Biology-guided precision medicine in rare cancers: Lessons from sarcomas and neuroendocrine tumours.

Rare cancers, which collectively account for almost 25 % of all malignancies, are poorly understood in terms of their aetiology and pathogenesis and are infrequently the focus of translational and clinical research to improve their diagnosis and treatment. Consequently, those affected have comparatively few treatment options, and their prognosis is worse than that of patients with more common entities. Here we review two relevant groups of rare cancers, bone and soft-tissue sarcomas and neuroendocrine tumours (NET), to illustrate recent efforts towards individualised, biology-guided clinical management to improve long-term outcomes. Specifically, we address how comprehensive, multi-layered molecular analyses, including the assessment of predisposing hereditary factors, and innovative imaging approaches can improve the diagnosis of these diseases, allow for better prognostic assessment, and provide new targets for pharmacologic and, in the case of NET, nuclear medicine interventions, whose clinical value must be determined in controlled trials optimally tailored to the particular patient population most likely to benefit. Furthermore, we describe the importance of multidisciplinary collaboration in dedicated reference centres for rare cancers and the increasingly acknowledged potential of networking across institutions at a national and international level. Finally, we illustrate the value of a learning health system based on the systematic collection and sharing of the biological and clinical profiles of patients with rare cancers to achieve continuous cross-fertilisation of scientific and clinical efforts, making the vision of stratified precision medicine in these long-overlooked diseases a reality.

Radiofrequency ablation for autonomously functioning nodules as treatment for hyperthyroidism: subgroup analysis of toxic adenoma and multinodular goitre and predictors for treatment success.

PURPOSE: Treatment of hyperthyroidism caused by autonomously functioning thyroid nodules (AFTN) with 131I often leads to undesirable hypothyroidism. Radiofrequency ablation (RFA) has emerged as a promising alternative. This retrospective analysis aimed to examine the efficacy of, and postprocedural hypothyroidism after, RFA for AFTN. METHODS: Patients with hyperthyroidism caused by AFTN and treated with RFA were included if follow-up of at least 1 year was available. Cure was defined as thyroid medication-free biochemical euthyroidism. To predict cure, patient and treatment factors were analysed. A distinction was made between solitary toxic adenoma (STA) and toxic multinodular goitre (TMG). RESULTS: Forty-eight patients (36 STA, 12 TMG) were included. One year post-RFA cure rate was 72% in STA versus 25% in TMG (p = 0.004). One patient developed hypothyroidism. In 11 patients that remained hyperthyroid, a second RFA was successful in 83% of STA and 40% of TMG patients. At last available follow-up, this amounted to a total cure rate of 81% in STA and 33% in TMG (p = 0.002). In STA, cured patients had a higher baseline TSH and a lower FT3 than non-cured patients (p = 0.026 and 0.031). Cure was observed in 91% of patients when > 2.1 kJ/mL was delivered during RFA, compared to 44% when less energy was administered. CONCLUSION: The efficacy of RFA was nearly 3 times higher in STA patients compared to TMG. Severity of hyperthyroidism and kJ/mL delivered during RFA predicts cure. Direct comparison to the current standard of care is needed to implement RFA in treatment of hyperthyroidism caused by AFTN.

Imaging angiogenesis in patients with head and neck squamous cell carcinomas by [68Ga]Ga-DOTA-E-[c(RGDfK)]2 PET/CT.

PURPOSE: Angiogenesis plays an important role in the growth and metastatic spread of solid tumours and is characterised by the expression of integrins on the cell surface of endothelial cells. Radiolabelled RGD peptides specifically target angiogenesis-related αvß3 integrins, expressed on the activated endothelial cells of sprouting blood vessels. Here, we validated the feasibility of 68Ga[Ga]-DOTA-E-[c(RGDfK)]2 (68Ga-RGD) PET/CT to visualise angiogenesis in patients with oral squamous cell carcinoma (OSCC). METHODS: Ten patients with OSCC and scheduled for surgical resection including elective neck dissection received an intravenously administration of 68Ga-RGD (42 ± 8 µg; 214 ± 9 MBq). All patients subsequently underwent dynamic (n = 5) or static PET/CT imaging (n = 5) for 60 min or for 4 min/bed position at 30, 60 and 90 min after injection, respectively. Quantitative tracer uptake in tumour lesions was expressed as standardised uptake values (SUV). Additionally, tumour tissue was immunohistochemically stained for αvß3 integrin to assess the expression pattern. RESULTS: 68Ga-RGD tumour accumulation was observed in all patients. At 60 min post injection, tumour SUVmax ranged between 4.0 and 12.7. Tracer accumulation in tumour tissue plateaued at 10 min after injection. Uptake in background tissue did not change over time, resulting in tumour-to-muscle tissue of 6.4 ± 0.7 at 60 min post injection. CONCLUSIONS: 68Ga-RGD PET/CT of αvß3 integrin expression in OSCC patients is feasible with adequate tumour-to-background ratios. It will provide more insight in angiogenesis as a hallmark of the head and neck squamous cell carcinomas' tumour microenvironment. TRIAL REGISTRATION: https://eudract.ema.europa.eu no. 2015-000917-31.

Correction to: [89Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer.

Missing Electronic Supplementary Materials.

[89Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer.

PURPOSE: One-third of patients with RAS wild-type mCRC do not benefit from anti-EGFR monoclonal antibodies. This might be a result of variable pharmacokinetics and insufficient tumor targeting. We evaluated cetuximab tumor accumulation on [89Zr]Zr-cetuximab PET/CT as a potential predictive biomarker and determinant for an escalating dosing strategy. PATIENTS AND METHODS: PET/CT imaging of [89Zr]Zr-cetuximab (37 MBq/10 mg) after a therapeutic pre-dose (500 mg/m2 ≤ 2 h) cetuximab was performed at the start of treatment. Patients without visual tumor uptake underwent dose escalation and a subsequent [89Zr]Zr-cetuximab PET/CT. Treatment benefit was defined as stable disease or response on CT scan evaluation after 8 weeks. RESULTS: Visual tumor uptake on [89Zr]Zr-cetuximab PET/CT was observed in 66% of 35 patients. There was no relationship between PET positivity and treatment benefit (52% versus 80% for PET-negative, P = 0.16), progression-free survival (3.6 versus 5.7 months, P = 0.15), or overall survival (7.1 versus 9.4 months, P = 0.29). However, in 67% of PET-negative patients, cetuximab dose escalation (750-1250 mg/m2) was applied, potentially influencing outcome in this group. None of the second [89Zr]Zr-cetuximab PET/CT was positive. Eighty percent of patients without visual tumor uptake had treatment benefit, making [89Zr]Zr-cetuximab PET/CT unsuitable as a predictive biomarker. Tumor SUVpeak did not correlate to changes in tumor size on CT (P = 0.23), treatment benefit, nor progression-free survival. Cetuximab pharmacokinetics were not related to treatment benefit. BRAF mutations, right-sidedness, and low sEGFR were correlated with intrinsic resistance to cetuximab. CONCLUSION: Tumor uptake on [89Zr]Zr-cetuximab PET/CT failed to predict treatment benefit in patients with RAS wild-type mCRC receiving cetuximab monotherapy. BRAF mutations, right-sidedness, and low sEGFR correlated with intrinsic resistance to cetuximab.

Molecular imaging as a tool to investigate heterogeneity of advanced HER2-positive breast cancer and to predict patient outcome under trastuzumab emtansine (T-DM1): the ZEPHIR trial.

BACKGROUND: Only human epidermal growth factor receptor (HER)2 status determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) has been validated to predict efficacy of HER2-targeting antibody-drug-conjugate trastuzumab emtansine (T-DM1). We propose molecular imaging to explore intra-/interpatient heterogeneity in HER2 mapping of metastatic disease and to identify patients unlikely to benefit from T-DM1. PATIENTS AND METHODS: HER2-positive mBC patients with IHC3+ or FISH ≥ 2.2 scheduled for T-DM1 underwent a pretreatment HER2-positron emission tomography (PET)/computed tomography (CT) with (89)Zr-trastuzumab. [(18)F]2-fluoro-2-deoxy-D-glucose (FDG)-PET/CT was performed at baseline and before T-DM1 cycle 2. Patients were grouped into four HER2-PET/CT patterns according to the proportion of FDG-avid tumor load showing relevant (89)Zr-trastuzumab uptake (>blood pool activity): patterns A and B were considered positive (>50% or all of the tumor load 'positive'); patterns C and D were considered negative (>50% or all of the tumor load 'negative'). Early FDG-PET/CT was defined as nonresponding when >50% of the tumor load showed no significant reduction of FDG uptake (<15%). Negative (NPV) and positive predictive values (PPV) of HER2-PET/CT, early FDG response and their combination were assessed to predict morphological response (RECIST 1.1) after three T-DM1 cycles and time-to-treatment failure (TTF). RESULTS: In the 56 patients analyzed, 29% had negative HER2-PET/CT while intrapatient heterogeneity (patterns B and C) was found in 46% of patients. Compared with RECIST1.1, respective NPV/PPV for HER2-PET/CT were 88%/72% and 83%/96% for early FDG-PET/CT. Combining HER2-PET/CT and FDG-PET/CT accurately predicted morphological response (PPV and NPV: 100%) and discriminated patients with a median TTF of only 2.8 months [n = 12, 95% confidence interval (CI) 1.4-7.6] from those with a TTF of 15 months (n = 25, 95% CI 9.7-not calculable). CONCLUSIONS: Pretreatment imaging of HER2 targeting, combined with early metabolic response assessment holds great promise for improving the understanding of tumor heterogeneity in mBC and for selecting patients who will/will not benefit from T-DM1. CLINICALTRIALSGOV IDENTIFIER: NCT01565200.

ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignancies in Western countries. Over the last 20 years, and the last decade in particular, the clinical outcome for patients with metastatic CRC (mCRC) has improved greatly due not only to an increase in the number of patients being referred for and undergoing surgical resection of their localised metastatic disease but also to a more strategic approach to the delivery of systemic therapy and an expansion in the use of ablative techniques. This reflects the increase in the number of patients that are being managed within a multidisciplinary team environment and specialist cancer centres, and the emergence over the same time period not only of improved imaging techniques but also prognostic and predictive molecular markers. Treatment decisions for patients with mCRC must be evidence-based. Thus, these ESMO consensus guidelines have been developed based on the current available evidence to provide a series of evidence-based recommendations to assist in the treatment and management of patients with mCRC in this rapidly evolving treatment setting.

Anti-CEA antibody fragments labeled with [(18)F]AlF for PET imaging of CEA-expressing tumors.

A facile and rapid method to label peptides with (18)F based on chelation of [(18)F]AlF has been developed recently. Since this method requires heating to 100 °C, it cannot be used to label heat-sensitive proteins. Here, we used a two-step procedure to prepare (18)F-labeled heat-labile proteins using the [(18)F]AlF method based on hot maleimide conjugation. 1,4,7-Triazacyclononae-1,4-diacetate (NODA) containing a methyl phenylacetic acid group (MPA) functionalized with N-(2-aminoethyl)maleimide (EM) was used as a ligand which was labeled with [(18)F]AlF and then conjugated to the humanized anti-CEA antibody derivatives hMN-14-Fab', hMN-14-(scFv)2 (diabody), and a Dock-and-Lock engineered dimeric fragment hMN-14 Fab-AD2 at room temperature. The in vivo tumor targeting characteristics of the (18)F-labeled antibody derivatives were determined by PET imaging of mice with s.c. xenografts. NODA-MPAEM was radiolabeled with [(18)F]AlF at a specific activity of 29-39 MBq/nmol and a labeling efficiency of 94 ± 2%. The labeling efficiencies of the maleimide conjugation ranged from 70% to 77%, resulting in [(18)F]AlF-labeled hMN14-Fab', hMN14-Fab-AD2, or hMN14-diabody with a specific activity of 15-17 MBq/nmol. The radiolabeled conjugates were purified by gel filtration. For biodistribution and microPET imaging, antibody fragments were injected intravenously into BALB/c nude mice with s.c. CEA-expressing LS174T xenografts (right flank) and CEA-negative SK-RC-52 xenografts (left flank). All [(18)F]AlF-labeled conjugates showed specific uptake in the LS174T xenografts with a maximal tumor uptake of 4.73% ID/g at 4 h after injection. Uptake in CEA-negative SK-RC-52 xenografts was significantly lower. Tumors were clearly visualized on microPET images. Using a [(18)F]AlF-labeled maleimide functionalized chelator, antibody fragments could be radiofluorinated within 4 h at high specific activity. Here, we translated this method to preclinical PET imaging studies and showed feasibility of [(18)F]AlF-fluorinated hMN-14-Fab', [(18)F]AlF-hMN-14-Fab-AD2, and [(18)F]AlF-hMN-14-diabody for microPET imaging of CEA-expressing colonic cancer.

PET and SPECT imaging of a radiolabeled minigastrin analogue conjugated with DOTA, NOTA, and NODAGA and labeled with (64)Cu, (68)Ga, and (111)In.

Cholecystokinin-2 (CCK-2) receptors, overexpressed in cancer types such as small cell lung cancers (SCLC) and medullary thyroid carcinomas (MTC), may serve as targets for peptide receptor radionuclide imaging. A variety of CCK and gastrin analogues has been developed, but a major drawback is metabolic instability or high kidney uptake. The minigastrin analogue PP-F11 has previously been shown to be a promising peptide for imaging of CCK-2 receptor positive tumors and was therefore further evaluated. The peptide was conjugated with one of the macrocyclic chelators DOTA, NOTA, or NODAGA. The peptide conjugates were then radiolabeled with either (68)Ga, (64)Cu, or (111)In. All (radio)labeled compounds were evaluated in vitro (IC50) and in vivo (biodistribution and PET/CT and SPECT/CT imaging). IC50 values were in the low nanomolar range for all compounds (0.79-1.51 nM). In the biodistribution studies, (68)Ga- and (111)In-labeled peptides showed higher tumor-to-background ratios than the (64)Cu-labeled compounds. All tested radiolabeled compounds clearly visualized the CCK2 receptor positive tumor in PET or SPECT imaging. The chelator did not seem to affect in vivo behavior of the peptide for (111)In- and (68)Ga-labeled peptides. In contrast, the biodistribution of the (64)Cu-labeled peptides showed high uptake in the liver and in other organs, most likely caused by high blood levels, probably due to dissociation of (64)Cu from the chelator and subsequent transchelation to proteins. Based on the present study, (68)Ga-DOTA-PP-F11 might be a promising radiopharmaceutical for PET/CT imaging of CCK2 receptor expressing tumors such as MTC and SCLC. Clinical studies are warranted to investigate the potential of this tracer.

Development of an imaging-guided CEA-pretargeted radionuclide treatment of advanced colorectal cancer: first clinical results.

BACKGROUND: Radiolabelled antibody targeting of cancer is limited by slow blood clearance. Pretargeting with a non-radiolabelled bispecific monoclonal antibody (bsMAb) followed by a rapidly clearing radiolabelled hapten peptide improves tumour localisation. The primary goals of this first pretargeting study in patients with the anti-CEACAM5 × anti-hapten (HSG) bsMAb, TF2, and the radiolabelled hapten-peptide, IMP288, were to assess optimal pretargeting conditions and safety in patients with metastatic colorectal cancer (CRC). METHODS: Different dose schedules were studied in four cohorts of five patients: (1) shortening the interval between the bsMAb and peptide administration (5 days vs 1 day), (2) escalating the TF2 dose (from 75 to 150 mg), and (3) reducing the peptide dose (from 100 to 25 µg). After confirmation of tumour targeting by (111)In-IMP288, patients were treated with a bsMAb/(177)Lu-IMP288 cycle. RESULTS: Rapid and selective tumour targeting of the radiolabelled peptide was visualised within 1 h, with high tumour-to-tissue ratios (>20 at 24 h). Improved tumour targeting was achieved with a 1-day interval between the administration of the bsMAb and the peptide and with the 25-µg peptide dose. High (177)Lu-IMP288 doses (2.5-7.4 GBq) were well tolerated, with some manageable TF2 infusion reactions, and transient grades 3-4 thrombocytopaenia in 10% of the patients who received (177)Lu-IMP288. CONCLUSION: This phase I study demonstrates for the first time that pretargeting with bsMAb TF2 and radiolabelled IMP288 in patients with CEA-expressing CRC is feasible and safe. With this pretargeting method, tumours are specifically and rapidly targeted.

Monitoring the effects of bevacizumab beyond progression in a murine colorectal cancer model: a functional imaging approach.

Clinical studies have shown that bevacizumab beyond progression to first line therapy is beneficial for overall survival in advanced stage colorectal cancer. We studied the utility of several functional imaging modalities to assess the efficacy of bevacizumab beyond progression (BBP). All BALB/c mice with s.c. LS174T xenografts were treated with capecitabine, oxaliplatin and bevacizumab combination therapy. Tumor volume was assessed using caliper measurements. Increase of 1.5 times the initial volume on two subsequent measurements, was considered progression. In half of the mice bevacizumab treatment was continued (n = 13) after progressive disease was established, while the others received saline injections (n = 12). Within 3 days after progression, multi-modal imaging was performed using FDG-PET, diffusion weighted imaging, T2* and dynamic contrast enhanced MRI. Measurements were repeated 7 and 10 days after the first measurements. Afterwards, tumors were analyzed for expression of carbonic anhydrase IX, glucose transporter 1, 9 F1 to stain the vasculature and Ki67 to assess proliferation. In the BBP group tumor growth after progression was reduced compared to the control group (p < 0.01). FDG-PET showed a trend towards lower FDG uptake in the BBP group (p = 0.08). DWI, T2* and DCE-MRI parameters were not significantly different between both groups. The immunohistochemical analyses showed higher CAIX-positive fraction (p < 0.01) and lower Ki67 expression (p = 0.06) in the BBP group. The relative vascular area was significantly lower in the BBP group (p = 0.03). GLUT-1 expression and vascular density did not significantly differ between both groups. Bevacizumab after progression resulted in significant changes in the tumor proliferation and microenvironment compared to discontinuation of bevacizumab. FDG-PET may be sensitive to BBP-induced effects.

Experimental study of radioimmunotherapy versus chemotherapy for colorectal cancer.

BACKGROUND: Radioimmunotherapy (RIT) has been shown to reduce the incidence of local recurrence of colorectal cancer in an experimental model. The aim of the present study was to investigate the survival benefit of RIT compared with chemotherapy. METHODS: An anastomosis was constructed in male Wag/Rij rats after intraluminal injection of CC531 tumour cells. The therapeutic efficacy of (177) Lu-labelled MG1 (single intravenous dose of 300 MBq/kg, n = 20) was compared with that of 5-fluorouracil-based chemotherapy (6 weekly cycles administered intraperitoneally, n = 20) and no treatment (n = 20). The primary endpoint was survival. Toxicity was monitored by bodyweight measurement. RESULTS: Both chemotherapy and RIT affected bodyweight, but the weight of animals in the RIT group remained significantly higher than in the chemotherapy group (median slope of bodyweight plot 0·48 versus 0·30 g/day; P < 0·001). Kaplan-Meier analysis showed that overall survival in the RIT and chemotherapy groups was significantly better than that in the control group (50 and 46 per cent versus 25 per cent respectively after 170 days; P = 0·024 and P = 0·029). Survival after treatment with RIT did not differ from that after chemotherapy (P = 0·911). CONCLUSION: RIT is as effective as chemotherapy in experimental colorectal cancer.

Long-term global quality of life in patients treated for colorectal liver metastases.

BACKGROUND: Surgical treatment of colorectal liver metastases has become increasingly aggressive. The influence of this more active surgical approach on patients' health-related quality of life (HRQoL) has hardly been evaluated. This study investigated the impact of surgical and systemic treatment on HRQoL in patients undergoing hepatic resection for colorectal metastases. METHODS: A total of 145 patients with colorectal liver metastases were entered prospectively into the study. Based on HRQoL values derived from the EuroQol-5D, health summary measures were calculated to express the overall impact on four distinct clinical states. The HRQoL instrument was used at baseline, 3 and 6 weeks after surgery, and every 3 months thereafter for up to 3 years. RESULTS: Patients showed a clear deterioration in HRQoL in the first weeks after surgery, followed by a recovery to baseline levels at 3 months after potentially curative surgery. In contrast, a sustained decline was noted when initial surgery for colorectal liver metastases was considered futile and palliative chemotherapy was started immediately. Three years after initial surgery, there were distinct differences in HRQoL between patients with or without recurrence. The latter group still had HRQoL scores at baseline levels, whereas patients with tumour recurrence showed a significant deterioration in HRQoL. Remarkably, there was no decline in HRQoL in patients with recurrent disease who could be treated by secondary surgical intervention. CONCLUSION: Superior overall HRQoL in the first 3 years after initial successful surgical intervention merits an aggressive surgical approach and intensive follow-up to detect recurrence early.

Comparison of two region of interest definition methods for metabolic response evaluation with [18F]FDG-PET.

AIM: In therapy response monitoring by [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), different tumor delineations are used, resulting in different values for change in glucose metabolic rate (DMRglu). We propose a technique to compare metabolic rates in a region of interest (ROI) based on fixed volumes rather than on fixed thresholds. This method involves change in lesion size. METHODS: In 49 patients with colorectal carcinoma (CRC) and 50 patients with non-small cell lung carcinoma (NSCLC) scheduled for chemotherapy, FDG-PET was performed at baseline and during chemotherapy. A ROIfixed thresholds was determined by using a 50% threshold on both baseline and follow-up FDG-PET. A ROIfixed volumes was determined by using a 50% threshold, determined on the series with the largest tumor volume. This ROIfixed volumes is used on consecutive scans. Predictive effects of both methods were investigated by survival analysis for overall and progression free survival. RESULTS: In CRC, only ROIfixed volumes based DMRglu showed significant predictive ability. In NSCLC, both techniques showed significant predictive ability. During multivariate analysis, ROIfixed volumes determined DMRglu was an independent predictor for both overall and progression free survival in NSCLC whereas ROIfixed thresholds determined MRglu was not. After dichotomization at the median DMRglu, median survival ratio was higher in ROIfixed volumes than ROIfixed thresholds for CRC (overall survival: 1.78 vs 1.25, progression free survival: 1.57 vs 1.21) and NSCLC (overall survival: 2.01 vs 2.01, progression free survival: 2.93 vs 2.13). CONCLUSION: ROIfixed volumes based DMRglu shows better correlation with survival than DMRglu determined from a ROIfixed thresholds.

New targeted probes for radioimaging of angiogenesis.

Angiogenesis, the formation of new blood vessels, is a multi-step process regulated by pro- and anti-angiogenic factors. In order to grow and metastasize, tumors need a constant supply of oxygen and nutrients. For their growth beyond the size of 1-2 mm tumors are dependent on angiogenesis. Recently, various new anti-cancer agents (e.g. bevacizumab, sorafenib and sunitinib) have become available that specifically inhibit angiogenesis in tumors. To evaluate the effects of these new anti-angiogenic agents it would be of interest to scintigraphically image the process of angiogenesis in tumors. Several markers have been described that are preferentially expressed on newly formed blood vessels in tumors (alpha(v)beta(3) integrin, vascular endothelial growth factor and its receptor, prostate-specific membrane antigen) and in the extracellular matrix surrounding newly formed blood vessels (extra-domain B of fibronectin, Tenascin-C, matrix metalloproteinases, Robo-4). Several ligands targeting these markers have been tested as a radiotracer for imaging angiogenesis in tumors. The potential of some of these tracers such as radiolabeled cyclic RGD peptides and radiolabeled anti-PSMA antibodies has already been tested cancer patients, while for markers such as Robo-4 the ligand has not yet been identified. Here the preclinical and clinical studies with these new tracers to image angiogenesis in tumors are reviewed.

The continuous debate in literature about the usage of iodine-131 dosing for the ablation of thyroid remnants and metastases.

UNLABELLED: Radioiodine plays an important role in the treatment of thyroid cancer. It is used for thyroid remnant ablation as well as for treatment of metastatic disease. Despite the fact that it is used all over the world for these indications, the exact administered dose is still a subject for DISCUSSION: Two methods are widely available: the so-called fixed empiric method and the dosimetric one. This review will highlight the aspects of radioiodine in treatment of thyroid cancer and discuss the advantages and disadvantages of the several methods for the calculation of the administered dose.

Chemotherapy response evaluation with FDG-PET in patients with colorectal cancer.

BACKGROUND: The aim of this prospective study was to evaluate the value of F-18-fluorodeoxyglucose-positron emission tomography (FDG-PET) for early assessment of chemotherapy response in patients with advanced colorectal cancer. METHODS: Dynamic FDG-PET was carried out before and at 2 (n = 50) and 6 months (n = 19) after the start of treatment. Quantitative Patlak analysis [metabolic rate of glucose (MRGlu)] and a simplified method to measure glucose metabolism [standardized uptake value (SUV)] were evaluated. The predictive value of changes in glucose metabolism was assessed with Cox proportional regression analysis. Overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier estimates. RESULTS: There was an increase in the rates of death (P = 0.049 for DeltaMRGlu PET1-2; P = 0.017 for DeltaSUV PET1-2; P = 0.032 for DeltaMRGlu PET1-3; P = 0.048 for DeltaSUV PET1-3) and progression (P = 0.026 for DeltaMRGlu PET1-2; P = 0.035 for DeltaSUV PET1-2; P = 0.041 for DeltaMRGlu PET1-3; P = 0.081 for DeltaSUV PET1-3) associated with worse response as assessed by PET on Cox proportional regression analysis. The OS and PFS analysis showed a significant predictive value at broad ranges of DeltaMRGlu and DeltaSUV cut-off levels. CONCLUSION: The degree of chemotherapy-induced changes in tumor glucose metabolism is highly predictive for patient outcome. The use of FDG-PET for therapy monitoring seems clinically feasible since simplified methods (SUV) are sufficiently reliable.

The effect of cholecalciferol supplementation on vitamin D levels and insulin sensitivity is dose related in vitamin D-deficient HIV-1-infected patients.

OBJECTIVE: The aim of this study was to explore the effects of cholecalciferol supplementation on vitamin D levels, bone mineral density (BMD), body fat distribution and insulin sensitivity in vitamin D-deficient HIV-1-infected patients. METHODS: Twenty vitamin D-deficient HIV-1-infected patients were prospectively treated with 2000 IU cholecalciferol/day for 14 weeks, whereafter treatment was continued with half this dosage until 48 weeks. BMD, body fat distribution, 1,25-dihydroxy vitamin D(3) (1,25(OH)2D3), fasting glucose, insulin, adiponectin, leptin, interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha were measured at baseline, and at 24 and 48 weeks. Parathyroid hormone (PTH), 25-hydroxy vitamin D(3) [25(OH)D(3)], cholesterol and triglycerides were measured at baseline, and at 12, 24 and 48 weeks. RESULTS: After 24 weeks, cholecalciferol supplementation significantly increased 25(OH)D3 and 1,25(OH)2D3 levels and decreased PTH and insulin sensitivity. After 48 weeks, however, only 25(OH)D3 levels remained significantly different from baseline, while the other parameter levels returned to baseline, suggesting a dose-response effect. Cholecalciferol had no effect on BMD, adipokines and triglycerides. CONCLUSIONS: The effect of cholecalciferol treatment in this cohort appears to be dose dependent. Cholecalciferol dosages of > or =2000 IU are necessary to achieve 1,25(OH)2D3 levels that significantly decrease PTH, but also negatively affect insulin sensitivity. The results of this hypothesis-driven explorative study need to be confirmed in larger clinical trials.

Assessment of mandibular invasion of squamous cell carcinoma by various modes of imaging: constructing a diagnostic algorithm.

The aim of this study was to determine the optimal combination of preoperative examination methods to predict mandibular invasion by squamous cell carcinoma of the oral cavity. Data were gathered prospectively but evaluated retrospectively. The preoperative results of clinical examination, conventional radiography, bone single photon emission computed tomography (SPECT), computed tomography and magnetic resonance imaging were compared to the histological results of resection specimens from 67 patients with tumours, adjacent or fixed to the mandible, histologically confirmed as squamous cell carcinoma. The examination methods with acceptable sensitivity and specificity were selected and diagnostic algorithms were constructed using all possible combinations. The preferred diagnostic algorithm was found to be either computed tomography or magnetic resonance imaging, followed by a bone SPECT in cases where the first scan is negative. A negative bone SPECT rules out mandibular invasion (100% sensitivity). This algorithm accurately predicted mandibular invasion in 85% of the patients, without yielding false negative results. In this study group, application of such an algorithm would have resulted in a reduction of the number of unnecessary mandibular resections by 50%. The suggested, preferred, diagnostic algorithm shortens the preoperative screening process, avoiding unnecessary costs, as well as considerably reducing the number of unnecessary mandibular resections.