18F-FDG-PET/CT Imaging for Gastrointestinal Malignancies.

Gastrointestinal malignancies encompass a variety of primary tumor sites, each with different staging criteria and treatment approaches. In this review we discuss technical aspects of 18F-FDG-PET/CT scanning to optimize information from both the PET and computed tomography components. Specific applications for 18F-FDG-PET/CT are summarized for initial staging and follow-up of the major disease sites, including esophagus, stomach, hepatobiliary system, pancreas, colon, rectum, and anus.

The utility of initial staging PET-CT as a baseline scan for surveillance imaging in stage II and III melanoma.

BACKGROUND: This study evaluates the utility of whole-body PET-CT for the initial staging and subsequent surveillance imaging of patients with completely resected stage II and stage III melanoma. METHODS: A single-center, retrospective review of patients who received perioperative whole-body PET-CT from January 1, 2005 to December 1, 2019 within three months of initial melanoma diagnosis was performed. RESULTS: Of 258 total patients with completely resected melanoma who had a PET-CT within 3 months after their melanoma diagnosis, 113 had stage II and 145 had stage III melanoma. PET-CT detected distant metastasis in 3 (2.7%) of 113 stage II patients and 7 (4.8%) of 145 stage III patients. 179 of 258 patients had adequate follow-up time to determine whether they received surveillance cross-sectional imaging and whether they had a melanoma recurrence. 143 (79.9%) received subsequent surveillance imaging, 74 of whom developed a recurrence. In 64 (86.5%) of 74 cases, recurrence was detected by routine surveillance. 26 (34.2%) of 76 stage II and 65 (63.1%) of 103 stage III patients developed a recurrence. The median time to recurrence among the 179 patients for stage II and III was 16.3 and 13.0 months, respectively. CONCLUSIONS: These findings indicate that baseline staging with whole-body PET-CT rarely provides information that changes initial management. Rather, the value of the initial PET-CT is as a baseline for subsequent surveillance scans. Therefore, it may be premature to discourage cross-sectional imaging for patients with stage II and III melanoma without supportive evidence or a reliable biomarker of recurrent disease.

Molecular Imaging in the Head and Neck: Diagnosis and Therapy.

This article is a summary of the most up-to-date applications of radiopharmaceuticals to the diagnosis and therapy of benign and malignant diseases involving endocrine or neuroendocrine organs of the head and neck, focusing on radiotracers approved by the US Food and Drug Administration, such as I-123- and I-131-sodium iodide, F-18-fluorodeoxyglucose, Tc99m-sestamibi, as well as the more recently approved tracers Ga-68 DOTATATE and Lu-177 DOTATATE.

Predictors of Survival in 211 Patients with Stage IV Pulmonary and Gastroenteropancreatic MIBG-Positive Neuroendocrine Tumors Treated with 131I-MIBG.

This retrospective analysis identifies predictors of survival in a cohort of patients with meta-iodobenzylguanidine (MIBG)-positive stage IV pulmonary and gastroenteropancreatic neuroendocrine tumor (P/GEP-NET) treated with 131I-MIBG therapy, to inform treatment selection and posttreatment monitoring. Methods: Survival, symptoms, imaging, and biochemical response were extracted via chart review from 211 P/GEP-NET patients treated with 131I-MIBG between 1991 and 2014. For patients with CT follow-up (n = 125), imaging response was assessed by RECIST 1.1 if images were available (n = 76) or by chart review of the radiology report if images could not be reviewed (n = 49). Kaplan-Meier analysis and Cox multivariate regression estimated survival and progression-free survival benefits predicted by initial imaging, biochemical response, and symptomatic response. Results: All patients had stage IV disease at the time of treatment. Median survival was 29 mo from the time of treatment. Symptomatic response was seen in 71% of patients, with the median duration of symptomatic relief being 12 mo. Symptomatic response at the first follow-up predicted a survival benefit of 30 mo (P < 0.001). Biochemical response at the first clinical follow-up was seen in 34% of patients, with stability of laboratory values in 48%; response/stability versus progression extended survival by 40 mo (P < 0.03). Imaging response (20% of patients) or stability (60%) at the initial 3-mo follow-up imaging extended survival by 32 mo (P < 0.001). Additionally, multiple 131I-MIBG treatments were associated with 24 mo of additional survival (P < 0.05). Conclusion: Therapeutic 131I-MIBG for metastatic P/GEP-NETs appears to be an effective means of symptom palliation. Imaging, biochemical, and symptomatic follow-up help prognosticate expected survival after 131I-MIBG therapy. Multiple rounds of 131I-MIBG are associated with prolonged survival.

Utility of Radionuclide Bone Scintigraphy in Complex Regional Pain Syndrome.

PURPOSE OF REVIEW: To describe the current understanding of the role of three-phase bone scintigraphy (TPBS) in the diagnosis and management of complex regional pain syndrome (CRPS), discuss its advantages and limitations, and present three examples of TPBS patterns typically seen in CRPS patients. RECENT FINDINGS: CRPS is a debilitating disorder frequently presenting with pain to ordinarily non-painful stimuli, redness, swelling, following fractures, stroke, myocardial infarction, surgery, or even minor trauma, and its diagnosis, based on clinical criteria and supportive imaging findings, is difficult. Of the available adjunctive diagnostic imaging modalities, radionuclide bone scintigraphy using a TPBS protocol is the most sensitive and specific for detecting abnormalities commonly seen with this condition-classically, increased periarticular uptake on delayed phase of TPBS, with variable increased uptake on perfusion phases, depending on chronicity. Recent studies have (1) demonstrated a more heterogeneous correlation of TPBS findings with CRPS diagnosis using the current Budapest criteria than in studies using older criteria, (2) pointed to the utility of novel quantitative scintigraphic techniques, and (3) highlighted the value of the early perfusion phases of TPBS in predicting treatment response. TPBS remains a valuable imaging adjunct to clinical diagnosis of CRPS. In combination with a multi-modal analgesic approach, TPBS can be used to follow disease course and potentially treatment response, although prospective trials are needed to further delineate its role.

A practical method of I-131 thyroid cancer therapy dose optimization using estimated effective renal clearance.

In thyroid cancer patients with renal impairment or other complicating factors, it is important to maximize I-131 therapy efficacy while minimizing bone marrow and lung damage. We developed a web-based calculator based on a modified Benua and Leeper method to calculate the maximum I-131 dose to reduce the risk of these toxicities, based on the effective renal clearance of I-123 as measured from two whole-body I-123 scans, performed at 0 and 24 h post-administration.

Unusual Soft Tissue Uptake of F-18 Sodium Fluoride in Three Patients Undergoing F-18 NaF PET/CT Bone Scans for Prostate Cancer.

Three males aged 71 to 80 years with known stage IV metastatic prostate cancer underwent F-18 sodium fluoride (NaF) PET/CT to assess osseous metastatic disease burden and stability. In addition to F-18 NaF avid known osseous metastases, each patient also exhibited increased F-18 NaF activity in soft tissues. The first patient exhibited multiple F-18 NaF avid enlarged retroperitoneal and pelvic lymph nodes on consecutive PET/CT scans. The second patient demonstrated an F-18 NaF avid thyroid nodule on consecutive PET/CT scans. The third patient exhibited increased F-18 NaF activity in a hepatic metastasis.

Comparison of Bayesian penalized likelihood reconstruction versus OS-EM for characterization of small pulmonary nodules in oncologic PET/CT.

OBJECTIVE: To determine whether the recently introduced Bayesian penalized likelihood PET reconstruction (Q.Clear) increases the visual conspicuity and SUVmax of small pulmonary nodules near the PET resolution limit, relative to ordered subset expectation maximization (OS-EM). METHODS: In this institutional review board-approved and HIPAA-compliant study, 29 FDG PET/CT scans performed on a five-ring GE Discovery IQ were retrospectively selected for pulmonary nodules described in the radiologist's report as "too small to characterize", or small lung nodules in patients at high risk for lung cancer. Thirty-two pulmonary nodules were assessed, with mean CT diameter of 8 mm (range 2-18). PET images were reconstructed with OS-EM and Q.Clear with noise penalty strength ß values of 150, 250, and 350. Lesion visual conspicuity was scored by three readers on a 3-point scale, and lesion SUVmax and background liver and blood pool SUVmean and SUVstdev were recorded. Comparison was made by linear mixed model with modified Bonferroni post hoc testing; significance cutoff was p < 0.05. RESULTS: Q.Clear improved lesion visual conspicuity compared to OS-EM at ß = 150 (p < 0.01), but not 250 or 350. Lesion SUVmax was increased compared to OS-EM at ß = 150 and 250 (p < 0.01), but not 350. CONCLUSION: In a cohort of small pulmonary nodules with size near an 8 mm PET full-width half maximum, Q.Clear significantly increased lesion visual conspicuity and SUVmax compared to our standard non- time-of-flight OS-EM reconstruction, but only with low noise penalization. Q.Clear with ß = 150 may be advantageous when evaluation of small pulmonary nodules is of primary concern.

Patient and tumor characteristics predictive of an elevated hepatopulmonary shunt fraction before radioembolization of hepatic tumors.

OBJECTIVE: To determine whether any patient or hepatic tumor characteristics are predictive of hepatopulmonary shunt fraction when performed before radioembolization. MATERIALS AND METHODS: A retrospective review was performed on 190 patients who underwent preradioembolization hepatic arteriography with calculation of hepatopulmonary shunt fraction using technetium-99m-labeled macroaggregated albumin perfusion scintigraphy. Patient and tumor characteristics including imaging features were reviewed for correlation with absolute shunt fraction, shunt fraction greater than 10%, and shunt fraction greater than 20%. RESULTS: Most tumor types showed some cases of elevated shunt fraction greater than 10%. Six patients had a shunt fraction greater than 20%: four were hepatocellular carcinoma and two were neuroendocrine tumor metastases. Univariate analysis showed that dominant tumor diameter, hepatic tumor burden, vascular invasion, hepatic venous invasion, and hypervascularity on angiography were associated with a shunt fraction greater than 10%. Only dominant tumor diameter and vascular invasion were associated with a shunt fraction greater than 20%. On multivariate analysis, only tumor diameter (odds ratio 1.2) and hepatic venous invasion (odds ratio 23.0) were associated independently with an increased shunt fraction greater than 10%. CONCLUSION: Multiple patient and tumor-related characteristics were significantly correlated with the hepatopulmonary shunt fraction on univariate analysis. However, on multivariate analysis, only the dominant tumor diameter and presence of hepatic venous invasion were associated independently with a greater than 10% shunt fraction.

Isolated recto-sigmoid colitis: a new imaging pattern of ipilimumab-associated colitis.

PURPOSE: The purpose of this study is to describe typical CT findings and distinct imaging patterns of ipilimumab-associated colitis in immunotherapeutic treatment of melanoma. MATERIALS AND METHODS: This HIPAA-compliant retrospective study included 86 patients with melanoma imaged with CT or PET/CT of the abdomen and pelvis during or shortly after administration of ipilimumab. Twelve of 86 patients (14%) developed symptoms of colitis and underwent CT imaging of the abdomen and pelvis while symptomatic. Two radiologists reviewed CT images to evaluate for the presence of CT findings of colitis including mesenteric vessel engorgement, pericolonic inflammatory change, hyperenhancement of colonic mucosa, colonic wall thickening, fluid-filled colonic distension, pneumoperitoneum, pneumatosis, and diverticulosis in the inflamed segment of colon. One nuclear medicine radiologist reviewed PET images for abnormally increased FDG uptake in the colon. The diagnosis of ipilimumab-associated colitis was made based on clinical presentation, imaging findings, and laboratory data. RESULTS: Common CT findings of ipilimumab-associated colitis included colonic mucosal hyperenhancement (10/12 [83%]), mesenteric vessel engorgement (9/12 [75.0%]), colonic wall thickening (9/12 [75%]), and pericolonic fat stranding (2/12 [16%]). No patient developed pneumatosis or pneumoperitoneum. Diffuse colitis was present in 4/12 (33%) patients. Segmental colitis with associated diverticulosis (was present in 2/12 (17%) patients). A third pattern, isolated recto-sigmoid colitis without diverticulosis, was observed in 6/12 (50%) patients. All patients with colitis demonstrated recto-sigmoid involvement. CONCLUSIONS: A third radiologic pattern of ipilimumab-associated colitis was observed in this study: isolated recto-sigmoid colitis without diverticulosis. All patterns of ipilimumab-associated colitis include recto-sigmoid involvement.

Difference in appearance between prone and supine myocardial perfusion images obtained on a high-efficiency cadmium zinc telluride SPECT camera.

OBJECTIVE: The recent introduction of high-efficiency solid-state gamma cameras for myocardial perfusion single photon emission computed tomography has enabled lower patient radiation dose, faster imaging, and improved image quality. However, artifacts still complicate interpretation. Prone imaging is a common maneuver to reduce artifacts and increase accuracy for detection of coronary artery disease, but its effect on imaging relative to supine imaging has not been fully characterized in these new systems. METHODS: In this IRB-approved, HIPAA-compliant retrospective study, 30 patients were reviewed, who underwent prone and supine imaging on the GE 530c multipinhole cadmium zinc telluride camera under both rest and stress conditions. Informed consent was waived. Perfusion was scored visually by two readers on a five-point scale according to the 17-segment model. Differences were assessed for significance using a multivariate linear effects model and restricted maximum likelihood method. RESULTS: Prone positioning resulted in increased activity in the basal inferior (P<0.001), basal inferolateral (P=0.009), basal inferoseptal (P<0.001), and mid-inferior (P<0.001) segments when taking into account factors such as stress versus rest, perfusion scores of other segments, and reader. CONCLUSION: Prone imaging on the GE 530c camera increases measured tracer activity in the basal inferior, basal inferolateral, basal inferoseptal, and mid-inferior segments. Caution is advised when diagnosing myocardial ischemia in these territories, particularly if clinical data are unavailable.

FDG Uptake on Positron Emission Tomography Correlates with Survival and Time to Recurrence in Patients with Stage I Non-Small-Cell Lung Cancer.

INTRODUCTION: Patients with stage I non-small-cell lung cancer (NSCLC) have a wide variation in outcomes, most likely because there are undetected metastases at presentation. We retrospectively reviewed patients with early stage lung cancer to determine if FDG uptake of the primary tumor as measured on positron emission tomography (PET) at the time of diagnosis was associated with overall survival (OS) or time to recurrence (TTR). METHODS: We reviewed the Tumor Registry at our institution and identified 336 consecutive patients diagnosed with stage I NSCLC over a 5-year period who underwent an FDG-PET/computed tomography within 90 days before surgery. Kaplan-Meier curves were used to describe the survival and TTR experience within subgroups defined by PET maximum standardized uptake value (SUVmax). Cox proportional hazards model was used to assess the impact of PET SUVmax as a continuous variable on OS and TTR. Logistic regression was used to analyze the effect of SUVmax on dichotomized outcomes. RESULTS: Three hundred thirty-six consecutive patients (176 women and 160 men) with stage I NSCLC were retrospectively reviewed. Mean SUVmax was 9.2 ± 6.9 (range 0.6-30.3). The hazard or risk of dying and recurrence increased significantly as SUVmax increased (p = 0.0008 and 0.024, respectively). CONCLUSIONS: Preoperative FDG uptake in the primary tumor in patients with stage I disease is associated with OS and TTR. This may be useful in identifying early stage patients who may benefit from more aggressive therapy after surgical resection.

Definitive diagnosis of cerebrospinal fluid leak into the pleural space using 111In-DTPA cisternography.

A 58-year-old woman with a calcified disk extrusion causing severe spinal stenosis underwent T8 to T9 diskectomy and spinal fusion. A postoperative pseudomeningocele was treated with lumbar drain and fibrin glue. Performed for persistent right pleural effusion, CT myelogram failed to show communication between the cerebrospinal fluid (CSF) and pleural space--even on 2-hour delayed images. Subsequent 111In-DTPA cisternogram clearly demonstrated CSF leakage into the right pleural space at 2 hours, and surgical repair yielded good results. Radionuclide cisternography is a highly useful method to detect CSF leak, especially when it is occult on CT yet suspected clinically.

Murine CD7 shares antigenic cross-reactivity with HSP-60.

Human (h) CD7 is a 40 kDa single chain Ig superfamily molecule that is expressed on thymocytes, a major subunit of peripheral T cells, and most natural killer cells. Ligands for hCD7 include the epithelial cell-produced molecule, K-12, and galectin. Mice deficient in CD7 have been shown to be resistant to LPS-induced endotoxic shock syndromes. However, monoclonal antibodies (MAb) to mouse (m) CD7 have yet to be produced, nor is the distribution of mCD7 protein in mice known. We have raised a panel of three rat MAbs to mCD7 by immunizing rats with recombinant mCD7 protein. However, using Western blot and immunoprecipitation of tissue extracts from mouse thymus, spleen, liver, brain, lymph node and skin, these anti-mouse CD7 MAbs bound only to murine heat shock protein 60 (HSP-60) present both in wild-type (CD7+/+) and CD7-deficient (CD7-/-) mice. Epitope mapping of the sites on HSP-60 and recombinant mCD7 recognized by mCD7 MAbs demonstrated non-homologous amino acid sequence epitopes recognized by anti-CD7 MAbs on both proteins. These data demonstrated molecular mimicry of mCD7 with HSP-60, and leave open the question of surface expression of mCD7.

Stable RNA interference-mediated suppression of cyclophilin A diminishes non-small-cell lung tumor growth in vivo.

Cyclophilin A (CypA) was recently reported to be overexpressed in non-small-cell lung cancer, and represents a potentially novel therapeutic target. To determine the role of CypA in oncogenesis, stable RNA interference (RNAi)-mediated knockdown of CypA was established in two non-small-cell lung cancer cell lines (ADLC-5M2 and LC-103H), and these cells were grown as xenografts in severe combined immunodeficient mice. Tumor cell proliferation, apoptosis, and angiogenesis were measured by Ki67, terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling, and CD31 immunohistochemistry, respectively. Tumor glucose metabolism was assessed by fluorodeoxyglucose positron emission tomography imaging. Knockdown of CypA correlated in vivo with slower growth, less fluorodeoxyglucose uptake, decreased proliferation, and a greater degree of apoptosis in the tumors. These results establish the relevance of CypA to tumor growth in vivo, specifically to proliferation and apoptosis. Elucidation of the precise role of CypA in these pathways may lead to new targeted therapies for lung cancer.

Translating biomarkers into clinical practice: prognostic implications of cyclophilin A and macrophage migratory inhibitory factor identified from protein expression profiles in non-small cell lung cancer.

Biomarkers have the potential to significantly change diagnostic strategies and influence therapeutic management. We developed a MALDI-TOF protein expression profiling platform for biomarker discovery and a proof-of-principle study identified two proteins, cyclophilin A (CyPA) and macrophage migration inhibitory factor (MIF), that were overexpressed in non-small cell lung cancer (NSCLC). The current study focused on evaluating the potential of CyPA and MIF as prognostic markers in patients with a new diagnosis of lung cancer for rapid translation into clinical practice. Two hundred and thirty-four primary NSCLC specimens reflecting a broad range of histologies and stages were examined for CyPA and MIF reactivity by tissue microarray immunohistochemistry (TMA-IHC). The percent tumor cell reactivity, staining intensity and a composite staining score were compared with overall patient survival by Kaplan-Meier curves, log rank test and Cox model statistics. Although both proteins were overexpressed in most NSCLC tumors, neither CypA nor MIF showed a correlation with outcome. This pilot project approach can expedite integration of newly discovered biomarkers into clinical practice, with the goal of improving stratification of patients into appropriate treatment regimens. While both proteins considered in this study were overexpressed in the vast majority of NSCLCs, they were not found to be of prognostic significance.

Thermodynamic analysis of cyclosporin a binding to cyclophilin a in a lung tumor tissue lysate.

We report on the application of SUPREX (stability of unpurified proteins from rates of H/D exchange) to the analysis of a protein-ligand binding interaction under the ex vivo solution conditions of a human lung tumor tissue lysate. A SUPREX-derived binding free energy (i.e. DeltaDeltaG(f) value) and dissociation constant (i.e., K(d) value) were determined for the binding of cyclosporin A (CsA) to a cyclophilin A (CypA) sample in which the protein was a component of a tissue lysate derived from fresh frozen lung tumor. The DeltaDeltaG(f) and K(d) values determined by SUPREX for CsA binding to CypA in this unpurified protein sample, 4.7 +/- 0.8 kcal/mol and 77 +/- 17 nM, respectively, were comparable to the those obtained when SUPREX was used to analyze the binding of CsA to a highly purified CypA sample, 4.2 +/- 1.0 kcal/mol and 32 +/- 20 nM, respectively. Moreover, the SUPREX-derived K(d) values determined in this work were both in the range of those previously reported for the CypA-CsA complex. The results of this proof-of-principle work validate the extension of SUPREX to the thermodynamic analysis of proteins and protein-ligand binding interactions in the unpurified, ex vivo conditions of human tissue lysates,and they represent the first K(d) measurement on a protein-ligand complex under such conditions

Identification and validation of a potential lung cancer serum biomarker detected by matrix-assisted laser desorption/ionization-time of flight spectra analysis.

Many abnormalities detected in the thorax by routine conventional imaging studies are benign, yet all require further evaluation because of the concern for cancer. To address this deficiency and develop a serum biomarker for lung cancer, we designed a matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) based platform to display the proteins present in the serum of patients with or without lung cancer, and then challenged the scientific community to analyze these data with the aim of determining specific ion signal differences among the resulting spectra. The most statistically significant ion peak identified by the various analysis algorithms that differentiated the serum of patients with lung cancer from the serum of individuals without lung cancer was found at m/z 11,702. We identified the protein responsible for this ion peak as serum amyloid A (SAA; M(r) = 11,682.7) by partial purification followed by in-gel digestion and peptide mapping. By enzyme-linked immunosorbent assay, we showed SAA to be present at 286 ng/mL in the serum of cancer patients vs. 34.1 ng/mL in the serum of individuals without cancer. These data suggest that the combination of MALDI-TOF MS and computer analysis can be a powerful tool in the search for serum biomarkers of lung cancer and other diseases.