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Achieving a metabolic complete response (mCR) before high-dose chemotherapy (HDC) and autologous peripheral blood stem cell transplant (auto-PBSCT) predicts progression-free survival (PFS) in relapsed/refractory classical Hodgkin lymphoma (R/R cHL). We added brentuximab vedotin (BV) to DHAP (dexamethasone, high-dose cytarabine, cisplatin) to improve the mCR rate. In a phase I dose-escalation part of the study in 12 patients, we showed that BV-DHAP is feasible. This phase II study included 55 R/R cHL patients (23 primary refractory). Treatment consisted of three 21-day cycles of BV 1.8 mg/kg on day 1, and DHAP (dexamethasone 40 mg days 1-4, cisplatin 100 mg/m² day 1 and cytarabine 2x2 g/m² day 2). Patients with a metabolic partial response (mPR) or mCR proceeded to HDC/auto-PBSCT. Based on independent central [18F]fluorodeoxyglucose (FDG) - positron emission tomography (PET) - computed tomography (CT) scan review, 42 of 52 evaluable patients (81% [95%CI: 67-90]) achieved an mCR before HDC/auto-PBSCT, five had an mPR and five had progressive disease (3 were not evaluable). After HDC/auto-PBSCT, four patients with an mPR converted to an mCR. Two-year PFS was 74% [95%CI: 63-86] and overall survival 95% [95%CI: 90-100]. Toxicity was manageable and mainly consisted of grade 3/4 hematologic toxicity, fever, nephrotoxicity, ototoxicity (grade 1/2), and transiently elevated liver enzymes during BV-DHAP. Eighteen patients developed new onset peripheral neuropathy (maximum grade 1/2); all recovered. In conclusion, BV-DHAP is a very effective salvage regimen in R/R cHL patients, but patients should be monitored closely for toxicity. (clinicaltrials.gov identifier: NCT02280993).

Active surveillance for patients with esophageal cancer and a clinically complete response (cCR) after neoadjuvant chemoradiotherapy (nCRT) is being studied. Active surveillance requires accurate clinical response evaluations. 18F-FDG PET/CT might be able to detect local tumor recurrence after nCRT as soon as the esophagus recovers from radiationinduced esophagitis. The aims of this study were to assess the value of serial 18F-FDG PET/CT scans for detecting local recurrence in patients beyond 3 mo after nCRT and to determine when radiation-induced esophagitis has resolved. Methods: This retrospectivemulticenter study included patients who had cCR after nCRT, who initially declined surgery, and who subsequently underwent active surveillance. Clinical response evaluations included 18F-FDG PET/CT, endoscopic biopsies, and endoscopic ultrasound with fine-needle aspiration at regular intervals. SUVmax normalized for lean body mass (SULmax) was measured at the primary tumor site. The percentage change in SULmax (D%SULmax) between the last follow-up scan and the scan at 3 mo after nCRT was calculated. Tumor recurrence was defined as biopsy-proven vital tumor at the initial tumor site. Results: Of 41 eligible patients, 24 patients had recurrent disease at a median of 6.5 mo after nCRT and 17 patients remained cancer free during a median follow-up of 24 mo after nCRT. Five of 24 patients with tumor recurrence had sudden intense SULmax increases of greater than 180%. In 19 of 24 patients with tumor recurrence, SULmax gradually increased (median D%SULmax, 118%), whereas SULmax decreased (median D%SULmax, -12%) in patients with ongoing cCR (P , 0.001, independent-samples t test). In patients with ongoing cCR, SULmax was lowest at 11 mo after nCRT. Conclusion: Serial 18F-FDG PET/CT might be a useful tool for detecting tumor recurrence during active surveillance. In patients with ongoing cCR, the lowest SULmax was reached at 11 mo after nCRT, suggesting that radiation-induced esophagitis had mostly resolved by that time. These findings warrant further evaluation in a larger cohort.

Objective The aim of this study was to perform a meta-analysis on the accuracy of endoscopic biopsies, EUS, and 18F-FDG PET(-CT) for detecting residual disease after neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer. Summary of background data After nCRT, one-third of patients have a pathologically complete response in the resection specimen. Before an active surveillance strategy could be offered to these patients, clinically complete responders should be accurately identified. Methods Embase, Medline, Cochrane, and Web-of-Science were searched until February 2018 for studies on accuracy of endoscopic biopsies, EUS, or PET(-CT) for detecting locoregional residual disease after nCRT for squamous cell- or adenocarcinoma. Pooled sensitivities and specificities were calculated using random-effect meta-analyses. Results Forty-four studies were included for meta-analyses. For detecting residual disease at the primary tumor site, 12 studies evaluated endoscopic biopsies, 11 qualitative EUS, 14 qualitative PET, 8 quantitative PET using maximum standardized uptake value (SUVmax), and 7 quantitative PET using percentage reduction of SUVmax (%ΔSUVmax). Pooled sensitivities and specificities were 33% and 95% for endoscopic biopsies, 96% and 8% for qualitative EUS, 74% and 52% for qualitative PET, 69% and 72% for PET-SUVmax, and 73% and 63% for PET-%ΔSUVmax. For detecting residual nodal disease, 11 studies evaluated qualitative EUS with a pooled sensitivity and specificity of 68% and 57%, respectively. In subgroup analyses, sensitivity of PET-%ΔSUVmax and EUS for nodal disease was higher in squamous cell carcinoma than adenocarcinoma. Conclusions Current literature suggests insufficient accuracy of endoscopic biopsies, EUS, and 18F-FDG PET(-CT) as single modalities for detecting residual disease after nCRT for esophageal cancer.

Objective:This study compared outcomes of patients with esophageal cancer and clinically complete response (cCR) after neoadjuvant chemoradiotherapy (nCRT) undergoing active surveillance or immediate surgery. Background:Since nearly one-third of patients with esophageal cancer show pathologically complete response after nCRT according to CROSS regimen, the oncological benefit of immediate surgery in cCR is topic of debate. Methods:Patients with cCR based on endoscopic biopsies and endoscopic ultrasonography with fine-needle aspiration initially declining or accepting immediate surgery after nCRT were identified between 2011 and 2018. Primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), rate and timing of distant dissemination, and postoperative outcomes. Results:Some 98 patients with cCR were identified: 31 in the active surveillance- and 67 in the immediate surgery group with median followup of survivors of 27.7 and 34.8 months, respectively. Propensity score matching resulted in 2 comparable groups (n = 29 in both groups). Patients undergoing active surveillance or immediate surgery had a 3-year OS of 77% and 55% (HR 0.41; 95% CI 0.14-1.20, P = 0.104), respectively. The 3-year PFS was 60% and 54% (HR 1.08; 95% CI 0.44-2.67, P = 0.871), respectively. Patients undergoing active surveillance or immediate surgery had a comparable distant dissemination rate (both groups 28%), radical resection rate (both groups 100%), and severity of postoperative complications (Clav- ien-Dindo grade ≥ 3: 43% vs 45%, respectively). Conclusion:In this retrospective study, OS and PFS in patients with cCR undergoing active surveillance or immediate surgery were not significantly different. Active surveillance with postponed surgery for recurrent disease was not associated with a higher distant dissemination rate or more severe adverse postoperative outcomes.

Myocardial perfusion imaging (MPI) using single-photon emission computed tomography (SPECT) is useful in the evaluation of cardiac allograft vasculopathy (CAV) in heart transplant (HTx) recipients. The current study evaluated the long-term prognostic value of stress SPECT MPI for predicting all-cause mortality and cardiac events in HTx recipients. The study population consisted of 166 HTx recipients (mean age 54 ± 10 years, 84% male) who underwent exercise or dobutamine stress 99mTc-tetrofosmin SPECT MPI for the assessment of CAV. An abnormal SPECT MPI was defined as the presence of a fixed or a reversible perfusion defect. Endpoints were all-cause mortality, cardiac mortality, and non-fatal myocardial infarction (MI). MPI abnormalities were detected in 55 patients (33%), including fixed defects in 28 patients (17%), partially reversible in 17 patients (10%), and completely reversible defects in 10 patients (6%). During a median follow-up of 12.8 years (range 0-15, mean follow-up 9.5 years), 109 (66%) patients died (all-cause mortality), of which 67 (40%) were due to cardiac causes. A total of 5 (3%) patients experienced a non-fatal MI. HTx recipients with a normal stress 99mTc-tetrofosmin SPECT MPI had a significantly better prognosis as compared with those with an abnormal study, up to 5 years after the initial test. The presence of a reversible perfusion defect was a significant predictor of all-cause mortality, cardiac mortality, and major cardiac events, during the entire follow-up period. Stress 99mTc-tetrofosmin SPECT MPI provides valuable prognostic information for the prediction of long-term outcome in HTx recipients. Patients with a normal stress 99mTc-tetrofosmin SPECT MPI have a significantly better prognosis as compared with those with an abnormal study, up to 5 years after initial testing.

Background The Surgery As Needed for Oesophageal cancer (SANO) trial compares active surveillance with standard oesophagectomy for patients with a clinically complete response (cCR) to neoadjuvant chemoradiotherapy. The last patient with a clinically complete response is expected to be included in May 2021. The purpose of this update is to present all amendments to the SANO trial protocol as approved by the Institutional Research Board (IRB) before accrual is completed. Design The SANO trial protocol has been published (10.1186/s12885-018-4034-1). In this ongoing, phase-III, non-inferiority, stepped-wedge, cluster randomised controlled trial, patients with cCR (i.e. after neoadjuvant chemoradiotherapy no evidence of residual disease in two consecutive clinical response evaluations [CREs]) undergo either active surveillance or standard oesophagectomy. In the active surveillance arm, CREs are repeated every 3 months in the first year, every 4 months in the second year, every 6 months in the third year, and yearly in the fourth and fifth year. In this arm, oesophagectomy is offered only to patients in whom locoregional regrowth is highly suspected or proven, without distant metastases. The primary endpoint is overall survival. Update Amendments to the study design involve the first cluster in the stepped-wedge design being partially randomised as well and continued accrual of patients at baseline until the predetermined number of patients with cCR is reached. Eligibility criteria have been amended, stating that patients who underwent endoscopic treatment prior to neoadjuvant chemoradiotherapy cannot be included and that patients who have highly suspected residual tumour without histological proof can be included. Amendments to the study procedures include that patients proceed to the second CRE if at the first CRE the outcome of the pathological assessment is uncertain and that patients with a non-passable stenosis at endoscopy are not considered cCR. The sample size was recalculated following new insights on response rates (34% instead of 50%) and survival (expected 2-year overall survival of 75% calculated from the moment of reaching cCR instead of 3-year overall survival of 67% calculated from diagnosis). This reduced the number of required patients with cCR from 264 to 224, but increased the required inclusions from 480 to approximately 740 patients at baseline. Conclusion Substantial amendments were made prior to closure of enrolment of the SANO trial. These amendments do not affect the outcomes of the trial compared to the original protocol. The first results are expected late 2023. If active surveillance plus surgery as needed after neoadjuvant chemoradiotherapy for oesophageal cancer leads to non-inferior overall survival compared to standard oesophagectomy, active surveillance can be implemented as a standard of care.

Background Lymphatic insufficiency might play a significant role in the pathophysiology of lipoedema. Liposuction is up to now the best treatment. As liposuction is invasive, the technique could destruct parts of the lymphatic system and by this aggravate the lymphatic component and/or induce lymphoedema. We investigated the function of the lymphatic system in lipoedema patients before and after tumescent liposuction and thus whether tumescent liposuction can be regarded as a safe treatment. Methods Lymphoscintigraphy was performed to quantify the lymph outflow of 117 lipoedema patients. Mean clearance percentages of radioactive protein loaded after 1 min with respect to the total injected dose and corrected for decay of the radiopharmaceutical in the subcutaneous lymphatics were used as functional quantitative parameters as well as the clearance percentages and inguinal uptake 2 h post injection. The results of lymphatic function in lipoedema patients were compared with values obtained from normal healthy volunteers. We also compared 50 lymphoscintigraphies out of the previous 117 lipoedema patients before and six months after tumescent liposuction. Results In 117 lipoedema patients clearance 2 h post injection in the right and left foot was disturbed in 79.5 and 87.2% respectively. The inguinal uptake 2 h post injection in the right and left groin was disturbed in 60.3 and 64.7% respectively. In 50 lipoedema patients mean clearance and inguinal uptake after tumescent liposuction were slightly improved, 0.01 (p = 0.37) versus 0.02 (p = 0.02), respectively. This is statistically not relevant in clearance. Conclusion Lipoedema legs have a delayed lymph transport. Tumescent liposuction does not diminish the lymphatic function in lipoedema patients, thus tumescent liposuction can be regarded as a safe treatment.

Background: Active surveillance after neoadjuvant therapies has emerged among several malignancies. During active surveillance, frequent assessments are performed to detect residual disease and surgery is only reserved for those patients in whom residual disease is proven or highly suspected without distant metastases. After neoadjuvant chemoradiotherapy (nCRT), nearly one-third of esophageal cancer patients achieve a pathologically complete response (pCR). Both patients that achieve a pCR and patients that harbor subclinical disseminated disease after nCRT could benefit from an active surveillance strategy. Summary: Esophagectomy is still the cornerstone of treatment in patients with esophageal cancer. Non-surgical treatment via definitive chemoradiotherapy (dCRT) is currently reserved only for patients not eligible for esophagectomy. Since salvage esophagectomy after dCRT (50–60 Gy) results in increased complications, morbidity and mortality compared to surgery after nCRT (41.4 Gy), the latter seems preferable in the setting of active surveillance. Clinical response evaluations can detect substantial (i.e., tumor regression grade [TRG] 3–4) tumors after nCRT with a sensitivity of 90%, minimizing the risk of development of non-resectable recurrences. Current scarce and retrospective literature suggests that active surveillance following nCRT might not jeopardize overall survival and postponed surgery could be performed safely. Key Message: Before an active surveillance approach could be considered standard treatment, results of phase III randomized trials should be awaited.

Aim In oesophageal cancer patients, clinical response to neoadjuvant chemoradiotherapy (nCRT) according to CROSS is assessed after 12 weeks, potentially followed by active surveillance in case of clinically complete response (cCR). Detection of residual tumour by FDG-PET/CT alone is inaccurate, since this cannot be distinguished reliably from post-radiation oesophagitis. We hypothesize that when inflammation diminishes, increasing FDG-uptake over time may be a sensitive parameter to detect local recurrence. We studied the detection of tumour recurrence with PET/CT during systematic follow-up in clinically complete responders beyond 12 weeks after nCRT. Background & Methods Patients from the preSANO- and SANO- trials were included who obtained cCR (no residual tumour on bite-on-bite biopsies and EUS with FNA of suspected lymph nodes) 12 weeks after completion of nCRT, but declined subsequent surgery. Patients were offered active surveillance, including PET/CT every 3 months. Standardised uptake values corrected for lean body mass (SUL) were measured at the primary tumour site. The percentage change in maximum SUL value (SULmax) between the last follow-up scan and the scan 12 weeks after nCRT was calculated. Tumour recurrence was defined as biopsy-proven vital tumour. Results Some 33 patients were eligible for analysis. In 17 of 33 (52%) patients, no biopsy-proven local recurrence was found during a median follow-up of 16 months (range 4.0-25) after CROSS. Some 16 of 33 (48%) patients had tumour recurrence within a median of 6.9 months after CROSS (range 5.3-36). We observed two different patterns of FDG uptake suggesting local recurrence. Three of 16 patients had sudden intense increase in SULmax (mean delta%-SULmax of 216%±42%). In the other 13 of 16 patients with local recurrence, an insidious gradual increase in FDG uptake was seen compared to patients without recurrence: mean delta%-SULmax of 21%±18% versus -10%±22% respectively. Conclusion Increasing FDG-uptake during active surveillance beyond 12 weeks after nCRT was associated with local recurrence and stable FDG-uptake with ongoing local tumour control. Thus, serial PET/CT might be a useful tool to distinguish tumour recurrence from SUL fluctuations in complete responders. To define a cut-off value of delta%-SULmax for local recurrence a larger number of patients is needed.

At present, treatment of potentially curable oesophageal cancer includes neoadjuvant chemoradiotherapy followed by oesophagectomy. Alternatively, neoadjuvant chemotherapy is used. To date, strong evidence on the superiority of one modality over the other has not been provided. Currently, up to one-third of patients show a pathologically complete response after neoadjuvant chemoradiotherapy. To optimise the efficacy of neoadjuvant treatment for individual patients, prediction of response to neoadjuvant treatment is highly desired. Therefore, several clinical diagnostic modalities have been investigated for early response evaluation, of which positron emission tomography (PET) has been studied most extensively. To identify patients who might benefit from postponing or even omitting surgery, recent advances have been made in evaluating response after completion of neoadjuvant chemoradiotherapy. This review provides an overview of current evidence and recent advances in neoadjuvant chemoradiotherapy for oesophageal cancer and discusses the use of neoadjuvant chemotherapy compared to chemoradiotherapy. Moreover, clinical response evaluation to neoadjuvant chemoradiotherapy is reviewed.

18FDG PET-CT is useful for early and differential diagnosis of dementia. ASL-MRI seems an attractive alternative. Visual agreement was calculated in 21 brain regions bilaterally in 9/11 patients with suspected early-stage dementia, excluding 2 patients due to ASL-MRI motion artefacts. Overall gross agreement was almost perfect and identical between and within modalities (κ=0.85-0.86, p

Background After neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer, high pathologically complete response (pCR) rates are being achieved especially in patients with squamous cell carcinoma (SCC). An active surveillance strategy has been proposed for SCC patients with clinically complete response (cCR) after nCRT. To justify omitting surgical resection, patients with residual disease should be accurately identified. The aim of this study is to assess the accuracy of response evaluations after nCRT based on the preSANO trial, including positron emission tomography with computed tomography (PET-CT), endoscopy with bite-on-bite biopsies and endoscopic ultrasonography (EUS) with fine-needle aspiration (FNA) in patients with potentially curable esophageal SCC. Methods Operable esophageal SCC patients who are planned to undergo nCRT according to the CROSS regimen and are planned to undergo surgery will be recruited from four Asian centers. Four to 6 weeks after completion of nCRT, patients will undergo a first clinical response evaluation (CRE-1) consisting of endoscopy with bite-on-bite biopsies. In patients without histological evidence of residual tumor (i.e. without positive biopsies), surgery will be postponed another 6 weeks. A second clinical response evaluation (CRE-2) will be performed 10–12 weeks after completion of nCRT, consisting of PET-CT, endoscopy with bite-on-bite biopsies and EUS with FNA. Immediately after CRE-2 all patients without evidence of distant metastases will undergo esophagectomy. Results of CRE-1 and CRE-2 as well as results of the three single diagnostic modalities will be correlated to pathological response in the resection specimen (gold standard) for calculation of sensitivity, specificity, negative predictive value and positive predictive value. Discussion If the current study shows that major locoregional residual disease (> 10% residual carcinoma or any residual nodal disease) can be accurately (i.e. with sensitivity of 80.5%) detected in patients with esophageal SCC, a prospective trial will be conducted comparing active surveillance with standard esophagectomy in patients with a clinically complete response after nCRT (SINO trial). Trial registration The preSINO trial has been registered at ClinicalTrials.gov as NCT03937362 (May 3, 2019).

Our purpose was to prospectively investigate optimal evaluation of qualitative and quantitative 18F-FDG PET/CT in response evaluations 12–14 wk after neoadjuvant chemoradiotherapy (nCRT) in esophageal cancer patients. Methods: This was a side study of the prospective diagnostic pre-SANO trial. 18F-FDG PET/CT scans at baseline and at 12–14 wk after nCRT were qualitatively assessed for the presence of tumor. Maximum SUVs normalized for lean body mass (SULmax) were measured in all scans. The primary endpoint was the proportion of false-negative patients with tumor regression grade (TRG) 3–4 (.10% vital residual tumor) in qualitative and quantitative analyses. Receiver-operating-characteristic curve analysis for TRG1 versus TRG3–4 using SULmax, SULmax tumor-to-esophagus ratio, and D%SULmax was performed to define optimal cutoffs. Secondary endpoints were sensitivity, specificity, negative predictive value, and positive predictive value for TRG1 versus TRG2–4. Results: In total, 129 of 219 patients were analyzed. Qualitative 18F-FDG PET/CT was unable to detect TRG3–4 in 15% of patients. Sensitivity, specificity, negative predictive value, and positive predictive value in qualitative analysis for detecting TRG1 versus TRG2–4 was 80%, 37%, 42%, and 77%, respectively. In 18 of 190 patients (10%) with follow-up scans after nCRT, 18F-FDG PET/CT identified new interval metastases. Quantitative parameters did not detect TRG3–4 tumor in 27%–61% of patients. The optimal cutoff for detecting TRG1 versus TRG2–4 was a post-nCRT SULmax of 2.93 (area under receiver-operating-characteristic curve, 0.70). Conclusion: Qualitative and quantitative analyses of 18F-FDG PET/CT are unable to accurately detect TRG3–4 and to discriminate substantial residual disease from benign inflammation-induced 18F-FDG uptake after nCRT. However, 18F-FDG PET/CT is useful for the detection of interval metastases and might become useful in an active surveillance strategy with serial 18F-FDG PET/CT scanning.

Current treatments for locally advanced esophageal cancer consist of neoadjuvant chemotherapy (nCT) or chemoradiotherapy (nCRT) followed by surgery. Nearly one-third of patients obtain a pathologically complete response (pCR) after nCRT. Patients with a complete (clinical) response to nCRT might therefore be candidates for active surveillance, which entails postponement of surgery until recurrence of tumor is detected during clinical response evaluations (CREs). CREs should be performed with accurate diagnostic modalities to timely detect locoregional and distant disease after nCRT. The combination of endoscopy with bite-on-bite biopsies, endoscopic ultrasound with fine-needle aspiration (EUS-FNA) of suspected lymph nodes, and positron emission tomography/computed tomography (PET/CT) has shown 90% sensitivity for detecting substantial (i.e., >10%) residual disease. In this literature review, we address the current state of diagnostic modalities used in CREs and how accuracy for detection of residual tumor after nCRT could be improved. With regard to the currently adopted bite-on-bite biopsy technique, sufficient bite-on-bite biopsies should be taken over larger mucosal areas within the initial tumor site to reduce sampling errors. Detection of positive lymph nodes with EUS-FNA could be improved by sampling all visible lymph nodes. Developments in the field of PET/CT and magnetic resonance imaging (MRI) with simultaneous PET (PET/MRI) have potential to improve CREs by qualitative and quantitative assessment. Other promising techniques require further determination. With wide-area transepithelial sampling (WATS) larger mucosal areas could be sampled compared to regular biopsies, although data in patients treated with nCRT are to be awaited. The detection of positive lymph nodes might be improved by EUS elastography or contrast-enhanced harmonic EUS (CEH-EUS), but these techniques still require further investigation in a setting after nCRT. Finally, image analysis with radiomics, novel biomarkers derived from breath [volatile organic compounds (VOCs)] and liquid biopsies [circulating tumor DNA (ctDNA) as detected in blood samples] might be of complementary value to current diagnostics.

Aims Many studies have examined the prognostic value of myocardial perfusion imaging (MPI) using single-photon emission computed tomography (SPECT) for the prediction of short- to medium-term outcomes. However, the long-term prognostic value of MPI in patients with diabetes mellitus remains unclear. Therefore, this study assessed the long-term prognostic value of MPI in a high-risk cohort of patients with diabetes mellitus. Methods and results A high-risk cohort of 207 patients with diabetes mellitus who were unable to undergo exercise testing underwent dobutamine stress MPI. Follow-up was successful in 206 patients; 12 patients were excluded due to early revascularization. The current data are based on the remaining 194 patients. Follow-up end points were all-cause mortality, cardiac mortality, and nonfatal myocardial infarction. The Kaplan–Meier survival curves were constructed, and univariable and multivariable analyses were performed to identify predictors of long-term outcome. During a mean follow-up of 8.1 ± 5.9 years, 134 (69%) patients died of which 68 (35%) died due to cardiac causes. Nonfatal myocardial infarction occurred in 24 patients (12%), and late (>60 days) coronary revascularization was performed in 61 (13%) patients. Survival analysis showed that MPI provided optimal risk stratification up to 4 years after testing. After that period, the outcome was comparable in patients with normal and abnormal MPI. Multivariable analyses showed that MPI provided incremental prognostic value up to 4 years after testing. Conclusion In high-risk patients with diabetes mellitus, dobutamine MPI provides incremental prognostic information in addition to clinical data for a 4-year period after testing.

QRS duration is of prognostic relevance in patients with several underlying heart diseases. Short-term data also show the prognostic value of QRS duration in lower risk groups of patients. The aim of this study was to investigate the long-term prognostic value of QRS duration in patients with known or suspected coronary artery disease. The study cohort consisted of 512 patients (308 men, mean age 60 ± 11 years) who underwent myocardial perfusion imaging (MPI) for the evaluation of suspected or known coronary artery disease. Follow-up data were collected to assess the prognostic value of QRS duration, alongside clinical characteristics and MPI results. End points were cardiac death and cardiac death or nonfatal myocardial infarction (MI). During a mean follow-up of 8.6 ± 5.2 years, 290 patients (60%) died, with 139 deaths (27%) attributable to cardiac causes. Nonfatal MI occurred in 28 patients (6%), and 127 patients (25%) underwent late coronary revascularization (>3 months). Patients with QRS duration

It is not entirely clear whether ischemia burden on stress single-photon emission computed tomography (SPECT) effectively identifies patients who have a long-term benefit from coronary revascularization. The study population consisted of 719 patients with ischemia on stress SPECT. Early coronary revascularization was defined as percutaneous coronary intervention or coronary artery bypass grafting ≤90 days after SPECT. Patients who underwent late revascularization (>90 days after SPECT) were excluded (n = 164). Of the 538 patients (73% men, mean age 59.8 ± 11 years), 348 patients had low ischemia burden (

Dobutamine stress myocardial perfusion imaging (MPI) is a useful alternative for the evaluation of coronary artery disease (CAD) in elderly patients who are unable to perform an exercise stress test. However, data on the long-term prognostic value of stress MPI in elderly patients are lacking. Therefore, this study evaluated the long-term prognostic value of dobutamine stress MPI in elderly patients unable to perform an exercise test. The study population consisted of 247 elderly patients (mean age 71 ± 5 years) who underwent dobutamine stress single-photon emission computed tomography (SPECT) MPI. An abnormal SPECT study was defined as the presence of fixed and/or reversible perfusion defects. A summed stress score (SSS) was obtained to estimate the extent and severity of perfusion defects. End points during follow-up were all-cause mortality, cardiac mortality, and nonfatal myocardial infarction (MI). During a median follow-up of 14 years (range 12-16), 168 (68%) patients died (all-cause mortality), of which 56 (23%) were due to cardiac causes. Nonfatal MI occurred in 19 (8%) patients. Kaplan-Meier survival curves showed that MPI provided optimal risk stratification in patients with normal and abnormal MPI. Multivariable analysis identified an abnormal MPI as a strong significant predictor of all-cause mortality and cardiac events. A multivariable analysis also revealed that a reversible defect and SSS were strong long-term predictors of cardiac mortality and hard cardiac events. Dobutamine stress 99mTc-tetrofosmin SPECT provides incremental prognostic information for the prediction of long-term cardiovascular outcomes in elderly patients, unable to perform exercise testing. Dobutamine stress MPI is useful in risk classifying elderly patients.

Summary Background After neoadjuvant chemoradiotherapy for oesophageal cancer, roughly half of the patients with squamous cell carcinoma and a quarter of those with adenocarcinoma have a pathological complete response of the primary tumour before surgery. Thus, the necessity of standard oesophagectomy after neoadjuvant chemoradiotherapy should be reconsidered for patients who respond sufficiently to neoadjuvant treatment. In this study, we aimed to establish the accuracy of detection of residual disease after neoadjuvant chemoradiotherapy with different diagnostic approaches, and the optimal combination of diagnostic techniques for clinical response evaluations. Methods The preSANO trial was a prospective, multicentre, diagnostic cohort study at six centres in the Netherlands. Eligible patients were aged 18 years or older, had histologically proven, resectable, squamous cell carcinoma or adenocarcinoma of the oesophagus or oesophagogastric junction, and were eligible for potential curative therapy with neoadjuvant chemoradiotherapy (five weekly cycles of carboplatin [area under the curve 2 mg/mL per min] plus paclitaxel [50 mg/m 2 of body-surface area] combined with 41·4 Gy radiotherapy in 23 fractions) followed by oesophagectomy. 4–6 weeks after completion of neoadjuvant chemoradiotherapy, patients had oesophagogastroduodenoscopy with biopsies and endoscopic ultrasonography with measurement of maximum tumour thickness. Patients with histologically proven locoregional residual disease or no-pass during endoscopy and without distant metastases underwent immediate surgical resection. In the remaining patients a second clinical response evaluation was done (PET–CT, oesophagogastroduodenoscopy with biopsies, endoscopic ultrasonography with measurement of maximum tumour thickness, and fine-needle aspiration of suspicious lymph nodes), followed by surgery 12–14 weeks after completion of neoadjuvant chemoradiotherapy. The primary endpoint was the correlation between clinical response during clinical response evaluations and the final pathological response in resection specimens, as shown by the proportion of tumour regression grade (TRG) 3 or 4 (>10% residual carcinoma in the resection specimen) residual tumours that was missed during clinical response evaluations. This study was registered with the Netherlands Trial Register (NTR4834), and has been completed. Findings Between July 22, 2013, and Dec 28, 2016, 219 patients were included, 207 of whom were included in the analyses. Eight of 26 TRG3 or TRG4 tumours (31% [95% CI 17–50]) were missed by endoscopy with regular biopsies and fine-needle aspiration. Four of 41 TRG3 or TRG4 tumours (10% [95% CI 4–23]) were missed with bite-on-bite biopsies and fine-needle aspiration. Endoscopic ultrasonography with maximum tumour thickness measurement missed TRG3 or TRG4 residual tumours in 11 of 39 patients (28% [95% CI 17–44]). PET–CT missed six of 41 TRG3 or TRG4 tumours (15% [95% CI 7–28]). PET–CT detected interval distant histologically proven metastases in 18 (9%) of 190 patients (one squamous cell carcinoma, 17 adenocarcinomas). Interpretation After neoadjuvant chemoradiotherapy for oesophageal cancer, clinical response evaluation with endoscopic ultrasonography, bite-on-bite biopsies, and fine-needle aspiration of suspicious lymph nodes was adequate for detection of locoregional residual disease, with PET–CT for detection of interval metastases. Active surveillance with this combination of diagnostic modalities is now being assessed in a phase 3 randomised controlled trial (SANO trial; Netherlands Trial Register NTR6803). Funding Dutch Cancer Society.

Despite multiple studies on the diagnostic and prognostic use of dobutamine myocardial perfusion imaging (MPI), information on its long-term prognostic value is scarce. The aim of this study was to assess the value of this technique for the prediction of very long-term outcome. A total of 721 patients with limited exercise capacity underwent dobutamine MPI for the evaluation of suspected or known coronary artery disease. 719 of 721 patients attended follow-up (99.7%). Twenty-eight patients who underwent early coronary revascularization were excluded from analysis. Endpoints were all-cause mortality, cardiac death, nonfatal infarction, and coronary revascularization. Kaplan-Meier survival curves were constructed, and univariate and multivariate analyses were performed to identify predictors of long-term outcome. The mean age of patients was 60 +/- A 11 years, and 61% were male. Myocardial perfusion abnormalities were present in 381 patients (55%) and included fixed defects in 190 patients (27%) and reversible defects in 191 patients (28%). During a median follow-up time of 14 years (range 0-16), 295 deaths occurred (43%), of which 158 were cardiac deaths (23%). Nonfatal myocardial infarction occurred in 35 (5%), and late coronary revascularization was performed on 133 patients (19%). An abnormal dobutamine MPI provided significant prognostic information for prediction of cardiac death, hard cardiac events, and MACE, after adjustment for significant clinical variables and stress test variables. Dobutamine MPI provides incremental prognostic information for the prediction of cardiovascular outcomes in patients with limited exercise capacity. The long-term prognosis of patients with limited exercise capacity who have an abnormal dobutamine MPI is significantly worse than those with a normal MPI.

Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is standard of care for locally advanced esophageal cancer in many countries. After nCRT up to one third of all patients have a pathologically complete response in the resection specimen, posing an ethical imperative to reconsider the necessity of standard surgery in all operable patients after nCRT. An active surveillance strategy following nCRT, in which patients are subjected to frequent clinical investigations after the completion of neoadjuvant therapy, has been evaluated in other types of cancer with promising results. In esophageal cancer, both patients who are cured by neoadjuvant therapy alone as well as patients with subclinical disseminated disease at the time of completion of neoadjuvant therapy may benefit from such an organ sparing approach. Active surveillance is currently applied in selected patients with esophageal cancer who refuse surgery or are medically unfit for major surgery after completion of nCRT, but this strategy is not (yet) adopted as an alternative to standard surgery or definitive chemoradiation. The available literature is scarce, but suggests that long-term oncological outcomes after active surveillance are noninferior compared to standard surgical resection, providing justification for comparison of both treatments in a phase III trial. This review gives an overview of the current knowledge regarding active surveillance after completion of nCRT in esophageal cancer and outlines future research perspectives.

Introduction: Pancreatic cancer is among the five most lethal malignancies in the world. Unfortunately, many malignant tumors go undetected by the current primary diagnostic tools. (18)FDG-PET and (18)FDG-PET/CT might be useful to confirm suspected pancreatic cancer. Methods: A meta-analysis was performed using all major search engines. Methodological quality of included studies was assessed as well as quality of the PET-protocol. The following pooled estimates served as primary outcome measures: sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy. Results: Thirty-five studies were included. Pooled estimates for (18)FDG-PET were: sensitivity 90%, specificity 76%, PPV 90%, NPV 76% and accuracy 86%. Pooled estimates for (18)FDG-PET/CT were: sensitivity 90%, specificity 76%, PPV 89%, NPV 78% and accuracy 86%. The pooled sensitivity and specificity for (18)FDG-PET to differentiate between pancreatic cancer and chronic pancreatitis were 90% and 84%, respectively. Conclusion: Both (18)FDG-PET and (18)FDG-PET/CT offer no benefit over the current primary diagnostic tools in diagnosing pancreatic cancer. However, the (18)FDG-PET/CT systems are still improving. We should investigate the sensitivity and specificity of these new systems while reevaluating the tradeoff between false positive and false negative results. Yet, (18)FDG-PET/CT may have a role in the staging of pancreatic cancer, in survival prediction, and may add to other diagnostic information, like histology. (C) 2014 Elsevier Ltd. All rights reserved.

Background After curatively intended neoadjuvant chemoradiotherapy (nCRT) according to CROSS plus surgery for esophageal cancer, 29% of patients have a pathologic complete response. Active surveillance after nCRT, in which patients undergo frequent clinical examinations and where esophagectomy is only offered to those with a locoregional regrowth without distant metastases, has been proposed as novel treatment option. This study provides a systematic review and meta-analysis of the literature regarding the accuracy of endoscopic biopsies, endoscopic ultrasound (EUS) and 18F-FDG PET(-CT) for detecting residual disease after nCRT for esophageal cancer. Methods A systematic literature search in Embase, Medline, Cochrane and Web of Science was performed. Two reviewers independently collected studies on the diagnostic accuracy of endoscopic biopsies, EUS and 18F-FDG PET(-CT) for detecting residual disease after nCRT at the primary tumor site or in regional lymph nodes for potentially curable esophageal adenocarcinoma (AC) or squamous cell carcinoma (SCC). Histopathological examination of the resection specimen was the reference standard. Study quality was appraised with the QUADAS-2 tool. Sensitivity and specificity values were calculated and pooled using meta-analyses. Subgroup analyses were performed to investigate possible sources of heterogeneity. Results 60 studies were included for qualitative analysis and 40 for quantitative analysis. For detecting residual disease at the primary tumor site, 11 studies evaluated endoscopic biopsies, 11 described EUS qualitatively, 14 evaluated PET qualitatively, 12 evaluated PET quantitatively, 6 of them using SUVmax and 6 of them using DSUVmax. Summary sensitivity values were 0.36 (95%CI 0.27–0.45), 0.97 (95%CI 0.94–0.98), 0.74 (95%CI 0.66–0.81), 0.68 (95%CI 0.61–0.74) and 0.68 (95%CI 0.54–0.79), respectively. Summary specificity values were 0.93 (95%CI 0.85–0.97), 0.09 (95%CI 0.04–0.19), 0.52 (95%CI 0.40–0.63), 0.70 (95%CI 0.61–0.78), 0.70 (95%CI 0.60–0.78) and respectively. For detecting residual malignant lymph nodes, 11 studies evaluated EUS with a summary sensitivity of 0.68 (95%CI 0.54–0.80) and a summary specificity of 0.58 (95%CI 0.45–0.70). Subgroup analyses demonstrated that sensitivity of endoscopic biopsy, PET DSUVmax and EUS for nodal was higher in SCC than in AC. Conclusion Current literature suggests insufficient accuracy of endoscopic biopsies, EUS and 18F-FDG PET(-CT) as individual modalities for detecting residual disease after nCRT for potentially curable esophageal cancer. Disclosure All authors have declared no conflicts of interest.

Background Neoadjuvant chemoradiotherapy (nCRT) induces a pathologically complete response in approximately 30% of patients with oesophageal cancer. To explore the possibility of safe postponement of surgery, accurate clinical response evaluations are needed to exclude residual disease. The present study aims to assess the value of F-18-FDG-PET/CT for the detection of residual tumour (> 10% tumour cells = TRG3–4 vs. no vital cells = TRG1) or metastases after nCRT. Methods FDG-PET/CT at baseline and 12 weeks after nCRT was performed according to the European Association of Nuclear Medicine guidelines 1.0 (2.3MBq/kg F-18-FDG; scanning 60 ± 5min.) and the protocol of the preSANO study. Qualitative analysis included sensitive reading of presence of residual tumour and/or metastases. A lesion was considered FDG-positive, when any uptake in the lesion itself was above the adjacent oesophageal background uptake. Quantitatively, SUV/lean body mass (SUL) measurements at tumour, lymph nodes, oesophagus, liver and bloodpool were recorded and compared with pathology (resection specimen: gold standard). Results Some 129 of 207 patients with FDG-avid tumours at baseline proceeded to FDG-PET/CT at around 12 weeks after nCRT just before surgery. Forty-one of 129 patients had TRG3–4, of whom 6 were missed on FDG-PET/CT (15% false negative) with SULmax 2.07 ± 0.25, SUL-ratio tumour/oesophagus (SULR) 1.35 ± 0.14. Sensitivity for TRG2–3-4 vs. TRG1 was 57/71 (80%). SULmax and SULR of FDG-positives were 3.76 ± 1.33 and 1.82 ± 0.69 respectively, compared to SULmax 2.21 ± 0.42 and SULR 1.31 ± 0.22 in FDG-negatives. Distant metastases were detected in 18 of 190 (10%) patients. Of all patients with postponed surgery, 12 had ≥ 1 additional FDG-PET/CT during follow-up (25–49.7 weeks after nCRT). Eventually, 4 patients underwent surgery. Three of 4 had increased FDG-signal and TRG3–4; 1 patient had decreased FDG-signal and no tumour left (TRG1). Conclusion FDG-PET/CT at around 12 weeks after nCRT misses TRG3–4 tumours in 15% and detects residual TRG2–3-4 in 80%. Furthermore, PET-CT detects distant metastases in 10% of patients after nCRT. These data indicate that serial FDG-PET may become valuable in an active surveillance approach. Disclosure All authors have declared no conflicts of interest.

Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are the most common types of dementia in the presenile population. Episodic memory impairment, the clinical hallmark of AD, can also be encountered in patients with FTD, complicating accurate diagnosis. Several studies in FTD have correlated memory deficits with neuroimaging findings, but lacked to compare neuroimaging results in FTD patients with and without memory impairment, while this latter analysis may give us insight into the underlying mechanisms of memory impairment in FTD. The aim of the present study was to compare 99m Tc-HMPAO SPECT hypoperfusion patterns between FTD with episodic memory impairment (n = 13), FTD patients without episodic memory impairment (n = 10) as well as early onset (< 70 yrs) AD patients (n = 13), and controls (n = 15). We performed our analyses by means of Statistical Parametric Mapping software (SPM5), and showed that FTD patients with episodic memory impairment had lower perfusion in the right temporal lobe compared with FTD patients without memory impairment. Lower perfusion in this region correlated with worse memory performance on the Clinical Dementia Rating scale in FTD patients. With equal performances on memory tests, patients with early onset AD showed posterior temporal and parietal lobe hypoperfusion in comparison with patients with FTD and memory impairment, while vice versa hypoperfusion in the anterior frontotemporal regions was found in FTD patients with memory impairment in comparison with AD.

Previous studies have reported a favorable outcome of patients with normal single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). The aim of this study was to assess the very long-term prognosis of patients with known coronary artery disease (CAD) and normal SPECT MPI results. The population consisted of 266 patients with known CAD (defined as a healed myocardial infarction and/or a previous coronary revascularization), who underwent exercise bicycle or dobutamine-atropine stress SPECT MPI and had normal perfusion during stress and at rest. End points during follow-up were all-cause mortality, cardiac mortality, and nonfatal myocardial infarction. Univariate and multivariate analyses were performed to identify predictors of long-term outcome. Follow-up was completed in 261 (98%) patients. During a median follow-up of 12 years, 94 (36%) patients died, of which 26 (10%) died due to cardiac causes, and 15 (6%) had a nonfatal myocardial infarction. The annualized mortality rate was 3.1%, annualized cardiac mortality rate was 0.9%, and the annualized event rate for cardiac death and/or nonfatal infarction was 1.2%. Independent predictors of total mortality were age, diabetes mellitus, and rate-pressure product at peak stress. Independent predictors of cardiac mortality were age, male gender, and rate-pressure product at peak stress. Patients with known CAD and a normal SPECT MPI study have a favorable long-term prognosis. Clinical and stress test variables can be used to identify patients with a higher risk status.

Background We have recently shown that treatment of mice with the neutral endopeptidase (NEP) inhibitor phosphoramidon (PA) improves the bioavailability and tumor uptake of biodegradable radiopeptides. For the truncated gastrin radiotracer [111In-DOTA]MG11 ([(DOTA)DGlu10]gastrin(10–17)), this method led to impressively high tumor-to-kidney ratios. Translation of this concept in the clinic requires the use of certified NEP inhibitors, such as thiorphan (TO) and its orally administered prodrug racecadotril (Race). Besides NEP, angiotensin-converting enzyme (ACE) has also been implicated in the catabolism of gastrin analogs. In the present study, we first compared the effects induced by NEP inhibition (using PA, TO, or Race) and/or by ACE inhibition (using lisinopril, Lis) on the biodistribution profile of [111In-DOTA]MG11 in mice. In addition, we compared the efficacy of PA and TO at different administered doses to enhance tumor uptake. Methods [111In-DOTA]MG11 was coinjected with (a) vehicle, (b) PA (300 μg), (c) TO (150 μg), (d) Lis (100 μg), (e) PA (300 μg) plus Lis (100 μg), or (f) 30–40 min after intraperitoneal (ip) injection of Race (3 mg) in SCID mice bearing AR42J xenografts. In addition, [111In-DOTA]MG11 was coinjected with vehicle, or with progressively increasing amounts of PA (3, 30, or 300 μg) or TO (1.5, 15, and 150 μg) in SCID mice bearing twin A431-CCK2R(+/−) tumors. In all above cases, biodistribution was conducted at 4 h postinjection (pi). Results During NEP inhibition, the uptake of [111In-DOTA]MG11 in the AR42J tumors impressively increased from 1.8 ± 1.0 % ID/g (controls) to 15.3 ± 4.7 % ID/g (PA) and 12.3 ± 3.6 % ID/g (TO), while with Race tumor values reached 6.8 ± 2.8 % ID/g. Conversely, Lis had no effect on tumor uptake and no additive effect when coinjected with PA. During the dose dependence study in mice, PA turned out to be more efficacious in enhancing tumor uptake of [111In-DOTA]MG11 in the CCK2R-positive tumors compared to equimolar amounts of TO. In all cases, renal accumulation remained low, resulting in notable increases of tumor-to-kidney ratios. Conclusions This study has confirmed NEP as the predominant degrading enzyme of [111In-DOTA]MG11 and ruled out the involvement of ACE in the in vivo catabolism of the radiotracer. NEP inhibition with the clinically tested NEP inhibitors TO and Race resulted in significant enhancement of tumor-to-kidney ratios vs. controls. However, compared with PA, TO and its prodrug Race induced less potent increases of tumor uptake, highlighting the significance of inhibitor type, administration route, and dose for implementing a first proof-of-principle study in human. Electronic supplementary material The online version of this article (doi:10.1186/s13550-015-0158-3) contains supplementary material, which is available to authorized users.

Background Exercise 99mTc-tetrofosmin single-photon emission computed tomography (SPECT) is a useful tool for short- and medium-term risk stratifications. Currently, the long-term prognostic application of this technique has not been evaluated. Methods and Results Exercise 99mTc-tetrofosmin was performed in 655 consecutive patients. Ten patients who underwent revascularization

Background Progressive supranuclear palsy (PSP) patients often exhibit cognitive decline and behavioural changes during the disease course. In a subset, these symptoms may be the presenting manifestation and can be similar to those in frontotemporal dementia (FTD). However, correlation studies between quantitative imaging measures and detailed neuropsychological assessment are scarce. The aim of this study was to investigate the functional role of affected brain regions in cognition in PSP compared with controls and subsequently examine these regions in FTD patients with known tau pathology (FTD tau). Methods 21 PSP patients, 27 healthy controls and 11 FTD tau patients were enrolled. All participants underwent neuropsychological testing and technetium-99m-hexamethyl-propylenamine-oxime single photon emission CT. Regression slope analyses were performed in statistical parametric mapping to find significant associations between neuropsychological test results and brain perfusion. Results PSP patients showed hypoperfusion in the midcingulate cortex (MCC) of which the posterior part correlated with Stroop III and Weigl. In FTD tau patients, MCC involvement was located more anterior and correlated with Stroop III and Wisconsin Card Sorting Test concepts. The degree of hypoperfusion in the anterior cortex and MCC in the disorders differed in the subgenual anterior cingulate cortex only. Conclusions The posterior part of the MCC is prominently involved in the neurodegenerative process of PSP, and the severity of its hypoperfusion correlated with the extent of executive dysfunction. In FTD tau, this cognitive domain was associated with anterior MCC involvement. The degree of hypoperfusion in these regions did not differ between PSP and FTD tau. These observations provide insight into the role of the cingulate cortex in cognitive dysfunction in these neurodegenerative disorders and warrant further investigations.

Megalin-mediated renal retention of radiolabeled somatostatin analogs may lead to nephrotoxicity during peptide receptor radionuclide therapy (PRRT). The cytoprotective agent amifostine protected rats from long-term nephrotoxicity after PART with Lu-177-DOTA,Tyr(3)-octreotate. This study describes the direct effect of amifostine on kidney and tumor uptake of In-111-DOTA,Tyr(3)-octreotate. Methods: In vivo biodistribution studies were performed using CA20948 tumor-bearing rats, with or without amifostine coadministration, via several routes. In vitro uptake was studied in somatostatin receptor-expressing CA20948 and megalin or cubilin receptor-expressing BN-16 cells, in the absence or presence of amifostine or its active metabolite WA-1065. Results: Coadministration of amifostine decreased renal uptake of radiolabeled octreotate in vivo, whereas tumor uptake was not affected. In agreement, amifostine and WR-1065 coincubation reduced uptake in BN-16 but not in CA20948 cells. Conclusion: Amifostine may provide renal protection during PART using somatostatin analogs, both by mitigation of radiation damage and the currently observed reduction of absorbed kidney radiation dose.

The goal of this study was to evaluate the very long-term outcome after normal exercise 99mTc-sestamibi myocardial perfusion single-photon emission computed tomography (SPECT). Exercise 99mTc-sestamibi SPECT is widely used for risk stratification, but data on very long-term outcome after a normal test are scarce. A consecutive group of 233 patients (122 men, mean age 54 ± 12 years) with known or suspected coronary artery disease (CAD) underwent exercise 99mTc-sestamibi SPECT and had normal myocardial perfusion at exercise and at rest. Follow-up endpoints were all-cause mortality, cardiac mortality, nonfatal myocardial infarction, and coronary revascularization. Predictors of outcome were identified by Cox proportional hazard regression models using clinical and exercise testing variables. During a mean follow-up of 15.5 ± 4.9 years, 41 (18%) patients died, of which 13 were cardiac deaths. A total of 18 (8%) patients had a nonfatal myocardial infarction, and 47 (20%) had coronary revascularization. The annualized event rates for all-cause mortality, cardiac mortality, cardiac mortality/nonfatal infarction, and major adverse cardiac events were, respectively, 1.1%, 0.3%, 0.7%, and 1.8%. Multivariate analysis demonstrated that the variables age, male gender, diabetes, diastolic blood pressure at rest, rate pressure product at rest, peak exercise heart rate, and ST segment changes were independent predictors of major adverse cardiac events. Patients with suspected or known CAD and normal exercise 99mTc-sestamibi myocardial perfusion SPECT have a favorable 15-year prognosis. Follow-up should be closer in patients with known CAD, and/or having clinical and exercise parameters indicating higher risk status.

Nuclear medicine plays a pivotal role in the imaging and treatment of neuroendocrine tumours (NETs). Somatostatin receptor scintigraphy (SRS) with [111In-DTPA0]octreotide has proven its role in the diagnosis and staging of gastroenteropancreatic NETs (GEP-NETs). New techniques in somatostatin receptor imaging include the use of different radiolabelled somatostatin analogues with higher affinity and different affinity profiles to the somatostatin receptor subtypes. Most of these analogues can also be labelled with positron-emitting radionuclides that are being used in positron emission tomography imaging. The latter imaging modality, especially in the combination with computed tomography, is of interest because of encouraging results in terms of improved imaging quality and detection capabilities. Considerable advances have been made in the imaging of NETs, but to find the ideal imaging method with increased sensitivity and better topographic localisation of the primary and metastatic disease remains the ultimate goal of research. This review provides an overview of the currently used imaging modalities and ongoing developments in the imaging of NETs, with the emphasis on nuclear medicine and puts them in perspective of clinical practice. The advantage of SRS over other imaging modalities in GEP-NETs is that it can be used to select patients with sufficient uptake for treatment with radiolabelled somatostatin analogues. Peptide receptor radionuclide therapy (PRRT) is a promising new tool in the management of patients with inoperable or metastasised NETs as it can induce symptomatic improvement with all Indium-111, Yttrium-90 or Lutetium-177-labelled somatostatin analogues. The results that were obtained with [90Y-DOTA0,Tyr3]octreotide and [177Lu-DOTA0,Tyr3]octreotate are even more encouraging in terms of objective tumour responses with tumour regression and documented prolonged time to progression. In the largest group of patients receiving PRRT, treated with [177Lu-DOTA0,Tyr3]octreotate, a survival benefit of several years compared with historical controls has been reported.

Context: Insulinomas are relatively rare neuroendocrine tumors of the pancreas. Only 10% are considered malignant. Control of insulin hypersecretion and hypoglycemia in patients with malignant insulinomas may be extremely difficult. Different medications and chemotherapy schedules have been used. Patients: Five patients with metastatic insulinomas and severe, poorly controllable, hypoglycemia are described. These patients required continuous glucose infusion to control severe hypoglycemia, which were induced by the high levels of insulin secretion. Conventional medications, such as diazoxide, or streptozotocin-based chemotherapies had been used to control hypoglycemia but were ineffective and/or produced adverse effects. All patients were treated with sc octreotide. Intervention: Peptide receptor radionuclide therapy with radiolabeled-somatostatin analogs was used. Results: After the start of radiolabeled somatostatin analog therapy, the five patients with metastatic insulinomas had stable disease for a mean period of 27 months. During these months, the patients were without any hypoglycemic episodes. Finally, three of five patients died because of progressive disease. Conclusions: Radiolabeled somatostatin analog therapy can stabilize tumor growth and can be very successful in further controlling severe hypoglycemia in malignant insulinomas. In our series, this eventually resulted in improved survival outside the hospital setting. (J Clin Endocrinol Metab 96: 3381-3389, 2011)

Objective: Frontotemporal lobar degeneration (FTLD) is a clinically, genetically, and pathologically heterogeneous disorder. The aim of this study was to compare clinical features and perfusion patterns on SPECT of patients with familial FTLD-TAR DNA binding protein 43 kDa (TDP) and MAPT mutations. Methods: Patients were included if they had MAPT or GRN mutations, positive family history with pathologically proven FTLD in the patient or first-degree relative, or were part of FTD-MND families. All patients and 10 age-and gender-matched controls underwent measurement of brain perfusion using (99m)Tc-HMPAO SPECT. We used SPM8 to perform image processing and voxel-based group analyses (p < 0.001). Gender and age were included as nuisance variables in the design matrices. Results: Of the 29 patients with familial FTLD, 19 had familial FTLD-TDP (GRN mutations in 6), and 10 had MAPT mutations. At clinical presentation, familial FTLD-TDP patients were older at onset (p = 0.030) and had more memory deficits (p = 0.011), whereas patients with MAPT had more naming deficits (p < 0.001) and obsessive-compulsive behavior (p = 0.001). The between-groups SPECT analyses revealed significantly less perfusion in the right frontal lobe, precuneus, cuneus, and inferior parietal lobule in familial FTLD-TDP, whereas significantly less perfusion was found in the left temporal and inferior frontal gyri in MAPT. Post hoc analysis of familial FTLD-TDP with unknown genetic defect vs MAPT revealed less perfusion in the right frontal and parietal lobe. Conclusion: Familial FTLD-TDP shows relatively more posterior hypoperfusion, including the precuneus and inferior parietal lobule, possibly related to significant memory impairment. Patients with MAPT were characterized by impaired perfusion of the temporal regions and naming deficits. Neurology (R) 2011; 77: 384-392

In the 1980s, the In-111-labeled somatostatin analog OctreoScan (Covidien, Hazelwood, MO) was developed for imaging of somatostatin receptor subtype 2 (sst(2)) overexpressing tumors. On the basis of this success, peptide receptor radionuclide therapy (PART) was developed using similar somatostatin analogs with different therapeutic radionuclides. Clinical application of PRRT demonstrated impressive results on tumor response, overall survival, and quality of life in patients with gastroenteropancreatic neuroendocrine tumors. The peptides 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), Tyr(3)-octreotate (DOTATATE) and DOTA, Tyr(3)-octreotide (DOTATOC) (brand name Onalta), predominantly targeting sst(2), have been granted Orphan Drug status by the European Medicines Agency and the US Food and Drug Administration for application in PART. Besides somatostatin receptor-targeting peptides, multiple other radiopeptide analogs were developed targeting several other receptors overexpressed on various tumors. Some of these peptide analogs, including cholecystokinin, gastrin, gastrin-releasing peptide, arginine-glycine-aspartate (RGD)-peptides, and glucagon-like peptide 1 analogs appeared very promising in preclinical and clinical imaging and PRRT studies. Although the success of PART with radiolabeled somatostatin analogs has been established, there is still room for improvement. The therapeutic window of PART could be enlarged by the use of new and improved targeting compounds, of which new antagonists with excellent tumor to background ratios are very promising. Furthermore, locoregional administration, improved healthy tissue protection, and combination treatment can be applied to increase the effectiveness of PART. Combination treatment might include cocktails of different peptide analogs of different therapeutic radionuclides and of radiolabeled peptides with chemotherapeutic or radiosensitizing agents. This review summarizes results of PART and describes clinical and preclinical studies regarding PRRT optimizing strategies. Semin Nucl Med 40:209-218 (C) 2010 Elsevier Inc. All rights reserved.

Contains fulltext : 87868.pdf (Publisher’s version ) (Closed access) This review focuses on the present status of kidney protection during peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues. This treatment modality for somatostatin receptor-positive tumours is limited by renal reabsorption and retention of radiolabelled peptides resulting in dose-limiting high kidney radiation doses. Radiation nephropathy has been described in several patients. Studies on the mechanism and localization demonstrate that renal uptake of radiolabelled somatostatin analogues largely depends on the megalin/cubulin system in the proximal tubule cells. Thus methods are needed that interfere with this reabsorption pathway to achieve kidney protection. Such methods include coadministration of basic amino acids, the bovine gelatin-containing solution Gelofusine or albumin fragments. Amino acids are already commonly used in the clinical setting during PRRT. Other compounds that interfere with renal reabsorption capacity (maleic acid and colchicine) are not suitable for clinical use because of potential toxicity. The safe limit for the renal radiation dose during PRRT is not exactly known. Dosimetry studies applying the principle of the biological equivalent dose (correcting for the effect of dose fractionation) suggest that a dose of about 37 Gy is the threshold for development of kidney toxicity. This threshold is lower when risk factors for development of renal damage exist: age over 60 years, hypertension, diabetes mellitus and previous chemotherapy. A still experimental pathway for kidney protection is mitigation of radiation effects, possibly achievable by cotreatment with amifostine (Ethylol), a radiation protector, or with blockers of the renin-angiotensin-aldosterone system. Future perspectives on improving kidney protection during PRRT include combinations of agents to reduce renal retention of radiolabelled peptides, eventually together with mitigating medicines. Moreover, new somatostatin analogues with lower renal retention may be developed. Furthermore, knowledge on kidney protection from radiolabelled somatostatin analogues may be expanded to other peptides. 01 mei 2010

Current developments in cardiovascular biology and imaging enable the noninvasive molecular evaluation of atherosclerotic vascular disease. Intraplaque neovascularization sprouting from the adventitial vasa vasorum has been identified as an independent predictor of intraplaque hemorrhage and plaque rupture. These intraplaque vasa vasorum result from angiogenesis, most likely under influence of hypoxic and inflammatory stimuli. Several molecular imaging techniques are currently available. Most experience has been obtained with molecular imaging using positron emission tomography and single photon emission computed tomography. Recently, the development of targeted contrast agents has allowed molecular imaging with magnetic resonance imaging, ultrasound and computed tomography. The present review discusses the use of these molecular imaging techniques to identify inflammation and intraplaque vasa vasorum to identify vulnerable atherosclerotic plaques at risk of rupture and thrombosis. The available literature on molecular imaging techniques and molecular targets associated with inflammation and angiogenesis is discussed, and the clinical applications of molecular cardiovascular imaging and the use of molecular techniques for local drug delivery are addressed.

Somatostatin receptor imaging (SRI) with [111In-DTPA0]octreotide has proven its role in the diagnosis and staging of gastroenteropancreatic neuroendocrine tumors (GEPNETs). Newer radiolabeled somatostatin analogs which can be used in positron emission tomography (PET) imaging, and which have a higher affinity for the somatostatin receptor, especially receptor subtype-2, have been developed. It would be desirable, however, if one radiolabeled analog became the new standard for PET imaging, because the current application of a multitude of analogs implies a fragmented knowledge on the interpretation of the images that are obtained in clinical practice. In our view, the most likely candidates for such a universal PET tracer for SRI are [68Ga-DOTA0,Tyr3]octreotate or [68Ga-DOTA0,Tyr3]octreotide. Treatment with radiolabeled somatostatin analogs is a promising new tool in the management of patients with inoperable or metastasized neuroendocrine tumors. Symptomatic improvement may occur with all 111In-, 90Y-, or 177Lu-labeled somatostatin analogs that have been used for peptide receptor radionuclide therapy (PRRT). The results that were obtained with [90Y-DOTA0,Tyr3]octreotide and [177Lu-DOTA0,Tyr3]octreotate are very encouraging in terms of tumor regression. Also, if kidney protective agents are used, the side effects of this therapy are few and mild, and the median duration of the therapy response for these radiopharmaceuticals is 30 and 40 months respectively. The patients' self-assessed quality of life increases significantly after treatment with [177Lu-DOTA0,Tyr3]octreotate. Lastly, compared to historical controls, there is a benefit in overall survival of several years from the time of diagnosis in patients treated with [177Lu-DOTA0,Tyr3]octreotate. These data compare favorably with the limited number of alternative treatment approaches. If more widespread use of PRRT can be guaranteed, such therapy may well become the therapy of first choice in patients with metastasized or inoperable GEPNETs.

Peptide-receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs, such as octreotide, is a promising option for the treatment of somatostatin-receptor-positive endocrine tumors. Here, van Essen et al. evaluate data from preliminary studies of PRRT, and discuss the pros and cons of this approach. The authors propose that PRRT might soon become the treatment of choice for patients with metastatic or inoperable endocrine tumors. Peptide-receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs is a promising option for the treatment of somatostatin-receptor-positive endocrine tumors. Treatment with somatostatin analogs labeled with 111In, 90Y or 177Lu can result in symptomatic improvement, although tumor remission is seldom achieved with 111In-labeled analogs. In this Review, the findings of several studies on the use of PRRT for endocrine tumors are evaluated. Large variation in the antitumor effects of 90Y-octreotide was reported between studies: an objective response (≥50% tumor regression) was achieved in 9–33% of patients. After treatment with 177Lu-octreotate, an objective response was achieved in 29% of patients and a minor response (25–50% tumor regression) was achieved in 16% of patients; stable disease was present in 35% of patients. Treatment with 177Lu-octreotate resulted in a survival benefit of several years and markedly improved quality of life. Serious, delayed adverse effects were rare after PRRT. Although randomized, clinical trials have not yet been performed, data on the use of PRRT compare favorably with those from other treatment approaches, such as chemotherapy. If these results can be replicated in large, controlled trials, PRRT might become the preferred option in patients with metastatic or inoperable gastroenteropancreatic neuroendocrine tumors.

Objective We estimated the absorbed doses for In-111-DTPA-D-Phe(1)-octreotide and Y-90-DOTA-D-Phe(1)-Tyr(3)-octreotide in the same patients in order to compare the potential effectiveness (tumour dose) and safety (kidney and red marrow dose) of these drugs for peptide-targeted radiotherapy of somatostatin receptor positive tumours. Methods Six patients with neuroendocrine tumours underwent quantitative In-111-DTPA-D-Phe(1)-octreotide SPECT and Y-86-DOTA-D-Phe(1)-Tyr(3)-octreotide PET scan at intervals of 1 week. All studies were performed with a co-infusion of amino acids for renal protection. PET and SPECT were reconstructed using iterative algorithms, incorporating attenuation and scatter corrections. Tissue uptakes (IA%) were measured and used to calculate residence times. Absorbed doses to tissues were estimated and the maximal allowed activity, defined as either the activity delivering 23 Gy to the kidneys (MAA(K)) or 2 Gy to the red marrow (MAA(RM)), was calculated and the resulting tumour absorbed doses were computed. Results For the MAA(K) the mean absorbed dose to the red marrow was lower for Y-90-DOTA-D-Phe(1)-Tyr(3)-octreotide than for In-111-DTPA-D-Phe(1)-octreotide (1.8 +/- 0.9 Gy vs. 6.4 +/- 1.6 Gy; P < 0.001). The median absorbed dose to tumours for the MAA(K) was two-fold higher for Y-90-DOTA-D-Phe(1)-Tyr(3)-octreotide as compared to In-111-DTPA-D-Phe(1)-octreotide (30.1 vs. 12.6 Gy; P < 0.05). The median absorbed dose to tumours estimated for the MAA(RM) was 10-fold higher for Y-90-DOTA-D-Phe(1)-Tyr(3)-octreotide than for In-111-DTPA-D-Phe(1)-octreotide (35.1 Gy vs. 3.9 Gy; P < 0.05). Conclusions This direct intra-patient comparison confirms that the use of Y-90-DOTA-D-Phe(1)-Tyr(3)-octreotide is more appropriate for therapy of somatostatin receptor bearing tumours. When using In-111-DTPA-D-Phe(1)-octreotide, the red marrow represents the major critical organ; this can result in significant toxicity if high activities have to be administered to obtain efficient tumour irradiation.

Renal irradiation is a dose-limiting factor in peptide receptor radionuclide therapy using radiolabelled somatostatin analogues. This irradiation is mainly caused by reabsorption of radiolabelled peptides in the proximal tubule. In the human kidney, somatostatin receptors are expressed in the vasa recta, tubuli and glomeruli. It is not clear to what extent these receptors contribute to the total kidney radioactivity uptake.Retrospectively, [(111)In-DTPA(0)]octreotide scans of ten selected patients with carcinoids (well-differentiated gastrointestinal endocrine tumour) with liver metastases were evaluated. For each patient, two scans were obtained: one scan was performed without (control) and one during treatment with unlabelled octreotide. Kidney, tumour, spleen and liver uptake was measured in both scans.The interval between the two scans per patient varied from 50 to 397 days. Octreotide treatment substantially lowered kidney [(111)In-DTPA(0)]octreotide uptake in eight out of ten patients. Kidney uptake in all patients was reduced to 82%+/-15% of control, (p0.01). A correlation between kidney uptake and spleen uptake was found (r=0.67, p0.05). Serum creatinine was unchanged. Surprisingly, tumour and liver [(111)In-DTPA(0)]octreotide uptake was not significantly influenced by unlabelled octreotide therapy, but spleen uptake was significantly lowered by treatment (30.6% of control, p0.002).We conclude that the somatostatin receptor plays a role in the total renal uptake of radiolabelled somatostatin analogues. The long interval between scans might explain the finding that tumour and liver metastasis uptake of [(111)In-DTPA(0)]octreotide was unchanged. Further studies are needed to confirm and eludicate the results of this study.

Treatment with radiolabeled somatostatin analogs is a promising new tool in the management of patients who have inoperable or metastasized endocrine tumors. Symptomatic improvement may occur with all (111)In-, (90)Y-, or (177)Lu-labeled somatostatin analogs that have been used for peptide receptor radionuclide therapy. The results that were obtained with [(90)Y-DOTA degrees ,Tyr(3)]octreotide and [(177)Lu-DOTA degrees ,Tyr(3)]octreotate are encouraging in tumor regression. Also, if kidney-protective agents are used, the side effects of this therapy are few and mild. These data compare favorably with the limited number of alternative treatment approaches.

Background Earlier studies have suggested a modest accuracy of stress thallium 201 myocardial perfusion imaging (MPI) for the diagnosis of coronary artery disease (CAD) in women. The accuracy of stress MPI with technetium 99m tetrofosmin has not been studied in women. The aim of this study was to assess the accuracy of stress Tc-99m tetrofosmin MPI for the diagnosis and localization of CAD in women. Methods and Results We studied 88 women who underwent exercise or dobutamine stress Tc-99m tetrofosmin tomography and coronary angiography within 3 months. Significant CAD was defined as a stenosis 50% or greater in diameter in at least 1 major epicardial coronary artery. Myocardial perfusion abnormalities were detected in 44 of 53 patients with significant CAD and in 7 of 35 patients without significant CAD (overall sensitivity, 83% [95% confidence interval (CI), 73%-93%]; specificity, 80% [95% CI, 67%-93%]; and accuracy, 82% [95% CI, 74%-90%]). The sensitivity was 72% (18/25) in patients with single-vessel CAD and 93% (26/28) in patients with multivessel CAD. Perfusion abnormalities were detected in 2 or more vascular distributions in 20 of 28 patients with multivessel CAD and in 4 of 60 patients without multivessel CAD (sensitivity for the identification of multivessel CAD, 71% [95% CI, 55%-88%]; specificity, 93% [95% CI, 86%-98%]; and accuracy, 86% [95% CI, 79%-93%]). The sensitivity, specificity, and accuracy were 82%, 84%, and 83%, respectively, for the diagnosis of CAD in the left anterior descending artery; 77%, 84%, and 81%, respectively, for CAD in the right coronary artery; and 74%, 80%, and 78%, respectively, for CAD in the left circumflex artery. Conclusion Stress Tc-99m tetrofosmin MPI is an accurate noninvasive technique for the diagnosis and localization of CAD in women.

Exercise stress electrocardiography is the recommended method for cardiac evaluation of patients with normal electrocardiograms (ECGs). There are no data to indicate an independent value of myocardial perfusion imaging (MPI) in predicting mortality in these patients. This study assessed the value of exercise stress MPI in predicting mortality in patients with normal baseline ECGs. We studied 319 patients (55 +/- 10 years of age; 180 men) with normal ECGs by exercise stress technetium-99m tetrofosmin MPI. End points during follow-up were cardiac and all-cause mortalities and hard cardiac events. A normal scan was detected in 190 patients (60%). Myocardial perfusion abnormalities were fixed in 59 patients (18%) and reversible in 70 (23%). During a mean follow-up of 7 +/- 1.2 years, 46 patients (14%) died. Death was considered cardiac in 28 patients (9%). Nonfatal myocardial infarction occurred in 12 patients (4%). Annual cardiac death rates were 0.4% in patients with normal perfusion, and 2.7% in patients with reversible defects. Annual total mortality rates were 1.1% in patients with normal perfusion and 3.4% in patients with reversible defects. In a multivariate analysis model, reversible perfusion abnormalities were associated with cardiac death (RR 2.8, 95% confidence interval 1.6 to 5.1) and hard cardiac events (RR 2.7, 95% confidence interval 1.5 to 4.5). Perfusion abnormalities in multivessel distribution were predictive of all-cause mortality (RR 2, 95% confidence interval 1.4 to 3.2). ST-segment depression was not significantly associated with events. In conclusion, stress technetium-99m tetrofosmin MPI provides independent information for predicting cardiac and overall mortalities in patients with normal ECGs. Reversible perfusion abnormalities, but not ischemic electrocardiographic changes, are predictive of outcome in these patients.

The aim of this study was to ascertain whether stress myocardial perfusion imaging can independently predict long-term mortality.We studied 1,386 patients with known or suspected coronary artery disease by means of stress 99mTc-tetrofosmin myocardial perfusion tomography. The end point during follow-up was death from any cause. Mortality rates were compared with that in a reference population using calculated age- and gender-specific data in the general population.Mean age was 60+/-11 years. There were 608 (44%) women. Perfusion abnormalities were fixed in 416 (30%) patients and reversible in 445 (32%) patients. During a mean follow-up of 6+/-1.9 years, 290 (21%) patients died. The annual mortality was 1.7% in patients with normal perfusion and 5.2% in patients with abnormal perfusion. Patients with multivessel distribution of perfusion abnormalities had the highest annual mortality (6.2%). The annual mortality in the reference population was 3.2%. In a multivariate analysis model, predictors of death were age [risk ratio (RR)=1.06, 95% CI 1.04-1.07], male gender (RR=2, CI 1.6-2.6), history of heart failure (RR=2.3, CI 1.8-3.1), diabetes mellitus (RR=2.1, CI 1.6-2.7), smoking (RR=1.8, CI 1.4-2.3), reversible perfusion defects (RR=1.8, CI 1.4-2.5) and fixed perfusion defects (RR=1.7, CI 1.3-2.1).Myocardial perfusion abnormalities on stress 99mTc-tetrofosmin tomography are independently associated with long-term risk of death. The extent of perfusion abnormalities is a major determinant of mortality. The presence of normal perfusion is associated with a lower mortality compared with the general population.