Dutch national guidelines for locally recurrent rectal cancer.

Due to improvements in treatment for primary rectal cancer, the incidence of LRRC has decreased. However, 6-12% of patients will still develop a local recurrence. Treatment of patients with LRRC can be challenging, because of complex and heterogeneous disease presentation and scarce - often low-grade - data steering clinical decisions. Previous consensus guidelines have provided some direction regarding diagnosis and treatment, but no comprehensive guidelines encompassing all aspects of the clinical management of patients with LRRC are available to date. The treatment of LRRC requires a multidisciplinary approach and overarching expertise in all domains. This broad expertise is often limited to specific expert centres, with dedicated multidisciplinary teams treating LRRC. A comprehensive, narrative literature review was performed and used to develop the Dutch National Guideline for management of LRRC, in an attempt to guide decision making for clinicians, regarding the complete clinical pathway from diagnosis to surgery.

The Additional Role of F18-FDG PET/CT in Characterizing MRI-Diagnosed Tumor Deposits in Locally Advanced Rectal Cancer.

Rationale: F18-FDG PET/CT may be helpful in baseline staging of patients with high-risk LARC presenting with vascular tumor deposits (TDs), in addition to standard pelvic MRI and CT staging. Methods: All patients with locally advanced rectal cancer that had TDs on their baseline MRI of the pelvis and had a baseline F18-FDG PET/CT between May 2016 and December 2020 were included in this retrospective study. TDs as well as lymph nodes identified on pelvic MRI were correlated to the corresponding nodular structures on a standard F18-FDG PET/CT, including measurements of nodular SUVmax and SUVmean. In addition, the effects of partial volume and spill-in on SUV measurements were studied. Results: A total number of 62 patients were included, in which 198 TDs were identified as well as 106 lymph nodes (both normal and metastatic). After ruling out partial volume effects and spill-in, 23 nodular structures remained that allowed for reliable measurement of SUVmax: 19 TDs and 4 LNs. The median SUVmax between TDs and LNs was not significantly different (p = 0.096): 4.6 (range 0.8 to 11.3) versus 2.8 (range 1.9 to 3.9). For the median SUVmean, there was a trend towards a significant difference (p = 0.08): 3.9 (range 0.7 to 7.8) versus 2.3 (range 1.5 to 3.4). Most nodular structures showing either an SUVmax or SUVmean ≥ 4 were characterized as TDs on MRI, while only two were characterized as LNs. Conclusions: SUV measurements may help in separating TDs from lymph node metastases or normal lymph nodes in patients with high-risk LARC.

External validation of 18 F-FDG PET-based radiomic models on identification of residual oesophageal cancer after neoadjuvant chemoradiotherapy.

OBJECTIVES: Detection of residual oesophageal cancer after neoadjuvant chemoradiotherapy (nCRT) is important to guide treatment decisions regarding standard oesophagectomy or active surveillance. The aim was to validate previously developed 18 F-FDG PET-based radiomic models to detect residual local tumour and to repeat model development (i.e. 'model extension') in case of poor generalisability. METHODS: This was a retrospective cohort study in patients collected from a prospective multicentre study in four Dutch institutes. Patients underwent nCRT followed by oesophagectomy between 2013 and 2019. Outcome was tumour regression grade (TRG) 1 (0% tumour) versus TRG 2-3-4 (≥1% tumour). Scans were acquired according to standardised protocols. Discrimination and calibration were assessed for the published models with optimism-corrected AUCs >0.77. For model extension, the development and external validation cohorts were combined. RESULTS: Baseline characteristics of the 189 patients included [median age 66 years (interquartile range 60-71), 158/189 male (84%), 40/189 TRG 1 (21%) and 149/189 (79%) TRG 2-3-4] were comparable to the development cohort. The model including cT stage plus the feature 'sum entropy' had best discriminative performance in external validation (AUC 0.64, 95% confidence interval 0.55-0.73), with a calibration slope and intercept of 0.16 and 0.48 respectively. An extended bootstrapped LASSO model yielded an AUC of 0.65 for TRG 2-3-4 detection. CONCLUSION: The high predictive performance of the published radiomic models could not be replicated. The extended model had moderate discriminative ability. The investigated radiomic models appeared inaccurate to detect local residual oesophageal tumour and cannot be used as an adjunct tool for clinical decision-making in patients.

Locally recurrent rectal cancer: Oncological outcomes for patients with a pathological complete response after neoadjuvant therapy.

BACKGROUND: For patients with locally recurrent rectal cancer, it is an ongoing pursuit to establish factors predicting or improving oncological outcomes. In locally advanced rectal cancer, a pCR appears to be associated with improved outcomes. The aim of this retrospective cohort study was to compare the oncological outcomes of patients with locally recurrent rectal cancer with and without a pCR. METHODS: Patients who underwent neoadjuvant treatment and surgery for locally recurrent rectal cancer with curative intent between January 2004 and June 2020 at a tertiary referral hospital were analysed. Primary outcomes included overall survival, disease-free survival, metastasis-free survival, and local re-recurrence-free survival, stratified according to whether the patient had a pCR. RESULTS: Of a total of 345 patients, 51 (14.8 per cent) had a pCR. Median follow-up was 36 (i.q.r. 16-60) months. The 3-year overall survival rate was 77 per cent for patients with a pCR and 51.1 per cent for those without (P < 0.001). The 3-year disease-free survival rate was 56 per cent for patients with a pCR and 26.1 per cent for those without (P < 0.001). The 3-year local re-recurrence-free survival rate was 82 and 44 per cent respectively (P < 0.001). Surgical procedures (for example soft tissue, sacrum, and urogenital organ resections) and postoperative complications were comparable between patients with and without a pCR. CONCLUSION: This study showed that patients with a pCR have superior oncological outcomes to those without a pCR. It may therefore be safe to consider a watch-and-wait approach in highly selected patients, potentially improving quality of life by omitting extensive surgical procedures without compromising oncological outcomes.

Metabolic positron emission tomography/CT response after induction chemotherapy and chemo(re)irradiation is associated with higher negative resection margin rate in patients with locally recurrent rectal cancer.

AIM: Positron emission tomography (PET)/CT can be used to monitor the metabolic changes that occur after intensified treatment with induction chemotherapy and chemo(re)irradiation for locally recurrent rectal cancer (LRRC). This study aimed to analyse the correlation between the PET/CT response and final histopathological outcomes. METHODS: All LRRC patients who underwent induction chemotherapy prior to surgery between January 2010 and July 2020 and were monitored with pretreatment and post-treatment PET/CT were included. Visual qualitative analysis was performed, and patients were scored as having achieved a complete metabolic response (CMR), partial metabolic response (PMR) or no response (NR). The histopathological response was assessed according to the Mandard tumour regression (TRG) score and categorized as major (TRG 1-2), partial (TRG 3) or poor (TRG 4-5). The PET/CT and TRG categories were compared, and possible confounders were analysed. RESULTS: A total of 106 patients were eligible for analysis; 24 (23%) had a CMR, 54 (51%) had a PMR and 28 (26%) had NR. PET/CT response was a significant predictor of the negative resection margin rate, achieving 96% for CMR, 69% for PMR and 50% for NR. The overall accuracy between PET score and pathological TRG was 45%, and the positive predictive value for CMR was 63%. A longer interval between post-treatment PET/CT and surgery negatively influenced the predictive value. CONCLUSION: Metabolic PET/CT response evaluation after neoadjuvant treatment proves to be a complementary diagnostic tool to standard MRI in assessing tumour response, and may play a role for treatment planning in LRRC patients.

Correction: Rijnsdorp et al. Impact of the Noise Penalty Factor on Quantification in Bayesian Penalized Likelihood (Q.Clear) Reconstructions of 68Ga-PSMA PET/CT Scans. Diagnostics 2021, 11, 847.

In the original article [...].

Evaluation of Quantitative Ga-68 PSMA PET/CT Repeatability of Recurrent Prostate Cancer Lesions Using Both OSEM and Bayesian Penalized Likelihood Reconstruction Algorithms.

RATIONALE: To formally determine the repeatability of Ga-68 PSMA lesion uptake in both relapsing and metastatic tumor. In addition, it was hypothesized that the BPL algorithm Q. Clear has the ability to lower SUV signal variability in the small lesions typically encountered in Ga-68 PSMA PET imaging of prostate cancer. METHODS: Patients with biochemical recurrence of prostate cancer were prospectively enrolled in this single center pilot test-retest study and underwent two Ga-68 PSMA PET/CT scans within 7.9 days on average. Lesions were classified as suspected local recurrence, lymph node metastases or bone metastases. Two datasets were generated: one standard PSF + OSEM and one with PSF + BPL reconstruction algorithm. For tumor lesions, SUVmax was determined. Repeatability was formally assessed using Bland-Altman analysis for both BPL and standard reconstruction. RESULTS: A total number of 65 PSMA-positive tumor lesions were found in 23 patients (range 1 to 12 lesions a patient). Overall repeatability in the 65 lesions was -1.5% ± 22.7% (SD) on standard reconstructions and -2.1% ± 29.1% (SD) on BPL reconstructions. Ga-68 PSMA SUVmax had upper and lower limits of agreement of +42.9% and -45.9% for standard reconstructions and +55.0% and -59.1% for BPL reconstructions, respectively (NS). Tumor SUVmax repeatability was dependent on lesion area, with smaller lesions exhibiting poorer repeatability on both standard and BPL reconstructions (F-test, p < 0.0001). CONCLUSION: A minimum response of 50% seems appropriate in this clinical situation. This is more than the recommended 30% for other radiotracers and clinical situations (PERCIST response criteria). BPL does not seem to lower signal variability in these cases.

Impact of the Noise Penalty Factor on Quantification in Bayesian Penalized Likelihood (Q.Clear) Reconstructions of 68Ga-PSMA PET/CT Scans.

Functional imaging with 68Ga prostate-specific membrane antigen (PSMA) and positron emission tomography (PET) can fulfill an important role in treatment selection and adjustment in prostate cancer. This article focusses on quantitative assessment of 68Ga-PSMA-PET. The effect of various parameters on standardized uptake values (SUVs) is explored, and an optimal Bayesian penalized likelihood (BPL) reconstruction is suggested. PET acquisitions of two phantoms consisting of a background compartment and spheres with diameter 4 mm to 37 mm, both filled with solutions of 68Ga in water, were performed with a GE Discovery 710 PET/CT scanner. Recovery coefficients (RCs) in multiple reconstructions with varying noise penalty factors and acquisition times were determined and analyzed. Apparent recovery coefficients of spheres with a diameter smaller than 17 mm were significantly lower than those of spheres with a diameter of 17 mm and bigger (p < 0.001) for a tumor-to-background (T/B) ratio of 10:1 and a scan time of 10 min per bed position. With a T/B ratio of 10:1, the four largest spheres exhibit significantly higher RCs than those with a T/B ratio of 20:1 (p < 0.0001). For spheres with a diameter of 8 mm and less, alignment with the voxel grid potentially affects the RC. Evaluation of PET/CT scans using (semi-)quantitative measures such as SUVs should be performed with great caution, as SUVs are influenced by scanning and reconstruction parameters. Based on the evaluation of multiple reconstructions with different ß of phantom scans, an intermediate ß (600) is suggested as the optimal value for the reconstruction of clinical 68Ga-PSMA PET/CT scans, considering that both detectability and reproducibility are relevant.

Diagnostic accuracy of 18F-fluciclovine PET/CT in primary lymph node staging of prostate cancer.

INTRODUCTION: To determine preoperative diagnostic accuracy of 18F-fluciclovine PET/CT-scan in detection (or exclusion) of lymph node metastases (LNM) in men with prostate cancer (PCa) in comparison to the histopathological results of the extended pelvic lymph node dissection (e-PLND). METHODS: A retrospective medical records-based cohort study, including 47 men with primary PCa who received 18F-fluciclovine PET/CT and subsequent e-PLND for lymph node staging. Incidence and number of visualized LNM, their locations and diameters on 18F-fluciclovine PET/CT were recorded in comparison to the histopathological results of the e-PLND as reference. Positive predictive value (PPV), negative predictive value (NPV), sensitivity, specificity and diagnostic accuracy of 18F-fluciclovine PET/CT were calculated on the basis of histopathology results after e-PLND. RESULTS: Forty-seven men were eligible for analysis. Median lymph node yield was 19 (range 10-70). A total of 996 lymph nodes were removed, and 59 metastases were found in 21 cases (45%). Preoperative PET was issued 'positive' in 11 men and in 9 of them (82%) this was histopathologically confirmed resulting in a PPV of 82% (95% CI, 51-96). On the contrary, PET was issued 'negative' in 36 cases, but in 12 of them (33%) metastases were detected in the e-PLND specimen, resulting in an NPV of 67% (95% CI, 50-80). The patient-based sensitivity was 43% (95% CI, 24-64) and the patient-based specificity rate was 92% (95% CI, 75-99), whereas overall diagnostic accuracy was established to be 70% in the present cohort. CONCLUSION: 18F-Fluciclovine PET/CT has a high specificity and positive predicted value for the presence of LNM in men with prostate cancer. However, the sensitivity and NPV seem to be limited to exclude the absence of LNM at a clinically acceptable level. Prospective evaluation is necessary to define patients who may benefit from 18F-fluciclovine PET/CT as a triage test for the indication for e-PLND.

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.

Surveillance of Clinically Complete Responders Using Serial 18F-FDG PET/CT Scans in Patients with Esophageal Cancer After Neoadjuvant Chemoradiotherapy.

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

Accuracy of 18F-FDG PET/CT in Predicting Residual Disease After Neoadjuvant Chemoradiotherapy for Esophageal Cancer.

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

Evaluation of a Bayesian penalized likelihood reconstruction algorithm for low-count clinical 18F-FDG PET/CT.

BACKGROUND: Recently, a Bayesian penalized likelihood (BPL) reconstruction algorithm was introduced for a commercial PET/CT with the potential to improve image quality. We compared the performance of this BPL algorithm with conventional reconstruction algorithms under realistic clinical conditions such as daily practiced at many European sites, i.e. low 18F-FDG dose and short acquisition times. RESULTS: To study the performance of the BPL algorithm, regular clinical 18F-FDG whole body PET scans were made. In addition, two types of phantoms were scanned with 4-37 mm sized spheres filled with 18F-FDG at sphere-to-background ratios of 10-to-1, 4-to-1, and 2-to-1. Images were reconstructed using standard ordered-subset expectation maximization (OSEM), OSEM with point spread function (PSF), and the BPL algorithm using ß-values of 450, 550 and 700. To quantify the image quality, the lesion detectability, activity recovery, and the coefficient of variation (COV) within a single bed position (BP) were determined. We found that when applying the BPL algorithm both smaller lesions in clinical studies as well as spheres in phantom studies can be detected more easily due to a higher SUV recovery, especially for higher contrast ratios. Under standard clinical scanning conditions, i.e. low number of counts, the COV is higher for the BPL (ß=450) than the OSEM+PSF algorithm. Increase of the ß-value to 550 or 700 results in a COV comparable to OSEM+PSF, however, at the cost of contrast, though still better than OSEM+PSF. At the edges of the axial field of view (FOV) where BPs overlap, COV can increase to levels at which bands become visible in clinical images, related to the lower local axial sensitivity of the PET/CT, which is due to the limited bed overlap of 23% such as advised by the manufacturer. CONCLUSIONS: The BPL algorithm performs better than the standard OSEM+PSF algorithm on small lesion detectability, SUV recovery, and noise suppression. Increase of the percentage of bed overlap, time per BP, administered activity, or the ß-value, all have a direct positive impact on image quality, though the latter with some loss of small lesion detectability. Thus, BPL algorithms are very interesting for improving image quality, especially in small lesion detectability.

[The quality of patient information brochures can be improved: a discussion using radium-223 therapy as an example]. / De kwaliteit van patiëntenfolders kan beter: een beschouwing aan de hand van radium-223-therapie.

Patients and their peers need to be adequately informed to ensure proper treatment selection, and to facilitate optimal realisation and outcome of treatment. Written patient information can contribute, but only when brochures are of sufficient quality. An evaluation of patient brochures for radium-223 therapy in the Netherlands revealed significant differences in the information provided, as well as discrepancies between the brochures and national guidelines and product documentation. This potentially leads to confusion, false expectations, wrong treatment decisions, suboptimal realisation and outcome of treatment, and unnecessary toxicity and in radiation hygiene risks. Here we discuss the option of national patient information brochures that can be used by all centres in order to circumvent such issues. This would require collaboration between all medical professions, patient organisations and other groups involved, and responsibilities for medical information, distribution and updates must be properly defined. A national patient information brochure of this kind is currently under development for radium-223 therapy.

Oncocytoma of the parotid gland causing false-positive result on I-131 whole-body scintigraphy.

A 50-year-old patient underwent near-total thyroidectomy in 1997 because of a T1N0M0 follicular carcinoma in the right lobe of the thyroid gland, followed by I-131 ablation (3700 MBq). Follow-up of I-131 whole-body scintigraphy after 9 years showed pathologic uptake at the left side of the neck. Histopathologic analyses of the resected specimen suggested a cystic metastasis within the parotid gland, probably originating from thyroid carcinoma. However, the patient had been disease-free for over 9 years and thyroglobulin was undetectable in plasma. Revision of the specimen with complementary immunohistochemical staining revealed histopathologic aspects more typical of oncocytoma.

Suppression of 18F-FDG Myocardial Uptake Using a Fat-Allowed, Carbohydrate-Restricted Diet.

UNLABELLED: Patients prepared by the generally used fasting protocol show variable myocardial (18)F-FDG uptake, which may result in difficult interpretation of mediastinal (18)F-FDG uptake. This retrospective study described the effect of a 1-d fat-allowed, carbohydrate-restricted diet on myocardial (18)F-FDG uptake. METHODS: The study included 100 patients on a carbohydrate-restricted diet from the Medical Center Leeuwarden and 100 patients on an unrestricted diet from the University Medical Center of Utrecht. A visual uptake scale was used, with category 0 indicating myocardial uptake less than liver uptake, category 1 indicating myocardial uptake comparable to liver uptake, and category 2 indicating myocardial uptake considerably higher than liver uptake. RESULTS: After a carbohydrate-restricted diet, 68% of patients had a homogeneously low myocardial uptake of (18)F-FDG (category 0), 14% had moderate myocardial uptake (category 1), and 18% had homogeneously intense myocardial uptake (category 2). Without a carbohydrate-restricted diet, 69% of patients showed a homogeneously intense myocardial uptake (category 2), 16% a moderate myocardial uptake (category 1), and 15% a homogeneously low myocardial uptake (category 0). CONCLUSION: A fat-allowed, carbohydrate-restricted diet starting the day before (18)F-FDG administration suppresses myocardial (18)F-FDG uptake satisfactorily.

The effects of muscle exercise and bed rest on [18F]methylcholine PET/CT.

PURPOSE: This study evaluated the impact of limited and strenuous physical exercise on [(18)F]methylcholine uptake in muscle. METHODS: Ten consecutive patients participated, three of whom had strict bed rest, three were allowed to walk around and four performed strenuous single arm exercise by lifting a 7.5-kg weight. [(18)F]Methylcholine uptake was measured in the biceps and gluteus muscles on both sides. RESULTS: Strenuous exercise resulted in a 202% increase in [(18)F]methylcholine uptake in the activated biceps muscle as well as a 112% increase in muscle groups used to retain body position. This resulted in asymmetrical images that were visually less easy to interpret. In walking patients there was a more limited increase in biceps (45%) and gluteus (74%) muscle uptake, without visually recognizable differences. CONCLUSION: Strenuous exercise may result in a considerable increase in [(18)F]methylcholine uptake in muscle and should be avoided prior to imaging. Strict bed rest does not seem to be required. Tracer injection while resting on the scanner remains a safe approach.

Colchicine must be stopped before imaging with [18F]-methylcholine PET/CT.

Choline is an essential amino acid, which is needed for the synthesis of membrane phospholipids. The choline uptake pathway is increasingly applied for molecular imaging of proliferating tumors. We describe a patient in whom we encountered an unexpected finding when he was referred for a routine [18F]-methylcholine PET/computed tomography scan to restage his prostate carcinoma. There was only visualization of circulating [18F]-methylcholine and no active uptake in any relevant organ. Owing to this abnormal biological behavior the scan was deemed uninterpretable. On checking his comorbidity and medication, the patient was found to take colchicine on a daily basis for his gout. After discontinuation of colchicine, the biodistribution of [18F]-methylcholine normalized. We present a possible explanation for these findings, with an impact on molecular imaging of the choline pathway and possibly reaching beyond colchicine alone.

Gluconeogenesis in humans with induced hyperlactatemia during low-intensity exercise.

We studied the role of lactate in gluconeogenesis (GNG) during exercise in untrained fasting humans. During the final hour of a 4-h cycle exercise at 33-34% maximal O(2) uptake, seven subjects received, in random order, either a sodium lactate infusion (60 micromol x kg(-1) x min(-1)) or an isomolar sodium bicarbonate infusion. The contribution of lactate to gluconeogenic glucose was quantified by measuring (2)H incorporation into glucose after body water was labeled with deuterium oxide, and glucose rate of appearance (R(a)) was measured by [6,6-(2)H(2)]glucose dilution. Infusion of lactate increased lactate concentration to 4.4 +/- 0.6 mM (mean +/- SE). Exercise induced a decrease in blood glucose concentration from 5.0 +/- 0.2 to 4.2 +/- 0.3 mM (P < 0.05); lactate infusion abolished this decrease (5.0 +/- 0.3 mM; P < 0.001) and increased glucose R(a) compared with bicarbonate infusion (P < 0.05). Lactate infusion increased both GNG from lactate (29 +/- 4 to 46 +/- 4% of glucose R(a), P < 0.001) and total GNG. We conclude that lactate infusion during low-intensity exercise in fasting humans 1). increased GNG from lactate and 2). increased glucose production, thus increasing the blood glucose concentration. These results indicate that GNG capacity is available in humans after an overnight fast and can be used to sustain blood glucose levels during low-intensity exercise when lactate, a known precursor of GNG, is available at elevated plasma levels.

Lactate disposal via gluconeogenesis is increased during exercise in patients with mitochondrial myopathy due to complex I deficiency.

This study evaluated lactate disposal via gluconeogenesis as well as effects of FFA availability on gluconeogenesis via pyruvate (GNG(PYR)) in patients with mitochondrial myopathy due to complex I deficiency (CID). The rates of GNG(PYR) were measured in three CID patients and six healthy controls at rest and during 90 min cycle exercise, using the deuterium-labeled water method. All subjects served as their own control: on one occasion they were studied in the fasting state, and on the second occasion they received an infusion of triacylglycerol plus heparin. At rest, the fractional rate of gluconeogenesis from pyruvate was higher in patients than in controls in the fasting state. Triacylglycerol infusion was associated with increased rates of GNG(PYR) at rest in controls (p < 0.05) but not in patients. Circulating lactate and pyruvate levels were increased 3-fold during exercise in the CID patients. During exercise, GNG(PYR) increased in the CID patients (p < 0.01) and remained unchanged in controls, resulting in 85% and 72% higher absolute rates of GNG(PYR) in the patients than in the controls during fasting and triacylglycerol infusion, respectively. During exercise, rates of GNG(PYR) were not different between fasting and triacylglycerol infusion within both groups. Our data show that 1) GNG(PYR) is increased during exercise in CID patients; 2) increased pyruvate availability contributes to the higher rates of GNG(PYR) in the CID patients; and 3) exogenous infusion of fatty acids is not associated with increased rates of GNG(PYR) in CID patients at rest or during exercise. GNG(PYR) is a significant mechanism of lactate disposal in exercising CID patients, but triglyceride infusion does not enhance their lactate disposal through this mechanism.