Arnaud Beddok
email: arnaud.beddok@curie.fr

Valentin Calugaru

Ludovic De Marzi

Ph.D Pierre Graff

Jean-Luc Dumas

Ph.D Farid Goudjil

Rémi Dendale

Pierre Verrelle

Irène Buvat

Ph.D Gilles Créhange

Clinical and technical challenges of cancer reirradiation: Words of wisdom Short running title: Challenges in reirradiation

Since the development of new radiotherapy techniques that have improved healthy tissue sparing, reirradiation (reRT) has become possible. The selection of patients eligible for reRT is complex given that it can induce severe or even fatal side effects. The first step should therefore be to assess, in the context of multidisciplinary staff meeting, the patient's physical status, the presence of sequelae resulting from the first irradiation and the best treatment option available. ReRT can be performed either curatively or palliatively to treat a cancerrelated symptom that is detrimental to the patient's quality of life. The selected techniques for reRT should provide the best protection of healthy tissue. The construction of target volumes and the evaluation of constraints regarding the doses that can be used in this context have not yet been fully codified. These points raised in the literature suggest that randomized studies should be undertaken to answer pending questions.

Introduction

In the early 2000 s, following a meeting on reirradiation (reRT), the British Journal of Radiology published a commentary encouraging radiation oncologists to provide international guidelines for the management of patients likely to undergo reRT [START_REF] Jones | Retreatment of cancer after radical radiotherapy[END_REF]. Special workflow processes, such as the reRT special medical physics consult (ReRT-SMPC) process, have recently been introduced in an attempt to standardize the management of these patients [START_REF] Paradis | The special medical physics consult process for reirradiation patients[END_REF]. However, to our knowledge, there are still no specific guidelines for reRT management, despite the fact that many cohorts of patients have undergone reirradiation at various cancer sites (Supplementary data 1) [START_REF] Wells | The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Non-Randomized Studies in Meta-Analysis[END_REF][START_REF] Myrehaug | Reirradiation spine stereotactic body radiation therapy for spinal metastases: systematic review: International Stereotactic Radiosurgery Society practice guidelines[END_REF][START_REF] Nieder | Update of human spinal cord reirradiation tolerance based on additional data from 38 patients[END_REF][START_REF] Kawashiro | Reirradiation of spinal metastases with intensity-modulated radiation therapy: an analysis of 23 patients[END_REF][START_REF] Loi | Stereotactic reirradiation for local failure of brain metastases following previous radiosurgery: Systematic review and metaanalysis[END_REF][START_REF] Straube | Reduced volume SIB-IMRT/IGRT to head and neck cancer in elderly and frail patients: outcome and toxicity[END_REF][START_REF] Kazmi | Re-irradiation for recurrent glioblastoma (GBM): a systematic review and meta-analysis[END_REF][START_REF] Montagne | Second conservative treatment for second ipsilateral breast tumor event: A systematic review of the different re-irradiation techniques[END_REF][START_REF] Boimel | Proton beam reirradiation for locally recurrent pancreatic adenocarcinoma[END_REF][START_REF] Mcduff | Liver reirradiation for patients with hepatocellular carcinoma and liver metastasis[END_REF][START_REF] Berman | Proton reirradiation of recurrent rectal cancer: dosimetric comparison, toxicities, and preliminary outcomes[END_REF][START_REF] Fernandes | A prospective study of proton beam reirradiation for esophageal cancer[END_REF][START_REF] Wild | Re-irradiation with stereotactic body radiation therapy as a novel treatment option for isolated local recurrence of pancreatic cancer after multimodality therapy: experience from two institutions[END_REF][START_REF] Owens | External beam re-irradiation in rectal cancer[END_REF][START_REF] Haque | Reirradiation to the abdomen for gastrointestinal malignancies[END_REF], Svajdova et al, Rulach et al., 2018[START_REF] Nicosia | What is the role of reirradiation in the management of locoregionally relapsed non small-cell lung cancer?[END_REF][START_REF] Tsang | Re-irradiation for paediatric tumours[END_REF][START_REF] Baty | Salvage reirradiation for local prostate cancer recurrence after radiation therapy. For who? When? How?[END_REF][START_REF] Sadozye | Re-irradiation in gynaecological malignancies: a review[END_REF][START_REF] Straube | A second course of radiotherapy in patients with recurrent malignant gliomas: clinical data on re-irradiation, prognostic factors, and usefulness of digital biomarkers[END_REF]). Yet, the vast majority of these studies did not include data from simultaneous control groups with primary irradiation at the same site.

Given the risk of life-threatening complications after reRT (or at least those that significantly affect the quality of life), patients with locoregional recurrences are more generally treated with surgery or systemic treatments alone, either chemotherapy or, increasingly, immunotherapy. However, the risk of second recurrence and toxicity after these treatments remains high, especially for head and neck cancers [START_REF] Shetty | Salvage surgery in recurrent oral squamous cell carcinoma[END_REF], and re-irradiation in this context could be a useful additional therapeutic modality. This study aimed to review the literature to identify the clinical and technical challenges of reRT, to propose criteria for patient selection, technical choice and target volume delineation, and organ-at-risk constraint definition.

Clinical challenges

Patient selection: Risk/benefit balance

The indication for reRT must weigh the expected efficacy of this salvage treatment against the risk of acute or late toxicity that could be fatal or impair quality of life, keeping in mind the adage "primum non nocere". The outcomes and toxicities experienced by patients reirradiated for curative purposes differ enormously depending on the cancer site reirradiated (Table 1). In pelvic cancer, severe toxicities of reRT can include fistula, bowel obstruction, abscess, general tissue necrosis, gastrointestinal bleeding, urinary strictures, skin ulcers, and pain [START_REF] Kamran | To radiate or not to radiate-the challenges of Pelvic Reirradiation[END_REF]. Retrospective studies on rectal cancer indicated that toxicity was notable, with 13 out of 50 (26%) patients experiencing grade 3 or 4 late toxicities. In lung cancer, severe pulmonary toxicity was observed in up to 21% of patients. This was usually radiation pneumonitis requiring oxygen or even respiratory support [START_REF] De Ruysscher | High-dose re-irradiation following radical radiotherapy for non-small-cell lung cancer[END_REF]. In locally recurrent gliomas, reRT may lead to a higher incidence and greater severity of adverse events, such as necrosis, cognitive disturbance and secondary malignancies, especially in the youngest patients. In a recent study, Liu et al. have prospectively compared endoscopic surgery and reRT for the treatment of resectable locally recurrent nasopharyngeal carcinoma. Twenty of the 101 patients who underwent reRT died due to late toxic effects specific to radio-therapy [START_REF] Liu | Endoscopic surgery compared with intensity-modulated radiotherapy in resectable locally recurrent nasopharyngeal carcinoma: a multicentre, open-label, randomised, controlled, phase 3 trial[END_REF]. Moreover, Tanvetyanon et al. studied the prognostic factors for survival after salvage reRT in 109 patients with HNC [START_REF] Tanvetyanon | Prognostic factors for survival after salvage reirradiation of head and neck cancer[END_REF]. They highlighted the profound nega-tive effect of co-morbidity and organ dysfunction on survival. In this series, acute and late toxicities of grade 3 or higher occurred in 45 pa-tients (43.7%) and 49 patients (47.5%), respectively. Nonetheless, tox-icities observed after reirradiation are not necessarily greater than those observed after a first irradiation. For example, Arthur et al. showed that reirradiation of patients with recurrent breast cancer did not result in a very high rate of radiation-induced fibrosis [START_REF] Arthur | Effectiveness of breast-conserving surgery and 3-dimensional conformal partial breast reirradiation for recurrence of breast cancer in the ipsilateral breast[END_REF]. Moreover, salvage surgery can sometimes induce more complications than reRT. For prostate carcinoma, a recent meta-analysis of 150 studies showed that reRT with high-dose-rate (HDR) brachytherapy, low-dose-rate (LDR) brachytherapy, or stereotactic body RT (SBRT) resulted in significantly lower rates of severe genitourinary toxicity than did salvage radical prostatectomy, and rates of severe gastrointestinal toxicity were significantly lower following HDR brachytherapy than following surgery [START_REF] Valle | A systematic review and meta-analysis of local salvage therapies after radiotherapy for prostate cancer (MASTER)[END_REF]. In addition, postoperative com-plications are more frequent and more severe when surgery is performed in a previously irradiated field [START_REF] Locatello | Estimating the risks and benefits before salvage surgery for recurrent head and neck squamous cell carcinoma[END_REF].

Therefore, all patients being considered for curative reirradiation (reRT) must be evaluated by a multidisciplinary team, including at least surgical oncologists, medical oncologists, radiation oncologists, pa-thologists, and radiologists specializing in oncology. If the patient has no surgical history, regardless of the time between initial irradiation and recurrence, salvage surgery should always be the first salvage option to be discussed in the light of the likelihood of harmful sequelae [START_REF] Goodwin | Salvage surgery for patients with recurrent squamous cell carcinoma of the upper aerodigestive tract: when do the ends justify the means?[END_REF]. If the histological and immunohistochemical analyses of the surgical specimen show unfavorable characteristics, such as incomplete resection, peritumoral vascular emboli, and lymph node invasion with capsular rupture, postoperative reRT and/or systemic therapy, including immunotherapy [START_REF] Plavc | Challenges in combining immunotherapy with radiotherapy in recurrent/metastatic head and neck cancer[END_REF], should be considered, especially for head and neck cancers (HNC) [START_REF] Foster | Is it worth It? Consequences of definitive head and neck reirradiation[END_REF]. For brain tumors, a neurosurgical evaluation is always essential, as surgery may increase survival [START_REF] Azoulay | Benefit of re-operation and salvage therapies for recurrent glioblastoma multiforme: results from a single institution[END_REF]. Surgery would also allow a histological evaluation for progressing glioblastoma. Systemic treatment must be included in the salvage treatment to enhance the effect of the RT or to take into account a possible although yet undetected metastatic recurrence. However, caution should again guide the choice of treatment. A recent study showed that unexpected lethal lung events may occur in patients receiving systemic therapy following thoracic re-irradiation [START_REF] Yang | Clinical outcomes and toxicity predictors of thoracic re-irradiation for locoregionally recurrent lung cancer[END_REF].

Time is a significant factor in reRT. Cancer-related life expectancy may be longer without reRT, which carries the risk of irreversible sequelae such as respiratory insufficiency, myelitis, necrosis or fistula, even though, in the short term, reRT may alleviate symptoms and impede local tumor progression. The likelihood of a high-risk of radiation-related cancers should be discussed only in patients with long life-expectancy even after local relapse.

Concerning the interval between RT courses, there is no proven correlation with reRT toxicities (see below). Some data suggested that reRT to the prostate area within 4.5 years of prior RT could be associated with a higher risk of grade 4 toxicity [START_REF] Nguyen | Magnetic resonance image-guided salvage brachytherapy after radiation in select men who initially presented with favorablerisk prostate cancer: a prospective phase 2 study[END_REF]. Conversely, if the progression-free interval is shortened, the reRT should be maximally aggressive [START_REF] Mcavoy | Definitive reirradiation for locoregionally recurrent non-small cell lung cancer with proton beam therapy or intensity modulated radiation therapy: predictors of high-grade toxicity and survival outcomes[END_REF]. Early local recurrence may be a sign of underdosing during the first irradiation, for example, after prostate brachytherapy [START_REF] Crehange | Cold spot mapping inferred from MRI at time of failure predicts biopsy-proven local failure after permanent seed brachytherapy in prostate cancer patients: implications for focal salvage brachytherapy[END_REF], or a sign of radioresistance. In the latter case, the reRT could allow to consecutively increase the dose at the target volume and therefore potentially improve the local control. In this perspective, for external beam RT, it could be useful to use other particles than those used in the first irradiation, such as proton versus photon, or to choose another dose rate (see below the section "techniques for reRT").

The selection of patients eligible for reRT therefore remains chal-lenging [START_REF] Shi | Investigating the effect of reirradiation or systemic therapy in patients with glioblastoma after tumor progression: a secondary analysis of nrg oncology/radiation therapy oncology group trial 0525[END_REF]. The assessment by the clinician in charge of reRT and the multidisciplinary approach are essential before clear guidelines can be drawn up from randomized trials.

Several authors have proposed nomograms and algorithms to help radiation oncologists choose the best option for patients with local recurrence after a first irradiation, particularly in HNC [START_REF] Tanvetyanon | Prognostic factors for survival after salvage reirradiation of head and neck cancer[END_REF][START_REF] Strojan | Recurrent and second primary squamous cell carcinoma of the head and neck: When and how to reirradiate[END_REF][START_REF] Boustani | Long-term outcomes and safety after reirradiation in locally recurrent nasopharyngeal carcinoma in a non-endemic area[END_REF]. The main prognostic factors included in these nomograms were: comorbidity, organ dysfunction, isolated neck recurrence, location of the recurrence, tumor bulk before reRT, dose of reRT and time since the first irradiation. More recently and more generally, Do rr et al. suggested that a decision on reRT should systematically take into account: [START_REF] Jones | Retreatment of cancer after radical radiotherapy[END_REF] the location of the recurrence (or second tumor) in relation to the primary tumor, [START_REF] Paradis | The special medical physics consult process for reirradiation patients[END_REF] the dosimetric parameters of the initial radiation therapy (RT), [START_REF] Wells | The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Non-Randomized Studies in Meta-Analysis[END_REF] the use of concomitant treatment, such as surgery, chemotherapy and targeted therapy for the first tumor and for recurrence, and [START_REF] Myrehaug | Reirradiation spine stereotactic body radiation therapy for spinal metastases: systematic review: International Stereotactic Radiosurgery Society practice guidelines[END_REF] the time since treatment of the first tumor (Do rr and Gabry ś, 2018). Machine learning-based models for predicting and classifying RT-induced com-plications, or for rapid dose predictions, are also evolving and could play an important role in the management of reRT [START_REF] Isaksson | Machine learning-based models for prediction of toxicity outcomes in radiotherapy[END_REF].

Techniques for reirradiation

Historically, reRT was limited to simple techniques, such as three-dimensional conformal radiation therapy (3D-CRT), and palliative doses. These led to a limited improvement in longterm survival, for instance, in locally recurrent non-small cell lung carcinoma (NSCLC) [START_REF] Green | Lung cancer: retreatment of local recurrence after definitive irradiation[END_REF]. Technological innovations over the past 20 years have made high-dose re-irradiation a possible treatment option. Indeed, as previously mentioned, healthy tissues are far better protected, especially in reRT. The technique used should limit as much as possible doses to organs-at-risk (OAR). Table 1 summarizes the main results of recent highlevel prospective studies using different reRT techniques at different sites.

Intensity-modulated radiation therapy (IMRT)

IMRT with IGRT was the first step in improving OAR sparing [START_REF] Chen | Prospective trial of high-dose reirradiation using daily image guidance with intensity-modulated radiotherapy for recurrent and second primary head-and-neck cancer[END_REF]. Nevertheless, the incidence of severe late toxicity remains high with IMRT in reRT. Takiar et al. retrospectively studied outcomes and toxicities in 201 patients reirradiated for HNC, and reported 2-year and 5-year grade 3 toxicity in 32% and 48% of the patients, respectively [START_REF] Takiar | Reirradiation of head and neck cancers with intensity modulated radiation therapy: outcomes and analyses[END_REF]. Similarly, in rectal carcinoma, Tao et al. recently evaluated outcomes and toxicity in 101 patients treated with hyper-fractionated pelvic reRT with IMRT. They found 34% of grade 3-4 late toxicity at 3 years [START_REF] Tao | Hyperfractionated accelerated reirradiation for rectal cancer: an analysis of outcomes toxicity[END_REF].

Proton therapy

PT, as compared with photon therapy, has the potential to optimize locoregional control while significantly reducing toxicity. The physical properties of protons allow energy to be deposited at a specific depth, called a Bragg peak, with a rapid drop in energy beyond this point (Beddok et al., 2020). These physical properties of protons are particu-larly important in reRT, because they allow definitive, rather than palliative doses of reRT [START_REF] Verma | Systematic assessment of clinical outcomes and toxicities of proton radiotherapy for reirradiation[END_REF].

Retrospective [START_REF] Mcavoy | Definitive reirradiation for locoregionally recurrent non-small cell lung cancer with proton beam therapy or intensity modulated radiation therapy: predictors of high-grade toxicity and survival outcomes[END_REF] and prospective [START_REF] Chao | Multi-institutional prospective study of reirradiation with proton beam radiotherapy for locoregionally recurrent non-small cell lung cancer[END_REF] data have also emerged showing an advantage of protons in reRT, with some severe toxicities but at a fairly low incidence. For instance, Chao et al. reported the results of 57 patients treated at three proton centers for recurrent NSCLC in or near their prior radiation field. Overall, grade 3 or higher acute and/or late toxicity developed in 24 (42%) patients, acute toxicity developed in 22 (39%) patients, and late toxicity developed in seven (12%) patients [START_REF] Chao | Multi-institutional prospective study of reirradiation with proton beam radiotherapy for locoregionally recurrent non-small cell lung cancer[END_REF]. PT can also be an optimal choice for the treatment of HNC, and particularly nasopharyngeal and sinonasal cancer, as intensity-modulated proton therapy (IMPT) has proved to be superior to intensity-modulated radiation therapy (IMRT) from a bio-logical and physical standpoint. PT also shows improved sparing (especially in terms of the integral dose) of critical healthy structures at the skull base (which are numerous, e.g., optic nerves, optic chiasm, pituitary gland, brainstem, temporal lobes, cochlea, cranial nerves, pterygoid muscles...) [START_REF] Blanchard | Proton therapy for head and neck cancers[END_REF]. Such sparing is particu-larly important in the reRT setting [START_REF] Phan | Reirradiation of head and neck cancers with proton therapy: outcomes and analyses[END_REF]. PT can be useful for rectal cancer recurrence, particularly in the case of inoperable iso-lated local recurrence in the presacral region, to better spare the bowel and bladder without having to sacrifice the hip joints and pelvic bones (Simone et al., 2020). PT can help reduce acute and late toxicities in reRT for gastrointestinal malignancies [START_REF] Verma | Clinical outcomes and toxicities of proton radiotherapy for gastrointestinal neoplasms: a systematic review[END_REF], and can be very useful in reRT for esophageal [START_REF] Decesaris | Assessing outcomes of patients treated with re-irradiation utilizing proton pencil-beam scanning for primary or recurrent malignancies of the esophagus and gastroesophageal junction[END_REF], pancreatic [START_REF] Boimel | Proton beam reirradiation for locally recurrent pancreatic adenocarcinoma[END_REF], anal, and rectal recurrences [START_REF] Moningi | Definitive hyperfractionated, accelerated proton reirradiation for patients with pelvic malignancies[END_REF].

Stereotactic body radiation therapy (SBRT)

SBRT makes use of extreme hypofractionation, up to a session of 20 Gy in the brain, and allows a very steep dose gradient-by definition. It delivers at least 50% of the prescribed dose 2 cm around the target volume [START_REF] Benedict | Stereotactic body radiation therapy: the report of AAPM Task Group 101[END_REF]. It is therefore a technique of choice for reRT, especially for the brain [START_REF] Sanders | Gamma Knife radiosurgery: scenarios and support for re-irradiation[END_REF][START_REF] Møller | Costa toxicity and efficacy of re-irradiation of high-grade glioma in a phase I dose-and volume escalation trial[END_REF], lung [START_REF] Milano | Review of thoracic reirradiation with stereotactic body radiation therapy: A focus on toxicity risks[END_REF], prostate [START_REF] Jereczek-Fossa | Salvage stereotactic body radiotherapy (SBRT) for intraprostatic relapse after prostate cancer radiotherapy: An ESTRO ACROP Delphi consensus[END_REF], spinal metastases [START_REF] Myrehaug | Reirradiation spine stereotactic body radiation therapy for spinal metastases: systematic review: International Stereotactic Radiosurgery Society practice guidelines[END_REF][START_REF] Garg | Prospective evaluation of spinal reirradiation by using stereotactic body radiation therapy[END_REF], head and neck cancer [START_REF] Vargo | A prospective phase 2 trial of reirradiation with stereotactic body radiation therapy plus cetuximab in patients with previously irradiated recurrent squamous cell carcinoma of the head and neck[END_REF] and pancreatic carcinomas [START_REF] Wild | Re-irradiation with stereotactic body radiation therapy as a novel treatment option for isolated local recurrence of pancreatic cancer after multimodality therapy: experience from two institutions[END_REF]. This technique again poses the problem of the risk/benefit ratio: a biologically higher dose par fraction is disadvantageous when considering OAR, especially in patients with a greater potential for late lethal complications. However, if the primary tumor has already demonstrated resilience to the initial course of RT, SBRT allows bio-logical doses much higher than IMRT.

Brachytherapy

Brachytherapy allows the desired dose to be very precisely delivered to the chosen location, because it involves putting a radioactive element in contact with the target. This technique therefore appears very useful in the setting of reRT, particularly in prostate cancer reRT, as a very high biological dose can be delivered to the area where the recurrence is located [START_REF] Murgic | Focal salvage high dose-rate brachytherapy for locally recurrent prostate cancer after primary radiation therapy failure: results from a prospective clinical trial[END_REF][START_REF] Crook | A prospective phase 2 trial of transperineal ultrasound-guided brachytherapy for locally recurrent prostate cancer after external beam radiation therapy (nrg oncology/RTOG-0526)[END_REF]. Brachytherapy is particularly useful in the management of local recurrence of breast cancer. A second breast conserving treatment could be possible if sur-gery is followed by re-irradiation using multi-catheter pulse dose rate (PDR) BT. The reported toxicities were mild [START_REF] Montagne | Second conservative treatment for second ipsilateral breast tumor event: A systematic review of the different re-irradiation techniques[END_REF][START_REF] Kauer-Dorner | Partial breast irradiation for locally recurrent breast cancer within a second breast conserving treatment: alternative to mastectomy? results from a prospective trial[END_REF].

It should be noted that in case of salvage BT after a first BT, it would be useful to use a different source or dose rate from those used the first time.

Technical challenges

Target volume definition

No consensus has been reached regarding the target volume definition definition in the context of reRT. Target volume definition thus varies considerably and depends on the target organ irradiated and the center in which the patient is treated. To limit the risk of radiationinduced toxicity, the target volume should nevertheless be as small as possible. This is particularly true if the target is adjacent to OAR, with a risk of life-threatening acute toxicity in patients with a short life expectancy, or late sequelae in other patients whose quality of life may be irreversibly impaired. Therefore, contrary to the usual approach for a first irradia-tion, in reRT, the target volume is often limited to the macroscopically visible part of the tumor (the so-called gross tumor volume [GTV]). Delineation of this GTV for local recurrence after prior RT can be particularly challenging, considering the often-significant degree of radiofibrosis in this zone. Multimodal imaging, especially dual energy CT [START_REF] Ng | Comparison of tumor delineation using dual energy computed tomography versus magnetic resonance imaging in head and neck cancer re-irradiation cases[END_REF], MRI and PET/CT, can significantly improve target delineation and should be used in this case to help define the GTV (Fig. 1). For instance, in their prospective study in glioma, Miwa et al. planned the reRT using 11 C-methionine positron emission tomography (MET-PET)/computed tomography (CT)/magnetic resonance imaging (MRI) fusion. The region of increased amino acid tracer uptake on MET-PET was defined as the GTV [START_REF] Miwa | Re-irradiation of recurrent glioblastoma multiforme using 11C-methionine PET/CT/MRI image fusion for hypofractionated stereotactic radiotherapy by intensity modulated radiation therapy[END_REF]. In the near future, radiomics for reRT will certainly also help to delineate the GTV (Akram et al., 2020). In addition, the GTV should not include doubtful structures of suspected malignancy. This is even more true than in the case of a first irradiation, and confirmation by cytological sampling or biopsy should not be delayed. For instance, in NSCLC, the patient could be referred to interventional pneumology for endobronchial ultrasound to resample the mediastinal and hilar lymph nodes, after which only those lymph nodes that have been found to be pathologically implicated should be included in the GTV. In this context, it is also suggested to work closely with the surgeon to define the GTV. In addition, the margin that takes into account microscopic invasion (clinical target volume [CTV]) should be very small, as described by Popovtzer et al. in HNC (Popovtzer et al., 2009). Similarly, modern IGRT techniques, such as daily CBCT or even better, MR-LINAC [START_REF] Doty | Stereotactic MR-guided online adaptive radiotherapy reirradiation (SMART reRT) for locally recurrent pancreatic adenocarcinoma: a case report[END_REF], can be used to reduce as much as possible the margin that usually takes into account set-up uncertainties (the provisional target volume [PTV]) [START_REF] Intven | Online adaptive MRguided radiotherapy for rectal cancer; feasibility of the workflow on a 1.5T MR-linac: clinical implementation and initial experience[END_REF].

Organ-at-risk sparing

Currently, there are no international recommendations regarding dose constraints to organs at risk (OAR) in reRT. However, it can be expected that reRT to an OAR that has already received a high or low dose in the first irradiation can induce high-grade toxicities. The radiation-induced toxicities of OAR with serial functional subunits (FSU) (i.e.: such as arteries, spinal cord, gastrointestinal tract etc....) are potentially very different from those in parallel FSU (liver, kidneys, lung etc. ...).

OAR organized in serial FSU

Very high cumulative doses could be catastrophic in OAR organized in serial FSU [START_REF] Crane | Balancing fractionation and advanced technology in consideration of reirradiation[END_REF] (2.6%) patients receiving salvage reRT for HNC, of which 76% were fatal [START_REF] Mcdonald | Risk of carotid blowout after reirradiation of the head and neck: a systematic review[END_REF]. No significant difference was observed between patients with or without salvage surgery prior to reRT or between those with or without con-current chemotherapy during reRT. Carotid blowout is also frequent in patients reirradiated with SBRT for relapsed HNC [START_REF] Yamazaki | Reirradiation using robotic image-guided stereotactic radiotherapy of recurrent head and neck cancer[END_REF]. The risk of carotid rupture is higher if the tumor has invaded the vessel, if there is ulceration, or if the patient has had neck lymph node dissection [START_REF] Yamazaki | Frequency, outcome and prognostic factors of carotid blowout syndrome after hypofractionated re-irradiation of head and neck cancer using CyberKnife: a multi-institutional study[END_REF]. As yet, there is no consensus on dose constraints for large vessels (e.g. carotid and aorta) in this specific context of reRT. Nevertheless, a cumulative dose greater than 120

Gy is related to a significant increase in the risk of vessel blowout [START_REF] Evans | Aortic dose constraints when reirradiating thoracic tumors[END_REF][START_REF] Dionisi | Organs at risk's tolerance and dose limits for head and neck cancer re-irradiation: a literature review[END_REF][START_REF] Isaksson | Machine learning-based models for prediction of toxicity outcomes in radiotherapy[END_REF]. The time between the first RT and reRT (30 months [1-185]) was not associated with the risk of serious toxicity induced by reRT.

One of the main issues in reRT, especially when the local recurrence is close to the spinal cord, is the risk of radiation myelitis. An extensive study of spinal reRT in rhesus monkeys showed that the risk of radiation myelopathy decreased over time, suggesting a forgetting factor at least for this organ, and nervous tissue in general [START_REF] Ang | Extent and kinetics of recovery of occult spinal cord injury[END_REF]. However, caution should be exercised in the transfer of these experimental data to humans, as the duration of follow-up in these experiments was limited to 2-2.5 years after reRT, whereas cases of human myelopathy sometimes occur after a longer latency. Increasing time between the initial irradi-ation and reRT is probably an important factor, although there is currently no consensus on a "time-dose factor" [START_REF] Nieder | Update of human spinal cord reirradiation tolerance based on additional data from 38 patients[END_REF]. Moreover, the kinetics of brachial plexus recovery seems to be similar to that of the spinal cord. In retrospective studies, the one-year freedom from brachial plexus-related neuropathy rates were 67% and 86% for patients who were treated with a maximum cumulative dose greater than and less than 95.0 Gy, respectively. The one-year complication-free rates were 66% and 87% for patients re-irradiated within two years of initial treatment, respectively [START_REF] Chen | Tolerance of the brachial plexus to high-dose reirradiation[END_REF].

A high cumulative dose could also induce many gastrointestinal tract complications including perforation, fistula, stricture, and adhesions, particularly when the reRT is administered near luminal structures, given the low recovery of bowel after multiple courses of RT. For the esophagus, previous dose escalation studies and limited reRT data sug-gest that the fistula threshold occurs at approximately 85-90 Gy of cu-mulative equivalent dose (EQD2) [START_REF] Meijneke | Reirradiation and stereotactic radiotherapy for tumors in the lung: dose summation and toxicity[END_REF].

OAR organized in parallel FSU

Although potentially less affected by a new irradiation than organs arranged in serial FSU, organs arranged in parallel FSU must also be spared during this second phase, in particular, to avoid organ in-sufficiencies. While De Ruysschser et al. did not provide lung dose constraints, the combined cumulative lung V20 < 40% should be limited, as recommended, to reduce the risk of grade 3 or higher toxicity [START_REF] Fischer-Valuck | Challenges in re-irradiation in the thorax: managing patients with locally recurrent non-small cell lung cancer[END_REF].

Moreover, there are few data on the tolerance of the liver to repeated doses of radiation Massachusetts General Hospital reported their results for 49 patients who were re-irradiated for liver lesion. Reirradiation appeared to be feasible, with only 4.1% of patients experiencing radiation-induced liver toxicity. They proposed to limit the volume of unirradiated liver to at least 800 cc under 15 Gy, a constraint similar to that used in primary liver radiotherapy [START_REF] Mcduff | Liver reirradiation for patients with hepatocellular carcinoma and liver metastasis[END_REF]. As for large vessels, the time between the first RT and reRT (9 months [START_REF] Straube | Reduced volume SIB-IMRT/IGRT to head and neck cancer in elderly and frail patients: outcome and toxicity[END_REF][START_REF] Kazmi | Re-irradiation for recurrent glioblastoma (GBM): a systematic review and meta-analysis[END_REF][START_REF] Montagne | Second conservative treatment for second ipsilateral breast tumor event: A systematic review of the different re-irradiation techniques[END_REF][START_REF] Boimel | Proton beam reirradiation for locally recurrent pancreatic adenocarcinoma[END_REF][START_REF] Mcduff | Liver reirradiation for patients with hepatocellular carcinoma and liver metastasis[END_REF][START_REF] Berman | Proton reirradiation of recurrent rectal cancer: dosimetric comparison, toxicities, and preliminary outcomes[END_REF][START_REF] Fernandes | A prospective study of proton beam reirradiation for esophageal cancer[END_REF][START_REF] Wild | Re-irradiation with stereotactic body radiation therapy as a novel treatment option for isolated local recurrence of pancreatic cancer after multimodality therapy: experience from two institutions[END_REF]) was not associated with the risk of serious RT-induced toxicity. A protocol using indocyanine green would make it possible to assess baseline liver function to determine dose prescription [START_REF] Suresh | Using indocyanine green extraction to predict liver function after stereotactic body radiation therapy for hepatocellular carcinoma[END_REF].

In this case, liver dose constraints can follow the model that titrates the mean liver dose (MLD) to indocyanine green, adjusted for the risk of decompensation. For patients off trial, constraints could be V19Gy < 700 cc and MLD < 15 Gy [START_REF] Benedict | Stereotactic body radiation therapy: the report of AAPM Task Group 101[END_REF]. For reRT cases, the same constraints can be used for a plan sum, considering the prior liver dose but with a 50% discount, assuming repair in the interval between treatment courses [START_REF] Owen | Challenges in reirradiation of intrahepatic tumors[END_REF].

Functional imaging of normal tissues might be an elegant approach to optimizing the beam arrangement in reRT [START_REF] De Bari | Should we include SPECT lung perfusion in radiotherapy treatment plans of thoracic targets? Evidences from the literature[END_REF].

Finally, no internationally defined guidelines are available for organ dose limits in reRT.

Nevertheless, the American Radium Society and American College of Radiology recently proposed composite dose con-straints in 2 Gy equivalent doses: esophagus, V60 < 40% and DMax < 100-110 Gy; lung, V20 < 40%; heart, V40 < 50%; aorta/great ves-sels, DMax < 120 Gy; trachea and proximal bronchial tree, DMax < 110 Gy; spinal cord, DMax < 57 Gy; and brachial plexus, DMax < 85 Gy (Simone et al., 2020). We summarized in Table 2 the main OAR constraints proposed in the different published studies.

Dose and fractionation

In view of what has been presented in the previous sections, one of the most important aspects of the initial evaluation of the patient for whom reRT is being considered would be to determine the dose that could be safely administered on the basis of the first irradiation. This requires an assessment of normal tissue tolerance doses for OARs, as well as of the potential consequences of late complications that may arise. This should be the basis for a fractionation choice to obtain an optimal bioequivalent dose. For instance, in brain tumor recurrences, no stan-dard of care fractionation scheme exists, but some possibilities for reRT could be 7.7-20 Gy in one fraction (SBRT), or a hypofractionated regimen with doses ranging from 18 Gy to 37.5 Gy in 3-15 fractions [START_REF] Shanker | Re-irradiation for recurrent high-grade gliomas: a systematic review and analysis of treatment technique with respect to survival and risk of radionecrosis[END_REF]. Fractionation must be considered with regard to the risk of cerebral radionecrosis. Individual radiosensitivity should also be considered in the decision to treat using reRT. Indeed, except for certain known syndromes that induce very high radiosensitivity and a high risk of serious radiation-induced toxicities (so called "over re-actors") [START_REF] Bentzen | Potential clinical impact of normal-tissue intrinsic radiosensitivity testing[END_REF], such as Fanconi's anemia syndrome (Beddok et al., 2020), each patient treated with radiation has individual radio-sensitivity.

Several tests exist and could be useful to determine radio-sensitivity before reRT. However, none of them are currently accepted as a reference test [START_REF] Ferlazzo | Functional assays for individual radiosensitivity: a critical review[END_REF]. A history of severe acute or late radiation-induced toxicities during a first irradiation remains, for the moment, the best objective endpoint in the decision to reirradiate, and in the choice of the dose and the fractionation of reRT [START_REF] Cosset | R éirradiations: quels crit`eres d écisionnels ?[END_REF]. Conversely, it should also be kept in mind that an early or late recurrence in the irradiated field results in radioresistance of the tumor (on the somatic level) and/or the patient (on the constitutional level). The dose used for curative reRT should therefore be at least as high (in biological equivalent if the particle or fractionation is changed) as the dose used for the first irradiation. For example, in HNC, the dose used in the first reRT protocols was 60 Gy (lower than the dose prescribed for the first exclusive irradiation) [START_REF] De Crevoisier | Full dose reirradiation combined with chemotherapy after salvage surgery in head and neck carcinoma[END_REF]. Recent studies have shown that increasing the dose beyond 66 Gy improved outcomes [START_REF] Caudell | Volume, dose, and fractionation considerations for IMRT-based reirradiation in head and neck cancer: a multiinstitution analysis[END_REF].

Conclusion

In conclusion, innovative techniques such as PT, SBRT or HDR-brachytherapy, which allow better OAR sparing than do more conven-tional techniques, are placing reRT back in the forefront. The selection of patients remains the critical point. The patient's general condition (WHO performance status) and the sequelae of the previous irradiation should always be taken into account. Decision-making on reRT based solely on dosimetric criteria is not an option, and a consultation with a radiation oncologist and a multidisciplinary approach should always be planned as soon as this therapeutic option is considered. Recommendations on target volume delineation and OAR dose constraints also remain unclear, and the use of IGRT and other techniques allowing PTV margin reduction should always be considered. This work emphasizes the urgent need for randomized clinical trials in this setting (Case Comprehensive Cancer Center, 2020).

Akram, F., Koh, P.E., Wang, F., et al., 2020. Exploring MRI based radiomics analysis of intratumoral spatial heterogeneity in locally advanced nasopharyngeal carcinoma treated with intensity modulated radiotherapy. PLoS One 15. Alterio, D., Turturici, I., Volpe, S., Ferrari, A., Russell-Edu, S.W., Vischioni, B., Mardighian, D., Preda, L., Gandini, S., Marvaso, G., Augugliaro, M., Durante, S., Arculeo, S., Patti, F., Boccuzzi, Table 1 Figure 1 Metabolic imaging for target volume definition and treatment planning in reirradiation. This figure shows the example of a patient reirradiated by proton therapy at the Institut Curie for a local recurrence of oropharyngeal cancer. To define the target volume, a registration was performed between the dosimetry scan and the PET scan showing the recurrence. The isodoses (green line: 5 Gy, yellow line: 20 Gy, orange line: 40 Gy, and pink line: 60 Gy) show that protons allow to considerably limit the irradiation of healthy tissues by focusing on the irradiation of the target volume (red line) defined using the PET hypermetabolism.

  (Table 2). McDonald et al. reported 41 cases of carotid blowout (CB) among 1554

Table 2


Mireille Babineau

Anne Christophe

SENSITIVITY TO GRAMMATICAL DEPENDENCIES 1 Preverbal infants' sensitivity to grammatical dependencies

Keywords: infants, language acquisition, syntax, word categories, distributional learning

During their first months of life, infants can already distinguish function words (e.g., pronouns, determiners) from content words (e.g., verbs, nouns). Little research has explored preverbal infants' sensitivity to the relationships between these two-word categories. This preregistered study examines whether French-learning 8-and 11-month-olds track the grammatical dependencies between determiners and nouns and pronouns and verbs. Using the Visual Fixation Procedure, infants were presented with lists containing either grammatical (e.g., tu manges "you eat", des biberons "some bottles") or ungrammatical (e.g., des manges "some eat', tu biberons "you bottle") phrases. In Experiment 1 (N=59), the lists involved common nouns and verbs, while in Experiment 2 (N=28), only common verbs were used. Elevenmonth-olds showed a clear preference for correct over incorrect co-occurrences in both experiments, while 8-month-olds showed a trend in the same direction. These results suggest that before their first birthday, infants' storage and access of words and word sequences is sufficiently sophisticated to include the means to track categorical dependencies. This early sensitivity to co-occurrence patterns may be greatly beneficial for constraining lexical access and later on for learning novel words' syntactic and semantic properties.

Introduction

The early lexicon does not lack organization. Even before their first birthday, infants have gained substantial knowledge about word categories. They can distinguish function words (e.g., determiners, pronouns) from content words (e.g., nouns, verbs) during their first months of life based on their acoustic, distributional, and phonological characteristics (e.g., [START_REF] Hochmann | Word frequency as a cue for identifying function words in infancy[END_REF][START_REF] Marino | Word frequency is a cue to lexical category for 8-month-old infants[END_REF][START_REF] Shi | Phonological and acoustic bases for earliest grammatical category assignment: a cross-linguistic perspective[END_REF][START_REF] Shi | Six-Month-Old Infants' Preference for Lexical Words[END_REF][START_REF] Shi | Newborn infants' sensitivity to perceptual cues to lexical and grammatical words[END_REF]. The distributional patterns of these word categories even guide infants' mapping strategies: they tend to associate referents (meaning) to infrequent syllables rather than to frequent syllables [START_REF] Hochmann | Word frequency as a cue for identifying function words in infancy[END_REF][START_REF] Hochmann | Word frequency, function words and the second gavagai problem[END_REF]. Despite of the fact that content words are conceived as carrying the main semantic weight, while function words are thought as being mostly important for indicating grammatical structure, extensive work has shown that preverbal infants pay attention to both categories. On the one hand, function words represent a small group of items so frequent that preverbal infants recognize their phonological form (e.g., [START_REF] Shafer | An electrophysiological study of infants' sensitivity to the sound patterns of English speech[END_REF]Shi, Werker, & Cutler, 2006), and use them to segment co-occurring content words [START_REF] Shi | The effect of functional morphemes on word segmentation in preverbal infants: Paper[END_REF]. On the other hand, a large body of work has shown that around 11 months of age infants are also sensitive to the phonological forms of common nouns such as "bottle" and "ball" (French: Hallé & Boysson-Bardies, 1994;Hallé & de Boysson-Bardies, 1996;English: Vihman, Nakai, DePaolis, & Hallé, 2004;Dutch: Swingley, 2005;Hebrew: Segal, Keren-Portnoy, & Vihman, 2020). Even more remarkable findings have been found in the domain of lexical semantics: from about 6 months of age infants start to understand the meaning of frequent concrete content words (e.g., "mommy", "hand"; [START_REF] Bergelson | At 6-9 months, human infants know the meanings of many common nouns[END_REF]Bortfeld, Morganm, Golinkoff, & Rathbun, 2005;[START_REF] Tincoff | Some beginnings of word comprehension in 6-montholds[END_REF], 2012), and more abstract ones a few months later (e.g., "eat"; [START_REF] Bergelson | The acquisition of abstract words by young infants[END_REF], 2015). Since parents rarely produce words in isolation (e.g., "Hand!"), but rather include them in short phrases or sentences (e.g., "hold my hand"; [START_REF] Aslin | Segmentation of fluent speech into words: Learning models and the role of maternal input[END_REF][START_REF] Brent | The role of exposure to isolated words in early vocabulary development[END_REF][START_REF] Van De Weijer | Language input for word discovery[END_REF], infants often encounter content words co-occurring with function words. This situation is advantageous, giving them the opportunity to learn how the different categories of words relate to one another.

Over the course of their second year of life, children develop more abstract syntactic knowledge enabling them to categorize novel words. This is possible because function words tend to be indicative of the word class of subsequent words (e.g., "the" is more likely to be followed by nouns than by verbs; e.g., [START_REF] Mintz | Frequent frames as a cue for grammatical categories in child directed speech[END_REF]. Experimental work has shown that at only 14 months of age infants can build syntactic expectations about the type of function words which is likely to co-occur with novel content words [START_REF] Babineau | 14-month-olds exploit verbs' syntactic contexts to build expectations about novel words[END_REF][START_REF] Höhle | Functional Elements in Infants' Speech Processing: The Role of Determiners in the Syntactic Categorization of Lexical Elements[END_REF][START_REF] Shi | Syntactic Categorization in French-Learning Infants[END_REF]. A novel word that co-occurs with determiners is expected to be used later on with another determiner, not a pronoun. Toddlers have also been shown to be sensitive to their native language's sub categorical dependencies [START_REF] Van Heugten | Infants' acquisition of grammatical gender dependencies[END_REF] as well as to non-adjacent dependencies (Höhle, Schmitz, Santelmann, & Weissenborn, 2006;[START_REF] Santelmann | Sensitivity to discontinuous dependencies in language learners: Evidence for limitations in processing space[END_REF]van Heugten & Johnson, 2010). For instance, in van Heugten & Christophe (2015), French-learning 18-month-olds distinguished between grammatical and ungrammatical lists in which a determiner either matched or not the gender of the co-occurring familiar noun (e.g. grammatical: unMAS biberonMAS; ungrammatical: uneFEM biberonMAS). From 18 months onward, not only are function words used to facilitate the recognition of familiar words [START_REF] Cauvet | Function Words Constrain On-Line Recognition of Verbs and Nouns in French 18-Month-Olds[END_REF]Gerken & McIntosh, 1993;Jones, Cabiddu, & Avila-Varela, 2020;Kedar, Casasola, & Lust, 2006;Van Heugten & Johnson, 2011;Zangl & Fernald, 2007), but they are also used to learn the meaning of novel nouns and verbs [START_REF] He | Verb Learning in 14-and 18-Month-Old English-Learning Infants[END_REF][START_REF] De Carvalho | Prosody and Function Words Cue the Acquisition of Word Meanings in 18-Month-Old Infants[END_REF]. For instance, when presented with a video in which a novel animated animal is performing a novel action, French-learning 18-month-olds can use function words to interpret a novel word such as bamoule as referring to the novel animal (if it is preceded by a determiner: Regarde, c'est une bamoule! "Look, it's a bamoule") or as referring to the novel action (if it is preceded by a pronoun: Regarde, elle bamoule! "Look, she's bamouling!"; de Carvalho, [START_REF] De Carvalho | Prosody and Function Words Cue the Acquisition of Word Meanings in 18-Month-Old Infants[END_REF]. Preschoolers' online processing of function words is even more efficient, enabling them to perform fast-mapping of novel words after only two repetitions (de Carvalho, [START_REF] De Carvalho | Studying the Real-Time Interpretation of Novel Noun and Verb Meanings in Young Children[END_REF]. Since function words convey information about the syntactic category of co-occurring words, they can also facilitate the processing of ambiguous words, such as homophoneswords that share the same phonological form but have different meanings. Recent work has found that, in natural languages, pairs of homophones tend to differ in syntactic and/or broad semantic characteristics, more than would be expected by chance alone (e.g. the word "fly", which designates a type of insect when used as a noun, and an action when used as a verb; the fly vs. they fly; Dautriche, Fibla, Fiévet, & Christophe, 2018). Toddlers make good use of the syntactic context of homophones, and experimental work has shown that they can easily learn that a novel noun homophonous with a known verb (a verb-homophone, e.g., un manger "an eat") refers to a novel object (e.g., an animal) based on the co-occurring determiner [START_REF] Dautriche | Learning novel phonological neighbors: syntactic category matters[END_REF][START_REF] Dautriche | Learning homophones in context: Easy cases are favored in the lexicon of natural languages[END_REF]. In sum, young children's knowledge and reliance on function words offer a great advantage for constraining lexical access and facilitating lexical acquisition.

Before being able to use function words to build expectations about co-occurring content words' syntactic and semantic class, infants must first notice the distributions of both word categories within their native language. Preverbal infants' sensitivity to co-occurrence patterns is well-established. For instance, a large body of work has shown that after being exposed to an artificial language or an unknown natural language, 8-month-old infants (and even younger ones) discriminate between frequent strings and infrequent strings of syllables (e.g., [START_REF] Pelucchi | Learning in reverse: Eight-month-old infants track backward transitional probabilities[END_REF][START_REF] Saffran | Statistical language learning in infancy[END_REF][START_REF] Saffran | Statistical learning by 8-month-old infants[END_REF]. Around one year of age, infants have also been shown to build abstract representations of word categories after being exposed to a short artificial language by discriminating new grammatical strings from ungrammatical ones (Gòmez & Gerken, 1999;[START_REF] Saffran | Grammatical pattern learning by human infants and cotton-top tamarin monkeys[END_REF]. In the real world, with a language containing a much larger vocabulary following more complex rules and an exposure spreading across time, tracking co-occurrence patterns is undeniably a much more arduous task. However, around the time when infants have well-developed abilities to track the distribution of words in their input, they also have a handful of words in their lexicon. Based on the semantic seed hypothesis [START_REF] Brusini | The Acquisition of Noun and Verb Categories by Bootstrapping from a few Known Words: A Computational Model[END_REF][START_REF] Christophe | Bootstrapping the syntactic bootstrapper[END_REF]Gutman, Dautriche, Crabbé, & Christophe, 2014, see also [START_REF] Christodoulopoulos | An incremental model of syntactic bootstrapping[END_REF], preverbal infants might start tracking the contexts in which this small group of known words occur to build proto-syntactic categories. That is, by the end of their first year of life, infants might start organizing their early lexicon by grouping words into basic semantic categories (e.g., object, action; Carey, 2009) and track the contexts in which these known words appear (e.g., this is a car; this is a ball; she is eating, she is sleeping). They could then use this information to infer coarse semantics for new words they encounter in the same syntactic contexts: this is a dax ⇒ dax possibly refers to an object, while she is daxing ⇒ dax possibly refers to an action. This end point represents the mechanism known as syntactic bootstrapping [START_REF] Gleitman | The Structural Sources of Verb Meanings[END_REF][START_REF] Fisher | Syntactic bootstrapping[END_REF]. Even though the semantic seed hypothesis has been proven feasible based on computational modeling [START_REF] Brusini | The Acquisition of Noun and Verb Categories by Bootstrapping from a few Known Words: A Computational Model[END_REF] and recent experimental work with toddlers and preschoolers [START_REF] Babineau | Familiar words can serve as a semantic seed for syntactic bootstrapping[END_REF]Barbir, Babineau, Fiévet, & Christophe, 2019), no research has yet explored the earliest stage of the mechanism during which preverbal infants develop their sensitivity to the relationship between function words and familiar content words. Based on past work showing that from 6 months of age infants use familiar content words to facilitate the segmentation of co-occurring words (Bortfeld, Morgan, Golinkoff, & Rathbun, 2005;Mersad & Nazzi, 2012), we posit that these familiar words also make their immediate context more salient, which would heighten their sensitivity to grammatical dependencies. Given preverbal infants' ability to track linguistic regularities and their blossoming knowledge of lexical semantics, how much attention have they paid to the immediate context of their first words, such as "bottle" and "eat"?

The current study aims at shedding light on preverbal infants' sensitivity to the cooccurrence patterns between function words and common content words. We investigated whether French-learning 8-and 11-month-olds track and store common nouns and verbs along with the preceding function words. Using a Visual Fixation Procedure, infants were presented with lists containing either grammatical or ungrammatical phrases. In Experiment 1, the grammatical lists involved nouns preceded by a determiner and verbs preceded by a pronoun (e.g., des biberons "some bottles", tu manges "you eat") and the ungrammatical lists involved nouns preceded by a pronoun and verbs preceded by a determiner (e.g., tu biberons "you bottle", des manges "some eats"). In Experiment 2, only common verbs were used, either in grammatical contexts (preceded by pronouns) or in ungrammatical contexts (preceded by determiners). If infants are indeed sensitive to noun and verb grammatical dependencies, a preference for the grammatical over the ungrammatical lists is expected in both experiments, based on previous work pitting grammatical and ungrammatical sentences using similar procedures (e.g., [START_REF] Santelmann | Sensitivity to discontinuous dependencies in language learners: Evidence for limitations in processing space[END_REF][START_REF] Van Heugten | Infants' acquisition of grammatical gender dependencies[END_REF]Van Heugten & Johnson, 2010;Van Heugten & Shi, 2010). We hypothesize that infants from both age groups can succeed in this task based on their proven word recognition skills (e.g., Hallé & Boysson-Bardies, 1994;[START_REF] Shi | The effect of functional morphemes on word segmentation in preverbal infants: Paper[END_REF], and their notorious ability to track simple cooccurrence patterns (e.g. [START_REF] Pelucchi | Learning in reverse: Eight-month-old infants track backward transitional probabilities[END_REF][START_REF] Saffran | Statistical learning by 8-month-old infants[END_REF].

Experiment 1

Method

The study reported in this paper, including the entire method, analyses, and criteria for exclusion of participants were pre-registered on the OSF (Open Science Framework) database before running the experiment. The preregistration can be accessed with the following link: https://osf.io/rcv5k/?view_only=0e69c74638014eb6b0649984d95ef5ac.The materials, collected data, and data analyses are also freely available to readers through this link.

Participants

A total of 28 French-learning 8-month-olds (15 female; age range=229-258 days; M=241) and 31 French-learning 11-month-olds (10 female; age range = 318-347 days; M=332) participated in the experiment. According to the parents, none of these children was known to have any language or hearing problem. An additional nine infants were tested, but excluded from the analyses due to extreme fussiness/crying (8-month-olds: 2; 11-month-olds: 4), parental interference (8-month-olds: 1; 11-month-olds: 1), or technical issue (11-month-olds: 1).

The present study was conducted according to guidelines laid down in the Declaration of Helsinki, with written informed consent obtained from a parent or guardian for each child before any assessment or data collection. Since our study involves human subjects, it was carried out in accordance with the recommendations of our local ethics committee, which approved our protocol beforehand.

Stimuli

Twelve common words (eight monosyllabic and four multisyllabic) were used in this study. Half of these words are nouns and the other half verbs; nouns: balles "balls", bananes "bananas", biberons "bottle", mains "hands", pieds "feet", pommes "apples"; verbs: descends "go down", donnes "give", dors "sleep", manges "eat", regardes "look", viens "come" (see Table 1). Several of the chosen nouns were used in past studies studying preverbal infants' phonological representation of common words (Hallé & Boysson-Bardies, 1994;Hallé & Boysson-Bardies, 1996), while the other nouns (and some of the chosen verbs) were used in studies investigating preverbal infants' word mapping (e.g., [START_REF] Bergelson | At 6-9 months, human infants know the meanings of many common nouns[END_REF][START_REF] Hochmann | Word frequency, function words and the second gavagai problem[END_REF]2015). High-frequency French functors (des /de/ "some", indefinite plural article; tu /ty/ "you" second person singular personal pronoun) preceded the content words, creating grammatical or ungrammatical phrases. A female native speaker of French (the last author) recorded the materials. To avoid recording ungrammatical utterances, potentially resulting in unnatural tokens, the stimuli were cross-spliced. For each item used in the study, three versions were recorded. One version contained the target word preceded by the correct function word (e.g., tu manges "you eat"). From this version, the content word was spliced. In the other two versions, two content words (one verb, one noun) starting with the same consonant-vowel sequence, were recorded preceded by the correct function word for their grammatical category (e.g., des mangues "some mangos", tu manques "you miss"). From these two tokens, the function word was spliced out from the phrase, just before the onset of the content word. The ungrammatical and grammatical phrases were formed by concatenating the two function words with the content word, such that the grammatical phrase contained the correct function word (e.g., tu manges) and the ungrammatical one contained the incorrect function word (e.g., des manges). The two phrases were similar in duration and intonation (average correct phrase length: 947 ms; average incorrect phrase length: 929 ms). *Note that des 'some' is an indefinite plural article that would be dropped in English (e.g., Il y a des vaches dans le pré 'There are *cows in the field').

Eight lists were created, four of which contained the correct phrases and four of which contained incorrect phrases. Each list contained two unique tokens of each of the twelve short phrases. These phrases were ordered differently across each of the correct and incorrect lists, but the order was identical across the two conditions. Interstimulus pauses were approximately 750 msec long. All lists lasted 40.7 sec.

Visual stimuli included a colorful checkerboard for all trials. As an attention-getter to attract infants' attention towards the screen between trials, we used a video of a butterfly perched on a leaf that is accompanied by a bubble sound.

Procedure

Two measures of infants' word knowledge were obtained from the caregivers before or during their visit to the laboratory: the French version of the MacArthur-Bates Communicative Development Inventory (CDI; short form for 12-month-olds: Kern, Langue, Zesiger & Boone, 2010), and an item exposure survey asking parents to estimate how often they tend to use these items in their day-to-day life when they speak to their child using the following scale: 1=rarely/once a week; 2=few times a week; 3=everyday.

The Visual Fixation Procedure was used to test infants' spontaneous listening preferences. Infants were individually tested in a sound-attenuated double-walled booth. During the experiment, they sat on their caregiver's lap, approximately 70 cm from a 27-inch monitor. Stimuli were presented using the Habit software (Cohen, Atkinson, & Chaput, 2004). Two loudspeakers positioned on each side of the TV screen presented the audio stimuli. The experimenter monitored the infant's behavior through a video camera that was set above the monitor in the booth and which was connected to a second monitor placed outside the booth. This set-up enabled the experimenter to observe infants' behavior from an adjacent room without being aware of the stimuli presentation. The procedure started by displaying the attention getter on the screen. Once the infant oriented toward the screen, the experimenter initiated the first trial, and she pressed another key whenever a look toward the monitor occurred during a trial. Trials ended either after the infant had looked away from the screen for more than two consecutive seconds or after the maximum trial length was reached. A new trial started when the infant looked back towards the screen. The experiment finished when all eight lists were presented. Note that the same lists were presented to all infants, but the order in which these lists appeared was pseudo-randomized so that no more than two consecutive trials of the same type (i.e. grammatical vs ungrammatical) were presented.

Results

The vocabulary checklist was filled out by the majority of caregivers (8-month-olds: 24/28; 11-month-olds: 25/31). Parental reports reveal that infants were not perceived as understanding most of the words used in the study (mean number of words scored as being comprehended by 8-month-olds: 1.17 of 12; range 0-5; mean number of words scored as being comprehended by 11-month-olds: 3.8 of 12; range 0-12). None of the parents of the 8-montholds reported that their child was producing any of the words used in the experiment, but two target words were produced by a few 11-month-olds (balle "ball" was produced by 2 children, banane "banana" by 1 child). Previous work with preverbal infants has shown that word knowledge is mostly not apparent to parents (e.g., [START_REF] Bergelson | At 6-9 months, human infants know the meanings of many common nouns[END_REF], so even though parents reported that most of the words used in our study are not comprehended, it does not mean that participants are clueless about the phonological form or the meaning of these common words. Furthermore, the survey confirmed that the majority of participants are exposed to the items on a regular basis at home (mean score for 8-month-olds: 2.23 out of 3; range: 1.58-2.5; for 11-month-olds: 2.31 out of 3; range: 1.92-2.67). On average, the 12 items received a score of 3 (everyday use) from 57% of the 11-month-olds' caregivers (score of 1: 9%; score of 2: 34%), and from 53% of 8-month-olds' caregivers (score of 1: 14 %; score of 2: 33%). Specific items were reported as rarely used by 8-month-olds' caregivers, with 50% of parents reported rarely using the noun balle "ball" and the verb descendre "go down" (with the remaining 10 words being used frequently by the majority of caregivers) 1 . Detailed information about the survey can be found on the OSF page.

The dependent variable for analysis was the average time that infants spend looking at the visual stimuli during each trial type (i.e. the average looking time for the four grammatical lists vs the average looking time for the four ungrammatical lists). An ANOVA 2 with Grammaticality (grammatical vs ungrammatical lists) as a within-participant factor, and Age (8 vs 11 months) as a between-participants factor, revealed a significant effect of the Grammaticality (F (1,57)=8.44, p=0.005, ηp 2 =0.129), but no effect of age (F(1,57)=1.73, p=0.2, ηp 2 = 0.029), nor an interaction between age and grammaticality (F (1,57) = 0.21, p=0.65, ηp 2 =0.004). As planned in our pre-registration, we used paired-sample t-tests (two-tailed) for each age group and found a significant difference only with the 11-month-olds (t (30) =2.686 p=.012; d =.482), but not with the 8-month-olds (t (27)=1.545, p=0.134, d=0.29). Nevertheless, 1 We measured parents' perception of input frequency, i.e. how often they think they are using these words when they talk to their child. This measure has its limits. For instance, the majority of participants attend a full-time care service (e.g. nanny, daycare). Hence, the item exposure survey is only giving us a glimpse into half of the language input of each child. 2 As stated in our preregistration, we initially intended to test solely 11-month-olds. After obtaining successful results with this age group, we wrote an amendment indicating our intention to test 8-month-olds with the same task. Hence, based on the preregistration, only the paired-sample t-tests can be considered as planned analyses, and the ANOVA was decided upon later. We present the ANOVA first because a reviewer mentioned that it was weird to present it after the paired t-tests. as shown in Figure 1, infants in both age groups looked toward the screen for a longer time during grammatical trials than during ungrammatical trials (8-month-olds: M= 13.24 (SE=1.57) vs. M= 11.6 (SE= 1.2); 11-month-olds: M=11.548 (SE=1.03) vs. M= 9.3 (SE=0.84) 3 . Most infants showed this pattern of looking time, i.e. 18 out of 28 8-month-olds (with 7 showing the opposite pattern and 3 not showing a clear preference 4 ) and 20 out of 31 11-month-olds (with 6 showing the opposite pattern and 5 not showing a clear preference).

Discussion

By 11 months of age, infants display a robust preference for correctly used over incorrectly used function words, indicating that they have managed to track the co-occurrence 3 Following a reviewer's suggestion, we conducted an exploratory analysis to see whether the size of the lexicon, measured via parental reports, had an impact on infants' performance, but found no correlation between vocabulary size and infants' preference for grammatical lists, in either age group (p>.5). 4 Following the suggestion of a reviewer, we ran exploratory binomial tests on these numbers. Infants who had a difference of less than 1 sec between their averaged looking time during the grammatical vs ungrammatical trials were removed from this analysis, which showed that both 8-month-olds and 11-month-olds significantly preferred to listen to grammatical lists than to ungrammatical lists (p=0.043; p=0.009, respectively). When all infants were included (however small their difference in looking times), 8-month-olds were found to significantly prefer the grammatical lists (p=0.036), but 11-month-olds only showed a trend (p=0.071).

between determiners and common nouns and between pronouns and common verbs during this early stage of language acquisition. This preference might be emerging in 8-month-olds, who showed a trend in the same direction. Even though no interaction between Age and Grammaticality was found, some caution is in order when interpreting 8-month-olds' results as infants' preference for the grammatical lists was not reliable enough to reach significance with the planned t test.

Since both nouns and verbs were used in Experiment 1, it fails to reveal if these young learners know noun and verb contexts to the same extent. Infants could have succeeded at discriminating grammatical from ungrammatical lists on the sole basis of their deeper knowledge of the nouns used in the study, and/or of their syntactic contexts. Across languages, nouns tend to constitute the predominant form in early lexicons (Braginsky, Yurovsky, Marchman, & Frank, 2019;Gentner, 1982;Saah et al., 1996), especially frequent concrete nouns and those strongly associated with babies (e.g. "bottle"). By 11 months, most infants have successfully mapped a few nouns to their referents, but they have established fewer mappings for words from other form classes (such as verbs). For instance, based on the parental reports of the 11-month-olds who participated in Experiment 1, an average of 7.33 concrete nouns (range: 0-33) and of 4.38 verbs (range: 0-16) were comprehended. This asymmetry was not found in 8-month-olds, who had overall smaller receptive vocabulary, with an average of 1.25 concrete nouns (range: 0-7) and 1.33 verbs (range: 0-8)5 . Since the "noun bias" is partly shaped by the linguistic and cultural environment, it might become more apparent as the child gains more exposure to his native language and as the size of his lexicon increases (e.g., [START_REF] Tardif | Putting the "noun bias" in context: A comparison of English and Mandarin[END_REF]. When it comes to noticing the syntactic contexts of these lexical items, it might be easier to track the contexts of common nouns than to track the contexts of common verbs. In French, nouns appear in more stable contexts (i.e., consistently co-occur with a preceding determiner in 71% of cases or with a preceding adjective in 26% of cases) than do verbs (i.e., co-occur with a preceding subject pronoun in 59% based on a corpus by [START_REF] Cécyre | Speech rate in maternal speech to French-learning infants[END_REF]. Nonetheless, the co-occurrence of verbs with pronouns might still be noticeable early on, based on recent work showing French-learning 14-month-olds' success at building syntactic expectations for both novel nouns and novel verbs [START_REF] Babineau | 14-month-olds exploit verbs' syntactic contexts to build expectations about novel words[END_REF]. Specifically, in that study, infants expected a novel verb that previously co-occurred with subject pronouns to co-occur with another subject pronoun, but not with a determiner. These results demonstrate that French-learning 14-month-olds are sensitive to the cooccurrence patterns of verbs with subject pronouns, which has clear benefits for the processing of novel words. Experiment 2 aims to test if younger infants (11-month-olds) are already tracking the co-occurrence patterns of common verbs with pronouns. If infants succeed at discriminating grammatical from ungrammatical lists, this will indicate that preverbal infants' verb knowledge and their ability to track their syntactic contexts is more sophisticated than previously thought.

Experiment 2

Method

Participants

A total of 28 French-learning 11-month-olds (8 female; age range = 322-362 days, M=338) participated in the experiment. Parents reported no hearing problems. An additional nine infants were tested, but excluded from the analyses due to extreme fussiness/crying (6) or parental interference (3).

Stimuli

Twelve common consonant-initial verbs (nine monosyllabic, three bisyllabic) were used in Experiment 2: cache "hide", chante "sing", dort "sleep", descend "go down", dessine "draw", donne "give", lave "wash", mange "eat", monte "go up", regarde "look", saute "jump", vient "come". These words were chosen based on early production and comprehension norms in older children from the same population (children who participated in previous experiments at the lab), as well as for their associations with common activities and routines. However, many highly commonly known verbs were excluded because of the presence of frequent noun homophones (e.g., couche can mean "to lay" or "a diaper", lit can mean "to read" or "a bed", etc.). High-frequency French functors (the masculine determiner un and the feminine determiner une "a", the pronouns elle "she" and il "he") preceded the verbs, creating grammatical or ungrammatical phrases (see Table 2).

The stimuli were recorded by the same speaker as in Experiment 1. As in Experiment 1, the stimuli were cross-spliced. For each item used in the study, three versions were recorded. One version contained the target word preceded by the correct function word (e.g., elle mange "she eats"). From this version, the content word was spliced. In the other two versions, two content words (one verb, one noun) starting with the same consonant-vowel sequence, were recorded preceded by the correct function word for their grammatical category (e.g., une mangue "a mango", elle manque "she misses"). From these two tokens, the function word was spliced out from the phrase, just before the onset of the content word (or after the onset consonant for words starting with a fricative). The ungrammatical and grammatical phrases were formed by concatenating the two function words with the content word, such that the grammatical phrase contained the correct function word (e.g., elle mange) and the ungrammatical one contained the incorrect function word (e.g., une mange). The two phrases were similar in duration and intonation.

As in Experiment 1, a total of eight lists were created, four with correct (grammatical) short phrases and four with incorrect (ungrammatical) short phrases. Each list contained two unique tokens of each of the twelve short phrases. These phrases were ordered differently across each of the four correct and incorrect lists. Interstimulus pauses were approximately 750 msec long. All lists lasted 43.6 sec.

Visual stimuli and the attention-getter were the same as in the previous pre-registered study.

Results

As in Experiment 1, two measures of infants' word knowledge were obtained from their caregivers. However, these measures offer limited information due to the low numbers of questionnaires6 : out of 28 participants, we gathered 12 French CDIs (short form) and 10 item surveys. As in Experiment 1, parental reports reveal that infants were not perceived as understanding most of the words used in the study (mean number of words scored as being comprehended: 2.83 of 12; range 0-12) and none of the infants produced the items. The survey confirmed that most participants are exposed to the items on a regular basis (mean score: 2.13 out of 3; range: 1.83-2.42). On average, the 12 items received a score of 3 (everyday use) from 52% of the 11-month-olds' caregivers (score of 1: 24%; score of 2: 24%). Eight of the 12 verbs were reported as being used frequently (i.e. score of 2 or 3) by more than 70% of parents. For descendre "go down" and monter "go up" more than 60% of caregivers used them frequently, while below 20% of caregivers reported using dessiner "to draw" and sauter "to jump" (detailed results can be found on OSF). Despite the rare use of two out of twelve items, the survey confirmed that participants are exposed to the majority of target verbs on a regular basis.

Infants oriented toward the screen for an average of 12.05 sec during the grammatical trials and for an average of 9.024 sec during the ungrammatical trials, with 18 out of 28 infants showing this listening preference (7 infants showing the opposite preference and 3 infants not showing a clear preference; see Figure 1). A paired-sample t test (two-tailed) comparing the average looking time during the grammatical vs the ungrammatical trials revealed a significant difference, t (27) = 3; p=.006; d =.567).7

Discussion

The results of Experiment 2 replicate the ones obtained in Experiment 1, confirming 11-month-olds' ability to track co-occurrence patterns involving pronouns and common verbs. Hence, although 11-month-olds might seem to know much more about nouns than about verbs based on their caregivers' report, they are nonetheless sensitive to common verbs' cooccurrence patterns.

General Discussion

The goal of the current set of experiments was to specify the scope of preverbal infants' sensitivity to grammatical dependencies involving familiar nouns and verbs. Using a Visual Fixation Procedure, 8-and 11-month-olds were presented with two types of lists containing either grammatical or ungrammatical phrases. Common nouns and verbs were used in Experiment 1, while only common verbs were used in Experiment 2. Eleven-month-olds showed a significant preference for grammatical lists in both experiments, while 8-month-olds showed a non-significant trend in the same direction. Future work should test the scope of 8month-olds' ability to track adjacent grammatical dependencies. All things considered, our findings indicate that during the second part of their first year of life, infants can track the cooccurrence patterns naturally present in their native language and more specifically, they develop a precocious sensitivity to the relationship between determiners and nouns, as well as pronouns and verbs.

Infants' familiarity with the individual content words and their immediate contexts is likely the driving force of the effect observed in the current set of experiments. Even though both 8-month-olds and 11-month-olds can quickly pickup speech patterns and regularities in laboratory settings, two obvious advantages of the 11-month-olds is their larger lexicon and their lengthier exposure to their native language. A recent meta-analysis on word-form recognition has reported an increase in effect sizes with age and items' familiarity (Carbajal, Peperkamp, & Tsuji, 2021). Hence, 11-month-olds are better equipped to distinguish familiar words from unfamiliar ones, and as found here, they seem to also be better at distinguishing grammatical from ungrammatical contexts for such familiar word forms. Note, however, that we should remain cautious in reporting this latter advantage, since no interaction between Age and Grammaticality was found in Experiment 1. This indicates that the participating 8-montholds and 11-month-olds did not behave differently during the task (both age groups showed a preference for grammatical over ungrammatical lists). As proposed by the semantic seed hypothesis (e.g., [START_REF] Christophe | Bootstrapping the syntactic bootstrapper[END_REF], the early lexicon has an essential role in language acquisition: it enables infants to build proto-syntactic categories. We show that around 11 months of age infants are tracking the contexts in which their first words appear. This helps them to notice what type of function words tend to precede certain categories (e.g., "the" and "a" before object words such as "bottle", "ball", and "car"). This knowledge can be used just a few months later to build expectations about novel words' syntactic (e.g., [START_REF] Babineau | 14-month-olds exploit verbs' syntactic contexts to build expectations about novel words[END_REF] and semantic properties (e.g., de Carvalho, [START_REF] De Carvalho | Prosody and Function Words Cue the Acquisition of Word Meanings in 18-Month-Old Infants[END_REF].

Our findings are also in line with usage-based accounts of language acquisition (e.g., Arnon, 2010;Arnon & Christiansen, 2017;Abbot-Smith & Tomasello, 2006;Bannard & Lieven, 2012;McCauley & Christiansen, 2019;Tomasello, 2003): from early on, infants extract and represent multiword sequences alongside and in parallel with individual words. While van [START_REF] Van Heugten | Infants' acquisition of grammatical gender dependencies[END_REF] has shown that French-learning 18-month-olds track gender marking between determiners and common nouns, we show that 11-month-olds (and possibly even younger infants) are also sensitive to simple co-occurrence patterns involving common nouns, as well as those involving common verbs. Our findings are building on recent work showing that 11-month-olds are sensitive to frequent sequences of words (e.g., the frequent sequence "clap your hands" vs the infrequent sequence "hold your hands"; Skarabela, Ota, O'Connor, & Arnon, 2021), and nonwords (e.g., the frequent string dans la [dɑ la] "in the" vs the infrequent string [dalɑ ]; [START_REF] Ngon | Non) words,(non) words,(non) words: evidence for a protolexicon during the first year of life[END_REF]. It remains unknown if 11-month-olds' success in our task could be linked to their blossoming sensitivity to the grammaticality of the phrases, and not purely on their well-developed ability to distinguish frequent sequences of words from infrequent ones. After all, just a few months later, at 14 months, they expect novel content words to co-occur with specific function words (e.g., [START_REF] Babineau | 14-month-olds exploit verbs' syntactic contexts to build expectations about novel words[END_REF]. More work is needed to uncover the abstractedness of preverbal infants' representations as well as the sources of their sensitivity to grammatical and sub-grammatical dependencies.

In sum, our findings provide the earliest account of infants' ability to track cooccurrence patterns between different word categories from their natural language input. Before one year of age, infants' syntactic knowledge is rudimentary, but they have nonetheless noticed simple yet powerful syntactic regularities which can bootstrap their lexical acquisition.

Figure 1 .

 1 Figure 1. On the left side: Mean looking time in seconds during the two trial types, i.e. grammatical (in orange) and ungrammatical (dark red), for the three experimental groups (Experiment 1: 8-month-olds, Experiment 1: 11-month-olds, Experiment 2: 11-month-olds). Error bars represent the standard error of the mean. On the right side: Box plot of the difference between looking times during the grammatical and the ungrammatical test trials for the three conditions. The black line represents the median and the white dotted line represents the mean. Each yellow dot represents one participant. Longer looking times for grammatical over ungrammatical lists is indicated by positive values.

Table 1 .

 1 Stimuli for Experiment 1.

	Grammatical	Ungrammatical
	des balles "some balls"	tu balles "you ball"
	tu dors "you sleep"'	des dors "some sleep"

tu viens "you come" des viens "some come" des pieds "some feet" tu pieds "you foot" des biberons "some bottles"' tu biberons "you bottle"

Table 2 .

 2 Stimuli for Experiment 2.

	Experiment 2

Proper nouns (such as infants' own names, "mommy" and "daddy") as well as social nouns (such as bonjour "hello" and au revoir "bye") were not counted as concrete nouns, but they were frequently known by the 8-month-olds.

During the testing phase of Experiment 2, the authors moved their office space. Sadly, we did not manage to recover the misplaced CDIs and item surveys.

An exploratory binomial test confirmed the significance of this preference (p =0.043).