A prospective cohort study on active surveillance after neoadjuvant chemoradiotherapy for esophageal cancer: protocol of Surgery As Needed for Oesophageal cancer-2.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy is a standard treatment for potentially curable esophageal cancer. Active surveillance in patients with a clinically complete response (cCR) 12 weeks after nCRT is regarded as possible alternative to standard surgery. The aim of this study is to monitor the safety, adherence and effectiveness of active surveillance in patients outside a randomized trial. METHODS: This nationwide prospective cohort study aims to accrue operable patients with non-metastatic histologically proven adenocarcinoma or squamous cell carcinoma of the esophagus or esophagogastric junction. Patients receive nCRT and response evaluation consists of upper endoscopy with bite-on-bite biopsies, endoscopic ultrasonography plus fine-needle aspiration of suspicious lymph nodes and 18F-fluorodeoxyglucose positron emission tomography/computed tomography scan. When residue or regrowth of tumor in the absence of distant metastases is detected, surgical resection is advised. Patients with cCR after nCRT are suitable to undergo active surveillance. Patients can consult an independent physician or psychologist to support decision-making. Primary endpoint is the number and severity of adverse events in patients with cCR undergoing active surveillance, defined as complications from response evaluations, delayed surgery and the development of distant metastases. Secondary endpoints include timing and quality of diagnostic modalities, overall survival, progression-free survival, fear of cancer recurrence and decisional regret. DISCUSSION: Active surveillance after nCRT may be an alternative to standard surgery in patients with esophageal cancer. Similar to organ-sparing approaches applied in other cancer types, the safety and efficacy of active surveillance needs monitoring before data from randomized trials are available. TRIAL REGISTRATION: The SANO-2 study has been registered at ClinicalTrials.gov as NCT04886635 (May 14, 2021) - Retrospectively registered.

Active Surveillance Versus Immediate Surgery in Clinically Complete Responders After Neoadjuvant Chemoradiotherapy for Esophageal Cancer: A Multicenter Propensity Matched Study.

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.

Combining brentuximab vedotin with dexamethasone, high-dose cytarabine and cisplatin as salvage treatment in relapsed or refractory Hodgkin lymphoma: the phase II HOVON/LLPC Transplant BRaVE study.

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 to improve the mCR rate. In a Phase I dose-escalation part 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 40mg days 1-4, cisplatin 100mg/m2; day 1 and cytarabine 2x2g/m2; day 2). Patients with a metabolic partial response (mPR) or mCR proceeded to HDC/auto-PBSCT. Based on independent central FDG-PET-CT 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 (three were not evaluable). After HDC/auto-PBSCT, four patients with an mPR converted to an mCR. The 2-year PFS was 74% [95% CI: 63-86], and the overall survival 95% [95% CI: 90-100]. Toxicity was manageable and mainly consisted of grade 3/4 hematological 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) and 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.

Accuracy of Detecting Residual Disease After Neoadjuvant Chemoradiotherapy for Esophageal Cancer: A Systematic Review and Meta-analysis.

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.

Accuracy of detecting residual disease after neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma (preSINO trial): a prospective multicenter diagnostic cohort study.

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).

Prediction of long-term (> 10 year) cardiovascular outcomes in heart transplant recipients: Value of stress technetium-99m tetrofosmin myocardial perfusion imaging.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Towards an Organ-Sparing Approach for Locally Advanced Esophageal Cancer.

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.

Detection of residual disease after neoadjuvant chemoradiotherapy for oesophageal cancer (preSANO): a prospective multicentre, diagnostic cohort study.

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/m2 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.

Neoadjuvant chemoradiotherapy plus surgery versus active surveillance for oesophageal cancer: a stepped-wedge cluster randomised trial.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard treatment for locally advanced oesophageal cancer. With this treatment, 29% of patients have a pathologically complete response in the resection specimen. This provides the rationale for investigating an active surveillance approach. The aim of this study is to assess the (cost-)effectiveness of active surveillance vs. standard oesophagectomy after nCRT for oesophageal cancer. METHODS: This is a phase-III multi-centre, stepped-wedge cluster randomised controlled trial. A total of 300 patients with clinically complete response (cCR, i.e. no local or disseminated disease proven by histology) after nCRT will be randomised to show non-inferiority of active surveillance to standard oesophagectomy (non-inferiority margin 15%, intra-correlation coefficient 0.02, power 80%, 2-sided α 0.05, 12% drop-out). Patients will undergo a first clinical response evaluation (CRE-I) 4-6 weeks after nCRT, consisting of endoscopy with bite-on-bite biopsies of the primary tumour site and other suspected lesions. Clinically complete responders will undergo a second CRE (CRE-II), 6-8 weeks after CRE-I. CRE-II will include 18F-FDG-PET-CT, followed by endoscopy with bite-on-bite biopsies and ultra-endosonography plus fine needle aspiration of suspected lymph nodes and/or PET- positive lesions. Patients with cCR at CRE-II will be assigned to oesophagectomy (first phase) or active surveillance (second phase of the study). The duration of the first phase is determined randomly over the 12 centres, i.e., stepped-wedge cluster design. Patients in the active surveillance arm will undergo diagnostic evaluations similar to CRE-II at 6/9/12/16/20/24/30/36/48 and 60 months after nCRT. In this arm, oesophagectomy will be offered only to patients in whom locoregional regrowth is highly suspected or proven, without distant dissemination. The main study parameter is overall survival; secondary endpoints include percentage of patients who do not undergo surgery, quality of life, clinical irresectability (cT4b) rate, radical resection rate, postoperative complications, progression-free survival, distant dissemination rate, and cost-effectiveness. We hypothesise that active surveillance leads to non-inferior survival, improved quality of life and a reduction in costs, compared to standard oesophagectomy. DISCUSSION: If active surveillance and surgery as needed after nCRT leads to non-inferior survival compared to standard oesophagectomy, this organ-sparing approach can be implemented as a standard of care.

Prediction of 14-year cardiovascular outcomes by dobutamine stress 99mTc-tetrofosmin myocardial perfusion SPECT in elderly patients unable to perform exercise testing.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Cardiac stress imaging for the prediction of very long-term outcomes: Dobutamine stress echocardiography or dobutamine 99mTc-sestamibi SPECT?

BACKGROUND: Both dobutamine stress echocardiography (DSE) and myocardial perfusion imaging (MPI) using single-photon emission computed tomography (SPECT) are frequently used for cardiac risk stratification. The long-term relative prognostic value of these modalities has not been studied. Therefore, this study evaluated the long-term prognostic value of DSE compared to MPI in patients unable to perform exercise testing. METHODS: This prospective, single center study included 301 patients (mean age 59 ± 12 years, 56% men) unable to perform exercise tests who underwent DSE and dobutamine stress 99mTc-sestamibi MPI. End points during follow-up were all-cause mortality, cardiac mortality, and nonfatal myocardial infarction (MI). Univariable and multivariable Cox proportional hazards regression models were used to identify independent predictors of outcome. The probability of survival was calculated using the Kaplan-Meier method. RESULTS: A total of 182 patients (60%) had an abnormal DSE and 198 (66%) patients had an abnormal MPI. The agreement between DSE and MPI was 82% (κ = 0.62). During a median follow-up of 14 years (range 5-18), 172 deaths (57%) occurred, of which 72 (24%) were due to cardiac causes. Nonfatal MI occurred in 46 patients (15%). The multivariable analysis demonstrated that an abnormal DSE was a significant predictor of cardiac mortality (HR 2.35, 95% CI [1.17-4.73]) and hard cardiac events (HR 2.11, 95% CI [1.25-3.57]). Also, an abnormal MPI result was a significant predictor of cardiac mortality (HR 3.03, 95% CI [1.33-6.95]) and hard cardiac events (HR 2.06, 95% CI [1.12-3.79]). CONCLUSIONS: DSE and MPI are comparable in predicting long-term cardiac mortality and hard cardiac events in patients unable to perform exercise testing.

Ischemia burden on stress SPECT MPI predicts long-term outcomes after revascularization in stable coronary artery disease.

BACKGROUND: 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. METHODS: 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). RESULTS: Of the 538 patients (73% men, mean age 59.8 ± 11 years), 348 patients had low ischemia burden (<3 ischemic segments) and 190 patients had moderate to high ischemia burden (≥3 ischemic segments). A total of 76 patients underwent early revascularization. During a median follow-up of 12 years (range 4-17), 283 patients died of whom 125 due to cardiac causes. Early revascularization was beneficial on all-cause mortality (HR 0.46, 95% CI 0.30-0.46) and cardiac mortality (HR 0.54, 95% CI 0.29-0.99). CONCLUSIONS: Patients with myocardial ischemia on stress SPECT who underwent early revascularization had a lower all-cause mortality and cardiac mortality during long-term follow-up as compared to patients who received pharmacological therapy alone. This difference in long-term outcomes was mainly influenced by the survival benefit of early revascularization in the patients with moderate to high ischemia burden.

Prediction of 14-year outcomes in patients with a limited exercise capacity: Utility of dobutamine myocardial perfusion imaging in a high-risk population.

OBJECTIVE: 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. METHODS: 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. RESULTS: The mean age of patients was 60 ± 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. CONCLUSIONS: 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.

18 F-FDG PET/MRI for restaging esophageal cancer after neoadjuvant chemoradiotherapy.

PURPOSE: The purpose of this study was to investigate whether 18F-fluorodeoxyglucose ( 18 F-FDG) PET/MRI may potentially improve tumor detection after neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer. METHODS: This was a prospective, single-center feasibility study. At 6-12 weeks after nCRT, patients underwent standard 18 F-FDG PET/computed tomography (CT) followed by PET/MRI, and completed a questionnaire to evaluate burden. Two teams of readers either assessed the 18 F-FDG PET/CT or the 18 F-FDG PET/MRI first; the other scan was assessed 1 month later. Maximum standardized uptake value corrected for lean body mass (SUL max ) and mean apparent diffusion coefficient (ADC mean ) were measured at the primary tumor location. Histopathology of the surgical resection specimen served as the reference standard for diagnostic accuracy calculations. When patients had a clinically complete response and continued active surveillance, response evaluations until 9 months after nCRT served as a proxy for ypT and ypN (i.e. 'ycT' and 'ycN'). RESULTS: In the 21 included patients [median age 70 (IQR 62-75), 16 males], disease recurrence was found in the primary tumor in 14 (67%) patients (of whom one ypM+, detected on both scans) and in locoregional lymph nodes in six patients (29%). Accuracy (team 1/team 2) to detect yp/ycT+ with 18 F-FDG PET/MRI vs. 18 F-FDG PET/CT was 38/57% vs. 76/61%. For ypN+, accuracy was 63/53% vs. 63/42%, resp. Neither SUL max (both scans) nor ADC mean were discriminatory for yp/ycT+ . Fourteen of 21 (67%) patients were willing to undergo a similar 18 F-FDG PET/MRI examination in the future. CONCLUSION: 18 F-FDG PET/MRI currently performs comparably to 18 F-FDG PET/CT. Improvements in the scanning protocol, increasing reader experience and performing serial scans might contribute to enhancing the accuracy of tumor detection after nCRT using 18 F-FDG PET/MRI. TRIAL REGISTRATION: Netherlands Trial Register NL9352.

Induction chemotherapy followed by response evaluation and esophagectomy for advanced esophageal cancer.

INTRODUCTION: Patients with limited metastatic/advanced esophageal cancer not amenable for neoadjuvant therapy plus surgery have a poor prognosis and often receive palliative care. Alternatively, induction chemotherapy with response evaluation can be considered and in some patients surgery with curative intent may become feasible. The aim of this study was to evaluate the outcomes of patients treated with induction chemotherapy and to identify patient and/or tumor characteristics associated with survival. MATERIAL AND METHODS: Patients with esophageal or junctional cancer who underwent induction chemotherapy between 2005 and 2021 were identified from an institutional database of a tertiary referral center. Response to therapy was assessed by (18F-FDG PET)/CT. Response to therapy and treatment options, including surgery or palliation, were discussed in the multidisciplinary tumor board. Overall survival (OS) was calculated using the Kaplan Meier method. Uni- and multivariable analyses were performed to identify prognostic factors for survival. RESULTS: 238 patients were identified. The majority had esophageal adenocarcinoma (68.9 %) and were treated with a taxane/platinum-based chemotherapy (79.4 %). Response evaluation was performed in 233 patients and 154 of 238 patients (64.7 %) underwent surgical exploration. Resection was performed in 127 patients (53.4 %) resulting in a median and 5-year OS of 26.3 months (95 % CI 18.8-33.8) and 29.6 %, respectively. Presence of T4b (HR = 2.01, 95 % CI 1.02-3.92) and poorly differentiated tumor (HR = 1.45, 95 % CI 1.02-2.10) was associated with worse survival (p = 0.04). CONCLUSION: In carefully selected patients with advanced disease not amenable for standard curative treatment, induction chemotherapy followed by esophagectomy may result in a 5-year overall survival of approximately 30 %.

Potential of PSMA-targeting radioligand therapy for malignant primary and secondary brain tumours using super-selective intra-arterial administration: a single centre, open label, non-randomised prospective imaging study.

BACKGROUND: The aim of this study was to provide quantitative evidence for the potential of PSMA-targeting radioligand therapy (RLT) as treatment approach for malignant brain tumours, and to explore whether tumour uptake could be enhanced by super-selective intra-arterial (ssIA)-administration. METHODS: Ten patients (n = 5 high-grade glioma, n = 5 brain metastasis) received 1.5 MBq/kg [68Ga]Ga-PSMA-11 intravenously and, within 7 days, intra-arterially (i.e., selectively in tumour-feeding arteries), followed twice by PET-MRI at 90, 165 and 240 min post-injection. Patient safety was monitored for each procedure. Standardised uptake values (SUVs) were obtained for tumour, healthy-brain, salivary glands and liver. Tumour-to-salivary-gland (T/SG) and tumour-to-liver (T/L) uptake-ratios were calculated. FINDINGS: No adverse events requiring study termination occurred. All patients showed uptake of [68Ga]Ga-PSMA-11 at the tumour site. Uptake was a median 15-fold higher following ssIA-administration (SUVmax median: 142.8, IQR: 102.8-245.9) compared to IV-administration (10.5, IQR:7.5-13.0). According to the bootstrap analysis, mean SUVmax after ssIA (168.8, 95% CI: 110.6-227.0) was well beyond the 95% confidence-interval of IV administration (10.5, 95% CI: 8.4-12.7). Uptake in healthy-brain was negligible, independent of administration route (SUVmean <0.1-0.1). Off-target uptake was comparable, resulting in more favourable T/SG- and T/L-ratios of 8.4 (IQR: 4.4-11.5) and 26.5 (IQR: 14.0-46.4) following ssIA, versus 0.5 (IQR: 0.4-0.7) and 1.8 (IQR: 1.0-2.7) for IV-administration. INTERPRETATION: ssIA-administration is safe and leads to a median fifteen-fold higher radioligand uptake at the tumour site, therewith qualifying more patients for treatment and enhancing the potential of therapy. These results open new avenues for the development of effective RLT-based treatment strategies for patients with brain tumours. FUNDING: Semmy Foundation.

What is the value of stress (99m)Tc-tetrofosmin myocardial perfusion imaging for the assessment of very long-term outcome in obese patients?

OBJECTIVE: There are no data regarding the long-term prognostic value of single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) in obese patients. The aim of this study was to examine the value of stress (99m)Tc-tetrofosmin MPI findings for the prediction of very long-term outcome in obese patients. METHODS: The study population consisted of 261 patients with a body mass index ≥30 kg/m(2) who underwent exercise or pharmacological stress (99m)Tc-tetrofosmin MPI for the assessment of known or suspected coronary artery disease. Endpoints during follow-up were all-cause mortality, cardiac death, nonfatal infarction, and coronary revascularization. Kaplan-Meier survival cures were constructed and univariate and multivariate analyses were performed to identify predictors of very long-term outcome. RESULTS: The mean age was 59 ± 10 years, 42% of the patients was male, and the body mass index was on average 37 ± 7 kg/m(2). MPI findings were normal in 109 patients (42%). Myocardial perfusion abnormalities were fixed in 62 patients (24%) and reversible in 90 patients (34%). During a median 12-year follow-up, 91 (35%) patients died, and 27 (10%) had a nonfatal myocardial infarction. Survival curves were compared using the log-rank test at subsequent follow-up durations. Obese patients with a normal stress (99m)Tc-tetrofosmin study had a significantly better prognosis as compared with those with an abnormal study, up to 6 years after the test was performed. CONCLUSION: Stress (99m)Tc-tetrofosmin MPI provides valuable prognostic information for the prediction of outcome in obese patients. Obese patients with a normal stress (99m)Tc-tetrofosmin study have a significantly better prognosis as compared with those with an abnormal study, up to 6 years after the test is performed.

Prediction of 8-year cardiovascular outcomes in patients with systemic arterial hypertension: value of stress (99m)Tc-tetrofosmin myocardial perfusion imaging in a high-risk cohort.

OBJECTIVE: Systemic arterial hypertension is a strong and prevalent cardiovascular risk factor. Currently, information on the very long-term prognostic value of single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) in patients with systemic arterial hypertension is lacking. The aim of this study was to assess the value of stress (99m)Tc-tetrofosmin MPI for the prediction of very long-term outcome in these patients. METHODS: The study population consisted of 608 patients with systemic arterial hypertension who underwent exercise or dobutamine stress (99m)Tc-tetrofosmin MPI for the assessment of known or suspected coronary artery disease. Follow-up was successful in 600 (99%) patients. The endpoints were all-cause mortality, cardiac death, nonfatal infarction, and coronary revascularization. Kaplan-Meier survival cures were constructed and univariate and multivariate analyses were performed to identify predictors of very long-term outcome. RESULTS: The mean age of the patients was 59 ± 10 years, and 65% of them were male. MPI findings were normal in 301 patients (50%). Myocardial perfusion abnormalities were fixed in 162 (27%) and reversible in 137 (23%) patients. During a median 8.1-year follow-up, 241 (40%) patients died (121 cardiac deaths), 52 (9%) had a nonfatal myocardial infarction, and 128 (21%) underwent coronary revascularization. Survival curves in patients with a low vs a high summed difference score diverged up to 5 years after the test was performed. Multivariate analyses demonstrated that SPECT MPI provided incremental prognostic information up to 5 years after the test. CONCLUSIONS: Stress (99m)Tc-tetrofosmin MPI provides incremental prognostic information for the prediction of cardiovascular outcome in patients with systemic arterial hypertension. Patients with normal stress MPI have a significantly better prognosis as compared with those with an abnormal study, up to 5 years after the test is performed.

12-Year outcome after normal myocardial perfusion SPECT in patients with known coronary artery disease.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.