Edward F. Patz

Prospective investigation of positron emission tomography in lung nodules.

PURPOSE Solitary pulmonary nodules (SPNs) are commonly identified by chest radiographs and computed tomography (CT). Biopsies are often performed to evaluate the nodules further. An accurate, noninvasive diagnostic test could avoid the morbidity and costs of invasive tissue sampling. We evaluated the ability of fluorine-18 deoxyglucose positron emission tomography (FDG-PET) to discriminate between benign and malignant pulmonary nodules in a prospective, multicenter trial. METHODS Eighty-nine patients who had newly identified indeterminate SPNs on chest radiographs and CT were evaluated with FDG-PET. PET data were analyzed semiquantitatively by calculating standardized uptake values (SUVs) as an index of FDG accumulation and also by a visual scoring method. PET results were compared with pathology results. RESULTS Sixty SPNs were malignant and 29 were benign. Using SUV data, PET had an overall sensitivity and specificity for detection of malignant nodules of 92% and 90%. Visual analysis provided a slightly higher, but not statistically significant, sensitivity of 98% and lower specificity of 69%. For SPNs < or = 1.5 cm (34 of 89), the sensitivity and specificity of SUV and visual analysis were 80% and 95% and 100% and 74%, respectively. CONCLUSION FDG-PET can accurately characterize indeterminate SPNs. PET imaging provides a noninvasive method to evaluate indeterminate SPNs, which can reduce the need for invasive tissue biopsy.

Overdiagnosis in Low-Dose Computed Tomography Screening for Lung Cancer

IMPORTANCE Screening for lung cancer has the potential to reduce mortality, but in addition to detecting aggressive tumors, screening will also detect indolent tumors that otherwise may not cause clinical symptoms. These overdiagnosis cases represent an important potential harm of screening because they incur additional cost, anxiety, and morbidity associated with cancer treatment. OBJECTIVE To estimate overdiagnosis in the National Lung Screening Trial (NLST). DESIGN, SETTING, AND PARTICIPANTS We used data from the NLST, a randomized trial comparing screening using low-dose computed tomography (LDCT) vs chest radiography (CXR) among 53 452 persons at high risk for lung cancer observed for 6.4 years, to estimate the excess number of lung cancers in the LDCT arm of the NLST compared with the CXR arm. MAIN OUTCOMES AND MEASURES We calculated 2 measures of overdiagnosis: the probability that a lung cancer detected by screening with LDCT is an overdiagnosis (PS), defined as the excess lung cancers detected by LDCT divided by all lung cancers detected by screening in the LDCT arm; and the number of cases that were considered overdiagnosis relative to the number of persons needed to screen to prevent 1 death from lung cancer. RESULTS During follow-up, 1089 lung cancers were reported in the LDCT arm and 969 in the CXR arm of the NLST. The probability is 18.5% (95% CI, 5.4%-30.6%) that any lung cancer detected by screening with LDCT was an overdiagnosis, 22.5% (95% CI, 9.7%-34.3%) that a non-small cell lung cancer detected by LDCT was an overdiagnosis, and 78.9% (95% CI, 62.2%-93.5%) that a bronchioalveolar lung cancer detected by LDCT was an overdiagnosis. The number of cases of overdiagnosis found among the 320 participants who would need to be screened in the NLST to prevent 1 death from lung cancer was 1.38. CONCLUSIONS AND RELEVANCE More than 18% of all lung cancers detected by LDCT in the NLST seem to be indolent, and overdiagnosis should be considered when describing the risks of LDCT screening for lung cancer.

Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients

Early stage lung cancer has a variable prognosis, and there are currently no markers that predict which patients will recur. This study examined the relation between tumor‐regulatory T (Treg) cells and total tumor‐infiltrating T‐cell lymphocytes (TIL) to determine whether they correlated with recurrence.

Panel of Serum Biomarkers for the Diagnosis of Lung Cancer

PURPOSE Currently, a blood test for lung cancer does not exist. Serum biomarkers that could aid clinicians in making case management decisions would be enormously valuable. We used two proteomic platforms and a literature search to select candidate serum markers for the diagnosis of lung cancer. METHODS We initially assayed six serum proteins, four discovered by proteomics and two previously known to be cancer associated, on a training set of sera from 100 patients (50 with a new diagnosis of lung cancer and 50 age- and sex-matched controls). Classification and Regression Tree (CART) analysis selected a panel of four markers that most efficiently predicted which patients had lung cancer. An independent, blinded validation set of sera from 97 patients (49 lung cancer patients and 48 matched controls) determined the accuracy of the four markers to predict which patients had lung cancer. RESULTS Four serum proteins-carcinoembryonic antigen, retinol binding protein, alpha1-antitrypsin, and squamous cell carcinoma antigen-were collectively found to correctly classify the majority of lung cancer and control patients in the training set (sensitivity, 89.3%; specificity, 84.7%). These markers also accurately classified patients in the independent validation set (sensitivity, 77.8%; specificity, 75.4%). Remarkably, 90% of patients who fell into any one of three groupings in the CART analysis had lung cancer. CONCLUSION This panel of four serum proteins is valuable in suggesting the diagnosis of lung cancer. These data may be useful for treating patients with an indeterminate pulmonary lesion, and potentially in predicting individuals at high risk for lung cancer.

Lung tumor growth correlates with glucose metabolism measured by fluoride-18 fluorodeoxyglucose positron emission tomography.

BACKGROUND The growth rate, or doubling time, of radiographically indeterminate pulmonary abnormalities is an important determinant of malignancy. Prospective calculation of doubling time, however, delays diagnosis and treatment. Positron emission tomography (PET) using the glucose analogue fluoride-18 fluorodeoxyglucose (FDG) measures the enhanced glucose uptake characteristic of neoplastic cells. We postulated that if FDG activity correlates with doubling time, then PET may allow prompt diagnosis of lung cancer. METHODS From March 1992 to July 1993, all patients with indeterminate focal pulmonary abnormalities were eligible for FDG PET imaging. In 53 patients, serial chest radiographs or computed tomograms were available and doubling time was computed. The FDG activity within the lesion was expressed as a standardized uptake ratio. RESULTS The mean standardized uptake ratio (+/- SD) was 5.9 +/- 2.7 in 34 patients with cancer, versus 2.0 +/- 1.7 in 19 with benign disease (p < 0.001). Using a criterion of standardized uptake ratio 2.5 or greater for malignancy, the accuracy of PET was 92% (49 of 53). The standardized uptake ratio was significantly correlated with doubling time (r = -0.89; p = 0.002). CONCLUSION These data suggest a direct relation between tumor growth and FDG uptake in lung cancer. The technique of FDG PET demonstrates exceptional accuracy and may permit prompt diagnosis of lung cancer.

Changes in the Use and Costs of Diagnostic Imaging Among Medicare Beneficiaries With Cancer, 1999-2006

CONTEXT Emerging technologies, changing diagnostic and treatment patterns, and changes in Medicare reimbursement are contributing to increasing use of imaging in cancer. Imaging is the fastest growing expense for Medicare but has not been examined among beneficiaries with cancer. OBJECTIVE To examine changes in the use of imaging and how those changes contribute to the overall cost of cancer care. DESIGN, SETTING, AND PATIENTS Analysis of a nationally representative 5% sample of claims from the US Centers for Medicare & Medicaid Services from 1999 through 2008. Patients were Medicare beneficiaries with incident breast cancer, colorectal cancer, leukemia, lung cancer, non-Hodgkin lymphoma, or prostate cancer. MAIN OUTCOME MEASURES Use and cost of imaging by modality, year, and cancer type. RESULTS There were 100,954 incident cases of breast cancer, colorectal cancer, leukemia, lung cancer, non-Hodgkin lymphoma, and prostate cancer from 1999 through 2006. Significant mean annual increases in imaging use occurred among all cancer types for positron emission tomography (35.9%-53.6%), bone density studies (6.3%-20.0%), echocardiograms (5.0%-7.8%), magnetic resonance imaging (4.4%-11.5%), and ultrasound (0.7%-7.4%). Conventional radiograph rates decreased or stayed the same. As of 2006, beneficiaries with lung cancer and beneficiaries with lymphoma incurred the largest overall imaging costs, exceeding a mean of

Detection of primary and recurrent lung cancer by means of F-18 fluorodeoxyglucose positron emission tomography (FDG PET)*

3000 per beneficiary within 2 years of diagnosis. By 2005, one-third of beneficiaries with breast cancer underwent bone scans and half of beneficiaries with lung cancer or lymphoma underwent positron emission tomography scans. Mean 2-year imaging costs per beneficiary increased at a rate greater than the increase in mean total costs per beneficiary for all cancer types. CONCLUSION Imaging costs among Medicare beneficiaries with cancer increased from 1999 through 2006, outpacing the rate of increase in total costs among Medicare beneficiaries with cancer.

Positron emission tomography in the pretreatment evaluation and follow-up of non-small cell lung cancer patients treated with radiotherapy: preliminary findings.

Positron emission tomography (PET), with the glucose analog F-18 fluoro-deoxyglucose (FDG), takes advantage of the enhanced glucose uptake observed in neoplastic cells. We examined whether the detection of preferential FDG uptake with PET permits differentiation between benign and malignant focal pulmonary lesions in patients with suspected primary or recurrent lung cancer. Between November 1991 and September 1993, 100 patients with indeterminate focal pulmonary abnormalities including 16 patients who had previous lung resections for cancer were prospectively studied. Tissue diagnosis was obtained by transbronchial or percutaneous biopsy (n = 49) and open biopsy or resection (n = 35). Three patients underwent extended observation (> 2 years) alone. Excluded were 13 patients lacking firm pathologic diagnoses and less than 2-year follow-up. FDG activity in the lesion was expressed as a calculated standardized uptake ratio. Mean standardized uptake ratio (+/- standard deviation) was 6.6 (+/- 3.1) in 59 patients with cancer versus 2.0 (+/- 1.6) in 28 with benign disease (p = 0.0001; unpaired t test, two-sided). With a standardized uptake ratio > or = 2.5 used for detecting malignancy, sensitivity, specificity, and accuracy were 97% (57/59), 82% (23/28), and 92% (80/87), respectively. Notably, in patients evaluated for pulmonary abnormalities after lung resection for cancer, all chest recurrences were correctly identified. The exceptional sensitivity of FDG PET demonstrates that malignant pulmonary lesions preferentially accumulate FDG, which results in a standardized uptake ratio > or = 2.5. PET may be useful for distinguishing recurrent tumor from postoperative, or postradiation, changes. If performed in all patients before open biopsy, PET increases the diagnostic yield by reducing the number of patients who have benign lesions at operation. Moreover, by lowering expenditures for hospitalization and other diagnostic procedures, FDG PET may significantly reduce health care costs.

Cytomegalovirus pneumonia in transplant patients: CT findings.

The purpose of this study was to prospectively evaluate positron emission tomography (PET) for delineating lung cancers preradiotherapy and to assess PETs ability to distinguish residual tumor from scarring following radiotherapy. Between April 1991 and October 1992, 20 patients underwent 18fluoro-2-deoxyglucose (18FDG) PET scanning of the chest prior to radiotherapy for lung cancer. Tumor volumes on chest x-ray (CXR) and computerized tomography (CT) scan were correlated with abnormalities on PET scans. Follow-up PET studies were compared to postradiotherapy chest x-ray and/or CT scans, and correlated with clinical outcome. Six of seven well-demarcated tumors showed increased uptake of 18FDG correlating with the CT/CXR tumor volume. Twelve poorly demarcated tumors demonstrated increased 18FDG uptake. In seven of 12, the CT/CXR abnormality correlated with changes on PET scan. In three of 12, CT/CXR abnormalities were larger than on PET, whereas in two of 12, abnormalities on PET extended outside the region of CT/CXR changes. The 13th patient in the poorly demarcated category had diffuse carcinoma in situ at the surgical margin that demonstrates increased 18FDG uptake, but was not visible by CT/CXR. Of 12 patients with follow-up studies, all had changes on CXR and/or CT that made it difficult to assess response. Four of 12 had a complete response by PET; all remain locally controlled. The remaining eight patients had either a partial response (n = 6) or no response (n = 2) by PET. Four of these eight patients remain alive and well 11-24 months after therapy. 18FDG PET may be useful for delineation of lung cancer volumes that are poorly defined by CXR and/or CT scan. The value of PET in differentiating tumor from fibrosis after radiotherapy for lung cancer remains to be established.

PET imaging in patients with bronchioloalveolar cell carcinoma

OBJECTIVE Our goal was to assess the CT findings of cytomegalovirus (CMV) pneumonia in transplant patients. MATERIALS AND METHODS The study included 10 transplant patients who had chest CT scan and pathologically proven isolated pulmonary CMV infection. Five patients had bone marrow transplant and five had solid organ transplant. The CT scans were retrospectively reviewed for pattern and distribution of disease and the CT findings compared with the findings on open lung biopsy (n = 9) and autopsy (n = 1). RESULTS Nine of 10 patients had parenchymal abnormalities apparent at CT and 1 had normal CT scans. The findings in the nine patients included small nodules (n = 6), consolidation (n = 4), ground-glass attenuation (n = 4), and irregular lines (n = 1). The nodules had a bilateral and symmetric distribution and involved all lung zones. The consolidation was most marked in the lower lung zones. CONCLUSION The CT findings of CMV pneumonia in transplant patients are heterogeneous. The most common patterns include small nodules and areas of consolidation.