Impact of therapeutic management and geriatric evaluation on patient of eighty years and older with diffuse large B-cell lymphoma on survival: A systematic review.

BACKGROUND: Diffuse large B cell lymphoma (DLBCL) is an aggressive disease. The first-line treatment is well defined in young patients; however, in oldest old patients treatment remains unclear. OBJECTIVES: To investigate the impact of therapeutics management and geriatric evaluation on survival in aged patients with DLBCL. METHODS: We performed a systematic review of PubMed and COCHRANE databases of published report on elderly patients (median age 80 and above) with DLBCL, from January 2002 to January 2020. RESULTS: We included 32 studies (6 prospective and 26 retrospective). Patients treated with anthracyclines-containing chemoimmunotherapy had a 2-year overall survival (OS) of 59%-74.3% in prospective studies and 48.1-64.6% in retrospective studies. With less intensive treatment without anthracyclines, 2-year OS was 28%-53%. Without specific treatment, median OS was 2 months. History of falls and severe comorbidities were associated with a decreased survival. CONCLUSIONS: Chemoimmunotherapy with anthracyclines increases survival in selected very elderly patients in comparison with less intensive regimen. Geriatric assessment, in particular altered mobility disorders and severe comorbidities, is predictive of survival and should be associated with the therapeutic decision. More comparative studies are needed to guide the management of frailer patients.

Inhibition of Recruitment and Activation of Neutrophils by Pyridazinone-Scaffold-Based Compounds.

In inflammatory diseases, polymorphonuclear neutrophils (PMNs) are known to produce elevated levels of pro-inflammatory cytokines and proteases. To limit ensuing exacerbated cell responses and tissue damage, novel therapeutic agents are sought. 4aa and 4ba, two pyridazinone-scaffold-based phosphodiesterase-IV inhibitors are compared in vitro to zardaverine for their ability to: (1) modulate production of pro-inflammatory mediators, reactive oxygen species (ROS), and phagocytosis; (2) modulate degranulation by PMNs after transepithelial lung migration. Compound 4ba and zardaverine were tested in vivo for their ability to limit tissue recruitment of PMNs in a murine air pouch model. In vitro treatment of lipopolysaccharide-stimulated PMNs with compounds 4aa and 4ba inhibited the release of interleukin-8, tumor necrosis factor-α, and matrix metalloproteinase-9. PMNs phagocytic ability, but not ROS production, was reduced following treatment. Using a lung inflammation model, we proved that PMNs transmigration led to reduced expression of the CD16 phagocytic receptor, which was significantly blunted after treatment with compound 4ba or zardaverine. Using the murine air pouch model, LPS-induced PMNs recruitment was significantly decreased upon addition of compound 4ba or zardaverine. Our data suggest that new pyridazinone derivatives have therapeutic potential in inflammatory diseases by limiting tissue recruitment and activation of PMNs.

Impact of a comprehensive geriatric assessment on decision-making in older patients with hematological malignancies.

OBJECTIVE: Hematological treatment decisions in older adults with hematological malignancies are complex. Our objective is to study the impact of a comprehensive geriatric assessment on hematological treatment decision in older patients and the factors associated with change in treatment plan. METHODS: We conducted a cross-sectional analysis of patients aged 65 years and above with hematological malignancies, hospitalized between 2008 and 2019 at the University Cancer Institute of Toulouse. They were assessed by a geriatrician/nurse team using a comprehensive geriatric assessment (CGA). A penalized logistic regression model with elastic net regularization was used to identify factors associated with change in hematological treatment plan. RESULTS: A total of 424 patients were included. Main hematological malignancies were lymphoma (36.1 %), acute myeloid leukemia (26.9 %) and myelodysplastic syndrome (19.8%). Change in hematological treatment plan was suggested after CGA for 92 patients (21.7%). Factors associated with change in treatment plan were functional impairment according to ADL and IADL scale, mobility impairment, the presence of comorbidity defined by the Charlson score >1 and increasing age. CONCLUSION: A CGA has a significant impact on hematological treatment decision in older patients. Functional and mobility impairment, comorbidities and age are predictive factors of change in treatment plan.

Impact of the comprehensive geriatric assessment on treatment decision in geriatric oncology.

BACKGROUND: The comprehensive geriatric assessment (CGA) is the gold standard in geriatric oncology to identify patients at high risk of adverse outcomes and optimize cancer and overall management. Many studies have demonstrated that CGA could modify oncologic treatment decision. However, there is little knowledge on which domains of the CGA are associated with this change. Moreover, the impact of frailty and physical performance on change in cancer treatment plan has been rarely assessed. METHODS: This is a cross-sectional study of older patients with solid or hematologic cancer referred by oncologists for a geriatric evaluation before cancer treatment. A comprehensive geriatric assessment was performed by a multidisciplinary team to provide guidance for treatment decision. We performed a multivariate analysis to identify CGA domains associated with change in cancer treatment plan. RESULTS: Four hundred eighteen patients, mean age 82.8 ± 5.5, were included between October 2011 and January 2016, and 384 of them were referred with an initial cancer treatment plan. This initial cancer treatment plan was changed in 64 patients (16.7%). In multivariate analysis, CGA domains associated with change in cancer treatment plan were cognitive impairment according to the MMSE score (p = 0.020), malnutrition according to the MNA score (p = 0.023), and low physical performance according to the Short Physical Performance Battery (p = 0.010). CONCLUSION: Cognition, malnutrition and low physical performance are significantly associated with change in cancer treatment plan in older adults with cancer. More studies are needed to evaluate their association with survival, treatment toxicity and quality of life. The role of physical performance should be specifically explored.

Mechanistic insights into Smiles rearrangement. Focus on π-π stacking interactions along the radical cascade.

The synthesis of new arene and heteroarene scaffolds of therapeutic interest has generated a renewed interest in the domino radical cyclisation-Smiles. In this work we present a detailed mechanistic investigation of the radical version of a cascade involving a desulfonative Smiles rearrangement on an aromatic ring bearing a sulfonamide linker. Competing routes have been explored to characterize the molecular mechanism of the studied reaction. The knowledge gained from previous experimental observations is explained through the energy profile obtained by means of quantum mechanical calculations. This study answers questions about the rate determining step and the type of mechanism involved (two-step or concerted). Supplementary rate constant calculations as well as quantum molecular dynamics support experimental observations. An IGM-δg analysis performed along the reaction path unveils and quantifies an intramolecular π-π stacking interaction accelerating the reaction. This novel post processing IGM-δg tool based on the electron density, turns out to be useful to monitor and quantify specific intramolecular weak interactions along a reaction path from wave functions. From this mechanistic investigation it turns out that Smiles rearrangement here takes place in two steps rather than in a direct intramolecular radical substitution. Furthermore, we show that chain length effects must be taken into account in the functionalization of new sulfonylated derivatives subjected to this radical cascade, given their influence in the reaction rate.

Low lean mass and chemotherapy toxicity risk in the elderly: the Fraction study protocol.

BACKGROUND: Half of cancer cases occur in patients aged 70 and above. Majority of older patients are eligible for chemotherapy but evidence for treating this population is sparse and severe toxicities affect more than half of them. Determining prognostic biomarkers able to predict poor chemotherapy tolerance remains one of the major issues in geriatric oncology. Ageing is associated with body composition changes (increase of fat mass and loss of lean mass) independently of weight-loss. Previous studies suggest that body composition parameters (particularly muscle mass) may predict poor chemotherapy tolerance. However, studies specifically including older adults on this subject remain sparse and the majority of them study body composition based on computed tomography (CT) scanner (axial L3 section) muscle mass estimation. This method is to date not validated in elderly cancer patients. METHODS: This trial (Fraction) will evaluate the discriminative ability of appendicular lean mass measured by dual-energy X-ray absorptiometry (DXA) to predict severe toxicity incidence in older cancer-patients treated with first-line chemotherapy. DXA is considered the gold standard in body composition assessment in older adults. Patient's aged ≥70 diagnosed with solid neoplasms or lymphomas at a locally advanced or metastatic stage treated for first-line chemotherapy were recruited. Patients completed a pre-chemotherapy assessment that recorded socio-demographics, tumor/treatment variables, laboratory test results, geriatric assessment variables (function, comorbidity, cognition, social support and nutritional status), oncological risk scores and body composition with DXA. Appendicular lean mass was standardized using evidence based international criteria. Participants underwent short follow-up geriatric assessments within the first 3 months, 6 months and a year after inclusion. Grade 3 to 5 chemotherapy-related toxicities, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) were assessed at each chemotherapy cycle. DISCUSSION: The finding that body composition is associated with poor tolerance of chemotherapy could lead to consider these parameters as well as improve current decision-making algorithms when treating older adults. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02806154 registered on October 2016.

[Humour therapy, laughter and the intervention of clowns in gerontology]. / La thérapie par l'humour, le rire et l'intervention de clowns en gérontologie.

Confronted with the growing incidence of age-related pathologies and the limits of so-called traditional medicine oriented towards the prescribing of medicines, non-pharmacological approaches have grown considerably in the geriatric community. A literature review focused on the therapeutic benefit of humour, laughter and the use of clowns on the physical and psychological health of elderly people.

Radical Smiles Rearrangement: An Update.

Over the decades the Smiles rearrangement and its variants have become essential synthetic tools in modern synthetic organic chemistry. In this mini-review we summarized some very recent results of the radical version of these rearrangements. The selected examples illustrate the synthetic power of this approach, especially if it is incorporated into a domino process, for the preparation of polyfunctionalized complex molecules.

TiCl4-promoted condensation of methyl acetoacetate, isobutyraldehyde, and indole: a theoretical and experimental study.

The mechanism of the TiCl4-promoted condensation of methyl acetoacetate, isobutyraldehyde, and indole was studied by a combination of theoretical and experimental techniques. The energy profile of plausible reaction paths was evaluated by DFT calculations, and various reaction intermediates were isolated or observed in solution by NMR spectroscopy. Theoretical and experimental results indicate that the reaction proceeds in three steps, all promoted by titanium: (1) formation of the enolate ion of methyl acetoacetate, (2) Knoevenagel condensation of the enolate ion and aldehyde, and (3) Michael addition of indole to the Knoevenagel adduct. The study sheds light on the role of titanium in the reaction, providing a mechanistic model for analogous reactions.

Diastereomer Interconversion via Enolization: A Case Study.

The three-component reaction of indole, isobutyraldehyde, and methyl acetoacetate affords methyl 2-(acetyl)-3-(1H-indol-3-yl)-4-methylpentanoate as a single diastereomer. To investigate the origin of the observed diastereoselectivity, the thermodynamics and kinetics of interconversion of diastereomers 1 and 2 in solution were studied by a combination of (1)H nuclear magnetic resonance (NMR) spectroscopy, high-performance liquid chromatography (HPLC), mass spectrometry, and deuteration experiments. The results indicate that interconversion is both acid- and base-catalyzed, and that the alpha carbon is the only stereolabile center in the molecule. The evidence points to an enolization mechanism for the interconversion process. The selective precipitation of 1 in the presence of the equilibrium 1⇆2 eventually results in the exclusive formation of 1 (crystallization-induced asymmetric transformation).

Photochemical aryl radical cyclizations to give (E)-3-ylideneoxindoles.

(E)-3-Ylideneoxindoles are prepared in methanol in reasonable to good yields, as adducts of photochemical 5-exo-trig of aryl radicals, in contrast to previously reported analogous radical cyclizations initiated by tris(trimethylsilyl)silane and azo-initiators that gave reduced oxindole adducts.

[Benign prostatic hypertrophy and prostate cancer]. / Hypertrophie bénigne et cancer de la prostate.

Prostatic diseases are extremely common, especially in older men. Amongst them, benign prostatic hypertrophy may affect significantly the quality of life of patients by the symptoms it causes. It requires appropriate care. Prostate cancer is the second most common cancer in men after lung cancer and the fifth leading cause of cancer deaths in the world. It affects preferentially older men. An oncogeriatric approach is required for personalised care.

Incidence and economical effects of pneumonia in the older population living in French nursing homes: design and methods of the INCUR study.

BACKGROUND: Among the most burdensome clinical conditions occurring in older persons, respiratory infections are particularly relevant. In fact, the onset of pneumonias is associated with a significant worsening of the individual's global health status and significant increase of healthcare costs. The clinical and economical negative consequences of pneumonia may be particularly evident among the frailest groups of elders, in particular those living in nursing home. Nevertheless, specific research on incidence and economical effects of pneumonia in nursing homes residents is still scarce. In the present article, we present the rationale, the design and the methods of the "Incidence of pNeumonia and related ConseqUences in nursing home Resident (INCUR) study, specifically aimed at filling some of the gaps currently present in the field. METHODS/DESIGN: INCUR is an observational longitudinal study recruiting 800 residents across 13 randomly selected nursing homes in France. Multidimensional evaluations of participants are conducted at the baseline, mid-term (at 6 months), and end of the study (at 12 months) visits in order to measure and follow-up their physical function, nutrition, cognition, depression, quality of life, and healthcare costs. Incident pneumonia as well as the onset/recurrence of other major health-related events are monitored during the study follow-up. DISCUSSION: The INCUR study will provide valuable information about older persons living in nursing homes. Results from INCUR study may constitute the basis for the development of future preventive campaigns against pneumonia and its consequences.

Synthesis, Hydrolytic Stability and In Vivo Biological Study of Bioconjugates of the Tetrapeptides FELL Containing Pyrrole Moiety.

BACKGROUND: Bioconjugates are promising alternatives for the multiple targeting of any disease. Pyrrole heterocycle is well known with many activities and is a building block of a lot of medical drugs. On the other hand, peptides are short molecules with many advantages such as small size, ability to penetrate the cell membrane and bond-specific receptors, vectorizing potential, etc. Thus, hybrid molecules between peptide and pyrrole moiety could be a promising alternative as an anti-pain tool. METHODS: New bioconjugates with a general formula Pyrrole (α-/ß-acid)-FELL-OH (NH2) were synthesized using Fmoc/OtBu peptide synthesis on solid support. HPLC was used to monitor the purity of newly synthesized bioconjugates. Their structures were proven by electrospray ionization mass spectrometry. The Paw Pressure test (Randall-Selitto test) was used to examinate the analgesic activity. Hydrolytic stability of targeted structures was monitored in three model systems with pH 2.0, 7.4 and 9.0, including specific enzymes by means of the HPLC-UV method. RESULTS: The obtained results reveal that all newly synthesized bioconjugates have analgesic activity according to the used test but free pyrrole acids have the best analgesic activity. CONCLUSIONS: Although free pyrrole acids showed the best analgesic activity, they are the most unstable for hydrolysis. Combination with peptide structure leads to the hydrolytic stabilization of the bioconjugates, albeit with slightly reduced activity.

Synthesis, In Silico Logp Study, and In Vitro Analgesic Activity of Analogs of Tetrapeptide FELL.

BACKGROUND: The inflammatory process represents a specific response of the organism's immune system. More often, it is related to the rising pain in the affected area. Independently of its origin, pain represents a complex and multidimensional acute or chronic subjective unpleasant perception. Currently, medical doctors prescribe various analgesics for pain treatment, but unfortunately, many of them have adverse effects or are not strong enough to suppress the pain. Thus, the search for new pain-relieving medical drugs continues. METHODS: New tetrapeptide analogs of FELL with a generaanalgesic-Glu-X3-X4-Z, where X = Nle, Ile, or Val and Z = NH2 or COOH, containing different hydrophobic amino acids at positions 3 and 4, were synthesized by means of standard solid-phase peptide synthesis using the Fmoc/OtBu strategy in order to study the influence of structure and hydrophobicity on the analgesic activity. The purity of all compounds was monitored by HPLC, and their structures were proven by ESI-MS. Logp values (partition coefficient in octanol/water) for FELL analogs were calculated. Analgesic activity was examined by the Paw-pressure test (Randall-Selitto test). RESULTS: The obtained results reveal that Leu is the best choice as a hydrophobic amino acid in the FELL structure. CONCLUSIONS: The best analgesic activity is found in the parent compound FELL and its C-terminal amide analog.

Synthesis of PDE IVb Inhibitors. 3. Synthesis of (+)-, (-)-, and (±)-7-[3-(cyclopentyloxy)-4-methoxyphenyl]hexahydro-3H-pyrrolizin-3-one via reductive domino transformations of 3-ß-carbomethoxyethyl-substituted six-membered cyclic nitronates.

Simple three-step asymmetric and racemic syntheses of GlaxoSmithKline's highly potent PDE IVb inhibitor 1 were developed. The suggested approach is based on reductive domino transformations of 3-ß-carbomethoxyethyl-substituted six-membered cyclic nitronates, which are easily accessed by a stereoselective [4 + 2] cycloaddition of an appropriate nitroalkene to vinyl ethers. In vitro studies of PDE IVb inhibition by enantiomeric pyrrolizidinones (+)-1 and (-)-1 were performed.

Spreading geriatric oncology culture through professional caregivers: Results of a French massive open online course (MOOC).

Geriatric oncology is based on the synergy between several professionals whose common goal is to improve care for older patients with cancer. This requires sharing a common core of knowledge to facilitate collaboration between them. To date, training in geriatric oncology has been limited in scope and difficult to access for caregivers, particularly nurses and healthcare aides. To meet this need, a massive open online course (MOOC), in geriatric oncology has been developed in France. This kind of course aims to provide simultaneous access for a large number of participants and to foster communication with the pedagogical team through discussion forums. The first session of the MOOC, which has been set up in the Occitania region of France, went online nationwide from March 6 to June 23, 2020. Despite the SARS CoV-2 global health crisis, 1020 people subscribed to the first session and 417 (40.9%) were certified at the end of the course. Most are nurses (35.2%) and work outside Occitania (56.3%). A survey revealed a high satisfaction level regarding relevance of lessons (97.9%), pedagogical quality of teaching team (97.9%), knowledge acquisition (93.6%), meeting learners' needs (90.4%) and practical value of the course (88.3%). This preliminary experience demonstrates the ability of this MOOC to spread the culture of geriatric oncology and the educational potential of this new type of online training.

Synergy between Indoloquinolines and Ciprofloxacin: An Antibiofilm Strategy against Pseudomonas aeruginosa.

Antibiotic treatments can participate in the formation of bacterial biofilm in case of under dosage. The interest of indoloquinoline scaffold for drug discovery incited us to study the preparation of new indolo [2,3-b]quinoline derivatives by a domino radical process. We tested the effect of two different "indoloquinoline" molecules (Indol-1 and Indol-2) without antimicrobial activity, in addition to ciprofloxacin, on biofilm formation thanks to crystal violet staining and enumeration of adhered bacteria. This association of ciprofloxacin and Indol-1 or Indol-2 attenuated the formation of biofilm up to almost 80% compared to ciprofloxacin alone, or even prevented the presence of adhered bacteria. In conclusion, these data prove that the association of non-antimicrobial molecules with an antibiotic can be a solution to fight against biofilm and antibiotic resistance emergence.

Pyridazinone Derivatives Limit Osteosarcoma-Cells Growth In Vitro and In Vivo.

Osteosarcoma is a rare primary bone cancer that mostly affects children and young adults. Current therapeutic approaches consist of combining surgery and chemotherapy but remain unfortunately insufficient to avoid relapse and metastases. Progress in terms of patient survival has remained the same for 30 years. In this study, novel pyridazinone derivatives have been evaluated as potential anti-osteosarcoma therapeutics because of their anti-type 4 phosphodiesterase activity, which modulates the survival of several other cancer cells. By using five-four human and one murine osteosarcoma-cell lines, we demonstrated differential cytotoxic effects of four pyridazinone scaffold-based compounds (mitochondrial activity and DNA quantification). Proapoptotic (annexin V positive cells and caspase-3 activity), anti-proliferative (EdU integration) and anti-migratory effects (scratch test assay) were also observed. Owing to their cytotoxic activity in in vitro conditions and their ability to limit tumor growth in a murine orthotopic osteosarcoma model, our data suggest that these pyridazinone derivatives might be hit-candidates to develop new therapeutic strategies against osteosarcoma.

Pyridazinone derivatives as potential anti-inflammatory agents: synthesis and biological evaluation as PDE4 inhibitors.

Cyclic nucleotide phosphodiesterase type 4 (PDE4), which controls the intracellular level of cyclic adenosine monophosphate (cAMP), has aroused scientific attention as a suitable target for anti-inflammatory therapy of respiratory diseases. This work describes the development and characterization of pyridazinone derivatives bearing an indole moiety as potential PDE4 inhibitors and their evaluation as anti-inflammatory agents. Among these derivatives, 4-(5-methoxy-1H-indol-3-yl)-6-methylpyridazin-3(2H)-one possesses promising activity, and selectivity towards PDE4B isoenzymes and is able to regulate potent pro-inflammatory cytokine and chemokine production by human primary macrophages.