83 results found
Dubash S, Keat N, Kozlowski K, et al., 2020, Clinical translation of 18F-fluoropivalate – a PET tracer for imaging short-chain fatty acid metabolism: safety, biodistribution, and dosimetry in fed and fasted healthy volunteers, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 47, Pages: 2549-2561, ISSN: 1619-7070
BackgroundFatty acids derived de novo or taken up from the extracellular space are an essential source of nutrient for cell growth and proliferation. Radiopharmaceuticals including 11C-acetate, and 18F-FAC (2-18F-fluoroacetate), have previously been used to study short-chain fatty acid (SCFA) metabolism. We developed 18F-fluoropivalate (18F-FPIA; 3-18F-fluoro-2,2-dimethylpropionic acid) bearing a gem-dimethyl substituent to assert metabolic stability for studying SCFA metabolism. We report the safety, biodistribution, and internal radiation dosimetry profile of 18F-FPIA in 24 healthy volunteers and the effect of dietary conditions.Materials and methodsHealthy volunteer male and female subjects were enrolled (n = 24), and grouped into 12 fed and 12 fasted. Non-esterified fatty acids (NEFA) and carnitine blood measurements were assessed. Subjects received 159.48 MBq (range, 47.31–164.66 MBq) of 18F-FPIA. Radiochemical purity was > 99%. Safety data were obtained during and 24 h after radiotracer administration. Subjects underwent detailed multiple whole-body PET/CT scanning with sampling of venous bloods for radioactivity and radioactive metabolite quantification. Regions of interest were defined to derive individual and mean organ residence times; effective dose was calculated using OLINDA 1.1.ResultsAll subjects tolerated 18F-FPIA with no adverse events. Over 90% of radiotracer was present in plasma at 60 min post-injection. The organs receiving highest absorbed dose (in mGy/MBq) were the liver (0.070 ± 0.023), kidneys (0.043 ± 0.013), gallbladder wall (0.026 ± 0.003), and urinary bladder (0.021 ± 0.004); otherwise there was low tissue uptake. The calculated effective dose using mean organ residence times over all 24 subjects was 0.0154 mSv/MBq (SD ± 0.0010). No differences in biodistribution or dosimetry were seen in fed and fasted subjects
Robertson JFR, Evans A, Henschen S, et al., 2020, A randomized, open-label, presurgical, window-of-opportunity study comparing the pharmacodynamic effects of the novel oral SERD AZD9496 with fulvestrant in patients with newly diagnosed ER+ HER2(-) primary breast cancer, Clinical Cancer Research, Vol: 26, Pages: 4242-4249, ISSN: 1078-0432
Purpose: Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic limitations. Pharmacodynamic data suggest complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This presurgical study (NCT03236974) compared the pharmacodynamic effects of fulvestrant with AZD9496, a novel, orally bioavailable, nonsteroidal, potent SERD, in treatment-naïve patients with ER+ HER2− primary breast cancer awaiting curative intent surgery.Patients and Methods: Patients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5–14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 pharmacokinetic/pharmacodynamic relationships and safety.Results: Forty-six women received treatment (AZD9496 n = 22; fulvestrant n = 24); 35 paired biopsies were evaluable (AZD9496 n = 15; fulvestrant n = 20). The least square mean estimate for ER H-score reduction was 24% after AZD9496 versus 36% after fulvestrant treatment (P = 0.86). AZD9496 also reduced PR H-scores (−33.3%) and Ki-67 levels (−39.9%) from baseline, but was also not superior to fulvestrant (PR: −68.7%, P = 0.97; Ki-67: −75.4%, P = 0.98). No new safety findings were identified.Conclusions: This was the first presurgical study to demonstrate that an oral SERD affects its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.
Robertson JFR, Evans A, Henschen S, et al., 2020, A pre-surgical, window of opportunity study comparing the novel oral SERD AZD9496 with fulvestrant in patients with newly diagnosed ER+HER2-primary breast cancer, 42nd Annual San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Coombes RC, Page K, Salari R, et al., 2019, Personalized detection of circulating tumor DNA antedates breast cancer metastatic recurrence, Clinical Cancer Research, Vol: 25, Pages: 4255-4263, ISSN: 1078-0432
Purpose: Up to 30% of patients with breast cancer relapse after primary treatment. There are no sensitive and reliable tests to monitor these patients and detect distant metastases before overt recurrence. Here, we demonstrate the use of personalized circulating tumor DNA (ctDNA) profiling for detection of recurrence in breast cancer.Experimental Design: Forty-nine primary patients with breast cancer were recruited following surgery and adjuvant therapy. Plasma samples (n = 208) were collected every 6 months for up to 4 years. Personalized assays targeting 16 variants selected from primary tumor whole-exome data were tested in serial plasma for the presence of ctDNA by ultradeep sequencing (average >100,000X).Results: Plasma ctDNA was detected ahead of clinical or radiologic relapse in 16 of the 18 relapsed patients (sensitivity of 89%); metastatic relapse was predicted with a lead time of up to 2 years (median, 8.9 months; range, 0.5–24.0 months). None of the 31 nonrelapsing patients were ctDNA-positive at any time point across 156 plasma samples (specificity of 100%). Of the two relapsed patients who were not detected in the study, the first had only a local recurrence, whereas the second patient had bone recurrence and had completed chemotherapy just 13 days prior to blood sampling.Conclusions: This study demonstrates that patient-specific ctDNA analysis can be a sensitive and specific approach for disease surveillance for patients with breast cancer. More importantly, earlier detection of up to 2 years provides a possible window for therapeutic intervention.
Anand P, Elsafa E, Privitera R, et al., 2019, Rational treatment of chemotherapy-induced peripheral neuropathy with capsaicin 8% patch: from pain relief towards disease modification, Journal of Pain Research, Vol: 12, Pages: 2039-2052, ISSN: 1178-7090
Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) with associated chronic pain is a common and disabling condition. Current treatments for neuropathic pain in CIPN are largely ineffective, with unfavorable side-effects. The capsaicin 8% patch (capsaicin 179 mg patch) is approved for the treatment of neuropathic pain: a single topical cutaneous application can produce effective pain relief for up to 12 weeks. We assessed the therapeutic potential of capsaicin 8% patch in patients with painful CIPN, and its mechanism of action.Patients and methods: 16 patients with chronic painful CIPN (mean duration 2.5 years), in remission for cancer and not receiving chemotherapy, were treated with 30 min application of capsaicin 8% patch to the feet. Symptoms were monitored using the 11-point numerical pain rating scale (NPRS), and questionnaires. Investigations were performed at baseline and three months after patch application, including skin biopsies with a range of markers, and quantitative sensory testing (QST).Results: Patients reported significant reduction in spontaneous pain (mean NPRS: −1.27; 95% CI 0.2409 to 2.301; p=0.02), touch-evoked pain (−1.823; p=0.03) and cold-evoked pain (−1.456; p=0.03). Short-Form McGill questionnaire showed a reduction in neuropathic (p=0.0007), continuous (p=0.01) and overall pain (p=0.004); Patient Global Impression of Change showed improvement (p=0.001). Baseline skin biopsies showed loss of intra-epidermal nerve fibers (IENF), and also of sub-epidermal nerve fibers quantified by image analysis. Post-patch application skin biopsies showed a significant increase towards normalization of intra-epidermal and sub-epidermal nerve fibers (for IENF: structural marker PGP9.5, p=0.009; heat receptor TRPV1, p=0.027; regenerating nerve marker GAP43, p=0.04). Epidermal levels of Nerve Growth Factor (NGF), Neurotrophin-3 (NT-3), and Langerhans cells were also normalized. QST remained unchanged and there were no systemic side-
Murphy R, Adams L, Brown A, et al., 2019, Impact of Routine Use of CDK4/6 Inhibitor Therapy on Breast Cancer Outpatient Clinic Workload and Patient Experience, Publisher: ELSEVIER SCIENCE LONDON, Pages: E112-E112, ISSN: 0936-6555
Varghese V, Magnani L, Harada N, et al., 2019, FOXM1 modulates 5-FU resistance in colorectal cancer through regulating TYMS expression, Scientific Reports, Vol: 9, ISSN: 2045-2322
Resistance to 5-Fluoruracil (5-FU) has been linked to elevated expression of the main target, thymidylate synthase (TYMS), which catalyses the de novo pathway for production of deoxythymidine monophosphate. The potent oncogenic forkhead box transcription factor, FOXM1 is is regulated by E2F1 which also controls TYMS. This study reveals a significant role of FOXM1 in 5-FU resistance. Overexpression and knock-down studies of FOXM1 in colon cancer cells suggest the importance of FOXM1 in TYMS regulation. ChIP and global ChIP-seq data also confirms that FOXM1 can also potentially regulate other 5-FU targets, such as TYMS, thymidine kinase 1 (TK-1) and thymidine phosphorylase (TYMP). In human colorectal cancer tissue specimens, a strong correlation of FOXM1 and TYMS staining was observed. Elevated FOXM1 and TYMS expression was also observed in acquired 5-FU resistant colon cancer cells (HCT116 5-FU Res). A synergistic effect was observed following treatment of CRC cells with an inhibitor of FOXM1, thiostrepton, in combination with 5-FU. The combination treatment decreased colony formation and migration, and induced cell cycle arrest, DNA damage, and apoptosis in CRC cell lines. In summary, this research demonstrated that FOXM1 plays a pivotal role in 5-FU resistance at least partially through the regulation of TYMS.
Dubash SR, Merchant S, Heinzmann K, et al., 2018, Clinical translation of [F-18]ICMT-11 for measuring chemotherapy-induced caspase 3/7 activation in breast and lung cancer, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 45, Pages: 2285-2299, ISSN: 1619-7070
BackgroundEffective anticancer therapy is thought to involve induction of tumour cell death through apoptosis and/or necrosis. [18F]ICMT-11, an isatin sulfonamide caspase-3/7-specific radiotracer, has been developed for PET imaging and shown to have favourable dosimetry, safety, and biodistribution. We report the translation of [18F]ICMT-11 PET to measure chemotherapy-induced caspase-3/7 activation in breast and lung cancer patients receiving first-line therapy.ResultsBreast tumour SUVmax of [18F]ICMT-11 was low at baseline and unchanged following therapy. Measurement of M30/M60 cytokeratin-18 cleavage products showed that therapy was predominantly not apoptosis in nature. While increases in caspase-3 staining on breast histology were seen, post-treatment caspase-3 positivity values were only approximately 1%; this low level of caspase-3 could have limited sensitive detection by [18F]ICMT-11-PET. Fourteen out of 15 breast cancer patients responded to first–line chemotherapy (complete or partial response); one patient had stable disease. Four patients showed increases in regions of high tumour [18F]ICMT-11 intensity on voxel-wise analysis of tumour data (classed as PADS); response was not exclusive to patients with this phenotype. In patients with lung cancer, multi-parametric [18F]ICMT-11 PET and MRI (diffusion-weighted- and dynamic contrast enhanced-MRI) showed that PET changes were concordant with cell death in the absence of significant perfusion changes.ConclusionThis study highlights the potential use of [18F]ICMT-11 PET as a promising candidate for non-invasive imaging of caspase3/7 activation, and the difficulties encountered in assessing early-treatment responses. We summarize that tumour response could occur in the absence of predominant chemotherapy-induced caspase-3/7 activation measured non-invasively across entire tumour lesions in patients with breast and lung cancer.
Kramer GM, Liu Y, de Langen AJ, et al., 2018, Repeatability of quantitative18F-FLT uptake measurements in solid tumors: an individual patient data multi-center meta-analysis, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 45, Pages: 951-961, ISSN: 1619-7070
INTRODUCTION: 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT) positron emission tomography (PET) provides a non-invasive method to assess cellular proliferation and response to antitumor therapy. Quantitative18F-FLT uptake metrics are being used for evaluation of proliferative response in investigational setting, however multi-center repeatability needs to be established. The aim of this study was to determine the repeatability of18F-FLT tumor uptake metrics by re-analyzing individual patient data from previously published reports using the same tumor segmentation method and repeatability metrics across cohorts. METHODS: A systematic search in PubMed, EMBASE.com and the Cochrane Library from inception-October 2016 yielded five18F-FLT repeatability cohorts in solid tumors.18F-FLT avid lesions were delineated using a 50% isocontour adapted for local background on test and retest scans. SUVmax, SUVmean, SUVpeak, proliferative volume and total lesion uptake (TLU) were calculated. Repeatability was assessed using the repeatability coefficient (RC = 1.96 × SD of test-retest differences), linear regression analysis, and the intra-class correlation coefficient (ICC). The impact of different lesion selection criteria was also evaluated. RESULTS: Images from four cohorts containing 30 patients with 52 lesions were obtained and analyzed (ten in breast cancer, nine in head and neck squamous cell carcinoma, and 33 in non-small cell lung cancer patients). A good correlation was found between test-retest data for all18F-FLT uptake metrics (R2 ≥ 0.93; ICC ≥ 0.96). Best repeatability was found for SUVpeak(RC: 23.1%), without significant differences in RC between different SUV metrics. Repeatability of proliferative volume (RC: 36.0%) and TLU (RC: 36.4%) was worse than SUV. Lesion selection methods based on SUVmax ≥ 4.0 improved the repeatability of volumetric metrics (RC: 26-28%), but did not affect the repe
Palmieri C, Stein RC, Liu X, et al., 2018, Correction to: IRIS study: a phase II study of the steroid sulfatase inhibitor Irosustat when added to an aromatase inhibitor in ER-positive breast cancer patients (vol 165, pg 343, 2017), Breast Cancer Research and Treatment, Vol: 167, Pages: 407-407, ISSN: 0167-6806
Palmieri C, Szydlo R, Miller M, et al., 2017, IPET study: an FLT-PET window study to assess the activity of the steroid sulfatase inhibitor irosustat in early breast cancer, Breast Cancer Research and Treatment, Vol: 166, Pages: 527-539, ISSN: 0167-6806
BACKGROUND: Steroid sulfatase (STS) is involved in oestrogen biosynthesis and irosustat is a first generation, irreversible steroid sulfatase inhibitor. A pre-surgical window-of-opportunity study with irosustat was undertaken in estrogen receptor-positive (ER+) breast cancer to assess the effect of irosustat on tumour cell proliferation as measured by 3'-deoxy-3'-[18F] fluorothymidine uptake measured by PET scanning (FLT-PET) and Ki67. METHODS: Postmenopausal women with untreated ER+ early breast cancer were recruited, and imaged with FLT-PET at baseline and after at least 2 weeks treatment with irosustat, 40 mg once daily orally. The primary endpoint was changed in FLT uptake; secondary endpoints included safety and tolerability of irosustat, changes in tumoral Ki67 and steroidogenic enzymes expression and circulating steroid hormone levels. RESULTS: Thirteen women were recruited, and ten started irosustat for 2 weeks, followed by repeat FLT-PET scans in eight. Defining response as decreases of ≥20% in standardized uptake value (SUV) or ≥30% in Ki, 1 (12.5% (95% CI 2-47%, p = 0.001)) and 3 (43% (95% CI 16-75%, p = <0.001) patients, respectively, responded. 6 out of 7 patients had a Ki67 reduction (range = -19.3 to 76.4%), and median percentage difference in Ki67 was 52.3% (p = 0.028). In one patient with a low baseline STS expression, a 19.7% increase in Ki67 was recorded. STS decreases were seen in tumours with high basal STS expression, significant decreases were also noted in aromatase, and 17β-hydroxysteroid dehydrogenase type 1 and 2. Irosustat was generally well tolerated with all adverse event CTCAE Grade ≤2. CONCLUSIONS: Irosustat resulted in a significant reduction in FLT uptake and Ki67, and is well tolerated. These data are the first demonstrating clinical activity of irosustat in early breast cancer. Baseline expression of STS may be a biomarker of sensitivity to irosustat.
Dubash SR, Merchant S, Mauri F, et al., 2017, Clinical translation of the caspase 3/7 specific PET radiotracer [F-18]ICMT-11 for measuring chemotherapy induced apoptosis in breast and lung cancer, Publisher: SPRINGER, Pages: S378-S379, ISSN: 1619-7070
Saleem A, Searle GE, Kenny LM, et al., 2017, Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer (vol 5, 30, 2015), EJNMMI RESEARCH, Vol: 7, ISSN: 2191-219X
Saleem A, Searle GE, Kenny LM, et al., 2017, Erratum to: Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer., EJNMMI Research, Vol: 7, Pages: 74-74, ISSN: 2191-219X
Palmieri C, Stein RC, Liu X, et al., 2017, IRIS study: a phase II study of the steroid sulfatase inhibitor Irosustat when added to an aromatase inhibitor in ER-positive breast cancer patients, Breast Cancer Research and Treatment, Vol: 165, Pages: 343-353, ISSN: 0167-6806
Purpose Irosustat is a first-generation, orally active, irreversiblesteroid sulfatase inhibitor. We performed a multicentre,open label phase II trial of the addition of Irosustatto a first-line aromatase inhibitor (AI) in patients withadvanced BC to evaluate the safety of the combination andto test the hypothesis that the addition of Irosustat to AImay further suppress estradiol levels and result in clinicalbenefit.Experimental design Postmenopausal women with ERpositivelocally advanced or metastatic breast cancer whohad derived clinical benefit from a first-line AI and whosubsequently progressed were enrolled. The first-line AIwas continued and Irosustat (40 mg orally daily) added.The primary endpoint was clinical benefit rate (CBR).Secondary endpoints included safety, tolerability, andpharmacodynamic end points.Results Twenty-seven women were recruited, four discontinuedtreatment without response assessment. Basedon local reporting, the CBR was 18.5% (95% CI6.3–38.1%) on an intent to treat basis, increasing to 21.7%(95% CI 7.4–43.7%) by per-protocol analysis. In thosepatients that achieved clinical benefit (n = 5), the median(interquartile range) duration was 9.4 months (8.1–11.3)months. The median progression-free survival time was2.7 months (95% CI 2.5–4.6) in both the ITT and perprotocolanalyses. The most frequently reported grade 3/4toxicities were dry skin (28%), nausea (13%), fatigue(13%), diarrhoea (8%), headache (7%), anorexia (7%) andlethargy (7%).Conclusions The addition of Irosustat to aromatase inhibitortherapy resulted in clinical benefit with an acceptablesafety profile. The study met its pre-defined successcriterion by both local and central radiological assessments.
Cysouw MCF, Kramer GM, Frings V, et al., 2017, Baseline and longitudinal variability of normal tissue uptake values of [F-18]-fluorothymidine-PET images, Nuclear Medicine and Biology, Vol: 51, Pages: 18-24, ISSN: 0969-8051
Purpose[18F]-fluorothymidine ([18F]-FLT) is a PET-tracer enabling in-vivo visualization and quantification of tumor cell proliferation. For qualitative and quantitative analysis, adequate knowledge of normal tissue uptake is indispensable. This study aimed to quantitatively investigate baseline tracer uptake of blood pool, lung, liver and bone marrow and their precision, and to assess the longitudinal effect of systemic treatment on biodistribution.Methods18F–FLT-PET(/CT) scans (dynamic or static) of 90 treatment-naïve oncological patients were retrospectively evaluated. Twenty-three patients received double baseline scans, and another 39 patients were also scanned early and late during systemic treatment with a tyrosine kinase inhibitor. Reproducible volume of interest were placed in blood pool, lung, liver, and bone marrow. For semi-quantitative analysis, SUVmean, SUVmax, and SUVpeak with several normalizations were derived.ResultsSUVs of basal lung, liver, and bone marrow were not significantly different between averaged dynamic and static images, in contrast with blood pool and apical lung. Highest repeatability was seen for liver and bone marrow, with repeatability coefficients of 18.6% and 20.4% when using SUVpeak. Systemic treatment with TKIs both increased and decreased normal tissue tracer uptake at early and late time points during treatment.ConclusionSimultaneous evaluation of liver and bone marrow uptake in longitudinal response studies may be used to assess image quality, where changes in uptake outside repeatability limits should trigger investigators to perform additional quality control on individual PET images.Advances in knowledgeFor [18F]-FLT PET images, liver and bone marrow have low intra-patient variability when quantified with SUVpeak, but may be affected by systemic treatment.Implications for patient careIn [18F]-FLT-PET response monitoring trials, liver and bone marrow uptake may be used for quality control of [18F]-FLT PET images
Kramer GM, Liu Y, de langen AJ, et al., 2016, Repeatability of Quantitative F-18-FLT Uptake Measurements in Solid Tumors: A multi-centre Meta-Analysis, Annual Congress of the European-Association-of-Nuclear-Medicine, Publisher: SPRINGER, Pages: S357-S358, ISSN: 1619-7070
Palmieri C, Szydlo R, Miller M, et al., 2016, The effects of the first in class steroid sulfatase inhibitor Irosustat on FLT uptake and Ki67 in estrogen receptor positive early breast cancer: Results of the perioperative IPET study., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Kenny L, 2016, The Use of Novel PET Tracers to Image Breast Cancer Biologic Processes Such as Proliferation, DNA Damage and Repair, and Angiogenesis, JOURNAL OF NUCLEAR MEDICINE, Vol: 57, Pages: 89S-95S, ISSN: 0161-5505
Merchant S, Aboagye EO, Lim A, et al., 2015, Evaluation of apoptosis in breast cancer using the novel PET probe [F-18]ICMT-11 in patients treated with neoadjuvant FEC chemotherapy: Initial assessment of optimum imaging time and relation to caspase-3 immunostaining, 37th Annual CTRC-AACR San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Harada N, Varghese V, Xie L, et al., 2015, Targeting lactate metabolism as a novel therapeutic target in platinum-resistant triple negative breast cancer (TNBC), 37th Annual CTRC-AACR San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Saleem A, Searle GE, Kenny LM, et al., 2015, Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer, EJNMMI Research, Vol: 5, ISSN: 2191-219X
BackgroundBrain metastases are common in human epidermal growth factor receptor (Her)-2-positive breast cancer. Drug access to brain metastases and normal brain is key to management of cranial disease. In this study, positron emission tomography (PET) scanning after administration of radiolabelled lapatinib was used to obtain direct evidence of cranial drug access.MethodsPatients with Her-2+ metastatic breast cancer either with at least one 1-cm diameter brain metastasis or without brain metastases underwent dynamic carbon-11 radiolabelled lapatinib ([11C]lapatinib)-PET. Less than 20 μg of [11C]lapatinib was administered before and after 8 days of oral lapatinib (1,500 mg once daily). Radial arterial blood sampling was performed throughout the 90-min scan. The contribution of blood volume activity to the tissue signal was excluded to calculate lapatinib uptake in normal brain and metastases. Partitioning of radioactivity between plasma and tissue (V T) was calculated and the tissue concentration of lapatinib derived. Plasma lapatinib levels were measured and adverse events noted.ResultsSix patients (three with brain metastases) were recruited. About 80% plasma radioactivity corresponded to intact [11C]lapatinib after 60 min. PET signal in the brain corresponded to circulating radioactivity levels, with no [11C]lapatinib uptake observed in normal brain tissue. In contrast, radioactivity uptake in cranial metastases was significantly higher (p = 0.002) than that could be accounted by circulating radioactivity levels, consistent with [11C]lapatinib uptake in brain metastases. There was no difference in lapatinib uptake between the baseline and day 8 scans, suggesting no effect of increased drug access by inhibition of the drug efflux proteins by therapeutic doses of lapatinib.ConclusionsIncreased lapatinib uptake was observed in brain metastases but not in normal brain.
Hoyng LL, Frings V, Hoekstra OS, et al., 2015, Metabolically active tumour volume segmentation from dynamic [F-18] FLT PET studies in non-small cell lung cancer, EJNMMI RESEARCH, Vol: 5, ISSN: 2191-219X
Varghese V, Magnani L, Harada N, et al., 2015, Inhibition of FOXM1 by thiostrepton increases sensitivity to 5-fluorouracil (5-FU) by downregulating thymidylate synthase (TS) in colorectal cancer, AACR Precision Medicine Conference on Drug Sensitivity and Resistance - Improving Cancer Therapy, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 1078-0432
Blighe K, Kenny L, Patel N, et al., 2014, Whole Genome Sequence Analysis Suggests Intratumoral Heterogeneity in Dissemination of Breast Cancer to Lymph Nodes, PLOS One, Vol: 9, ISSN: 1932-6203
Background: Intratumoral heterogeneity may help drive resistance to targetedtherapies in cancer. In breast cancer, the presence of nodal metastases is a keyindicator of poorer overall survival. The aim of this study was to identify somaticgenetic alterations in early dissemination of breast cancer by whole genome nextgeneration sequencing (NGS) of a primary breast tumor, a matched locally-involvedaxillary lymph node and healthy normal DNA from blood.Methods: Whole genome NGS was performed on 12 mg (range 11.1–13.3 mg) ofDNA isolated from fresh-frozen primary breast tumor, axillary lymph node andperipheral blood following the DNA nanoball sequencing protocol. Single nucleotidevariants, insertions, deletions, and substitutions were identified through abioinformatic pipeline and compared to CIN25, a key set of genes associated withtumor metastasis.Results: Whole genome sequencing revealed overlapping variants between thetumor and node, but also variants that were unique to each. Novel mutations uniqueto the node included those found in two CIN25 targets, TGIF2 and CCNB2, whichare related to transcription cyclin activity and chromosomal stability, respectively,and a unique frameshift in PDS5B, which is required for accurate sister chromatidsegregation during cell division. We also identified dominant clonal variants thatprogressed from tumor to node, including SNVs in TP53 and ARAP3, whichmediates rearrangements to the cytoskeleton and cell shape, and an insertion in TOP2A, the expression of which is significantly associated with tumor proliferationand can segregate breast cancers by outcome.Conclusion: This case study provides preliminary evidence that primary tumor andearly nodal metastasis have largely overlapping somatic genetic alterations. Therewere very few mutations unique to the involved node. However, significantconclusions regarding early dissemination needs analysis of a larger number ofpatient samples.
Kenny LM, Aboagye EO, 2014, Clinical Translation of Molecular Imaging Agents Used in PET Studies of Cancer, EMERGING APPLICATIONS OF MOLECULAR IMAGING TO ONCOLOGY, Vol: 124, Pages: 329-374, ISSN: 0065-230X
Varghese V, Magnani L, Harada N, et al., 2014, Forkhead box transciption factor M1 (FOXM1) plays a critical role in colorectal cancer resistance by regulating thymidylate synthase (TS), 105th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Kenny LM, Tomasi G, Turkheimer F, et al., 2014, Preliminary clinical assessment of the relationship between tumor alphavbeta3 integrin and perfusion in patients studied with [F-18]fluciclatide kinetics and [O-15]H2O PET, EJNMMI RESEARCH, Vol: 4, ISSN: 2191-219X
Tharayil IA, Harada N, Patel N, et al., 2013, Measurement of tumour lesion glycolysis by FDG-PET in triple negative breast cancer, CANCER RESEARCH, Vol: 73, ISSN: 0008-5472
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