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Background: In glioblastoma (GBM), tumor progression occurs mainly within the irradiated tumor volume. To address this challenge, a radiosensitization strategy with intravenous gadolinium-based theranostic nanoparticles (AGuIX) is being explored in the NANO-GBM phase1b/2R trial (NCT04881032). Here, we present the results of the phase 1b part, which is the first-in-human use of these nanoparticles with radiotherapy and chemotherapy for the treatment of newly diagnosed GBM. Material and Methods: Eligible patients were aged 18 to 75 years with newly diagnosed and histologically confirmed GBM, with incomplete resection (biopsy or partial surgery). The phase 1b part was a dose escalation approach (Time-to-event Continuous Reassessment Method) with three dose levels: 50, 75, and 100 mg/kg. Patients were treated with RT (60 Gy), and concomitant and adjuvant TMZ, and 4 injections of AGuIX (D-3/-7, D1, D8, and D15). Dose-limiting-toxicity (DLT) was defined as any grade 3–4 adverse event (CTCAE v5.0), excluding alopecia, nausea, and rapidly controlled vomiting. Pharmacokinetic (PK), and biodistribution based on MRI were evaluated. Results: Between March 2022 and March 2023, eight patients were enrolled: 1 at 50 mg/kg, 1 at 75 mg/kg, and 6 at 100 mg/kg. All patients received the four AGuIX injections. Only one patient experienced a DLT (at 100 mg/kg): a grade 3 lymphopenia (related to TMZ). The RP2D of AGuIX was determined as 100 mg/kg. AGuIX mean AUC increased with dose. Regions of GBM with moderate (36–123 µM), and high (123–291 µM) or very high (>291 µM) AGuIX concentrations accounted in average for 38.7 and 26.8 %, respectively. Conclusion: These results confirm the lack of AGuIX-related toxicity and the widespread dispersion of nanoparticles throughout GBM. This supports progression to the randomized phase 2 part, utilizing an RP2D of AGuIX of 100 mg/kg (4 injections).

Abstract Background The optimization of the management for elderly glioblastoma patients is crucial given the demographics of aging in many countries. We report the outcomes for a “real-life” patient cohort (i.e. unselected) comprising consecutive glioblastoma patients aged 70 years or more, treated with different radiotherapy +/− temozolomide regimens. Methods From 2003 to 2016, 104 patients ≥ 70 years of age, consecutively treated by radiotherapy for glioblastoma, were included in this study. All patients were diagnosed with IDH-wild type glioblastoma according to pathological criteria. Results Our patient cohort comprised 51 female patients (49%) and 53 male. The median cohort age was 75 years (70–88), and the median Karnofsky performance status (KPS) was 70 (30–100). Five (5%) patients underwent macroscopic complete resection, 9 (9%) had partial resection, and 90 (86%), a stereotactic biopsy. The MGMT promoter was methylated in 33/73 cases (45%). Fifty-two (50%), 38 (36%), and 14 (14%) patients were categorized with RPA scores of III, IV, and I-II. Thirty-three (32%) patients received normofractionated radiotherapy (60 Gy, 30 sessions) with temozolomide (Stupp), 37 (35%) received hypofractionated radiotherapy (median dose 40 Gy, 15 sessions) with temozolomide (HFRT + TMZ), and 34 (33%) HFRT alone. Patients receiving only HFRT were significantly older, with lower KPSs. The median overall survival (OS; all patients) was 5.2 months. OS rates at 12, 18, and 24 months, were 19%, 12%, and 5%, respectively, with no statistical differences between patients receiving Stupp or HFRT + TMZ (P = 0.22). In contrast, patients receiving HFRT alone manifested a significantly shorter survival time (3.9 months vs. 5.9 months, P = 0.018). In multivariate analyses, the prognostic factors for OS were: i) the type of surgery (HR: 0.47 [0.26–0.86], P = 0.014), ii) RPA class (HR: 2.15 [1.17–3.95], P = 0.014), and iii) temozolomide use irrespective of radiotherapy schedule (HR: 0.54 [0.33–0.88], P

Background/aim: Triple-negative breast cancer (TNBC) is the most heterogeneous breast cancer subtype, posing numerous challenges in clinical decision-making. Biomarkers are essential to personalize management of TNBC patients. While tumor infiltrating lymphocytes (TILs) are validated prognostic biomarkers, the requirement for tumor biopsy limits their routine use. Therefore, more accessible and reliable quantitative biomarkers are needed. Given the significant role of systemic inflammatory response in tumor onset and progression, assessing inflammatory cells via liquid biopsies emerges as a promising alternative., Patients and Methods: The PERCEPTION study, conducted at Centre Jean Perrin in France, aims to determine the correlation between TILs and peripheral blood components at diagnosis. An interim analysis was conducted after enrolling 50% of the estimated population, to evaluate study feasibility and preliminary correlations between blood cell counts and TILs., Results: Sixty-one patients were enrolled over 4.5 years, demonstrating a good inclusion rate with minimal missing data. Preliminary results for 36 analyzable patients showed no correlation between the neutrophil-to-lymphocyte ratio (NLR) and TILs (r s =-0.19, 95%CI=-0.49-0.16, p=0.3). However, a moderate, positive, statistically significant correlation was found between NLR and the CD8/FoxP3 TILs ratio (r s =0.36, 95%CI=0.03-0.64, p=0.043). The probabilistic index of 0.7 (p=0.06) between NLR-high and NLR-low groups for this ratio supports the correlation., Conclusion: The interim analysis of the PERCEPTION study confirms the feasibility of correlating blood cell counts with TILs in TNBC. Although no significant correlation was observed between NLR and TILs, the moderate positive correlation between the CD8/FoxP3 ratio and TILs suggests a potential link between systemic inflammation and local immune response. These findings underscore the potential of blood-based markers as non-invasive surrogates for TILs, encouraging further research to enhance prognosis and guide treatment strategies in TNBC., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: In glioblastoma (GBM), tumor progression occurs mainly within the irradiated tumor volume. To address this challenge, a radiosensitization strategy with intravenous gadolinium-based theranostic nanoparticles (AGuIX) is being explored in the NANO-GBM phase1b/2R trial (NCT04881032). Here, we present the results of the phase 1b part, which is the first-in-human use of these nanoparticles with radiotherapy and chemotherapy for the treatment of newly diagnosed GBM., Material and Methods: Eligible patients were aged 18 to 75 years with newly diagnosed and histologically confirmed GBM, with incomplete resection (biopsy or partial surgery). The phase 1b part was a dose escalation approach (Time-to-event Continuous Reassessment Method) with three dose levels: 50, 75, and 100 mg/kg. Patients were treated with RT (60 Gy), and concomitant and adjuvant TMZ, and 4 injections of AGuIX (D-3/-7, D1, D8, and D15). Dose-limiting-toxicity (DLT) was defined as any grade 3-4 adverse event (CTCAE v5.0), excluding alopecia, nausea, and rapidly controlled vomiting. Pharmacokinetic (PK), and biodistribution based on MRI were evaluated., Results: Between March 2022 and March 2023, eight patients were enrolled: 1 at 50 mg/kg, 1 at 75 mg/kg, and 6 at 100 mg/kg. All patients received the four AGuIX injections. Only one patient experienced a DLT (at 100 mg/kg): a grade 3 lymphopenia (related to TMZ). The RP2D of AGuIX was determined as 100 mg/kg. AGuIX mean AUC increased with dose. Regions of GBM with moderate (36-123 µM), and high (123-291 µM) or very high (>291 µM) AGuIX concentrations accounted in average for 38.7 and 26.8 %, respectively., Conclusion: These results confirm the lack of AGuIX-related toxicity and the widespread dispersion of nanoparticles throughout GBM. This supports progression to the randomized phase 2 part, utilizing an RP2D of AGuIX of 100 mg/kg (4 injections)., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Introduction: Patients with high-grade gliomas are at risk of developing increased intracranial hypertension (ICHT) in relation to the increase in volume of their tumor. ICP change cannot be measured by invasive method but can be estimated by using routine clinical signs, in combination with a standard imaging method, magnetic resonance imaging (MRI). A non-invasive monitoring of ICP could be of interest in high-grade glioma, in particular after radiotherapy treatment with as major side effect a cerebral oedema., Patients and Methods: This prospective clinical study aimed to compare the ICP changes (estimated by a non-invasive method based upon distortion product otoacoustic emissions (DPOAE) monitoring) with volume changes observed on MRI in patients with high-grade gliomas treated with radiotherapy. DPOAE measurements were performed one month after the end of radiotherapy and then every 3 months for one year. At each visit, the patient also underwent MRI as well as an evaluation of clinical signs., Results: The variation in the estimate of intracranial pressure readout measured at each follow-up visit (in absolute value with respect to the baseline measurements) was significantly associated with the variation of T2/FLAIR volume (n=125; p<0.001) with a cut off value of change ICP readout of 40.2 degrees (e.i. an estimated change of 16 mm Hg)., Discussion: The GMaPIC trial confirm the hypothesis that the ICP change estimated by DPOAEs measurement using a non-invasive medical device is correlated with the change of the tumor or edema in high grade glioma after radiotherapy. The device could thus become an easy-to-use and non-invasive intracranial pressure monitoring tool for these patients., Clinical Trial Registration: Clinicaltrials.gov, identifier (NCT02520492)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Casile, Thivat, Giraudet, Ginzac, Molnar, Biau, Brehant, Lourenco, Avan and Durando.)

Purpose: Previous studies have reported the benefit of dual HER2-targeting combined to neoadjuvant chemotherapy in HER2-amplified breast cancer (HER2 + BC). Moreover, besides the cardiac toxicity following their association to Trastuzumab, anthracyclines chemotherapy may not profit all patients. The NeoTOP study was designed to evaluate the complementary action of Trastuzumab and Pertuzumab, and the relevance of an anthracycline-based regimen according to TOP2A amplification status., Methods: Open-label, multicentre, phase II study. Eligible patients were aged ≥ 18 with untreated, operable, histologically confirmed HER2 + BC. After centralized review of TOP2A status, TOP2A-amplified (TOP2A+) patients received FEC100 for 3 cycles then 3 cycles of Trastuzumab (8 mg/kg then 6 mg/kg), Pertuzumab (840 mg/kg then 420 mg/kg), and Docetaxel (75mg/m 2 then 100mg/m 2 ). TOP2A-not amplified (TOP2A-) patients received 6 cycles of Docetaxel (75mg/m 2 ) and Carboplatin (target AUC 6 mg/ml/min) plus Trastuzumab and Pertuzumab. Primary endpoint was pathological Complete Response (pCR) using Chevallier's classification. Secondary endpoints included pCR (Sataloff), Progression-Free Survival (PFS), Overall Survival (OS), and toxicity., Results: Out of 74 patients, 41 and 33 were allocated to the TOP2A + and TOP2A- groups respectively. pCR rates (Chevallier) were 74.4% (95%CI: 58.9-85.4) vs. 71.9% (95%CI: 54.6-84.4) in the TOP2A + vs. TOP2A- groups. pCR rates (Sataloff), 5-year PFS and OS were 70.6% (95%CI: 53.8-83.2) vs. 61.5% (95%CI: 42.5-77.6), 82.4% (95%CI: 62.2-93.6) vs. 100% (95%CI: 74.1-100), and 90% (95%CI: 69.8-98.3) vs. 100% (95%CI: 74.1-100). Toxicity profile was consistent with previous reports., Conclusion: Our results showed high pCR rates with Trastuzumab and Pertuzumab associated to chemotherapy. They were similar in TOP2A + and TOP2A- groups and the current role of neoadjuvant anthracycline-based chemotherapy remains questioned., Trial Registration Number: NCT02339532 (registered on 14/12/14)., (© 2024. The Author(s).)

Purpose: Irinotecan has considerable importance in the treatment of metastatic colorectal cancer (mCRC). UDP-glucoronyltransferase (UGT) 1A1 is responsible for the inactivation of SN-38, a metabolite of irinotecan. Depending on UGT1A1 polymorphism, the activity of the UGT enzyme can be reduced leading to more frequent occurrence of adverse events related to irinotecan. The present study aimed to assess the safety and efficacy of different doses of irinotecan adjusted according to UGT1A1 polymorphism., Methods: Thirty-four patients treated with FOLFIRI as first-line treatment for mCRC were included in this study. The irinotecan dosage was adapted on the basis of UGT1A1 polymorphisms: *1/*1 (370 mg/m 2 ); *1/*28 (310 mg/m 2 ), and *28/*28 (180 mg/m 2 ). The incidence of grades 3 and 4 toxicities (neutropenia, febrile neutropenia, and diarrhoea) was recorded. Response was assessed according to the RECIST 1.1 criteria., Results: On the basis of UGT1A1 genotyping, 20 patients were *1/*1 (58.8%), 12 were *1/*28 (35.3%) and 2 were *28/*28 (5.9%). Seven patients experienced at least one severe toxicity, i.e., 21% of the population, amounting to eleven adverse events. Concerning the response rate, 15 patients (44%) had partial or complete response., Conclusion: This study demonstrates that mCRC patients treated with FOLFIRI can tolerate a higher dose of irinotecan than the standard dose, i.e., > 180 mg/m 2 , on the basis of their UGT1A1 genotype, without increased toxicities., Trial Registration: NCT01963182 (registered on 16/10/2013, Clermont-Ferrand, France)., (© 2023. The Author(s).)

Background: Real-world data (RWD) related to the health status and care of cancer patients reflect the ongoing medical practice, and their analysis yields essential real-world evidence. Advanced information technologies are vital for their collection, qualification, and reuse in research projects., Methods: UNICANCER, the French federation of comprehensive cancer centres, has innovated a unique research network: Consore. This potent federated tool enables the analysis of data from millions of cancer patients across eleven French hospitals., Results: Currently operational within eleven French cancer centres, Consore employs natural language processing to structure the therapeutic management data of approximately 1.3 million cancer patients. These data originate from their electronic medical records, encompassing about 65 million medical records. Thanks to the structured data, which are harmonized within a common data model, and its federated search tool, Consore can create patient cohorts based on patient or tumor characteristics, and treatment modalities. This ability to derive larger cohorts is particularly attractive when studying rare cancers., Conclusions: Consore serves as a tremendous data mining instrument that propels French cancer centres into the big data era. With its federated technical architecture and unique shared data model, Consore facilitates compliance with regulations and acceleration of cancer research projects.

Background: Temozolomide (TMZ) oral suspension (Ped-TMZ, KIZFIZO ® ) is being developed for the treatment of relapsed or refractory neuroblastoma, a rare cancer affecting infants and young children. The study assessed the safety and the bioequivalence of this novel pediatric formulation with existing TMZ oral capsules., Methods: In vitro dissolution profiles and the bioequivalence were evaluated following the European Medicines Agency "Guidelines on the investigation of Bioequivalence". The phase I, multicenter, randomized, open-label, crossover, single-dose bioequivalence study enrolled 36 adult patients with glioblastoma multiforme or lower-grade glioma. Each patient received 200 mg/m 2 Ped-TMZ suspension and TMZ capsules (Temodal ® ) on 2 consecutive days, with the order being randomly assigned. Fourteen blood samples were collected up to 10 h post-dosing. Bioequivalence was assessed by comparing the 90% confidence interval for the ratio of the geometric means of maximum TMZ plasma concentration (C max ) and the area under the curve (AUCt). Other endpoints included further pharmacokinetic parameters and safety., Results: Both formulations exhibited a fast in vitro dissolution profile with more than 85% of TMZ dissolved within 15 min. For the bioequivalence study, thirty patients completed the trial as per the protocol. The ratio of Ped-TMZ/TMZ capsule geometric means (90% CI) for AUCt and C max were 97.18% (95.05-99.35%) and 107.62% (98.07-118.09%), respectively, i.e., within the 80-125% bioequivalence limits. No buccal toxicity was associated with Ped-TMZ liquid formulation., Conclusions: This study showed that Ped-TMZ oral suspension and TMZ oral capsule treatment are immediate release and bioequivalent medicines. There were also no unexpected safety signals or local toxicity (funded by ORPHELIA Pharma; ClinicalTrials.gov number, NCT04467346).

Background: Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in women. Approximately 50% of breast cancers are discovered at an early stage in patients for whom conservative surgery is indicated. Intraoperative localization of non-palpable breast lesions is generally accomplished using a hook wire to mark the area of concern under ultrasound or stereotactic localization. But this technique has several drawbacks (painful, stressful…). We propose the use of a wire-free breast lesion system using miniature radiofrequency identification (RFID) tags. This technique could improve patient comfort and surgical comfort for surgeons. We therefore propose a study to assess the interest of introducing the RFID localization technique at the Jean PERRIN comprehensive cancer center., Methods: This is a single-center prospective trial designed to assess the interest in introducing the RFID localization technique at the Jean Perrin center. It aims to show the superiority of the RFID technique in terms of patient tolerance compared to the gold-standard (hook wire). A sequential inclusion in time will be performed: 20 inclusions in the gold-standard group, then 20 patients in the RFID group before repeating the inclusion scheme. Any patient requiring preoperative localization will receive a senology consultation. The RFID tag will be placed during this consultation. The hook wire localization will be done the day before the surgery. Patients will fill out a Hospital Anxiety and Depression scale (HAD) questionnaire at the time of inclusion. They will then fill out a satisfaction questionnaire in 2 steps: during the placement of the device (RFID tag or hook wire) or during the postoperative consultation at 1 month. Radiologists and surgeons will fill out a questionnaire to evaluate the localization technique, respectively after the localization and surgery procedures., Discussion: The RFID study is the first study in France which specifically assesses the interest of the RFID localization in terms of patients comfort. Patient comfort is one of the key elements to take into consideration when managing patients in oncology and new technologies such as RFID tags could improve it., Trial Registration: ClinicalTrials.gov ID; NCT04750889 registered on February 11, 2021., (© 2023. The Author(s).)

Background: Sensitive and reproducible detection of residual disease after treatment is a major challenge for patients with locally advanced head and neck cancer. Indeed, the current imaging techniques are not always reliable enough to determine the presence of residual disease. The aim of the NeckTAR trial is to assess the ability of circulating DNA (cDNA), both tumoral and viral, at three months post-treatment, to predict residual disease, at the time of the neck dissection, among patients with partial cervical lymph node response on PET-CT, after potentiated radiotherapy., Methods: This will be an interventional, multicentre, single-arm, open-label, prospective study. A blood sample will be screened for cDNA before potentiated radiotherapy and after 3 months if adenomegaly persists on the CT scan 3 months after the end of treatment. Patients will be enrolled in 4 sites in France. Evaluable patients, i.e. those with presence of cDNA at inclusion, an indication for neck dissection, and a blood sample at M3, will be followed for 30 months. Thirty-two evaluable patients are expected to be recruited in the study., Discussion: The decision to perform neck dissection in case of persistent cervical adenopathy after radio-chemotherapy for locally advanced head and neck cancer is not always straightforward. Although studies have shown that circulating tumour DNA is detectable in a large proportion of patients with head and neck cancer, enabling the monitoring of response, the current data is insufficient to allow routine use of this marker. Our study could lead to better identification of patients who do not have residual lymph node disease in order to avoid neck dissection and preserve their quality-of-life while maintaining their prospects of survival., Trial Registration: Clinicaltrials.gov: NCT05710679, registered on 02/02/2023, https://clinicaltrials.gov/ct2/show/ . Identifier with the French National Agency for the Safety of Medicines and Health Products (ANSM): N°ID RCB 2022-A01668-35, registered on July 15 th , 2022., (© 2023. The Author(s).)

Endometrial cancer (EC) accounts for 2% of all new cancers. Advanced forms have a poor prognosis with barely 17% 5-year survival. The last few years improved our knowledge of EC with a new molecular classification derived from The Cancer Genome Atlas (TCGA). They are now divided between POLE mutant, Microsatellite Instability High (MSI-H) or deficient in Mismatch Repair System (dMMR), TP53 mutant and no specific molecular profile. Until now, treatments for advanced EC have included conventional platinum-based chemotherapy or hormonotherapy. The revolution in oncology represented by the advent of immune checkpoints inhibitors (ICI) has also led to a major advance in the management of recurrent and metastatic EC. Pembrolizumab, a well-known anti PD-1, has firstly been approved as monotherapy in the second-line setting for dMMR/MSI-H advanced EC. More recently, a combination of lenvatinib with pembrolizumab offered a new effective option in the second line setting irrespectively of the MMR status, giving a new opportunity for these patients who had no actual standard of care before. This combination is currently being evaluated as frontline therapy. Despite exciting results, the main problem in identifying solid biomarkers remains unresolved and further investigations are required. New original combinations of pembrolizumab with other drugs including chemotherapy, poly ADPribose polymerase inhibitors (PARP-i) or tyrosine kinase inhibitors are being tested and promise exciting new therapeutic evolutions in a close future., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 El-ghazzi et al.)

Background: Despite standard treatments including chemoradiotherapy with temozolomide (TMZ) (STUPP protocol), the prognosis of glioblastoma patients remains poor. AGuIX nanoparticles have a high radiosensitizing potential, a selective and long-lasting accumulation in tumors and a rapid renal elimination. Their therapeutic effect has been proven in vivo on several tumor models, including glioblastoma with a potential synergetic effect when combined with TMZ based chemoradiotherapy, and they are currently evaluated in 4 ongoing Phase Ib and II clinical trials in 4 indications (brain metastases, lung, pancreatic and cervix cancers) (> 100 patients received AGuIX). Thus, they could offer new perspectives for patients with newly diagnosed glioblastoma. The aim of this study is to determine the recommended dose of AGuIX as a radiosensitizer in combination with radiotherapy and TMZ during the concurrent radio-chemotherapy period for phase II (RP2D) and to estimate the efficacy of the combination., Methods: NANO-GBM is a multicenter, phase I/II, randomized, open-label, non-comparative, therapeutic trial. According to a dose escalation scheme driven by a TITE-CRM design, 3 dose levels of AGuIX (50, 75 and 100 mg/kg) will be tested in phase I added to standard concomitant radio-chemotherapy. Patients with grade IV glioblastoma, not operated or partially operated, with a KPS ≥ 70% will be eligible for the study. The primary endpoints are i) for phase I, the RP2D of AGuIX, with DLT defined as any grade 3-4 NCI-CTCAE toxicity and ii) for phase II, the 6-month progression-free survival rate. The pharmacokinetics, distribution of nanoparticles, tolerance of the combination, neurological status, overall survival (median, 6-month and 12-month rates), response to treatment, and progression-free survival (median and 12-month rates) will be assessed as secondary objectives. Maximum sixty-six patients are expected to be recruited in the study from 6 sites., Discussion: The use of AGuIX nanoparticles could allow to overpass the radioresistance to the reference treatment of newly diagnosed glioblastomas that have the poorest prognosis (incomplete resection or biopsy only)., Trial Registration: Clinicaltrials.gov: NCT04881032 , registered on April 30, 2021. Identifier with the French National Agency for the Safety of Medicines and Health Products (ANSM): N°Eudra CT 2020-004552-15., Protocol: version 3, 23 May 2022., (© 2023. The Author(s).)

Background: Currently, the long-term prognosis and survival rate of patients with high-grade glial tumors remains poor and there are no biomarkers. hPG 80 (circulating progastrin) secreted into the blood by tumor cells has been widely studied in colorectal cancer. Its involvement in tumorigenesis has been demonstrated in the literature. Moreover, according to a recent study, hPG 80 is expressed in the blood of cancer patients at a significantly higher concentration than in the control group composed of healthy blood donors., Methods: The PROGLIO study is a pilot, single-center, longitudinal study that primarily seeks to evaluate circulating plasma hPG 80 concentrations over time in patients with high-grade glial tumors. A fasting blood sample will be taken on the start and end day of radiotherapy and during the adjuvant chemotherapy (every 3 cycles). Follow-up monitoring will be performed for 9 months, with a blood sample taken every 3 months on the day of the follow-up MRI. The study plans to recruit 30 patients and recruitment started in February 2022., Trial Registration: ClinicalTrials.gov, ID NCT05157594; registered on October 27, 2021., Competing Interests: BV is a Medical Science Liaison of BIODENA CARE. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Casile, Passildas, Vire, Molnar and Durando.)

Background: 99m Tc-NTP 15-5 is a SPECT radiotracer targeting proteoglycans (PG), components of the cartilaginous extracellular matrix. Imaging of PGs would be useful for the early detection of cartilage disorders (osteoarthritis, arthritis and chondrosarcoma, Aromatase Inhibitor associated arthralgia (AIA) in breast cancer), and the follow-up of patients under treatment. According to preclinical study results, 99m Tc-NTP 15-5, is a good candidate for a specific functional molecular imaging of joints. We intend to initiate a first in-human study to confirm and quantify 99m Tc-NTP 15-5 uptake in healthy joints., Methods: As the clinical development of this radiotracer would be oriented toward the functional imaging of joint pathologies, we have chosen to include patients with healthy joints (unilateral osteoarthritis of the knee or breast cancer with indication of AI treatment). This phase I study will be an open-label, multicenter, dose-escalation trial of a radiopharmaceutical orientation to determine the recommended level of activity of 99m Tc-NTP 15-5 to obtain the best joint tracer contrasts on images, without dose limiting toxicity (DLT). The secondary objectives will include the study of the pharmacology, biodistribution (using planar whole body and SPECT-CT acquisitions), toxicity, and dosimetry of this radiotracer. The dose escalation with 3 activity levels (5, 10, and 15 MBq/kg), will be conditioned by the absence at the previous level of DLT and of a visualized tracer accumulation on more than 80% of healthy joints as observed on scintigraphy performed at ≤ 2 h post-injection., Discussion: This first in-human phase I trial will be proof-of-concept of the relevance of 99m Tc-NTP 15-5 as a cartilage tracer, with the determination of the optimal methodology (dose and acquisition time) to obtain the best contrast to provide a functional image of joints with SPECT-CT., Trial Registration Number: Clinicaltrials.gov: NCT04481230. Identifier in French National Agency for the Safety of Medicines and Health Products (ANSM): N°EudraCT 2020-000495-37., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Thivat, Chanchou, Mathieu, Levesque, Billoux, Auzeloux, Sas, Molnar, Jouberton, Rouanet, Fois, Maigne, Galmier, Penault-Llorca, Miot-Noirault, Durando and Cachin.)

Breast cancer (BC) is the most common cancer and among the leading causes of cancer death in women. It is a heterogeneous group of tumours with numerous morphological and molecular subtypes, making predictions of disease evolution and patient outcomes difficult. Therefore, biomarkers are needed to help clinicians choose the best treatment for each patient. For the last years, studies have increasingly focused on biomarkers obtainable by liquid biopsy. Circulating proteins (from serum or plasma) can be used for inexpensive and minimally invasive determination of disease risk, early diagnosis, treatment adjusting, prognostication and disease progression monitoring. We provide here a review of the main published studies on serum proteins in breast cancer and elaborate on the potential of circulating proteins to be predictive and/or prognostic biomarkers in breast cancer., (© 2022. The Author(s).)

Background: High-grade epithelial ovarian cancer (HGEOC) is a heterogeneous disease and among the deadliest types of cancer. It often acquires resistance to conventional chemotherapy and its prognosis remains highly poor. The tissue protein nestin, implicated in the assembly and disassembly of intermediate filaments, has been reported to be an unfavourable prognostic factor in several cancer types. We hypothesized that HGEOC progression is regulated by the proliferation of chemoresistant cancer stem cells, in which nestin might be implicated. This preliminary study aimed to evaluate nestin as a prognostic biomarker in HGEOC treated by neoadjuvant chemotherapy (NACT) followed by cytoreductive surgery., Patients and Methods: A retrospective study (2009-2019) was conducted on 92 patients with primary ovarian, fallopian tube or peritoneal HGEOC who underwent NACT followed by cytoreductive surgery. Nestin expression in tissue samples was semi-quantitatively evaluated defining nestin positivity for those with histochemical score ≥30. We then evaluated the prognostic value of nestin expression., Results: The median progression-free survival was similar between nestin-positive (22 months) and nestin-negative (19 months) groups (p=0.57). Interestingly, the median overall survival was shorter for the nestin-positive group (48 vs. 67 months, respectively), however the difference did not reach statistical significance (p=0.43)., Conclusion: Tissue nestin expression does not appear to be a relevant prognostic biomarker in HGEOC treated by NACT. However, we believe that prospective studies in larger cohorts should be conducted and evaluation of nestin in pre-NACT HGEOC samples needs to be explored., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The objective of our study was to report predictive factors of local control (LC) and radionecrosis (RN) of brain metastases (BM) of non-small cell lung carcinoma (NSCLC) treated by multifractionated stereotactic radiotherapy (MF-SRT) according to French recommendations., Method: From 2012 to 2020, 87 patients with 101 BM were retrospectively included. The median age was 63 years (37-85). GTV was defined using contrast-enhanced T1w MRI and was isotropically extended by 2 mm to form PTV. Mean maximum BM diameter was 24.5 mm (10-46). Patients were treated with dynamic arctherapy from May 2012 to February 2016 and then with VMAT. The total prescribed dose was 23.1 Gy prescribed to the encompassing 70% isodose, in 3 fractions., Results: LC rates at 6 months, 1 year and 2 years was 95.7%, 90.7% and 87.9% respectively. In multivariate analysis, high GTV Dmin (HR = 0.822, p = 0.012) was in favor of better LC whereas a large maximum diameter was predictive of poor LC (HR = 1.124, p = 0.02). GTV Dmin of 27.4 Gy was identified as a discriminant threshold of LC. In case of GTV Dmin ≥ 27.4 Gy, LC at 1 year was 95.3% versus 75.1% with GTV Dmin < 27.4 Gy. Cumulative incidence of RN at 6 months, 1 year and 2 years was 6.3%, 15.4% and 18.1%, respectively. In multivariate analysis, only dyslipidemia was predictive of RN (HR = 2.69, p = 0.03). No dosimetric predictive factor of RN was found in our study., Conclusion: MF-SRT (3x7.7 Gy on 70% isodose line, with PTV = GTV + 2 mm; according to French recommendations) of BM from NSCLC gives high LC rates with acceptable RN rate. A GTV Dmin of at least 27.4 Gy could be proposed to optimize dosimetric objectives. No dosimetric predictive factors of RN were found in this study. However, dyslipidemia was identified as a potential predictive factor of RN., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

(1) Background: Glioblastoma multiforme (GBM) shows complex mechanisms of spreading of the tumor cells, up to remote areas, and little is still known of these mechanisms, thus we focused on MRI abnormalities observable in the tumor and the brain adjacent to the lesion, up to the contralateral hemisphere, with a special interest on tensor diffusion imaging informing on white matter architecture; (2) Material and Methods: volumes, macroscopic volume (MV), brain-adjacent-tumor (BAT) volume and abnormal color-coded DTI volume (aCCV), and region-of-interest samples (probe volumes, ipsi, and contra lateral to the lesion), with their MRI characteristics, apparent diffusion coefficient (ADC), fractional anisotropy (FA) values, and number of fibers (DTI fiber tracking) were analyzed in patients suffering GBM ( n = 15) and metastasis ( n = 9), and healthy subjects ( n = 15), using ad hoc statistical methods (type I error = 5%) (3) Results: GBM volumes were larger than metastasis volumes, aCCV being larger in GBM and BAT ADC was higher in metastasis, ADC decreased centripetally in metastasis, FA increased centripetally either in GBM or metastasis, MV and BAT FA values were higher in GBM, ipsi FA values of GBM ROIs were higher than those of metastasis, and the GBM ipsi number of fibers was higher than the GBM contra number of fibers; (4) Conclusions: The MV, BAT and especially the aCCV, as well as their related water diffusion characteristics, could be useful biomarkers in oncology and functional oncology.

Background: Benzamide-based radioligands targeting melanin were first developed for imaging melanoma and then for therapeutic purpose with targeted radionuclide therapy (TRT). [ 131 I]ICF01012 presents a highly favorable pharmacokinetics profile in vivo for therapy. Tumour growth reduction and increase survival have been established in preclinical models of melanoma. According the these preclinical results, we initiate a first-in-human study aimed to determine the recommended dose of [ 131 I]ICF01012 to administer for the treatment of patients with pigmented metastatic melanoma., Methods: The MELRIV-1 trial is an open-label, multicentric, dose-escalation phase I trial. The study is divided in 2 steps, a selection part with an IV injection of low activity of [ 131 I]ICF01012 (185 MBq at D0) to select patients who might benefit from [ 131 I]ICF01012 TRT in therapeutic part, i.e. patient presenting at least one tumour lesion with [ 131 I]ICF01012 uptake and an acceptable personalized dosimetry to critical organs (liver, kidney, lung and retina). According to dose escalation scheme driven by a Continual Reassessment Method (CRM) design, a single therapeutic injection of 800 MBq/m 2 , or 1600 MBq/m 2 , or 2700 MBq/m 2 or 4000 MBq/m 2 of [ 131 I]ICF01012 will be administered at D11 (± 4 days). The primary endpoint is the recommended therapeutic dose of [ 131 I]ICF01012, with DLT defined as any grade 3-4 NCI-CT toxicity during the 6 weeks following therapeutic dose. Safety, pharmacokinetic, biodistribution (using planar whole body and SPECT-CT acquisitions), sensitivity / specificity of [ 131 I]ICF01012, and therapeutic efficacy will be assessed as secondary objectives. Patients who received therapeutic injection will be followed until 3 months after TRT. Since 6 to 18 patients are needed for the therapeutic part, up to 36 patients will be enrolled in the selection part., Discussion: This study is a first-in-human trial evaluating the [ 131 I]ICF01012 TRT in metastatic malignant melanomas with a diagnostic dose of the [ 131 I]ICF01012 to select the patients who may benefit from a therapeutic dose of [ 131 I]ICF01012, with at least one tumor lesion with [ 131 I]ICF01012 uptake and an acceptable AD to healthy organ., Trial Registration: Clinicaltrials.gov : NCT03784625 . Registered on December 24, 2018. Identifier in French National Agency for the Safety of Medicines and Health Products (ANSM): N°EudraCT 2016-002444-17., (© 2022. The Author(s).)

Introduction: The advent of immune checkpoint inhibitors (ICIs) such as nivolumab has enabled outcomes for metastatic renal cell carcinoma (mRCC) to be improved. However, only around 25% of patients respond to these therapies without being able to formally identify them. Data on relevant predictive markers are still lacking. The obesity paradox has been shown as a relevant prognostic marker in mRCC with better outcomes for obese patients. Nevertheless, the impact of weight variation and the presence of sarcopenia during ICI treatment is not known for now., Methods: In a retrospective study, weight and its variations were collected at first day of ICI and at 6 weeks of treatment. Scanographic imagery was used to define the skeletal muscle index (SMI) as a reflect of sarcopenia. The impact of these parameters as predictive and prognostic factors for mRCC with nivolumab was evaluated., Results: A higher body mass index (BMI) at baseline was significantly associated with response at the first scan (p = 0.036). Longer overall survival (OS) was observed for patients with a weight gain compared to the group with weight loss (p = 0.00028). Median OS for sarcopenic patients was 17.2 months and 31.6 months for the non-sarcopenic group of patients, but there was no statistical difference., Conclusion: This trial showed that a higher BMI and weight gain during nivolumab treatment were good predictive markers for outcomes in mRCC with nivolumab. Sarcopenia and variations in SMI could thus be of interest, but further studies are required., (© 2021 S. Karger AG, Basel.)

Background: The standard care for HER2-positive breast cancer is chemotherapy plus a HER2-directed therapy. This can lead to treatment-induced cardiotoxicity. On the other hand, the practice of physical activity is known to improve cardiac function; thus HER2-positive breast cancer patients could draw particular benefit from physical activity during treatment. However, at the time of diagnosis for breast cancer, the majority of patients are insufficiently active according to physical activity recommendations of World Health Organisation, and it is difficult to remain or become active during the treatment. There is a lack of data in the literature on the optimal program to propose to patients to encourage them to be active during treatment. The aim of our study is to assess the feasibility of a home-based physical activity program during neoadjuvant chemotherapy and trastuzumab for HER2-positive breast cancer., Methods: The APACAN2 study is a single-centre, non-randomized interventional trial. Patients with HER2-positive breast cancer treated with anthracycline-based neoadjuvant chemotherapy and trastuzumab are eligible for enrolment. The supervised home-based physical activity program takes place during neoadjuvant chemotherapy (NACT). It combines aerobic and strengthening exercises. The primary endpoint is the proportion of patients reaching the international physical activity recommendations, i.e. 150 minutes of moderate-intensity activity per week at the end of NACT. The study started in April 2018 and seventy patients are expected to be recruited., Discussion: In the literature, the majority of studies on practice of physical activity in breast cancer focus on adjuvant chemotherapy or on the period after the end of treatment. To the best of our knowledge, the APACAN2 study is the first to evaluate a home-based physical activity program during neoadjuvant chemotherapy for HER2-positive breast cancer., Trial Registration Number: Clinicaltrials.gov: NCT02963363, registered on July 11, 2016. Identifier with the French National Agency for the Safety of Medicines and Health Products N°ID RCB 2016-A01344-47, registered in August 2016. Protocol: version 8, 24 February 2021., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ginzac, Bernadach, Molnar, Duclos, Thivat and Durando.)

Background: Despite improvements in the management of renal cell carcinomas (RCC) with the advent of immunotherapy, only a few patients respond to these treatments. Predictors of response to nivolumab are currently being investigated but are still lacking., Aim of the Study: To evaluate eosinophil levels and their variations during treatment as an accurate biomarker for outcome in metastatic RCC treated with nivolumab., Methods: A retrospective analysis was carried out for patients with metastatic RCC treated with nivolumab. Absolute eosinophil counts, their variation, and relative change were evaluated at six weeks. Relative eosinophil change was categorized in three groups (≥10%-decrease, no change, ≥10%-increase). Univariable and multivariable analyses were performed to determine whether eosinophils and their variations were prognostic markers for response at the first scan evaluation, progression-free survival, and overall survival., Results: Sixty-five patients aged on average 66 years, 68% men, and 77% with good or intermediate International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group were included. The median follow-up was 16.6 months. Median overall survival (OS) was not reached for good prognosis and was 22.5 and 6.5 months for intermediate and poor prognosis, respectively. An increase in eosinophils and relative eosinophil change at six weeks of nivolumab was associated with a good response to immunotherapy (p = 0.012 and p = 0.024 respectively). In the group of patients with a 10%-decrease in relative change, PFS reduced significantly compared to the other groups (p = 0.0044 with the 10%-increase group and p = 0.03 with the no-change group). This relative increase was independent of IMDC risks factors for better OS (HR = 3.3 [1.45-7.4]; p = 0.004). The eosinophil baseline level was not associated with response to treatment., Conclusion: Eosinophil levels and relative eosinophil change at 6 weeks might be good prognostic markers for response to nivolumab for metastatic RCC, and were associated with better PFS and OS., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Surgery is an important therapeutic option for brain metastases. Currently, postoperative stereotactic radiosurgery (SRT) leads to 6-month and 1-year local control estimated at 70 and 62% respectively. However, there is an increased risk of radio-necrosis and leptomeningeal relapse. Preoperative SRT might be an alternative, providing local control remains at least equivalent. It is an innovative concept that could enable the stereotactic benefits to be retained with advantages over post-operative SRT., Methods: STEP has been designed as a national, multicentre, open-label, prospective, non-randomized, phase-II trial. Seventeen patients are expected to be recruited in the study from 7 sites and they will be followed for 12 months. Patients with more than 4 distinct brain metastases, including one with a surgical indication, and an indication for SRT and surgery, are eligible for enrolment. The primary objective of the trial is to assess 6-month local control after preoperative SRT. The secondary objectives include the assessment of local control, radio-necrosis, overall survival, toxicities, leptomeningeal relapse, distant control, cognitive function, and quality of life. The experimental design is based on a Flemming plan., Discussion: There is very little data available in the literature on preoperative SRT: there have only been 3 American single or two-centre retrospective studies. STEP is the first prospective trial on preoperative SRT in Europe. Compared to postoperative stereotactic radiotherapy, preoperative stereotactic radiotherapy will enable reduction in the irradiated volume, leptomeningeal relapse and the total duration of the combined treatment (from 4 to 6 weeks to a few days)., Trial Registration Number: Clinicaltrials.gov: NCT04503772 , registered on August 07, 2020. Identifier with the French National Agency for the Safety of Medicines and Health Products (ANSM): N°ID RCB 2020-A00403-36, registered in February 2020., Protocol: version 4, 07 December 2020., (© 2021. The Author(s).)

Introduction: Triple negative breast cancer (TNBC) is highly heterogeneous, but still most of the patients are treated by the anthracycline/taxane-based neoadjuvant therapy (NACT). Tumor-infiltrating lymphocytes (TILs) are a strong predictive and prognostic biomarker in TNBC, however are not always available. Peripheral blood counts, which reflect the systemic inflammatory/immune status, are easier to obtain than TILs. We investigated whether baseline white cell or platelet counts, as well as, Neutrophil-to-Lymphocyte Ratio (NLR) or Platelet-to-Lymphocyte Ratio (PLR) could replace baseline TILs as predictive or prognostic biomarkers in a series of TNBC treated by standard NACT., Patients and Methods: One hundred twenty patients uniformly treated by FEC/taxane NACT in a tertiary cancer care center were retrospectively analyzed. The presence of pathological complete response (pCR: ypT0/Tis, ypN0) or the presence of pCR and/small residual disease (ypT0/Tis/T1ab, ypN0) were considered as good responses in data analysis. Baseline/pre-NACT blood count, NLR, PLR and TILs were evaluated as predictors of response, distant recurrence rate and distant recurrence-free survival (DRFS)., Results: TILs ≥30% and ≥1.5% were best predictors of pCR and distant recurrence risk, respectively (p = 0.007, p = 0.012). However, in this cohort, pCR status was not significantly associated with recurrence. Only the ensemble of patients with pCR and small residual disease had lower recurrence risk and longer survival DRFS (p = 0.042, p = 0.024, respectively) than the rest of the cohort (larger residual disease). The only parameter which could predict the pCR/small residual disease status was PLR: patients with values lower than 133.25 had significantly higher chance of reaching that status after NACT (p = 0.045). However, no direct correlation could be established between baseline PLR and metastatic recurrence. No correlation either was found between TIL and individual blood counts, or between TILs and NLR or PLR., Conclusion: In this cohort, TILs retained their pCR predictive value; however PLR was a better predictor of the ensemble of responses which had good outcome in terms of less distant recurrences or longer DRFS (pCR or small residual disease). Thus, baseline PLR is worth further, prospective investigation together with baseline TILs, as it might indicate a good TNBC response to NACT when TILs are unavailable., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lusho, Durando, Mouret-Reynier, Kossai, Lacrampe, Molnar, Penault-Llorca, Radosevic-Robin and Abrial.)

Purpose: Stereotactic radiotherapy (SRT) is the standard treatment for brain metastases of non-small-cell lung cancer (NSCLC) and melanoma, mostly in combination with immunotherapy. The objective was to retrospectively evaluate the influence of the time-lapse between immunotherapy and stereotactic radiotherapy on toxicity., Patients and Methods: From 2016 to 2019, 59 patients treated with SRT for 103 brain metastases of NSCLC (60%) and melanoma (40%) in combination with concomitant immunotherapy (≤30 days) were included. The prescribed dose was 20Gy/1f or 33Gy/3f at the isocentre and 14Gy or 23.1Gy (70%) respectively at the PTV envelope (PTV=GTV+2mm). The mean tumour diameter was 14mm (4-52mm). The immunotherapies used were anti-PD1 and anti-PDL1. The 103 metastases were classified into 3 groups according to the time-lapse between instatement of immunotherapy and instatement of SRT for the patient concerned: 7 (7%) in group A (≤7 days), 38 (37%) in group B (7 to 14 days) and 58 (56%) in group C (14 to 30 days)., Results: The mean follow-up was 10.1 months. The median overall survival was 11.5 months for NSCLC and 12.5 months for melanoma. The percentage of local control (LC) at one year was 65.1% (93.6% for NSCLC and 26.5% for melanoma). The time-lapse between immunotherapy and SRT was not a significant predictor of LC (P=0.86), while the histology was (P<0.001). The proportion of grade≥3 toxicities was 5.1%, and that of radionecrosis was 9.7% (among these patients, 80% were non-symptomatic): 0%, 13.1% and 8.6% for groups A, B and C respectively. The time-lapse between immunotherapy and SRT was not a significant predictor of toxicity. Only tumour volume was a significant predictive factor (P=0.03)., Conclusion: The time lapse between immunotherapy and SRT does not influence brain toxicity. The tumour volume remains the main factor., (Copyright © 2021. Published by Elsevier Masson SAS.)