Identifying optimal combination regimens for therapy of Mycobacterium tuberculosis with an algorithmic approach: prospective predictions and validations

BackgroundPre-clinical models are commonly used to determine human antibiotic dosage regimens using pharmacokinetic/pharmacodynamic (PKPD) indices. The murine thigh infection model (MTIM) is most commonly used for PKPD index determination, while the hollow fibre infection model (HFIM) may be a viable alternative. However, there is no standardized method for determining the PKPD index and R2 may not be the ideal metric to determine goodness of fit for nonlinear models. This study aimed to reanalyse PKPD indices published in MTIM and HFIM, using a standardized modelling approach.MethodsSystematic literature review was conducted to identify MTIM and HFIM dose fractionation studies. Searches covered databases including PubMed, MEDLINE, BIOSIS, SCOPUS and EMBASE. Data were extracted and modelled using eight variations of Emax model, with model selection based on the lowest Akaike information criterion (AIC) and parameter plausibility in terms of precision and interpretability.ResultsA total of 53 studies were included: 50 MTIM (of 1138) and 3 HFIM (of 316). Among the 53 studies, reporting issues included an infrequent use of AIC for model selection as applied in only one paper, and a lack of methodological transparency in 29 papers. Remodelling revealed some disagreement in optimal PKPD indices in six studies.ConclusionsThis study suggests a standard method for PKPD index model selection and provides a database on PKPD index analysis. Building the Emax model from one to four estimated parameters and assessing them with AIC is recommended to avoid over fitting. Too few HFIM dose fractionation studies were found to allow comparison of PKPD index with MTIM.

Small-animal positron emission tomography as a tool for neuropharmacology

17113 Background: MPM is a rapidly progressive malignancy with a median survival of 6 to 9 months. Studies in non-small cell lung cancer, gastrointestinal stromal tumours, and breast cancer suggest that Positron Emission Tomography (PET) scanning may predict the clinical outcome of chemotherapy at an early stage of treatment. The role of PET in predicting and monitoring response to treatment in MPM is unclear. In this study we assessed if baseline and early interval PET scanning could be of benefit in MPM, correlating the results with standard Computerised Tomography (CT) assessment using the modified Response Evaluation Criteria In Solid Tumours (RECIST) of Byrne and Nowak. Methods: 10 patients with histologically proven MPM proceeded to baseline PET and CT scanning prior to chemotherapy. In 8 patients a second PET scan was performed within three weeks of commencing treatment. The following PET derived parameters were calculated: Standard Uptake Value (SUV)maximum, SUVaverage, PETvolume, and Total Lesion Glycolysis (TLG). Baseline SUVmaximum and early PET response was compared with CT response and survival. Results: Baseline SUVmaximum predicted subsequent CT response in the 10 patients studied. Four out of 5 patients with baseline SUVmaximum of <15 showed a subsequent partial response on CT, whilst the 5th patient had resolution of a pleural effusion. All 5 patients with baseline SUVmaximum of >15 had stable or progressive disease on CT. In contrast change in early SUVmaximum from baseline to 3 weeks did not predict subsequent CT response (Kappa value 0.07) in the 8 patients evaluated. Change in PET volume and TLG correlated with subsequent CT response (Kappa value= 0.80 for both). Only 1 patient with a partial response on % PETvolume and %TLG has died 14 months after commencing treatment. The other 3 patients are alive at 17+, 19+ and 20+ months. The 4 patients with stable or progressive disease using these parameters were deceased at 5, 6, 10, and 12 months respectively. Conclusion: PET may be useful in predicting and evaluating response to treatment in MPM. Furthermore, the results suggest that PET response may be a useful prognostic tool in this disease. It is important to use the appropriate PET derived parameters. Further study with a larger patient population is warranted. No significant financial relationships to disclose.

X-ray computed tomography (CT) imaging plays an essential role in disease diagnosis due to its noninvasive, painless mode and superior penetration depth. However, the resolution of the soft tissue ...

The Case Against Heavy PETing

9:45—10:00: Positron Emission Tomography (PET) is Superior to Computerized Tomography (CT) for Metastatic Staging in Melanoma Patients

Positron emission tomography (PET) is a useful tool in the selection of patients with esophageal cancer who may not benefit from esophageal resection. Case series. Tertiary care hospital. Eighty-one patients with newly diagnosed esophageal cancer who underwent PET and computer tomography (CT) of the chest and abdomen (and of the neck in 45 patients) within 45 days were included. We calculated the sensitivity and specificity in detecting metastatic sites on the basis of 31 histologically verified lesions. In addition to results obtained on CT, the information provided by PET was evaluated with a view to the choice of management strategies. The PET findings had a higher specificity (89% vs 11%) but a lower sensitivity (38% vs 63%) than CT findings in the detection of metastatic sites. The CT results showed greater agreement with histopathological findings than did PET results. In 8 patients (10%), PET detected distant metastases that were not identified with CT. In 4 patients (5%), PET detected bone metastases only, but in all of these patients metastases in other locations were detected by CT. Although PET led to upstaging (M1) in 2 patients (2%), it did not enable the exclusion of esophageal resection. Preoperative PET was not characterized by greater accuracy in the detection of metastatic sites previously identified by CT. Therefore, PET did not lead to a change in the indication for esophagectomy. An increase in the sensitivity and the combined use of CT and PET may lead to new indications for this staging procedure.

Numerous authors have reported the potential usefulness of positron emission tomography (PET). These studies have had conflicting results, at least partly owing to limited sample sizes. The objective of this study is to define not only the uses, but also the limitations of PET in patients with head and neck cancer. Nonrandomized, retrospective analysis of PET at an academic institution. The authors performed 146 PET scans on 133 patients with head and neck cancer. Eighteen patients (19 PET scans) with thyroid disorders were excluded. A minimum 1 year of follow-up was available in 84 patients, who were separated into groups based on whether the PET was used to detect unknown primary cancers (n = 20), stage neck nodal and distant metastases (n = 8), monitor response to nonsurgical therapy (n = 22), or detect recurrent or residual cancers (n = 34). The results of PET were compared with results from computed tomography (CT) and magnetic resonance imaging (MRI) performed in the same patients. Of the unknown primary cancers, PET correctly identified 7 of 20 primary sites, giving a sensitivity of 35%. When combined with CT or MRI, the sensitivity increased to 40%. When used for detection of metastatic disease, PET demonstrated five of five nodal metastases (100%) and two of four distant metastases (50%). In evaluating the response to nonsurgical therapy, PET had a sensitivity of 50% and a specificity of 83% for detecting tumor at the primary site and a sensitivity of 86% and a specificity of 73% for detecting nodal disease. When used for evaluation of recurrent/residual disease, PET identified seven of seven cases of local recurrences/residual disease and had a specificity of 85%. PET also detected seven of seven cases of nodal disease and had a specificity of 89%. For staging purposes, PET is limited by its lack of anatomic detail. However, PET compares favorably with CT and MRI in detecting recurrent/residual cancers. PET imaging complements the more traditional imaging modalities (CT or MRI), especially for an unknown primary cancer.

Respiratory motion blurs positron emission tomography (PET) images in thorax and abdominal regions, and can cause attenuation-related errors in quantitative parameters. In addition, this motion can cause localization error and disappearance of tumor(s) near the diaphragm. Respiratory gated PET imaging, or 4D PET imaging, is an attractive solution. For 4D PET, a surrogate measurement of the patient's breathing is made during the scan, and based on this measurement the list-mode PET data are sorted and reconstructed into multiple images. In several studies, it has been reported that 4D PET imaging recovers tumor volume more accurately than 3D PET imaging, and yields more accurate standard uptake values. In spite of its promise, 4D PET images suffer from statistical noise because only a fraction of the acquired data can be used in each image. Moreover, they also suffer from inconsistent attenuation correction due to mismatches between PET and CT images. In this paper, we propose a novel framework for phased attenuation correction and respiratory motion compensation for a 3D PET image by using a 3D CT image and multiple respiratory-phase 3D MR images. For phased attenuation correction, we generate and utilize 4D CT image obtained via non-rigid registrations among a 3D CT image and multiple respiratory-phase 3D MR images. A 3D PET image at a selected respiratory phase is then obtained by adding attenuation corrected multiple 3D PET images through non-rigid transformation. Experimental result for a clinical dataset shows that the proposed algorithm can provide much clearer organ boundary with improved quality than the conventional method in a 3D PET image.

To retrospectively compare fluorine 18 fluorodeoxyglucose (FDG) positron emission tomographic (PET) and computed tomographic (CT) findings at the same anatomic locations in patients with lymphoma by using a combined PET/CT scanner and to analyze the lesions on metabolic and anatomic bases to evaluate causes of discrepant findings between the two modalities. The institutional review board allowed an exempt retrospective review of cancer PET database, and informed consent was waived. The study was HIPAA compliant. Fifty-three patients with lymphoma (20 Hodgkin and 33 non-Hodgkin; mean age, 43 years; range, 12-83 years) who underwent FDG PET/CT were included. The PET and CT images were interpreted by two nuclear medicine physicians and one radiologist, respectively, blinded to the other imaging findings. Concordant PET and CT findings were regarded as positive or negative for lymphoma. The site with discordant findings was defined as positive for disease if it was accompanied by other PET- and CT-positive sites in the same patient or was confirmed clinically (histologic examination or progressive disease). Staging results were also compared by one nuclear medicine physician. Of a total of 1537 anatomic sites in 53 patients, 48 had discordant findings between PET and CT. Forty (83%) of the 48 sites had correct PET findings (31 positive, nine negative), five had correct CT findings, and three were unresolved. The 31 PET-positive and CT-negative sites accounted for 23% of all 134 true-positive PET sites. PET provided accurate staging in an incremental nine (17%, upstaging in four and downstaging in five) of 53 patients in whom CT staging was incorrect. CT provided correct upstaging in two patients. FDG PET/CT as a combined modality may contribute substantially to lesion characterization and staging in patients with lymphoma.

The detection of lymphoma by computed tomography (CT) scanning is known to be improved by positron emission tomography (PET) and/or gallium scanning, although the direct comparative accuracy of these imaging modalities remains a subject of ongoing review. The aim of the present study was to compare PET scanning with conventional imaging (CT and/or gallium scanning) in patients with lymphoma. A retrospective study of 38 patients (25 men; 13 women; median age 39.5 years; range 18.0-81.0 years) who had had PET scans (24 scans at initial staging and 46 scans at restaging, including suspected disease relapse) was carried out. Thirty-one concurrent gallium scans had been performed. Disease was validated with clinical follow up or biopsy. The sensitivities of PET and CT at initial staging were 96 and 71%, respectively. PET identified additional sites of disease compared with CT in 29% of patients. Of the 15 patients who had had all three imaging modalities, the sensitivities of PET, CT and gallium were 93, 67 and 87%, respectively. At treatment completion, the positive predictive values of PET, CT and gallium scans for relapse given a residual mass were 100, 33 and 0%, respectively (P = 0.006 for PET and CT comparison). The negative predictive values of PET, CT and gallium were 76, 0 and 70%, respectively (P-value not significant). In suspected disease relapse, PET results changed management in 50% of patients. Compared with CT and gallium scans, PET has superior accuracy in staging and restaging, and its greatest value lies in its positive predictive value for relapse in patients with residual masses.

The purpose of the investigation was to assess positron emission tomography (PET), computed tomography (CT) and the image fusion of PET and CT (PET/CT) in the detection of metastases from gastrointestinal neuroendocrine tumors. In a prospective study, thirty-one patients were consecutively examined using a state-of-the-art PET/CT. PET was performed with a carbohydrated F-18-labeled somatostatin receptor ligand (Gluc-Lys([(18)F]FP-TOCA) from the base of the skull to the proximal thigh using a Pico-3D PET scanner. CT was performed with a noncontrast low-dose CT (LD-CT) and a venous-dominant contrast-enhanced CT (VD-CT) from the base of the skull to the proximal thigh and a hepatic arterial-dominant contrast-enhanced CT (AD-CT) from the epigastric region using a 16-slice CT. The data sets from PET and CT (LD-CT and VD-CT) were fused automatically. To assess a relative sensitivity of each imaging modality, the total number of metastases by summing the number of metastases depicted for each patient by the highest sensitive modality was used as reference standard. PET, LD-CT, AD-CT, VD-CT, PET/LD-CT and PET/VD-CT showed a lesion-by-lesion based overall detection rate for liver metastases (n=858) of 90.8% (P<0.001), 29.4% (P<0.001), 45.5% (P<0.001), 73.9% (P<0.001), 91.5% (P<0.001) and 100%. PET, LD-CT, VD-CT, PET/LD-CT and PET/VD-CT showed an overall detection rate for lymph node metastases (n=193) of 93.8% (P<0.001), 25.4% (P<0.001), 64.8% (P<0.001), 93.8% (P<0.001) and 100% and for osseous metastases (n=567) of 98.6% (P<0.005), 40.7% (P<0.001), 40.7% (P<0.001), 100% and 100%. Furthermore, PET revealed 2 (22.2%) of 9 intrapulmonal lesions seen on LD-CT, VD-CT, PET/LD-CT and PET/VD-CT. PET as single modality revealed most liver, lymph node and osseous metastases. The combination of molecular/metabolic with anatomical/morphological information improves the diagnostic accuracy for the detection of metastases in comparison to any single imaging modality. LD-CT cannot replace VD-CT in the detection of liver and lymph node metastases, but was equal in the detection of osseous metastases and identifying of pulmonary lesions.

Whole-body positron emission tomography (PET) with F-fluorodeoxyglucose (FDG) has proven to be a very effective staging imaging modality in manymalignant tumours, particularly in lung cancer, malignant melanoma, lymphoma, colorectal cancer and head and neck tumours [1–7]. Since PET images have a fairly high resolution (,6 mm), even small lesions with an increased FDG uptake can be detected. This represents a critical advantage of PET over the conventional cross-sectional imaging modalities CT and MRI. PET can be used to identify tumour tissue on the basis of FDG uptake, rather than on the basis of morphological appearance or size, and thus also in lesions with a size less than 1 cm. Unfortunately, FDG–PET provides little anatomical information, and therefore it is sometimes difficult to determine where the lesions detected are located and what they represent. It is important for the surgeon to know precisely where lesions are located, especially for small tumours. Currently, comparison and juxtaposition of PET images and CT images serves to define the localization of the lesions. Owing to the different image slice thickness, the different positioning of the patient during the two examinations and the different states of nutrition, i.e. fasting for 4 h prior to FDG–PET, it is often very difficult and time consuming to match the images for exact anatomical localization. Image co-registration has been used to overcome these problems [8]. It has been recognized that proper image co-registration is rather difficult for whole-body examinations with separate scanners. For identical patient positioning during PET and CT scanning, special ‘‘cast forming’’ vacuum mattresses or other immobilization methods should be used. However, patients frequently find these methods of immobilization uncomfortable. Logistic problems also limit the use of image co-registration of PET and CT with separate scanners. Scheduling problems arise when performing the two examinations one after the other. These limitations restrict image co-registration with separate scanners to individual cases. In our experience, the exact localization of lesions is often not possible when juxtaposing PET and CT images. Examinations had to be repeated for exact image co-registration. As a result, image co-registration with separate scanners has never become routine in our practice. To overcome the problems related to software fusion, various prototype systems combining molecular and morphologic imaging have been developed. Hasegawa and colleagues proposed an integrated SPECT/CT scanner [9], and in 1999 Townsend and his colleagues at the University of Pittsburgh presented a prototype integrated PET/CT scanner by combining a CT scanner and a partial ring, rotating PET scanner in a single gantry [10, 11]. Such systems are attractive not only because of the ‘‘hardware’’ image coregistration capabilities but also because the CT data can be used to correct PET scans for patient self-absorption of the PET emission rays. This decreases the acquisition time for the correcting attenuation scans by an order of magnitude compared with the conventional techniques used in PET for this purpose, and decreases the overall imaging time by up to 30% depending on the CT system used. In March 2001, the first clinical integrated PET/ CT device (Discovery LS, GE Medical Systems, Milwaukee, USA) was installed at the University Hospital of Zurich in Switzerland. This novel inline system consists of a dedicated high resolution/ high sensitivity full-ring PET scanner (Advance Nxi) and a very fast high-end multi-detector spiral CT scanner (Light Speed Plus). The axes of both systems are mechanically aligned so that simple translation of the patient table by 60 cm moves the patient from the CT into the PET gantry. The resulting PET and CT images are ‘‘hardware’’ coregistered to an accuracy in the range of 1 mm. Data acquisition in the combined system is as follows. At 45–55 min post-injection of FDG and after bladder emptying a multidetector computed tomography scan is performed from the pelvic floor to the head (scan length, 86.7 cm) and normal end-expiration. Immediately after CT scanning, a PET emission scan is obtained covering the identical axial field of view using six PET fields of view. The acquisition time is 4 min at each table position. With this protocol it is The British Journal of Radiology, 75 (2002), S36–S38 E 2002 The British Institute of Radiology

The value of combined positron emission tomography (PET)/computed tomography (CT) in the follow-up of patients with breast cancer with elevated tumor markers but without proven metastases or local recurrence was assessed. Thirty-four women underwent PET/CT. The PET and CT images were first analyzed separately; fused findings were then interpreted, blinded to the results of the other modalities. The results of CT, PET, and PET/CT were compared with each other and correlated to the final diagnosis. The PET/CT identified 149 malignant foci in 24 patients (71%). The CT detected 96 of these foci in 18 patients, whereas PET identified 124 foci in 17 patients. Differences between CT and PET were not significant. Differences between PET/CT and CT (P < 0.01) and PET/CT and PET (P < 0.01) were significant. The person-based sensitivity of PET/CT, PET, and CT was 96%, 88% and 96%, respectively. Specificity of PET/CT, PET, and CT was 89%, 78%, and 78%, respectively. The PET/CT is a valuable modality for the follow-up of patients with breast cancer and elevated levels of tumor markers.

Use of PET and CT for noninvasive detection of distant metastatic disease in lung cancer has been validated by many detailed studies, including Maziak and colleagues' study in this issue. Given acc...