Melissa N. Loja

Optical molecular imaging detects changes in extracellular pH with the development of head and neck cancer

Noninvasive localized measurement of extracellular pH in cancer tissues can have a significant impact on the management of cancer. Despite its significance, there are limited approaches for rapid and noninvasive measurement of local pH in a clinical environment. In this study, we demonstrate the potential of noninvasive topical delivery of Alexa‐647 labeled pHLIP (pH responsive peptide conjugated with Alexa Fluor® 647) to image changes in extracellular pH associated with head and neck squamous cell carcinoma using widefield and high resolution imaging. We report a series of preclinical analyses to evaluate the optical contrast achieved after topical delivery of Alexa‐647 labeled pHLIP in intact fresh human tissue specimens using widefield and high‐resolution fluorescence imaging. Using topical delivery, Alexa‐647 labeled pHLIP can be rapidly delivered throughout the epithelium of intact tissues with a depth exceeding 700 µm. Following labeling with Alexa‐647 labeled pHLIP, the mean fluorescent contrast increased four to eight fold higher in clinically abnormal tissues as compared to paired clinically normal biopsies. Furthermore, the imaging approach showed significant differences in fluorescence contrast between the cancer and the normal biopsies across diverse patients and different anatomical sites (unpaired comparison). The fluorescence contrast differences between clinically abnormal and normal tissues were in agreement with the pathologic evaluation. Topical application of fluorescently labeled pHLIP can detect and differentiate normal from cancerous tissues using both widefield and high resolution imaging. This technology will provide an effective tool to assess tumor margins during surgery and improve detection and prognosis of head and neck cancer.

Widefield Optical Imaging of Changes in Uptake of Glucose and Tissue Extracellular pH in Head and Neck Cancer

The overall objective of this study was to develop an optical imaging approach to simultaneously measure altered cell metabolism and changes in tissue extracellular pH with the progression of cancer using clinically isolated biopsies. In this study, 19 pairs of clinically normal and abnormal biopsies were obtained from consenting patients with head and neck cancer at University of California, Davis Medical Center. Fluorescence intensity of tissue biopsies before and after topical delivery of 2-NBDG (2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose) and Alexa 647-pHLIP [pH (low) insertion peptide] was measured noninvasively by widefield imaging, and correlated with pathologic diagnosis. The results of widefield imaging of clinical biopsies demonstrated that 2-NBDG and pHLIP peptide can accurately distinguish the pathologically normal and abnormal biopsies. The results also demonstrated the potential of this approach to detect subepithelial lesions. Topical application of the contrast agents generated a significant increase in fluorescence contrast (3- to 4-fold) in the cancer biopsies as compared with the normal biopsies, irrespective of the patient and location of the biopsy within a head and neck cavity. This unpaired comparison across all the patients with cancer in this study highlights the specificity of the imaging approach. Furthermore, the results of this study indicated that changes in intracellular glucose metabolism and cancer acidosis are initiated in the early stages of cancer, and these changes are correlated with the progression of the disease. In conclusion, this novel optical molecular imaging approach to measure multiple biomarkers in cancer has a significant potential to be a useful tool for improving early detection and prognostic evaluation of oral neoplasia. Cancer Prev Res; 7(10); 1035–44. ©2014 AACR.

Racial Disparities in Outcomes of Endovascular Procedures for Peripheral Arterial Disease: An Evaluation of California Hospitals, 2005–2009

BACKGROUND Racial/ethnic disparities in treatment outcomes of peripheral arterial disease (PAD) are well documented. Compared with non-Hispanic (NH) whites, blacks and Hispanics are more likely to undergo amputation and less likely to undergo bypass surgery for limb salvage. Endovascular procedures are being increasingly performed as first line of therapy for PAD. In this study, we examined the outcomes of endovascular PAD treatments based on race/ethnicity in a contemporary large population-based study. METHODS We used Patient Discharge Data from Californias Office of Statewide Health Planning and Development to identify all patients over the age of 35 who underwent a lower extremity arterial intervention from 2005 to 2009. A look-back period of 5 years was used to exclude all patients with prior lower extremity arterial revascularization procedures or major amputation. Cox proportional hazards regression was used to compare amputation-free survival and time to death within 365 days. Logistic regression was used for comparison of 1-month myocardial infarction, 1-month major amputation, 1-month all-cause mortality, 12-month major amputation, 12-month reintervention, and 12-month all-cause mortality rates among NH white, black, and Hispanic patients. These analyses were adjusted for age, gender, insurance status, severity of PAD, comorbidities, history of coronary artery angioplasty or bypass surgery, or history of carotid endarterectomy. RESULTS Between 2005 and 2009, a total of 41,507 individuals underwent PAD interventions, 25,635 (61.7%) of whom underwent endovascular procedures. There were 17,433 (68%) NH whites, 4,417 (17.2%) Hispanics, 1,979 (7.7%) blacks, 1,163 (4.5%) Asian/Native Hawaiians, and 643 (2.5%) others in this group. There was a statistically significant difference in the amputation-free survival within 365 days among the NH white, Hispanic, and black groups (P < 0.0001); the hazard ratio for amputation within 365 days was 1.69 in Hispanics (95% confidence interval [CI] 1.51-1.90, P < 0.0001) and 1.68 in blacks (95% CI 1.44-1.96, P < 0.001) compared with NH whites following endovascular procedures after adjusting for age, gender, insurance status, comorbidities, severity of PAD, history of coronary artery angioplasty or bypass surgery, or history of carotid endarterectomy. After adjusting for the aforementioned confounders, the first reintervention within 12 months was also significantly associated with race/ethnicity (P = 0.002). Odds ratio for reintervention was 1.17 in blacks (95% CI 1.06-1.30, P = 0.002) and 1.084 in Hispanics (95% CI 1.00-1.16, P = 0.04) compared with NH whites. CONCLUSIONS In this contemporary large population-based study, we demonstrated that even among matched cohorts Hispanics and blacks have worse amputation-free survival than NH whites following endovascular therapy. Our study also found that Hispanics and blacks are more likely to undergo lower extremity arterial reinterventions than NH whites. Further research is crucial in understanding if higher reintervention rates in Hispanics and blacks are because of more severe disease and/or poor access to proper follow-up care and optimal medical management.

Staged Definitive Repair after Carotid Blowout: A Case Report

Carotid blowout syndrome is a highly morbid complication of head and neck cancer. We present the case of a 51-year-old woman with common carotid artery blowout, initially temporized with an endovascular stent graft and ultimately reconstructed using autologous superficial femoral artery. The patient recovered without sequelae and continues to be asymptomatic at 1 year. We present the modern hybrid management of this complex case.

Successful Reconstruction of Asymptomatic Bilateral External Carotid Artery Aneurysms

True aneurysms of the external carotid artery (ECA) are extremely rare with an unknown incidence and natural history. We present the successful operative management of an asymptomatic 65-year-old man found to have bilateral internal carotid artery stenosis and bilateral ECA aneurysms. His bilateral carotid arteries were reconstructed with bifurcated interposition grafts in a staged fashion. The patient recovered without sequelae and continues to be asymptomatic 1 year after reconstruction. We present the operative management of this rare case.