Ashok Muthukrishnan

Intratumoral Epidermal Growth Factor Receptor Antisense DNA Therapy in Head and Neck Cancer: First Human Application and Potential Antitumor Mechanisms

PURPOSE Squamous cell carcinoma of the head and neck (SCCHN) is characterized by upregulation of the epidermal growth factor receptor (EGFR). We developed a novel strategy to target EGFR by using a therapeutic gene that consisted of an EGFR antisense (AS) gene sequence under U6 promoter control. A phase I clinical trial was conducted to evaluate the safety and biologic effects of EGFR AS. PATIENTS AND METHODS Patients with advanced SCCHN who were refractory to standard therapies and who had at least one assessable and accessible lesion were enrolled. The EGFR AS dose was escalated in successive cohorts (six dose levels; 60 to 1,920 microg/injection). Patients received four weekly intratumoral EGFR AS injections. Tumor biopsies were performed before and after completion of therapy. Treatment response was assessed by tumor volume measurements (positron emission tomography/computed tomography), and levels of target proteins were assessed by immunohistochemistry. RESULTS Seventeen assessable patients were treated. No grades 3 to 4 or dose-limiting toxicities were noted, and a maximum-tolerated dose was not reached. Five patients (29%) achieved a clinical response, which included two complete responses (CRs) and three partial responses (PRs); two additional patients had stable disease (SD) as the best response. Patients with disease control (CR + PR + SD) had tumors with higher EGFR and lower STAT3 expression at baseline compared with patients who had progressive disease (P = .0312 and P = .095, respectively). CONCLUSION Intratumoral EGFR AS was safe and resulted in antitumor activity in patients with advanced SCCHN. Baseline levels of high EGFR and low STAT3 may be associated with antitumor effects.

Improved Benefit of SPECT/CT Compared to SPECT Alone for the Accurate Localization of Endocrine and Neuroendocrine Tumors

Objective: To assess the clinical utility of SPECT/ CT in subjects with endocrine and neuroendocrine tumors compared to SPECT alone. Material and Methods: 48 subjects (31 women;17 men; mean age 54±11) with clinical suspicion or diagnosis of endocrine and neuroendocrine tumor had 50 SPECT/CT scans (32 Tc-99m MIBI, 5 post treatment I-131, 8 In-111 Pentetreotide, and 5 I-123 MIBG). SPECT alone findings were compared to SPECT/CT and to pathology or radiological follow up. Results: From the 32 Tc-99m MIBI scans, SPECT accurately localized the lesion in 22 positive subjects while SPECT/CT did in 31 subjects. Parathyroid lesions not seen on SPECT alone were smaller than 10 mm. In five post treatment I-131 scans, SPECT alone neither characterized, nor localized any lesions accurately. SPECT/CT revealed 3 benign etiologies, a metastatic lymph node, and one equivocal lesion. In 8 In-111 Pentetreotide scans, SPECT alone could not localize primary or metastatic lesions in 6 subjects all of which were localized with SPECT/CT. In five I-123 MIBG scans, SPECT alone could not detect a 1.1 cm adrenal lesion or correctly characterize normal physiologic adrenal uptake in consecutive scans of the same patient with prior history of adrenelectomy, all of which were correctly localized and characterized with SPECT/CT. Conclusion: SPECT/CT is superior to SPECT alone in the assessment of endocrine and neuroendocrine tumors. It is better in lesion localization and lesion characterization leading to a decrease in the number of equivocal findings. SPECT/CT should be included in the clinical work up of all patients with diagnosis or suspicion of endocrine and neuroendocrine tumors. Conflict of interest:None declared.

Absorptive clearance of DTPA as an aerosol-based biomarker in the cystic fibrosis airway

Biomarkers providing in vivo quantification of the basic elements of cystic fibrosis (CF) lung disease are needed. A study was performed to determine whether the absorption of a small radiolabelled hydrophilic molecule (Indium-111 (In-)DTPA) would be increased in CF airways. DTPA clearance has been used previously to assess epithelial permeability and may also be useful for quantifying liquid absorption. The absorptive clearance rate of DTPA was quantified in 10 CF and 11 control subjects using a novel aerosol technique. Subjects inhaled an aerosol containing nonabsorbable technetium-99m sulfur colloid (Tc-SC) particles and In-DTPA. Tc-SC clearance from the lung is exclusively mucociliary, while In-DTPA is cleared by both absorption and mucociliary clearance. The difference between the In-DTPA and Tc-SC clearance rates estimates In-DTPA absorption. Tc-SC (mucociliary) clearance was similar in central and peripheral zones in CF and non-CF lungs. Total In-DTPA clearance was increased in both zones in CF lungs. The absorptive component of In-DTPA clearance was increased in the airway-dominated central lung zones in CF (42%·h−1 versus 32%·h−1, p = 0.03). The absorption of In-DTPA is increased in the CF airway. Further study is needed to understand the relative roles of fluid absorption, inflammation and other mechanisms potentially affecting epithelial permeability and DTPA absorption.

Left ventricular myocardium metastasis in a patient with primary renal cell carcinoma detected by 18F-FDG PET/CT.

Cardiac metastases from renal cell carcinoma are rare but should be recognized when present. We report PET/CT findings in a patient with headache and diplopia and cerebral metastasis from an unknown primary of clear cell adenocarcinoma origin. PET/CT revealed uptake with a left renal cell carcinoma, and revealed multiple metastatic lesions, including an FDG-avid metastasis within the left ventricular myocardium.

Delayed development of radiation vasculopathy of the brain stem confirmed by F-18 FDG PET in a case of anaplastic astrocytoma.

We present the imaging findings of a 38-year-old female patient who underwent resection and radiation therapy for an anaplastic astrocytoma in her left temporal lobe 12 years ago. She was symptom-free until 1 month before admission at which time she presented with symptoms of right hemiparesis, right facial droop, and slurred speech. Magnetic resonance imaging (MRI) of the brain showed a new mass lesion in the left pontine region of the brain stem. Magnetic resonance spectroscopy imaging of the lesion demonstrated an increase in choline (Ch)/N-acetyl aspartate (NAA) metabolite values which were nondiagnostic. Since viable tumor recurrence was strongly suspected, a biopsy was planned, although this posed significant risk. Therefore, an F-18 FDG brain PET scan was performed, which demonstrated no metabolic activity in the pontine lesion leading to the less common diagnosis of long-term postradiation vasculopathy. Over the next 6 months, the patients symptoms slowly improved and a follow-up MRI scan showed a decrease in the size of the lesion, consistent with postradiation vasculopathy and infarction. This case illustrates the importance of considering the rare diagnosis of radiation-induced vasculopathy in the differential diagnosis when symptoms of recurrent brain tumor occur.

Accuracy of early‐phase versus dual‐phase single‐photon emission computed tomography/computed tomography in the localization of Parathyroid disease

Preoperative localization for parathyroid disease has improved in recent years with the advent of dual‐phase 99mTc‐sestamibi single‐photon emission computed tomography/computed tomography (SPECT/CT) imaging. However, dual‐phase imaging is associated with increased cost, time, and radiation dose. The aim of this study was to investigate the need for late‐phase imaging when using SPECT/CT for the preoperative localization of parathyroid disease.

INTERPRETABILITY OF PET/CT IMAGING IN HEAD AND NECK CANCER PATIENTS FOLLOWING COMPOSITE MANDIBULAR RESECTION AND OSTEOCUTANEOUS FREE FLAP RECONSTRUCTION

We investigated positron emission tomography (PET)/CT scanning following segmental resections and osteocutaneous free‐flap reconstruction. The interpretability of PET/CT imaging with healing osteotomies and reconstruction hardware was analyzed.

Pseudomonas infection and mucociliary and absorptive clearance in the cystic fibrosis lung.

Airway surface liquid hyperabsorption and mucus accumulation are key elements of cystic fibrosis lung disease that can be assessed in vivo using functional imaging methods. In this study we evaluated experimental factors affecting measurements of mucociliary clearance (MCC) and small-molecule absorption (ABS) and patient factors associated with abnormal absorption and mucus clearance. Our imaging technique utilises two radiopharmaceutical probes delivered by inhalation. Measurement repeatability was assessed in 10 adult cystic fibrosis subjects. Experimental factors were assessed in 29 adult and paediatric cystic fibrosis subjects (51 scans). Patient factors were assessed in a subgroup with optimal aerosol deposition (37 scans; 24 subjects). Paediatric subjects (n=9) underwent initial and 2-year follow-up scans. Control subjects from a previously reported study are included for comparison. High rates of central aerosol deposition influenced measurements of ABS and, to a lesser extent, MCC. Depressed MCC in cystic fibrosis was only detectable in subjects with previous Pseudomonas aeruginosa infection. Cystic fibrosis subjects without P. aeruginosa had similar MCC to control subjects. Cystic fibrosis subjects had consistently higher ABS rates. We conclude that the primary experimental factor affecting MCC/ABS measurements is central deposition percentage. Depressed MCC in cystic fibrosis is associated with P. aeruginosa infection. ABS is consistently increased in cystic fibrosis. Depressed mucus clearance in cystic fibrosis was only detectable in subjects with Pseudomonas aeruginosa infection http://ow.ly/YggZy

Afferent loop syndrome: the role of Tc-99m mebrofenin hepatobiliary scintigraphy.

Afferent loop syndrome is caused by intermittent mechanical obstruction of the afferent loop of a gastrojejunostomy and may present early as an acute type or late as a chronic type. The authors describe two patients who were examined for a history of bilious vomiting after gastrojejunostomy, and who were thought to have afferent loop syndrome (chronic type) based on clinical findings. Results of routine investigations, such as upper gastrointestinal endoscopy, and ultrasonography were inconclusive. Findings from the barium meal follow-through studies were normal in the first patient and revealed a dilated duodenum in the second patient. Tc-99m bromotriethyl-iminodiacetic acid has been used to identify afferent loop obstruction as represented in these studies.

Serendipitous detection of urothelial carcinoma with F-18 FDG PET/CT: usefulness of low intensity PET window setting in areas of high physiologic FDG distribution.

FDG PET/CT is widely accepted in diagnosing and staging various malignancies. However, the usefulness of PET in detecting urothelial tumors has been disputed because of high physiologic FDG excretion into the urinary bladder. Various techniques like bladder irrigation and furosemide administration have been employed to improve the diagnostic yield of PET. We report a patient who underwent PET/CT for staging or non-small cell lung cancer. Initial review of PET images in the pelvis was unremarkable, whereas the CT images revealed an exophytic lesion in the urinary bladder. Re-examination of the PET images under a low intensity window setting revealed intense FDG uptake in the lesion. Careful review of PET in different window settings in conjunction with CT images, especially in regions of high physiologic FDG distribution could facilitate detection of possible lesions.