Time-adaptive Lagrangian Variational Integrators for Accelerated Optimization on Manifolds

A variational framework for accelerated optimization was recently introduced on normed vector spaces and Riemannian manifolds in Wibisono et al. (2016) and Duruisseaux and Leok (2021). It was observed that a careful combination of timeadaptivity and symplecticity in the numerical integration can result in a significant gain in computational efficiency. It is however well known that symplectic integrators lose their near energy preservation properties when variable time-steps are used. The most common approach to circumvent this problem involves the Poincare transformation on the Hamiltonian side, and was used in Duruisseaux et al. (2021) to construct efficient explicit algorithms for symplectic accelerated optimization. However, the current formulations of Hamiltonian variational integrators do not make intrinsic sense on more general spaces such as Riemannian manifolds and Lie groups. In contrast, Lagrangian variational integrators are well-defined on manifolds, so we develop here a framework for time-adaptivity in Lagrangian variational integrators and use the resulting geometric integrators to solve optimization problems on normed vector spaces and Lie groups.Comment: 30 pages, 4 figure

Signature moléculaire des adénocarcinomes pulmonaires de type lépidique prédominant et mucineux invasif et dérégulation

Lepidic predominant adenocarcinoma (LPA) represents an original entity in terms of histological, clinical and biological characteristics among adenocarcinomas of the lung. While LPA is typically a non-mucinous adenocarcinoma, a mucinous variant does exist, termed invasive mucinous adenocarcinoma (IMA), associated with a worse prognosis and a lack of effective treatment in advanced diseases. This work sought to study molecular differences between LPA and IMA, and explore their biological meanings. A cohort of LPA and AMI has been studied in regard of clinical characteristics and oncogenic drivers and samples from this cohort were exploited. An immunohistochemical study of expression of mucins MUC1, 2, 5B, 5AC and 6 in surgical samples of 27 LPA and 27 IMA showed different profile of expression between LPA and IMA. MUC1 expression was associated to MUC1 and MUC5AC, 5B and 6 to IMA. MUC1 was associated to EGFR mutations and MUC5B and 5AC to KRAS mutations. One NRG1 rearrangement was detected by FISH in one in 25 IMA. The CXCL10 chemokine was overexpressed in bronchoalveolar lavage fluid (BALF) supernatants of IMA (n=38) compared to LPA (n=25). This overexpression was linked to worse prognosis. The cytokine/receptor axis CXCL10/CXCR3-A was overexpressed in IMA and promoted migration of mucinous tumoral cells and drived tumoral expression of VEGF. VEGF from BALF of patients significantly enhanced human lung endothelial tubes formation in vitro which was inhibited by anti-VEGF bevacizumab. CXCL10/CXCR3 and VEGF could present valuable therapeutic targets in IMA. These results improve knowledge in biology of LPA and AMI and identify new lines of research which could lead to development of new therapies.Les adénocarcinomes lépidiques prédominant (ALP) sont une entité originale sur le plan histologique, clinique et biologique parmi les adénocarcinomes pulmonaires. Il s’agit de tumeurs non-mucineuses mais il existe un variant mucineux, l’adénocarcinome mucineux invasif (AMI), caractérisé par un plus mauvais pronostic et l’absence de traitement efficace dans les formes avancées. L’objectif de ce travail était d’étudier les différences moléculaires distinguant ALP et AMI et d’en dégager les implications biologiques. Après avoir détaillé les caractéristiques cliniques et les altérations oncogéniques d’une cohorte d’ALP et d’AMI, nous avons exploité les banques de prélèvements issus de cette cohorte. Une étude de l’expression en immunohistochimie des mucines MUC1, 2, 5B, 5AC et 6 au sein des pièces opératoires de 27 ALP et 27 AMI montrait un profil d’expression spécifique entre ALP et AMI. L’expression de MUC1 était associée aux ALP, celle de MUC5AC, 5B et 6 aux AMI. L’expression de MUC1 était associée aux mutations EGFR et MUC5B et 5AC aux mutations KRAS. Un réarrangement NRG1 a été détecté par FISH dans 1 AMI sur 25. La chimiokine CXCL10 était surexprimée dans les surnageants de lavages broncho-alvéolaires (LBA) de patients avec AMI (n=38) comparés aux ALP (n=25), et cette surexpression était de mauvais pronostic. La voie cytokine/récepteur CXCL10/CXCR3-A était surexprimée dans les AMI, faisait la promotion de la migration des cellules tumorales mucineuses et gouvernait l’expression tumorale de VEGF. Le VEGF issu du LBA des patients était à l’origine in vitro d’une augmentation significative de la formation de tubes vasculaires inhibée par l’anti-VEGF bevacizumab. Le ciblage de CXCL10/CXCR3-A et du VEGF pourraient être des options thérapeutiques dans les AMI. Ces résultats permettent d’affiner les connaissances biologiques des ALP et des AMI et dégagent des voies de recherche originales qui pourraient amener au développement de nouveaux traitement

Simplifying Momentum-based Positive-definite Submanifold Optimization with Applications to Deep Learning

Riemannian submanifold optimization with momentum is computationally challenging because, to ensure that the iterates remain on the submanifold, we often need to solve difficult differential equations. Here, we simplify such difficulties for a class of structured symmetric positive-definite matrices with the affine-invariant metric. We do so by proposing a generalized version of the Riemannian normal coordinates that dynamically orthonormalizes the metric and locally converts the problem into an unconstrained problem in the Euclidean space. We use our approach to simplify existing approaches for structured covariances and develop matrix-inverse-free $2^\text{nd}$-order optimizers for deep learning with low precision by using only matrix multiplications. Code: https://github.com/yorkerlin/StructuredNGD-DLComment: An updated version of the ICML 2023 paper. Updated the main text and added more numerical results for DNNs including a new baseline method and improving existing baseline method

RET-MAP: An International Multicenter Study on Clinicobiologic Features and Treatment Response in Patients With Lung Cancer Harboring a RET Fusion

Chemotherapy; Non–small cell lung cancer; RET inhibitorsQuimioteràpia; Càncer de pulmó de cèl·lules no petites; Inhibidors de RETQuimioterapia; Cáncer de pulmón de células no pequeñas; Inhibidores de RETIntroduction Nearly 1% to 2% of NSCLCs harbor RET fusions. Characterization of this rare population is still incomplete. Methods This retrospective multicenter study included patients with any-stage RET positive (RET+) NSCLC from 31 cancer centers. Molecular profiling included DNA/RNA sequencing or fluorescence in situ hybridization analyses. Clinicobiological features and treatment outcomes (per investigator) with surgery, chemotherapy (CT), immune checkpoint blockers (ICBs), CT-ICB, multityrosine kinase inhibitors, and RET inhibitors (RETis) were evaluated. Results For 218 patients included between February 2012 and April 2022, median age was 63 years, 56% were females, 93% had adenocarcinoma, and 41% were smokers. The most frequent fusion partner was KIF5B (72%). Median tumor mutational burden was 2.5 (range: 1–4) mutations per megabase, and median programmed death-ligand 1 expression was 10% (range: 0%–55%). The most common metastatic sites were the lung (50%), bone (43%), and pleura (40%). Central nervous system metastases were found at diagnosis of advanced NSCLC in 21% of the patients and at last follow-up or death in 31%. Overall response rate and median progression-free survival were 55% and 8.7 months with platinum doublet, 26% and 3.6 months with single-agent CT, 46% and 9.6 months with CT-ICB, 23% and 3.1 months with ICB, 37% and 3 months with multityrosine kinase inhibitor, and 76% and 16.2 months with RETi, respectively. Median overall survival was longer in patients treated with RETi versus no RETi (50.6 mo [37.7–72.1] versus 16.3 mo [12.7–28.8], p < 0.0001). Conclusions Patients with RET+ NSCLC have mainly thoracic and bone disease and low tumor mutational burden and programmed death-ligand 1 expression. RETi markedly improved survival, whereas ICB may be active in selected patients.Writing assistance was provided by Mrs. Sarah Mackenzie. Dr. Marinello was the recipient for the grant for DUERTECC/EURONCO (Diplôme Universitaire Européen de Recherche Translationnelle Et Clinique en Cancérologie). Dr. Mezquita received support from the Contrato Juan Rodes 2020 (ISCIII, Ministry of Health); Ayuda de la Acción Estratégica en Salud-ISCIII FIS 2021 (PI21/01653); Ayuda SEOM-Juan Rodés 2020. Dr. Cortellini acknowledges the support from the National Institute for Health Research Imperial Biomedical Research Centre. Dr. Pinato acknowledges the support from the Wellcome Trust Strategic Fund (PS3416), Associazione Italiana per la Ricerca sul Cancro (Associazione Italiana per la Ricerca sul Cancro MFAG Grant ID 25697), National Institute for Health Research Imperial Biomedical Research Centre, Imperial Experimental Cancer Medicine Centre, and the Imperial College Tissue Bank

Efficacy of First-Line Chemotherapy in Patients with Advanced Lung Sarcomatoid Carcinoma

Background:Sarcomatoid carcinomas (SCs) are rare tumors that may arise in the lung, accounting for 0.4% of non–small-cell lung cancers; the prognosis is poor. Only few retrospective small-size series have studied the efficacy of chemotherapy (CT) for metastatic SC.Methods:Multicenter study of patients with advanced or metastatic SC who received first-line CT. Clinical characteristics at baseline, response to first-line CT (Response Evaluation Criteria in Solid Tumors version 1.1), progression-free survival (PFS), and overall survival (OS) were retrospectively collected.Results:Ninety-seven patients were included. Median age was 62 (54–72) years. The majority of patients were men (70%), white (84%), and smokers (84%). Overall, 73% of patients received first-line platinum-based CT. At first tumor evaluation, 69% of patients experienced progression, 31% had disease control, and 16.5% had partial response. Partial response was observed in 20% of patients receiving platinum-based CT, and in none of those receiving non–platinum-based CT (p = 0.018). Median PFS was 2.0 months (confidence interval [CI] 95%: 1.8–2.3). PFS was not statistically different between patients receiving or not receiving a platinum-based CT. Median OS was 6.3 months (CI 95%: 4.7–7.8). There was a trend toward better OS for patients treated with platinum-based CT (7.0 months [CI 95%: 4.9–9.0] versus 5.3 months [CI 95%: 2.8–7.6]; p = 0.096). In multivariate analysis, disease control at first evaluation (hazard ratio = 0.38 [CI 95%: 0.21–0.59]) and at platinum-based CT (hazard ratio = 0.92 [CI 95%: 0.85–0.99]) was associated with better OS.Conclusion:SC is associated with poor prognosis and high rate of resistance to conventional first-line CT. New therapeutic strategies are needed, based on better knowledge of the carcinogenesis of SC

Prognostic Impact of Paraneoplastic Cushing’s Syndrome in Small-Cell Lung Cancer

Introduction:Paraneoplastic Cushing’s syndrome (CushingPS) in small-cell lung cancer is rare but severe.Methods:We studied 383 patients with small-cell lung cancer diagnosed between 1998 and 2012. Among them, 23 patients had CushingPS, 56 had other paraneoplastic syndrome (OtherPS), and 304 had no paraneoplastic syndrome (NoPS).Results:After comparison of the three groups, we observed that CushingPS patients had more extensive disease: 82.6% versus 67.8% versus 53.3% (p = 0.005), respectively, with more than two metastatic sites: 63.2% versus 15.8% and 24.1% (p ⩽ 0.001), a higher World Health Organization performance status (2–4): 73.9% versus 57.1% versus 43.7% (p = 0.006), greater weight loss (≥10%): 47.8% versus 33.9% versus 16.4% (p ⩽ 0.001), reduced objective response to first-line treatment: 47.6% versus 74.1% versus 71.1% (p = 0.04), and poorer sensitivity to first-line treatment: 19% versus 38.9% versus 48.6% (p = 0.01). NoPS patients, with World Health Organization performance status of 3–4, had extensive disease at diagnosis, with response, sensitivity to first-line treatment, and survival similar to the CushingPS group. At relapse, the CushingPS group had no objective response to second-line treatment versus 25% versus 42.8% in OtherPS and NoPS groups, respectively (p = 0.005). The median survival of CushingPS patients was 6.6 months versus 9.2 months for OtherPS and 13.1 months for NoPS patients (p ⩽ 0.001). CushingPS is a prognostic factor of death (hazard ratio, 2.31; p ⩽ 0.001).Conclusion:CushingPS is the worst form of the paraneoplastic syndromes with particularly extensive tumors. Reduced objective response and sensitivity to first-line treatment and no response to second-line treatment suggest starting palliative care early at first line and exclusively at relapse

Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicenter, retrospective analysis

Background: Anti-programmed death-1 (PD-1) treatment for advanced non-small-cell lung cancer (NSCLC) has improved the survival of patients. However, a substantial percentage of patients do not respond to this treatment. We examined the use of DNA methylation profiles to determine the efficacy of anti-PD-1 treatment in patients recruited with current stage IV NSCLC. Methods: In this multicentre study, we recruited adult patients from 15 hospitals in France, Spain, and Italy who had histologically proven stage IV NSCLC and had been exposed to PD-1 blockade during the course of the disease. The study structure comprised a discovery cohort to assess the correlation between epigenetic features and clinical benefit with PD-1 blockade and two validation cohorts to assess the validity of our assumptions. We first established an epigenomic profile based on a microarray DNA methylation signature (EPIMMUNE) in a discovery set of tumour samples from patients treated with nivolumab or pembrolizumab. The EPIMMUNE signature was validated in an independent set of patients. A derived DNA methylation marker was validated by a single-methylation assay in a validation cohort of patients. The main study outcomes were progression-free survival and overall survival. We used the Kaplan-Meier method to estimate progression-free and overall survival, and calculated the differences between the groups with the log-rank test. We constructed a multivariate Cox model to identify the variables independently associated with progression-free and overall survival. Findings: Between June 23, 2014, and May 18, 2017, we obtained samples from 142 patients: 34 in the discovery cohort, 47 in the EPIMMUNE validation cohort, and 61 in the derived methylation marker cohort (the T-cell differentiation factor forkhead box P1 [FOXP1]). The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0·010, 95% CI 3·29 × 10 −4–0·0282; p=0·0067) and overall survival (0·080, 0·017–0·373; p=0·0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0·330, 0·149–0·727; p=0·0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0·415, 0·209–0·802; p=0·0063) and overall survival (0·409, 0·220–0·780; p=0·0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy. Interpretation: Our study shows that the epigenetic milieu of NSCLC tumours indicates which patients are most likely to benefit from nivolumab or pembrolizumab treatments. The methylation status of FOXP1 could be associated with validated predictive biomarkers such as PD-L1 staining and mutational load to better select patients who will experience clinical benefit with PD-1 blockade, and its predictive value should be evaluated in prospective studies

Molecular profile of lepidic predominant adenocarcinoma and invasive mucinous adenocarcinoma and deregulation

Les adénocarcinomes lépidiques prédominant (ALP) sont une entité originale sur le plan histologique, clinique et biologique parmi les adénocarcinomes pulmonaires. Il s’agit de tumeurs non-mucineuses mais il existe un variant mucineux, l’adénocarcinome mucineux invasif (AMI), caractérisé par un plus mauvais pronostic et l’absence de traitement efficace dans les formes avancées. L’objectif de ce travail était d’étudier les différences moléculaires distinguant ALP et AMI et d’en dégager les implications biologiques. Après avoir détaillé les caractéristiques cliniques et les altérations oncogéniques d’une cohorte d’ALP et d’AMI, nous avons exploité les banques de prélèvements issus de cette cohorte. Une étude de l’expression en immunohistochimie des mucines MUC1, 2, 5B, 5AC et 6 au sein des pièces opératoires de 27 ALP et 27 AMI montrait un profil d’expression spécifique entre ALP et AMI. L’expression de MUC1 était associée aux ALP, celle de MUC5AC, 5B et 6 aux AMI. L’expression de MUC1 était associée aux mutations EGFR et MUC5B et 5AC aux mutations KRAS. Un réarrangement NRG1 a été détecté par FISH dans 1 AMI sur 25. La chimiokine CXCL10 était surexprimée dans les surnageants de lavages broncho-alvéolaires (LBA) de patients avec AMI (n=38) comparés aux ALP (n=25), et cette surexpression était de mauvais pronostic. La voie cytokine/récepteur CXCL10/CXCR3-A était surexprimée dans les AMI, faisait la promotion de la migration des cellules tumorales mucineuses et gouvernait l’expression tumorale de VEGF. Le VEGF issu du LBA des patients était à l’origine in vitro d’une augmentation significative de la formation de tubes vasculaires inhibée par l’anti-VEGF bevacizumab. Le ciblage de CXCL10/CXCR3-A et du VEGF pourraient être des options thérapeutiques dans les AMI. Ces résultats permettent d’affiner les connaissances biologiques des ALP et des AMI et dégagent des voies de recherche originales qui pourraient amener au développement de nouveaux traitementsLepidic predominant adenocarcinoma (LPA) represents an original entity in terms of histological, clinical and biological characteristics among adenocarcinomas of the lung. While LPA is typically a non-mucinous adenocarcinoma, a mucinous variant does exist, termed invasive mucinous adenocarcinoma (IMA), associated with a worse prognosis and a lack of effective treatment in advanced diseases. This work sought to study molecular differences between LPA and IMA, and explore their biological meanings. A cohort of LPA and AMI has been studied in regard of clinical characteristics and oncogenic drivers and samples from this cohort were exploited. An immunohistochemical study of expression of mucins MUC1, 2, 5B, 5AC and 6 in surgical samples of 27 LPA and 27 IMA showed different profile of expression between LPA and IMA. MUC1 expression was associated to MUC1 and MUC5AC, 5B and 6 to IMA. MUC1 was associated to EGFR mutations and MUC5B and 5AC to KRAS mutations. One NRG1 rearrangement was detected by FISH in one in 25 IMA. The CXCL10 chemokine was overexpressed in bronchoalveolar lavage fluid (BALF) supernatants of IMA (n=38) compared to LPA (n=25). This overexpression was linked to worse prognosis. The cytokine/receptor axis CXCL10/CXCR3-A was overexpressed in IMA and promoted migration of mucinous tumoral cells and drived tumoral expression of VEGF. VEGF from BALF of patients significantly enhanced human lung endothelial tubes formation in vitro which was inhibited by anti-VEGF bevacizumab. CXCL10/CXCR3 and VEGF could present valuable therapeutic targets in IMA. These results improve knowledge in biology of LPA and AMI and identify new lines of research which could lead to development of new therapies