Kinetics of BCR::ABL1 transcript levels and molecular relapse after tyrosine kinase inhibitors discontinuation in chronic myeloid leukemia patients: preliminary results from the DES-CML study.

Tyrosine kinase inhibitors (TKI) have revolutionized the treatment of patients with chronic myeloid leukemia. Patients who achieve sustained deep molecular response are eligible for treatment discontinuation. DES-CML is an ongoing, phase 2 multicentric discontinuation trial. Adult patients with CML in chronic phase with typical BCR::ABL1 transcripts, stable deep molecular response (MR4.5 IS) for two years, and no previous resistance were eligible. Patients underwent a phase of TKI dose de-escalation for six months before discontinuation. TKI was reintroduced at the previous dose if the patient lost major molecular response (MMR) at any time. This study aimed to assess the impact of BCR-ABL transcript kinetics during TKI de-escalation and discontinuation phases on treatment-free survival. So far, the study recruited 41 patients, and 38 patients discontinued therapy (4 were in the second discontinuation attempt). Eleven patients lost MMR, one during the de-escalation phase and ten after discontinuation. 24-month treatment-free survival was 66% (95% CI: 48-84%) in a median follow-up of 7 (1-30) months. No patient lost hematological response or had disease progression. A higher rate of molecular relapses occurred in patients with fluctuating BCR::ABL1 levels after the discontinuation phase (with loss of MR4.5, but no loss of MMR) (P=0.04, HR-4.86 (1.03-22.9) but not confirmed in the multivariate analysis. The longer duration of TKI treatment (P=0.03, HR-1.02, 95%CI - 1.00-1.04) and MMR (P=0.004, HR-0.95, 95%CI - 0.92-098) were independent factors of a lower relapse rate.

Hype or hope? A review of challenges in balancing tumor control and treatment toxicity in breast cancer from the perspective of the radiation oncologist.

The aim of this article is to discuss the challenges and new strategies in managing breast cancer patients, with a specific focus on radiation oncology and the importance of balancing oncologic outcomes with quality of life and post-treatment morbidity. A comprehensive literature review was conducted to identify advances in the management of breast cancer, exploring de-escalation strategies, hypofractionation schemes, predictors and tools for reducing toxicity (radiation-induced lymphocyte apoptosis, deep inspiration breath-hold, adaptive radiotherapy), enhancer treatments (hyperthermia, immunotherapy) and innovative diagnostic modalities (PET-MRI, omics). Balancing oncologic outcomes with quality of life and post-treatment morbidity is crucial in the era of personalized medicine. Radiotherapy plays a critical role in the management of breast cancer patients. Large randomized trials are necessary to generalize some practices and cost remains the main obstacle for many innovations that are already applicable.

Does neoadjuvant chemotherapy provide any benefit for surgical de-escalation in luminal B, HER2(-) breast cancers?

BACKGROUND: The use of neoadjuvant chemotherapy (NAC) in less aggressive breast cancer (BC) is controversial. OBJECTIVE: To investigate the effect of neoadjuvant chemotherapy in HER2 negative luminal B breast cancer. PATIENTS AND METHODS: Patients between January 2016 and December 2021 were retrospectively evaluated. RESULTS: A total of 128 patients were included in the study. Patients with pathological complete response (pCR) were younger and had higher ki67 levels. Cutoff levels for ki67 based on pCR and ypT status were ≤ 40% and ≤ 35%, respectively. According to pre-NAC magnetic resonance imaging findings, only mastectomy was viable in 90 patients, but after NAC breast-conserving surgery (BCS) was possible in 29 (32%). Moreover, 68.5% became eligible for sentinel lymph node biopsy (SLNB) after NAC. Since SLNB was positive in 45 (54.2%), axillary lymph node dissection (ALND) was performed and the remainder, 38 (31.4%), avoided ALND. CONCLUSION: In patients with Luminal B, HER2(-) BC a low pCR rate should not discourage the use of NAC. The ki67 level is a guide for individualizing treatment. Especially in young patients with high ki67 levels, NAC increases the chance of breast-conserving surgery and may spare patients from ALND.

ANTECEDENTES: El uso de quimioterapia neoadyuvante (QTN) en cáncer de mama (CB) menos agresivo es controversial. OBJETIVO: Investigar el efecto de la quimioterapia neoadyuvante en el cáncer de mama HER2 negativo luminal B. MÉTODO: Se evaluaron retrospectivamente pacientes entre enero de 2016 y diciembre de 2021. RESULTADOS: Se incluyeron 128 pacientes. Los valores de corte para ki67 basados en el estado de respuesta patológica completa y el estadio tumoral tras la quimioterapia neoadyuvante fueron ≤ 40% y ≤ 35%, respectivamente. Según los hallazgos de la resonancia magnética previa a la quimioterapia neoadyuvante, la mastectomía solo fue viable en 90 pacientes, pero después de la quimioterapia neoadyuvante la cirugía conservadora de la mama fue posible en 29 (32%). Además, el 68.5% se volvieron elegibles para biopsia del ganglio linfático centinela después de la quimioterapia neoadyuvante, y se evitó la disección de ganglios linfáticos axilares en 38 pacientes (31.4%). CONCLUSIONES: En las pacientes con cáncer de mama HER2 negativo luminal B, una tasa baja de respuesta patológica completa no debe desalentar el uso de quimioterapia neoadyuvante. En especial en pacientes jóvenes con niveles altos de ki67, la quimioterapia neoadyuvante aumenta la posibilidad de una cirugía conservadora de la mama y puede evitar que las pacientes sufran disección de ganglios linfáticos axilares.

Impacto clínico del desescalamiento a ertapenem en pacientes críticos con infecciones por Enterobacteriaceae / Clinical impact of ertapenem de-escalation in critically-ill patients with Enterobacteriaceae infections

Resumen Introducción: Ertapenem ha demostrado eficacia frente a Enterobacteriaceae productoras de β-lactamasas de espectro extendido, pero carece de actividad contra bacterias no fermentadoras; el desescalamiento a este antimicrobiano cuando no existe la presencia de P. aeruginosa podría reducir la presión selectiva contra esta bacteria y mejorar los resultados clínicos. Objetivo: Evaluar el impacto clínico del desescalamiento de antimicrobianos con cobertura anti-pseudomonas a ertapenem, un agente sin este espectro, en pacientes críticos con infecciones por Enterobacteriaceae. Métodos: Se realizó un estudio de cohorte prospectivo en adultos admitidos a Unidades de Cuidado Intensivo (UCI) con infecciones por Enterobacteriaceae, que habían sido desescalados de una cobertura anti-pseudomonas, a un antimicrobiano sin la misma (ertapenem). Se realizó un modelo de riesgo proporcional de Cox comparando mortalidad por cualquier causa y duración de estancia hospitalaria entre aquellos pacientes que permanecieron con cobertura anti-pseudomonas versus aquellos que fueron desescalados a ertapenem. Resultados: 105 pacientes en el grupo anti-pseudomonas fueron comparados con 148 pacientes del grupo de desescalamiento a ertapenem. El desescalamiento estuvo asociado con una menor mortalidad por cualquier causa comparado con los pacientes que permanecieron con cobertura anti-pseudomonas (hazard ratio ajustado 0,24; IC 95%: 0,12-0,46). La estancia hospitalaria en UCI fue similar en ambos grupos. Discusión: Los pacientes de UCI con infecciones por Enterobacteriaceae desescalados a terapia con ertapenem, tuvieron mejores resultados clínicos comparados con aquellos que permanecieron en terapia anti-pseudomonas, sugiriendo que el desescalamiento es una práctica segura en esta población.

Background: Ertapenem has proven to be effective for extended-spectrum beta-lactamases-producing Enterobacteriaceae but lacks activity against non-fermenters; de-escalation to this antibiotic may reduce the selection of resistance to Pseudomonas aeruginosa and improve clinical outcomes. Aim: To evaluate the clinical impact of de-escalation from broad-spectrum anti-pseudomonal agents to ertapenem, a non-pseudomonal antibiotics for Enterobacteriaceae infections in critically-ill patients. Methods: We conducted a prospective cohort study in adult patients admitted to intensive care units (ICUs) who had Enterobacteriaceae infections and were de-escalated from empiric anti-pseudomonal coverage to non-pseudomonal antibiotics. Cox proportional hazards models were performed comparing all-cause mortality and length of hospital stay between patients who remained on anti-pseudomonal coverage versus those who were de-escalated to ertapenem. Results: 105 patients in the anti-pseudomonal group were compared to 148 patients in the ertapenem de-escalation group. De-escalation was associated with lower all-cause mortality compared to patients who remained on anti-pseudomonal coverage (adjusted Hazard Ratio 0.24; 95% CI: 0.12-0.46). The length of ICU stay was similar between the groups. Discussion: ICU patients with Enterobacteriaceae infections de-escalated to ertapenem therapy had better outcomes compared to patients who remained on broad-spectrum, anti-pseudomonal therapy, suggesting that de-escalation is a safe approach amongst ICU patients.

Tratamiento antimicrobiano específico de las infecciones quirúrgicas / Specific antimicrobial treatment of surgical infections

El paciente complicado con una infección quirúrgica requiere una terapia antibiótica integral con la colaboración del cirujano, del infectólogo y del microbiólogo. La selección inicial antimicrobiana es un punto clave que define la evolución posterior. La terapia de de-escalación permite disminuir el espectro de cobertura antimicrobiana inicial manteniendo el adecuado tratamiento para el paciente y disminuyendo la selección de microorganismos resistente. El uso adecuado de antimicrobianos comprende la selección inicial ajustada a la patología, la evaluación del riesgo individual e institucional a determinados gérmenes o mecanismos de resistencia, la elección de la dosis correcta, la de-escalación según el resultado bacteriológico y la reevaluación constante de la evolución para nuevo control del foco, ajuste o suspensión oportuna del esquema antimicrobiano(AU)

The complicated patient with a surgical infection requires comprehensive antibiotic therapy with the collaboration of the surgeon, the infectologist and the microbiologist. Initial antimicrobial selection is a key point that defines subsequent evolution. De-escalation therapy allows decreasing the initial antimicrobial coverage spectrum while maintaining proper treatment for the patient and reducing the selection of resistant microorganisms. The appropriate use of antimicrobials includes the initial selection adjusted to the pathology, the assessment of individual and institutional risk to certain germs or resistance mechanisms, the choice of the correct dose, the de-escalation according to the bacteriological result and the constant re-evaluation of the evolution for new control of the focus, adjustment or timely suspension of the antimicrobial scheme(AU)

Ventilator-associated pneumonia: the influence of bacterial resistance, prescription errors, and de-escalation of antimicrobial therapy on mortality rates

Abstract Ventilator-associated pneumonia is the most prevalent nosocomial infection in intensive care units and is associated with high mortality rates (14–70%). Aim This study evaluated factors influencing mortality of patients with Ventilator-associated pneumonia (VAP), including bacterial resistance, prescription errors, and de-escalation of antibiotic therapy. Methods This retrospective study included 120 cases of Ventilator-associated pneumonia admitted to the adult adult intensive care unit of the Federal University of Uberlândia. The chi-square test was used to compare qualitative variables. Student's t-test was used for quantitative variables and multiple logistic regression analysis to identify independent predictors of mortality. Findings De-escalation of antibiotic therapy and resistant bacteria did not influence mortality. Mortality was 4 times and 3 times higher, respectively, in patients who received an inappropriate antibiotic loading dose and in patients whose antibiotic dose was not adjusted for renal function. Multiple logistic regression analysis revealed the incorrect adjustment for renal function was the only independent factor associated with increased mortality. Conclusion Prescription errors influenced mortality of patients with Ventilator-associated pneumonia, underscoring the challenge of proper Ventilator-associated pneumonia treatment, which requires continuous reevaluation to ensure that clinical response to therapy meets expectations.

Ventilator-associated pneumonia: the influence of bacterial resistance, prescription errors, and de-escalation of antimicrobial therapy on mortality rates.

UNLABELLED: Ventilator-associated pneumonia is the most prevalent nosocomial infection in intensive care units and is associated with high mortality rates (14-70%). AIM: This study evaluated factors influencing mortality of patients with Ventilator-associated pneumonia (VAP), including bacterial resistance, prescription errors, and de-escalation of antibiotic therapy. METHODS: This retrospective study included 120 cases of Ventilator-associated pneumonia admitted to the adult adult intensive care unit of the Federal University of Uberlândia. The chi-square test was used to compare qualitative variables. Student's t-test was used for quantitative variables and multiple logistic regression analysis to identify independent predictors of mortality. FINDINGS: De-escalation of antibiotic therapy and resistant bacteria did not influence mortality. Mortality was 4 times and 3 times higher, respectively, in patients who received an inappropriate antibiotic loading dose and in patients whose antibiotic dose was not adjusted for renal function. Multiple logistic regression analysis revealed the incorrect adjustment for renal function was the only independent factor associated with increased mortality. CONCLUSION: Prescription errors influenced mortality of patients with Ventilator-associated pneumonia, underscoring the challenge of proper Ventilator-associated pneumonia treatment, which requires continuous reevaluation to ensure that clinical response to therapy meets expectations.

Treating Staphylococcus aureus infections in an intensive care unit at a University Hospital in Brazil.

BACKGROUND: Optimizing antimicrobial therapy is important for treating patients who are critically ill with Staphylococcus aureus infection, and susceptibility tests are necessary. OBJECTIVE: The aim of the present study was to evaluate antibacterial therapy after susceptibility testing of S. aureus infections. Setting The setting was an intensive care unit at a University Hospital in Brazil. METHODS: An observational and retrospective study was conducted over 6 years. The antimicrobials that were used for S. aureus infection treatment were calculated as the defined daily dose per 1000 patient-days (DDD1000). Antimicrobial susceptibility data were obtained by reviewing bacteriological tests. Patient profiles and treatment were determined by analyzing patient charts. RESULTS: Methicillin-resistant S. aureus (MRSA) was prevalent in this study (76.13 %). Patients who were infected with MRSA had total antimicrobial consumption that was three-times higher (9567.2 DDD1000) than patients who were infected with methicillin-susceptible S. aureus (MSSA; 3101.1 DDD1000). The average length of stay in the intensive care unit was 19 days (interquartile range 17 days) for MSSA and 20 days (interquartile range 20 days) for MRSA. Mortality in patients who were infected with MSSA was higher (52.17 %) than in patients who were infected with MRSA (33.80 %), and de-escalation was not identified in 73.90 % of MSSA patients.

Dynamics of antibiotic usage in the Intensive Care Unit at the University Hospital of the West Indies / Dinámica del uso de Antibióticos en la Unidad de Cuidados Intensivos del Hospital Universitario de West Indies

OBJECTIVE: To determine antibiotic usage patterns in the Intensive Care Unit (ICU) at the University Hospital of the West Indies (UHWI). METHOD: A cross-sectional, analytical study of consecutive patients admitted to the ICU was conducted between July and December 2007. Exclusion criteria were HIV-positive patients, patients < 12 years and those discharged or who died within 48 hours of admission. Data were collected from medical records, stored and analysed using the SPSS Version 12. RESULTS: Of the 150 eligible patients, 109 had complete data (73%). Mean age was 50.8 ± 20.7 years, with mean APACHE II score of 15.6 ± 6.7. Forty-five patients (41.3%) received prophylactic antibiotics, most commonly ceftriaxone (31.7%) and metronidazole (19.0%). Appropriate discontinuation within 24 hours occurred in only 11.1%. Two-thirds of patients (67.9%) were treated with empiric antibiotics, most commonly piperacillin/tazobactam (32.1%), ceftazidime (27.5%) or metronidazole (27.5%). Reasons for empiric choice were primarily coverage of organisms based on presumed source of sepsis (45.6%), and broad spectrum, high-powered coverage (23.5%). Courses ranged from 1 - 42 days and were adequate based on subsequent cultures in 71% of cases. Culture reports took between 2 - 8 days with a mean of 3.7 days to become available. De-escalation was practised in only 2 of 26 (7.7%) cases and intravenous to oral switch therapy in only 3.3%. Thirty-two (29.4%) patients died, with sepsis being a cause in 12 (37.5%). CONCLUSIONS: Improved attention to discontinuation of prophylactic antibiotics, appropriate duration of antibiotic courses and de-escalation are essential if the antibiotic practices in the ICU at the UHWI are to compare favourably with international recommendations.

OBJETIVO: Determinar los patrones de uso de antibióticos en la Unidad de Cuidados Intensivos (UCI) en el Hospital Universitario de West Indies. MÉTODO: Se llevó a cabo un estudio analítico transversal de un número de pacientes consecutivos ingresados a la UCI entre julio y diciembre de 2007. Los criterios de exclusión fueron los siguientes: pacientes positivos al VIH, pacientes < 12 años, y pacientes dados de alta o fallecidos dentro de las 48 horas de su ingreso. Los datos fueron tomados de las historias clínicas, y luego almacenados y analizados usando la versión doce de SPSS. RESULTADOS: De los 150 pacientes elegibles, 109 completaron los datos (73%). La edad promedio fue 50.8 ± 20.7 años, con una puntuación APACHE II media de 15.6 ± 6.7. Cuarenta y cinco pacientes (41.3%) recibieron antibióticos profilácticos, por lo general ceftriaxona (31.7%) y metronidazol (19.0%). Una descontinuación adecuada dentro de las 24 horas se produjo en sólo 11.1%. Dos tercios de los pacientes (67.9%) recibieron tratamiento antibiótico empírico, por lo general con piperacillinatazobactam (32.1%), ceftazidima (27.5%) o metronidazol (27.5%). Las razones para la opción empírica fueron principalmente la cobertura de organismos sobre la base de fuentes de sepsis presuntiva (45.6%), y el espectro ancho, cobertura de alta potencia (23.5%). Los cursos fluctuaron de 1 - 42 días y fueron adecuados a juzgar por los cultivos subsiguientes en 71% de los casos. Los reportes de cultivos tomaron entre 2 - 8 días con un promedio de 3.7 días para hallarse disponibles. El desescalamiento fue practicado en sólo 2 de 26 (7.7%) de los casos y cambio de terapia intravenosa a oral en sólo 3.3%. Treinta y dos (29.4%) pacientes murieron, siendo la sepsis la causa en 12 (37.5%). CONCLUSIONES: Una mayor atención en cuanto a descontinuar el uso de antibióticos profilácticos, una duración apropiada de cursos antibióticos, y el desescalamiento, son esenciales si se quiere que las prácticas antibióticas en las UCI en el HUWI puedan compararse favorablemente con las recomendaciones que se hacen a nivel internacional.