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The clinical course for patients with neuroendocrine neoplasms (NENs) ranges from indolent to highly aggressive. Noninvasive tools to improve prognostication and guide decisions on treatment are warranted. Expression of urokinase plasminogen activator receptor (uPAR) is present in many cancer types and associated with a poor outcome. Therefore, using an in-house–developed uPAR PET tracer [(68)Ga]Ga-NOTA-Asp-Cha-Phe-D-Ser-D-Arg-Tyr-Leu-Trp-Ser-OH ((68)Ga-NOTA-AE105), we aimed to assess uPAR expression in NENs. We hypothesized that uPAR expression was detectable in a significant proportion of patients and associated with a poorer outcome. In addition, as uPAR-targeted radionuclide therapy has previously proven effective in preclinical models, the study would also indicate the potential for uPAR-targeted radionuclide therapy in NEN patients. Methods: In a prospective clinical phase II trial, we included 116 patients with NENs of all grades, of whom 96 subsequently had uPAR PET/CT performed with evaluable lesions. PET/CT was performed 20 min after injection of approximately 200 MBq of (68)Ga-NOTA-AE105. uPAR target-to-liver ratio was used to define lesions as uPAR-positive when lesion SUV(max)–to–liver SUV(mean) ratio was at least 2. Patients were followed for at least 1 y to assess progression-free and overall survival. Results: Most patients had small intestinal NENs (n = 61) and metastatic disease (n = 86). uPAR-positive lesions were seen in 68% (n = 65) of all patients and in 75% (n = 18) of patients with high-grade (grade 3) NENs. During follow-up (median, 28 mo), 59 patients (62%) experienced progressive disease and 28 patients (30%) died. High uPAR expression, defined as a uPAR target-to-liver ratio above median, had a hazard ratio of 1.87 (95% CI, 1.11–3.17) and 2.64 (95% CI, 1.19–5.88) for progression-free and overall survival, respectively (P < 0.05 for both). Conclusion: When (68)Ga-NOTA-AE105 PET was used to image uPAR in patients with NENs, uPAR-positive lesions were seen in most patients, notably in patients with both low-grade and high-grade NENs. Furthermore, uPAR expression was associated with a worse prognosis. We suggest that uPAR PET is relevant for risk stratification and that uPAR may be a promising target for therapy in patients with NENs.

Accurate grading of patients with neuroendocrine neoplasms (NENs) is essential for risk stratification and optimal choice of therapy. Currently, grading is based on histologically assessed degree of tumor proliferation. The aim of the present study was to assess the long-term prognostic value of (18)F-FDG PET imaging for risk stratification of NENs and compare it with tumor grading (World Health Organization 2010 classification). Methods: We conducted a prospective cohort study evaluating the prognostic value of (18)F-FDG PET imaging and compared it with histologic grading. Enrolled were 166 patients of all grades and with histologically confirmed NENs of gastroenteropancreatic origin. The primary endpoint was overall survival (OS). Progression-free survival (PFS) was a secondary endpoint. In addition, OS in relation to peptide receptor radionuclide therapy (PRRT) was analyzed as an exploratory endpoint. The median follow-up time was 9.8 y. Results: Analysis of the whole cohort revealed that a positive (18)F-FDG PET scan was associated with a shorter OS than a negative (18)F-FDG PET scan (hazard ratio: 3.8; 95% CI: 2.4–5.9; P < 0.001). In G1 and G2 patients (n = 140), a positive (18)F-FDG PET scan was the only identifier of high risk for death (hazard ratio: 3.6; 95% CI, 2.2–5.9; P < 0.001). In multivariate analysis, (18)F-FDG PET, G3 tumor, ≥2 liver metastases, and ≥2 prior therapies were independent prognostic factors for OS, and (18)F-FDG PET, G3 tumor, and ≥3 liver metastases were independent prognostic factors for PFS. For patients receiving PRRT, (18)F-FDG–negative cases had a significantly longer survival than (18)F-FDG–positive cases, whereas no difference was identified for tumor grading. (18)F-FDG–positive patients receiving PRRT had a significantly longer median survival than patients not receiving PRRT (4.4 vs. 1.4 y, P = 0.001), whereas no difference was seen for (18)F-FDG–negative patients. Conclusion: (18)F-FDG PET is useful for risk stratification of all NEN grades and is superior to histologic grading. (18)F-FDG PET could differentiate G1 and G2 tumors into low- and high-risk groups. In the selection of therapy and for risk stratification of NEN patients, (18)F-FDG PET status should be considered.

In the 2019 WHO guidelines, the classification of gastro-entero-pancreatic neuroendocrine neoplasms (GEP NEN) has changed from one being based on Ki-67 proliferation index alone to one that also includes tumor differentiation. Consequently, GEP NENs are now classified as well-differentiated neuroendocrine tumor (NET), NET G1 (Ki-673%), NET G2 (Ki-67 3-20%) and NET G3 (Ki-6720%), and poorly differentiated neuroendocrine carcinoma (NEC) (Ki-6720%). It has been suggested that NET G3 should be treated as NET G2 with respect to surgery, while surgical management of NEC should be expanded from local disease to also include patients with advanced disease where curative surgery is possible. High grade mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) have a neuroendocrine and a non-neuroendocrine component mostly with a poor prognosis. All studies evaluating the effect of surgery in NEC and MiNEN are observational and hold a risk of selection bias, which may overestimate the beneficial effect of surgery. Further, only a few studies on the effect of surgery in MiNEN exist. This review aims to summarize the data on the outcome of surgery in patients with GEP NET G3, GEP NEC and high grade MiNEN. The current evidence suggests that patients with NEN G3 and localized disease and NEN G3 patients with metastatic disease where curative surgery can be achieved may benefit from surgery. In patients with MiNEN, it is currently not possible to evaluate on the potential beneficial effect of surgery due to the low number of studies.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are implemented as standard treatment for patients with advanced non-small cell lung cancer (NSCLC) in first-line and subsequent-line treatment. However, certain subgroups such as patients with older age, poor performance status (PS), and severe comorbidity are underrepresented in the randomized controlled trials (RCTs). This study aimed to assess overall survival (OS), treatment data, and clinical features affecting second- or subsequent-line ICI efficacy in an unselected, Danish, nationwide NSCLC population.METHODS: Patients with advanced NSCLC who started nivolumab or pembrolizumab as second-line or subsequent-line treatment between 1 September 2015, and 1 October 2018, were identified from institutional records of all Danish oncology departments. Clinical and treatment data were retrospectively collected. Descriptive statistics and survival analyses were performed.RESULTS: Data were available for 840 patients; 49% females. The median age was 68 years (19% were ≥75 years), 19% had PS ≥2, and 36% had moderate to severe comorbidity. The median OS (mOS) was 12.2 months; 15.1 months and 10.0 months in females and males, respectively. The median time-to-treatment discontinuation (mTTD) and median progression-free survival (mPFS) was 3.2 and 5.2 months, respectively. Patients with PS ≥2 had a mOS of 4.5 months, mTTD of 1.1 month, and mPFS of 2.0 months. In multivariable Cox regression analysis, male sex (HR = 1.35, 95% CI 1.11-1.62), PS >0 (PS 1, HR = 1.88, 95% CI 1.52-2.33; PS ≥2, HR = 4.15, 95% CI 3.13-5.5), liver metastases (HR = 1.72, 95% CI 1.34-2.22), and bone metastases (HR = 1.27, 95% CI 1.03-1.58) were significant poor prognostic OS factors.CONCLUSIONS: Danish real-world patients with advanced NSCLC treated with second- or subsequent-line ICI had an OS comparable to results from RCTs. Women, frail and older patients constituted a higher proportion than in previous RCTs. Clinical features associated with poor OS were male sex, PS ≥1 (in particular PS ≥2), bone-, and liver metastases.

Tissue factor (TF) expression in cancers correlates with poor prognosis. Recently, the first TF-targeted therapy was approved by the US Food and Drug Administration for cervical cancer. To unfold the potential of TF-targeted therapies, correct stratification and selection of patients eligible for treatments may become important for optimization of patient outcomes. TF-targeted PET imaging based on 18F-radiolabeled active-site inhibited versions of the TF natural ligand coagulation factor VII (18F-ASIS) has in preclinical models convincingly demonstrated its use for non-invasive quantitative measurements of TF expression in tumor tissue. 18F-ASIS PET imaging thus has the potential to act as a diagnostic companion for TF-targeted therapies in the clinical setting. Methods: In this first-in-human trial we included 10 cancer patients (4 pancreatic, 3 breast, 2 lung, and 1 cervical cancer patient) for 18F-ASIS PET imaging. The mean and standard deviation of administered 18F-ASIS activity was 157 ± 35 MBq (range, 93-198 MBq). PET/CT acquisition was performed after 1, 2, and 4 hours. The primary objectives were to establish the safety, biodistribution, pharmacokinetics, and dosimetry of 18F-ASIS. Secondary objectives included quantitative measurements of standardized uptake values (SUV) in tumor tissue with PET and evaluation of the correlation (Pearson correlation) between tumor SUVmax and ex vivo TF expression in tumor tissue. Results: Administration of 18F-ASIS was safe, and no adverse events were observed. No clinically significant changes in vital signs, electrocardiograms, or blood parameters were observed following injection of 18F-ASIS. Mean 18F-ASIS plasma half-life was 3.2 hours, and the radiotracer was predominantly excreted in the urine. For an administered dose of 200 MBq of 18F-ASIS, effective whole-body dose was 4 mSv and no prohibitive organ-specific absorbed doses were found. Heterogeneous radiotracer uptake was observed across patients and within tumors. We found a trend of a positive correlation between tumor SUVmax and ex vivo TF expression (p=0.08, r=0.84, n=5). Conclusion: 18F-ASIS can safely be administered to cancer patients for PET imaging of TF expression in tumors. The trial marks the first test of a TF-targeted PET radiotracer in humans (first-in-class). The findings represent important first steps towards clinical implementation of 18F-ASIS PET imaging of TF expression.

64Cu-DOTATATE PET/CT imaging 1 hour (h) post-injection (p.i.) is excellent for lesion detection in patients with neuroendocrine neoplasms (NEN). We hypothesized that the imaging time window can be extended up to 3h p.i. without significant differences in the number of lesions detected. Methods From a prospective study, we compared, on a head-to-head basis, sets of 64Cu-DOTATATE PET/CT images from 35 patients with NEN scanned 1h and 3h p.i. of 200 MBq 64Cu-DOTATATE. The number of lesions on both scans were counted and grouped according to organs or regions and compared with negative binomial regression. Discordant lesions (visible on the 1h or 3h p.i. 64Cu-DOTATATE PET but not the other) were considered true if found on simultaneous CT or later MR, CT or somatostatin receptor imaging. We measured lesion maximal standardized uptake values (SUVmax), reference normal organ or tissue mean SUV (SUVmean) and tumor-to-normal tissue ratios (TTN) calculated from SUVmax/ SUVmeanResults We found 822 concordant lesions (visible on both the 1h and 3h p.i. 64Cu-DOTATATE PET) and five discordant lesions of which four were considered true. One discordant case in one patient involved a discordant organ system (lymph node) detected on the 3h p.i. but not the 1h p.i. 64Cu-DOTATATE PET that did not alter the patient's disease stage (stage IV) because the patient had 11 additional concordant liver lesions. We found no significant differences between the number of lesions detected on the 1h and 3h p.i. 64Cu-DOTATATE PET. Throughout the 1-3 h p.i. imaging window, TTN (mean [95% confidence interval]) remained high in all key organs: Liver (1h p.i.: 12.6 [10.2; 14.9] , 3h p.i.: 11.0 [8.7; 13.4]), intestines (1h p.i.: 24.2 [14.9; 33.4], 3h p.i.: 28.2 [16.5; 40.0]), pancreas (1h p.i.: 42.4 [12.3; 72.5], 3h p.i.: 41.1 [8.7; 73.4]) and bone (1h p.i.: 103.0 [38.6; 167.4], 3h p.i.: 124.2 [57.1; 191.2]). Conclusion The imaging time window of 64Cu-DOTATATE PET/CT of patients with NEN can be expanded from 1h p.i. to 1-3 hours p.i. without significant differences in the number of lesions detected.

Background High grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) with a Ki67 proliferation index > 20%, include well-differentiated tumours grade 3 (NET G3) and poorly differentiated (PD) neuroendocrine carcinomas (NEC). Abnormal p53-expression is a feature of PD tumours, while expression of chromogranin A (CgA) and somatostatin-receptor 2a (SSTR-2a) may be a feature of well-differentiated tumours. The aim of this study was to elucidate the expression and prognostic value of these three markers in 163 GEP-NEN patients with a Ki67-index > 20%. Method Clinical data, histopathology and overall survival were analysed according to Kaplan-Meier’s method and Cox regression. The expression of SSTR-2a, CgA and synaptophysin was analysed in tumour specimens by immunohistochemistry, and semi-quantitatively scored as negative ( 30%). P53 was defined as normal when scored as heterogeneously positive (1–30%), and abnormal when negative (0%) or strongly positive (> 30%). Results In multivariate analysis, better survival was observed among patients with heterogeneously positive p53 compared to strongly positive (p p = 0.002). Survival was significantly worse for negative CgA compared to heterogeneously positive CgA (p = 0.02). Strongly positive SSTR-2a expression was found in 26% of the 163 included patients. Well-differentiated morphology correlated with strong expression of SSTR-2a and CgA, and heterogeneously positive p53-staining, and was more frequent in pancreatic primaries. In pancreatic primaries, strongly positive SSTR-2a was associated with longer survival (univariate analysis, p = 0.02). A significantly lower Ki67 proliferation index was found in patients with a heterogeneously positive p53, a positive SSTR-2a and CgA expression. Conclusion Our results suggest that abnormal p53-expression is an independent negative prognostic marker in GEP-NEN with a Ki67-index > 20%. Patients with heterogeneously positive p53 had the best prognosis. SSTR-2a was a positive prognostic marker in pancreatic NEN. Negative CgA was associated with a significantly worse OS compared to heterogeneously positive CgA-expression in a multivariate sub-analysis. Lower Ki67 index correlated significantly with heterogeneously positive p53, positive SSTR-2a and CgA expression.

Background: The incidence of small intestinal (SI) and pancreatic neuroendocrine tumors (siNETs and pNETs) seems to have increased. The increased frequency of incidental findings might be a possible explanation. The study aimed to examine (1) changes in incidence and the stage at diagnosis (2010–2011 vs. 2019–2020), (2) changes in the initial indication for diagnostic workup and 3) the differences in stage between incidentally discovered vs. symptomatic disease during the entire study period. Methods: We performed a retrospective study, that includes consecutive siNET and pNET patients referred to the Copenhagen ENETS center of excellence in 2010–2011 and 2019–2020. Results: The annual incidence of siNET per 100,000 increased from 1.39 to 1.84, (p = 0.05). There was no change in the stage at diagnosis, and in both periods approximately 30% of patients were incidentally diagnosed (p = 0.62). Dissemination was found in 72/121 (60%) of symptomatic vs. 22/50 (44%) of incidentally discovered SI tumors in the entire cohort, (p = 0.06). The annual incidence of pNET increased from 0.42 to 1.39 per 100,000, (p &lt, 0.001). The proportion of patients with disseminated disease decreased from 8/21 (38%) to 12/75 (16%), (p = 0.02) and the number of incidental findings increased from 4/21 (19%) to 43/75 (57%), (p = 0.002). More symptomatic patients had disseminated disease compared to patients with incidentally discovered tumors (15/49 (31%) vs. 5/47 (11%), (p = 0.01)). Conclusion: The incidence of siNET and pNETs increased over the past decade. For siNETs, the stage of disease and the distribution of symptomatic vs. incidentally discovered tumors were unchanged between the two periods. Patients with pNETs presented with more local and incidentally discovered tumors in the latter period. Patients with incidentally discovered siNETs had disseminated disease in 44% of the overall cases. The vast majority of incidentally found pNETs were localized.

An increase in the Ki-67 index in neuroendocrine neoplasms over time in relation to prognosis has scarcely been investigated. We aimed to assess whether the Ki-67 index changed over time and also whether a change influenced prognosis. Second, we investigated the difference in the Ki-67 index between primary tumour and metastases. From 1 January 1995 to 31 December 2019, 108 consecutive patients with gastroenteropancreatic tumours were included. Patients were followed with regard to an increase in the Ki-67 index and all-cause mortality. Ki-67 determination of the primary tumour at diagnosis and at the time of radiological progression, including developed metastases, was performed. A significant increase in the Ki-67 index was defined as a doubling of the value at disease progression compared to the value at diagnosis. In addition, in 14 patients, the Ki-67 index of the primary tumour and present metastases at the time of diagnosis was investigated. At diagnosis, there were no differences in the Ki-67 index between primary tumours and metastases (P = .41). Sixty-five patients had a doubling of the Ki-67 index. The median Ki-67 index at the time of progression 17% (1%-90%) vs 5% (1%-60%) at the time of diagnosis (P = .006). A doubling of the Ki-67 index was independently associated with all-cause mortality (hazard ratio = 2.7 [1.3-6.3], P = 0.02), after adjustment for relevant co-variables including the Ki-67 index at baseline. Doubling of the Ki-67 index at the time of disease progression was associated with a significantly higher risk of all-cause mortality. We recommend that a Ki-67 index is obtained whenever disease progression is recorded by demonstrated progression because it may have impact on the choice of treatment.

Diagnosing relapse after radiotherapy for lung cancer is challenging. The specificity of both CT and 18F-FDG PET/CT is low because of radiation-induced changes. 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) PET has previously demonstrated higher specificity for malignancy than 18F-FDG PET. We investigated the value of 18F-FLT PET/CT for diagnosing relapse in irradiated lung cancer. Methods: Patients suspected of relapse of lung cancer after definitive radiotherapy (conventional fractionated radiotherapy [cRT] or stereotactic body radiotherapy [SBRT]) were included. Sensitivity and specificity were analyzed both within the irradiated high-dose volume (HDV) and on a patient basis. Marginal differences and interobserver agreement were assessed. Results: Sixty-three patients who had received radiotherapy in 70 HDVs (34 cRT; 36 SBRT) were included. The specificity of 18F-FLT PET/CT was higher than that of 18F-FDG PET/CT (HDV, 96% [95% CI, 87-100] vs. 71% [95% CI, 57-83] [P = 0.0039]; patient-based, 90% [95% CI, 73-98] vs. 55% [95% CI, 36-74] [P = 0.0020]). The difference in specificity between 18F-FLT PET/CT and 18F-FDG PET/CT was higher after cRT than after SBRT. The sensitivity of 18F-FLT PET/CT was lower than that of 18F-FDG PET/CT (HDV, 69% [95% CI, 41-89] vs. 94% [95% CI, 70-100] [P = 0.1250]; patient-based, 70% [95% CI, 51-84] vs. 94% [95% CI, 80-99] [P = 0.0078]). Adding 18F-FLT PET/CT when 18F-FDG PET/CT was positive or inconclusive improved the diagnostic value compared with 18F-FDG PET/CT alone. In cRT HDVs, the probability of malignancy increased from 67% for 18F-FDG PET/CT alone to 100% when both tracers were positive. Conclusion:18F-FLT PET/CT adds diagnostic value to 18F-FDG PET/CT in patients with suspected relapse. The diagnostic impact of 18F-FLT PET/CT was highest after cRT. We suggest adding 18F-FLT PET/CT when 18F-FDG PET/CT is inconclusive or positive within the previously irradiated volume to improve diagnostic value in patients for whom histologic confirmation is not easily obtained.

IntroductionDiagnosis and pathological classification of insulinomas are challenging.AimTo characterize localization of tumors, surgery outcomes, and histopathology in patients with insulinoma.MethodsPatients with surgically resected sporadic insulinoma were included.ResultsEighty patients were included. Seven had a malignant tumor. A total of 312 diagnostic examinations were performed: endoscopic ultrasonography (EUS; n = 59; sensitivity, 70%), MRI (n = 33; sensitivity, 58%), CT (n = 55; sensitivity, 47%), transabdominal ultrasonography (US; n = 45; sensitivity, 40%), somatostatin receptor imaging (n = 17; sensitivity, 29%), 18F-fluorodeoxyglucose positron emission tomography/CT (n = 1; negative), percutaneous transhepatic venous sampling (n = 10; sensitivity, 90%), arterial stimulation venous sampling (n = 20; sensitivity, 65%), and intraoperative US (n = 72; sensitivity, 89%). Fourteen tumors could not be visualized. Invasive methods were used in 7 of these 14 patients and localized the tumor in all cases. Median tumor size was 15 mm (range, 7 to 80 mm). Tumors with malignant vs benign behavior showed less staining for insulin (3 of 7 vs 66 of 73; P = 0.015) and for proinsulin (3 of 6 vs 58 of 59; P < 0.001). Staining for glucagon was seen in 2 of 6 malignant tumors and in no benign tumors (P < 0.001). Forty-three insulinomas stained negative for somatostatin receptor subtype 2a.ConclusionLocalization of insulinomas requires many different diagnostic procedures. Most tumors can be localized by conventional imaging, including EUS. For nonvisible tumors, invasive methods may be a useful diagnostic tool. Malignant tumors showed reduced staining for insulin and proinsulin and increased staining for glucagon.

Bronchopulmonary neuroendocrine tumours are divided into typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung cancer (SCLC).To thoroughly describe a cohort of 252 patients with TC, AC and LCNEC (SCLC excluded).Collection of data from 252 patients referred to and treated at Rigshospitalet 2008-2016. Data was collected from electronic patient files and our prospective NET database. Statistics were performed in SPSS.162 (64%) had TC, 29 (12%) had AC and 61 (24%) had LCNEC. Median age at diagnosis was 69 years (range: 19-89) with no difference between genders. Thoraco-abdominal CT was performed in all patients at diagnosis. FDG-PET/CT was performed in 207 (82%) at diagnosis and was positive in 95% of the entire cohort, with no difference between tumour types. Synaptophysin was positive in 98%, chromogranin A in 92% and CD56 in 97%. Mean Ki67 index was 5% in TC, 16% in AC and 69% in LCNEC (p 0.001). Metastatic disease was found in 4% of TC, 27% of AC and 58% of LCNEC at time of initial diagnosis (p 0.001). In total 179 patients (71%) underwent surgical resection; TC: 87%, AC: 72% and LCNEC: 28% (p 0.001). Of the resected patients, 11 (6%) had recurrence. Five-year survival rate was 88% for TC, 63% for AC and 20% for LCNEC.In this comprehensive study of a cohort of 252 patients, one of the largest until date, with TC, AC and LCNEC, the gender distribution showed female predominance with 68%. FDG-PET/CT was positive in 95% of the patients independent of tumour type, which confirms that FDG-PET/CT should be a part of the preoperative work-up for TC, AC and LCNEC. Tumour type was the single most potent independent prognostic factor.

Background: Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare subtype of lung cancer with dismal prognosis. Long-term outcomes after primarily video-assisted thoracoscopic surgery (VATS) have not yet been described in LCNEC. This study aims to determine overall survival and recurrence-free survival after VATS as well as to identify prognostic factors for survival and recurrence. Methods: Data were obtained from a prospective institutional database. Kaplan-Meier estimates of overall survival and recurrence-free survival were determined and compared across prognostic factors using log-rank analysis and the Cox proportional hazards model. Results: Data from 82 consecutive patients undergoing surgical resection from 2009 to 2020 were included. All patients underwent surgical resection with curative intent, of whom 96.3% were by a VATS approach. Morbidity was low without any conversions or 30-day mortality. Lobectomy was performed in 87.8% of patients, followed by wedge resection in 4.9% and segmentectomy in 3.7%. No pneumonectomies were performed. Radical resection (R0) was achieved in 97.6%. Thirty-four patients (41.5%) had adjuvant platinum-based chemotherapy and high proportion completed at least four series (76.7%). The mean follow-up was 5.1 years. The 1-year, 3-year, and 5-year overall survival rates were 86%, 54%, and 45%, while the corresponding recurrence-free survival rates were 67%, 45%, and 35%. Advanced age was an independent predictor of poor overall survival (HR 2.08; 95% CI 1.04–4.17; p = 0.038). Conclusion: A 96.3% VATS rate was feasible in LCNEC and associated with a low morbidity rate and a high compliance with adjuvant chemotherapy. Overall survival and recurrence-free survival was comparable to previous series using thoracotomy.

Little is known about the optimal amount and timing of exercise strain in concern of the operation wound and with regard improvement of physical function and quality of life (QOL) after surgery for lung cancer. On this background, we decided to investigate the effect of early vs. late initiated postoperative rehabilitation in patients with operable lung cancer on exercise capacity, functional capacity, muscle strength, and QOL.The study was designed as a two-armed randomized controlled trial with randomization to either early initiated postoperative rehabilitation (14 days after surgery (ERG)) or a control arm with late initiated postoperative rehabilitation (14 weeks after surgery (LRG)). The primary endpoint was a change in maximum oxygen consumption (VO2peak) from baseline to post intervention 26 weeks following lung resection. Fatigue was measured with EORTC QLQ C30 LC13.From April 2013 to June 2016, 582 patients with operable NSCLC were screened for eligibility. With 119 patients randomized in the early rehabilitation group (ERG) and 116 randomized to late rehabilitation group (LRG). There was no significant difference from baseline to 26 weeks between ERG and LRG (p = 0.926). There was a significant difference from baseline to 14 weeks between groups (p = 0.0018). There was a significant difference from 14 weeks to 26 weeks between the two groups (p 0.001). We found no significant differences in QOL but we found a significant difference between ERG and LRG from baseline to 14 weeks in fatigue level in favour of ERG.This is the first randomized controlled trial to investigate the effects of early vs. late initiated postoperative rehabilitation in patients with lung cancer. There is no difference in the commencement (early vs. late) of a postoperative exercise program for patients with lung cancer on exercise capacity. But to reduce fatigue patients should be recommended to initiate early exercise programs.

Gastroenteropancreatic (GEP) mixed neuroendocrine–non-neuroendocrine neoplasms (MiNEN), are rare tumors [1,2] comprising a neuroendocrine and a non-neuroendocrine component, both accounting for at ...

The benefit of surgery in high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) is uncertain. The present study aimed to investigate outcomes after tumour surgery in patients with high-grade (Ki-67 > 20%) GEP NEN or MiNEN stage I-III or stage IV. We analysed data from patients treated in the period 2007-2015 at eight Nordic university hospitals. Overall survival (OS) and progression-free survival (PFS)/disease-free survival (DFS) were analysed by Kaplan-Meier estimates. Prognostic factors were evaluated using Cox regression. We included 201 surgically resected patients, 143 stage I-III and 58 stage IV, with 68% having neuroendocrine carcinoma, 23% MiNEN, 5% neuroendocrine tumour G3 and 4% uncertain NEN G3. Primary tumours were located in colon/rectum (52%), oesophagus/cardia (19%), pancreas (10%), stomach (7%), jejunum/ileum (5%), duodenum (4%), gallbladder (2%) and anal canal (1%). For patients with stage I-III, median DFS was 12 months (95% confidence interval [CI] = 5.5-18.5) and median OS was 32 months (95% CI = 24.0-40.0). For patients with stage I-III and an R0 resection, median DFS was 21 months (95% CI = 4.9-37.1) and median OS was 39 months (95% CI = 25.0-53.0). For patients with stage IV, median PFS/DFS was 4 months (95% CI = 1.9-6.1) and median OS was 11 months (95% CI = 4.8-17.2). For patients with stage IV and an R0 resection, median DFS was 6 months (95% CI = 0-16.4) and median OS was 32 months (95% CI = 25.5-38.5). Performance status > 1 and colorectal primary were associated with poor prognosis. There was no difference in survival between patients with high-grade GEP NEN and MiNEN. Surgery of the primary tumour in patients with loco-regional high-grade GEP NEN or MiNEN led to good long-term results and should be considered if an R0 resection is considered achievable. Highly selected patients with stage IV disease may also benefit from surgery.

Many studies have suggested a prognostic value of one or several positron emission tomography (PET) parameters in patients with small cell lung cancer (SCLC). However, studies are often small, and there is a considerable interstudy disagreement about which PET parameters have a prognostic value. The objective of this study was to perform a review and meta-analysis to identify the most promising PET parameter for prognostication. PubMed®, Cochrane, and Embase® were searched for papers addressing the prognostic value of any PET parameter at any treatment phase with any endpoint in patients with SCLC. Pooled hazard ratios (HRs) were calculated by a random effects model for the prognostic value of the baseline maximum standardized uptake value (SUVmax) and metabolic tumor volume (MTV). The qualitative analysis included 38 studies, of these, 19 studies were included in the meta-analyses. The pooled results showed that high baseline MTV was prognostic for overall survival (OS) (HR: 2.83 (95% confidence interval [CI]: 2.00–4.01) and progression-free survival (PFS) (HR: 3.11 (95% CI: 1.99–4.90)). The prognostic value of SUVmax was less pronounced (OS: HR: 1.50 (95% CI: 1.17–1.91); PFS: HR: 1.24 (95% CI: 0.94–1.63)). Baseline MTV is a strong prognosticator for OS and PFS in patients with SCLC. MTV has a prognostic value superior to those of other PET parameters, but whether MTV is superior to other prognosticators of tumor burden needs further investigation.

OBJECTIVE: The aim of this study was to determine overall survival and recurrence-free survival after resection of bronchopulmonary carcinoids by means of predominantly minimally invasive surgery and lung-sparing resections. In addition, we aimed to identify prognostic factors for overall survival.MATERIALS AND METHODS: Retrospective review of consecutive patients operated for bronchopulmonary carcinoids between January 2009 and October 2020 identified from a prospectively collected database.RESULTS: A total of 236 patients representing 240 cases of bronchopulmonary carcinoids were included. Of these, 212 (88.3 %) were typical carcinoids, while 28 (11.7 %) were atypical carcinoids. A Video-Assisted Thoracoscopic Surgery (VATS) approach was used in 75 % of cases. There was no 30-day mortality. The median follow-up was 5.6 years for overall survival and 4.7 years for recurrence-free survival. 5- and 10-year overall survival rates were 89 % and 71 %, while 5- and 10-year recurrence-free survival rates were 84 % and 71 %. Patients with atypical carcinoids had significantly reduced overall survival and recurrence-free survival rates (HR 3.4; 95 % CI 1.5-7.6; p = 0.003 and HR 5.4; 95 % CI 2.6-11.4; p 60 years (HR 2.9; 95 % CI 1.2-7.3; p = 0.021).CONCLUSION: Surgery for bronchopulmonary carcinoids by means of predominantly VATS and lung-sparing resections provides favorable long-term survival. Atypical carcinoids and age > 60 years are independent predictors of poor overall survival.

Background The diagnostic work-up and treatment of patients with gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) has undergone major advances and new methods are introduced. Furthermore, an update of the WHO classification has resulted in a new nomenclature for GEP-NEN that is implemented in the clinic. Aim These Nordic guidelines summarise the Nordic Neuroendocrine Tumour Group’s current view on how to diagnose and treat GEP-NEN patients and aims to be useful in the daily practice for clinicians. publishedVersion

Patients with neuroendocrine neoplasms (NENs) have heterogeneous somatostatin receptor expression, with highly differentiated lesions having higher expression. Receptor expression of the total tumor burden may be visualized by somatostatin receptor imaging, such as with (64)Cu-DOTATATE PET/CT. Assessment of maximal lesion uptake is associated with progression-free survival (PFS) but not overall survival (OS). We hypothesized that the lesion with the lowest, rather than the highest, (64)Cu-DOTATATE uptake would be more prognostic, and we developed a semiautomatic method for evaluating this hypothesis. Methods: Patients with NENs underwent (64)Cu-DOTATATE PET/CT. A standardized semiautomatic tumor delineation method was developed and used to identify the lesion with the lowest uptake, that is, with the lowest SUV(mean). Additionally, we assessed total tumor volume derived from the semiautomatic tumor delineation. Kaplan–Meier and Cox regression analyses were used to determine whether there was any association with OS and PFS. Results: In 116 patients with NENs, median PFS (95% CI) was 23 mo (range, 20–31 mo) and median OS was 85 mo (range, 68–113 mo). Minimum SUV(mean) and total tumor volume were significantly associated with PFS and OS in univariate Cox regression analyses, whereas SUV(max) was significant only for PFS. In multivariate Cox analyses, both minimum SUV(mean) and total tumor volume remained statistically significant. Minimum SUV(mean) and total tumor volume were then dichotomized by their median, and patients were categorized into 4 groups: high or low total tumor volume and high or low minimum SUV(mean). Patients with a low total tumor volume and high minimum SUV(mean) had a hazard ratio of 0.32 (95% CI, 0.20–0.51) for PFS and 0.24 (95% CI, 0.13–0.43) for OS, both with P values of less than 0.001 (reference: high total tumor volume and low minimum SUV(mean)). Conclusion: We propose a standardized semiautomatic tumor delineation method to identify the lesion with the lowest (64)Cu-DOTATATE uptake and total tumor volume. Assessment of the lowest, rather than the highest, lesion uptake greatly increases prognostication by (64)Cu-DOTATATE PET/CT. Combining lesion uptake and total tumor volume, we derived a novel prognostic classification system for patients with NENs.

BACKGROUND: Concurrent chemoradiotherapy is standard treatment for limited stage small-cell lung cancer (SCLC). Twice-daily thoracic radiotherapy of 45 Gy in 30 fractions is considered to be the most effective schedule. The aim of this study was to investigate whether high-dose, twice-daily thoracic radiotherapy of 60 Gy in 40 fractions improves survival.METHODS: This open-label, randomised, phase 2 trial was done at 22 public hospitals in Norway, Denmark, and Sweden. Patients aged 18 years and older with treatment-naive confirmed limited stage SCLC, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1 were eligible. All participants received four courses of intravenous cisplatin 75 mg/m2 or carboplatin (area under the curve 5-6 mg/mL × min, Calvert's formula) on day 1 and intravenous etoposide 100 mg/m2 on days 1-3 every 3 weeks. Participants were randomly assigned (1:1) in permuted blocks (sized between 4 and 10) stratifying for ECOG performance status, disease stage, and presence of pleural effusion to receive thoracic radiotherapy of 45 Gy in 30 fractions or 60 Gy in 40 fractions to the primary lung tumour and PET-CT positive lymph node metastases starting 20-28 days after the first chemotherapy course. Patients in both groups received two fractions per day, ten fractions per week. Responders were offered prophylactic cranial irradiation of 25-30 Gy. The primary endpoint, 2-year overall survival, was assessed after all patients had been followed up for a minimum of 2 years. All randomly assigned patients were included in the efficacy analyses, patients commencing thoracic radiotherapy were included in the safety analyses. Follow-up is ongoing. This trial is registered at ClinicalTrials.gov, NCT02041845.FINDINGS: Between July 8, 2014, and June 6, 2018, 176 patients were enrolled, 170 of whom were randomly assigned to 60 Gy (n=89) or 45 Gy (n=81). Median follow-up for the primary analysis was 49 months (IQR 38-56). At 2 years, 66 (74·2% [95% CI 63·8-82·9]) patients in the 60 Gy group were alive, compared with 39 (48·1% [36·9-59·5]) patients in the 45 Gy group (odds ratio 3·09 [95% CI 1·62-5·89]; p=0·0005). The most common grade 3-4 adverse events were neutropenia (72 [81%] of 89 patients in the 60 Gy group vs 62 [81%] of 77 patients in the 45 Gy group), neutropenic infections (24 [27%] vs 30 [39%]), thrombocytopenia (21 [24%] vs 19 [25%]), anaemia (14 [16%] vs 15 [20%]), and oesophagitis (19 [21%] vs 14 [18%]). There were 55 serious adverse events in 38 patients in the 60 Gy group and 56 serious adverse events in 44 patients in the 45 Gy group. There were three treatment-related deaths in each group (one neutropenic fever, one aortic dissection, and one pneumonitis in the 60 Gy group; one thrombocytic bleeding, one cerebral infarction, and one myocardial infarction in the 45 Gy group).INTERPRETATION: The higher radiotherapy dose of 60 Gy resulted in a substantial survival improvement compared with 45 Gy, without increased toxicity, suggesting that twice-daily thoracic radiotherapy of 60 Gy is an alternative to existing schedules.FUNDING: The Norwegian Cancer Society, The Liaison Committee for Education, Research and Innovation in Central Norway, the Nordic Cancer Union, and the Norwegian University of Science and Technology.