Antibody-based imaging strategies for cancer.

Although mainly developed for preclinical research and therapeutic use, antibodies have high antigen specificity, which can be used as a courier to selectively deliver a diagnostic probe or therapeutic agent to cancer. It is generally accepted that the optimal antigen for imaging will depend on both the expression in the tumor relative to normal tissue and the homogeneity of expression throughout the tumor mass and between patients. For the purpose of diagnostic imaging, novel antibodies can be developed to target antigens for disease detection, or current FDA-approved antibodies can be repurposed with the covalent addition of an imaging probe. Reuse of therapeutic antibodies for diagnostic purposes reduces translational costs since the safety profile of the antibody is well defined and the agent is already available under conditions suitable for human use. In this review, we will explore a wide range of antibodies and imaging modalities that are being translated to the clinic for cancer identification and surgical treatment.

Dynamic contrast-enhanced MRI evaluates the early response of human head and neck tumor xenografts following anti-EMMPRIN therapy with cisplatin or irradiation.

PURPOSE: To assess the early therapeutic effects of anti-EMMPRIN (extracellular matrix metalloprotease inducer) antibody with/without cisplatin or X-ray radiation in head and neck cancer mouse models using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). MATERIALS AND METHODS: Mice bearing SCC1 (or OSC19) tumor xenografts were treated with anti-EMMPRIN antibody, radiation, cisplatin, or anti-EMMPRIN antibody plus cisplatin (or radiation) for a week (n = 4-5 per group). DCE-MRI was carried out on a 9.4T small animal MR scanner on days 0, 3, and 7, and K(trans) values were averaged in a 0.5-mm-thick peripheral tumor region. Ki67 and CD31 staining were implemented for all tumors after imaging. RESULTS: The K(trans) changes of SCC1 and OSC19 tumors treated with anti-EMMPRIN antibody for 3 days were -18 ± 8% and 4 ± 7%, respectively, which were significantly lower than those of control groups (39 ± 5% and 45 ± 7%; P = 0.0025 and 0.0220, respectively). When cisplatin was added, those were -42 ± 9% and -44 ± 9%, respectively, and with radiation, -45 ± 9% and -27 ± 10%, respectively, which were also significantly lower than those of control groups (P < 0.0001 for all four comparisons). In the eight groups untreated (served as control) or treated with anti-EMMPRIN antibody with/without cisplatin or radiation, the mean K(trans) change for 3 days was significantly correlated with the mean tumor volume change for 7 days (r = 0.74, P = 0.0346), Ki67-expressing cell density (r = 0.96, P = 0.0001), and CD31 density (r = 0.84, P = 0.0084). CONCLUSION: DCE-MRI might be utilized to assess the early therapeutic effects of anti-EMMPRIN antibody with/without chemotherapy or radiotherapy in head and neck cancer.

Laparoscopic Fluorescent Visualization of the Ureter With Intravenous IRDye800CW.

OBJECTIVES: Ureter injury is a serious complication of laparoscopic surgery. Current strategies to identify the ureters, such as placement of a ureteral stent, carry additional risks for patients. We hypothesize that the systemically injected near-infrared (NIR) dye IRDye800CW-CA can be used to visualize ureters intraoperatively. METHODS: Adult female mixed-breed pigs weighing 24 to 41 kg (n = 2 per dose) were given a 30, 60, or 120 µg/kg systemic injection of IRDye800CW-CA. Using the Food and Drug Administration-cleared Pinpoint laparoscopic NIR system, images of the ureter and bladder were captured every 10 minutes for 60 minutes after injection. To determine the biodistribution of the dye, tissues were collected for ex vivo analysis with the Pearl Impulse system. ImageJ software was used to quantify fluorescence signal and signal-to-background ratio (SBR) for the intraoperative images. RESULTS: The ureter was identified in all pigs at each dose, with peak intensity reached by 30 minutes and remaining elevated throughout the duration of imaging (60 minutes). The 60 µg/kg dose was determined to be optimal for differentiating ureters according to absolute fluorescence (>60 counts/pixel) and SBR (3.1). Urine fluorescence was inversely related to plasma fluorescence (R(2) = -0.82). Ex vivo imaging of kidney, ureter, bladder, and abdominal wall tissues revealed low fluorescence. CONCLUSION: Systemic administration of IRDye800CW-CA shows promise in providing ureteral identification with high specificity during laparoscopic surgery. The low dose required, rapid time to visualization, and absence of invasive ureteral instrumentation inherent to this technique may reduce complications related to pelvic surgery.

Assessment of erlotinib as adjuvant chemoprevention in high-risk head and neck cancer patients.

PURPOSE: To determine the tolerability and efficacy of long-term treatment with erlotinib for head and neck squamous cell carcinoma after salvage surgery. METHODS: An open-label study was conducted of 150 mg of daily erlotinib for 12 months in patients who completed definitive surgical therapy for recurrent head and neck squamous cell carcinoma. The primary outcome measures were tolerability of prolonged erlotinib therapy and disease-free survival and overall survival at 1 and 2 years. RESULTS: Thirty-one patients were enrolled onto this study. Mean duration of erlotinib therapy was 5 months (range 2-374 days), with 8 patients completing the full 12-month course of erlotinib. Of the remaining patients, 8 discontinued therapy as a result of recurrence, 10 for medical or surgical complications deemed unrelated to the study medication, and 3 for drug-related toxicities. There were 25 grade 3 adverse events; 4 were classified as possibly related to study medication. The most common adverse events included acneiform rash (n = 26 patients), fatigue (n = 22), and diarrhea (n = 22). Overall survival was 61 % at 1 year and 56 % at 2 years. Disease-free survival was 54 % at 1 year and 45 % at 2 years. Mean time to recurrence (n = 16) was 8.7 months. CONCLUSIONS: Long-term erlotinib is safe and demonstrates some potential survival benefit compared to historical controls. However, despite the absence of grade 3/4 adverse events attributable to the drug, tolerance of long-term erlotinib was a significant barrier to completion of a 12-month course of therapy.

Evaluating the Effect of Recurrent Respiratory Papillomatosis on Work Productivity.

OBJECTIVE: Patients with recurrent respiratory papillomatosis (RRP) have significant vocal dysfunction which affects their performance at work. This study aimed to evaluate voice-related work productivity before and after ablative treatment for RRP. METHODS: This is a prospective case series conducted at 2 academic laryngology outpatient clinics. Adult employed patients with RRP completed the Work Productivity & Activity Impairment instrument (WPAI), Voice Handicap Index (VHI-10), WorkHoarse, Hospital Anxiety and Depression Scale (HADS), and a demographics questionnaire immediately before and 1 month after ablative treatment of papilloma. The primary outcome measure was the change in work productivity impairment domain of the WPAI, and changes in ratings before and after ablation were compared using a Wilcoxon Signed-Rank test. RESULTS: The 32 participants (mean age 45, 84% male) had a median (interquartile range) voice-related work productivity impairment score of 48.8% (30.0) at baseline which was improved to 5.0% (10.0) at 1 month after surgical ablation of papillomata (difference 30.0% (30.0) improvement). For the secondary outcome measures, there were significant improvements in VHI-10 (P < .001), self-reported voice quality (P = .002), and Workhoarse (P = .001), but no significant change in HADS. CONCLUSION: Patients with RRP experience significant voice-related work productivity impairment, and ablation of papillomata significantly improves work productivity.

Effect of chronic dissection on early and late outcomes after descending thoracic and thoracoabdominal aneurysm repair.

OBJECTIVE: Although chronic aortic dissection (CD) has traditionally been considered a predictor of perioperative morbidity and mortality after descending thoracic/thoracoabdominal aneurysm repair (thoracoabdominal aortic aneurysm [TAA]), recent reports have rejected this assertion. Still, few contemporary studies document late outcomes after TAA for CD, which is the goal of this study. METHODS: From August 1987 to December 2005, 480 patients underwent TAA; 73 (15%) CD and 407 (85%) degenerative aneurysms (DA). Operative management consisted of a clamp-and-sew technique with adjuncts in 53 (78%) CD and 355 (93%) DA patients (P < .001). Epidural cooling was used to prevent spinal cord injury (SCI) in 51 (70%) CD and 214 (53%) DA patients (P = .007). Study end points included perioperative SCI/mortality, freedom from reintervention, and long-term survival. RESULTS: CD patients were younger (mean age 64.5 years CD vs 72.5 years DA, P < .001) and more frequently had a family history of aneurysmal disease (23% CD vs 6% DA, P < .001). Forty-three (59%) CD patients had elective TAA (vs 322 (79%) DA, P = .001). Eleven (15%) CD patients had Marfan's syndrome (vs 0% DA, P < .001), and 17 (23%) CD patients had a prior arch or ascending aortic repair (vs 16 [4%] DA, P < .001). CD patients were more likely to have Crawford type I & II thoracoabdominal aneurysms (44 [60%] vs 120 [29%] DA, P < .001), while only two (3%) CD patients had type IV aneurysms (vs 99 [24%] DA). There was no difference in perioperative mortality between the two groups (11% CD vs 8.6% DA, P = .52), nor was there a difference in flaccid paralysis, which occurred in five (7%) CD and 22 (5%) DA patients (P = .92). At 5 years, 70% of CD patients were free from reintervention versus 74% of DA (P = .36). The actuarial survival was 53% and 32% at 5 and 10 years for CD versus 47% and 17% for DA (P = .07). CONCLUSIONS: Despite increased operative complexity, CD does not appear to increase perioperative SCI or mortality after TAA when compared with DA. Long-term freedom from aneurysm-related reintervention is similar for both groups as is survival, despite patients with CD being of younger age at presentation.

Psychiatric comorbidity and treatment response in patients with tuberous sclerosis complex.

BACKGROUND: Behavioral and psychiatric comorbidity are common in tuberous sclerosis complex (TSC), but information regarding psychopharmacologic management is lacking. METHODS: We reviewed clinical records of patients evaluated over a 20-month period at a large, quaternary referral center specializing in the comprehensive management of patients with TSC. Data were collected regarding psychiatric diagnoses, psychopharmacologic medications used to treat these disorders, and clinical response to treatment at follow-up. RESULTS: There were 113 encounters by 62 pediatric and adult patients with TSC, which were included in the present analysis. Behavioral and anxiety disorders were most prevalent, as were autism spectrum disorders and attention-deficit/hyperactivity disorder. Antipsychotics, antidepressants, and anticonvulsants with mood-stabilizing properties were the most often prescribed psychoactive medications and were associated with an overall improvement or stabilization of psychiatric symptoms 65% of the time. CONCLUSIONS: Psychiatric comorbidity, especially behavioral disorders, is very common among patients with TSC. Pharmacologic treatment can be very effective and should be considered for optimal disease management in affected individuals.

Outcomes after carotid endarterectomy: is there a high-risk population? A National Surgical Quality Improvement Program report.

OBJECTIVE: Carotid endarterectomy (CEA) is the standard treatment of carotid stenosis for symptomatic and asymptomatic patients. Carotid angioplasty and stenting (CAS), however, has been proposed as alternative therapy for patients deemed at high-risk for CEA. This study examined 30-day adjudicated outcomes in a contemporary series of CEAs and assessed the validity of criteria used to define a potential high-risk patient population for CEA. METHODS: Patients undergoing isolated CEA in private sector hospitals between Jan 1, 2005, and Dec 31, 2006, were identified using the prospectively gathered National Surgical Quality Improvement Program database. The primary study end points were 30-day stroke and death rates. Demographic, preoperative, and intraoperative variables were examined using multivariate models to identify variables associated with the study end points. Variables used to define systemic "high-risk" patients in the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) study (active cardiac disease, severe chronic obstructive pulmonary disease, and octogenarian status) were examined individually and in composite fashion for association with study endpoints. RESULTS: Of the 3949 CEAs performed, 59% were in men, 30% were "high-risk" (19% age >80), and 43% had a previous neurologic event. The 30-day stroke rate was 1.6%, the death rate was 0.7%, and combined stroke/death rate was 2.2%. Multivariate analysis showed that intraoperative transfusion (odds ratio [OR], 5.95; 95% confidence interval [CI], 1.71-20.66; P = .005), prior major stroke (OR, 5.34; 95% CI, 2.96-9.64; P < .0001), shorter height (surrogate for small artery size; OR, 1.09; 95% CI, 1.02-1.16; P = .010), and increased anesthesia time (OR, 1.02; 95% CI, 1.00-1.03; P = .008) were predictive of stroke. Critical limb ischemia (OR, 12.72; 95% CI, 3.49-46.40; P < .0001) and poor functional status (OR, 7.05; 95% CI, 2.95-16.82; P < .0001) were independent correlates of death. Systemic high-risk variables, either combined or individually, did not increase risk of stroke or death on multivariate analysis. CONCLUSION: CEA is associated with favorable 30-day outcomes across a spectrum of patient comorbidity features including octogenarian status. Anatomic and technical features are the important predictors of perioperative stroke, whereas critical limb ischemia and poor functional status are important predictors of death for patients undergoing CEA. These data refute the concept that CAS is preferred for patients deemed high-risk by virtue of systemic comorbidities.

Renal artery revascularization: outcomes stratified by indication for intervention.

OBJECTIVES: Application of endovascular therapy has led to increasing rates of renal artery intervention with unclear effect on hypertension (HTN) and/or renal salvage (RS). We evaluated the role of procedure indication on outcomes of both open (OR) and percutaneous (PR) revascularization. METHODS: Retrospective review of all consecutive renal artery interventions performed from January 1, 2002 to December 31, 2006 was conducted. OR patients were included for analysis only if independent renovascular indications for revascularization existed. RESULTS: Forty-seven OR and 203 PR (97% stent) patients were treated with 98% initial technical success. Patients with OR were younger (65 +/- 11 vs 72 +/- 9; P < .01), on more blood pressure (BP) medications (2.3 +/- 1.2 vs 1.8 +/- 1.2; P < .05), had more peripheral arterial disease (75% vs 37%; P < .01), and higher baseline creatinine (2.2 +/- 1.6 mg% vs 1.8 +/- 1 mg%; P < .05). Indications for PR were HTN in 46% and RS in 54%, and indications for OR were HTN in 51% and RS in 49% of cases. PR was unilateral in 169 (83%) and bilateral in 44/203 (17%). OR consisted of bypass in 26 (53%) and endarterectomy in 21/47 (47%) with 20 (43%) bilateral procedures. Peri-procedural complications were different (P < .01) and more frequent in OR (23% vs 12%). Survival was similar at three years (72% +/- 4% PR vs 71% +/- 9% OR; P = .9). Assisted patency was similar (P = .6) at one (94% +/- 2% PR vs 97% +/- 3% OR) and three years (90% +/- 3% PR vs 91% +/- 5% OR). One year (97% +/- 1% PR vs 97% +/- 3% OR) and three year (93% +/- 3% PR vs 91% +/- 7% OR) freedom from reintervention was similar (P = .8). Clinical outcomes showed patients with OR and PR having similar rates of cure or improvement in BP (76% PR vs 90% OR; P = .1) and favored OR with stable or improved renal function (97% vs 89%; P < .01) by the first postoperative visit. Hypertension control remained similar (P = .2) in both groups with cure/improvement in BP in 74% of PR and 89% of OR patients at one year. OR remained durable in regards to renal salvage with 52% of OR patients having improved renal function compared with 24% of PR (P < .01) patients at one year. At one year, BP control was achieved if treatment indication was HTN in 100% (18/18) of OR patients and 74% (46/63) (P = .04) of those having PR. Renal function stabilized or improved in 16/19 (85%) of OR and 70/81 (86%) of PR patients when performed for RS (P = .4). CONCLUSIONS: PR and OR are similarly efficacious for treatment of HTN associated with renal artery stenosis. While immediate and long-term outcomes favor OR for RS, this may impart from the triage of patients more likely to benefit from renal artery revascularization to OR.

Thoracoabdominal aneurysm repair: hybrid versus open repair.

OBJECTIVE: Hybrid repair of thoracoabdominal aortic aneurysms (TAAA) may reduce morbidity and mortality in high-risk candidates for open repair. This study reviews the outcomes of hybrid TAAA repair for Crawford extent I-III TAAA in high-risk patients in comparison to patients who underwent concurrent open TAAA repair. METHODS: During the interval from June 2005 to December 2007, a total of 23 high-risk patients with TAAA (type I: 9 [39%], II: 5 [22%], and III: 9 [39%]) underwent renal and/or mesenteric debranching (11 [48%] with four vessel debranching) with subsequent placement of a thoracic stent graft; 77 patients underwent open TAAA repair (type I: 13 [17%], II: 11 [14%], III: 27 [35%], and IV: 26 [34%]) during the same interval. The primary high-risk criteria for hybrid TAAA included advanced age/poor functional status (n = 14), major pulmonary dysfunction (n = 8), and technical consideration (prior thoracic aortic aneurysm repair [n = 4] or prior thoracoabdominal aneurysm repair [n = 2] and obesity [n = 2]) with 6 patients having overlapping high-risk criteria. Composite (30-day) mortality and/or permanent paraplegia (PP) were the major study endpoints. RESULTS: The hybrid and open TAAA groups had (respectively) no statistical difference in mean age (76.6 vs 72.7 years), aneurysm size (6.51 vs 6.52 cm), and non-elective operation (30.4% vs 26.0%). The hybrid group had a higher mean Society for Vascular Surgery (SVS) risk score (9.1 vs 6.0; P

Functional outcome after thoracoabdominal aneurysm repair.

OBJECTIVES: Previous reports have documented perioperative outcomes and major complications (renal failure, spinal cord ischemia, death) after repair of aneurysms of the thoracoabdominal aorta (TAA). This study documented long-term functional outcomes after open TAA repair. METHODS: The Medical Outcomes Study Short-Form 36-Item Survey (SF-36) was administered to 134 survivors (83 men, 51 women; mean age, 69.5 years) of TAA repair at a mean follow-up from surgery of 60 +/- 38.7 months. Raw scores were compared against cohorts adjusted for age and comorbidity (cardiovascular disease). Assessed was the influence of preoperative and intraoperative factors, as well as postoperative complications on long-term quality of life (QOL). RESULTS: Raw scores for the eight SF-36 domains and the composite physical and mental component scores were lower (P < .01) in the TAA cohort compared with an age-adjusted reference population. Female gender and age >75 years decreased the physical functioning (P = .02) and role physical (P = .04) domains compared with male gender and patients <65 years old. Previously recognized systemic vascular disease lowered QOL in three SF-36 domains: general health (P = .013), social functioning (P = .003), and role emotional (P = .003); systemic vascular disease also showed a strong trend toward reduction in physical functioning (P = .09) compared with patients without systemic vascular disease. Neither TAA extent (I to IV) nor elective vs urgent/emergency operation influenced long-term QOL in our cohort. Patients with postoperative paraplegia, cerebrovascular accident/cardiac event, and those requiring reoperation showed lower scores in the physical functioning (P = .036), general health (P = .02), and Mental Health (P = .04) domains. Increased length of stay negatively impacted long-term QOL. The TAA cohort and the cardiovascular disease cohort had similar SF-36 scores for four domains (general health, bodily pain, vitality, and social functioning) and physical component scores. The cardiovascular disease group had higher scores in the physical functioning, role physical, role emotional, and mental health domains, and in mental component scores (P < .01). CONCLUSION: Permanent loss of functional capacity, measured at a mean of 5 years postoperatively, occurs rarely in survivors of TAA repair. Further studies are needed to define the role of hybrid or endovascular strategies, including their impact on long-term functional outcome compared with open TAA repair.

Common femoral artery occlusive disease: contemporary results following surgical endarterectomy.

OBJECTIVE: Proliferation of endovascular techniques with perceived reduction in treatment morbidity repetitively question the precept that surgical endarterectomy is the preferred treatment for occlusive disease of the common femoral artery (CFA). This study details a contemporary experience with common femoral endarterectomy (CFE) with and without concomitantly performed endovascular therapies. METHODS: Technical, hemodynamic, and clinical success of CFE performed between 2002 and 2005 were determined according to the Society of Vascular Surgery reporting standards. Primary and assisted patencies of the CFA segment, freedom from reintervention in the ipsilateral limb, and survival were assessed using Kaplan-Meier life-table analysis. Multivariate analysis was performed to evaluate factors associated with patency and survival. RESULTS: CFE was performed on 65 limbs in 58 patients (mean age 71 +/- 10; male 77%; diabetes 28%; creatinine >/= 1.5 mg/dL 19%). Forty-four cases (68%) were performed for claudication, and 21 cases (32%) for critical limb ischemia. Thirty-seven cases (57%) were performed as a hybrid procedure wherein concomitant endovascular interventions were performed. Twenty iliac (TASC II A-30%; B-35%; C-20%; D-15%) and 25 femoropopliteal (TASC II A-24%; B-60%; C-12%; D-4%) lesions were treated. Technical success was achieved in 100% of the cases. Hemodynamic success was achieved in 95% of the cases with mean postoperative increase in ankle-brachial index (ABI) of 0.24 +/- 0.24. All but one patient (98.5%) had improvement in symptoms and/or ABI. Average hospital stay was 3.2 days (range 1-12 days). There were 3 (5%) major complications requiring reintervention (early failure secondary to untreated inflow lesion, hematoma, and wound infection), six (9%) minor complications which were treated conservatively (five wound infections, one lymph leak), and no perioperative mortality. With a mean follow-up period of 27 months (range 1-58 months), 1- and 5-year primary patencies were 93% and 91%, respectively. Assisted patency was 100% at both time points. There was no difference in patencies between CFE performed alone or as a hybrid procedure. Multivariate analysis showed congestive heart failure (CHF) as the only predictor of primary failure (odds ratio [OR] 18.5 [2.6-142.9]; P = .004). Freedom from reintervention in the ipsilateral limb was 82% at 1 year and 78% at 5 years, with CHF again as the only predictor of reintervention (OR 5.3 [1.4-19.6]; P =.012). Survival was 89% at 1 year and 70% at 5 years. There were no amputations. CONCLUSIONS: These data suggest CFE should remain the standard of care for occlusive disease of the CFA. Its safety and efficacy establish a standard for comparison with emerging endovascular therapies.

Characterizing the Utility and Limitations of Repurposing an Open-Field Optical Imaging Device for Fluorescence-Guided Surgery in Head and Neck Cancer Patients.

The purpose of this study was to assess the potential of U.S. Food and Drug Administration-cleared devices designed for indocyanine green-based perfusion imaging to identify cancer-specific bioconjugates with overlapping excitation and emission wavelengths. Recent clinical trials have demonstrated potential for fluorescence-guided surgery, but the time and cost of the approval process may impede clinical translation. To expedite this translation, we explored the feasibility of repurposing existing optical imaging devices for fluorescence-guided surgery. METHODS: Consenting patients (n = 15) scheduled for curative resection were enrolled in a clinical trial evaluating the safety and specificity of cetuximab-IRDye800 (NCT01987375). Open-field fluorescence imaging was performed preoperatively and during the surgical resection. Fluorescence intensity was quantified using integrated instrument software, and the tumor-to-background ratio characterized fluorescence contrast. RESULTS: In the preoperative clinic, the open-field device demonstrated potential to guide preoperative mapping of tumor borders, optimize the day of surgery, and identify occult lesions. Intraoperatively, the device demonstrated robust potential to guide surgical resections, as all peak tumor-to-background ratios were greater than 2 (range, 2.2-14.1). Postresection wound bed fluorescence was significantly less than preresection tumor fluorescence (P < 0.001). The repurposed device also successfully identified positive margins. CONCLUSION: The open-field imaging device was successfully repurposed to distinguish cancer from normal tissue in the preoperative clinic and throughout surgical resection. This study illuminated the potential for existing open-field optical imaging devices with overlapping excitation and emission spectra to be used for fluorescence-guided surgery.

Reengineering clinical research with informatics.

The future success of the translational research spectrum depends on the clinical research enterprise's ability to break through the barriers that constrain its productivity. As more basic science discoveries emerge, our ability to effectively translate this knowledge into improved patient care rests squarely on the manner in which we answer clinical questions. Informatics--the science of effective information use--is poised to help advance the conduct of science. However, incorporating informatics into the enterprise comes with its own set of challenges. To harness the benefits of improved information use, it is important to first establish how information flows within research. A thoughtful implementation of informatics--one that factors in social and organizational nuances--will undoubtedly lead to a more efficient and effective clinical research enterprise.

The use of image-guidance during transsphenoidal pituitary surgery in the United States.

BACKGROUND: Intraoperative image guidance is a useful modality for transsphenoidal pituitary surgery. However, the outcomes associated with this technology have not been systematically evaluated. OBJECTIVE: The purpose of the study was to quantify complication rates with and without the use of image guidance during transsphenoidal pituitary surgery using a nationwide database with broadly applicable results. METHODS: A retrospective analysis of the Nationwide Inpatient Sample was performed from 2007 to 2011. Transsphenoidal pituitary resections for adenomas were identified by International Classification of Diseases-9th Revision, Clinical Modification code. The effect of image guidance on cerebrospinal fluid (CSF) leak complications and cost-benefit was analyzed. RESULTS: A total of 48,848 transsphenoidal pituitary resections were identified, of which 77.5% were partial resections and 22.5% were complete. Pathologic indications included benign (89.3%), malignant primary (0.6%), and malignant secondary (0.4%). Complications included same-stay death (0.4%), CSF leak (8.8%), postoperative CSF rhinorrhea (1.9%), diabetes insipidus (12.4%), and meningitis (0.4%). Image guidance was employed in 7% (n = 3401) of all cases. When analyzed by modality, computed tomography (CT)-assisted procedures had lower CSF rhinorrhea rates (1.1%) compared with cases with no image guidance (1.9%), whereas magnetic resonance (MR)-assisted procedures had the highest rates (2.7%, χ2 p < 0.001). Rates of CSF leak demonstrated a similar pattern (CT 6.4%, no image guidance 8.9%, MR 9.2%, χ2 p < 0.001). CT-assisted surgery had significantly shorter length of stay (2.9 days) versus no image guidance (3.7 days, p < 0.001), lower total charges ($47,589 versus $62,629, p < 0.001), and lower total cost ($16,748 versus $20,530, p < 0.001). CONCLUSIONS: CT-assisted surgery is associated with a lower rate of CSF leak, shorter length of stay, and lower cost compared with patients without image guidance. Further studies that control for severity and extent of disease are warranted to confirm this finding.

Time-dependent pretreatment with bevacuzimab increases tumor specific uptake of cetuximab in preclinical oral cavity cancer studies.

Inadequate delivery of therapeutics into tumors has been suggested as a reason for poor response. We hypothesize that bevacizumab, an antibody to vascular endothelial growth factor (VEGF), can improve cetuximab uptake in squamous cell carcinoma tumors. Athymic nude mice were implanted with OSC19 and SCC1 human cancer lines in a subcutaneous flank model. Mice were imaged daily for 14 days after intravenous tail vein injections of the following groups: IgG-IRDye800 (Control), cetuximab-IRDye800 (CTX800 Only), bevacizumab-IRDye800 (BVZ800 Only), cetuximab-IRDye800 + bevacuzimuab-IRDye800 (Simultaneous), and unlabeled bevacizumab followed by cetuximab-IRDye800 3 days later (Neoadjuvant). Within single-agent groups, the CTX800 Only tumor-specific uptake (TSU) was significantly higher than BVZ800 Only at Day 13 (TSU 8.6 vs 2.8, P < 0.001). The Simultaneous treatment with BVZ800 and CTX800 demonstrated no increase in antibody delivery. However, administration of unlabeled bevacizumab 3 days prior to CTX800 (Neoadjuvant group) resulted in significantly higher tumor specific delivery than administration of both antibodies at the same time (11.8 vs Simultaneous 5.0, P < 0.001). This difference can be attributed to a slower decline in tumor fluorescence intensity (-6.8% vs. Simultaneous -11.5% per day, respectively). Structural changes in pericyte coverage and functional vessel changes demonstrating decreased proliferation and tumor growth corroborate these fluorescence results. Although simultaneous administration of bevacizumab with cetuximab failed to increase antibody delivery to the tumor, pretreatment with bevacizumab improved TSU reflecting an increase in tumor-specific uptake of cetuximab as a result of vessel normalization.

Multimodality management of high-risk head and neck basal cell carcinoma requiring free-flap reconstruction.

OBJECTIVES: (1) Investigate overall survival (OS) and disease-free survival (DFS) for high-risk head and neck basal cell carcinoma (HNBCC) requiring large extirpation with free-flap reconstruction. (2) Determine impact of prognostic features-tumor size, subsite, number of high-risk features, perineural invasion, and bony invasion-on high-risk HNBCC survival. (3) Determine survival benefit of adjuvant radiation for high-risk HNBCC. STUDY DESIGN: Case series with chart review (2002-2013). SETTING: Academic tertiary care center. SUBJECTS AND METHODS: Consecutive head and neck patients (N = 431) required free-flap reconstruction following tumor extirpation, 38 for aggressive HNBCC. All cases were high risk. DFS and OS were examined using Kaplan-Meier analysis. Prognostic variables and adjuvant radiation were analyzed utilizing Student's t test for continuous variables and Fisher's exact testing for categorical dependent variables. Complications were reported. RESULTS: Mean tumor diameter was 5.17 cm (range, 1.2-15.0 cm). Mean follow-up was 19.9 months. Overall 2-year survival was 80%, falling to 66% at 5 years. Two-year disease-free survival was 72%. Six patients recurred (n = 5 local, 1 distant). Adjuvant radiotherapy improved DFS (P < .01) but not OS (P = .66). Tumors >2.5 cm did not affect OS (P = .61), regardless of subsite. Bone involvement (44.7% cases) did not affect DFS (P = .39) or OS (P = .18). CONCLUSIONS: Larger HNBCC warranting free tissue transfer do not confer worse outcomes, independent of subsite. Adjuvant radiotherapy does not improve OS but significantly affected DFS, allowing for 13.7 additional months of DFS. Bone involvement does not influence DFS or OS and should not preclude surgery, even in advanced cases requiring free-flap reconstruction.

Transoral robotic surgery for oropharyngeal and tongue cancer in the United States.

OBJECTIVES/HYPOTHESIS: To compare the clinical and cost outcomes of transoral robotic surgery (TORS) versus open procedures following the U.S. Food and Drug Administration approval in December 2009. STUDY DESIGN: Retrospective analysis of the Nationwide Inpatient Sample from 2008 to 2011. METHODS: Elective partial pharyngectomies and partial glossectomies for neoplasm were identified by International Classification of Diseases, 9th Revision, Clinical Modification code. RESULTS: TORS represented 2.1% in 2010 and 2.2% in 2011 of all transoral ablative procedures. Patients undergoing open partial pharyngectomy for oropharyngeal neoplasms (n = 1426) had more severe illness compared to TORS (n = 641). However, after controlling for minor-to-moderate severity of illness, open partial pharyngectomy was associated with longer hospital stay (5.2 vs. 3.7 days, P < 0.001), higher charge ($98,228 vs. $67,317, P < 0.001), higher cost ($29,365 vs. $20,706, P < 0.001), higher rates of tracheostomy and gastrostomy tube placement, and more wound and bleeding complications. TORS was associated with a higher rate of dysphagia (19.5% vs. 8.0%, P < 0.001). The lower cost of TORS remained significant in the major-to-extreme severity of illness group but was associated with higher complication rates when compared to open cases of the same severity of illness. A similar analysis of TORS partial glossectomy for base of tongue tumors had similar cost and length of stay benefits, whereas TORS partial glossectomy for anterior tongue tumors revealed longer hospital stays and no benefit in charge or cost compared to open. CONCLUSIONS: Early data demonstrate a clinical and cost benefit in TORS partial pharyngectomy and partial glossectomy for the base of tongue but no benefit in partial glossectomy of the anterior tongue. It is likely that anatomic accessibility and extent of surgery factor into the effectiveness of TORS.

In Vivo Fluorescence Immunohistochemistry: Localization of Fluorescently Labeled Cetuximab in Squamous Cell Carcinomas.

Anti-EGFR (epidermal growth factor receptor) antibody based treatment strategies have been successfully implemented in head and neck squamous cell carcinoma (HNSCC). Unfortunately, predicting an accurate and reliable therapeutic response remains a challenge on a per-patient basis. Although significant efforts have been invested in understanding EGFR-mediated changes in cell signaling related to treatment efficacy, the delivery and histological localization in (peri-)tumoral compartments of antibody-based therapeutics in human tumors is poorly understood nor ever made visible. In this first in-human study of a systemically administered near-infrared (NIR) fluorescently labeled therapeutic antibody, cetuximab-IRDye800CW (2.5 mg/m(2), 25 mg/m(2), and 62.5 mg/m(2)), we show that by optical molecular imaging (i.e. denominated as In vivo Fluorescence Immunohistochemistry) we were able to evaluate localization of fluorescently labeled cetuximab. Clearly, optical molecular imaging with fluorescently labeled antibodies correlating morphological (peri-)tumoral characteristics to levels of antibody delivery, may improve treatment paradigms based on understanding true tumoral antibody delivery.

Safety and Tumor Specificity of Cetuximab-IRDye800 for Surgical Navigation in Head and Neck Cancer.

PURPOSE: Positive margins dominate clinical outcomes after surgical resections in most solid cancer types, including head and neck squamous cell carcinoma. Unfortunately, surgeons remove cancer in the same manner they have for a century with complete dependence on subjective tissue changes to identify cancer in the operating room. To effect change, we hypothesize that EGFR can be targeted for safe and specific real-time localization of cancer. EXPERIMENTAL DESIGN: A dose escalation study of cetuximab conjugated to IRDye800 was performed in patients (n = 12) undergoing surgical resection of squamous cell carcinoma arising in the head and neck. Safety and pharmacokinetic data were obtained out to 30 days after infusion. Multi-instrument fluorescence imaging was performed in the operating room and in surgical pathology. RESULTS: There were no grade 2 or higher adverse events attributable to cetuximab-IRDye800. Fluorescence imaging with an intraoperative, wide-field device successfully differentiated tumor from normal tissue during resection with an average tumor-to-background ratio of 5.2 in the highest dose range. Optical imaging identified opportunity for more precise identification of tumor during the surgical procedure and during the pathologic analysis of tissues ex vivo. Fluorescence levels positively correlated with EGFR levels. CONCLUSIONS: We demonstrate for the first time that commercially available antibodies can be fluorescently labeled and safely administered to humans to identify cancer with sub-millimeter resolution, which has the potential to improve outcomes in clinical oncology.