Concurrent chemoradiotherapy (CRT) with blockade of the PD-1 pathway may enhance immune-mediated tumor control through increased phagocytosis, cell death, and antigen presentation. The NiCOL phase 1 ...trial (NCT03298893) is designed to determine the safety/tolerance profile and the recommended phase-II dose of nivolumab with and following concurrent CRT in 16 women with locally advanced cervical cancer. Secondary endpoints include objective response rate (ORR), progression free survival (PFS), disease free survival, and immune correlates of response. Three patients experience grade 3 dose-limiting toxicities. The pre-specified endpoints are met, and overall response rate is 93.8% 95%CI: 69.8-99.8% with a 2-year PFS of 75% 95% CI: 56.5-99.5%. Compared to patients with progressive disease (PD), progression-free (PF) subjects show a brisker stromal immune infiltrate, higher proximity of tumor-infiltrating CD3
T cells to PD-L1
tumor cells and of FOXP3
T cells to proliferating CD11c
myeloid cells. PF show higher baseline levels of PD-1 and ICOS-L on tumor-infiltrating EMRA CD4
T cells and tumor-associated macrophages, respectively; PD instead, display enhanced PD-L1 expression on TAMs, higher peripheral frequencies of proliferating Tregs at baseline and higher PD-1 levels at week 6 post-treatment initiation on CD4 and CD8 T cell subsets. Concomitant nivolumab plus definitive CRT is safe and associated with encouraging PFS rates. Further validation in the subset of locally advanced cervical cancer displaying pre-existing, adaptive immune activation is warranted.
To prospectively evaluate the clinical impact and the diagnostic performance of FCH-PET/CT in patients with occult biochemical recurrence of prostate cancer (PCa).
Results of 179 patients (mean PSA = ...7.5ng/mL) with negative/inconclusive results of pelvic-MRI and of bone-scintigraphy were analysed. To determine the impact of FCH-PET/CT on diagnostic thinking and on patient management, the referring physicians prospectively filled-in a 1st and 2nd questionnaire related to patient's planned management before and after FCH-PET/CT. Based on data from a 6-month follow-up after FCH-PET/CT, an independent assessor blinded to results of FCH-PET/CT determined the adequacy of management changes motivated by FCH-PET/CT.
FCH-PET/CT localised foci evocative of recurrent PCa in 59% (105/179) of patients. Results of FCH-PET/CT motivated a change in scheduled patient management in 56% (100/179) of patients; which was considered as adequate in 89% (89/100) of patients. FCH-PET/CT also led to the detection of lung cancer in two patients.
FCH PET/CT is a powerful tool to localise the sites of occult biochemical recurrence of PCa, leading to an adequate management change in half of patients.
Background. Positron emission tomography-computed tomography (PET/CT) with 18F-fluorocholine (FCH) is routinely performed in patients with prostate cancer. In this clinical context, foci of FCH ...uptake in the head or in the neck were considered as incidentalomas, except for those suggestive of multiple bone metastases.
Results. In 8 patients the incidental focus corresponded to a benign tumour. The standard of truth was histology in two cases, correlative imaging with MRI in four cases, 99mTc-SestaMIBI scintigraphy, ultrasonography and biochemistry in one case and biochemistry including PTH assay in one case. The final diagnosis of benign tumours consisted in 3 pituitary adenomas, 2 meningiomas, 2 hyperfunctioning parathyroid glands and 1 thyroid adenoma. Malignancy was proven histologically in 2 other patients: 1 papillary carcinoma of the thyroid and 1 cerebellar metastasis.
Conclusions. To the best of our knowledge, FCH uptake by pituitary adenomas or hyperfunctioning parathyroid glands has never been described previously. We thus discuss whether there might be a future indication for FCH PET/ CT when one such tumour is already known or suspected: to detect a residual or recurrent pituitary adenoma after surgery, to guide surgery or radiotherapy of a meningioma or to localise a hyperfunctioning parathyroid gland. In these potential indications, comparative studies with reference PET tracers or with 99mTc-sestaMIBI in case of hyperparathyroidism could be undertaken.
Context:
Preoperative ultrasonography and scintigraphy using 99mTc-sestamibi are commonly used to localize abnormal parathyroid glands. In cases of discrepant results between scintigraphy and ...ultrasonography, it is important to rely on another diagnostic imaging modality. 18F-fluorodeoxyglucose (FDG) and 11C-methionine positron emission tomography (PET) have been studied, but are imperfect to detect abnormal parathyroid glands. Recently, first cases of abnormal parathyroid glands taking-up radiolabelled choline were discovered incidentally in men referred to 11C-choline or 18F-fluorocholine (FCH)-PET/CT for prostate cancer. We checked if FCH uptake was a general feature of adenomatous or hyperplastic parathyroid glands.
Methods:
FCH-PET/CT was performed in 12 patients with primary (n = 8) or secondary hyperparathyroidism (1 dialyzed, 3 grafted) and with discordant or equivocal results on preoperative ultrasonography (US) and/or 123I/99mTc-sestamibi dual-phase scintigraphy. The results of the FCH-PET/CT were evaluated, with surgical exploration and histopathologic examination as the standard of truth.
Results:
On a per-patient level, the detection rate of FCH-PET/CT (at least one FCH focus corresponding to an abnormal parathyroid gland in a given patient) was 11/12 = 92%. FCH-PET/CT detected 18 foci interpreted as parathyroid glands and correctly localized 17 abnormal parathyroid glands (7 adenomas and 10 hyperplasias). On a per-lesion level, FCH-PET/CT results were 17 TP, 2 false negative ie, a lesion-based sensitivity of 89%, and 1 false positive.
Conclusion:
As the main result of this pilot study, we show that in patients with hyperparathyroidism and with discordant or equivocal results on scintigraphy or on ultrasonography, adenomatous or hyperplastic parathyroid glands can be localized by FCH-PET/CT with good accuracy. Furthermore, FCH-PET/CT can solve discrepant results between preoperative ultrasonography and scintigraphy and has thus a potential as a functional imaging modality in the detection of abnormal parathyroid glands. Our preliminary results are encouraging and prompt us to further evaluate FCH-PET/CT as a functional imaging agent in patients with biochemical hyperparathyroidism.
Dendritic cells (DCs) represent essential antigen-presenting cells that are critical for linking innate and adaptive immunity, and influencing T-cell responses. Among pattern recognition receptors, ...DCs express C-type lectin receptors triggered by both exogenous and endogenous ligands, therefore dictating pathogen response, and also shaping T-cell immunity. We previously described in rat, the expression of the orphan C-type lectin-like receptor-1 (CLEC-1) by DCs and demonstrated in vitro its inhibitory role in downstream T helper 17 (Th17) activation. In this study, we examined the expression and functionality of CLEC-1 in human DCs, and show a cell-surface expression on the CD16− subpopulation of blood DCs and on monocyte-derived DCs (moDCs). CLEC-1 expression on moDCs is downregulated by inflammatory stimuli and enhanced by transforming growth factor β. Moreover, we demonstrate that CLEC-1 is a functional receptor on human moDCs and that although not modulating the spleen tyrosine kinase-dependent canonical nuclear factor-κB pathway, represses subsequent Th17 responses. Interestingly, a decreased expression of CLEC1A in human lung transplants is predictive of the development of chronic rejection and is associated with a higher level of interleukin 17A (IL17A). Importantly, using CLEC-1–deficient rats, we showed that disruption of CLEC-1 signaling led to an enhanced Il12p40 subunit expression in DCs, and to an exacerbation of downstream in vitro and in vivo CD4+ Th1 and Th17 responses. Collectively, our results establish a role for CLEC-1 as an inhibitory receptor in DCs able to dampen activation and downstream effector Th responses. As a cell-surface receptor, CLEC-1 may represent a useful therapeutic target for modulating T-cell immune responses in a clinical setting.
•CLEC-1 is restricted to CD16− myeloid DCs in human blood and acts as an inhibitory receptor to restrain downstream Th17 activation.•CLEC-1–deficient rats highlight an in vivo function for CLEC-1 in preventing excessive T-cell priming and effector Th responses.
The aims of this cohort study were to evaluate initial tumor hypoxia in metastatic renal cell carcinoma (mRCC) and its changes after sunitinib treatment, using (18)F-fluoromisonidazole PET/CT, and ...investigate the possible prognostic value of initial tumor hypoxia or its changes under sunitinib therapy.
Antiangiogenic-naive patients with mRCC were prospectively enrolled in this cohort study. Before initiation of sunitinib, CT defined up to 10 targets that were assessed at 1 and 6 mo according to the response evaluation criteria in solid tumors (RECIST). Pretreatment target uptake of (18)F-fluoromisonidazole was compared with uptake at 1 mo. Targets were considered hypoxic when their maximal standard uptake value was above mean blood value + 2 SDs. Hypoxic volumes were also computed. Relationships between initial hypoxia status, initial degree of hypoxia, its change at 1 mo, and overall or progression-free survival (OS and PFS, respectively) were assessed by survival analysis.
Fifty-three patients were included. Median follow-up was 16.8 mo. (18)F-fluoromisonidazole uptake significantly decreased in initially hypoxic target metastases but did not change in others (-22%, P < 10(-4), vs. +1.5%, P = 0.77; P = 10(-3) between groups). Seventy-five percent of patients with hypoxic metastases were free of progressive disease at 4.8 mo (95% confidence interval, 2.99-11.83), compared with 11.3 mo (95% confidence interval, 3.08-36.9) for other patients (P = 0.02), whereas OS was not significantly different. Changes in tumor hypoxia were not related to PFS or OS.
Sunitinib reduced hypoxia in initially hypoxic RECIST target metastases but did not induce significant hypoxia in nonhypoxic RECIST target metastases. Patients with initially hypoxic targets have shorter PFS than others.
A 71-year-old woman with a history of back pain and recent weight loss presented to the emergency department with hematuria. A CT scan was performed and showed left retroperitoneal mass with left ...renal vein thrombus extended to the vena cava. Tumor biopsy revealed plasmablastic lymphoma. Staging with 18F-FDG PET/CT scan was performed and revealed pulmonary, hepatic, and left supraclavicular lymph node extension. The left retroperitoneal mass showed intense FDG uptake and was associated with widespread tumor thrombus in the peripheral abdominal veins. Differentiating tumor thrombus from bland thrombosis has a significant impact on patient's management.
Abstract Tumor evasion has recently been associated with a novel member of the B7 family, HERV‐H LTR‐associating 2 (HHLA2), which is mostly overexpressed in PDL‐1 neg tumors. HHLA2 can either induce ...a costimulation signal when bound to CD28H or inhibit it by binding to KIR3DL3 on T‐ and NK cells. Given the broad distribution of CD28H expression on NK cells and its role, we compared two monoclonal antibodies targeting this novel NK‐cell engager in this study. We show that targeting CD28H at a specific epitope not only strongly activates Ca 2+ flux but also results in NK‐cell activation. CD28H‐activated NK cells further display increased cytotoxic activity against hematopoietic cell lines and bypass HHLA2 and HLA‐E inhibitory signals. Additionally, scRNA‐seq analysis of clear cell renal cancer cells revealed that HHLA2 + clear cell renal cancer cell tumors were infiltrated with CD28H + NK cells, which could be targeted by finely chosen anti‐CD28H Abs.
To determine if pretreatment 18FFDG PET/CT could contribute to predicting complete pathological complete response (pCR) in patients with early-stage triple-negative breast cancer (TNBC) undergoing ...neoadjuvant chemotherapy with or without pembrolizumab.
In this retrospective bicentric study, we included TNBC patients who underwent 18FFDG PET/CT before neoadjuvant chemotherapy (NAC) or chemo-immunotherapy (NACI) between March 2017 and August 2022. Clinical, biological, and pathological data were collected. Tumor SUVmax and total metabolic tumor volume (TMTV) were measured from the PET images. Cut-off values were determined using ROC curves and a multivariable model was developed using logistic regression to predict pCR.
N = 191 patients were included. pCR rates were 53 and 70% in patients treated with NAC (N = 91) and NACI (N = 100), respectively (p < 0.01). In univariable analysis, high Ki67, high tumor SUVmax (> 12.3), and low TMTV (≤ 3.0 cm
) were predictors of pCR in the NAC cohort while tumor staging classification (< T3), BRCA1/2 germline mutation, high tumor SUVmax (> 17.2), and low TMTV (≤ 7.3 cm
) correlated with pCR in the NACI cohort. In multivariable analysis, only high tumor SUVmax (NAC: OR 8.8, p < 0.01; NACI: OR 3.7, p = 0.02) and low TMTV (NAC: OR 6.6, p < 0.01; NACI: OR 3.5, p = 0.03) were independent factors for pCR in both cohorts, albeit at different thresholds.
High tumor metabolism (SUVmax) and low tumor burden (TMTV) could predict pCR after NAC regardless of the addition of pembrolizumab. Further studies are warranted to validate such findings and determine how these biomarkers could be used to guide neoadjuvant therapy in TNBC patients.
Purpose
Hybrid positron emission tomography/computed tomography (PET/CT) has now become available, as well as whole-body, low-dose multidetector row computed tomography (MDCT) or magnetic resonance ...imaging (MRI). The radioactive glucose analogue 18F-fluorodeoxyglucose (FDG) is the most widely used tracer but has a relatively low sensitivity in detecting multiple myeloma (MM). We compared FDG with a more recent metabolic tracer, 18F-fluorocholine (FCH), for the detection of MM lesions at time of disease relapse or progression.
Methods
We analyzed the results of FDG and FCH imaging in 21 MM patients undergoing PET/CT for suspected relapsing or progressive MM. For each patient and each tracer, an on-site reader and a masked reader independently determined the number of intraosseous and extraosseous foci of tracer and the intensity of uptake as measured by their SUVmax and the corresponding target/non-target ratio (T/NT).
Results
In the skeleton of 21 patients, no foci were found for two cases, uncountable foci were observed in four patients, including some mismatched FCH/FDG foci. In the 15 patients with countable bone foci, the on-site reader detected 72 FDG foci vs. 127 FCH foci (+76 %), whereas the masked reader detected 69 FDG foci vs. 121 FCH foci (+75 %), both differences being significant. Interobserver agreement on the total number of bone foci was very high, with a kappa coefficient of 0.81 for FDG and 0.89 for FCH. Measurement of uptake in the matched foci that took up both tracers revealed a significantly higher median SUVmax and T/NT for FCH vs. FDG. Almost all unmatched foci were FCH-positive FDG-negative (57/59 = 97 % on-site and 56/60 = 93 % on masked reading); they were more frequently observed than matched foci in the head and neck region.
Conclusions
These findings suggest that PET/CT performed for suspected relapsing or progressive MM would reveal more lesions when using FCH rather than FDG.
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