Chaitanya Divgi

Positron Emission Tomography/Computed Tomography Identification of Clear Cell Renal Cell Carcinoma: Results From the REDECT Trial

PURPOSEnA clinical study to characterize renal masses with positron emission tomography/computed tomography (PET/CT) was undertaken.nnnPATIENTS AND METHODSnThis was an open-label multicenter study of iodine-124 ((124)I) -girentuximab PET/CT in patients with renal masses who were scheduled for resection. PET/CT and contrast-enhanced CT (CECT) of the abdomen were performed 2 to 6 days after intravenous (124)I-girentuximab administration and before resection of the renal mass(es). Images were interpreted centrally by three blinded readers for each imaging modality. Tumor histology was determined by a blinded central pathologist. The primary end points-average sensitivity and specificity for clear cell renal cell carcinoma (ccRCC)-were compared between the two modalities. Agreement between and within readers was assessed.nnnRESULTSn(124)I-girentuximab was well tolerated. In all, 195 patients had complete data sets (histopathologic diagnosis and PET/CT and CECT results) available. The average sensitivity was 86.2% (95% CI, 75.3% to 97.1%) for PET/CT and 75.5% (95% CI, 62.6% to 88.4%) for CECT (P = .023). The average specificity was 85.9% (95% CI, 69.4% to 99.9%) for PET/CT and 46.8% (95% CI, 18.8% to 74.7%) for CECT (P = .005). Inter-reader agreement was high (κ range, 0.87 to 0.92 for PET/CT; 0.67 to 0.76 for CECT), as was intrareader agreement (range, 87% to 100% for PET/CT; 73.7% to 91.3% for CECT).nnnCONCLUSIONnThis study represents (to the best of our knowledge) the first clinical validation of a molecular imaging biomarker for malignancy. (124)I-girentuximab PET/CT can accurately and noninvasively identify ccRCC, with potential utility for designing best management approaches for patients with renal masses.

Preparation and Characterization of l-[5-11C]-Glutamine for Metabolic Imaging of Tumors

Recently, there has been a renewed interest in the study of tumor metabolism above and beyond the Warburg effect. Studies on cancer cell metabolism have provided evidence that tumor-specific activation of signaling pathways, such as the upregulation of the oncogene myc, can regulate glutamine uptake and its metabolism through glutaminolysis to provide the cancer cell with a replacement of energy source. Methods: We report a convenient procedure to prepare l-[5-11C]-glutamine. The tracer was evaluated in 9L and SF188 tumor cells (glioma and astrocytoma cell lines). The biodistribution of l-[5-11C]-glutamine in rodent tumor models was investigated by dissection and PET. Results: By reacting 11C-cyanide ion with protected 4-iodo-2-amino-butanoic ester, the key intermediate was obtained in good yield. After hydrolysis with trifluoroacetic and sulfonic acids, the desired optically pure l-[5-11C]-glutamine was obtained (radiochemical yield, 5% at the end of synthesis; radiochemical purity, >95%). Tumor cell uptake studies showed maximum uptake of l-[5-11C]-glutamine reached 17.9% and 22.5% per 100 μg of protein, respectively, at 60 min in 9L and SF188 tumor cells. At 30 min after incubation, more than 30% of the activity appeared to be incorporated into cellular protein. Biodistribution in normal mice showed that l-[5-11C]-glutamine had significant pancreas uptake (7.37 percentage injected dose per gram at 15 min), most likely due to the exocrine function and high protein turnover within the pancreas. Heart uptake was rapid, and there was 3.34 percentage injected dose per gram remaining at 60 min after injection. Dynamic small-animal PET studies in rats bearing xenografted 9L tumors and in transgenic mice bearing spontaneous mammary gland tumors showed a prominent tumor uptake and retention. Conclusion: The data demonstrated that this tracer was favorably taken up in the tumor models. The results suggest that l-[5-11C]-glutamine might be useful for probing in vivo tumor metabolism in glutaminolytic tumors.

Current Role of Metaiodobenzylguanidine in the Diagnosis of Pheochromocytoma and Medullary Thyroid Cancer

Despite early reports of excellent diagnostic characteristics of [(131)I]/[(123)I]-metaiodobenzylguanidine (MIBG) in the evaluation of pheochromocytomas/paragangliomas (PHEOs/PGLs) or medullary thyroid cancer as experience with it was accumulated, the sensitivity dropped. Nevertheless, this modality is still useful in the diagnostic work-up of PHEOs/PGLs because it is widely available, and in case of positive scans it might indicate patients who are potential candidates for [(131)I]MIBG therapy.

Single Institution Experience with Lymphatic Microsurgical Preventive Healing Approach (LYMPHA) for the Primary Prevention of Lymphedema

BackgroundAs many as 40xa0% of breast cancer patients undergoing axillary lymph node dissection (ALND) and radiotherapy develop lymphedema. We report our experience performing lymphatic–venous anastomosis using the lymphatic microsurgical preventive healing approach (LYMPHA) at the time of ALND. This technique was described by Boccardo, Campisi in 2009.MethodsLYMPHA was offered to node-positive women with breast cancer requiring ALND. Afferent lymphatic vessels, identified by injection of blue dye in the ipsilateral arm, were sutured into a branch of the axillary vein distal to a competent valve. Follow-up was with pre- and postoperative lymphoscintigraphy, arm measurements, and (L-Dex®) bioimpedance spectroscopy.ResultsOver 26xa0months, 37 women underwent attempted LYMPHA, with successful completion in 27. Unsuccessful attempts were due to lack of a suitable vein (nxa0=xa03) and lymphatic (nxa0=xa05) or extensive axillary disease (nxa0=xa01). There were no LYMPHA-related complications. Mean follow-up time was 6xa0months (range 3–24xa0months). Among completed patients, 10 (37xa0%) had a body mass index of ≥30xa0kg/m2 (mean 27.9xa0±xa06.8xa0kg/m2, range 17.4–47.6xa0kg/m2), and 17 (63xa0%) received axillary radiotherapy. Excluding two patients with preoperative lymphedema and those with less than 3-month follow-up, the lymphedema rate was 3 (12.5xa0%) of 24 in successfully completed and 4 (50xa0%) of 8 in unsuccessfully treated patients.ConclusionsOur transient lymphedema rate in this high-risk cohort of patients was 12.5xa0%. Early data show that LYMPHA is feasible, safe, and effective for the primary prevention of breast cancer-related lymphedema.

Dosimetric Considerations in Radioimmunotherapy and Systemic Radionuclide Therapies: A Review

Radiopharmaceutical therapy, once touted as the “magic bullet” in radiation oncology, is increasingly being used in the treatment of a variety of malignancies; albeit in later disease stages. With ever-increasing public and medical awareness of radiation effects, radiation dosimetry is becoming more important. Dosimetry allows administration of the maximum tolerated radiation dose to the tumor/organ to be treated but limiting radiation to critical organs. Traditional tumor dosimetry involved acquiring pretherapy planar scans and plasma estimates with a diagnostic dose of intended radiopharmaceuticals. New advancements in single photon emission computed tomography and positron emission tomography systems allow semi-quantitative measurements of radiation dosimetry thus allowing treatments tailored to each individual patient.

Whither goest thou, radiopharmaceutical therapy?

This issue of the Journal of Nuclear Medicine includes a report of a promising agent for the radiopharmaceutical therapy of metastatic melanoma (1). The report is provocative for several reasons: it provides a potential unmet therapeutic need in a disease with a dismal prognosis, it underscores the need for a companion diagnostic imaging biomarker to appropriately select patients for therapy, it highlights the changing spectrum of molecularly targeted therapies in diseases beyond the pale of standard cytotoxic chemotherapy, and it raises the issue of whether radiopharmaceutical therapy will ever be meaningfully used in patients with cancer. This perspective details the challenges and potential of radiopharmaceutical therapy development, particularly when associated with a companion diagnostic imaging biomarker.

Trans-Arterial I-131 Lipiodol Therapy of Liver Tumors

Trans-arterial radiotherapy for liver malignancies began with iodine-131 labeled lipiodol for hepatocellular carcinoma (HCC). This agent continues to be used, labeled with 131I as well as with other radionuclides that emit β-particles, notably rhenium-188. Particulates such as glass and albumin microspheres labeled with yttrium-90 have also been utilized, and their physical characteristics have enabled evaluation of their utility in metastatic liver cancers as well, with considerable success.

Targeted Therapy for Bone Metastasis

Bone metastases markedly reduce the quality of life due to bone pain, pathologic fractures, loss of mobility, and hypercalcemia. A graded three step approach, as recommended by WHO, is used to treat pain according to its severity. Usually nonsteroidal anti-inflammatory drugs are used in patients with mild to moderate pain. When pain persists or increases a weak opioid, such as codeine or hydrocodone is added. Higher doses or more potent opioids are used if the pain persists or becomes more severe. Bisphosphonates are useful in the treatment of osteoporosis and metastatic disease by decreasing the resorption of bone. They bind to bone mineral and directly interfere with the activation of osteoclasts. Bisphosphonates are internalized in the osteoclasts and inhibit specific biochemical and metabolic pathways in these cells. Bisphosphonates reduce skeletal complications and reduce the rate of development of new lesions and delay progression in bone metastases. External beam radiation therapy is effective for localized bone pain due to bone metastasis. It provides rapid pain relief that can start as early as 48 h after the commencement of therapy. Radiation destroys viable tumor cells and enables osteoblastic repair of damaged bone. Radiotherapy may be given as a single dose or multifractionated dose. There is preferential use of the multifractionated dose method in USA. Therapy with bone-seeking radiopharmaceuticals is efficacious to reduce pain in patients with widespread painful bone metastases. Beta-emitting nuclide phosphorus-32 (32P) sodium phosphate or orthophosphate, strontium-89 (89Sr) chloride, and samarium-153 ethylene diamine tetramethylene phosphonic acid (153Sm-EDTMP) have been approved for clinical use in the USA. All agents have advantages and side effects. Moreover, the sources of radiation within bone differ with the radiopharmaceutical used. The metallic chelated radiotracers tend to chemically absorb to the trabecular surface, whereas 32P-sodium orthophosphate and 89Sr-chloride distribute more widely throughout bone. 89Sr-chloride is one of the two FDA-approved radiopharmaceuticals that has largely replaced 32P-sodium orthophosphate in the treatment of metastatic bone pain. The onset of pain relief commonly occurs within 7–21 days, and mean duration of relief is about 2–6 months. Retreatment can be given after 90 days, although multiple xadtherapies may lead to greater marrow toxicity. 89Sr-chloride has been extensively used, mainly in the treatment of bone pain from breast and prostate cancer. Radionuclide therapy can be administered in association with chemotherapy. The combination may enhance pain relief and delay the onset of new painful metastases. 153Sm-EDTMP is a stable complex that selectively accumulates in skeletal tissue. Bone metastasis may contain 3–5 times more 153Sm-EDTMP than healthy bone tissue. The low energy of the beta particle reduces the radiation burden to bone marrow. Hematological side effects are generally mild. Pain relief is generally noted within 5–10 days and can last up to 4 months. Repeated dosing of 153Sm-EDTMP is feasible if pain returns or increases. Patients referred for bone pain therapy have multiple painful bone metastases confirmed by a bone scan which shows multiple focal sites of increased radiopharmaceutical uptake and who is experiencing worsening of bone pain, in spite of narcotic pain medication. In patients with established bone metastases, hormonal or chemotherapy can palliate symptoms, but rarely produces durable control. Recent data offer a compelling rationale to combine chemotherapy with bone-seeking radiopharmaceuticals for prolonging survival and enhance quality of life.

A Clinician’s Guide to Next Generation Imaging in Patients With Advanced Prostate Cancer (Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence [RADAR] III)

Purpose: The advanced prostate cancer therapeutic landscape has changed dramatically in the last several years, resulting in improved overall survival of patients with castration naïve and castration resistant disease. The evolution and development of novel next generation imaging techniques will affect diagnostic and therapeutic decision making. Clinicians must navigate when and which next generation imaging techniques to use and how to adjust treatment strategies based on the results, often in the absence of correlative therapeutic data. Therefore, guidance is needed based on best available information and current clinical experience. Materials and Methods: The RADAR (Radiographic Assessments for Detection of Advanced Recurrence) III Group convened to offer guidance on the use of next generation imaging to stage prostate cancer based on available data and clinical experience. The group also discussed the potential impact of next generation imaging on treatment options based on earlier detection of disease. Results: The group unanimously agreed that progression to metastatic disease is a seminal event for patient treatment. Next generation imaging techniques are able to detect previously undetectable metastases, which could redefine the phases of prostate cancer progression. Thus, earlier systemic or locally directed treatment may positively alter patient outcomes. Conclusions: The RADAR III Group recommends next generation imaging techniques in select patients in whom disease progression is suspected based on laboratory (biomarker) values, comorbidities and symptoms. Currently 18F-fluciclovine and 68Ga prostate specific membrane antigen positron emission tomography/computerized tomography are the next generation imaging agents with a favorable combination of availability, specificity and sensitivity. There is ongoing research of additional next generation imaging technologies, which may offer improved diagnostic accuracy and therapeutic options. As next generation imaging techniques evolve and presumably result in improved global accessibility, clinician ability to detect micrometastases may be enhanced for decision making and patient outcomes.

Do We Need Yet Another Hybrid Imaging Device

The arrival of another hybrid imaging modality fills us with excitement and despair. Excitement at the prospect of simultaneously using different ways of interrogating pathophysiology non-invasively in vivo; despair at the invariable increase in costs associated with its use. Is it any use, we ask, is it worth it? The accompanying article by Fraum et al (1) provides a broad and sweeping overview of the various ways in which whole body positron emission tomography/magnetic resonance imaging (PET/MRI) can identify and characterize numerous malignancies. The article provides comparisons of PET/MRI and positron emission tomography/computed tomography (PET/CT)—the latter the current standard for hybrid imaging—and concludes that this novel hybrid imaging modality can provide comparable and sometimes clinical information in a variety of cancers. The new modality does seem to be of use. We, however, need to determine its incremental utility. There are now two classes of PET/MRI devices: nontime of flight (non-ToF) devices with avalanche photodiodes (APD), and time of flight (ToF) devices with silicon photodiodes. Attenuation correction using magnetic resonance (MR) remains challenging for bone as well as air (2), with consequent impact on PET quantification. Although acquisition of the MR signal (for attenuation correction as well as for MRspecific sequences) occupies more of the acquisition time necessary for PET, it is indeed simultaneous, in contrast to the sequential nature of PET/CT. Moreover, additional MR sequences—of the same area, at the same time—can be obtained during the PET acquisition. PET/MRI thus enables simultaneous acquisition of linked imaging characteristics—for example, kinetics of exogenous choline (administered as a PET tracer) with changes in endogenous choline (measured by MR proton spectroscopy). CT provides structural information (as a radiodensity map); MR provides much more pathophysiologic information: water content, oxygenation, molecular concentrations. The marriage of PET and MRI may, by enabling the interrogation of multiple pathophysiologic characteristics, potentially provide far greater information than currently available with PET/CT (3). PET/MRI can certainly provide comparable and complementary clinical information to PET/CT. Data regarding its utility are being gathered in prospective trials, as recommended recently at a workshop, where reimbursement considerations were also discussed (4). What only time will answer, however, is whether imaging groups will commit to the high investments necessary for PET/MRI, especially given current health-care cost constraints (not to mention the investments already made in PET/CT). What is more certain is the potential for PET/MRI to uniquely enhance our understanding of pathophysiology by providing complementary functional information. For those of us fortunate enough to be able to acquire such a device, many questions can now be explored; the device is worth it. Glutamine uptake measured by PET could be compared to endogenous hydroxyglutarate levels measured by MR, glucose uptake with tissue oxygenation. Such correlative assessments would yield new knowledge into the functional states of disease, enabling better drug discovery, development, and eventually selection. This last item will demonstrate the incremental utility of PET/MRI, enabling its optimal use in our clinical practice, and making it truly worth it.