a positive nodal status (p < 0.001) and any incidence of disease recurrence (p = 0.003). Low serum levels of IGFBP5 also predicted poor recurrence-free survivals in the overall cohort (p ≤ 0.001) and in patients with no nodal metastases (p = 0.027). Conversely, a high serum level of IGFBP7 correlated with positive nodal status (p = 0.008), but was not prognostic for recurrence-free survival. No significant correlations were found for IGFBP5 or IGFBP7 for sex, age, race, smoking history, tumor histology, or fasting state. CONCLUSIONS IGFBP5 and IGFBP7 had value as biomarkers for identifying NSCLC progression and patient outcome.

Myocardial hydrophilic polymer emboli following cardiac catheterization: a case report and literature review.

BACKGROUND Intravascular polymer emboli have been reported in the skin, lungs, and brain following vascular procedures utilizing hydrophilic polymer coated devices. The Cook arterial introducer sheath was the first of these devices to be introduced, after which case reports followed documenting sterile inflammation at the sheath access site, characterized histologically by perivascular granulomas containing hydrophilic polymer. More recently, hydrophilic polymer emboli have been reported in the vessels of the lungs and brain in association with ischemia and infarct following vascular procedures using polymer coated devices. METHODS We report a case of intravascular myocardial emboli associated with acute myocardial infarction following cardiac catheterization. The patient was a 65-year-old man who received cardiac catheterization with placement of a bare metal stent following myocardial infarction. One month later, the patient presented with angina and died shortly after admission. RESULTS Autopsy revealed hemopericardium with rupture of the left ventricle through an aneurismal defect within the area of prior infarction. Microscopically, an area of acute infarction was present within the aneurismal defect. Numerous small and medium-sized vessels within the left ventricle were occluded by basophilic amorphous granular material with an inflammatory giant cell response. CONCLUSION The emboli were most frequent in the area of acute infarction, suggesting that the emboli may have resulted in ischemia leading to the patients death. This is the third documented case of intramyocardial polymer emboli following cardiac catheterization and the first case to our knowledge to document an association between intravascular myocardial polymer emboli and acute myocardial infarction.

Benign Cystic Mesothelioma Associated with Ipsilateral Renal Agenesis: A Case Report and Review of Literature

Benign Cystic Mesothelioma (BCM) is an uncommon peritoneal lesion that usually occurs in reproductive age females with a history of abdominal surgery. Occasional expression of estrogen and progesterone receptor in these cells may explain female predilection. Reports of BCM in males are rare. We describe a case of BCM associated with ipsilateral renal agenesis in a young male without any surgical history. The cyst lining stained positive for cytokeratin, Wilms Tumor-1, epithelial membrane antigen, CD10, estrogen receptor, and progesterone receptor, and negative for PAX-8. Only three cases of BCM associated with congenital renal anomalies have been reported. To the best of our knowledge, this is the first case of BCM associated with ipsilateral renal agenesis in an adult male and the first male case of BCM displaying estrogen and progesterone receptor positivity. Such a case reveals the presence of congenital anomalies should be considered in patients with BCM.

Breast implant‑associated anaplastic large‑cell lymphoma and the role of brentuximab vedotin (SGN‑35) therapy: A case report and review of the literature

Breast implant-associated (BIA) anaplastic large-cell lymphoma (ALCL) is a rare disease, comprising a small percentage of all non-Hodgkin lymphomas (NHLs), reportedly 2-3%. There is currently no established standard approach to the treatment of BIA ALCL. The first case on the development of ALCL in the presence of a breast implant was reported in 1997 and the association was first identified by the Food and Drug Administration in 2011. We herein describe a case of BIA ALCL in a patient with a previous history of breast cancer and breast reconstruction who presented with hardening of her breast implant. The patient underwent capsulectomy and the findings of the pathological examination were consistent with ALCL. The patient completed three cycles of combination chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP regimen) followed by radiation consolidation therapy, and has maintained a complete remission ever since. The aim of the present study was to review the treatment options for BIA ALCL and suggest an investigation of the CD30-directed antibody-drug conjugate, brentuximab vedotin, as a potential treatment option for BIA ALCL.

Abstract 1730: Expression of serum biomarkers related to epithelial-to-mesenchymal transition in non-small cell lung cancer recurrence

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Objective: Recurrent disease in stage I non-small cell lung cancer (NSCLC) is primarily attributed to metastatic dissemination at the time of surgery undetected by current staging practices. We hypothesized that metastatic progression is driven by epithelial-to-mesenchymal transition (EMT) resulting in differences in tumor-shed protein biomarkers. The objective of this study was to evaluate the difference in expression of these biomarkers in patients with recurrent stage 1 NSCLC. Methods: We used the Luminex immunobead platform, including the MILLIPLEX map human angiogenesis/growth factor magnetic bead panel, to evaluate 80 biomarkers related to EMT against a total of 75 patients who underwent a complete anatomic resection. Patients were divided into the following cohorts: a) stage I NSCLC without recurrence in 2 years (n=50), and b) stage I NSCLC with recurrence within 2 years of follow up (n=25). Peripheral blood was collected and processed using standard phlebotomy techniques. Specimens were obtained in compliance with institutional IRB standards and consent. The Mann-Whitney test and receiver operator characteristics (ROC) curves were used to assess differences in biomarker concentrations between cohorts. Results: Univariate analysis revealed 19 biomarkers with significant (ROC >0.6) differences in expression between the patient cohorts including: angiopoietin 2, MCP-1, MIP-IB, TNF-R1, IGFBP-5, VEGF-D, IGF-1, IGFBP-3, follistatin, sICAM-1, sE-SELECTIN, CYFRA 21.1, RANTES, IL-Ira, M-CSF, IGFBP-1, IGFBP-6, HB-EGF, and PGF. The Mann-Whitney test revealed five biomarkers highly significant (p<0.05) for recurrence in stage 1 NSCLC, including MCP-1, VEGF-D, follistatin, sICAM-1, and placental growth factor (PGF). Evaluation of these biomarkers with the Ingenuity Pathway Analysis (IPA) suite identified several highly significant (p<1x10−5) biological themes, including ten IPA-defined processes associated with development (e.g. embryonic development and cardiovascular system development), seven processes associated with pathological processes (e.g. cancer, cell death, and respiratory disease), and seven processes associated with metastasis (e.g. cellular movement, immune cell trafficking, and cell-to-cell signaling and interaction). Random Forest analysis generated a 6-analyte panel consisting of MCP-1, IP-10, sICAM-1, IGFBP2, RANTES, and IGFBP3 that provided 71.1% classification accuracy with 66.1% sensitivity and 73.3% specificity. Conclusions: Here we report observations concerning the expression of EMT pathway members that may provide key insights into the role of circulating biomarkers related to recurrence in stage 1 NSCLC. Upon further validation, these biomarkers may serve as convenient surrogates to help guide molecular diagnostics and treatment strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1730. doi:1538-7445.AM2012-1730

Bendamustine and Rituximab: Complete Response in a 62-Year-Old Female with an Aggressive Lymphoma and an Ejection Fraction of 20%

The treatment of diffuse large B-cell lymphoma in the presence of cardiac comorbidities can be challenging considering that the standard treatment regimen used for this aggressive subtype of non-Hodgkin lymphoma (NHL) consists of a combination of rituximab, cyclophosphamide, doxorubicin hydrochloride, Oncovin (vincristine), and prednisone (R-CHOP). The use of the anthracycline doxorubicin has been associated with arrhythmias and cardiomyopathy, making patients with cardiac dysfunction poor candidates for R-CHOP. As such, it is imperative to find alternative regimens that omit cardiac toxicity without compromising efficacy for this patient population. We report a case of composite NHL in a patient who received frontline bendamustine with rituximab with encouraging results. Our patient had a left ventricular ejection fraction of 20%, making her a poor candidate for anthracycline-based therapy. We opted to administer bendamustine with rituximab for a total of 6 cycles. She remains disease free 18 months after the completion of therapy.

Abstract 2404: Correlation of OGlcNAc modification components and EMT/Stem cell markers in lung adenocarcinoma

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Background: O-GlcNAcylation, post-ribosomal protein modification with an N-acetylglucosamine (O-GlcNAc) residue is functionally similar to phosphorylation in cellular physiology in that it is vital to cellular regulation and homeostasis. The enzymes responsible for the addition and removal of O-GlcNAc have been identified as O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). It has been proposed that O-GlcNAcylation may be an important regulator of cancer initiation and progression, based on the O-GlcNAcylation of many oncogenes/ proto-oncolgenes and tumor suppressors, but with few citations in the literature on the subject. Here, we investigated the correlation of O-GlcNAc modification components with expression of Epithelial-Mesenchymal-Transition (EMT)/Stem cell markers in 65 cases of lung adenocarcinoma. Methods: Immunohistochemical staining for O-GlcNAcylation, OGT, OGA, E-cadherin, vimentin, CD133, CD34 and CXCR-4 were performed on 65 primary lung adenocarcinoma and matching metastatic lymph nodes. All patients were treated by complete anatomic resections and limited to T1-2N0-2M0 (pathological). Scoring was accomplished by evaluating localization (membrane, cytoplasm, peri-nuclear, and nuclear), stain intensity (0: no staining, 1: weak staining, 2: strong staining) and frequency for at least 200 cells per field (400X magnification), with 25 random fields surveyed per section. This was done by two readers, and a score was then calculated based on these parameters for statistical comparisons (0: lowest, 2: highest). We then evealuated the correlation of these markers with each other through Pearsons correlation in SPSS v18.0. Results: Higher expression of cytoplasmic OGT was correlated with higher cytoplasmic OGlcNAcylation in primary tumor (r=0.40, p=0.001) and lymph node metastasis (r=0.567, p=0.001). However, we did not observe any relationship between OGA and OGlcNAcylation level. Vimentin showed positive correlation with nuclear OGlcNAcylation in both primary (r=0.281, p=0.031) and lymph node (r=0.380, p=0.035). but no relationship was observed with cytoplasmic OGlcNacylation. Also, CD133 demontrated positive correlation with cytoplasmic OGT in both primary (r=0.510, p=<0.001) and lymph node (r=0.555, p=0.001). Conclusion: Our results suggest that O-GlcNAcylation might play important roles in lung adenocarcinoma initiation and progression and may be a potential prognostic factor to predict patient risk of recurrence after surgery. Also, these findings may provide us with added insights regarding the mechanism of metastasis, although, further investigations are warranted to validate our results. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2404. doi:1538-7445.AM2012-2404