Clinical utility of tumor genomic profiling in patients with high plasma circulating tumor DNA burden or metabolically active tumors.

BACKGROUND: This retrospective study was undertaken to determine if the plasma circulating tumor DNA (ctDNA) level and tumor biological features in patients with advanced solid tumors affected the detection of genomic alterations (GAs) by a plasma ctDNA assay. METHOD: Cell-free DNA (cfDNA) extracted from frozen plasma (N = 35) or fresh whole blood (N = 90) samples were subjected to a 62-gene hybrid capture-based next-generation sequencing assay FoundationACT. Concordance was analyzed for 51 matched FoundationACT and FoundationOne (tissue) cases. The maximum somatic allele frequency (MSAF) was used to estimate the amount of tumor fraction of cfDNA in each sample. The detection of GAs was correlated with the amount of cfDNA, MSAF, total tumor anatomic burden (dimensional sum), and total tumor metabolic burden (SUVmax sum) of the largest ten tumor lesions on PET/CT scans. RESULTS: FoundationACT detected GAs in 69 of 81 (85%) cases with MSAF > 0. Forty-two of 51 (82%) cases had ≥ 1 concordance GAs matched with FoundationOne, and 22 (52%) matched to the National Comprehensive Cancer Network (NCCN)-recommended molecular targets. FoundationACT also detected 8 unique molecular targets, which changed the therapy in 7 (88%) patients who did not have tumor rebiopsy or sufficient tumor DNA for genomic profiling assay. In all samples (N = 81), GAs were detected in plasma cfDNA from cancer patients with high MSAF quantity (P = 0.0006) or high tumor metabolic burden (P = 0.0006) regardless of cfDNA quantity (P = 0.2362). CONCLUSION: This study supports the utility of using plasma-based genomic assays in cancer patients with high plasma MSAF level or high tumor metabolic burden.

High-resolution (18)F-FDG PET/CT for assessing disease activity in rheumatoid and psoriatic arthritis: findings of a prospective pilot study.

OBJECTIVE: Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) commonly affect the small joints of the wrist and hand. We evaluated the performance of a new, high-resolution extremity positron emission tomography (PET)/CT scanner for characterizing and quantifying pathologies associated with the two arthritides in the wrist and hand joints. METHODS: Patients with RA or PsA underwent fluorine-18 fludeoxyglucose ((18)F-FDG) PET/CT wrist and hand imaging, respectively, on the high-resolution scanner. Calibrated CT images and co-registered PET images were reconstructed. PET/CT was derived for the radiocarpal and pisiform-triquetral compartments, joints with erosive changes, sites of synovitis or tenosynovitis and the nail bed and were correlated with clinical and MRI findings. RESULTS: Significantly elevated (18)F-FDG uptake was measured for the radiocarpal and pisiform-triquetral compartments and at sites of bone erosion, synovitis, pannus and oedema, compared with unaffected joints (p < 0.05) in patients with RA, consistent with their clinical findings. In patients with PsA, significantly elevated (18)F-FDG uptake was measured for joints with synovitis compared with unaffected joints (p < 0.05), with patterns of (18)F-FDG uptake along the tendons, at the enthesis and in the nail bed, consistent with tenosynovitis, enthesitis and nail dystrophy, respectively. CONCLUSION: High-resolution (18)F-FDG PET/CT imaging of the wrist and hand is feasible in an RA or PsA patient cohort and is capable of providing quantifiable measures of disease activity (synovitis, enthesitis, oedema and bone destruction). ADVANCES IN KNOWLEDGE: High-resolution PET/CT imaging shows promise as a tool for understanding the pathogenesis of the arthritic process and for non-invasive, objective assessment of RA or PsA severity and therapy selection.

Hybrid imaging for pancreatic malignancy: clinical applications, merits, limitations, and pitfalls.

The role of PET/CT in pancreatic malignancy is evolving with new scientific evidence emerging continuously. PET/CT applications in imaging the pancreas and its organ-specific merits, limitations, and potential pitfalls are still evolving. This article provides an overview of the state-of-the-art applications of PET/CT imaging in evaluating pancreatic malignancy, comparing with conventional imaging modalities, such as contrast-enhanced CT and MRI. Current PET/MRI is also reviewed, along with brief discussion on cost-benefit analysis.

Observation versus neck dissection for positron-emission tomography-negative lymphadenopathy after chemoradiotherapy.

OBJECTIVES/HYPOTHESIS: To analyze outcomes among patients with residual positron-emission tomography (PET)-negative lymphadenopathy after chemoradiotherapy for head and neck cancer based on whether or not they underwent neck dissection. STUDY DESIGN: Retrospective review. METHODS: Fifty-five patients with stage III/IV squamous cell carcinoma of the head and neck were identified with residual PET-negative lymphadenopathy based on standardized uptake value of <3. All patients had been treated with chemoradiotherapy to a median dose of 70 Gy (range, 60-4 Gy). RESULTS: With a median follow-up of 30 months (range, 6-67 months), the 3-year overall survival (85% vs. 81%, P = .57), progression-free survival (88% vs. 88%, P = .42), and local-regional control (96% vs. 100%, P = .68), did not differ between patients treated by neck dissection or observation. CONCLUSIONS: Omission of neck dissection appears to be reasonable for patients with residual lymphadenopathy but negative PET after chemoradiotherapy for head and neck cancer. LEVEL OF EVIDENCE: 4.

Molecular imaging in pulmonary diseases.

OBJECTIVE: In this article, we consider a multitude of the latest techniques used for evaluating benign and malignant pulmonary diseases. Our review will include mostly clinically pertinent studies, but we have also included breakthrough basic science research that has potentially significant clinical implications. CONCLUSION: Molecular imaging enables noninvasive visualization and measurement of the dynamic molecular processes within living organisms. Early recognition of molecular and cellular malfunctions can help optimize diagnostic and therapeutic strategies.

Novel computed tomographic chest metrics to detect pulmonary hypertension.

BACKGROUND: Early diagnosis of pulmonary hypertension (PH) can potentially improve survival and quality of life. Detecting PH using echocardiography is often insensitive in subjects with lung fibrosis or hyperinflation. Right heart catheterization (RHC) for the diagnosis of PH adds risk and expense due to its invasive nature. Pre-defined measurements utilizing computed tomography (CT) of the chest may be an alternative non-invasive method of detecting PH. METHODS: This study retrospectively reviewed 101 acutely hospitalized inpatients with heterogeneous diagnoses, who consecutively underwent CT chest and RHC during the same admission. Two separate teams, each consisting of a radiologist and pulmonologist, blinded to clinical and RHC data, individually reviewed the chest CT's. RESULTS: Multiple regression analyses controlling for age, sex, ascending aortic diameter, body surface area, thoracic diameter and pulmonary wedge pressure showed that a main pulmonary artery (PA) diameter ≥29 mm (odds ratio (OR)=4.8), right descending PA diameter ≥19 mm (OR=7.0), true right descending PA diameter ≥16 mm (OR=4.1), true left descending PA diameter ≥21 mm (OR=15.5), right ventricular (RV) free wall ≥6 mm (OR=30.5), RV wall/left ventricular (LV) wall ratio ≥0.32 (OR=8.8), RV/LV lumen ratio ≥1.28 (OR=28.8), main PA/ascending aorta ratio ≥0.84 (OR=6.0) and main PA/descending aorta ratio ≥1.29 (OR=5.7) were significant predictors of PH in this population of hospitalized patients. CONCLUSION: This combination of easily measured CT-based metrics may, upon confirmatory studies, aid in the non-invasive detection of PH and hence in the determination of RHC candidacy in acutely hospitalized patients.

Initial characterization of a dedicated breast PET/CT scanner during human imaging.

UNLABELLED: We have constructed a dedicated breast PET/CT scanner capable of high-resolution functional and anatomic imaging. Here, we present an initial characterization of scanner performance during patient imaging. METHODS: The system consisted of a lutetium oxyorthosilicate-based dual-planar head PET camera (crystal size, 3 x 3 x 20 mm) and 768-slice cone-beam CT. The position of the PET heads (separation and height) could be adjusted for varying breast dimensions. For scanning, the patient lay prone on a specialized bed and inserted a single pendent breast through an aperture in the table top. Compression of the breast as used in mammography is not required. PET and CT systems rotate in the coronal plane underneath the patient sequentially to collect fully tomographic datasets. PET images were reconstructed with the fully 3-dimensional maximum a posteriori method, and CT images were reconstructed with the Feldkamp algorithm, then spatially registered and fused for display. Phantom scans were obtained to assess the registration accuracy between PET and CT images and the influence of PET electronics and activity on CT image quality. We imaged 4 women with mammographic findings highly suggestive of breast cancer (breast imaging reporting and data system, category 5) in an ongoing clinical trial. Patients were injected with (18)F-FDG and imaged for 12.5 min per breast. From patient data, noise-equivalent counting rates and the singles-to-trues ratio (a surrogate for the randoms fraction) were calculated. RESULTS: The average registration error between PET and CT images was 0.18 mm. PET electronics and activity did not significantly affect CT image quality. For the patient trial, biopsy-confirmed cancers were visualized on dedicated breast PET/CT on all patient scans, including the detection of ductal carcinoma in situ in 1 case. The singles-to-trues ratio was found to be inversely correlated with breast volume in the field of view, suggesting that larger breasts trend toward increased noise-equivalent counting rates for all other things equal. CONCLUSION: Scanning of the uncompressed breast with dedicated breast PET/CT can accurately visualize suspected lesions in 3 dimensions.

The management of painful bone metastases with an emphasis on radionuclide therapy.

OBJECTIVE: This review provides an update on the management of painful bone metastases, with an emphasis on radionuclide therapy, and introduces oligometastases and quantitative imaging evaluations for clinical trials. METHODS: The current use of radionuclides, alone and in combination with chemotherapy and radiation therapy for painful bone metastases, is discussed, including toxicity, cost and overall outcomes. RESULTS: Radionuclide therapy is shown to be a useful and cost-effective means of alleviating bone pain in metastatic disease and may be more effective when combined with chemotherapy, bisphosphonates and radiation therapy. Early use of radionuclides in pain therapy may limit cancer progression by inhibiting oligometastases development. Thus, radionuclides can significantly decrease patient morbidity, prolong patient survival, and may decrease the occurrence of new bone metastases. CONCLUSION: Palliative pain therapy is critical for effectively managing bone metastases, with treatment options including analgesics, external beam radiotherapy, chemotherapy and radionuclides. Radionuclide therapy is underutilized. Recent studies using radionuclides with chemotherapy and bisphosponates, or using newer radionuclides or combinations of radionuclides and treatment paradigms (e.g., higher activities, repetitive or cyclic administration, chemo sensitization, chemo supplementation), are encouraging. A comprehensive, inter-disciplinary clinical approach is needed. Clinical collaborations will optimize radionuclide therapy for pain palliation and increase awareness of its benefits.

Independent review of interstitial lung disease associated with death in TRIBUTE (paclitaxel and carboplatin with or without concurrent erlotinib) in advanced non-small cell lung cancer.

INTRODUCTION: A rare but serious complication of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy is a lung injury syndrome commonly referred to as a drug-induced interstitial lung disease (ILD). It has a typical clinical presentation of rapidly progressive acute or subacute dyspnea and a histopathology of diffuse alveolar damage (DAD). The incidence, severity, and risk factors for EGFR TKI-induced ILD remain poorly understood. Whether concurrent chemotherapy increases its risk is also unclear. The primary focus of this blinded review was to determine the incidence of ILD leading to death in 1059 TRIBUTE patients randomized to chemotherapy plus erlotinib or placebo. METHODS: All fatal serious adverse events (SAEs) were reviewed by an independent three-person panel composed of a medical oncologist, radiologist, and pulmonologist not associated with the study and without knowledge of treatment assignment. Fatal respiratory SAEs were identified and assigned to one of four potential attributions: progressive cancer, concurrent illness, drug-induced ILD, or other toxicities not related to ILD. Each panel member first made an independent assignation; then each case was discussed jointly. If needed, consensus was reached by vote. RESULTS: Fatal SAEs were reported in 80 of 1059 patients (7.6%): 53 of 526 patients on erlotinib (10.1%) and 27 of 533 on placebo (5.1%) (p < 0.05). Consensus assignation for 41 fatal respiratory SAEs was as follows: cancer, 18 (44%); concurrent illness, 15 (37%); other toxicities not related to ILD, five (12%); ILD, three (7%). All three ILD cases occurred in the erlotinib arm (3/526; 0.6%). The one biopsy-confirmed case of ILD revealed bronchiolitis obliterans organizing pneumonia, a histopathologic finding that has not previously been reported. All three cases of fatal ILD had a typical clinical presentation of acute or subacute onset of dyspnea with rapid progression to respiratory failure. CONCLUSIONS: This independent blinded analysis of the TRIBUTE study identified fatal ILD in 0.6% of cases treated with the combination of erlotinib plus chemotherapy, possibly higher than previous reports of EGFR TKIs alone in the non-Japanese population. Fatal ILD alone does not fully account for the imbalance in fatal SAEs observed in TRIBUTE. EGFR TKI-induced fatal ILD typically presents with acute or subacute dyspnea with rapid progression and a typical histopathology of diffuse alveolar damage both consistent with the acute respiratory distress syndrome, but can also be associated with a histopathology of bronchiolitis obliterans organizing pneumonia. Further studies designed to better understand the underlying pathophysiology and risk factors for ILD are needed.

Interstitial lung disease associated with epidermal growth factor receptor tyrosine kinase inhibitor therapy in non-small-cell lung carcinoma.

Interstitial lung disease is a rare but serious complication of epidermal growth factor receptor tyrosine kinase inhibitor therapy. Although our understanding of this phenomenon remains incomplete, recently there have been significant insights made into the mechanisms of injury, incidence, risk factors, and its clinical manifestations. Japanese patients appear to be at a higher risk (1.6%-3.5%) than patients in the rest of the world (0.3%), and other risk factors, such as coincident interstitial lung disease, concurrent chemotherapy, previous radiation, preexisting pulmonary fibrosis, and male sex, have been identified. In the majority of cases, the histopathology, the acute and often dramatic clinical presentation, and the radiographic findings resemble acute respiratory distress syndrome. Aside from immediate cessation of the offending agent, the treatment is largely supportive, although corticosteroids appear to be of benefit. The mortality remains high at approximately 30%-50%. We present a review of the incidence, risk factors, clinical manifestations, diagnosis, management, and outcome of this disorder.

Radiologic bone assessment in the evaluation of osteoporosis.

Osteoporosis affects nearly 28 million elderly Americans. Its major clinical manifestation is fragility fractures of the spine, hip, and distal radius. Low bone mass is the most important risk factor for a fragility fracture. In 1994, the World Health Organization defined osteoporosis on the basis of a bone mineral density that is 2.5 standard deviations below that in peak young normal persons. Three common imaging modalities used to assess bone strength are dual-energy x-ray absorptiometry, quantitative computed tomography, and calcaneal ultrasonography. The first two modalities measure bone mineral density in both the lumbar spine and peripheral sites. It is thought that calcaneal ultrasonography measures bone architecture and density. Unlike the other studies, ultrasonography currently cannot be used for monitoring skeletal changes over time or evaluating response to therapy.