Intensive follow-up of patients after curative surgery for colorectal cancer is common in clinical practice, but evidence of a survival benefit is limited.
To examine overall mortality, colorectal ...cancer-specific mortality, and colorectal cancer-specific recurrence rates among patients with stage II or III colorectal cancer who were randomized after curative surgery to 2 alternative schedules for follow-up testing with computed tomography and carcinoembryonic antigen.
Unblinded randomized trial including 2509 patients with stage II or III colorectal cancer treated at 24 centers in Sweden, Denmark, and Uruguay from January 2006 through December 2010 and followed up for 5 years; follow-up ended on December 31, 2015.
Patients were randomized either to follow-up testing with computed tomography of the thorax and abdomen and serum carcinoembryonic antigen at 6, 12, 18, 24, and 36 months after surgery (high-frequency group; n = 1253 patients) or at 12 and 36 months after surgery (low-frequency group; n = 1256 patients).
The primary outcomes were 5-year overall mortality and colorectal cancer-specific mortality rates. The secondary outcome was the colorectal cancer-specific recurrence rate. Both intention-to-treat and per-protocol analyses were performed.
Among 2555 patients who were randomized, 2509 were included in the intention-to-treat analysis (mean age, 63.5 years; 1128 women 45%) and 2365 (94.3%) completed the trial. The 5-year overall patient mortality rate in the high-frequency group was 13.0% (161/1253) compared with 14.1% (174/1256) in the low-frequency group (risk difference, 1.1% 95% CI, -1.6% to 3.8%; P = .43). The 5-year colorectal cancer-specific mortality rate in the high-frequency group was 10.6% (128/1248) compared with 11.4% (137/1250) in the low-frequency group (risk difference, 0.8% 95% CI, -1.7% to 3.3%; P = .52). The colorectal cancer-specific recurrence rate was 21.6% (265/1248) in the high-frequency group compared with 19.4% (238/1250) in the low-frequency group (risk difference, 2.2% 95% CI, -1.0% to 5.4%; P = .15).
Among patients with stage II or III colorectal cancer, follow-up testing with computed tomography and carcinoembryonic antigen more frequently compared with less frequently did not result in a significant rate reduction in 5-year overall mortality or colorectal cancer-specific mortality.
clinicaltrials.gov Identifier: NCT00225641.
Introduction
The lungs are the second most common site for metachronous metastases in colorectal cancer. No treatment algorithm is established, and the role of adjuvant chemotherapy is unclear. This ...study aimed to map pulmonary recurrences in a modern multimodal treated population, and to evaluate survival depending on management.
Methods
Retrospective study based on the COLOFOL‐trial population of 2442 patients, radically resected for colorectal cancer stage II–III. All recurrences within 5 years were identified and medical records were scrutinized.
Results
Of 165 (6.8%) patients developing lung metastases as first recurrence, 89 (54%) were confined to the lungs. Potentially curative treatment was possible in 62 (37%) cases, of which 33 with surgery only and 29 with surgery and chemotherapy combined. The 5‐year overall survival (5‐year OS) for all lung recurrences was 28%. In patients treated with chemotherapy only the 5‐year OS was 7.5%, compared with 55% in patients treated with surgery, and 72% when surgery was combined with chemotherapy. Hazard ratio for mortality was 2.9 (95% confidence interval 1.40–6.10) for chemotherapy only compared to surgery.
Conclusion
A high proportion of metachronous lung metastases after colorectal surgery were possible to resect, yielding good survival. The combination of surgery and chemotherapy might be advantageous for survival.
Selective serotonin reuptake inhibitors (SSRIs) are widely used for treating neuropsychiatric disorders. However, the exact mechanism of action and why effects can take several weeks to manifest is ...not clear. The hypothesis of neuroplasticity is supported by preclinical studies, but the evidence in humans is limited. Here, we investigate the effects of the SSRI escitalopram on presynaptic density as a proxy for synaptic plasticity. In a double-blind placebo-controlled study (NCT04239339), 32 healthy participants with no history of psychiatric or cognitive disorders were randomized to receive daily oral dosing of either 20 mg escitalopram (n = 17) or a placebo (n = 15). After an intervention period of 3-5 weeks, participants underwent a
CUCB-J PET scan (29 with full arterial input function) to quantify synaptic vesicle glycoprotein 2A (SV2A) density in the hippocampus and the neocortex. Whereas we find no statistically significant group difference in SV2A binding after an average of 29 (range: 24-38) days of intervention, our secondary analyses show a time-dependent effect of escitalopram on cerebral SV2A binding with positive associations between
CUCB-J binding and duration of escitalopram intervention. Our findings suggest that brain synaptic plasticity evolves over 3-5 weeks in healthy humans following daily intake of escitalopram. This is the first in vivo evidence to support the hypothesis of neuroplasticity as a mechanism of action for SSRIs in humans and it offers a plausible biological explanation for the delayed treatment response commonly observed in patients treated with SSRIs. While replication is warranted, these results have important implications for the design of future clinical studies investigating the neurobiological effects of SSRIs.
•Construction of a multimodality brain atlas for the domestic pig.•Automatized spatial normalization and delineation of brain regions on new PET scans.•The method uses a perfusion-weighted image of ...the dynamic PET scan.•Validated across radiotracers with different brain kinetics and spatial distributions.•Freely available to standardize pig PET image quantification.
The increasing use of the pig as a research model in neuroimaging requires standardized processing tools. For example, extraction of regional dynamic time series from brain PET images requires parcellation procedures that benefit from being automated.
Manual inter-modality spatial normalization to a MRI atlas is operator-dependent, time-consuming, and can be inaccurate with lack of cortical radiotracer binding or skull uptake.
A parcellated PET template that allows for automatic spatial normalization to PET images of any radiotracer.
MRI and 11CCimbi-36 PET scans obtained in sixteen pigs made the basis for the atlas. The high resolution MRI scans allowed for creation of an accurately averaged MRI template. By aligning the within-subject PET scans to their MRI counterparts, an averaged PET template was created in the same space. We developed an automatic procedure for spatial normalization of the averaged PET template to new PET images and hereby facilitated transfer of the atlas regional parcellation. Evaluation of the automatic spatial normalization procedure found the median voxel displacement to be 0.22±0.08mm using the MRI template with individual MRI images and 0.92±0.26mm using the PET template with individual 11CCimbi-36 PET images. We tested the automatic procedure by assessing eleven PET radiotracers with different kinetics and spatial distributions by using perfusion-weighted images of early PET time frames.
We here present an automatic procedure for accurate and reproducible spatial normalization and parcellation of pig PET images of any radiotracer with reasonable blood-brain barrier penetration.
Outcome after colorectal liver metastases (CRLM) resection has improved over time, despite increased resection rates. Hence, it's crucial to identify all patients possible to treat with curative ...intent. The objectives of this study were to map recurrence pattern, treatment strategy and survival depending on treatment and follow-up strategy.
In the COLOFOL-trial, patients with radically resected stage II-III colorectal cancer were randomized to high-frequency (6, 12, 18, 24 and 36 months; HF) or low-frequency (12 and 36 months; LF) follow-up. In this study, all CRLM within 5 years were identified and medical files scrutinized. Overall survival (OS) was analysed in uni- and multivariable analyses. Primary endpoint was 5-year OS.
Of 2442 patients, 235 (9.6%) developed metachronous CRLM of which 123 (52.3%) underwent treatment with curative intent, resulting in 5-year OS of 58%. Five-year OS for patients with CRLM was 43% after HF versus 24% after LF. The survival benefit was confirmed for HF 8 years from resection of the primary tumour, HR 0.63 (CI 0.46–0.85).
A high proportion of metachronous CRLM was possible to treat with curative intent, yielding high survival rates. More intense follow-up after colorectal cancer resection might be of value in high-risk patients.
Patients with colorectal cancer were examined to determine (1) whether elevated carcinoembryonic antigen (CEA) levels, either before treatment or after surgery, was associated with an increased risk ...of overall or colorectal cancer-specific mortality or recurrence, and (2) whether high intensity follow-up would benefit those patients.
Post-hoc analysis based on 2509 patients that underwent surgery for colorectal cancer, stage II or III, in the COLOFOL randomized trial with 5-year follow-up. Serum CEA levels were ascertained before treatment and one month after surgery. Follow-up examinations included computed tomography of the thorax and abdomen and serum CEA sampling. Patients were randomized to examinations at either 6, 12, 18, 24, and 36 months (high-intensity group) or at 12 and 36 months after surgery (low-intensity group). Levels of CEA >5 μg/l were defined as elevated.
Elevated CEA levels before treatment were associated with increased risk of recurrence (hazard ratio HR, 1.49; 95% confidence interval CI: 1.22–1.83), colorectal cancer-specific mortality (HR, 1.44; 95% CI: 1.08–1.91), and overall mortality (HR, 1.38; 95% CI: 1.07–1.78). Elevated CEA levels after surgery were associated with increased colorectal cancer-specific mortality (HR, 1.68; 95% CI: 1.08–2.61) and overall mortality (HR, 1.79; 95% CI: 1.22–2.63). The intensity of the follow-up regimen had no effect on 5-year outcomes in patients with elevated CEA levels.
Both pre-treatment and post-surgery elevated serum CEA levels were associated with increased overall and cancer-specific mortality. Intensified follow-up showed no benefit over low-intensity follow-up in this high-risk group of patients with elevated CEA levels.
The COLOFOL trial, a prospective randomized multicenter trial comparing two follow-up regimes after curative surgical treatment for colorectal cancer, focuses on detection of asymptomatic ...recurrences. This paper aims to describe the design and recruitment procedure in the COLOFOL trial, comparing demographic characteristics between randomized patients and eligible patients not included in the study.
COLOFOL was designed as a pragmatic trial with wide inclusion criteria and few exclusion criteria, in order to obtain a sample reflecting the general patient population. To be eligible, patients had to be 75 years or younger and curatively resected for stage II or III colorectal cancer. Exclusion criteria were hereditary colorectal cancer, no signed consent, other malignancy, and life expectancy less than 2 years due to concomitant disease. In four of the 24 participating centers, we scrutinized hospital inpatient data to identify all colorectal cancer patients who underwent surgery, in order to ascertain all eligible patients who were not included in the study and to compare them with enrolled patients.
Of a total of 4,445 eligible patients, 2,509 patients were randomized (56.4% inclusion rate). A total of 1,221 eligible patients were identified in the scrutinized hospitals, of which 684 (56%) were randomized. No difference in age or sex distribution was observed between randomized and nonrandomized eligible patients. However, a difference was noted in tumor location and stage distribution, with 5.6% more patients in the randomized group having colon cancer and 6.7% more patients having stage II disease.
Patients in the two study arms were not only demographically similar, but also similar to nonincluded eligible patients, apart from stage and localization. The analyses will be stratified by these variables. Taken together, we conclude that our trial results will be robust and possible to extrapolate to the target population.
The advantage of combining molecular and morphological imaging, e.g. positron emission tomography and magnetic resonance imaging (PET/MRI), is reflected in the increased use of these modalities as ...surrogate end-points in clinical trials. This study aimed at evaluating plaque inflammation using 18F-fluorodeoxyglucose (18F-FDG)-PET/MRI, and gene expression in a minipig model of atherosclerosis.
Göttingen Minipigs were fed for 60 weeks with fat/fructose/cholesterol-rich diet (FFC), chow (Control) or FFC-diet changed to chow midway (diet normalization group; DNO). In all groups, 18F-FDG-PET/MRI of the abdominal aorta was assessed midway and at study-end. The aorta was analyzed using histology and gene expression.
At study-end, FFC had significantly higher FDG-uptake compared to Control (target-to-background maximal uptake, TBRMax (95% confidence interval) CITBRMax: 0.092; 7.32) and DNO showed significantly decreased uptake compared to FFC (CITBRMax: -5.94;-0.07). No difference was observed between DNO and Control (CITBRMax: −2.71; 4.11). FFC displayed increased atherosclerosis and gene expression of inflammatory markers, including vascular cell adhesion molecule 1 (VCAM-1), cluster of differentiation 68 (CD68), matrix metalloproteinase 9 (MMP9), cathepsin K (CTSK) and secreted phosphoprotein 1 (SPP1) compared to Control and DNO (all, p < 0.05). FDG-uptake correlated with gene expression of inflammatory markers, including CD68, ρs = 0.58; MMP9, ρs = 0.46; SPP1, ρs = 0.44 and CTSK, ρs = 0.49; (p ≤ 0.01 for all).
In a model of atherosclerosis, 18F-FDG-PET/MRI technology allows for detection of inflammation in atherosclerotic plaques, consistent with increased inflammatory gene expression. Our findings corroborate clinical data and are important in pre-clinical drug development targeting plaque inflammation.
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•Diet-induced minipig model displays advanced human-like atherosclerosis.•Correlation between ex vivo and in vivo assessment of plaque inflammation.•Translational large animal model for targeting inflammation in atherosclerosis.
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