18FDG-PET/CT for predicting the outcome in ER+/HER2- breast cancer patients: comparison of clinicopathological parameters and PET image-derived indices including tumor texture analysis.

BACKGROUND: This study investigated the value of some clinicopathological parameters and 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography (18FDG-PET/CT) indices, including textural features, to predict event-free survival (EFS) in estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) locally advanced breast cancer (BC) patients. METHODS: FDG-PET/CT indices and clinicopathological parameters were assessed before neoadjuvant chemotherapy (NAC). After completion of chemotherapy, all patients had breast surgery with axillary lymph node dissection, followed by radiation therapy and endocrine therapy for 5 years. EFS was estimated using the Kaplan-Meier method. A Cox proportional hazard regression model was used for multivariate analysis. RESULTS: One hundred forty-three consecutive patients with stage II-III ER+/HER2- BC and without distant metastases at baseline PET were included. High standardized uptake values (SUVs), were associated with shorter EFS (HR = 3.51, P < 0.01 for SUVmax; HR = 2.76, P = 0.02 for SUVmean; and HR = 4.40 P < 0.01 for SUVpeak). Metabolically active tumor volume (MATV, HR = 3.47, P < 0.01) and total lesion glycolysis (TLG, HR = 3.10, P < 0.01) were also predictive of EFS. Homogeneity was not predictive (HR = 2.27, P = 0.07) and entropy had weak prediction (HR = 2.89, P = 0.02). Among clinicopathological parameters, EFS was shorter in progesterone receptor (PR)-negative tumor (vs. PR-positive tumor; HR = 3.25, P < 0.01); histology was predictive of EFS (lobular vs. ductal invasive carcinoma; HR = 3.74, P = 0.01) but not tumor grade (grade 3 vs. grade 1-2; HR = 1.64, P = 0.32). Pathological complete response after NAC was not correlated to the risk of relapse. Three parameters remained significantly associated with EFS in multivariate analysis. MATV (HR = 1.01, P < 0.01), progesterone receptor expression (HR = 2.90, P = 0.03) and tumor histology (HR = 3.80, P = 0.02). CONCLUSIONS: Baseline PET parameters measured before neoadjuvant treatment have prognostic values in ER+/HER2- locally advanced breast cancer patients. After multivariate analysis, metabolically active tumor volume remains significant while textural analysis of PET images is not of added value. Considering histopathological parameters, our study shows that patients with PR-negative or lobular invasive tumor have poorer prognosis than patients with PR-positive or ductal carcinoma, respectively.

Correlation between tumour characteristics, SUV measurements, metabolic tumour volume, TLG and textural features assessed with 18F-FDG PET in a large cohort of oestrogen receptor-positive breast cancer patients.

PURPOSE: The study was designed to evaluate 1) the relationship between PET image textural features (TFs) and SUVs, metabolic tumour volume (MTV), total lesion glycolysis (TLG) and tumour characteristics in a large prospective and homogenous cohort of oestrogen receptor-positive (ER+) breast cancer (BC) patients, and 2) the capability of those parameters to predict response to neoadjuvant chemotherapy (NAC). METHODS: 171 consecutive patients with large or locally advanced ER+ BC without distant metastases underwent an 18F-FDG PET examination before NAC. The primary tumour was delineated with an adaptive threshold segmentation method. Parameters of volume, intensity and texture (entropy, homogeneity, contrast and energy) were measured and compared with tumour characteristics determined on pre-treatment breast biopsy (Wilcoxon rank-sum test). The correlation between PET-derived parameters was determined using Spearman's coefficient. The relationship between PET features and pathological findings was determined using the Wilcoxon rank-sum test. RESULTS: Spearman's coefficients between SUVmax and TFs were 0.43, 0.24, -0.43 and -0.15 respectively for entropy, homogeneity, energy and contrast; they were higher between MTV and TFs: 0.99, 0.86, -0.99 and -0.87. All TFs showed a significant association with the histological type (IDC vs. ILC; 0.02 < P < 0.03) but didn't with immunohistochemical characteristics. SUVmax and TLG predicted the pathological response (P = 0.0021 and P = 0.02 respectively); TFs didn't (P: 0.27, 0.19, 0.94, 0.19 respectively for entropy, homogeneity, energy and contrast). CONCLUSIONS: The correlation of TFs was poor with SUV parameters and high with MTV. TFs showed a significant association with the histological type. Finally, while SUVmax and TLG were able to predict response to NAC, TFs failed.

Early Metabolic Response to Neoadjuvant Treatment: FDG PET/CT Criteria according to Breast Cancer Subtype.

PURPOSE: To investigate parameters based on fluorine 18 fluorodeoxyglucose (FDG) positron emission tomographic (PET) imaging that are best correlated with pathologic complete response (PCR) in human epidermal growth factor receptor type 2 (HER2)-positive cancer and triple-negative breast cancer (TNBC) and with partial or complete response in ER-positive/HER2-negative breast cancer. MATERIALS AND METHODS: This study was approved by institutional review board with waivers of informed written consent and included consecutive patients treated by neoadjuvant chemotherapy. Five PET examination-derived parameters were tested: standard uptake value (SUV) maximum (SUV(max)), peak (SUV(peak)), and mean (SUV(mean)), metabolically active tumor volume, and total lesion glycolysis (TLG). Absolute values at baseline PET, at PET imaging after two cycles of chemotherapy, and variation (ie, change) were measured. Correlations with pathologic response (Wilcoxon rank-sum test) and predictive power assessed (area under the curve [AUC] on the basis of receiver operating characteristic analysis) were examined. RESULTS: Included were 169 consecutive patients (mean age, 50 years). PCR was more frequent in HER2-positive tumors (16 of 33 patients [48.5%]) and TNBCs (20 of 54 patients [37%]) than in ER positive/HER2-negative tumors (four of 82 [4.9%]) (P < .001). Among patients with ER-positive/HER2-negative cancers, 33 patients had partial response. In TNBC, best association with PCR was obtained with change in SUV(max) (AUC, 0.86) or change in TLG (AUC, 0.88). In HER2-positive phenotype, absolute SUV(max) (or SUV(peak)) values at PET imaging after two cycles of chemotherapy (AUC for each cycle, 0.93) were better correlated with PCR than change in SUV(max) (AUC, 0.78; P = .11) or change in TLG (AUC, 0.62; P = .005). Regarding ER-positive/HER2-negative cancers, change in SUV(max) or change in TLG (AUC, 0.75) were parameters best correlated with partial or complete response. Baseline SUV(max) was higher in lymph nodes than in primary tumor in 31 patients. Findings were similar considering the site with highest FDG uptake. CONCLUSION: Quantitative indexes of tumor glucose use that are best correlated with pathologic response vary by phenotype: change in SUV(max) or TLG are most adequate for TNBCs and ER-positive/ HER2-negative cancers and absolute SUV(max) after two cycles of chemotherapy for HER2-positive breast cancers.

Do clinical, histological or immunohistochemical primary tumour characteristics translate into different (18)F-FDG PET/CT volumetric and heterogeneity features in stage II/III breast cancer?

PURPOSE: The aim of this retrospective study was to determine if some features of baseline (18)F-FDG PET images, including volume and heterogeneity, reflect clinical, histological or immunohistochemical characteristics in patients with stage II or III breast cancer (BC). METHODS: Included in the present retrospective analysis were 171 prospectively recruited patients with stage II/III BC treated consecutively at Saint-Louis hospital. Primary tumour volumes were semiautomatically delineated on pretreatment (18)F-FDG PET images. The parameters extracted included SUVmax, SUVmean, metabolically active tumour volume (MATV), total lesion glycolysis (TLG) and heterogeneity quantified using the area under the curve of the cumulative histogram and textural features. Associations between clinical/histopathological characteristics and (18)F-FDG PET features were assessed using one-way analysis of variance. Areas under the ROC curves (AUC) were used to quantify the discriminative power of the features significantly associated with clinical/histopathological characteristics. RESULTS: T3 tumours (>5 cm) exhibited higher textural heterogeneity in (18)F-FDG uptake than T2 tumours (AUC <0.75), whereas there were no significant differences in SUVmax and SUVmean. Invasive ductal carcinoma showed higher SUVmax values than invasive lobular carcinoma (p = 0.008) but MATV, TLG and textural features were not discriminative. Grade 3 tumours had higher FDG uptake (AUC 0.779 for SUVmax and 0.694 for TLG), and exhibited slightly higher regional heterogeneity (AUC 0.624). Hormone receptor-negative tumours had higher SUV values than oestrogen receptor-positive (ER-positive) and progesterone receptor-positive tumours, while heterogeneity patterns showed only low-level variation according to hormone receptor expression. HER-2 status was not associated with any of the image features. Finally, SUVmax, SUVmean and TLG significantly differed among the three phenotype subgroups (HER2-positive, triple-negative and ER-positive/HER2-negative BCs), but MATV and heterogeneity metrics were not discriminative. CONCLUSION: SUV parameters, MATV and textural features showed limited correlations with clinical and histopathological features. The three main BC subgroups differed in terms of SUVs and TLG but not in terms of MATV and heterogeneity. None of the PET-derived metrics offered high discriminative power.

Performance of FDG PET/CT at initial diagnosis in a rare lymphoma: nodular lymphocyte-predominant Hodgkin lymphoma.

PURPOSE: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare Hodgkin lymphoma distinguished from classical Hodgkin lymphoma (cHL) by the nature of the neoplastic cells which express B-cell markers. We wanted to determine the diagnostic performance of FDG PET/CT in initial assessment and its therapeutic impact on staging. METHODS: We retrospectively studied a population of 35 patients with NLPHL (8 previously treated for NLHPL, 27 untreated). All patients underwent an initial staging by pretherapeutic FDG PET/CT. The impact on initial stage or relapse stage was assessed by an independent physician. RESULTS: In a per-patient analysis, the sensitivity of the pretherapeutic FDG PET/CT was 100%. In a per-site analysis, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy of pretherapeutic FDG PET/CT were 100%, 99%, 97%, 100% and 99%, respectively. Pretherapeutic FDG PET/CT led to a change in the initial stage/relapse stage in 12 of the 35 patients (34%). In contrast to previous results established without FDG PET/CT, 20% of patient had osteomedullary lesions. CONCLUSION: Pretherapeutic FDG PET/CT has excellent performance for initial staging or relapse staging of NLPHL.

Yield of FDG PET/CT for Defining the Extent of Disease in Patients with Kaposi Sarcoma.

BACKGROUND: Positron emission tomography/computed tomography with fluorodeoxyglucose (F-18) (FDG PET/CT) is increasingly used in Kaposi sarcoma (KS), but its value has not been assessed. OBJECTIVES: In this study, we aimed to evaluate the diagnostic accuracy of FDG PET/CT to define the extent of disease in KS. METHODS: Consecutive patients with KS referred to our department for FDG PET/CT were included. The diagnostic accuracy of FDG PET/CT for cutaneous and extra-cutaneous KS staging was assessed on a per lesion basis compared to staging obtained from clinical examination, standard imaging, endoscopy, histological analyses, and follow-up. RESULTS: From 2007 to 2017, 75 patients with FDG PET/CT were analyzed. The sensitivity and specificity of FDG PET/CT for the overall detection of KS lesions were 71 and 98%, respectively. Sensitivity and specificity were 100 and 85% for lymph nodes, 87 and 98% for bone, 87 and 100% for lungs, and 100 and 100% for muscle involvement, whereas sensitivity was only 17% to detect KS digestive involvement. The sensitivity of the diagnostic for KS cutaneous involvement increased from 73 to 88% when using a whole-body examination. CONCLUSION: FDG PET/CT showed good sensitivity and specificity for KS staging (digestive involvement excepted) and could be used for staging patients with active KS.

18FDG PET Assessment of Therapeutic Response in Patients with Advanced or Metastatic Melanoma Treated with First-Line Immune Checkpoint Inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICI) are currently the first-line treatment for patients with metastatic melanoma. We investigated the value of positron emission tomography (PET) response criteria to assess the therapeutic response to first-line ICI in this clinical context and explore the potential contribution of total tumor metabolic volume (TMTV) analysis. METHODS: We conducted a retrospective study in patients treated with first-line ICI for advanced or metastatic melanoma, with 18F-FDG PET/CT performed at baseline and 3 months after starting treatment. Patients' metabolic response was classified according to PERCIST5 and imPERCIST 5 criteria. TMTV was recorded for each examination. RESULTS: Twenty-nine patients were included. The median overall survival (OS) was 51.2 months (IQR 13.6-not reached), and the OS rate at 2 years was 58.6%. Patients classified as responders (complete and partial response) had a 90.9% 2-year OS rate versus 38.9% for non-responders (stable disease and progressive disease) (p = 0.03), for PERCIST5 and imPERCIST 5 criteria. The median change in metabolic volume was 9.8% (IQR -59-+140%). No significant correlation between OS and changes in TMTV was found. CONCLUSION: The evaluation of response to immunotherapy using metabolic imaging with PERCIST5 and imPERCIST5 was significantly associated with OS in patients with advanced or metastatic melanoma.

First Extensive Analysis of 18F-Labeled Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography in a Large Cohort of Patients With HIV-Associated Hodgkin Lymphoma: Baseline Total Metabolic Tumor Volume Affects Prognosis.

PURPOSE: 18F-labeled fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET-CT) data in HIV-associated Hodgkin lymphoma (HIV-HL) are scarcely reported. In addition to the description of the characteristics of both baseline and interim 18F-FDG PET-CT examinations (PET1 and iPET, respectively), the aim of this study was to assess the prognostic value of PET1 and previously identified clinical parameters in this population. PATIENTS AND METHODS: PET1 of 109 patients with HIV-HL, treated with doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy regimen since 2007, and 104 iPET were centrally reviewed. All the patients were enrolled in an ongoing prospective single-center cohort of HIV-associated lymphoma. RESULTS: Most patients had a disseminated disease according to the Ann Arbor classification (30% stage III and 43% stage IV), with especially bone marrow and liver as extranodal localizations. After a median follow-up of 6.7 years, 12 patients relapsed (11%) and 13 died (12%). Five-year progression-free survival (PFS) was 75.1%, and 5-year overall survival was 86.1%. Median total metabolic tumor volume (TMTV) was 121.4 cm3. The optimal TMTV cutoff identified for prognostic analysis was 527 cm3, with a 2-year PFS of 71% in the 20 patients with TMTV > 527 cm3, compared with 91% in the 89 patients with TMTV ≤ 527 cm3 (P = .004). On multivariate analysis, a high TMTV was the only parameter independently associated with PFS. CONCLUSION: In this large series of HIV-HL patients with a homogeneous management, high TMTV on PET1 examination was associated with a poor prognosis.

Translating Molecules into Imaging-The Development of New PET Tracers for Patients with Melanoma.

Melanoma is a deadly disease that often exhibits relentless progression and can have both early and late metastases. Recent advances in immunotherapy and targeted therapy have dramatically increased patient survival for patients with melanoma. Similar advances in molecular targeted PET imaging can identify molecular pathways that promote disease progression and therefore offer physiological information. Thus, they can be used to assess prognosis, tumor heterogeneity, and identify instances of treatment failure. Numerous agents tested preclinically and clinically demonstrate promising results with high tumor-to-background ratios in both primary and metastatic melanoma tumors. Here, we detail the development and testing of multiple molecular targeted PET-imaging agents, including agents for general oncological imaging and those specifically for PET imaging of melanoma. Of the numerous radiopharmaceuticals evaluated for this purpose, several have made it to clinical trials and showed promising results. Ultimately, these agents may become the standard of care for melanoma imaging if they are able to demonstrate micrometastatic disease and thus provide more accurate information for staging. Furthermore, these agents provide a more accurate way to monitor response to therapy. Patients will be able to receive treatment based on tumor uptake characteristics and may be able to be treated earlier for lesions that with traditional imaging would be subclinical, overall leading to improved outcomes for patients.

Intermittent Versus Continuous Dosing of MAPK Inhibitors in the Treatment of BRAF-Mutated Melanoma.

The development of BRAF and MEK inhibitors (BRAFi/MEKi) has led to major advances in melanoma treatment. However, the emergence of resistance mechanisms limits the benefit duration and a complete response occurs in less than 20% of patients receiving BRAFi ± MEKi. In this study, we evaluated the impact of an intermittent versus continuous dosing schedule of BRAF/MEK inhibition in a melanoma model mildly sensitive to a BRAF inhibitor. The combination of a BRAFi with three different MEKi was studied with a continuous or intermittent dosing schedule in vivo, in a xenografted melanoma model and ex vivo using histoculture drug response assays (HDRAs) of patient-derived xenografts (PDX). To further understand the underlying molecular mechanisms of therapeutic efficacy, a biomarker pharmacodynamic readout was evaluated. An equal impact on tumor growth was observed in monotherapy or bitherapy regimens whether we used continuous and intermittent dosing schedules, with no significant differences in biomarkers expression between the treatments. The antitumoral effect was mostly due to modulations of expression of cell cycle and apoptotic mediators. Moreover, ex vivo studies did not show significant differences between the dosing schedules. In this context, our preclinical and pharmacodynamic results converged to show the similarity between intermittent and continuous treatments with either BRAFi or MEKi alone or with the combination of both.

Predictive factors of early progression after CAR T-cell therapy in relapsed/refractory diffuse large B-cell lymphoma.

Chimeric antigen receptor (CAR) T-cell therapy has emerged as an option for relapsed/refractory aggressive B-cell lymphomas that have failed 2 lines of therapy. Failures usually occur early after infusion. The purpose of our study was to identify factors that may predict failure, particularly early progression (EP), within the first month after infusion. Characteristics of 116 patients were analyzed at the time of decision (TD) to use commercial CAR (axicabtagene ciloleucel, n = 49; tisagenlecleucel n = 67) and at the time of treatment (TT), together with total metabolic tumor volume (TMTV) at TT. With a median follow-up of 8.2 months, 55 patients failed treatment; 27 (49%) were early progressors. The estimated 12-month progression-free survival (PFS) and overall survival (OS) were 47.2% (95% confidence interval [CI], 38.0-58.6) and 67.0% (95% CI, 57-79), respectively. Univariate analyses for PFS and OS identified Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2, stage III/IV disease, extranodal (EN) sites ≥2, elevated lactate dehydrogenase (LDH), increased C-reactive protein (CRP), high International Prognostic Index at TD and at TT, as well as increased CRP, bulky mass, and high TMTV at TT, as risk factors. Multivariate analyses for PFS, EP, and OS identified elevated LDH and EN sites ≥2 at TD and the same predictors at TT (ie, increased CRP, EN sites ≥2, and TMTV >80 mL). In summary, risk factors identified for early progression at TD and at TT were EN involvement (≥2 sites) and lymphoma burden (LDH, TMTV).

Myocardial uptake of 99mTc-annexin-V and 111In-antimyosin-antibodies after ischemia-reperfusion in rats.

OBJECTIVES: Phosphatidylserin exposure on cell surfaces occurs early during apoptosis and is detected in vivo by using (99m)Tc-annexin-V (ANX). Cardiomyocyte membrane disruption is detected in vivo by using (111)In-antimyosin-antibodies (AM). We aimed to determine if ANX and AM allow evaluation of the time-course of these two distinct cell death events after myocardial ischemia-reperfusion. METHODS: Coronary tying (20 min) followed by reperfusion (IR) was performed in 31 rats. Twelve of the rats were injected with ANX, 11 with AM, and eight with both tracers. Myocardial uptake of tracers was studied 1-2 h, 4 h, or 24 h after IR by scintigraphy (ANX, n = 14) and autoradiography (all cases), and compared to histology and Apostain staining. RESULTS: Scintigraphy was positive in all rats 2 h after IR and in three of five rats at 24 h. On autoradiography, ANX activity was intense in myocardial lesions as early as 1 h post-IR, whereas AM activity was mild at 2 h then increased at 4 h post-IR. ANX and AM uptakes evolved from mid-myocardium to endocardial and epicardial regions from 2 h to 24 h post-IR. Apostain staining was significant in myocardial lesions (p < 10(6) compared to six sham-operated rats). On histology, myocardial lesion was characterized by interstitial oedema, myocytes necrosis, and dramatic thinning at 24 h. CONCLUSION: These data suggest that ANX and AM allow temporal and regional evaluations of PS exposure and membrane disruption, respectively, during myocytes death after 20-min myocardial ischemia followed by reperfusion. Also, (i) apoptosis starts very early in injured myocardium, (ii) myocyte necrosis occurs later (3-4 h post-reperfusion), and (iii) most dead cells are removed from mid-myocardium between 6 h and 24 h after reperfusion.

18FDG-PET/CT and molecular markers to predict response to neoadjuvant chemotherapy and outcome in HER2-negative advanced luminal breast cancers patients.

BACKGROUND: The efficacy of neoadjuvant chemotherapy regimens in advanced luminal breast cancer patients is difficult to predict. Intrinsic properties of breast tumors, including altered gene expression profile and dynamic evaluation of metabolic properties of tumor cells using positron emission tomography/computed tomography (PET/CT) of tumor cells, have been identified to guide patient's prognosis. The aim of this study is to determine if both analyses may improve the prediction of response to neoadjuvant chemotherapy in ER-positive / HER2-negative breast cancers (BCs) patients. METHODS: We used metabolic PET parameters, at diagnosis and after two cycles of chemotherapy and proliferation gene expression profile on biopsy at diagnosis, in particular, the genomic grade index (GGI) analyzed by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). The pathological response was the surrogate endpoint. RESULTS: The change of FDG uptake between baseline PET and interim PET after 2 cycles of neoadjuvant chemotherapy (ΔSUVmax) was highly associated with pCR (p=0.008). We also observed an ability of P53 mutated status (p=0.042), in addition to histological grade (p=0. 0004), and PR expression (p=0.01) to predict pCR in ER-positive BCs, whereas no proliferation marker predicted pCR (P=0.39 for GGI). Finally, only ΔSUVmax was significantly associated with event free survival (p=0.047). CONCLUSIONS: Our results confirm the predictive and prognostic value of tumor ΔSUVmax in ER-positive /HER2-negative advanced BCs patients. These findings can be helpful to select high-risk patients within trials investigating novel treatment strategies.

99mTc-annexin-V functional imaging of luminal thrombus activity in abdominal aortic aneurysms.

BACKGROUND: The mural thrombus of abdominal aortic aneurysms (AAA) is involved in aneurysm progression via several interdependent biological processes including platelet activation. 99mTc-annexin V (ANX) is a scintigraphic tracer that binds to phosphatidylserine exposed on activated platelets and apoptotic cells. Here, we evaluated the potential of ANX imaging to assess mural thrombus biological activity in an experimental AAA model. The clinical applicability was further tested ex vivo on human samples of excised AAA thrombi. METHODS AND RESULTS: Experimental AAA was created by infusing elastase into infrarenal abdominal aorta in 17 rats, and 6 sham-operated rats were used as controls. Abdominal ANX scintigraphy was performed 2 weeks later followed by quantitative autoradiography and histological studies. Among the 13 rats which developed AAA, 11 displayed intense ANX uptake within AAA by scintigraphy. ANX uptake in the aneurysms on planar and single-photon emission computed tomography (SPECT) imaging was higher than that observed in infrarenal aorta of sham-operated controls (target/background ratio: 5.7+/-0.9 versus 1.33+/-0.21; P<0.005 for SPECT). Aneurysm-to-background activity ratios obtained by scintigraphy correlated with ANX activity in corresponding autoradiograms (R=0.69; P<0.02). This activity was located in the thrombus area where activated platelets and polymorphonuclear leukocytes accumulated. Similar patterns were also found in all of the 7 human AAA thrombi harvested during surgery. CONCLUSIONS: ANX imaging may assess mural thrombus renewal activity linked to permanent flowing blood interface.

Assessing Bone Marrow Activity in Patients with Myelofibrosis: Results of a Pilot Study of 18F-FLT PET.

An emerging noninvasive approach to assess tissue proliferation uses the PET tracer 3'-deoxy-3'-18F-fluorothymidine (18F-FLT). To evaluate the diagnostic value of this technique in myelofibrosis, 18F-FLT PET imaging results were compared with bone marrow histology and bone marrow scintigraphy (BMS), the gold standard techniques in this clinical situation. Methods: Fifteen patients with histology-proven myelofibrosis were included consecutively in the study. Tracers' distributions were assessed using a visual grading assessment score of the uptake in the axial skeleton, proximal and distal limbs, liver, and spleen. This visual score was used to define patterns of tracer distribution and to compare the information provided either by PET or by BMS. A semiquantitative analysis with determination of SUVmax in the same localizations was performed for 18F-FLT PET. Results: The histology grade of fibrosis correlated with the SUVmax in the axial skeleton (spine and iliac crests) and proximal limbs. 18F-FLT uptake in these areas was much lower in patients with grade 3 fibrosis than in patients with grade 1 or 2 fibrosis. 18F-FLT PET showed the same distribution of uptake as BMS in 13 of 14 patients (1 patient did not undergo BMS). In 1 patient, 18F-FLT PET clearly showed an intense abnormal splenic uptake, whereas spleen uptake was inconclusive with BMS. Conclusion:18F-FLT PET appears to be a reliable and convenient technique to assess hematopoietic activity in bone marrow. It yields results close to those observed with BMS. In our study population, 18F-FLT uptake in the axial skeleton and proximal limbs assessed by SUVmax correlated with the grade of fibrosis. Thus, 18F-FLT PET may be a useful tool to measure the severity of myelofibrosis, and to monitor noninvasively the patients' status during follow-up. Finally, 18F-FLT PET may be foreseen as an alternative to BMS.

Impact of liver transplantation on cardiac autonomic denervation in familial amyloid polyneuropathy.

Familial amyloid polyneuropathy (FAP) is a rare and severe hereditary form of amyloidosis, due to the deposition of a genetic variant transthyretin essentially produced by the liver, and characterized by both sensorimotor and autonomic neuropathy. Liver transplantation (LT) is the most effective treatment to stop the progression of the disease. Cardiac amyloid infiltration is usually associated with cardiac denervation, restrictive cardiomyopathy, conduction disturbances, and sometimes sudden death. Whether the cardiac involvement related to amyloid deposition may be altered after LT remains unclear. We conducted the present study to define the outcome of cardiac involvement after LT in 31 patients with FAP (age, 39 +/- 12 yr). Patients were evaluated before and after LT (24 +/- 15 mo). Cardiac sympathetic denervation was assessed by both iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy and heart rate variability (HRV) analysis. The scintigraphic importance of sympathetic denervation was evaluated globally on planar imaging using heart-to-mediastinum activity ratio (H/M) measured 4 hours after injection, and regionally using single-photon emission tomography (SPET) imaging. Amyloid myocardial infiltration was assessed by echocardiography. Diffuse sympathetic denervation was found when using cardiac MIBG planar imaging in patients evaluated before LT and compared with 12 control subjects (H/M: 1.45 +/- 0.29 vs. 1.98 +/- 0.35, p < 0.001). On SPET images, defects were diffuse in 12 patients and focal in 19 patients, with predominance at the inferior and apical segments. No change in sympathetic innervation was found in patients after LT as assessed either with planar imaging (H/M after LT: 1.46 +/- 0.28, p = not significant vs. H/M before LT) or with SPET imaging. HRV nonspectral indexes showed that the standard deviation of all cycles was significantly lower in patients compared with control subjects, and remained unchanged after LT. Conduction disturbances and ventricular arrhythmias were associated with low cardiac MIBG uptake, and progressed after LT. The left ventricular wall was slightly thickened in patients, and a further increase was observed after LT (posterior wall from 9.2 +/- 1.8 to 10.1 +/- 2.3 mm, p = 0.02; septal wall from 10.6 +/- 2.7 to 12.1 +/- 4, p = 0.046). Neurologic status stabilized in 26 patients, but worsened in the 5 patients who had the most severe cardiac sympathetic denervation before LT as measured by MIBG imaging. The magnitude of the cardiac sympathetic denervation remained stable 2 years after LT in patients with FAP, whereas the cardiac amyloid infiltration progressed. The importance of cardiac sympathetic denervation found in FAP patients before LT was associated with a neurologic worsening after LT.

Radiation dose and long term risk of cardiac pathology following radiotherapy and anthracyclin for a childhood cancer.

PURPOSE: To determine the cardiac status in children 15 years (yrs) or more after a solid tumour treatment. PATIENTS AND METHODS: Of the 447 patients, 229 were fully studied and 218 were not. The following cardiac evaluation was proposed to all the 447 consecutive patients: (1) cardiac Doppler US by one of two expert cardiologists; (2) cardiac rhythm and conduction abnormalities including 24-h holter ECG; (3) (131)I-mIBG myocardial scintigraphy; (4) serum brain natriuretic peptide levels at rest; (5) an exercise test with VO(2)max measurement. The radiation dose delivered to 7 points in the heart was estimated for all patients who had received radiotherapy. RESULTS: Cardiac disorder was diagnosed in 89 evaluated patients (39%) including 24 heart failures and 65 other asymptomatic cardiac diseases. When adjusting on potential confounders, cardiac disorder and cardiac failure risks were respectively linear (ERR at 1 Gy: 26%) and linear-quadratic (ERR at 1 Gy: 19%) functions of the average radiation dose received to the heart. No interaction between cumulative dose of adriamycin and average radiation dose was evidenced for cardiac disorders, but the ERR/Gy of cardiac failure was higher for patients receiving less than 350 mg/m(2) of Adriamycin. CONCLUSION: Long term heart pathologies are probably one of the major iatrogenic risks encored by patients who survived a childhood cancer. This study strongly emphasizes the need to limit the heart irradiation during radiotherapy, particularly, for patients who also received or were susceptible to later received adriamycin.

¹8F-FDG PET/CT for the Early Evaluation of Response to Neoadjuvant Treatment in Triple-Negative Breast Cancer: Influence of the Chemotherapy Regimen.

UNLABELLED: Patients with triple-negative breast cancer (TNBC) have poor outcome when pathologic complete response (pCR) is not reached after neoadjuvant chemotherapy. Early prediction would be helpful. We evaluated the association between metabolic response after 2 cycles of neoadjuvant chemotherapy, pCR, and outcome in patients receiving 2 different anthracycline-based regimens (conventional and intensified). METHODS: Of 77 consecutive TNBC patients, 23 received EC-D (4 cycles of epirubicin + cyclophosphamide followed by 4 cycles of docetaxel at conventional doses) and 55 received a dose-intensified, dose-dense concomitant regimen of epirubicin + cyclophosphamide (historically called SIM) for 6 cycles. PET/CT with (18)F-FDG was performed at baseline and after 2 cycles of neoadjuvant chemotherapy. The associations between clinical factors, biologic factors, early metabolic change, pCR, and event-free survival (EFS) were examined (log-rank test). RESULTS: Of the 78 patients, 29 (37%) achieved pCR. The change in SUVmax (∆SUVmax) after 2 cycles was more pronounced in patients who achieved pCR (-72% vs. -42%;P< 0.0001). ∆SUVmax was more pronounced under SIM than under EC-D (-68% vs. -35%, P= 0.009), and there was a trend for a higher pCR rate (44% vs. 22%, P= 0.078). Twenty-two patients relapsed and 10 of them died (median follow-up, 34 mo). pCR was associated with EFS (log-rank, P= 0.001). ∆SUVmax was also significantly associated with EFS both in patients receiving SIM (P= 0.028) and in those receiving EC-D (P= 0.021). The optimal ∆SUVmax for predicting pCR and EFS was, however, specific to the treatment regimen. EFS was not associated with tumor grade (P= 0.98), histologic subtype (P= 0.17), or clinical stage (P= 0.097). CONCLUSION: Early metabolic change during neoadjuvant chemotherapy can predict pathologic response and EFS in TNBC patients under different chemotherapy regimens. However, the metabolic response varies with the type of chemotherapy.

[18F]MEL050 as a melanin-targeted PET tracer: Fully automated radiosynthesis and comparison to 18F-FDG for the detection of pigmented melanoma in mice primary subcutaneous tumors and pulmonary metastases.

INTRODUCTION: Melanoma is a highly malignant cutaneous tumor of melanin-producing cells. MEL050 is a synthetic benzamide-derived molecule that specifically binds to melanin with high affinity. Our aim was to implement a fully automated radiosynthesis of [18F]MEL050, using for the first time, the AllInOne™ synthesis module (Trasis), and to evaluate the potential of [18F]MEL050 for the detection of pigmented melanoma in mice primary subcutaneous tumors and pulmonary metastases, and to compare it with that of [18F]FDG. METHODS: Automated radiosynthesis of [18F]MEL050, including HPLC purification and formulation, were performed on an AllInOne™ synthesis module. [18F]MEL050 was synthesized using a one-step bromine-for-fluorine nucleophilic heteroaromatic substitution. Melanoma models were induced by subcutaneous (primary tumor) or intravenous (pulmonary metastases) injection of B16-F10-luc2 cells in NMRI mice. The maximum percentage of [18F]MEL050 Injected Dose per g of lung tissue (%ID/g Max) was determined on PET images, compared to [18F]FDG and correlated to in vivo bioluminescence imaging. RESULTS: The automated radiosynthesis of [18F]MEL050 required an overall radiosynthesis time of 48min, with a yield of 13-18% (not-decay corrected) and radiochemical purity higher than 99%. [18F]MEL050 PET/CT images were concordant with bioluminescence imaging, showing increased radiotracer uptake in all primary subcutaneous tumors and pulmonary metastases of mice. PET quantification of radiotracers uptake in tumors and muscles demonstrated similar tumor-to-background ratio (TBR) with [18F]MEL050 and [18F]FDG in subcutaneous tumors and higher TBR with [18F]MEL050 than with [18F]FDG in pulmonary metastases. CONCLUSION: We successfully implemented the radiosynthesis of [18F]MEL050 using the AllInOne™ module, including HPLC purification and formulation. In vivo PET/CT validation of [18F]MEL050 was obtained in mouse models of pigmented melanoma, where higher [18F]MEL050 uptake was observed in sub-millimetric pulmonary metastases, comparatively to [18F]FDG.