Gene therapy and cell therapy for the management of radiation damages to healthy tissues: Rationale and early results.

Nowadays, ionizing radiations have numerous applications, especially in medicine for diagnosis and therapy. Pharmacological radioprotection aims at increasing detoxification of free radicals. Radiomitigation aims at improving survival and proliferation of damaged cells. Both strategies are essential research area, as non-contained radiation can lead to harmful effects. Some advances allowing the comprehension of normal tissue injury mechanisms, and the discovery of related predictive biomarkers, have led to developing several highly promising radioprotector or radiomitigator drugs. Next to these drugs, a growing interest does exist for biotherapy in this field, including gene therapy and cell therapy through mesenchymal stem cells. In this review article, we provide an overview of the management of radiation damages to healthy tissues via gene or cell therapy in the context of radiotherapy. The early management aims at preventing the occurrence of these damages before exposure or just after exposure. The late management offers promises in the reversion of constituted late damages following irradiation.

Use of 4D-CT for radiotherapy planning and reality in France: Data from a national survey.

PURPOSE: Lung and some digestive tumours move during a respiratory cycle. Four-dimensional scanography (4D-CT) is commonly used in treatment planning to account for respiratory motion. Although many French radiotherapy centres are now equipped, there are no guidelines on this subject to date. We wanted to draw up a description of the use of the 4D-CT for the treatment planning in France. METHODS AND MATERIAL: We conducted a survey in all French radiotherapy centres between March and April 2017. RESULTS: One hundred and seventy-two were contacted. The participation rate was 88.37%. The use of the 4D-CT seems to be common and concerned planning for 15.28% of kidney and adrenal cancers, 19.72% of pancreatic cancers, 27.78% of oesophageal cancers and 73.24% of lung cancers in case of normofractionated treatments. The use of the 4D-CT was also widespread in the case of stereotactic body radiation therapy: with 61.11% in the case of pulmonary irradiation and 34.72% in the case of hepatic irradiation. Many centres declared they carried out several 4D-CT for treatment planning (29, 55% in case of stereotactic body radiation therapy for lung tumours and 20% for liver tumours). Private centres tend to repeat 4D-CT more. CONCLUSION: Although the use of the 4D-CT appears to be developing, it remains very heterogeneous. To date, the repetition of the 4D-CT has been very poorly studied and could be the subject of clinical studies, allowing to define in which indications and for which populations there is a real benefit.

[Physiopathology and pharmacological perspectives in the treatment of radiation enteritis]. / Physiopathologie et modulation pharmacologique de l'entérite radique.

The small intestine is an organ frequently exposed in abdominal and pelvic irradiations. Acute and late toxicity can sometimes be difficult to manage and can significantly affect the quality of life of patients. Currently there is no guideline on the management of acute and late side effects induced by therapeutic irradiation. The aim of this review is to summarize available data on the pathophysiology of radiation enteritis, and to highlight potential preventive strategies and principles of treatment of radiation enteritis.

[Use of 4D-CT: Main technical aspects and clinical benefits]. / Utilisation de la scanographie quadridimensionnelle : principaux aspects techniques et intérêts cliniques.

The four-dimensional scannography, also called 4D-CT, was created in the early 2000s. This method enables the aquistion of CT-scans synchronised with the patient's breathing. It allows an anatomical observation depending on the time. Different systems have been marketed. They are commonly used in treatment planning. It allows to take into account respiratory motion, considering the changes of shape and position of the tumor and organs. In the age of new techniques and stereotactic irradiations, 4D-CT is a valuable tool for estimating the uncertainties associated with respiratory movements, This technique also presents some limitations, including artifacts. The quality of the examination can be degraded in some patients with irregular respiration. Here we propose a summary of this technique detailing its principle of operation, its advantages and its main limits.

[Medical prevention and treatment of radiation-induced urological and nephrological complications]. / Prévention médicale et traitement des complications urologiques et néphrologiques secondaires à la radiothérapie.

Abdominal and pelvic irradiations play a major place in the management of patients with cancer and present a risk of acute and late side effects. Radiation-induced lesions can affect kidney or urological structures. These side effects can have an impact in the quality of life of patients. The aim of this article is to describe the physiopathology, the symptomatology, and the principles of management of radiation-induced nephropathy, uretheritis, cystitis, and urethritis.

Outcomes and treatments of IB1 cervical cancers with high recurrence risk: A 13 years' experience.

PURPOSE: The aim of the present study was to identify management strategies and outcomes of patients with stage IB1 cervical cancer with high recurrence risk. MATERIALS AND METHODS: Medical files of all consecutive patients treated between 2004 and 2017 with external beam radiotherapy and/or brachytherapy for IB1 cervical cancer, whatever the lymph node status, were retrospectively reviewed. RESULTS: Forty-two patients were included, with a median age of 49.8 years old. Median tumour size, estimated with the initial pelvic magnetic resonance imaging, was 26mm (interquartile range [IQR]=19.5-35). Histological types were mainly squamous cell carcinoma (59.5%) and adenocarcinoma (33.3%). Lymphovascular invasion was reported for 38.1% of patients. Pelvic lymph nodes were involved for eight patients (19.0%). Surgery was performed for 39 patients (92.9%). A neoadjuvant treatment was delivered for 20 patients (47.6%), an adjuvant treatment for 19 patients (45.2%) and an exclusive radiotherapy (with or without chemotherapy) followed by brachytherapy for three patients (7.1%). Pathologic complete response was achieved in 61.5% of patients. With a median follow-up of 5.8 years (IQR=2.6-9.4), five patients (11.9%) experienced a tumour relapse. The five-year disease-free survival was 79.5% (95% confident interval [CI]=66.9-94.4), the five-year overall survival was 87.8% (95% CI=77.2-99.8), and the five-year disease-specific survival was 94.2% (95% CI=86.7-100). CONCLUSION: In current clinical practice, tailored treatments are delivered, and seems to give correct therapeutic index. However, clinical trials are needed to standardise treatment according to patient characteristics and recurrence risk factors.

Harnessing drug/radiation interaction through daily routine practice: Leverage medical and methodological point of view (MORSE 02-17 study).

BACKGROUND: Safety profile of the interaction between anticancer drugs and radiation is a recurrent question. However, there are little data regarding the non-anticancer treatment (NACT)/radiation combinations. The aim of the present study was to investigate concomitant NACTs in patients undergoing radiotherapy in a French comprehensive cancer center. METHODS: A prospective cross-sectional study was conducted. All cancer patients undergoing a palliative or curative radiotherapy were consecutively screened for six weeks in 2016. Data on NACTs were collected. RESULTS: Out of 214 included patients, a NACT was concomitantly prescribed to 155 patients (72%), with a median number of 5 NACTs per patient (range: 1-12). The most prescribed drugs were anti-hypertensive drugs (101 patients, 47.2%), psychotropic drugs (n = 74, 34.6%), analgesics (n = 78, 36.4%), hypolipidemic drugs (n = 57, 26.6%), proton pump inhibitors (n = 46, 21.5%) and antiplatelet drugs (n = 38, 17.8%). Although 833 different molecules were reported, only 20 possible modifiers of cancer biological pathways (prescribed to 74 patients (34.5%)) were identified. Eight out of the 833 molecules (0.9%), belonging to six drug families, have been investigated in 28 ongoing or published clinical trials in combo with radiotherapy. They were prescribed to 63 patients (29.4%). CONCLUSION: Drug-radiation interaction remains a subject of major interest, not only for conventional anticancer drugs, but also for NACTs. New trial designs are thus required.

Navigating the highlights of phase III trials: a watchful eye on evidence-based radiotherapy.

BACKGROUND: Phase III randomized controlled trials (RCTs) are the cornerstone of evidence-based oncology. However, there is no exhaustive review describing the radiotherapy RTCs characteristics. The objective of the present study was to describe features of all phase III RCTs including at least a radiation therapy. METHODS AND MATERIALS: Requests were performed in the Medline database (via PubMed). The latest update was performed in April 2016, using the following MESH terms: 'clinical trials: phase III as topic', 'radiotherapy', 'brachytherapy', as keywords. RESULTS: A total of 454 phase III RCTs were identified. Studies were mainly based on open (92.1%) multicenter (77.5%) designs, analyzed in intend to treat (67.6%), aiming at proving superiority (91.6%) through overall survival assessment (46.5%). Most frequently studied malignancies were head and neck (21.8%), lung (14.3%) and prostate cancers (9.9%). Patients were mainly recruited with a locally advanced disease (73.7%). Median age was 59 years old. Out of 977 treatment arms, 889 arms experienced radiotherapy, mainly using 3D-conformal radiotherapy (288 arms, 32.4%). Intensity-modulated techniques were tested in 12 arms (1.3%). The intervention was a non-cytotoxic agent addition in 89 studies (19.6%), a radiation dose/fractionation modification in 74 studies (16.3%), a modification of chemotherapy regimen in 63 studies (13.9%), a chemotherapy addition in 63 studies (13.9%) and a radiotherapy addition in 53 trials (11.7%). With a median follow-up of 50 months, acute all-grade and grade 3-5 toxicities were reported in 49.6% and 69.4% of studies, respectively. Radiotherapy technique, follow-up and late toxicities were reported in 60.1%, 74%, and 31.1% of studies, respectively. CONCLUSION: Phase III randomized controlled trials featured severe limitations, since a third did not report radiotherapy technique, follow-up or late toxicities. The fast-paced technological evolution creates a discrepancy between literature and radiotherapy techniques performed in daily-routine, suggesting that phase III methodology needs to be reinvented.

Genomic alterations and radioresistance in breast cancer: an analysis of the ProfiLER protocol.

BACKGROUND: Breast cancer (BC) patients with comparable prognostic features have heterogeneous outcomes, party related to a possible radiotherapy resistance leading to local-regional recurrences (LRR). The objective of the present study was to identify predictive molecular biomarkers of LRR of BC. PATIENTS AND METHODS: Genetic profile of 146 BC patients' tumours included in the ProfiLER clinical trial (NC01774409) between 2013 and 2016 were analysed using next-generation-sequencing and comparative-genomic-hybridization tests. Patients and tumour characteristics were retrospectively collected and analysed for association with genomic rearrangements (mutations, amplification, deletions). Only gene alterations observed in >3% of the tumours were selected. RESULTS: A total of 193 genomic rearrangements were identified, and 16 were observed in >3% of tumours. One was statistically correlated to the risk of local relapse. A median loco-regional progression-free survival (LRPFS) of 23.6 years was reported for PIK3CA mutation carriers (n = 31, 21.2%) versus 9.9 years for PIK3CA wild-type patients (HR 0.27, 95% CI 0.12-0.65, P = 0.002 in univariate analysis). PIK3CA mutation was identified as an independent protective factor on LRR using multivariate analysis (HR 0.29, 95% CI 0.09-0.99, P = 0.047). All other mutations, amplifications or deletions were not found associated with LRPFS. CONCLUSION: PIK3CA mutation was associated with a lower risk of local relapse in this population of BCs. This is consistent with recent studies suggesting PIK3CA to be part of biological pathways impacting the radiosensitivity.

Biomarkers of resistance to radiation therapy: a prospective study in cervical carcinoma.

BACKGROUND: Clinical parameters and proteins have recently been suggested as possible causes of radiotherapy (RT) resistance in cervical carcinoma (CC). The objective of the present study was to validate prognostic biomarkers of radiation resistance. METHODS: The present prospective study included patients undergoing RT with curative intent for histologically proven locally advanced squamous cell CC. Tissues and blood samples were systematically collected before RT initiation. Immuno-histochemistry was performed (IGF-IR α and ß, GAPDH, HIF-1 alpha, Survivin, GLUT1, CAIX, hTERT and HKII). Response to radiation was assessed through tumour response 3 months after RT completion, through overall survival (OS) and through progression-free survival (PFS). RESULTS: One hundred forty nine patients with a mean age of 46 years were included, with FIGO IIB (n = 53) and FIGO IIIB (n = 96) CCs. 61 patients were treated with exclusive RT + brachytherapy and 88 underwent chemo-radiotherapy + brachytherapy. Our findings suggest an association between hemoglobin level (Hb) (>11 g/dL) and 3 months complete response (p = 0.02). Hb level < 11 g/dL was associated with decreased PFS (p = 0.05) and OS (p = 0.08). Overexpression of IGF-1R ß was correlated with a decreased OS (p = 0.007). Overexpression of GLUT1 was marginally correlated with reduced OS (p = 0.05). PFS and OS were significantly improved in patients undergoing chemoradiation versus exclusive radiotherapy (PFS: p = 0.04; OS: p = 0.01). CONCLUSIONS: IGF-1R ß overexpression and Hb level (≤11 g/dl) were associated with poor prognosis, and thus appear to be possible interesting biomarkers of radiation resistance. Our results corroborate previous pre-clinical studies suggesting IGF-1R and hypoxia to be part of the biological pathways leading to radio-resistance.

[Medical prevention and treatment of radiation-induced pulmonary complications]. / Prévention médicale et traitement des complications pulmonaires secondaires à la radiothérapie.

Radiation-induced lung injuries mainly include the (acute or sub-acute) radiation pneumonitis, the lung fibrosis and the bronchiolitis obliterans organizing pneumonia (BOOP). The present review aims at describing the diagnostic process, the current physiopathological knowledge, and the available (non dosimetric) preventive and curative treatments. Radiation-induced lung injury is a diagnosis of exclusion, since clinical, radiological, or biological pathognomonic evidences do not exist. Investigations should necessarily include a thoracic high resolution CT-scan and lung function tests with a diffusing capacity of the lung for carbon monoxide. No treatment ever really showed efficacy to prevent acute radiation-induced lung injury, or to treat radiation-induced lung fibrosis. The most promising drugs in order to prevent radiation-induced lung injury are amifostine, angiotensin-converting-enzyme inhibitors and pentoxifylline. Inhibitors of collagen synthesis are currently tested at a pre-clinical stage to limit the radiation-induced lung fibrosis. Regarding available treatments of radiation-induced pneumonitis, corticoids can be considered the cornerstone. However, no standardized program or guidelines concerning the initial dose and the gradual tapering have been scientifically established. Alternative treatments can be prescribed, based on clinical cases reporting on the efficacy of immunosuppressive drugs. Such data highlight the major role of the lung dosimetric protection in order to efficiently prevent radiation-induced lung injury.

Bilateral Breast Cancer After Prophylactic Bilateral Pulmonary Irradiation.

The purpose of this article is to report a new case of a probably radio-induced bilateral breast cancer occurred after prophylactic bilateral pulmonary irradiation in the treatment of osteosarcoma. A 42-year-old woman, treated at the age of 12 years for osteosarcoma at the right lower limb with chemotherapy (methotrexate, adriamycin and cisplatin) followed by non-conservative surgery and adjuvant radiotherapy. Eighteen years after, she developed her first breast cancer, and five years later, her second contralateral breast cancer. The patient was treated for her two non-metastatic cancers and is currently in complete remission. This publication adds to several previous publications the very probable effect of ionizing radiation in the occurrence of secondary cancers.

HPV-16 variants' impact on uterine cervical cancer response to radiotherapy: A descriptive pilot study.

PURPOSE: Although the large impact of Human papilloma virus (HPV) in cervical cancer is established, its place as a therapeutic target is new and according to the growing literature, could be promising. In the present study, radiosensitivity's difference based on HPV-16 variants is assessed. PATIENTS AND METHODS: Variants of Human papilloma virus were identified before the exclusive radiotherapy in patients with cervical cancer. Data were prospectively collected. Fifty-nine patients were screened. RESULTS: Among the 59 screened patients, 34 (57.6%) were identified to be HPV-16 (+), with 13 European and two non-European variants. Of the 34 patients, 15 experienced exclusive radiotherapy. Among them, eight had complete response (seven with European and one with non-European variants), four with European variant had partial response, three with European variant had tumour persistence and one with non-European variant progressed at 3 months. CONCLUSION: No radiosensitivity difference was established, probably because of the limited population. Non-European variant aggressiveness might be suggested in accordance with the literature, as it was associated with the only tumour progression. Exclusive radiotherapy provides a unique and "pure" model of radioresistance in cervical cancer and could be the missing link between in vitro studies and state of the art chemoradiotherapy studies that probably feature too many parameters to identify radioresistance causes. The present study was a first step, with the future prospects of building a larger cohort study in order to better understand HPV-induced radioresistance and then to be able to propose new made-to-measure treatments.

[Ototoxicity in head and neck cancers after radiotherapy and chemoradiotherapy: From primary prevention to tertiary prevention]. / Ototoxicité radio-induite et chimio-induite dans les cancers ORL : de la prévention primaire à la prévention tertiaire.

Each year, 15,000 head and neck cancer are treated in France. Prognosis is steadily improving. Consequently, limitation of late toxicities becomes essential. Ototoxicity is common, disabling and undervalued. We aimed to inventory primary, secondary and tertiary prevention measures to reduce ototoxicity induced by radiotherapy and chemotherapy, as well as its impact on quality of life of patients treated for head and neck cancer. External radiation therapy induced 30 to 40% of ototoxicity, including irreversible sensorineural hearing loss. Primary prevention of this risk is based on limiting the dose to the cochlea: 40Gy in case of radiotherapy alone, 10Gy during concomitant chemoradiotherapy with cisplatin. Dose gradients allowed by intensity-modulated radiotherapy help respecting these limits. Concurrent chemotherapy with high dose cisplatin (100mg/m2) also causes hearing loss by cochlear damages. Prescription of carboplatin-5-fluorouracil combination or cetuximab should be preferred in case of high risk of ototoxicity. This risk must be precisely evaluated before treatment. Ototoxicity monitoring during treatment allows early management, and lower long-term impact. Radiosensitivity predictive tests and research of genetic factors predisposing to chemo-induced ototoxicity should enable optimization of therapeutic choices and monitoring.

Real-life efficacy of volumetric modulated arc therapy in head and neck squamous cell carcinoma.

OBJECTIVES: There is paucity of data on the efficacy of volumetric modulated arc therapy (VMAT) in head and neck squamous cell carcinoma (HNSCC). The objective of the present study was to investigate outcomes and patterns of recurrence in locally advanced HNSCC treated by VMAT. METHODS: A retrospective study included all patients with stage III or IV HNSCC undergoing curative VMAT. RESULTS: From 2010 to 2013, 130 patients were treated for locally advanced oropharynx (n=55; 42%), hypopharynx (n=38; 29%), larynx (n=22; 17%) or oral cavity (n=15; 12%) SCC. Median age was 60 years (range, 39-85). Median follow-up was 18.1 months (range, 0-43.7). By end of follow-up, 60 patients (46%) had died. Two-year progression-free and overall survival were respectively 63.6% and 77.3% for laryngeal tumors, 60% and 60% for oral cavity tumors, 52.6% and 57.6% for oropharyngeal tumors, and 38.8% and 54.7% for hypopharyngeal tumors. Most recurrences were located within or marginal to radiation therapy fields. CONCLUSION: This retrospective analysis is, to our knowledge, the largest study of the efficacy of VMAT in HNSCC. Recurrence patterns and outcomes were consistent with those previously reported for intensity-modulated radiotherapy.

[Radiotherapy phase I trials' methodology: Features]. / Méthodologie des essais de phase I en radiothérapie : particularités.

In clinical research, biostatistical methods allow the rigorous analysis of data collection and should be defined from the trial design to obtain the appropriate experimental approach. Thus, if the main purpose of phase I is to determine the dose to use during phase II, methodology should be finely adjusted to experimental treatment(s). Today, the methodology for chemotherapy and targeted therapy is well known. For radiotherapy and chemoradiotherapy phase I trials, the primary endpoint must reflect both effectiveness and potential treatment toxicities. Methodology should probably be complex to limit failures in the following phases. However, there are very few data about methodology design in the literature. The present study focuses on these particular trials and their characteristics. It should help to raise existing methodological patterns shortcomings in order to propose new and better-suited designs.

[Hyperbaric oxygen and radiotherapy: From myth to reality]. / Oxygénothérapie hyperbare et radiothérapie : entre mythe et réalité.

Worldwide, more than a million people receive each year a curative radiotherapy. While local control and overall survival are steadily increasing, 5 to 15% of patients still develop above grade 2 late toxicities. Late toxicities treatments are complex. Hyperbaric oxygenation was shown to induce revascularization and healing of injured tissues, but indications are still debated. Through a literature review, we summarized the hyperbaric oxygenation indications in radiation-induced late toxicities. We also studied the knowledge and practice of French local radiation therapists. It seems that hyperbaric oxygen therapy can be a conservative treatment of haemorrhagic cystitis and radiation-induced pain, in case of drug therapies failure. Often associated with a significant morbidity and mortality, surgery could be avoided. The risk of complications in case of tooth extraction in irradiated tissues is also reduced. However, the role of hyperbaric oxygenation for mandibular osteoradionecrosis, radiation-induced proctitis, enteritis, lymphoedema, brachial plexopathy, skin and neurological sequelae seems more questionable since studies results are conflicting. Future outcomes of phase III studies are expected to clarify the role of hyperbaric oxygenation in the management of radio-induced toxicities, including for head and necks complications.

[Rhabdomyosarcoma of adult genital tract: A short review]. / Rhabdomyosarcomes d'origine gynécologique chez l'adulte : revue générale et principes de prise en charge.

Rhabdomyosarcoma, most common soft tissue tumor in children, represent 8% of solid tumors in children. Conversely, in adults, this histology is very rare and no consensual recommendation is supported. If gynecological localization is one of the most frequent in children, it is a minority in adults. The management of this type of tumor is based on treatment multimodality combining surgery, chemotherapy, radiotherapy and brachytherapy. This pathological separate entity differs from other sarcomas by its greater sensitivity to chemotherapy and radiotherapy. The aim of this study is to conduct a general review of diagnostic and treatment of genital tract rhabdomyosarcoma in adults, and to report pathological characteristics of this type of tumor.

Combination of low dose of the anti-adipogenic agents resveratrol and phenelzine in drinking water is not sufficient to prevent obesity in very-high-fat diet-fed mice.

PURPOSE: Resveratrol inhibits lipid accumulation but suffers from limited bioavailability. The anti-depressive agent phenelzine limits adipogenesis in various models of cultured preadipocytes, and this hydrazine derivative also inhibits de novo lipogenesis in mature adipocytes. It was therefore tested whether resveratrol effects on adiposity reduction and glucose tolerance improvement could be reinforced by co-administration with phenelzine. METHODS: Mice fed a very-high-fat diet (VHFD, 60% calories as fat) were subjected to drinking solution containing low dose of resveratrol (0.003%) and/or 0.02% phenelzine for 12 weeks. Body fat content, glucose tolerance, food and water consumption were checked during treatment while fat depot mass was determined at the end of supplementation. Direct influence of the agents on lipogenesis and glucose uptake was tested in adipocytes. RESULTS: Epididymal fat depots were reduced in mice drinking phenelzine alone or with resveratrol. No limitation of body weight gain or body fat content was observed in the groups drinking resveratrol or phenelzine, separately or in combination. The altered glucose tolerance and the increased fat body composition of VHFD-fed mice were not reversed by resveratrol and/or phenelzine. Such lack of potentiation between resveratrol and phenelzine prompted us to verify in vitro their direct effects on mouse adipocytes. Both molecules inhibited de novo lipogenesis, but did not potentiate each other at 10 or 100 µM. Only resveratrol inhibited hexose uptake in a manner that was not improved by phenelzine. CONCLUSIONS: Phenelzine has no interest to be combined with low doses of resveratrol for treating/preventing obesity, when considering the VHFD mouse model.

Lysophosphatidic acid impairs glucose homeostasis and inhibits insulin secretion in high-fat diet obese mice.

AIMS/HYPOTHESIS: Lysophosphatidic acid (LPA) is a lipid mediator produced by adipocytes that acts via specific G-protein-coupled receptors; its synthesis is modulated in obesity. We previously reported that reducing adipocyte LPA production in high-fat diet (HFD)-fed obese mice is associated with improved glucose tolerance, suggesting a negative impact of LPA on glucose homeostasis. Here, our aim was to test this hypothesis. METHODS: First, glucose tolerance and plasma insulin were assessed after acute (30 min) injection of LPA (50 mg/kg) or of the LPA1/LPA3 receptor antagonist Ki16425 (5 mg kg(-1) day(-1), i.p.) in non-obese mice fed a normal diet (ND) and in obese/prediabetic (defined as glucose-intolerant) HFD mice. Glucose and insulin tolerance, pancreas morphology, glycogen storage, glucose oxidation and glucose transport were then studied after chronic treatment (3 weeks) of HFD mice with Ki16425. RESULTS: In ND and HFD mice, LPA acutely impaired glucose tolerance by inhibiting glucose-induced insulin secretion. These effects were blocked by pre-injection of Ki16425 (5 mg/kg, i.p.). Inhibition of glucose-induced insulin secretion by LPA also occurred in isolated mouse islets. Plasma LPA was higher in HFD mice than in ND mice and Ki16425 transiently improved glucose tolerance. The beneficial effect of Ki16425 became permanent after chronic treatment and was associated with increased pancreatic islet mass and higher fasting insulinaemia. Chronic treatment with Ki16425 also improved insulin tolerance and increased liver glycogen storage and basal glucose use in skeletal muscle. CONCLUSIONS/INTERPRETATION: Exogenous and endogenous LPA exerts a deleterious effect on glucose disposal through a reduction of plasma insulin; pharmacological blockade of LPA receptors improves glucose homeostasis in obese/prediabetic mice.