Comparison of Post-injection Site Pain Between Technetium Sulfur Colloid and Technetium Tilmanocept in Breast Cancer Patients Undergoing Sentinel Lymph Node Biopsy.

BackgroundNo prior studies have examined injection pain associated with Technetium-99m Tilmanocept (TcTM).MethodsThis was a randomized, double-blinded study comparing postinjection site pain between filtered Technetium Sulfur Colloid (fTcSC) and TcTM in breast cancer lymphoscintigraphy. Pain was evaluated with a visual analogue scale (VAS) (0-100 mm) and the short-form McGill Pain Questionnaire (SF-MPQ). The primary endpoint was mean difference in VAS scores at 1-min postinjection between fTcSC and TcTM. Secondary endpoints included a comparison of SF-MPQ scores between the groups at 5 min postinjection and construction of a linear mixed effects model to evaluate the changes in pain during the 5-min postinjection period.ResultsFifty-two patients underwent injection (27-fTcSC, 25-TcTM). At 1-min postinjection, patients who received fTcSC experienced a mean change in pain of 16.8 mm (standard deviation (SD) 19.5) compared with 0.2 mm (SD 7.3) in TcTM (p = 0.0002). At 5 min postinjection, the mean total score on the SF-MPQ was 2.8 (SD 3.0) for fTcSC versus 2.1 (SD 2.5) for TcTM (p = 0.36). In the mixed effects model, injection agent (p < 0.001), time (p < 0.001) and their interaction (p < 0.001) were associated with change in pain during the 5-min postinjection period. The model found fTcSC resulted in significantly more pain of 15.2 mm (p < 0.001), 11.3 mm (p = 0.001), and 7.5 mm (p = 0.013) at 1, 2, and 3 min postinjection, respectively.ConclusionsInjection with fTcSC causes significantly more pain during the first 3 min postinjection compared with TcTM in women undergoing lymphoscintigraphy for breast cancer

Generation of orthotopic patient-derived xenografts from gastrointestinal stromal tumor.

BackgroundGastrointestinal stromal tumor (GIST) is the most common sarcoma and its treatment with imatinib has served as the paradigm for developing targeted anti-cancer therapies. Despite this success, imatinib-resistance has emerged as a major problem and therefore, the clinical efficacy of other drugs has been investigated. Unfortunately, most clinical trials have failed to identify efficacious drugs despite promising in vitro data and pathological responses in subcutaneous xenografts. We hypothesized that it was feasible to develop orthotopic patient-derived xenografts (PDXs) from resected GIST that could recapitulate the genetic heterogeneity and biology of the human disease.MethodsFresh tumor tissue from three patients with pathologically confirmed GISTs was obtained immediately following tumor resection. Tumor fragments (4.2-mm3) were surgically xenografted into the liver, gastric wall, renal capsule, and pancreas of immunodeficient mice. Tumor growth was serially assessed with ultrasonography (US) every 3-4 weeks. Tumors were also evaluated with positron emission tomography (PET). Animals were sacrificed when they became moribund or their tumors reached a threshold size of 2500-mm3. Tumors were subsequently passaged, as well as immunohistochemically and histologically analyzed.ResultsHerein, we describe the first model for generating orthotopic GIST PDXs. We have successfully xenografted three unique KIT-mutated tumors into a total of 25 mice with an overall success rate of 84% (21/25). We serially followed tumor growth with US to describe the natural history of PDX growth. Successful PDXs resulted in 12 primary xenografts in NOD-scid gamma or NOD-scid mice while subsequent successful passages resulted in 9 tumors. At a median of 7.9 weeks (range 2.9-33.1 weeks), tumor size averaged 473 ± 695-mm³ (median 199-mm3, range 12.6-2682.5-mm³) by US. Furthermore, tumor size on US within 14 days of death correlated with gross tumor size on necropsy. We also demonstrated that these tumors are FDG-avid on PET imaging, while immunohistochemically and histologically the PDXs resembled the primary tumors.ConclusionsWe report the first orthotopic model of human GIST using patient-derived tumor tissue. This novel, reproducible in vivo model of human GIST may enhance the study of GIST biology, biomarkers, personalized cancer treatments, and provide a preclinical platform to evaluate new therapeutic agents for GIST

Comparative evaluation of [(99m)tc]tilmanocept for sentinel lymph node mapping in breast cancer patients: results of two phase 3 trials.

BackgroundSentinel lymph node (SLN) surgery is used worldwide for staging breast cancer patients and helps limit axillary lymph node dissection. [(99m)Tc]Tilmanocept is a novel receptor-targeted radiopharmaceutical evaluated in 2 open-label, nonrandomized, within-patient, phase 3 trials designed to assess the lymphatic mapping performance.MethodsA total of 13 centers contributed 148 patients with breast cancer. Each patient received [(99m)Tc]tilmanocept and vital blue dye (VBD). Lymph nodes identified intraoperatively as radioactive and/or blue stained were excised and histologically examined. The primary endpoint, concordance (lower boundary set point at 90 %), was the proportion of nodes detected by VBD and [(99m)Tc]tilmanocept.ResultsA total of 13 centers contributed 148 patients who were injected with both agents. Intraoperatively, 207 of 209 nodes detected by VBD were also detected by [(99m)Tc]tilmanocept for a concordance rate of 99.04 % (p < 0.0001). [(99m)Tc]tilmanocept detected a total of 320 nodes, of which 207 (64.7 %) were detected by VBD. [(99m)Tc]Tilmanocept detected at least 1 SLN in more patients (146) than did VBD (131, p < 0.0001). In 129 of 131 patients with ≥1 blue node, all blue nodes were radioactive. Of 33 pathology-positive nodes (18.2 % patient pathology rate), [(99m)Tc]tilmanocept detected 31 of 33, whereas VBD detected only 25 of 33 (p = 0.0312). No pathology-positive SLNs were detected exclusively by VBD. No serious adverse events were attributed to [(99m)Tc]tilmanocept.Conclusion[(99m)Tc]Tilmanocept demonstrated success in detecting a SLN while meeting the primary endpoint. Interestingly, [(99m)Tc]tilmanocept was additionally noted to identify more SLNs in more patients. This localization represented a higher number of metastatic breast cancer lymph nodes than that of VBD

Quantification and parametric imaging of renal cortical blood flow in vivo based on Patlak graphical analysis

Quantification and parametric imaging of renal cortical blood flow in vivo based on Patlak graphical analysis. Patlak graphical analysis was applied to quantify renal cortical blood flow with N-13 ammonia and dynamic positron emission tomography. Measurements were made in a swine model of kidney transplantation with a wide range of normal and abnormal renal blood flows (N = 57 studies) and in 20 healthy human volunteers (N = 45 studies). Estimates of renal cortical blood flow by the Patlak method were compared to those from a two-compartment model for N-13 ammonia. In addition, estimates of renal cortical blood flow by the N-13 ammonia PET approach were compared in 10 normal human volunteers to estimates by the metabolically inert, freely diffusible O-15 water and a one-compartment model. Patlak graphical analysis estimates of renal cortical blood flow correlated linearly with the standard two-compartment model in pigs (y = -0.05 + 1.01x, r = 0.99) and in humans (y = 0.57 + 0.88x, r = 0.93). Estimates of renal cortical blood flow by O-15 water in human volunteers were also linearly correlated with those by N-13 ammonia and the Patlak graphical analysis (y = 0.71 + 0.84x, r = 0.86). Renal cortical blood flow estimates were highly reproducible both with N-13 ammonia and O-15 water measurements in humans. It is concluded that the Patlak graphical analysis with N-13 ammonia dynamic positron emission tomographic imaging renders accurate and reproducible estimates of renal cortical blood flow. Moreover, the graphical analysis approach is 1,000 times faster than the standard model fitting approach and suitable for generating parametric images of renal blood flow in the clinical setting

Comparison of Post-injection Site Pain Between Technetium Sulfur Colloid and Technetium Tilmanocept in Breast Cancer Patients Undergoing Sentinel Lymph Node Biopsy

BACKGROUND: No prior studies have examined injection pain associated with Technetium-99m Tilmanocept (TcTM). METHODS: This was a randomized, double-blinded study comparing postinjection site pain between filtered Technetium Sulfur Colloid (fTcSC) and TcTM in breast cancer lymphoscintigraphy. Pain was evaluated with a visual analogue scale (VAS) (0–100 mm) and the short-form McGill Pain Questionnaire (SF-MPQ). The primary endpoint was mean difference in VAS scores at 1-min postinjection between fTcSC and TcTM. Secondary endpoints included a comparison of SF-MPQ scores between the groups at 5 min postinjection and construction of a linear mixed effects model to evaluate the changes in pain during the 5-min postinjection period. RESULTS: Fifty-two patients underwent injection (27-fTcSC, 25-TcTM). At 1-min postinjection, patients who received fTcSC experienced a mean change in pain of 16.8 mm (standard deviation (SD) 19.5) compared with 0.2 mm (SD 7.3) in TcTM (p = 0.0002). At 5 min postinjection, the mean total score on the SF-MPQ was 2.8 (SD 3.0) for fTcSC versus 2.1 (SD 2.5) for TcTM (p = 0.36). In the mixed effects model, injection agent (p < 0.001), time (p < 0.001) and their interaction (p < 0.001) were associated with change in pain during the 5-min postinjection period. The model found fTcSC resulted in significantly more pain of 15.2 mm (p < 0.001), 11.3 mm (p = 0.001), and 7.5 mm (p = 0.013) at 1, 2, and 3 min postinjection, respectively. CONCLUSIONS: Injection with fTcSC causes significantly more pain during the first 3 min postinjection compared with TcTM in women undergoing lymphoscintigraphy for breast cancer

Variant allele fraction of genomic alterations in circulating tumor DNA (%ctDNA) correlates with SUV

The relationship between higher variant allele fraction (VAF) of genomic alterations in circulating tumor DNA (%ctDNA), an indicator of poor outcome, and maximum standardized uptake value (SU

[99mTc]MAG3-mannosyl-dextran: a receptor-binding radiopharmaceutical for sentinel node detection

Technetium-99m-labeled benzoyl-mercaptoacetylglycylglycyl-glycine-mannosyl-dextran ([(99m)Tc]MAG(3)-mannosyl-dextran) is a receptor-binding radiotracer that binds to mannose-binding protein, a receptor expressed by recticuloendothelial tissue. This agent is composed of a 10.5-kilodalton molecule of dextran and multiple units of mannose, and benzoyl-mercaptoacetylglycylglycyl-glycine (BzMAG(3)). The tetraflorophenol-activated ester of BzMAG(3) and the imidate of thiomannose were used to covalently attach BzMAG(3) and mannose to an amino-terminated conjugate of dextran. This yielded a 19-kilodalton macromolecule consisting of 3 BzMAG(3) and 21 mannose units per dextran. Dynamic light scattering was used to measure a mean diameter of 5.5 nanometers for BzMAG(3)-mannosyl-dextran and 0.28 microns for filtered Tc-99m sulfur colloid. A preliminary sentinel node detection study employing right fore and hind footpad injections of [(99m)Tc]MAG(3)-mannosyl-dextran and left fore and hind footpad injections of filtered Tc-99m sulfur colloid demonstrated greater sentinel lymph node uptake by the receptor-binding agent

[99mTc]MAG3-mannosyl-dextran: a receptor-binding radiopharmaceutical for sentinel node detection

Technetium-99m-labeled benzoyl-mercaptoacetylglycylglycyl-glycine-mannosyl-dextran ([(99m)Tc]MAG(3)-mannosyl-dextran) is a receptor-binding radiotracer that binds to mannose-binding protein, a receptor expressed by recticuloendothelial tissue. This agent is composed of a 10.5-kilodalton molecule of dextran and multiple units of mannose, and benzoyl-mercaptoacetylglycylglycyl-glycine (BzMAG(3)). The tetraflorophenol-activated ester of BzMAG(3) and the imidate of thiomannose were used to covalently attach BzMAG(3) and mannose to an amino-terminated conjugate of dextran. This yielded a 19-kilodalton macromolecule consisting of 3 BzMAG(3) and 21 mannose units per dextran. Dynamic light scattering was used to measure a mean diameter of 5.5 nanometers for BzMAG(3)-mannosyl-dextran and 0.28 microns for filtered Tc-99m sulfur colloid. A preliminary sentinel node detection study employing right fore and hind footpad injections of [(99m)Tc]MAG(3)-mannosyl-dextran and left fore and hind footpad injections of filtered Tc-99m sulfur colloid demonstrated greater sentinel lymph node uptake by the receptor-binding agent

TP53 mutations and number of alterations correlate with maximum standardized uptake value (SUVmax) determined by positron emission tomography/computed tomography (PET/CT) [18F] fluorodeoxyglucose (18F-FDG PET).

BackgroundOur study explored the relationship between the molecular changes in cancer and the maximum standardized uptake value (SUVmax) determined by positron emission tomography/computed tomography (PET/CT) with [18F] fluorodeoxyglucose (18F-FDG).ResultsA higher SUVmax correlated with TP53 alterations, but not with histologic diagnosis or other gene/pathway mutations or copy number alterations. In data from breast, lung and colon cancer, patients with the highest SUVmax show more genomic anomalies compared to those with the lowest SUVmax (P &lt; 0.005).ConclusionsA higher SUVmax on 18F-FDG PET/CT is associated with TP53 tumor suppressor gene anomalies and the presence of more genomic anomalies. Since TP53 alterations and high SUVmax both correlate with a poor prognosis, the underlying mechanism/implications of this association merit further study.MethodsOverall, 176 patients with diverse cancers had a tumor biopsy within 6 months after a PET/CT image for SUVmax measurement. The biopsy was interrogated by next generation sequencing (182 to 315 genes). TP53, EGFR, ALK, MYC, MET and FGF/FGFR genes and DNA repair, PI3K/Akt/mTOR (PAM), MEK, CYCLIN, and WNT pathway genes were analyzed