Characterization of a new mouse line triggering transient oligodendrocyte progenitor depletion.

Oligodendrocyte progenitor cells (OPC) are the main proliferative cells in the healthy adult brain. They produce new myelinating oligodendrocytes to ensure physiological myelin remodeling and regeneration after various pathological insults. Growing evidence suggests that OPC have other functions. Here, we aimed to develop an experimental model that allows the specific ablation of OPC at the adult stage to unravel possible new functions. We generated a transgenic mouse expressing a floxed human diphtheria toxin receptor under the control of the PDGFRa promoter, crossed with an Olig2Cre mouse to limit the recombination to the oligodendrocyte lineage in the central nervous system. We determined a diphtheria toxin dose to substantially decrease OPC density in the cortex and the corpus callosum without triggering side toxicity after a few daily injections. OPC density was normalized 7 days post-treatment, showing high repopulation capacity from few surviving OPC. We took advantage of this strong but transient depletion to show that OPC loss was associated with behavioral impairment, which was restored by OPC recovery, as well as disruption of the excitation/inhibition balance in the sensorimotor cortex, reinforcing the hypothesis of a neuromodulatory role of OPC in the adult brain.

Evaluating H295R steroidogenesis assay data for robust interpretation.

The in vitro H295R steroidogenesis assay (OECD TG 456) is used to determine a chemical's potential to interfere with steroid hormone synthesis/metabolism. As positive outcomes in this assay can trigger significant higher tiered testing, we compiled a stakeholder database of reference and test item H295R data to characterize assay outcomes. Information concerning whether a Level 5 reproductive toxicity study was triggered due to a positive outcome in the H295R assay was also included. Quality control acceptance criteria were not always achieved, suggesting this assay is challenging to conduct within the guideline specifications. Analysis of test item data demonstrated that pairwise significance testing to controls allowed for overly sensitive statistically significant positive outcomes, which likely contribute to the assay's high positive hit rate. Complementary interpretation criteria (e.g., 1.5-fold change threshold) markedly reduced the rate of equivocal and positive outcomes thus improving identification of robust positive effects in the assay. Finally, a case study (positive H295R outcome and no endocrine adversity in vivo) is presented, which suggests that stricter data interpretation criteria could refine necessary in vivo follow-up testing. Overall, the described additional criteria could improve H295R data interpretation and help inform on how to best leverage this assay for regulatory purposes.

Controlled donation after circulatory death lung transplantation: Results of the French protocol including in situ abdominal normothermic regional perfusion and ex vivo lung perfusion.

BACKGROUND: The French national protocol for controlled donation after circulatory determination of death (cDCD) includes normothermic regional perfusion (NRP) in case of abdominal organ procurement and additional ex-vivo lung perfusion (EVLP) before considering lung transplantation (LT). METHODS: We made a retrospective study of a prospective registry that included all donors considered for cDCD LT from the beginning of the program in May 2016 to November 2021. RESULTS: One hundred grafts from 14 donor hospitals were accepted by 6 LT centers. The median duration of the agonal phase was 20 minutes [2-166]. The median duration from circulatory arrest to pulmonary flush was 62 minutes [20-90]. Ten lung grafts were not retrieved due to prolonged agonal phases (n = 3), failure of NRP insertion (n = 5), or poor in situ evaluation (n = 2). The remaining 90 lung grafts were all evaluated on EVLP, with a conversion rate of 84% and a cDCD transplantation rate of 76%. The median total preservation time was 707 minutes [543-1038]. Seventy-one bilateral LTs and 5 single LTs were performed for chronic obstructive pulmonary disease (n = 29), pulmonary fibrosis (n = 21), cystic fibrosis (n = 15), pulmonary hypertension (n = 8), graft-versus-host disease (n = 2), and adenosquamous carcinoma (n = 1). The rate of PGD3 was 9% (n = 5). The 1-year survival rate was 93.4%. CONCLUSION: After initial acceptance, cDCD lung grafts led to LT in 76% of cases, with outcomes similar to those already reported in the literature. The relative impacts of NRP and EVLP on the outcome following cDCD LT should be assessed prospectively in the context of comparative studies.

[Updated indications and contraindications in 2022 for lung transplantation in France]. / Transplantation pulmonaire en France : actualisation des indications et contre-indications en 2022.

Lung transplantation (LTx) is the last-resort treatment for end-stage respiratory insufficiency, whatever its origin, and represents a steadily expanding field of endeavor. Major developments have been impelled over the years by painstaking efforts at LTx centers to improve donor and recipient selection, and multifaceted attempts have been made to meet the challenges raised by surgical management, perioperative care, and long-term medical complications. The number of procedures has increased, leading to improved post-LTx prognosis. One consequence of these multiple developments has been a pruning away of contraindications over time, which has, in some ways, complicated the patient selection process. With these considerations in mind, the Francophone Pulmonology Society (Société de Pneumology de Langue Française [SPLF]) has set up a task force to produce up-to-date working guidelines designed to assist pulmonologists in managing end-stage respiratory insufficiency, determining which patients may be eligible for LTx, and appropriately timing LTx-center referral. The task force has examined the most recent literature and evaluated the risk factors that continue to limit patient survival after LTx. Ideally, the objectives of LTx are to prolong life while improving quality of life. The guidelines developed by the task force apply to a limited resource and are consistent with the ethical principles described below.

[Radiotherapy for oligometastatic non-small cell lung cancer patients]. / Place de la radiothérapie dans la prise en charge des patients atteints d'un cancer bronchique non à petites cellules oligométastatique.

The oligometastatic disease concept suggests that patients with a limited number of metastases have a favorable prognosis. Radical local treatment of oligometastatic patients has then increased given developments in imaging (mainly positron emission tomography and brain magnetic resonance imaging) and access to effective and better tolerated treatments. Stereotactic radiotherapy has the advantage of being noninvasive, allowing a good rate of local control and a limited number of side effects. A better definition of oligometastatic disease, particularly for non-small cell lung cancer (NSCLC), has recently been published. For patients with NSCLC, two randomized phase II trials also suggested that the addition of a radical local treatment results in encouraging survival data, with a good safety profile. A single-arm phase II finally showed a benefit when combining a radical local treatment with an anti-PD1 immunotherapy. This review describes the definitions of oligometastatic disease, the main prospective findings including radiation therapy, and prospects for oligometastatic NSCLC patients.

Radiofrequency ablation versus surgical resection for the treatment of oligometastatic lung disease.

PURPOSE: The purpose of this study was to compare efficacy and tolerance between radiofrequency ablation (RFA) and surgery for the treatment of oligometastatic lung disease. MATERIALS AND METHODS: This retrospective study reviewed patients treated in two institutions for up to 5 pulmonary metastases with a maximal diameter of 4cm and without associated pleural involvement or thoracic lymphadenopathy. Patient demographics, tumor characteristics, treatment outcome, and length of hospital stay were compared between the two groups. Efficacy endpoints were overall survival (OS), progression-free survival (PFS) and pulmonary or local tumor progression rates. RESULTS: Among 204 patients identified, 78 patients (42 men, 36 women; mean age, 53.3±14.9 [SD]; age range: 15-81 years) were treated surgically, while 126 patients (59 men, 67 women; mean age, 62.2±10.8 [SD]; age range: 33-80 years) were treated by RFA. In the RFA cohort, patients were significantly older (P<0.0001), with more extra-thoracic localisation (P=0.015) and bilateral tumour burden (P=0.0014). In comparison between surgery and RFA cohorts, respectively, the 1- and 3-year OS were 94.8 and 67.2% vs. 94 and 72.1% (P=0.46), the 1- and 3-year PFS were 49.4% and 26.1% vs. 38.9% and 14.8% (P=0.12), the pulmonary progression rates were 39.1% and 56% vs. 41.2% and 65.3% (P>0.99), and the local tumour progression rates were 5.4% and 10.6% vs. 4.8% and 18.6% (P=0.07). Tumour size>2cm was associated with a significantly higher local tumor progression in the RFA group (P=0.010). Hospitalisation stay was significantly shorter in the RFA group (median of 3 days; IQR=2 days; range: 2-12 days) than in the surgery group (median of 9 days; IQR=2 days; range: 6-21 days) (P<0.01). CONCLUSION: RFA should be considered a minimally-invasive alternative with similar OS and PFS to surgery in the treatment of solitary or multiple lung metastases measuring less than 4cm in diameter without associated pleural involvement or thoracic lymphadenopathy.

[Role of immunotherapy in locally advanced non-small cell lung cancer]. / Place de l'immunothérapie dans le cancer bronchique non à petites cellules localement avancé.

Concomitant radiochemotherapy has been the standard of care for unresectable stage III non-small cell lung cancer (NSCLC), irrespective of histological sub-type or molecular characteristics. Currently, only 15-30 % of patients are alive five years after radiochemotherapy, and this figure remains largely unchanged despite multiple phase III randomised trials. In recent years, immune-checkpoint blockades with anti-PD-(L)1 have revolutionised the care of metastatic NSCLC, becoming the standard front- and second-line strategy. Several preclinical studies reported an increased tumour antigen release, improved antigen presentation, and T-cell infiltration in irradiated tumours. Immunotherapy has therefore recently been evaluated for patients with locally advanced stage III NSCLC. Following the PACIFIC trial, the anti-PD-L1 durvalumab antibody has emerged as a new standard consolidative treatment for patients with unresectable stage III NSCLC whose disease has not progressed following concomitant platinum-based chemoradiotherapy. Immunoradiotherapy therefore appears to be a promising association in patients with localised NSCLC. Many trials are currently evaluating the value of concomitant immunotherapy and chemoradiotherapy and/or consolidative chemotherapy with immunotherapy in patients with locally advanced unresectable NSCLC.

[Therapeutic options for oligoprogressive non-small cell lung cancer]. / Prise en charge thérapeutique des cancers bronchiques non à petites cellules oligoprogressifs.

Lung cancer is the leading cause of cancer-related mortality and more than half of the cases are diagnosed at a metastatic stage. Major progress in terms of systemic treatments has been achieved in recent decades. Access to new anti-PD-(L) 1 immunotherapies and targeted therapies for non-small cell lung cancer (NSCLC) with oncogenic addiction such as EGFR mutation or ALK rearrangement have led to improved outcomes. Patients with limited progression of their disease during systemic treatment may be a particular subgroup. This oligoprogressive state is characterized by a limited number of sites in progression, implying that the other sites remain controlled and therefore sensitive to systemic treatments. The advent of non-invasive techniques such as stereotactic radiotherapy, radiofrequency, and mini-invasive surgery has led to a precise re-evaluation of local ablative treatments in this situation. Local treatment of the oligoprogressive lesion(s) may allow modification of the natural history of the disease, maintenance of effective systemic targeted treatment and, ultimately, to improved survival. Data validating an aggressive local therapeutic approach in oligoprogressive NSCLC patients are currently limited and essentially retrospective. Several international trials are underway that could confirm the clinical benefit of radical local treatment in oligoprogressive advanced NSCLC patients.

[Treatment of chronic thromboembolic pulmonary hypertension in elderly patients]. / Traitement du cœur pulmonaire post-embolique chez le sujet âgé.

AIM OF THE STUDY: To establish efficacy and security of invasive treatments for chronic thromboembolic pulmonary hypertension (CTEPH) in elderly patients (≥80 years old): pulmonary endarterectomy (PEA) and balloon pulmonary angioplasty (BPA). PATIENTS AND METHODS: Between 2014 and 2017, 549 CTEPH patients were addressed to our hospital for PEA (364 patients) or BPA (225). From this total, patients 80 years old and over were: 17 treated by PEA and 21 by BPA. Demographic characteristics as well as hemodynamic parameters, results and complications were compared for both groups (Young - Y - versus Old - O). RESULTS: Elderly BPA patients presented a higher functional class (mean O: 3,16 versus Y: 2,73; P=0,001), with similar hemodynamics parameters compared with the younger patients. Indication for BPA in the elderly was the presence of comorbidities contraindicating surgery in 33% of cases vs. 9,3% in the younger group (P=0,005). Response to treatment was comparable in both groups with significant reductions of mPAP, PVR and improvement of functional class. Complications rate was alike between groups for hemoptysis, reperfusion lesions or mortality, with the exception of a higher incidence of contrast-induced nephropathy, without need for dialysis, in the elderly group (O: 8,4% versus 2,6%; P=0,010). Elderly PEA patients were more often male (O: 76,5% versus Y: 50,1%; P=0,034) and with a lower creatinine clearance (O: 57,6±13,4 versus Y: 72,2±21,2mL/min/m2; P=0,004). Functional class, hemodynamics, surgical times and in-hospital stay was similar between groups. There is a non-significant trend towards higher in-hospital mortality in the elderly group, CONCLUSIONS: In our experience, treatment of CPC PE in elderly patients, either by PEA or BPA is effective with acceptable complication rates.

[Massive pulmonary embolism. When medical treatment is not enough]. / Embolie pulmonaire massive. Quand le traitement médical ne suffit pas.

Emergency bedside veno-arterious ECMO implantation can be the only saving gesture in the suspicion of acute massive pulmonary embolism leading to haemodynamic failure, even before CT-scan imaging. Once the massive pulmonary embolism is confirmed it is possible to undergo surgical or percutaneous pulmonary thrombectomy, when thrombolytic therapy is contraindicated.

Inactivation of p53 Is Sufficient to Induce Development of Pulmonary Hypertension in Rats.

OBJECTIVE: Pulmonary artery smooth muscle cells (PA-SMCs) in pulmonary arterial hypertension (PAH) show similarities to cancer cells. Due to the growth-suppressive and pro-apoptotic effects of p53 and its inactivation in cancer, we hypothesized that the p53 pathway could be altered in PAH. We therefore explored the involvement of p53 in the monocrotaline (MCT) rat model of pulmonary hypertension (PH) and the pathophysiological consequences of p53 inactivation in response to animal treatment with pifithrin-α (PFT, an inhibitor of p53 activity). METHODS AND RESULTS: PH development was assessed by pulmonary arterial pressure, right ventricular hypertrophy and arterial wall thickness. The effect of MCT and PFT on lung p53 pathway expression was evaluated by western blot. Fourteen days of daily PFT treatment (2.2 mg/kg/day), similar to a single injection of MCT (60 mg/kg), induced PH and aggravated MCT-induced PH. In the first week after MCT administration and prior to PH development, p53, p21 and MDM2 protein levels were significantly reduced; whereas PFT administration effectively altered the protein level of p53 targets. Anti-apoptotic and pro-proliferative effects of PFT were revealed by TUNEL and MTT assays on cultured human PA-SMCs treated with 50 µM PFT. CONCLUSIONS: Pharmacological inactivation of p53 is sufficient to induce PH with a chronic treatment by PFT, an effect related to its anti-apoptotic and pro-proliferative properties. The p53 pathway was down-regulated during the first week in the rat MCT model. These in vivo experiments implicate the p53 pathway at the initiation stages of PH pathogenesis.

Lung transplantation with donation after circulatory determination of death donors and the impact of ex vivo lung perfusion.

The growing demand for suitable lungs for transplantation drives the quest for alternative strategies to expand the donor pool. The aim of this study is to evaluate the outcomes of lung transplantation (LTx) with donation after circulatory determination of death (DCDD) and the impact of selective ex vivo lung perfusion (EVLP). From 2007 to 2013, 673 LTx were performed, with 62 (9.2%) of them using DCDDs (seven bridged cases). Cases bridged with mechanical ventilation/extracorporeal life support were excluded. From 55 DCDDs, 28 (51%) underwent EVLP. Outcomes for LTx using DCDDs and donation after neurological determination of death (DNDD) donors were similar, with 1 and 5-year survivals of 85% and 54% versus 86% and 62%, respectively (p = 0.43). Although comparison of survival curves between DCDD + EVLP versus DCDD-no EVLP showed no significant difference, DCDD + EVLP cases presented shorter hospital stay (median 18 vs. 23 days, p = 0.047) and a trend toward shorter length of mechanical ventilation (2 vs. 3 days, p = 0.059). DCDDs represent a valuable source of lungs for transplantation, providing similar results to DNDDs. EVLP seems an important technique in the armamentarium to safely increase lung utilization from DCDDs; however, further studies are necessary to better define the role of EVLP in this context.

[Aneurysmal rupture complicating aortitis: a case report]. / Aortite polyanévrismale compliquée de rupture : à propos d'un cas.

Tropical aortitis is a rare and poorly described aortic disease, sometimes confounded with Takayasu's disease, mainly in people from Africa. In this case report, the panaortic aneurysmal disease in a young woman from Haiti, first diagnosed after a work-up on renovascular hypertension, would appear to approach this particular arterial disease with no clinical, radiological or biological argument for an infectious etiology. The initially suspected diagnosis of Takayasu's disease had to be rethought because of the presence of several saccular aneurysms extending from the aortic arch to the infrarenal aorta, rarely described in Takayasu's aortitis. Expert opinions from vascular surgeons and clinicians tagged this aortic disease as similar to tropical aortitis which remained asymptomatic for more than a decade. Hypertension was managed with successful balloon angioplasty of the left renal artery stenosis and anti-hypertensive combination therapy. Surgical management of the extended aortic aneurysms was not proposed because of the stability and asymptomatic nature of the aneurysmal disease and the high risk of surgical morbidity and mortality. More than ten years after diagnosis, the course was marked with inaugural and sudden-onset chest pain concomitant with contained rupture of the descending thoracic aortic aneurysm. This case report underlines the persistent risk of aneurysmal rupture and the importance of an anatomopathological study for the diagnosis of complex aortic disease.

Computed tomography findings of pulmonary venoocclusive disease in scleroderma patients presenting with precapillary pulmonary hypertension.

OBJECTIVE: Pulmonary venoocclusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by obstruction of small pulmonary veins. Pulmonary venous involvement has been reported in pathologic assessment of patients with systemic sclerosis (SSc) presenting with precapillary PH. High-resolution computed tomography (HRCT) of the chest is a noninvasive diagnostic tool used to screen for PVOD. No HRCT data are available on SSc patients with precapillary PH. We undertook this study to evaluate the frequency and effect on prognosis of HRCT signs of PVOD in SSc patients with precapillary PH. METHODS: We reviewed chest HRCT data from 26 SSc patients with precapillary PH and 28 SSc patients without pulmonary arterial hypertension (PAH) or interstitial lung disease (ILD). RESULTS: The radiographic triad of HRCT signs of PVOD (lymph node enlargement [57.7% versus 3.6%], centrilobular ground-glass opacities [46.2% versus 10.7%], and septal lines [88.5% versus 7.1%]) was significantly more frequent in SSc patients with precapillary PH than in SSc patients without PAH or ILD (all P < 0.005). Indeed, 61.5% of SSc patients with precapillary PH had ≥ 2 of these signs. Cardiomegaly (P < 0.0001), pulmonary artery enlargement (P < 0.0001), and pericardial effusion (P < 0.0005) were also significantly more frequent in SSc patients with precapillary PH. Pulmonary venous involvement was histologically confirmed in 2 patients with radiographic signs of PVOD. The presence of ≥ 2 radiographic signs of PVOD was associated with the occurrence of pulmonary edema after initiation of PAH-specific therapy (in 8 of 16 patients) and with more rapid progression from diagnosis of PH to death. CONCLUSION: HRCT signs of PVOD are frequently observed in SSc patients with precapillary PH, correlated with histologic assessment, and were associated with a high risk of pulmonary edema.

[Surgical treatment of pulmonary arterial hypertension]. / Traitement chirurgical de l'hypertension artérielle pulmonaire.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a severe disease that has undergone a dramatic improvement in therapeutic management over the past 20 years. Among the new therapeutic options, surgery has the potential to dramatically improve or, in some cases, cure PAH. BACKGROUND: Surgical treatment of PAH includes pulmonary endarterectomy which can cure PAH when the cause is obstruction of the pulmonary arteries by fibrous tissue resulting from pulmonary embolism, by tumours as angiosarcomas, and echinococcus cysts. Transplantation is required in end-stage PAH after failure of medical treatment. Atrial septostomy and Potts procedure are palliative surgical procedures that can delay transplantation. VIEWPOINT: Extracorporeal cardiopulmonary support is the latest surgical improvement, not only as a bridge to transplantation in end-stage PAH but also during recovery after transplantation or pulmonary endarterectomy. CONCLUSIONS: Surgery is part of the therapeutic management of PAH. Dialogue between physicians and surgeons is a prerequisite for any reasoned therapeutic decision.

Cautious epoprostenol therapy is a safe bridge to lung transplantation in pulmonary veno-occlusive disease.

Pulmonary veno-occlusive disease (PVOD) carries a poor prognosis and lung transplantation is the only curative treatment. In PVOD, epoprostenol therapy is controversial, as this condition may be refractory to specific therapy with an increased risk of pulmonary oedema. We retrospectively reviewed clinical, functional and haemodynamic data of 12 patients with PVOD (10 with histological confirmation) treated with continuous intravenous epoprostenol and priority listed for lung transplantation after January 1, 2003. All PVOD patients had severe clinical, functional and haemodynamic impairment at presentation. Epoprostenol was used at low dose ranges with slow dose increases and high dose diuretics. Only one patient developed mild reversible pulmonary oedema. After 3-4 months, improvements were seen in the New York Heart Association functional class (class IV to III in seven patients), cardiac index (1.99+/-0.68 to 2.94+/-0.89 L x min(-1) x m(-2)) and indexed pulmonary vascular resistance (28.4+/-8.4 to 17+/-5.2 Wood units x m(-2); all p<0.01). A nonsignificant improvement in the 6-min walk distance was also observed (+41 m, p = 0.11). Two patients died, one patient was alive on the transplantation waiting list on December 1, 2008 and nine patients were transplanted. Cautious use of continuous intravenous epoprostenol improved clinical and haemodynamic parameters in PVOD patients at 3-4 months without commonly causing pulmonary oedema, and may be a useful bridge to urgent lung transplantation.

Surgical treatment of celiac artery aneurysm associated with median arcuate ligament.

Celiac artery aneurysms are rare but potentially fatal because of the risk of rupture. Atherosclerosis and fibrous dysplasia are the two most common etiologies. Median arcuate ligament compression of the celiac artery is common but usually asymptomatic. We report three cases of post-stenotic celiac artery aneurysm with median arcuate ligament compression admitted to our hospital over the past two years. Although the incidence is rare with only 8 cases reported in the literature, a median arcuate ligament may have a role in the development of celiac artery aneurysms and its presence can influence the surgical strategy.