David Macfarlane

Changes in 18F-Fluorodeoxyglucose and 18F-Fluorodeoxythymidine Positron Emission Tomography Imaging in Patients with Non–Small Cell Lung Cancer Treated with Erlotinib

Purpose: Assessing clinical activity of molecularly targeted anticancer agents, especially in the absence of tumor shrinkage, is challenging. To evaluate on-treatment 18F-fluorodeoxyglucose (FDG) and/or 18F-fluorodeoxythymidine (FLT) positron emission tomography (PET) for this purpose, we conducted a prospective multicenter trial assessing PET response rates and associations with progression-free (PFS) and overall survival (OS) in 2nd/3rd-line non–small-cell lung cancer patients treated with erlotinib. Experimental Design: PET/computed tomography (CT) scans were conducted at baseline, day (d)14 and d56 after the first daily erlotinib dose, with diagnostic CT at baseline and d56 (all scans centrally reviewed). PET partial metabolic response (PMR) was defined as a mean decrease (in ≤5 lesions/patient) of 15% or more maximum standardized uptake value. PFS was investigator-determined. Results: Of 74 erlotinib-treated patients, 51 completed all imaging assessments through d56; 13 of 51 (26%) FDG-evaluable patients had PMR at d14, as did 9 of 50 (18%) FLT-evaluable patients. Four (7.8%) showed partial responses (PR) by d56 CT; all 4 had PMR by d14 FDG-PET with 3 PMRs by d14 FLT-PET. Three of the 4 patients with CT PR had evaluable archival tumor tissue; all 3 had epidermal growth factor receptor mutations. D14 and d56 PMRs by FDG or FLT were associated with improved PFS; HRs for PET responders versus nonresponders were 0.3 to 0.4. D14 FDG-PET PMR was associated with improved OS (P = 0.03) compared with FDG-PET nonresponders. Conclusion: Early (d14) FDG-PET PMR is associated with improved PFS and OS, even in the absence of subsequent Response Evaluation Criteria in Solid Tumors response. These data support inclusion of FDG-PET imaging in clinical trials testing novel targeted therapies, particularly those with anticipated cytostatic effects. Clin Cancer Res; 17(10); 3304–15. ©2011 AACR.

Prospective evaluation of 2-[18F]-2-deoxy-D-glucose positron emission tomography in staging of regional lymph nodes in patients with cutaneous malignant melanoma.

PURPOSE To assess prospectively the accuracy of 2-[l8F]-2-deoxy-D-glucose positron emission tomography (FDG-PET) for predicting regional node involvement in cutaneous malignant melanoma (CMM). PATIENTS AND METHODS Twenty-three patients with CMM (primary lesions > 1.5 mm thick) scheduled for lymph node dissection (LND) were preoperatively studied with FDG-PET. Thirteen patients underwent therapeutic LND of 14 node basins, while nine patients had elective LND of 10 node basins. Medical problems precluded surgery in one patient. Two observers unaware of the clinical node status-apart from whether a recent surgical scar was present-read attenuation-corrected reconstructed transverse images acquired between 50 and 60 minutes after injection. Intensity of FDG uptake was scored as 0 to 3 + on a semiquantitative four-point scale: 0, no uptake; 1 +, faint; 2 +, moderate; and 3 +, intense uptake. A node group was considered positive on FDG-PET if it contained at least one focus of FDG uptake of > or = 2+ intensity. Histopathologic examination of the 24 dissected node groups served as a reference. RESULTS Considering regional node basins, PET imaging demonstrated 11 true-positive (TP), 10 true-negative (TN), two false-negative (FN), and one false-positive (FP) result, for an overall accuracy of 88%. Histopathologic from one FN case showed seven malignant cells in a marginal node sinus. The FP was due to reactive changes postbiopsy. In one patient, clinically involved lymph nodes were correctly categorized TN by PET. At least four additional 2 + foci seen outside the dissected regions on PET may represent metastases and are being monitored. CONCLUSION FDG-PET accurately predicted regional node status in 88% of CMM cases. The failure to detect micrometastatic disease may be due to the limitations of the imaging equipment and technique used here.

Phase I biodistribution and pharmacokinetic study of Lewis Y-targeting immunoconjugate CMD-193 in patients with advanced epithelial cancers.

Purpose: This phase I study explored the biodistribution and pharmacokinetics of the immunoconjugate CMD-193 [a humanized anti–Lewis Y (Ley) antibody conjugated with calicheamicin in patients with advanced cancers expressing the Ley antigen. Experimental Design: The primary objectives were to determine biodistribution and pharmacokinetics of CMD-193. Secondary objectives included response rates and change in tumor metabolism. Patients with progressive, measurable, and Ley positive malignancies were eligible for enrollment in one of two dose cohorts, 1.0 and 2.6 mg/m2. The first cycle was trace labeled with 111In for biodistribution assessment using γ camera imaging. Subsequent cycles were administered every 3 weeks up to a maximum of six cycles, depending on toxicity and response. Pharmacokinetic analysis was based on radioassay and ELISA. Results: Nine patients were enrolled in the study. Biodistribution images showed initial blood pool activity, followed by markedly increased hepatic uptake by day 2, and fast blood clearance in all patients. There was low uptake in tumor in all patients. The overall T½β of 111In-CMD-193 was 102.88 ± 35.67 hours, with no statistically significant difference between the two dose levels. One patient had a partial metabolic response on 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG PET) after four cycles, but no radiological responses were observed. Myelosuppression and effects on liver function were the most significant adverse effects. Conclusions: CMD-193 shows rapid blood clearance and increased hepatic uptake compared with prior studies of the parental antibody hu3S193. These results highlight the importance of biodistribution and pharmacodynamic assessment in early phase studies of new biologics to assist in clinical development. (Clin Cancer Res 2009;15(21):6709–15)

Mechanism of exercise hypotension in patients with ischemic heart disease. Role of neurocardiogenically mediated vasodilation.

BackgroundExercise-induced hypotension in patients with coronary artery disease (CAD) has been considered to be due to an inability to achieve an adequate increase in cardiac output to match the demands of exercise. We investigated 10 consecutive patients (9 men and 1 woman; age, 38 to 71 years; mean, 52 years) with angiographically documented CAD and exercise-induced hypotension (EIH) (BPPeak < BPRest). Ten approximately age- and sex-matched patients with documented CAD and normal exercise blood pressure response (NBP) served as control subjects. Methods and ResultsNine patients with EIH and all 10 control subjects underwent forearm plethysmography and radionuclide ventriculography (RNV) during semierect cycle exercise. Forearm vascular resistance (FVR) fell by 35 ± 21% in exercise-induced hypotension patients versus an increase of 78 ± 65% in patients with an NBP response (P < .0001). Left ventricular ejection fraction increased by 5.1 ± 7.5% in the group with EIH versus a fall of 4.1 ± 6.2% in the control group (P = .004). Cardiac output at peak exercise (RNV) increased by 2.2 ± 0.89-fold in the group with EIH versus 1.49 ± 0.47-fold in the control group (P = .04). The tenth patient in the group with EIH underwent invasive hemodynamic evaluation during erect exercise. Systolic blood pressure fell (136/80Rest to 50/40Peak) and cardiac output (Fick) tripled, whereas calculated systemic vascular resistance decreased by a factor of 10. Successful angioplasty to an isolated circumflex lesion resulted in resolution of symptoms and abnormal hemodynamic responses during exercise. ConclusionsAbnormal vasodilation associated with a normal or even increased rather than decreased cardiac output response appears to be an important mechanism underlying EIH in some patients with CAD. In the present study, this appears to have been the dominant mechanism in 8 and contributory in 2 of the consecutive patients studied.

FDG PET imaging of paragangliomas of the neck: comparison with MIBG SPET

Two patients with cervical paragangliomas underwent positron emission tomography (PET) with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG). There was marked tumor uptake and retention of FDG. Adjacent salivary gland accumulation of FDG was minimal, though quite prominent withmeta-iodobenzylguanidine. FDG PET offers another potentially useful approach to functional imaging of these uncommon tumors, independent of the presence of specific amine uptake mechanisms or cell surface receptors required by other scintigraphic techniques.

Treatment of recalcitrant actinomycosis with ciprofloxacin.

We describe a case of actinomycosis with several unusual features. The patient has been under medical supervision for more than 20 years; the disease has spread in an atypical manner and did not respond to standard therapy. Finally, there has been an unexpected response to a prolonged course of a member of the quinolone group of antibiotics.

Imaging of deep venous thrombosis in patients using a radiolabelled anti-D-dimer Fab′ fragment (99mTc-DI-DD3B6/22-80B3): results of a phase I trial

Purpose99mTc-DI-DD3B6/22-80B3 (ThromboView®, hereafter abbreviated to 99mTc-DI-80B3 Fab′) is a radiolabelled humanised monoclonal Fab′ fragment with affinity and specificity for D-dimer domains of cross-linked fibrin. Detection of thromboembolic events has been demonstrated in canine models. The study objectives were evaluation of safety and characterisation of biodistribution, immunogenicity and pharmacokinetic profile of increasing doses of 99mTc-DI-80B3 Fab′ in subjects with acute lower-limb DVT.MethodsTwenty-six patients with acute lower limb DVT were enrolled. Of these, 21 received a single intravenous dose of 0.5 mg (n = 6), 1.0 mg (n = 9) or 2 mg (n = 6) 99mTc-DI-80B3 Fab′. Blood and urine samples and gamma camera images were collected to 24 h after administration for pharmacokinetic and dosimetry analysis. Vital signs, electrocardiography, hematological and biochemical data and human anti-human antibody (HAHA) levels were monitored for up to 30 days following administration. Patients were assigned to either planar or single photon emission computed tomographic (SPECT) imaging of the thorax at 4 h following injection.ResultsThirty-five adverse events were reported in 15 of the 21 subjects. Those deemed possibly related to administration of 99mTc-DI-80B3 Fab′ included mild hypertension, mild elevation of LD (lactate dehydrogenase) and moderate elevation of ALT (alanine transaminase). HAHA assays remained negative. Pharmacokinetics and organ dosimetry were comparable to prior normal volunteer data. Localisation of Thromboview® to sites of known thrombus was evident as early as 30 min post-injection.ConclusionsIn subjects with acute DVT, 99mTc-DI-80B3 Fab′ was well tolerated with favourable characteristics for the detection of acute venous thrombosis.

A prospective study of the impact of fluorodeoxyglucose positron emission tomography with concurrent non‐contrast CT scanning on the management of operable pancreatic and peri‐ampullary cancers

BACKGROUND The role of fluorodeoxyglucose (FDG) positron emission tomography (PET/CT) scanning in operable pancreas cancer is unclear. We, therefore, wanted to investigate the impact of PET/CT on management, by incorporating it into routine work-up. METHODS This was a single-institution prospective study. Patients with suspected and potentially operable pancreas, distal bile duct or ampullary carcinomas underwent PET/CT in addition to routine work-up. The frequency that PET/CT changed the treatment plan or prompted other investigations was determined. The distribution of standard uptake values (SUV) among primary tumours, and adjacent to biliary stents was characterised. RESULTS Fifty-six patients were recruited. The surgical plan was abandoned in 9 (16%; 95% CI: 6-26) patients as a result of PET/CT identified metastases. In four patients, metastases were missed and seven were inoperable at surgery, not predicted by PET/CT. Unexpected FDG uptake resulted in seven additional investigations, of which two were useful. Among primary pancreatic cancers, a median SUV was 4.9 (range 2-12.1). SUV was highest around the biliary stent in 17 out of 28 cases. PET/CT detected metastases in five patients whose primary pancreatic tumours demonstrated mild to moderate avidity (SUV < 5). CONCLUSIONS PET/CT in potentially operable pancreas cancer has limitations. However, as a result of its ability to detect metastases, PET/CT scanning is a useful tool in the selection of such patients for surgery.

Increased skeletal uptake of Tc-99m methylene diphosphonate in milk-alkali syndrome.

A case of milk-alkali syndrome is described in a 34-year-old man taking an over-the-counter antacid preparation for gastroesophageal reflux, A Tc-99m MDP bone scan performed in the initial investigation of the hypercalcemia was markedly abnormal with a “metabolic” pattern of tracer uptake similar to that seen in hyperparathyroidism and humoral hypercalcemia. Following withdrawal of the antacid and calcium, the bone scan appearance returned to normal, as did the biochemical markers of his disease.

Blood–brain barrier dysfunction following traumatic brain injury: correlation of Ktrans (DCE-MRI) and SUVR (99mTc-DTPA SPECT) but not serum S100B

Abstract Objective: Damage to the blood–brain barrier (BBB) is an important secondary mechanism that occurs following traumatic brain injury (TBI) and may provide a potential therapeutic target to improve patient outcome. For such a progress to be realised, an accurate assessment of BBB compromise needs to be established. Methods: Fourteen patients with TBI were prospectively recruited. Post-traumatic BBB dysfunction was assessed using dynamic contrast-enhanced MRI (DCE-MRI), single-photon emission computerised tomography (SPECT) and serum S100B levels. Results: A statistically significant correlation between standardised uptake value ratio (SUVR) calculated from 99mTc-DTPA SPECT and Ktrans (a volume transfer constant) from DCE-MRI was found for those eight patients who had concurrent scans. The positive correlation persisted when the data were corrected for patient age, number of days following trauma and both parameters combined. We found no statistically significant correlation between either of the imaging modalities and concurrent serum S100B levels. Discussion: The correlation of SPECT with DCE-MRI suggests that either scan may be used to assess post-traumatic BBB damage. We could not support serum S100B to be an accurate measure of BBB damage when sampled a number of days following injury but the small number of patients, the heterogeneity in TBI patients and the delay following injury makes any firm conclusions regarding S100B and BBB difficult.