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OBJECTIVE: Patients with acute respiratory failure often require mechanical ventilation to reduce the work of breathing and improve gas exchange; however, this may exacerbate lung injury. Protective ventilation strategies, characterized by low tidal volumes (≤ 8mL/kg of predicted body weight) and limited plateau pressure below 30cmH2O, have shown improved outcomes in patients with acute respiratory distress syndrome. However, in the transition to spontaneous ventilation, it can be challenging to maintain tidal volume within protective levels, and it is unclear whether low tidal volumes during spontaneous ventilation impact patient outcomes. We developed a study protocol to estimate the prevalence of low tidal volume ventilation in the first 24 hours of spontaneous ventilation in patients with hypoxemic acute respiratory failure and its association with ventilator-free days and survival. METHODS: We designed a multicenter, multinational, cohort study with a 28-day follow-up that will include patients with acute respiratory failure, defined as a partial oxygen pressure/fraction of inspired oxygen ratio < 300mmHg, in transition to spontaneous ventilation in intensive care units in Latin America. RESULTS: We plan to include 422 patients in ten countries. The primary outcomes are the prevalence of low tidal volume in the first 24 hours of spontaneous ventilation and ventilator-free days on day 28. The secondary outcomes are intensive care unit and hospital mortality, incidence of asynchrony and return to controlled ventilation and sedation. CONCLUSION: In this study, we will assess the prevalence of low tidal volume during spontaneous ventilation and its association with clinical outcomes, which can inform clinical practice and future clinical trials.
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Unidades de Cuidados Intensivos , Síndrome de Dificultad Respiratoria , Volumen de Ventilación Pulmonar , Humanos , América Latina/epidemiología , Síndrome de Dificultad Respiratoria/terapia , Síndrome de Dificultad Respiratoria/epidemiología , Síndrome de Dificultad Respiratoria/fisiopatología , Síndrome de Dificultad Respiratoria/mortalidad , Respiración Artificial , Insuficiencia Respiratoria/terapia , Insuficiencia Respiratoria/epidemiologíaRESUMEN
INTRODUCTION: The evolution of MCGR technique has led to modifications in the configuration of the proximal construct to decrease the incidence of implant-related complications (IRC) and revision surgeries. However, there is no data characterizing the performance of the most used configurations reducing the risk of complications. METHODS: 487 patients were identified from an international multicenter EOS database. INCLUSION CRITERIA: EOS patients, primary dual MCGR, complete radiographs, and minimum of 2-year follow-up. 76 patients had incomplete X-rays, 5 had apical fusions, and 18 had inconclusive complications, leaving 388 patients for review. A digital spine template was created to document UIV; number of levels; number, type, and location of anchors; as well as implant configuration. First available postoperative and latest follow-up radiographs were reviewed by two senior surgeons and two spine fellows. UPROR due to IRC was defined as any change in proximal anchors between the postoperative and final follow-up radiographs. RESULTS: The most common proximal construct configuration: UIV at T2 (50.0%) with 17.5% UPROR, followed by T3 (34.0%) with 12.1% UPROR; number of levels was three (57.1%) with 16.8% UPROR and two (26.0%) with 17.0% UPROR; number of proximal anchors was six (49.9%) with 14.1% UPROR and four (27.0%) with 18.3% UPROR. The most common anchors were all screws (42.0%) with 9.9% UPROR, and all hooks (26.4%) with 31.4% UPROR (P < 0.001). The construct with the lowest rate of UPROR was a UIV at T2, with six anchors (all screws) across three levels (42 cases), with 0% UPROR. Other construct combinations that yielded 0% UPROR rates were UIV of T3, six anchors (all screws) across three levels (25 cases), and a UIV of T3 with six anchors (screws and hooks) across three3 levels (9 cases). CONCLUSION: Proximal anchor configuration impacts the incidence of UPROR due to IRC in MCGR. UIV at T2 and T3 compared to T4, and the use of all screws or combination of screws and hooks compared to all hooks were associated with a lower UPROR rate. The most common construct configuration was T2 UIV, three levels, six anchors, and all screws. The use of a combination of six anchors (screws or screws and hooks) across three levels with a UIV at T2 or T3 was associated with a lower UPROR rate. Additional research is needed to further evaluate the variables contributing to configuration selection and their association with IRC.
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BACKGROUND AND OBJECTIVE: We assessed the safety of atezolizumab in unselected patients (including understudied populations typically excluded from clinical trials) with pretreated urinary tract carcinoma (UTC). The prespecified final analysis updates previously reported safety and efficacy data. METHODS: The single-arm prospective SAUL study (NCT02928406) enrolled 1004 patients with locally advanced/metastatic urothelial/non-urothelial UTC that had progressed during/after one to three prior treatment lines for advanced UTC (or <12 mo after [neo]adjuvant therapy). Broad eligibility criteria allowed enrollment of patients with complex comorbidities approximating the real-world setting. Patients received atezolizumab 1200 mg every 3 wk until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included duration of response and overall survival (OS). KEY FINDINGS AND LIMITATIONS: The treated cohort included 10% of patients with poor performance status, 5% with creatinine clearance <30 ml/min, and 4% with autoimmune disease. At median follow-up of 55 mo, median atezolizumab duration was 2.8 mo (range 0-62); 68 patients (7%) continued atezolizumab for >4 yr. Treatment-related grade ≥3 adverse events occurred in 16% of patients (death in 1%); 8% discontinued atezolizumab for adverse events. Median OS was 8.6 mo (95% confidence interval 7.8-9.7) and 136 patients (14%) had OS longer than 4 yr. Limitations include the small sample size for some subgroups of special interest. CONCLUSIONS AND CLINICAL IMPLICATIONS: Long-term safety and efficacy data continue to show a benefit of atezolizumab in unselected patients with UTC. Remarkably, 14% of patients lived for >4 yr after starting atezolizumab. These results can inform multidisciplinary team discussions and treatment decision-making for patients with UTC with complex comorbidities. PATIENT SUMMARY: The SAUL study looked at how well tolerated a drug called atezolizumab was in patients with urinary tract cancer who had already received up to three previous treatments for their cancer, including people who are usually not included in clinical trials because of other medical conditions. The length of survival after starting treatment was also assessed. Overall, the results show that atezolizumab was well tolerated. People for whom other therapies had failed lived for about 8.6 months on average after starting treatment, and 14% of the patients were still alive after 4 years.
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Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are recurrent oncogenic drivers found in a variety of solid tumours, including lung cancer. Several tropomyosin receptor kinase (TRK) inhibitors have been developed to treat tumours with NTRK gene fusions. Larotrectinib and entrectinib are first-generation TRK inhibitors that have demonstrated efficacy in patients with TRK fusion lung cancers. Genomic testing is recommended for all patients with metastatic non-small cell lung cancer for optimal drug therapy selection. Multiple testing methods can be employed to identify NTRK gene fusions in the clinic and each has its own advantages and limitations. Among these assays, RNA-based next-generation sequencing (NGS) can be considered a gold standard for detecting NTRK gene fusions; however, several alternatives with minimally acceptable sensitivity and specificity are also available in areas where widespread access to NGS is unfeasible. This review highlights the importance of testing for NTRK gene fusions in lung cancer, ideally using the gold-standard method of RNA-based NGS, the various assays that are available, and treatment algorithms for patients.
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Neoplasias Pulmonares , Receptor trkA , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Receptor trkA/genética , Fusión Génica , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Proteínas de Fusión Oncogénica/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor trkB/genéticaRESUMEN
CONTEXT.: Rapid advancements in the understanding and manipulation of tumor-immune interactions have led to the approval of immune therapies for patients with non-small cell lung cancer. Certain immune checkpoint inhibitor therapies require the use of companion diagnostics, but methodologic variability has led to uncertainty around test selection and implementation in practice. OBJECTIVE.: To develop evidence-based guideline recommendations for the testing of immunotherapy/immunomodulatory biomarkers, including programmed death ligand-1 (PD-L1) and tumor mutation burden (TMB), in patients with lung cancer. DESIGN.: The College of American Pathologists convened a panel of experts in non-small cell lung cancer and biomarker testing to develop evidence-based recommendations in accordance with the standards for trustworthy clinical practice guidelines established by the National Academy of Medicine. A systematic literature review was conducted to address 8 key questions. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, recommendations were created from the available evidence, certainty of that evidence, and key judgments as defined in the GRADE Evidence to Decision framework. RESULTS.: Six recommendation statements were developed. CONCLUSIONS.: This guideline summarizes the current understanding and hurdles associated with the use of PD-L1 expression and TMB testing for immune checkpoint inhibitor therapy selection in patients with advanced non-small cell lung cancer and presents evidence-based recommendations for PD-L1 and TMB testing in the clinical setting.
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Antígeno B7-H1 , Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Mutación , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/diagnóstico , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inhibidores , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , InmunoterapiaRESUMEN
PURPOSE: Transcriptomic subtyping holds promise for personalized therapy in extensive-stage small cell lung cancer (ES-SCLC). In this study, we aimed to assess intratumoral transcriptomic subtype diversity and to identify biomarkers of long-term chemoimmunotherapy benefit in human ES-SCLC. EXPERIMENTAL DESIGN: We analyzed tumor samples from 58 patients with ES-SCLC enrolled in two multicenter single-arm phase IIIb studies evaluating frontline chemoimmunotherapy in Spain: n = 32 from the IMfirst trial and n = 26 from the CANTABRICO trial. We used the GeoMx Digital Spatial Profiler system to perform multi-region transcriptomic analysis. For subtype classification, we performed hierarchical clustering using the relative expression of ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1 (SCLC-Y). RESULTS: Subtype distribution was found to be similar between bothcohorts, except for SCLC-P, which was not identified in the CANTABRICO_DSP cohort. A total of 44% of the patients in both cohorts had tumors with multiple coexisting transcriptional subtypes. Transcriptional subtypes or subtype heterogeneity was not associated with outcomes. Most potential targets did not show subtype-specific expression. Consistently in both cohorts, tumors from patients with long-term benefit (time to progression ≥12 months) contained an IFNγ-dominated mRNA profile, including enhanced capacity for antigen presentation. Hypoxia and glycolytic pathways were associated with resistance to chemoimmunotherapy. CONCLUSIONS: This work suggests that intratumoral heterogeneity, inconsistent association with outcome, and unclear subtype-specific target expression might be significant challenges for subtype-based precision oncology in SCLC. Preexisting IFNγ-driven immunity and mitochondrial metabolism seem to be correlates of long-term efficacy in this study, although the absence of a chemotherapy control arm precludes concluding that these are predictive features specific for immunotherapy.
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Biomarcadores de Tumor , Perfilación de la Expresión Génica , Inmunoterapia , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Transcriptoma , Humanos , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/terapia , Biomarcadores de Tumor/genética , Masculino , Femenino , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Anciano , Inmunoterapia/métodos , Persona de Mediana Edad , Estadificación de Neoplasias , Resultado del Tratamiento , Regulación Neoplásica de la Expresión Génica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , PronósticoRESUMEN
Introduction: RET inhibitors with impressive overall response rates are now available for patients with NSCLC, yet the identification of RET fusions remains a difficult challenge. Most guidelines encourage the upfront use of next-generation sequencing (NGS), or alternatively, fluorescence in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction (RT-PCR) when NGS is not possible or available. Taken together, the suboptimal performance of single-analyte assays to detect RET fusions, although consistent with the notion of encouraging universal NGS, is currently widening some of the clinical practice gaps in the implementation of predictive biomarkers in patients with advanced NSCLC. Methods: This situation prompted us to evaluate several RET assays in a large multicenter cohort of RET fusion-positive NSCLC (n = 38) to obtain real-world data. In addition to RNA-based NGS (the criterion standard method), all positive specimens underwent break-apart RET FISH with two different assays and were also tested by an RT-PCR assay. Results: The most common RET partners were KIF5B (78.9%), followed by CCDC6 (15.8%). The two RET NGS-positive but FISH-negative samples contained a KIF5B(15)-RET(12) fusion. The three RET fusions not identified with RT-PCR were AKAP13(35)-RET(12), KIF5B(24)-RET(9) and KIF5B(24)-RET(11). All three false-negative RT-PCR cases were FISH-positive, exhibited a typical break-apart pattern, and contained a very high number of positive tumor cells with both FISH assays. Signet ring cells, psammoma bodies, and pleomorphic features were frequently observed (in 34.2%, 39.5%, and 39.5% of tumors, respectively). Conclusions: In-depth knowledge of the advantages and disadvantages of the different RET testing methodologies could help clinical and molecular tumor boards implement and maintain sensible algorithms for the rapid and effective detection of RET fusions in patients with NSCLC. The likelihood of RET false-negative results with both FISH and RT-PCR reinforces the need for upfront NGS in patients with NSCLC.
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In the past two decades, the treatment of metastatic non-small cell lung cancer (NSCLC), has undergone significant changes due to the introduction of targeted therapies and immunotherapy. These advancements have led to the need for predictive molecular tests to identify patients eligible for targeted therapy. This review provides an overview of the development and current application of targeted therapies and predictive biomarker testing in European patients with advanced stage NSCLC. Using data from eleven European countries, we conclude that recommendations for predictive testing are incorporated in national guidelines across Europe, although there are differences in their comprehensiveness. Moreover, the availability of recently EMA-approved targeted therapies varies between European countries. Unfortunately, routine assessment of national/regional molecular testing rates is limited. As a result, it remains uncertain which proportion of patients with metastatic NSCLC in Europe receive adequate predictive biomarker testing. Lastly, Molecular Tumor Boards (MTBs) for discussion of molecular test results are widely implemented, but national guidelines for their composition and functioning are lacking. The establishment of MTB guidelines can provide a framework for interpreting rare or complex mutations, facilitating appropriate treatment decision-making, and ensuring quality control.
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Many patients with non-small cell lung cancer do not receive guideline-recommended, biomarker-directed therapy, despite the potential for improved clinical outcomes. Access to timely, accurate, and comprehensive molecular profiling, including targetable protein overexpression, is essential to allow fully informed treatment decisions to be taken. In turn, this requires optimal tissue management to protect and maximize the use of this precious finite resource. Here, a group of leading thoracic pathologists recommend factors to consider for optimal tissue management. Starting from when lung cancer is first suspected, keeping predictive biomarker testing in the front of the mind should drive the development of practices and procedures that conserve tissue appropriately to support molecular characterization and treatment selection.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/tratamiento farmacológico , Patólogos , Biomarcadores de Tumor/metabolismo , Terapia Molecular DirigidaRESUMEN
CONTEXT.: The neurotrophic tropomyosin receptor kinase (NTRK) family gene rearrangements have been recently incorporated as predictive biomarkers in a "tumor-agnostic" manner. However, the identification of these patients is extremely challenging because the overall frequency of NTRK fusions is below 1%. Academic groups and professional organizations have released recommendations on the algorithms to detect NTRK fusions. The European Society for Medical Oncology proposal encourages the use of next-generation sequencing (NGS) if available, or alternatively immunohistochemistry (IHC) could be used for screening with NGS confirmation of all positive IHC results. Other academic groups have included histologic and genomic information in the testing algorithm. OBJECTIVE.: To apply some of these triaging strategies for a more efficient identification of NTRK fusions within a single institution, so pathologists can gain practical insight on how to start looking for NTRK fusions. DESIGN.: A multiparametric strategy combining histologic (secretory carcinomas of the breast and salivary gland; papillary thyroid carcinomas; infantile fibrosarcoma) and genomic (driver-negative non-small cell lung carcinomas, microsatellite instability-high colorectal adenocarcinomas, and wild-type gastrointestinal stromal tumors) triaging was put forward. RESULTS.: Samples from 323 tumors were stained with the VENTANA pan-TRK EPR17341 Assay as a screening method. All positive IHC cases were simultaneously studied by 2 NGS tests, Oncomine Comprehensive Assay v3 and FoundationOne CDx. With this approach, the detection rate of NTRK fusions was 20 times higher (5.57%) by only screening 323 patients than the largest cohort in the literature (0.30%) comprising several hundred thousand patients. CONCLUSIONS.: Based on our findings, we propose a multiparametric strategy (ie, "supervised tumor-agnostic approach") when pathologists start searching for NTRK fusions.
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Neoplasias de la Mama , Carcinoma , Neoplasias , Humanos , Femenino , Receptor trkA/genética , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/patología , Genómica , Proteínas de Fusión Oncogénica/genéticaRESUMEN
This review addresses the phenomenon of "reverse triggering", an asynchrony that occurs in deeply sedated patients or patients in transition from deep to light sedation. Reverse triggering has been reported to occur in 30-90% of all ventilated patients. The underlying pathophysiological mechanisms remain unclear, but "entrainment" is proposed as one of them. Detecting this asynchrony is crucial, and methods such as visual inspection, esophageal pressure, diaphragmatic ultrasound and automated methods have been used. Reverse triggering may have effects on lung and diaphragm function, probably mediated by the level of breathing effort and eccentric activation of the diaphragm. The optimal management of reverse triggering has not been established, but may include the adjustment of ventilatory parameters as well as of sedation level, and in extreme cases, neuromuscular block. It is important to understand the significance of this condition and its detection, but also to conduct dedicated research to improve its clinical management and potential effects in critically ill patients.
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PURPOSE: Lower respiratory tract infections (LRTI) are the most frequent infectious complication in patients admitted to the intensive care unit (ICU). We aim to report the clinical characteristics of ICU-admitted patients due to nosocomial LRTI and to describe their microbiology and clinical outcomes. METHODS: A prospective observational study was conducted in 13 countries over two continents from 9th May 2016 until 16th August 2019. Characteristics and outcomes of ventilator-associated pneumonia (VAP), ventilator-associated tracheobronchitis (VAT), ICU hospital-acquired pneumonia (ICU-HAP), HAP that required invasive ventilation (VHAP), and HAP in patients transferred to the ICU without invasive mechanical ventilation were collected. The clinical diagnosis and treatments were per clinical practice and not per protocol. Descriptive statistics were used to compare the study groups. RESULTS: 1060 patients with LRTI (72.5% male sex, median age 64 [50-74] years) were included in the study; 160 (15.1%) developed VAT, 556 (52.5%) VAP, 98 (9.2%) ICU-HAP, 152 (14.3%) HAP, and 94 (8.9%) VHAP. Patients with VHAP had higher serum procalcitonin (PCT) and Sequential Organ Failure Assessment (SOFA) scores. Patients with VAP or VHAP developed acute kidney injury, acute respiratory distress syndrome, multiple organ failure, or septic shock more often. One thousand eight patients had microbiological samples, and 711 (70.5%) had etiological microbiology identified. The most common microorganisms were Pseudomonas aeruginosa (18.4%) and Klebsiella spp (14.4%). In 382 patients (36%), the causative pathogen shows some antimicrobial resistance pattern. ICU, hospital and 28-day mortality were 30.8%, 37.5% and 27.5%, respectively. Patients with VHAP had the highest ICU, in-hospital and 28-day mortality rates. CONCLUSION: VHAP patients presented the highest mortality among those admitted to the ICU. Multidrug-resistant pathogens frequently cause nosocomial LRTI in this multinational cohort study.
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Infección Hospitalaria , Neumonía Asociada al Ventilador , Infecciones del Sistema Respiratorio , Humanos , Masculino , Persona de Mediana Edad , Femenino , Estudios de Cohortes , Estudios Prospectivos , Infección Hospitalaria/diagnóstico , Infecciones del Sistema Respiratorio/epidemiología , Neumonía Asociada al Ventilador/diagnóstico , Hospitales , Unidades de Cuidados IntensivosRESUMEN
Background and Objective: This narrative review is intended to provide pragmatic knowledge of current methods for the search of anaplastic lymphoma kinase (ALK) fusions in patients with non-small cell lung carcinoma (NSCLC). This information is very timely, because a recent survey has identified that almost 50% of patients with advanced NSCLC were not candidates for targeted therapies because of biomarker testing issues. Methods: PubMed was searched from January 1st, 2012 to February 28th, 2023 using the following keywords: "ALK" and "lung", including reviews and our own work. Key Content and Findings: Testing rates have not reached 85% among patients' candidates to ALK inhibition. The advantages and disadvantages of the different analytical options [immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), real-time polymerase chain reaction and next-generation sequencing (NGS)] are discussed. The key factor for success in ALK testing is a deep understanding of the concept of "molecular redundancy". This notion has been recommended and endorsed by all the major professional organizations in the field and can be summarized as follows: "laboratories should ensure that test results that are unexpected, discordant, equivocal, or otherwise of low confidence are confirmed or resolved using an alternative method or sample". In-depth knowledge of the different ALK testing methodologies can help clinical and molecular tumor boards implement and maintain sensible algorithms for a rapid and effective detection of predictive biomarkers in patients with NSCLC. Conclusions: Multimodality testing has the potential to increase both the testing rate and the accuracy of ALK fusion identification.
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BACKGROUND: Acute kidney injury (AKI) is associated with high morbidity and mortality rates in the intensive care unit (ICU). In low- and middle-income countries (LMICs), epidemiological information about this condition is still scarce. Our main objective was to characterize its epidemiology, prognosis, and its treatment. METHODS: This multicenter prospective cohort study included 1466 patients from 35 ICUs during 6 months in Argentina in 2018. Risk factors and outcomes in patients with and without AKI, and between AKI on admission (AKIadm) and that developed during hospitalization (AKIhosp) were analyzed. RESULTS: AKI occurred in 61.3% of patients (900/1466); 72.6% were AKIadm and 27.3% AKIhosp. Risk factors were age, BMI, arterial hypertension, cardiovascular diseases, diabetes, SOFA, APACHE II, dehydration, sepsis, vasopressor use, radiocontrast, diuresis/h and mechanical ventilation. Independent predictors for AKI were sepsis, diabetes, dehydration, vasopressors on admission, APACHE II and radiocontrast use. Renal replacement therapies (RRT) requirement in AKI patients was 14.8%. Hospital mortality in AKI vs. non-AKI was 38.7% and 23.3% (p < 0.001); and in AKIadm vs. AKIhosp, 41.2% and 37.8% (p = 0.53). CONCLUSIONS: ICU-acquired AKI has high incidence, complications and mortality. Risk factors for AKI and RRT utilization were similar to those described in other epidemiological studies. AKIadm was more frequent than AKIhosp, but had equal prognosis.
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Lesión Renal Aguda , Sepsis , Humanos , Estudios Prospectivos , Enfermedad Crítica/epidemiología , Argentina/epidemiología , Deshidratación/complicaciones , Pronóstico , Unidades de Cuidados Intensivos , Factores de Riesgo , Lesión Renal Aguda/epidemiología , Lesión Renal Aguda/terapia , Lesión Renal Aguda/etiología , Estudios RetrospectivosRESUMEN
INTRODUCTION: Cisplatin-based chemotherapy is currently considered the gold-standard treatment for metastatic urothelial carcinoma (mUC). Nevertheless, most mUC patients develop resistance to chemotherapy. Immune checkpoint inhibitors (ICI) have emerged as a therapeutic option for mUC. ICI are used as both first- and second-line therapy for patients with mUC but also for maintenance following chemotherapy and durable responses may be expected in these settings. AREAS COVERED: Patients with mUC who experience progression after platinum-based chemotherapy regimens, those who are cisplatin-ineligible and have positive PD-L1 expression, and those who are platinum-ineligible, regardless of PD-L1 status, are the target population. The role of ICI monotherapy or drug combinations and newer proposals for mUC therapy are reviewed. The current status of biomarkers to guide ICI treatments in mUC is also provided, focusing on PD-L1, tumor mutational load, and liquid biopsies using ctDNA. EXPERT OPINION: Current challenges to improve the role of ICI in mUC could be summarized as i) development of better drugs; ii) advances in drug-combinations schemes; iii) development of novel biomarkers and techniques to better select patients for this treatment; iv) providing the drugs in the optimal clinical setting; v) promoting trials covering more demographic and clinical heterogeneity (i.e. wider age range, gender, and diverse clinical representation).
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genética , Carcinoma de Células Transicionales/tratamiento farmacológico , Cisplatino/uso terapéutico , Antígeno B7-H1 , Inmunoterapia/métodosRESUMEN
PURPOSE: The aim of this study was to assess the cost-effectiveness of using next-generation sequencing (NGS) versus single-gene testing (SgT) for the detection of genetic molecular subtypes and oncogenic markers in patients with advanced non-small-cell lung cancer (NSCLC) in the setting of Spanish reference centers. METHODS: A joint model combining decision tree with partitioned survival models was developed. A two-round consensus panel was performed to describe clinical practice of Spanish reference centers, providing data on testing rate, prevalence of alterations, turnaround times, and treatment pathways. Treatment efficacy data and utility values were obtained from the literature. Only direct costs (euros, 2022), obtained from Spanish databases, were included. A lifetime horizon was considered, so a 3% discount rate for future costs and outcomes was considered. Both deterministic and probabilistic sensitivity analyses were performed to assess uncertainty. RESULTS: A target population of 9,734 patients with advanced NSCLC was estimated. If NGS was used instead of SgT, 1,873 more alterations would be detected and 82 more patients could potentially be enrolled in clinical trials. In the long term, using NGS would provide 1,188 additional quality-adjusted life-years (QALYs) in the target population compared with SgT. On the other hand, the incremental cost of NGS versus SgT in the target population was 21,048,580 euros for a lifetime horizon (1,333,288 for diagnosis phase only). The obtained incremental cost-utility ratios were 25,895 per QALY gained, below the standard cost-effectiveness thresholds. CONCLUSION: Using NGS in Spanish reference centers for the molecular diagnosis of patients with metastatic NSCLC would be a cost-effective strategy over SgT.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/genética , Análisis Costo-Beneficio , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Pruebas GenéticasRESUMEN
AIM: To investigate the association between 11 oral conditions and oral health related quality of life (OHRQoL). MATERIALS AND METHODS: This cross-sectional study used a multistage sampling strategy to draw a representative sample of adults aged ≥35 years living in Porto Alegre, Brazil. OHRQoL was assessed using OHIP-14. Oral examinations were conducted to assess gingivitis, dental calculus, tooth loss, gingival recession (GR), dentine hypersensitivity (DHS), dental caries (DFT), dental erosion, and non-carious cervical lesions (NCCL). Questionnaires recorded the following self-reported oral variables: xerostomia, halitosis, and perceived need for dental treatment. Structural Equation Models were used to assess the associations adjusting to demographic and behavioral variables. RESULTS: 1022 individuals were analyzed. The overall OHIP mean equaled 9.2 ± 9.7 points. Xerostomia [coefficient (coef)=0.10], halitosis (coef=0.28), DFT (coef=0.16), and DHS (coef=0.19) were significantly and directly associated with negative impacts of OHIP-14. GR was significantly and indirectly associated with poor OHRQoL due to higher DHS. Perceived need for dental treatment was significantly and directly associated with higher OHIP-14 (coef=0,40). CONCLUSIONS: Poor OHRQoL was observed in a sample of Brazilian adults and old people. Five important oral conditions were associated to poor OHRQoL. Tooth loss, gingivitis, calculus, dental erosion and NCCL did not associate with OHRQoL. CLINICAL SIGNIFICANCE: Poorer oral health related quality of life is observed in a Brazilian urban area compared to other parts of the world. Xerostomia, halitosis, dental caries, gingival recession, and dentine hypersensitivity may be targeted to improve oral health and consequently oral health related quality of life.
Asunto(s)
Caries Dental , Sensibilidad de la Dentina , Recesión Gingival , Gingivitis , Halitosis , Enfermedades de la Boca , Pérdida de Diente , Xerostomía , Adulto , Humanos , Caries Dental/epidemiología , Brasil/epidemiología , Estudios Transversales , Calidad de Vida , Enfermedades de la Boca/epidemiología , Salud Bucal , Gingivitis/epidemiología , Xerostomía/epidemiología , Encuestas y CuestionariosRESUMEN
OBJECTIVE: To investigate whether the classification of a patient's caries activity based on lesion activity assessment can predict the increment and progression of coronal and root caries lesions among adults. METHODS: This population-based prospective cohort study followed 413 individuals (mean age 54.1) from southern Brazil for 4 years. Data collection included a questionnaire and clinical examination to record coronal/root caries and gingival recession. The main outcomes were caries increment measured as decayed, missing and filled tooth surfaces (DMFS) and caries progression (surface-level analysis). The main predictor variable was patients' caries activity at baseline ("caries-inactive" or "caries-active"). Negative binomial regression models (unadjusted and adjusted) were used. RESULTS: Caries-active individuals were more likely to present DMFS increment than caries-inactive ones when migrations among DMFS components were considered (IRR [incidence risk ratio] = 1.26, 95%CI [confidence interval] = 1.01-1.58). On the other hand, no such association was found when these migrations were disregarded. The risk for coronal caries progression on filled surfaces was 90% higher among caries-active patients (IRR=1.9; 95%CI=1.4-2.6). In addition, patient's caries activity was able to predict higher risk for root caries progression in newly exposed root surfaces (IRR=1.9; 95%CI=1.0-3.6). CONCLUSION: The classification of a patient's caries activity based on lesion activity was able to foresee lesion progression on the coronal and root surfaces more susceptible to caries among adults. Clinical relevance Classifying a patient's caries activity is a useful tool for the clinical management of dental caries in adults.