Prediction of response to immune checkpoint blockade in patients with metastatic colorectal cancer with microsatellite instability.

BACKGROUND: Mismatch repair-deficient (dMMR) tumors displaying microsatellite instability (MSI) represent a paradigm for the success of immune checkpoint inhibitor (ICI)-based immunotherapy, particularly in patients with metastatic colorectal cancer (mCRC). However, a proportion of patients with dMMR/MSI mCRC exhibit resistance to ICI. Identification of tools predicting MSI mCRC patient response to ICI is required for the design of future strategies further improving this therapy. PATIENTS AND METHODS: We combined high-throughput DNA and RNA sequencing of tumors from 116 patients with MSI mCRC treated with anti-programmed cell death protein 1 ± anti-cytotoxic T-lymphocyte-associated protein 4 of the NIPICOL phase II trial (C1, NCT03350126, discovery set) and the ImmunoMSI prospective cohort (C2, validation set). The DNA/RNA predictors whose status was significantly associated with ICI status of response in C1 were subsequently validated in C2. Primary endpoint was progression-free survival by immune RECIST (iRECIST) (iPFS). RESULTS: Analyses showed no impact of previously suggested DNA/RNA indicators of resistance to ICI, e.g. MSIsensor score, tumor mutational burden, or specific cellular and molecular tumoral contingents. By contrast, iPFS under ICI was shown in C1 and C2 to depend both on a multiplex MSI signature involving the mutations of 19 microsatellites hazard ratio cohort C2 (HRC2) = 3.63; 95% confidence interval (CI) 1.65-7.99; P = 1.4 × 10-3] and the expression of a set of 182 RNA markers with a non-epithelial transforming growth factor beta (TGFB)-related desmoplastic orientation (HRC2 = 1.75; 95% CI 1.03-2.98; P = 0.035). Both DNA and RNA signatures were independently predictive of iPFS. CONCLUSIONS: iPFS in patients with MSI mCRC can be predicted by simply analyzing the mutational status of DNA microsatellite-containing genes in epithelial tumor cells together with non-epithelial TGFB-related desmoplastic RNA markers.

[Phalloplasty by radial forearm free flap in the context of female-to-male gender reassignment surgery]. / Phallopoièse par lambeau antébrachial radial libre dans la chirurgie de réassignation sexuelle femme à homme.

AIMS: The aims of this article are to provide an overview of the technique of phalloplasty by radial forearm free flap in the context of female-to-male gender reassignment surgery, with a specific focus on surgical technical details and the prevention of postoperative complications. METHODS: In the light of our 30 years of experience in caring for female-to-male transgender individuals and conducting a critical review of the literature, we exhaustively present our technique of radial forearm free flap phalloplasty in female-to-male gender reassignment surgery. RESULTS: The technique of radial forearm free flap phalloplasty, utilizing a one-stage approach for neourethral and neophallus construction based on the "tube within a tube" principle, not only achieves an aesthetically pleasing appearance of the neophallus resembling a normal penis with tactile and erogenous sensitivities but also yields a functional neourethra and satisfactory penile rigidity using implants for standing voiding and sexual intercourse. This intricate surgical procedure demands not only meticulous execution of all surgical maneuvers but also high-level postoperative care. Despite refinements in technique over recent decades, aesthetic sequelae at the donor site of the flap remain subject to criticism, and postoperative complications, particularly of vascular and urological nature, remain significant. CONCLUSION: Future optimization of the surgical technique for this procedure will be imperative to minimize postoperative complications and establish a true technical "gold standard" for phalloplasty in female-to-male transgender individuals.

Excited-State Dynamics of Dithienylethenes Functionalized for Self-Supramolecular Assembly.

The photoswitching and competitive processes of two photochromic dithienylethenes (DTEs) functionalized at both sides with 2-ureido-4[1H]-pyrimidone (UPy) quadruple hydrogen-bonding recognition patterns have been investigated with NMR experiments, ultrafast spectroscopy, and density functional theory (DFT) calculations. The originality of these molecules is their ability to form large supramolecular assemblies induced by light for the closed form (CF) species while the open form (OF) species exist as small oligomers. Photochromic parameters have been determined and photochemical pathways have been rationalized with clear distinction between the antiparallel (OF-AP) and parallel (OF-P) species. A new photocyclization pathway via triplet manifold has been evidenced. The effect of the supramolecular assembly on the photochemical response is discussed. Unlike the photoreversion process, which is unaffected by supramolecular assembly, rate constants of the photocyclization reaction and intersystem crossing process are sensitive to the presence of small OF oligomers.

Detection of a few DNA copies by real-time electrochemical polymerase chain reaction.

In the current work, accurate quantification over 10 to 108 DNA copies has been successfully achieved for the first time by real-time electrochemical PCR. This has been made possible thanks to the combined use of a fully automated house-built electrochemical qPCR device, optimized for parallel heating and electrochemical monitoring of up to 48 PCR solutions, and the appropriate selection of a DNA intercalating redox probe retaining a strong affinity binding to ds-DNA at the PCR measurement temperature of 72 °C (corresponding to the PCR elongation step). This has also been achieved through the identification of the key parameters governing the onset electrochemical signal decrease and amplitude signal decrease as a function of the PCR cycle for a given DNA intercalating redox probe, thus allowing us to predict the electrochemical PCR kinetic plots from the values of the DNA affinity binding constant determined as a function of temperature. To the best of our knowledge, the analytical performances of the current electrochemical qPCR outperform all of those previously published, in terms of detection limit, dynamic range, reproducibility and melting curve analysis compared to that achieved on a commercialized bench-top fluorescence-based qPCR instrument.

Can betaine pyridinium derivatives be used to control the photoejection of cation?

Using a combination of advanced DFT/TDDFT calculations together with ultrafast and stationary spectroscopies we have investigated the photochemistry and cationic complexation ability of 1-pyridinio-benzimidazolate (PyB) and analogs substituted by 15-aza-5-crown (PyB-Aza) or dimethyl-amino groups (PyB-DiMe). Focusing on PyB-Aza, the first aim was to assess the competitive complexation of the imidazole bridge vs. the macrocycle. In acetonitrile, it was found by absorption and emission that the imidazole moiety binds efficiently through lateral electrostatic interaction of high charge density cations and especially Ca(2+) to form a 1 : 1, metal : ligand (M : L) complex. Modulation of the complexation toward para substitution of the phenyl ring with a donor group is reported with values ranging from log K = 3.4 to 6.8. Complexation values are properly predicted by DFT calculations. From a photochemical point of view, for the same series, the trend is parallel to the rate of the photo-release process, found to be less than 200 femtosecond (fs), the fastest photorelease characteristic time reported so far. Unlike photoinduced charge transfer molecules linked with an aza-crown group, the mechanism appears simpler with no participation of loose complexes due to the macrocavity effect. Relaxation mechanisms after cation ejection are discussed as well. Finally, even if any photoinduced translocation of cation is reported for the PyB-Aza molecule between two complexation sites, a discussion about the use of betaine pyridinium as a molecular tool for the smart manipulation of cation systems is initiated.

New insights into the photoswitching mechanisms of normal dithienylethenes.

The photoswitching and competitive processes of the referent photochromic diarylethene derivative 1,2-bis(2,4-dimethyl-5-phenyl-3-thienyl)perfluorocyclopentene (DTE) and a novel bridged analog DTE-m5 have been investigated by state-of-the-art TD-DFT calculations and ultrafast spectroscopy supported by advanced chemometric data treatments. Focusing on DTE, the overall deactivation pathway of both antiparallel (AP) and parallel (P) conformers of the open form (OF) (1 : 1 in solution) has been resolved and rationalized starting from the Franck-Condon (FC) region to the ground state recovery. For the photo-excited P conformer, after ultrafast relaxation (∼200 fs) towards the S1 relaxed state, an expected ISC occurred (55 ps) to produce a triplet state, 3P, the latter relaxing within 2.5 µs. Concerning the AP conformer, the photocyclization reaction is reported to proceed immediately (100 fs) starting from the FC region while the relaxed singlet state is populated in parallel. For the first time, we discovered that the latter state evolves through an unexpected ISC process (1 ps) giving rise to a second triplet state,3AP. For DTE-m5, by slightly constraining the molecule with the bridge, this triplet becomes reactive and participates in the formation of 10% of closed form (CF) probably through an adiabatic mechanism. Concerning the photoreversion, in accordance with the literature, we report on a two-step process, a 190 fs vibrational relaxation followed by a 6 ps ring-opening reaction. For the overall species at the singlet or triplet manifold, the use of advanced MCR-ALS allows us to obtain specific spectral signatures. This study is therefore a new step within the comprehension of DTE photochemistry.

[Anticoagulation for atrial fibrillation in the patient at risk for falls]. / Anticoagulation chez le patient en fibrillation auriculaire à risque de chutes.

The incidence of atrial fibrillation increases with age as does the risk of subsequent ischemic stroke. Falls are a frequent problem in the geriatric population and often hamper the clinician in prescribing anticoagulants despite an indication based on the CHA2DS2-VASc score for fear of intracranial bleeding. This paper reviews the evidence on the safety of oral anticoagulants in this population. Based on observational data, being at risk for falls does not appear to be an absolute contraindication to oral anticoagulants.

[Does treatment improve prognosis of heart failure with preserved ejection fraction?]. / Insuffisance cardiaque à fraction d'éjection préservée: le traitement améliore-t-il le pronostic?

Heart failure with preserved ejection fraction (HF-PEF) represents half of all heart failure. Morbi-mortality for HF-PEF is similar to that of reduced ejection fraction HF (HF-REF). Diagnosis of HF-REF is difficult because of the lack of highly specific criteria. It is based on the presence of signs and symptoms of heart failure, associated with a preserved or moderately decreased left ventricular function, the absence of left ventricular dilatation, and the presence of relevant structural disease such as left ventricular hypertrophy. Despite the use of prognosis modifying drugs commonly used for HF-REF, no therapeutic strategy has been shown to reduce morbi-mortality of HF-PEF. Evidence based guidelines are limited. Management of HF-PEF therefore resides in treatment of high blood pressure and cardiac rate, that of comorbidities, and the use of diuretics in case of congestion.

Regenerative medicine in Huntington's disease: current status on fetal grafts and prospects for the use of pluripotent stem cell.

Huntington's disease is currently incurable, but cell therapy is seen as a promising alternative treatment. We analyze the safety and efficacy of the intrastriatal transplantation of human fetal neuroblasts from ganglionic eminences in patients with Huntington's disease. A few rare surgical incidents were reported, but the main difficulty associated with this therapeutic approach is the occurrence of recipient alloimmunization against the graft and the lack of availability, standardization and quality control for the fetus-derived products required for cell therapy. Some patients showed sustained cognitive improvement over periods of more than six years, and motor improvements for more than four years. Grafting outcomes are variable even within individual transplantation centers. The reasons for this variability are poorly understood, highlighting the need for further research in this specific area. With the perspective of additional trials in the future, we review here the development of human pluripotent stem cell-derived cell therapy products for HD, and their advantages and disadvantages with respect to fetal cells.

[Antiplatelet agents in secondary prevention of stroke]. / Traitements antiagrégants dans la prévention secondaire des accidents vasculaires cérébraux non cardioemboliques.

Stroke is responsible for high morbidity and mortality. Antiplatelet agents are the cornerstone for secondary prevention of stroke and prescription of aspirin, clopidogrel or aspirin and dipyridamole are recommended based on strong evidence. Whether combining two antiplatelet agents would be more effective is still debated. Studies conducted in the early phase of stroke (from 24 hours to 3 months) show the superiority of dual antiplatelet the- rapy compared to aspirin alone. In contrast, long-term dual antiplatelet therapy is associated with an increased risk of intracranial hemorrhage and therefore deleterious. This article reviews current evidence and outlines future perspectives.

[Atrial fibrillation and obstructive sleep apnea: a fortuitous association?]. / Fibrillation auriculaire et syndrome d'apnées du sommeil: une association fortuite?

Atrial fibrillation (AF) is a frequent arrhythmia and is associated with important morbidity and mortality. It is particularly frequent in patients with obstructive sleep apnea (OSA), occurring in 3 to 5% of these patients. Numerous studies show an association of these two pathologies, independently of classical cardiovascular risk factors and otherconfounders. A pathophysiological link between repeated apnea and cardiac modifications, inflammation and autonomic nervous system disequilibrium has also been demonstrated. The severity of OSA influences development of AF, and appears to make management more complicated. Success of catheter ablation of AF appears to be inferior in patients with OSA. Whilst more robust studies are required to better define the role of OSA in AF, the existing literature establishes a link between these two entities.

[Age-adjusted D-dimers and pulmonary embolism]. / D-dimères et suspicion d'embolie pulmonaire: seuil adapté à l'age.

Plasma D-dimer measurement is the first diagnostic test performed in patients with a non-high or an unlikely clinical probability of pulmonary embolism (PE) but its clinical usefulness is limited in elderly patients due to a low specificity in this subgroup. PE can be excluded based on D-dimers and clinical probability only in about 5% of patients over 80 years when using the conventional cut-off. Age-adjusted D-dimer cut-off (adjusted cut-off value = age x 10 in patients over 50) increases the specificity of the test without significantly reducing its sensitivity. Using the age-adjusted D-dimer cut-off markedly reduces the need for further diagnostic studies such as computed tomography pulmonary angiography (CTPA). The age-adjusted cut-off has been widely validated in retrospective cohorts, and more recently in a prospective management study.

[Diagnosing pulmonary embolism during pregnancy: how should we do?]. / Diagnostic de l'embolie pulmonaire chez la femme enceinte: comment faire?

No diagnostic strategy for pulmonary embo- lism (PE) during pregnancy is based on strong evidence and unanimously accepted. Clinical scores are not validated. The diagnostic yield of the non radiating tests is low: D-dimer is rarely negative in pregnant women and lower limb venous compression ultrasonography is poorly sensitive. Nevertheless, they are still recommended as first line exams. The radia- ting exams (ventilation-perfusion scintigra- phy and thoracic angio-CT) have an equiva- lent diagnostic yield (more than 90%). But both raise the risk of cancer: any childhood cancer for the fetus (scintigraphy), and breast cancer for the mother (angio-CT). However, the diagnosis of PE in the pregnant woman has a major impact and must be established with certainty, even if this requires performing radiation imaging.

[Pneumonia in the elderly: are there any specificities? ]. / Pneumonie chez Le sujet âgé: y a-t-il des spécificités?

Pneumonia is one of the leading causes of death in the elderly. Streptococcus pneumoniae is the leading etiological agent, but the identification of a pathogen remains infrequent despite advances in microbiological methods. Antibiotic resistant organisms should be considered as potential causal agents in recently hospitalized patients and patients with recent antibiotic exposure and influenza during the flu season. The clinical diagnosis is difficult due to frequent atypical presentation. Prognostic scores are not always appropriate to predict the need for hospitalization in very old patients. Studies on the role of low-dose chest CT for the diagnosis, management and prevention should help improve the management of this disease in the future.

[How should we organize health care for multimorbidity patients?]. / Quelle organisation des soins pour le patient polymorbide?

Polymorbidity affects an increasing number of patients of all ages as demonstrated by a recent epidemiological study and represents a real challenge for the organization of health care. Appropriate management of polymorbid patients requires an interdisciplinary approach associating generalist and specialist physicians, but also nurses, other health professionals and social workers. An improvement in transition care between the community and the hospital is necessary in both directions. Prioritizing the treatment objectives is essential to allow patient adherence and avoid cumulative drug interactions and adverse effects. Those objectives are difficult to attain in the context of our present health care organization. This paper attempts to identify the difficulties involved in caring for polymorbid patients and propose ways to improve it.

[Usefulness of preemptive anticoagulation in patients with suspected pulmonary embolism]. / Utilité d'une anticoagulation avant le diagnostic définitif d'embolie pulmonaire.

The usefulness of anticoagulation in patients with suspected non-massive pulmonary embolism (PE) is uncertain. We recently published a decision analysis model suggesting a benefit for preemptive anticoagulation in patients with an intermediate or high probability of PE, even with short diagnostic delays (0-3 h). In case of a low probability of PE, the decision to treat or not could partly rely on the expected diagnostic delay. Once the diagnosis is confirmed, achieving rapidly therapeutic anticoagulation levels decreases future thrombotic complications.

[Hospital based internal medicine in 2012]. / Médecine interne hospitalière: l'année 2012 en revue.

In an era in which primary and secondary prevention have important implications for public health and health care costs, a series of publications and guidelines give added weight or precision to current medical practice in the fields of hospital based internal medicine. This article presents a selective review of new guidelines and therapeutic options for areas of cardiovascular disease, pulmonary disease, gastroenterology and oncology.

Safety assessment of intraportal liver cell application in New Zealand white rabbits under GLP conditions.

Liver cell transplantation (LCT) is considered a new therapeutic strategy for the treatment of acute liver failure and inborn metabolic defects of the liver. Although minimally invasive, known safety risks of the method include portal vein thrombosis and pulmonary embolism. Since no systematic data on these potential side effects exist, we investigated the toxicological profile of repeated intraportal infusion of allogeneic liver cells in 30 rabbits under GLP conditions. Rabbit liver cells were administered once daily for 6 consecutive days at 3 different dose levels, followed by a 2-week recovery period. No test item-related mortality was observed. During cell infusion, clinical findings such as signs of apathy and hyperventilation, moderate elevations of liver enzymes ALT and AST and a slight decrease in AP were observed, all fully reversible. Cell therapy-related macroscopic and histological findings, especially in liver and lungs, were observed in animals of all dose groups. In conclusion, the liver and lungs were identified as potential toxicological target organs of intraportal allogeneic liver cell infusion. A NOAEL (no observed adverse effect level) was not defined because of findings observed also in the low-dose group. No unexpected reactions became apparent in this GLP study. Overall, LCT at total doses up to 12 % (2 % daily over 6 days) of the total liver cell count were tolerated in rabbits. Observed adverse effects are not considered critical for treatment in the intended patient populations provided that a thorough monitoring of safety relevant parameters is in place during the application procedure.

[Performance of natriuretic peptide as a marker in patients with chronic obstructive pulmonary disease]. / Faut-il doser le BNP chez les patients avec BPCO?

The dosage of natriuretic peptides improves diagnostic performance in patients with acute dyspnea when combined with clinical elements. The high sensitivity of this test allows reasonably excluding heart failure when the value is normal. Nevertheless, an increased level of this biomarker is not specific of heart failure and can be observed in different pathologies such as renal failure, sepsis or elevated pulmonary arterial pressure. We therefore analyse the diagnostic performance of natriuretic peptide in COPD patients and discuss its use for the detection of heart failure in this population.

[Hospital based internal medicine: a review of 2011]. / Médecine interne hospitalière: l'année 2011 en revue.

Numerous prospective randomised trials recently demonstrated the importance of an aggressive approach towards controlling cardiovascular risk factors. New studies reinforce the plethora of available data and confirm that interventional revascularisation strategies for stable coronary heart disease or cerebral vascular disease offer few benefits as compared to medical treatment, and can even lead to worse outcomes. This selective review describes some recent studies in the areas of cardiovascular disease, pulmonary disease, such as chronic obstructive pulmonary disease or screening of lung cancer, and gastroenterology.