Faculty Bibliography

The success of chemotherapy in the treatment of malignancies may be limited by cellular mechanisms leading to drug resistance. In hematological malignancies, mechanisms leading to the development of multidrug resistance (MDR) include overexpression of the membrane-based export pump P-glycoprotein (Pgp) and the MDR-associated protein (MRP). Recently, the overexpression of the lung-resistance protein (LRP) has also been associated with reduced intracellular drug accumulation. A major problem in assessing the significance of the expression of these resistance proteins in clinical MDR has been the variability of detection techniques either at the mRNA or protein level. Currently, the detection of resistance proteins relies heavily on antibody and cDNA probes, and these methods may not be informative about the in vivo function of Pgp, MRP, or LRP. Nuclear medicine imaging techniques such as single-photon emission tomography (SPECT) and positron emission tomography (PET) have been evaluated for noninvasive determination of the presence and the function of Pgp- and MRP-mediated transport systems. Technetium 99m ((99m)Tc)-sestamibi, an agent in clinical use for myocardial perfusion and tumor imaging, is recognized as a substrate for Pgp and MRP, and has been used to visualize Pgp expression. (99m)Tc-tetrofosmin is also a substrate for the Pgp efflux pump mechanism and is used to evaluate Pgp function in in vitro and in vivo studies. Recently, radiopharmaceuticals including carbon 11-labeled colchicine, verapamil, and daunorubicin have been used in cell line and animal studies for the evaluation of Pgp-mediated transport functions using PET technology. Preliminary results suggest that the potential to detect MDR in tumors prior to or after exposure to chemotherapeutic agents exists in imaging using either (99m)Tc-labeled compounds and SPECT or positron emitting compounds and PET.

UNLABELLED:Early identification of chemotherapy-refractory lymphoma patients provides a basis for alternative treatment strategies. Metabolic imaging with (18)F-FDG PET offers functional tissue characterization that is useful for assessing response to therapy. Our objective was to determine the predictive value of (18)F-FDG PET early during chemotherapy (after 1 cycle) and at the completion of chemotherapy for subsequent progression-free survival (PFS) in patients with aggressive non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD). METHODS:(18)F-FDG PET (dual-head coincidence camera with attenuation correction) was performed before and after 1 cycle of chemotherapy on 30 patients (17 NHL, 13 HD; mean age, 52.3 +/- 16.0 y). For 23 of the 30 patients, (18)F-FDG PET data were also obtained after the completion of chemotherapy. The patients had a median follow-up of 19 mo (range, 18-24 mo). Follow-up of PFS was compared between patients with positive and negative (18)F-FDG PET results obtained after the first cycle of chemotherapy and at the completion of chemotherapy. RESULTS:Positive (18)F-FDG PET results obtained both after the first cycle and at the completion of therapy were associated with a shorter PFS (median, 5 and 0 mo, respectively) than were negative (18)F-FDG PET results (PFS medians not reached). A statistically significant difference in PFS between positive and negative (18)F-FDG PET results was obtained both after the first cycle and at the completion of chemotherapy (P < or = 0.001). The PFS and (18)F-FDG PET results obtained after the first cycle correlated better than those obtained after the completion of chemotherapy (r(2) = 0.45 vs. 0.17). (18)F-FDG PET had more false-negative results after the last cycle (6/17 cases, or 35%) than after the first cycle (2/13 cases, or 15%). Thus, (18)F-FDG PET had greater sensitivity and positive predictive values after the first cycle (82% vs. 45.5% and 90% vs. 83%, respectively) than after the last cycle. CONCLUSION/CONCLUSIONS:(18)F-FDG PET after 1 cycle of chemotherapy is predictive of 18-mo outcome in patients with aggressive NHL and HD and may earlier identify patients who would benefit from more intensive treatment programs.

Monoclonal antibodies (mAbs) to prostate-specific antigens, such as PSMA, have great potential as diagnostic and therapeutic tools in the management of advanced prostate cancer. PSMA is a very attractive target for mAb-based imaging. It is expressed by virtually all prostate cancers and its expression is further increased in poorly differentiated, metastatic, and hormone-refractory carcinomas. The ProstaScint scan (Cytogen, Princeton, NJ), based on the mAb 7E11-C5.3, is currently approved for the imaging of prostate cancer in soft tissue but is not approved for imaging bone metastases. It appears superior to conventional imaging studies for soft-tissue disease but has limitations attributed to its intracellular binding site on PSMA. Overcoming this limitation, new mAbs to the extracellular domain of PSMA have been developed. The radioisotopes, (111)Indium, (90)Yttrium, and (177)Lutetium have been conjugated to one such mAb, J591. Radioimmunoscintigraphy with this immunoconjugate has demonstrated excellent tumor targeting of prostate cancer sites not only in soft tissue but also in bone.

In hematological malignancies, multidrag resistance (MDR) has been associated with the drag efflux pumps: one is the classical Mr 170,000 P-glycoprotein (Pgp) and the other Mr 190,000 multidrag resistance-associated protein (MRP). In addition, the overexpression of a recently identified protein, lung resistance protein (LRP), is also associated with reduced intracellular drag accumulation and retention. Currently available detection methods may provide variable results among laboratories, as there is no single set of standards for detection techniques at the mRNA or protein level. Moreover, these methods may not be informative about the in vivo function of Pgp, MRP or LRP. Single-photon emission tomography (SPECT) and positron emission tomography (PET) have been evaluated for the non-invasive determination of Pgp- and MRP- mediated transport systems. Tc-99m-hexaxis-2-methoxyisobutyl isonitrile (Tc-99m-Sestamibi), an agent used in myocardial perfusion and tumor imaging, is a substrate for Pgp and MRP, and has been used for tumor imaging, and to visualize Pgp expression. Tc-99m-Tetrofosmin and several Tc-99m-Q complexes, are also recognized as substrates by Pgp pump mechanism. Moreover, radiopharmaceuticals including carbon-11-labeled colchicine, verapamil and daunorabicin have been used for the assessment of Pgp-mediated transport functions in vivo using PET technology. The results suggest that the potential exists for nuclear medicine imaging using either Tc-99m-labeled compounds and SPECT or carbon-11-labeled compounds and PET to detect MDR in tumors prior to or after exposure to chemotherapeutic agents.

Tomographic imaging with either F-18 fluoro deoxyglucose (FDG) (a nonmetabolizable glucose analog that reflects tumor increased glucose metabolism) or technetium Tc-99m Depreotide (a synthetic peptide that binds with high affinity to cell surface receptors with increased expression on certain tumor cells) provides improved sensitivity and specificity in the differential diagnosis of solitary pulmonary nodules (SPN) compared with noninvasive and some invasive procedures. F-18 FDG requires instrumentation capable of coincident imaging whereas Tc-99m Depreotide can be imaged on standard gamma cameras equipped to perform single photon emission computed tomography (SPECT) imaging. Either technique performs better than CT alone, and both are cost effective on the basis of reducing unnecessary biopsies and thoracotomies in patients with negative studies indicating that the SPN is nonmalignant.

Although nuclear medicine imaging is still widely under-appreciated and underused by the medical and radiologic communities, FDG PET imaging and Tc 99m depreotide SPECT imaging are safe, cost-effective methods with advantages over CT and other imaging methods in the diagnosis and management of patients suspected or known to have lung cancer. Physicians involved in the care of these patients should familiarize themselves with both of these relatively new nuclear medicine imaging procedures. Both F-18 FDG PET imaging and Tc 99m depreotide SPECT imaging have a high degree of sensitivity, specificity, overall accuracy, and both PPV and NPV in the management of patients with a solitary pulmonary nodule. Nuclear imaging with either of these agents provides a noninvasive, cost-effective method to select patients for aggressive intervention without contributing to increased morbidity. There has not been a direct comparison of these two techniques in terms of their relative role and cost-effectiveness in the management of patients with a solitary pulmonary nodule. Both methods have incremental value over CT imaging in selecting patients with solitary pulmonary nodules either for invasive biopsy or for thoracotomy. To date, only FDG PET has been proved to have additional application in: 1. Improving the staging of patients by identifying or excluding mediastinal disease. Some authors are reluctant at the present time to deny patients an opportunity for curative resection based on the finding of foci of increased metabolism in the mediastinum (characterized by increased FDG activity) because there are occasional false-positive studies. They propose, however, that a negative study justifies a surgical approach (and an opportunity for cure) regardless of the findings on CT. 2. Evaluation of therapy and early detection of recurrence by using FDG PET imaging as a monitoring procedure. Tc 99m depreotide may have a role also in these other clinical indications for imaging in patients with lung carcinoma. It is too soon, however, to know if Tc 99m depreotide SPECT imaging, properly performed, can mimic the success of FDG PET in the detection or exclusion of mediastinal metastases, evaluating the response to therapy, and the early detection of recurrent disease during post-therapeutic monitoring.

Positron emission tomography (PET) imaging has become a very useful technique for staging and monitoring therapy response in lymphoma, providing unique information about the biological behavior of disease. Increased fluorine-18 fluorodeoxyglucose (FDG) uptake in lymphoma is based on elevated glycolysis and longer residence time of FDG in malignant cells compared with most normal tissues. The metabolic information provided by this technique suggests that FDG-PET may be more sensitive than the anatomical imaging modalities. Computed tomography (CT) is the principal imaging modality for the staging and restaging of lymphoma. Nonetheless, this technique has significant shortcomings, particularly in the post-therapy setting. Gallium-67 scintigraphy has played an important role in monitoring response to therapy and follow-up of patients; however, the sensitivity of 67Ga depends on the subtype of lymphoma and the size and location of disease. Published results strongly indicate that FDG-PET is superior to 67Ga imaging and may be equal or superior to CT for the detection of nodal as well as extranodal involvement in lymphoma.

With the advent of positron emission tomography (PET), metabolic imaging has become a reality for tumor staging and monitoring response to therapy in lymphoma. Increased Fluorine-18 fluorodeoxyglucose ([(18)F]FDG) uptake in lymphomas has been well documented in the literature; it is based upon elevated glycolysis and longer residence time of FDG in malignant cells compared to most normal tissues. This suggests that in tumor staging, FDG-PET may be more sensitive and specific than the anatomic imaging modalities. Computed tomography (CT) is the standard imaging modality for the staging and restaging of lymphoma, and Gallium-67 ((67)Ga) scintigraphy has played an important role in monitoring response to therapy and follow-up of patients. Published results suggest that FDG-PET is superior to (67)Ga imaging and may be equal or superior to CT for the detection of nodal as well as extranodal involvement in lymphoma.

UNLABELLED:In a prospective study, we correlated the washout rates of 99mTc-sestamibi (MIBI) and the degree of MIBI accumulation with the expression of P-glycoprotein (Pgp) in tumor tissues in a total of 46 patients with lung cancer. METHODS:All patients underwent early (30 min) and delayed (3 hr) MIBI imaging and bronchoscopic biopsy before initiation of chemo- or radiotherapy. The interval between biopsy and imaging varied between 2 and 10 days. All patients had radiologically detectable tumors. Immunohistochemical studies were performed on paraffin sections using a monoclonal antibody, JSB-1, developed against the internal epitope of Pgp. Normal tissue and tumor washout rates and tumor-to-background ratios were correlated with the level of Pgp expression. RESULTS:There was an inverse correlation between tumor-to-background ratios and the density of Pgp (p = 0.001), whereas there was no appreciable correlation between tumor washout rates of MIBI and the level of Pgp expression (p = 0.414). CONCLUSION/CONCLUSIONS:The current data strongly suggest that, although the reduced ability for the tumors to accumulate MIBI correlates well with the increased levels of Pgp expression, tumor washout rates of MIBI do not correlate with the density of Pgp in tumor tissues. Our results also warrant additional research for correlating immunohistological and imaging findings with messenger RNA levels determined by polymerase chain reaction and flow cytometry.

UNLABELLED:We prospectively studied a total of 30 patients with breast cancer to evaluate the relationship between the degree of accumulation of 99mTc-sestamibi (MIBI) and the heterogeneity of p-glycoprotein expression in tumor tissues. METHODS:Twenty patients during initial presentation and 10 patients during post-therapy evaluation underwent contemporaneous 99mTc-MIBI imaging and surgery or biopsy. Immunohistochemical studies were performed on multiple nonconsecutive sections of the same tumor using a p-glycoprotein-specific monoclonal antibody, JSB-1. Tumor-to-background (T/B) ratios were correlated with the level and heterogeneity of p-glycoprotein expression determined by immunohistochemical studies. RESULTS:The T/B ratios were lower for those tumors with strong p-glycoprotein expression (Group 1) than those with strong-to-weak expression (Group 2) or those with weak-to-no expression (Group 3) (1.32 +/- 0.19 and 1.85 +/- 0.56 and 2.86 +/- 1.06, respectively). There was statistically significant difference in T/B ratios between all 3 groups (p < 0.005). Although T/B ratios for Group 1 and Group 3 were clearly distinct from one another with no overlapping values, the values for Group 2 overlapped with those of Group 1 and Group 3. When we evaluated the entire patient group with excluding those with strong-to-weak expression, although the p value remained the same (p < 0.001), we obtained a stronger correlation between T/B ratios and p-glycoprotein expression (r = 0.808 versus 0.735). CONCLUSION/CONCLUSIONS:Due to the heterogeneous expression of p-glycoprotein, both immunohistochemistry and 99mTc-MIBI scintigraphy may yield confounding results by contrasting with one another if the presence or absence of p-glycoprotein is not extensively explored. Although our data confirmed that 99mTc-MIBI imaging is useful in the determination of the presence of multidrug resistance in patients with breast cancer, the issue of heterogeneous expression of the antigen should be further investigated when unexpected results are obtained.