Diagnostic Performance of 18F-FDG PET/CT According to Delay After Treatment to Detect Subclinical Recurrence of Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) remains a malignancy with high rates of locoregional recurrence and poor prognosis for recurrent cases. Early detection of subclinical lesions is challenging but critical for effective patient management. Imaging surveillance after treatment, particularly 18F-FDG PET/CT, has shown promise in the diagnosis of HNSCC recurrence. The aim was to evaluate the diagnostic performance of 18F-FDG PET/CT according to delay after treatment in detecting subclinical recurrence (SCR) in HNSCC patients. Methods: In this retrospective study, all 18F-FDG PET/CT scans were performed at a single center. All adults with histologically proven HNSCC who were treated with curative intent between January 1, 2006, and December 31, 2021, were included. They had a normal clinical examination before each scan. Patients who underwent an intensive follow-up strategy after treatment had 18F-FDG PET/CT with an intravenous contrast agent at 3-6 mo and annually thereafter for 5 y. The primary endpoint was diagnostic performance (positive and negative predictive values, sensitivity, specificity, and accuracy). Results: In total, 2,566 18F-FDG PET/CT scans were performed among 852 patients, with an average of 3 scans per patient. The overall diagnostic performance measures were as follows: positive predictive value (88%), negative predictive value (98%), sensitivity (98%), specificity (89%), and accuracy (93%). There were no significant differences in diagnostic performance over time. The scans detected 126 cases of SCR (14.8%) and 118 cases of metachronous cancer (13.8%). The incidence of SCR decreased over time, with the highest detection rate in the first 2 y after treatment. Positive predictive value improved over time, reaching 90% for the digital Vision 600 system (third period) compared with 76% for the analog Gemini GXLi system (first period, P < 0.001). Multivariate analysis identified advanced stage, high body mass index, and initial PET/CT upstaging as predictive factors for detection of SCR. Conclusion: Our study demonstrates that 18F-FDG PET/CT has high diagnostic performance in detecting SCR during follow-up after treatment of HNSCC, especially in the first 2 y. Advanced tumor stage, initial PET/CT upstaging, and high body mass index were associated with a higher likelihood of SCR detection. The routine use of 18F-FDG PET/CT during follow-up seems justified for patients with HNSCC.

[18F]DCFPyL PET/CT versus [18F]fluoromethylcholine PET/CT in Biochemical Recurrence of Prostate Cancer (PYTHON): a prospective, open label, cross-over, comparative study.

PURPOSE: Primary objective was to compare the per-patient detection rates (DR) of [18F]DCFPyL versus [18F]fluoromethylcholine positron emission tomography/computed tomography (PET/CT), in patients with first prostate cancer (PCa) biochemical recurrence (BCR). Secondary endpoints included safety and impact on patient management (PM). METHODS: This was a prospective, open label, cross-over, comparative study with randomized treatment administration of [18F]DCFPyL (investigational medicinal product) or [18F]fluoromethylcholine (comparator). Men with rising prostate-specific antigen (PSA) after initial curative therapy were enrolled. [18F]DCFPyL and [18F]fluoromethylcholine PET/CTs were performed within a maximum time interval of 12 days. DR was defined as the percentage of positive PET/CT scans identified by 3 central imaging readers. PM was assessed by comparing the proposed pre-PET/CT treatment with the local treatment", defined after considering both PET/CTs. RESULTS: A total of 205 patients with first BCR after radical prostatectomy (73%; median PSA = 0.46 ng/ml [CI 0.16;27.0]) or radiation therapy (27%; median PSA = 4.23 ng/ml [CI 1.4;98.6]) underwent [18F]DCFPyL- and/or [18F]fluoromethylcholine -PET/CTs, between July and December 2020, at 22 European sites. 201 patients completed the study. The per-patient DR was significantly higher for [18F]DCFPyL- compared to [18F]fluoromethylcholine -PET/CTs (58% (117/201 patients) vs. 40% (81/201 patients), p < 0.0001). DR increased with higher PSA values for both tracers (PSA ≤ 0.5 ng/ml: 26/74 (35%) vs. 22/74 (30%); PSA 0.5 to ≤ 1.0 ng/ml: 17/31 (55%) vs. 10/31 (32%); PSA 1.01 to < 2.0 ng/ml: 13/19 (68%) vs. 6/19 (32%);PSA > 2.0: 50/57 (88%) vs. 39/57 (68%) for [18F]DCFPyL- and [18F]fluoromethylcholine -PET/CT, respectively). [18F]DCFPyL PET/CT had an impact on PM in 44% (90/204) of patients versus 29% (58/202) for [18F]fluoromethylcholine. Overall, no drug-related nor serious adverse events were observed. CONCLUSIONS: The primary endpoint of this study was achieved, confirming a significantly higher detection rate for [18F]DCFPyL compared to [18F]fluoromethylcholine, in men with first BCR of PCa, across a wide PSA range. [18F]DCFPyL was safe and well tolerated.

Characterization of the First Animal Toxin Acting as an Antagonist on AT1 Receptor.

The renin-angiotensin system (RAS) is one of the main regulatory systems of cardiovascular homeostasis. It is mainly composed of angiotensin-converting enzyme (ACE) and angiotensin II receptors AT1 and AT2. ACE and AT1 are targets of choice for the treatment of hypertension, whereas the AT2 receptor is still not exploited due to the lack of knowledge of its physiological properties. Peptide toxins from venoms display multiple biological functions associated with varied chemical and structural properties. If Brazilian viper toxins have been described to inhibit ACE, no animal toxin is known to act on AT1/AT2 receptors. We screened a library of toxins on angiotensin II receptors with a radioligand competition binding assay. Functional characterization of the selected toxin was conducted by measuring second messenger production, G-protein activation and ß-arrestin 2 recruitment using bioluminescence resonance energy transfer (BRET) based biosensors. We identified one original toxin, A-CTX-cMila, which is a 7-residues cyclic peptide from Conus miliaris with no homology sequence with known angiotensin peptides nor identified toxins, displaying a 100-fold selectivity for AT1 over AT2. This toxin shows a competitive antagonism mode of action on AT1, blocking Gαq, Gαi3, GαoA, ß-arrestin 2 pathways and ERK1/2 activation. These results describe the first animal toxin active on angiotensin II receptors.

PSMA-11 PET/CT for Detection of Recurrent Prostate Cancer in Patients With Negative Choline PET/CT.

INTRODUCTION: Prostate adenocarcinoma (CaP) is the leading cancer in men. After curative treatment, from 27% to 53% of patients will experience biochemical recurrence (BR). With the development of focal therapies, precise early identification of recurrence's sites is of utmost importance in order to deliver individualized treatment on positive lesions. The aim of this study was to assess the detection rate (DR) of 68Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) in selected patients with prostate cancer BR and recent negative 18F-choline PET/CT. PATIENTS AND METHODS: We performed a retrospective analysis including all patients with CaP referred for BR with a negative 18F-choline PET/CT, and who underwent 68Ga-PSMA-11 PET/CT between October, 2018 and December, 2019. The overall DR of 68Ga-PSMA-11 PET/CT was calculated, and described according to BR characteristics especially PSA levels and velocity. Patients were followed up for at least 1 year. Patient management following 68Ga-PSMA-11 PET/CT and PSA levels evolution after treatment were also recorded. RESULTS: One hundred fifty-nine patients comprising 164 examinations were analyzed. The overall DR of 68Ga-PSMA-11 PET/CT for BR was 65.9% (95CI, 58.6-73.1). The DR was 52.5% (95CI, 39.9-65.0), 70.6% (95CI, 55.3-85.9), 70.4% (95CI, 53.1-87.6), and 78.6% (95CI, 66.2-91.0) for PSA levels between 0.2 and 0.49 ng/mL, 0.5 to 0.99 ng/mL, 1 to 1.99 ng/mL and PSA ≥ 2 ng/mL, respectively. The DR was 70.7% (95CI, 59.0-82.4) with a PSA doubling time (PSA-DT) ≤6 months and 65.2% (95CI, 55.5-74.9) with a PSA-DT >6 months. Around 3/4 of patients (75.9%) with a positive 68Ga-PSMA-11 PET/CT initiated treatment, including surgery (2.4%), stereotactic radiotherapy ± androgen deprivation therapy (ADT) (22%) or external conformational radiotherapy ± ADT (46.3%). Patient management changed in 43 cases (39.8%). CONCLUSION: Our study confirmed the ability of 68Ga-PSMA-11 PET/CT to detect occult biochemical recurrence, even in a selected population of CaP patients with negative 18F-choline PET/CT, even at low PSA levels.

Radiation exposure to nuclear medicine technologists performing a V/Q PET: Comparison with conventional V/Q scintigraphy, [18F]FDG PET and [68Ga]Ga DOTATOC PET procedures.

Introduction: Ventilation/Perfusion (V/Q) PET/CT is an emerging imaging modality for regional lung function evaluation. The same carrier molecules as conventional V/Q scintigraphy are used but they are radiolabelled with gallium-68 (68Ga) instead of technetium-99m (99mTc). A recurrent concern regarding V/Q PET imaging is the radiation dose to the healthcare workers. The aim of this study was to evaluate the total effective dose and the finger dose received by the technologist when performing a V/Q PET procedure, and to compare them with the radiations doses received with conventional V/Q scintigraphy, FDG PET and Ga DOTATOC PET procedures. Materials and methods: The whole body dose measurement was performed 10 times for each of the evaluated procedures using an electronic personal dosimeter (ED). For V/Q PET and V/Q scintigraphy procedures, ventilation and perfusion stages were separately evaluated. Internal exposure was measured for ventilation procedures. Finger dose measurements were performed 5 times for each of the PET procedures using Thermoluminescence (TL) pellets. Results: The technologist effective dose when performing a V/Q PET procedure was 2.83 ± 0.67 µSv, as compared with 1.16 ± 0.34 µSv for conventional V/Q scintigraphy, 2.13 ± 0.77 µSv for [68Ga]Ga-DOTATOC, and 2.86 ± 1.79 µSv for FDG PET procedures, respectively. The finger dose for the V/Q PET procedure was similar to the dose for a [68Ga]Ga-DOTATOC scan (0.35 mSv and 0.32 mSv, respectively). Conclusion: The technologist total effective dose for a V/Q PET procedure is ~2.4 higher than the dose for a conventional V/Q scintigraphy, but in the same range than the radiation exposure when performing common PET procedures, both in terms of total effective dose or finger dose. These results should be reassuring for the healthcare workers performing a V/Q PET procedure.

18F-Fluorodeoxyglucose positron emission/computed tomography for occult cancer among patients with unprovoked venous thromboembolism: What do we know?

18F-Fluorodeoxyglucose Positron Emission/Computed Tomography (FDG PET/CT) is a non-invasive whole-body imaging modality that has the potential for replacing multiple cancer screening tests by one. Previous studies showed that FDG PET/CT has an excellent sensitivity and negative predictive value for occult cancer screening in patients with unprovoked venous thromboembolism (VTE). In this patient population, FDG PET/CT is a reproducible imaging procedure with a kappa value estimated at 0.75. Although false positive results may lead to unnecessary investigations, it seems from recent evidence that invasive procedures triggered by a positive scan often resulted in cancer diagnosis. Trials assessing use of FDG PET/CT for occult cancer screening in patients with VTE at high risk for occult cancer diagnosis are ongoing.

MT9, a natural peptide from black mamba venom antagonizes the muscarinic type 2 receptor and reverses the M2R-agonist-induced relaxation in rat and human arteries.

All five muscarinic receptors have important physiological roles. The endothelial M2 and M3 subtypes regulate arterial tone through direct coupling to Gq or Gi/o proteins. Yet, we lack selective pharmacological drugs to assess the respective contribution of muscarinic receptors to a given function. We used mamba snake venoms to identify a selective M2R ligand to investigate its contribution to arterial contractions. Using a bio-guided screening binding assay, we isolated MT9 from the black mamba venom, a three-finger toxin active on the M2R subtype. After sequencing and chemical synthesis of MT9, we characterized its structure by X-ray diffraction and determined its pharmacological characteristics by binding assays, functional tests, and ex vivo experiments on rat and human arteries. Although MT9 belongs to the three-finger fold toxins family, it is phylogenetically apart from the previously discovered muscarinic toxins, suggesting that two groups of peptides evolved independently and in a convergent way to target muscarinic receptors. The affinity of MT9 for the M2R is 100 times stronger than that for the four other muscarinic receptors. It also antagonizes the M2R/Gi pathways in cell-based assays. MT9 acts as a non-competitive antagonist against acetylcholine or arecaine, with low nM potency, for the activation of isolated rat mesenteric arteries. These results were confirmed on human internal mammary arteries. In conclusion, MT9 is the first fully characterized M2R-specific natural toxin. It should provide a tool for further understanding of the effect of M2R in various arteries and may position itself as a new drug candidate in cardio-vascular diseases.

Risk stratification for predicting recurrent venous thromboembolism after discontinuation of anticoagulation: a post hoc analysis of a French prospective multicentre study.

BACKGROUND: We aimed to validate and to refine current recurrent venous thromboembolism (VTE) risk classification. METHODS: We performed a post hoc analysis of a multicentre cohort including 1881 patients with a first symptomatic VTE prospectively followed after anticoagulation discontinuation. The primary objective was to validate the International Society of Thrombosis and Haemostasis (ISTH) risk classification in predicting recurrence risk. The secondary objective was to evaluate a refined ISTH classification based on the recurrence risk estimate for each individual risk factor. RESULTS: During a 4.8-year median follow-up after anticoagulation discontinuation, symptomatic recurrent VTE occurred in 230 patients (12.2%). Based on the ISTH classification, patients with unprovoked VTE or VTE with minor or major persistent risk factors had a 2-fold increased recurrence risk compared with those with VTE and major transient risk factors. Recurrence risk was not increased in patients with minor transient factors (hazard ratio (HR) 1.31, 95% CI 0.84-2.06). Individual risk factors analysis identified hormone-related VTE (pregnancy: HR 0.26, 95% CI 0.08-0.82; oestrogens: HR 0.25, 95% CI 0.14-0.47) and amyotrophic lateral sclerosis (HR 5.84, 95% CI 1.82-18.70). After reclassification of these factors as major transient for the former and major persistent for the latter, the modified ISTH classification allowed us to accurately discriminate between patients at low risk of recurrence (i.e. with major transient risk factors) and those at high risk of recurrence (i.e. without major transient risk factors). CONCLUSIONS: Among patients who stopped anticoagulation after a first VTE, a refined ISTH classification based on recurrence risk intensity of individual factors allowed discrimination between patients at low recurrence risk, including hormonal exposure in women, and patients at high recurrence risk.

Structural and Functional Diversity of Animal Toxins Interacting With GPCRs.

Peptide toxins from venoms have undergone a long evolutionary process allowing host defense or prey capture and making them highly selective and potent for their target. This has resulted in the emergence of a large panel of toxins from a wide diversity of species, with varied structures and multiple associated biological functions. In this way, animal toxins constitute an inexhaustible reservoir of druggable molecules due to their interesting pharmacological properties. One of the most interesting classes of therapeutic targets is the G-protein coupled receptors (GPCRs). GPCRs represent the largest family of membrane receptors in mammals with approximately 800 different members. They are involved in almost all biological functions and are the target of almost 30% of drugs currently on the market. Given the interest of GPCRs in the therapeutic field, the study of toxins that can interact with and modulate their activity with the purpose of drug development is of particular importance. The present review focuses on toxins targeting GPCRs, including peptide-interacting receptors or aminergic receptors, with a particular focus on structural aspects and, when relevant, on potential medical applications. The toxins described here exhibit a great diversity in size, from 10 to 80 amino acids long, in disulfide bridges, from none to five, and belong to a large panel of structural scaffolds. Particular toxin structures developed here include inhibitory cystine knot (ICK), three-finger fold, and Kunitz-type toxins. We summarize current knowledge on the structural and functional diversity of toxins interacting with GPCRs, concerning first the agonist-mimicking toxins that act as endogenous agonists targeting the corresponding receptor, and second the toxins that differ structurally from natural agonists and which display agonist, antagonist, or allosteric properties.

[18F]FDG PET radiomics to predict disease-free survival in cervical cancer: a multi-scanner/center study with external validation.

PURPOSE: To test the performances of native and tumour to liver ratio (TLR) radiomic features extracted from pre-treatment 2-[18F] fluoro-2-deoxy-D-glucose ([18F]FDG) PET/CT and combined with machine learning (ML) for predicting cancer recurrence in patients with locally advanced cervical cancer (LACC). METHODS: One hundred fifty-eight patients with LACC from multiple centers were retrospectively included in the study. Tumours were segmented using the Fuzzy Local Adaptive Bayesian (FLAB) algorithm. Radiomic features were extracted from the tumours and from regions drawn over the normal liver. Cox proportional hazard model was used to test statistical significance of clinical and radiomic features. Fivefold cross validation was used to tune the number of features. Seven different feature selection methods and four classifiers were tested. The models with the selected features were trained using bootstrapping and tested in data from each scanner independently. Reproducibility of radiomics features, clinical data added value and effect of ComBat-based harmonisation were evaluated across scanners. RESULTS: After a median follow-up of 23 months, 29% of the patients recurred. No individual radiomic or clinical features were significantly associated with cancer recurrence. The best model was obtained using 10 TLR features combined with clinical information. The area under the curve (AUC), F1-score, precision and recall were respectively 0.78 (0.67-0.88), 0.49 (0.25-0.67), 0.42 (0.25-0.60) and 0.63 (0.20-0.80). ComBat did not improve the predictive performance of the best models. Both the TLR and the native models performance varied across scanners used in the test set. CONCLUSION: [18F]FDG PET radiomic features combined with ML add relevant information to the standard clinical parameters in terms of LACC patient's outcome but remain subject to variability across PET/CT devices.

Convolutional neural networks for PET functional volume fully automatic segmentation: development and validation in a multi-center setting.

PURPOSE: In this work, we addressed fully automatic determination of tumor functional uptake from positron emission tomography (PET) images without relying on other image modalities or additional prior constraints, in the context of multicenter images with heterogeneous characteristics. METHODS: In cervical cancer, an additional challenge is the location of the tumor uptake near or even stuck to the bladder. PET datasets of 232 patients from five institutions were exploited. To avoid unreliable manual delineations, the ground truth was generated with a semi-automated approach: a volume containing the tumor and excluding the bladder was first manually determined, then a well-validated, semi-automated approach relying on the Fuzzy locally Adaptive Bayesian (FLAB) algorithm was applied to generate the ground truth. Our model built on the U-Net architecture incorporates residual blocks with concurrent spatial squeeze and excitation modules, as well as learnable non-linear downsampling and upsampling blocks. Experiments relied on cross-validation (four institutions for training and validation, and the fifth for testing). RESULTS: The model achieved good Dice similarity coefficient (DSC) with little variability across institutions (0.80 ± 0.03), with higher recall (0.90 ± 0.05) than precision (0.75 ± 0.05) and improved results over the standard U-Net (DSC 0.77 ± 0.05, recall 0.87 ± 0.02, precision 0.74 ± 0.08). Both vastly outperformed a fixed threshold at 40% of SUVmax (DSC 0.33 ± 0.15, recall 0.52 ± 0.17, precision 0.30 ± 0.16). In all cases, the model could determine the tumor uptake without including the bladder. Neither shape priors nor anatomical information was required to achieve efficient training. CONCLUSION: The proposed method could facilitate the deployment of a fully automated radiomics pipeline in such a challenging multicenter context.

Survey by the French Medicine Agency (ANSM) of the imaging protocol, detection rate, and safety of 68Ga-PSMA-11 PET/CT in the biochemical recurrence of prostate cancer in case of negative or equivocal 18F-fluorocholine PET/CT: 1084 examinations.

INTRODUCTION: Despite growing evidence of a superior diagnostic performance of 68Ga-PSMA-11 over 18F-fluorocholine (FCH) PET/CT, the number of PET/CT centres able to label on site with gallium-68 is still currently limited. Therefore, patients with biochemical recurrence (BCR) of prostate cancer frequently undergo FCH as the 1st-line PET/CT. Actually, the positivity rate (PR) of a second-line PSMA-11 PET/CT in case of negative FCH PET/CT has only been reported in few short series, in a total of 185 patients. Our aims were to check (1) whether the excellent PR reported with PSMA-11 is also obtained in BCR patients whose recent FCH PET/CT was negative or equivocal; (2) in which biochemical and clinical context a high PSMA-11 PET/CT PR may be expected in those patients, in particular revealing an oligometastatic pattern; (3) whether among the various imaging protocols for PSMA-11 PET/CT used in France, one yields a significantly highest PR; (4) the tolerance of PSMA-11. PATIENTS AND METHODS: Six centres performed 68Ga-PSMA-11 PET/CTs during the first 3 years of its use in France. Prior to each PET/CT, the patient's data were submitted prospectively for authorisation to ANSM, the French Medicine Agency. The on-site readings of 1084 PSMA-11 PET/CTs in BCR patients whose recent FCH PET/CTs resulted negative or equivocal were pooled and analysed. RESULTS: (1) The overall PR was 68%; for a median serum PSA level (sPSA) of 1.7 ng/mL, an oligometastatic pattern (1-3 foci) was observed in 31% of the cases overall; (2) PR was significantly related to sPSA (from 41% if < 0.2 ng/mL to 81% if ≥ 2 ng/mL), to patients' age, to initial therapy (64% if prostatectomy vs. 85% without prostatectomy due to frequent foci in the prostate fossa), to whether FCH PET/CT was negative or equivocal (PR = 62% vs. 82%), and to previous BCR (PR = 63% for 1st BCR vs. 72% in case of previous BCR); (3) no significant difference in PR was found according to the imaging protocol: injected activity, administration of a contrast agent and/or of furosemide, dose length product, one single or multiple time points of image acquisition; (4) no adverse event was reported after PSMA-11 injection, even associated with a contrast agent and/or furosemide. CONCLUSION: Compared with the performance of PSMA-11 PET/CT in BCR reported independently of FCH PET/CT in 6 large published series (n > 200), the selection based on FCH PET/CT resulted in no difference of PSMA-11 PR for sPSA < 1 ng/mL but in a slightly lower PR for sPSA ≥ 1 ng/mL, probably because FCH performs rather well at this sPSA and very occult BCR was over-represented in our cohort. An oligometastatic pattern paving the way to targeted therapy was observed in one fourth to one third of the cases, according to the clinico-biochemical context of the BCR. Systematic dual or triple acquisition time points or administration of a contrast agent and/or furosemide did not bring a significant added value for PSMA-11 PET/CT positivity and should be decided on individual bases.

Diagnostic value of positron-emission tomography textural indices for malignancy of 18F-fluorodeoxyglucose-avid adrenal lesions.

BACKGROUND: PET Textural indices could have an add-on diagnostic value for diagnosis of malignancy in patients with FDG-avid adrenal lesions. METHODS: Consecutive patients referred for a FDG-PET/CT to our nuclear medicine department from June 2012 to June 2017 were retrospectively screened. Inclusion criteria were: patients with a FDG-avid adrenal lesion (uptake≥liver background); malignant/benign lesion confirmed histologically or with follow-up imaging examination. Pheochromocytomas were not included in the analysis. For each adrenal lesion, 5 quantitative PET parameters (SUVmax, MTV, TLG, TLRmax and TLRmean) were calculated. Thirty-seven textural indices were extracted using LIFEx software®. Diagnostic performance to determine malignancy was assessed with a ROC analysis. Parameters with a significantly AUC>0.5 were selected and groups of highly correlated (r>0.8) parameters were created. A scoring system combining PET and textural indices was examined. RESULTS: PET textural indices were calculated for 53 lesions (37 malignant, 16 benign). Three PET metabolic parameters (SUVmax, TLRmax, TLRmean) and 13 textural indices had an AUC>0.5. Seven groups of highly correlated parameters (r>0.8) were extracted. For PET parameters, SUVmax had the best AUC (0.89 95% CI [0.79-0.98]; cut-off=7.0). For textural indices, ZLNU had the best AUC (0.87 95% CI [0.78-0.96]; cut-off=34.7) and specificity of 100%. Three scores combining the best four textural indices alone (ContrastGLCM, LRHGE, SZE and ZLNU) or with one PET parameters (SUVmax, TLRmax) were developed but did not increase the diagnostic performance (AUC≤0.89). ZLNU was the best parameter to distinguish primary adrenal cancer from adrenal metastases in malignant lesions (P<0.001). CONCLUSIONS: Our study highlighted excellent diagnostic performance of several PET textural indices comparable to that of PET metabolic parameters. However, our results did not find any additional diagnostic value of textural indices when combined with metabolic parameters.

Prognostic value of interim FDG PET-CT in patients older than 60 years with diffuse large B-cell lymphoma treated by PMitCEBO plus rituximab. Comparison between Deauville 5-point scale and International Harmonization Project criteria.

BACKGROUND: Advanced age is an independent poor prognostic factor of diffuse large B-cell lymphoma (DLBCL). PMitCEBO (mitoxantrone, cyclophosphamide, etoposide, vincristine, bleomycin, and prednisolone) is an alternative to the cyclophosphamide, doxorubicin, vincristine, and prednisolone regimen to decrease side effects in elderly patients. Many studies have shown prognostic value of an interim FDG PET-CT to predict survival. A recent consensus (ICML, Lugano 2013) has suggested using the 5-point scale Deauville criteria instead of those of the International Harmonization Project (IHP) to visually assess the response on interim PET. The objective of this study was to evaluate the prognostic value of an interim FDG PET-CT in patients older than 60 with treated DLBCL and to compare IHP and 5-PS Deauville visual interpretation to predict survival. METHODS: Forty-eight patients (mean age 73.2±5.2 years) treated by R-PMitCEBO for DLBCL undergoing FDG PET-CT before and after 3 cycles of treatment were retrospectively included. Event-free survival and overall survival were determined by Kaplan-Meier method and compared with interim PET-CT results using IHP and 5-PS Deauville criteria. RESULTS: Interim PET results using 5-PS Deauville criteria were significantly correlated with EFS (P<0.0001) and OS (P=0.001) whereas they were moderately correlated with EFS (P=0.046) and not with OS (P=0.106) using IHP criteria. Two-year EFS and OS rates were 86.5% and 89.2%, respectively, for patients in 1-3 score group, and 27.3% and 36.4%, respectively, for patients in ≥4 score group using the Deauville criteria. CONCLUSIONS: Our results confirmed the prognostic value of an interim PET-CT in elderly patients with DLBCL and the better performance of the 5-PS Deauville criteria.

A snake toxin as a theranostic agent for the type 2 vasopressin receptor.

Rationale: MQ1, a snake toxin which targets with high nanomolar affinity and absolute selectivity for the type 2 vasopressin receptor (V2R), is a drug candidate for renal diseases and a molecular probe for imaging cells or organs expressing V2R. Methods: MQ1's pharmacological properties were characterized and applied to a rat model of hyponatremia. Its PK/PD parameters were determined as well as its therapeutic index. Fluorescently and radioactively labeled MQ1 were chemically synthesized and associated with moderate loss of affinity. MQ1's dynamic biodistribution was monitored by positron emission tomography. Confocal imaging was used to observe the labeling of three cancer cell lines. Results: The inverse agonist property of MQ1 very efficiently prevented dDAVP-induced hyponatremia in rats with low nanomolar/kg doses and with a very large therapeutic index. PK (plasma MQ1 concentrations) and PD (diuresis) exhibited a parallel biphasic decrease. The dynamic biodistribution showed that MQ1 targets the kidneys and then exhibits a blood and kidney biphasic decrease. Whatever the approach used, we found a T1/2α between 0.9 and 3.8 h and a T1/2ß between 25 and 46 h and demonstrated that the kidneys were able to retain MQ1. Finally, the presence of functional V2R expressed at the membrane of cancer cells was, for the first time, demonstrated with a specific fluorescent ligand. Conclusion: As the most selective V2 binder, MQ1 is a new promising drug for aquaresis-related diseases and a molecular probe to visualize in vitro and in vivo V2R expressed physiologically or under pathological conditions.

Performance of 18F-fluorodesoxyglucose positron-emission tomography/computed tomography for cancer screening in patients with unprovoked venous thromboembolism: Results from an individual patient data meta-analysis.

INTRODUCTION: Venous thromboembolism (VTE) may be the first manifestation of cancer. We aimed at evaluating the performance of 18F-Fluorodesoxyglucose Positron-Emission Tomography/Computed Tomography (FDG PET/CT) for occult cancer screening in patients with unprovoked VTE. METHODS: This was a pre-specified analysis of a systematic review and individual patient data meta-analysis including prospective studies assessing cancer screening in patients with unprovoked VTE. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FDG PET/CT were calculated based on cancer diagnosis during a 1-year follow-up period. RESULTS: Four studies were identified as using FDG PET/CT as part of their extensive screening strategy. Out of the 332 patients who underwent FDG PET/CT, the scan was interpreted as positive in 67 (20.2%), as equivocal in 27 (8.1%), and as negative in 238 (71.7%). Seventeen (5.1%) patients were diagnosed with cancer at inclusion or during the 12-month follow up period. All cancers were diagnosed at initial screening. Pooled sensitivity, specificity, NPV, and PPV were 87.3% (95% CI, 55.3 to 97.4), 70.2% (95% CI, 48.2 to 85.6), 98.9% (95% CI, 94.3 to 99.7), and 17.9% (95% CI, 8.5 to 33.6), respectively. CONCLUSION: FDG PET/CT appears to have satisfactory accuracy indices for cancer diagnosis in patients with unprovoked VTE. In particular, it exhibits a very high negative predictive value and could be used to rule out the presence of an underlying occult malignancy in this setting.

Integration of 18-FDG PET/CT in the Initial Work-Up to Stage Head and Neck Cancer: Prognostic Significance and Impact on Therapeutic Decision Making.

Background: The objective of this study was to assess the therapeutic and prognostic impact of integrating18F-fluorodeoxyglucose (18-FDG) positron emission tomography (PET)/computed tomography (CT) into work-up (WU) at initial staging of patients with head and neck squamous cell carcinoma (HNSCC). Method: 477 consecutive patients (414M/63F, mean age 62.3 ± 9.7 years) with newly diagnosed HNSCC who underwent pre-treatment 18-FDG PET/CT were retrospectively included. The 18-FDG PET/CT stage (sPET) was compared to the conventional work-up stage (sCWU). A group of cancer specialists determined whether integrating PET/CT into WU at initial staging had an impact on the therapeutic decision, classifying the clinical impact as high (change in therapeutic modality), medium (change in the radiotherapy or surgical procedure), or low (modification of TNM staging and/or detection of synchronous cancer without high or medium impact). Three-year overall survival (OS) was considered as primary endpoint of the prognostic analysis. Results: 18-FDG PET/CT had a clinical impact in 221 patients (46.3%) with a medium or high impact on management in 94 (19.5%) patients. Medium and high impact of 18-FDG PET/CT was statistically equivalent between sCWU-stage I/II and III/IV subgroups (p = 0.02). 42 patients were PET/CT-upstaged from early stage I/II to advanced stage III/IV and had a significantly lower 3-year OS than those with concordant CWU and 18-FDG PET/CT early stage (54.8 vs. 82.6%, p = 0.001). Conclusion: This study demonstrated that implementing 18-FDG PET/CT in the initial WU of HNSCC provides valuable staging information with a better prognostic stratification. Patient management was modified for any disease stage, even for early stage I-II, with consequences on survival.

Risk scores for occult cancer in patients with unprovoked venous thromboembolism: Results from an individual patient data meta-analysis.

BACKGROUND: The Registro Informatizado de Pacientes con Enfermedad TromboEmbólica (RIETE) score and the Screening for Occult Malignancy in Patients with Idiopathic Venous Thromboembolism (SOME) risk scores aim to identify patients with acute unprovoked venous thromboembolism (VTE) at high risk of occult cancer, but their predictive performance is unclear. METHODS: The scores were evaluated in an individual patient data meta-analysis. Studies were eligible if enrolling consecutive adults with unprovoked VTE who underwent protocol-mandated screening for cancer. The primary outcome was a cancer diagnosis between 30 days and 2 years of follow-up. The discriminatory performance was evaluated by computing the area under the receiver (ROC) curve in random-effects meta-analyses. RESULTS: The RIETE score could be calculated in 1753 patients, of whom 63 (3.6%) were diagnosed with cancer. The pooled area under the ROC curve was 0.59 (95% confidence interval [CI], 0.52-0.66; I2  = 0%). Of the 427 patients (24%) classified as high risk, 25 (5.9%) were diagnosed with cancer compared with 38 of 1326 (2.9%) low-risk patients (hazard ratio [HR], 2.0; 95% CI, 1.3-3.4). The SOME score was calculated in 925 patients, of whom 37 (4.0%) were diagnosed with cancer. The pooled area under the ROC curve was 0.56 (95% CI, 0.46-0.65; I2  = 46%). Of the 161 patients (17%) classified as high risk (≥2 points), eight (5.0%) were diagnosed with cancer compared with 29 of 764 (3.8%) low-risk patients (HR, 1.2; 95% CI, 0.55-2.7). CONCLUSIONS: The predictive discriminatory performance of both scores is poor. When used dichotomously, the RIETE score is able to discriminate between low- and high-risk patients. Because this is largely driven by advanced age, these results do not support the use of these scores in daily clinical practice.