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BACKGROUND: Reduced muscle strength (dynapenia) and mass (atrophy) are prognostic factors in oncology. Measuring maximal handgrip strength with dynamometers is feasible but limited by the cost of the reference device (JAMAR). METHODS: A cross-sectional study was conducted on colorectal cancer outpatients treated with chemotherapy or under active surveillance in our center from September 2022 to July 2023. Accuracy, reliability, and concordance were compared for two handheld dynamometers: the JAMAR Plus (the gold-standard device) and the Camry EH101 (a low-cost index device). A simultaneous nutritional diagnosis with GLIM criteria and bioelectrical impedance analysis (BIA) was carried out. RESULTS: A total of 134 participants were included. The median of maximal strength for the JAMAR Plus had a non-significant difference of 1.4 kg from the Camry EH101. The accuracy and reliability of the devices were high. Bland-Altman analysis showed a 0.8 kg bias and -4.1 to 5.6 kg limits of agreement (LoA); a 0.1 kg bias and -5.3 to 5.4 kg LoA in men; a 1.5 kg bias and -2.2 to 5.3 kg LoA in women. In total, 29.85% of the participants were malnourished. Prevalence of dynapenia increased from 3.67% with the JAMAR Plus to 5.14% with the Camry EH101. Both devices had a moderate and significant correlation with BIA-estimated muscle mass. CONCLUSIONS: The Camry EH101 was a cost-effective alternative to JAMAR Plus in our sample.
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Neoplasias Colorrectales , Impedancia Eléctrica , Estado Nutricional , Humanos , Neoplasias Colorrectales/diagnóstico , Masculino , Femenino , Estudios Transversales , Persona de Mediana Edad , Anciano , Reproducibilidad de los Resultados , Fuerza de la Mano , Dinamómetro de Fuerza Muscular , Evaluación Nutricional , AdultoRESUMEN
BACKGROUND: Programmed death-1 (PD-1) inhibitors, including nivolumab, have demonstrated long-term survival benefit in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (CRC). PD-1 and lymphocyte-activation gene 3 (LAG-3) are distinct immune checkpoints that are often co-expressed on tumor-infiltrating lymphocytes and contribute to tumor-mediated T-cell dysfunction. Relatlimab is a LAG-3 inhibitor that has demonstrated efficacy in combination with nivolumab in patients with melanoma. Here, we present the results from patients with MSI-H/dMMR metastatic CRC treated with nivolumab plus relatlimab in the CheckMate 142 study. METHODS: In this open-label, phase II study, previously treated patients with MSI-H/dMMR metastatic CRC received nivolumab 240 mg plus relatlimab 160 mg intravenously every 2 weeks. The primary end point was investigator-assessed objective response rate (ORR). RESULTS: A total of 50 previously treated patients received nivolumab plus relatlimab. With median follow-up of 47.4 (range 43.9-49.2) months, investigator-assessed ORR was 50% (95% CI 36% to 65%) and disease control rate was 70% (95% CI 55% to 82%). The median time to response per investigator was 2.8 (range 1.3-33.1) months, and median duration of response was 42.7 (range 2.8-47.0+) months. The median progression-free survival per investigator was 27.5 (95% CI 5.3 to 43.7) months with a progression-free survival rate at 3 years of 38%, and median overall survival was not reached (95% CI 17.2 months to not estimable), with a 56% overall survival rate at 3 years. The most common any-grade treatment-related adverse events (TRAEs) were diarrhea (24%), asthenia (16%), and hypothyroidism (12%). Grade 3 or 4 TRAEs were reported in 14% of patients, and TRAEs of any grade leading to discontinuation were observed in 8% of patients. No treatment-related deaths were reported. CONCLUSIONS: Nivolumab plus relatlimab provided durable clinical benefit and was well tolerated in previously treated patients with MSI-H/dMMR metastatic CRC. TRIAL REGISTRATION NUMBER: NCT02060188.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorrectales , Inestabilidad de Microsatélites , Nivolumab , Humanos , Nivolumab/uso terapéutico , Nivolumab/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Femenino , Masculino , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Adulto , Reparación de la Incompatibilidad de ADN , Anciano de 80 o más Años , Metástasis de la NeoplasiaRESUMEN
People with asthma may be particularly vulnerable to pandemic-related psychological distress, and research is needed to understand the impact of the coronavirus disease 19 (COVID-19) pandemic on their health and well-being. We sought to study the well-being of people with asthma relative to non-asthmatic controls during the COVID-19 pandemic. We also investigated asthma symptoms and COVID-19-related anxiety as potential mediators of distress. Participants completed self-report measures of psychological functioning, including anxiety, depression, stress, and burnout. Controlling for potential confounds, multiple-regression analyses examined differences in psychological health between people with and without asthma. Mediator analyses investigated the role of asthma symptoms and COVID-19-related anxiety in this relationship. 234 adults (111 with asthma, 123 without) participated in an online survey from July to November 2020. During this time, people with asthma reported higher levels of anxiety, perceived stress, and burnout symptoms compared to controls. Elevations in burnout symptoms were found beyond general anxiety and depression (sr2 = .03, p < .001). Reported symptoms typical in both asthma and COVID-19 partially mediated this relationship (Pm = .42, p < .05). People with asthma reported unique psychological challenges during the COVID-19 pandemic including elevated burnout symptoms. Experience of asthma symptoms played a key role in vulnerability to emotional exhaustion. Clinical implications include increased attention to asthma symptom burden within the context of heightened environmental stress and restricted healthcare access.
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BACKGROUND: Antimicrobial stewardship programs (ASPs) are recommended in nursing homes (NHs), although data are limited. We aimed to determine the clinical and ecological impact of an ASP for NHs. METHODS: We performed a cluster, randomized, controlled trial and a before-after study with interrupted time-series analyses in 14 NHs for 30 consecutive months from July 2018 to December 2020 in Andalusia, Spain. Seven facilities implemented an ASP with a bundle of 5 educational measures (general ASP) and 7 added 1-to-1 educational interviews (experimental ASP). The primary outcome was the overall use of antimicrobials, calculated monthly as defined daily doses (DDD) per 1000 resident days (DRD). RESULTS: The total mean antimicrobial consumption decreased by 31.2% (-16.72 DRD; P = .045) with respect to the preintervention period; the overall use of quinolones and amoxicillin-clavulanic acid dropped by 52.2% (P = .001) and 42.5% (P = .006), respectively; and the overall prevalence of multidrug-resistant organisms (MDROs) decreased from 24.7% to 17.4% (P = .012). During the intervention period, 12.5 educational interviews per doctor were performed in the experimental ASP group; no differences were found in the total mean antimicrobial use between groups (-14.62 DRD; P = .25). Two unexpected coronavirus disease 2019 waves affected the centers increasing the overall mean use of antimicrobials by 40% (51.56 DRD; P < .0001). CONCLUSIONS: This study suggests that an ASP for NHs appears to be associated with a decrease in total consumption of antimicrobials and prevalence of MDROs. This trial did not find benefits associated with educational interviews, probably due to the coronavirus disease 2019 pandemic. Clinical Trials Registration. NCT03543605.
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Antiinfecciosos , COVID-19 , Humanos , Antibacterianos/uso terapéutico , Antiinfecciosos/uso terapéutico , Casas de Salud , Combinación Amoxicilina-Clavulanato de PotasioRESUMEN
The serial analysis of cell-free DNA (cfDNA) enables minimally invasive monitoring of tumor evolution, providing continuous genetic information. PERSEIDA was an observational, prospective study assessing the cfDNA RAS (KRAS/NRAS) mutational status evolution in first-line, metastatic CRC, RAS wild-type (according to baseline tumor tissue biopsy) patients. Plasma samples were collected before first-line treatment, after 20 ± 2 weeks, and at disease progression. One hundred and nineteen patients were included (102 received panitumumab and chemotherapy as first-line treatment-panitumumab subpopulation). Fifteen (12.6%) patients presented baseline cfDNA RAS mutations (n = 14 [13.7%], panitumumab subpopulation) (mutant allele fraction ≥0.02 for all results). No patients presented emergent mutations (cfDNA RAS mutations not present at baseline) at 20 weeks. At disease progression, 11 patients (n = 9; panitumumab subpopulation) presented emergent mutations (RAS conversion rate: 19.0% [11/58]; 17.7% [9/51], panitumumab subpopulation). In contrast, three (5.2%) patients presenting baseline cfDNA RAS mutations were RAS wild-type at disease progression. No significant associations were observed between overall response rate or progression-free survival and cfDNA RAS mutational status in the total panitumumab subpopulation. Although, in patients with left-sided tumors, a significantly longer progression-free survival was observed in cfDNA RAS wild-type patients compared to those presenting cfDNA RAS mutations at any time. Continuous evaluation of RAS mutations may provide valuable insights on tumor molecular dynamics that can help clinical practice.
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BACKGROUND: In the intent-to-treat (ITT) population of the RAINBOW study, objective response rate (ORR) was 28% and 16% in the ramucirumab and control arms, respectively. To further characterize tumor response, we present details on timing and extent of tumor shrinkage, as well as associations with symptom palliation. MATERIALS AND METHODS: Tumor response was assessed with RECIST v1.1, and quality of life (QoL) was assessed with the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (EORTC QLQ-C30) v3.0. Prespecified and post hoc analyses were conducted in the ITT population, patients with measurable disease, or responders, and included best overall response (BOR), ORR, disease control rate (DCR), duration of response, time to response (TtR), change in tumor size, and associations of QoL with tumor shrinkage and BOR. RESULTS: In both treatment arms, median TtR was 1.5 months. Responses were more durable in the ramucirumab versus control arm (median 4.4 vs. 2.8 months). In patients with measurable disease (78% of ITT), ORR was 36% versus 20%; DCR was 81% versus 61% in the ramucirumab versus control arms. Waterfall plots demonstrated more tumor shrinkage in the ramucirumab versus control arm. Regardless of treatment, tumor response and stable disease were associated with improved or stable QoL, with more tumor shrinkage associated with greater symptom palliation. CONCLUSION: Treatment with ramucirumab plus paclitaxel yielded the highest ORR reported to date for patients with previously treated advanced gastric or gastroesophageal junction adenocarcinoma. Additional details demonstrate robustness of tumor response results. The extent of tumor shrinkage is directly associated with symptom palliation and should be considered when evaluating patient needs and treatment selection. Clinical trial identification number. NCT01170663. IMPLICATIONS FOR PRACTICE: Ramucirumab plus paclitaxel is a recognized standard of care as it improves survival for patients with advanced gastric or gastroesophageal junction adenocarcinoma who have been previously treated with recommended first-line therapy. These additional data on tumor response demonstrate a positive association between tumor shrinkage and symptom palliation in a patient population that is often symptomatic. These observations included patients with nonmeasurable disease, a group of patients often underrepresented in clinical trials. This knowledge can inform treatment decisions, which align individual patient characteristics and needs with demonstrated benefits.
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Neoplasias Gástricas , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Humanos , Paclitaxel/uso terapéutico , Calidad de Vida , Neoplasias Gástricas/tratamiento farmacológico , RamucirumabRESUMEN
BACKGROUND: Bevacizumab, a VEGF-A inhibitor, in combination with chemotherapy, has proven to increase progression-free survival (PFS) and overall survival in multiple lines of therapy of metastatic colorectal cancer (mCRC). The angiogenic factor angiopoetin-2 (Ang-2) is associated with poor prognosis in many cancers, including mCRC. Preclinical models demonstrate improved activity when inhibiting both VEGF-A and Ang-2, suggesting that the dual VEGF-A and Ang-2 blocker vanucizumab (RO5520985 or RG-7221) may improve clinical outcomes. This phase II trial evaluated the efficacy of vanucizumab plus modified (m)FOLFOX-6 (folinic acid (leucovorin), fluorouracil (5-FU) and oxaliplatin) versus bevacizumab/mFOLFOX-6 for first-line mCRC. PATIENTS AND METHODS: All patients received mFOLFOX-6 and were randomized 1:1 to also receive vanucizumab 2,000 mg or bevacizumab 5 mg/kg every other week. Oxaliplatin was given for eight cycles; other agents were continued until disease progression or unacceptable toxicity for a maximum of 24 months. The primary endpoint was investigator-assessed PFS. RESULTS: One hundred eighty-nine patients were randomized (vanucizumab, n = 94; bevacizumab, n = 95). The number of PFS events was comparable (vanucizumab, n = 39; bevacizumab, n = 43). The hazard ratio was 1.00 (95% confidence interval, 0.64-1.58; p = .98) in a stratified analysis based on number of metastatic sites and region. Objective response rate was 52.1% and 57.9% in the vanucizumab and bevacizumab arm, respectively. Baseline plasma Ang-2 levels were prognostic in both arms but not predictive for treatment effects on PFS of vanucizumab. The incidence of adverse events of grade ≥3 was similar between treatment arms (83.9% vs. 82.1%); gastrointestinal perforations (10.8% vs. 8.4%) exceeded previously reported rates in this setting. Hypertension and peripheral edema were more frequent in the vanucizumab arm. CONCLUSION: Vanucizumab/mFOLFOX-6 did not improve PFS and was associated with increased rates of antiangiogenic toxicity compared with bevacizumab/mFOLFOX-6. Our results suggest that Ang-2 is not a relevant therapeutic target in first-line mCRC. IMPLICATIONS FOR PRACTICE: This randomized phase II study demonstrates that additional angiopoietin-2 (Ang-2) inhibition does not result in superior benefit over anti-VEGF-A blockade alone when each added to standard chemotherapy. Moreover, the performed pharmacokinetic and pharmacodynamic analysis revealed that vanucizumab was bioavailable and affected its intended target, thereby strongly suggesting that Ang-2 is not a relevant therapeutic target in the clinical setting of treatment-naïve metastatic colorectal cancer. As a result, the further clinical development of the dual VEGF-A and Ang-2 inhibitor vanucizumab was discontinued.
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Neoplasias Colorrectales , Compuestos Organoplatinos , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/efectos adversos , Camptotecina/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Supervivencia sin Enfermedad , Fluorouracilo/efectos adversos , Humanos , Leucovorina/efectos adversos , Metástasis de la Neoplasia , Compuestos Organoplatinos/efectos adversosRESUMEN
BACKGROUND: The Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling pathway plays a key role in the systemic inflammatory response in many cancers, including colorectal cancer (CRC). This study evaluated the addition of ruxolitinib, a potent JAK1/2 inhibitor, to regorafenib in patients with relapsed/refractory metastatic CRC. METHODS: In this two-part, multicenter, phase 2 study, eligible adult patients had metastatic adenocarcinoma of the colon or rectum; an Eastern Cooperative Oncology Group performance status of 0-2; received fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor therapy (if no contraindication); and if KRAS wild-type (and no contraindication), an anti-epidermal growth factor receptor therapy; and progressed following the last administration of approved therapy. Patients who received previous treatment with regorafenib, had an established cardiac or gastrointestinal disease, or had an active infection requiring treatment were excluded. The study was conducted in 95 sites in North America, European Union, Asia Pacific, and Israel. After an open-label, safety run-in phase (part 1; ruxolitinib 20 mg twice daily [BID] plus regorafenib 160 mg once daily [QD]), the double-blind, randomized phase (part 2) was conducted wherein patients were randomized 1:1 to receive ruxolitinib 15 mg BID plus regorafenib 160 mg QD [ruxolitinib group] or placebo plus regorafenib 160 mg QD [placebo group]. Part 2 included substudy 1 (patients with high systemic inflammation, ie, C-reactive protein [CRP] >10 mg/L) and substudy 2 (patients with low systemic inflammation, ie, CRP ≤10 mg/L); the primary endpoint was overall survival (OS). RESULTS: The study was terminated early; substudy 1 was terminated for futility at interim analysis and substudy 2 was terminated per sponsor decision. Ruxolitinib 20 mg BID was well tolerated in the safety run-in (n = 11). Overall, 396 patients were randomized (substudy 1: n = 175 [ruxolitinib group, n = 87; placebo group, n = 88]; substudy 2: n = 221 [ruxolitinib group, n = 110; placebo group, n = 111]). There was no significant difference in OS or progression-free survival (PFS) between treatments in substudy 1 (OS: hazard ratio [HR] = 1.040 [95% confidence interval: 0.725-1.492]; PFS: HR = 1.004 [0.724-1.391]) and substudy 2 (OS: HR = 0.767 [0.478-1.231]; PFS: HR = 0.787 [0.576-1.074]). The most common hematologic adverse event was anemia. No new safety signals with ruxolitinib were identified. CONCLUSIONS: Although addition of ruxolitinib to regorafenib did not show increased safety concerns in patients with relapsed/refractory metastatic CRC, this combination did not improve OS/PFS vs. regorafenib plus placebo.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/patología , Método Doble Ciego , Resistencia a Antineoplásicos , Femenino , Humanos , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 2/antagonistas & inhibidores , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Nitrilos , Pirimidinas , Recurrencia , Resultado del TratamientoRESUMEN
Background The first-in-class antibody-drug conjugate TAK-264 (formerly MLN0264) consists of an antibody targeting guanylyl cyclase C (GCC) conjugated to monomethyl auristatin E (MMAE) via a peptide linker. This phase II study evaluated the efficacy and safety of TAK-264 in patients with adenocarcinoma of the stomach or gastroesophageal junction expressing GCC, who had progressed on ≥1 line of prior therapy. Methods This study used a two-stage design, with an interim analysis conducted after stage I to determine whether to continue to stage II or discontinue on the grounds of futility. Adult patients with gastric and gastroesophageal junction adenocarcinoma expressing low, intermediate, or high GCC levels received TAK-264 1.8 mg/kg as a 30-min intravenous infusion once every 21 days, for up to 1 year. The primary endpoint was objective response rate. Radiographic assessments of tumor burden were performed every 2 cycles (6 weeks). Results A total of 38 patients participated in the study. Patients received a median of 2 (range 1-14) cycles; 8 (21%) received at least 6 cycles. The most common adverse events were nausea (53%), fatigue (32%), and decreased appetite (29%). Grade ≥3 events including anemia, diarrhea, and neutropenia were seen in 14 (37%) patients. Systemic exposure to TAK-264 was maintained throughout each treatment cycle. Two patients (6%) with intermediate GCC expression had objective responses. Conclusions TAK-264 demonstrated a manageable safety profile in this patient population. The stage I interim analysis did not support continuation to stage II of the study.
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Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Inmunoconjugados/uso terapéutico , Receptores de Enterotoxina/inmunología , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Unión Esofagogástrica/patología , Femenino , Humanos , Inmunoconjugados/efectos adversos , Inmunoconjugados/farmacocinética , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Receptores de Enterotoxina/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacosRESUMEN
BACKGROUND: In France, women represent approximately 20% of alcohol-dependent subjects. Although general practitioners (GPs) are often these women's first medical contact, GPs may be reluctant to probe for alcohol dependence. METHOD: In this context, in 1996 and 2006 we conducted a cross-sectional survey using self-completion postal questionnaires sent to all GPs in a French département (administrative area), with the aim to explore and to compare after a ten-year time lapse, expectations and relational difficulties in managing alcohol dependence in women. RESULTS: A total of 300 GPs returned the questionnaire for the two data collection times. According to the GPs, comparing 1996 and 2006, there was less embarrassment among female patient to talk about alcohol consumption and a lesser tendency to break off medical care (33.7% vs. 47.3%, p < 0.001, and 13.3% vs. 23.0%, p = 0.002, respectively). In 2006, more GPs considered they were well informed about specialized care in alcohol dependence than in 1996 (76.8% vs. 59.9%, p < 0.0001), and more often reported referring their female patients to specialized centers (73.0% vs. 52.7%, p < 0.0001), rather than medical or psychiatric wards. Young GPs, aged under 40, seem rather to have had difficulty using the managed care network than lacking medical knowledge related to female alcohol dependence. CONCLUSIONS: The results suggest that over ten years there has been a decrease in the tendency among women to deny their alcohol dependence, and that they more readily accept specific care. In the same period, GPs have benefited from better information about specialized management.
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Alcoholismo/diagnóstico , Medicina Familiar y Comunitaria , Adulto , Consumo de Bebidas Alcohólicas/epidemiología , Consumo de Bebidas Alcohólicas/psicología , Alcoholismo/epidemiología , Alcoholismo/psicología , Estudios Transversales , Medicina Familiar y Comunitaria/tendencias , Femenino , Francia/epidemiología , Humanos , Encuestas y Cuestionarios , Revelación de la VerdadRESUMEN
A hand-held luminometer for measuring electrochemiluminescence (ECL) for lactate determination and based on one-shot biosensors fabricated using screen-printed electrodes is described. The lactate recognition system is based on lactate oxidase and the transduction system consists of electro-oxidation of luminol, with all the reagents immobilized in a Methocel membrane. The membrane composition and reaction conditions have been optimized to obtain adequate sensitivity. The luminometer is based on a large silicon photodiode as detector and includes a programmable potentiostat to initialize the chemical reaction and signal processing circuitry, designed to acquire a low level photocurrent with offset cancelation, low pass filtering for noise attenuation and adjustable gain up to 10(12) V/A. The one-shot biosensor responds to lactate rapidly, with an acquisition time of 2.5 min, obtaining a linear dependence from 8 × 10(-6) to 2 × 10(-4) M, a detection limit of 2.4 × 10(-6) M and a sensor-to-sensor reproducibility (relative standard deviation, RSD) of around 7-10 % at the medium level of the range.