Pharmacokinetics, Dose-Proportionality, and Tolerability of Intravenous Tanespimycin (17-AAG) in Single and Multiple Doses in Dogs: A Potential Novel Treatment for Canine Visceral Leishmaniasis.

In the New World, dogs are considered the main reservoir of visceral leishmaniasis (VL). Due to inefficacies in existing treatments and the lack of an efficient vaccine, dog culling is one of the main strategies used to control disease, making the development of new therapeutic interventions mandatory. We previously showed that Tanespimycin (17-AAG), a Hsp90 inhibitor, demonstrated potential for use in leishmaniasis treatment. The present study aimed to test the safety of 17-AAG in dogs by evaluating plasma pharmacokinetics, dose-proportionality, and the tolerability of 17-AAG in response to a dose-escalation protocol and multiple administrations at a single dose in healthy dogs. Two protocols were used: Study A: four dogs received variable intravenous (IV) doses (50, 100, 150, 200, or 250 mg/m2) of 17-AAG or a placebo (n = 4/dose level), using a cross-over design with a 7-day "wash-out" period; Study B: nine dogs received three IV doses of 150 mg/m2 of 17-AAG administered at 48 h intervals. 17-AAG concentrations were determined by a validated high-performance liquid chromatographic (HPLC) method: linearity (R2 = 0.9964), intra-day precision with a coefficient of variation (CV) ≤ 8%, inter-day precision (CV ≤ 20%), and detection and quantification limits of 12.5 and 25 ng/mL, respectively. In Study A, 17-AAG was generally well tolerated. However, increased levels of liver enzymes-alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT)-and bloody diarrhea were observed in all four dogs receiving the highest dosage of 250 mg/m2. After single doses of 17-AAG (50-250 mg/m2), maximum plasma concentrations (Cmax) ranged between 1405 ± 686 and 9439 ± 991 ng/mL, and the area under the curve (AUC) plotting plasma concentration against time ranged between 1483 ± 694 and 11,902 ± 1962 AUC 0-8 h µg/mL × h, respectively. Cmax and AUC parameters were dose-proportionate between the 50 and 200 mg/m2 doses. Regarding Study B, 17-AAG was found to be well tolerated at multiple doses of 150 mg/m2. Increased levels of liver enzymes-ALT (28.57 ± 4.29 to 173.33 ± 49.56 U/L), AST (27.85 ± 3.80 to 248.20 ± 85.80 U/L), and GGT (1.60 ± 0.06 to 12.70 ± 0.50 U/L)-and bloody diarrhea were observed in only 3/9 of these dogs. After the administration of multiple doses, Cmax and AUC 0-48 h were 5254 ± 2784 µg/mL and 6850 ± 469 µg/mL × h in plasma and 736 ± 294 µg/mL and 7382 ± 1357 µg/mL × h in tissue transudate, respectively. In conclusion, our results demonstrate the potential of 17-AAG in the treatment of CVL, using a regimen of three doses at 150 mg/m2, since it presents the maintenance of high concentrations in subcutaneous interstitial fluid, low toxicity, and reversible hepatotoxicity.

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.

A review of dose escalation for FDA-approved products treating solid tumors and hematological malignancies in first-in-human trials.

First-in-human (FIH) dose-escalation trials on oncology should prioritize safety and emphasize efficacy. We reviewed the FIH trials of 67 anti-tumor products approved by the Food and Drug Administration between 2018 and 2023 and found that the "3 + 3" design remains the predominant dose-escalation method (66.2%). The number of patients receiving sub-therapeutic doses is positively correlated with the maximum tolerated dose (MTD) or maximum dose (MD) to starting dose ratio (P = 0.056) and the number of dose levels in trials (P < 0.001). In addition, the proportion of products with a high ratio in antibody drugs is higher than that in small molecules (P < 0.001). The MTD or MD exceeded the label dose by three or more doses in 22.03% of the products. In conclusion, optimizing the starting dose selection method, refining the way of determining doses, and finding alternative indicators to replace toxicity as the endpoints will increase the effectiveness and broaden the beneficiary scope.

A Phase I Dose-Escalation Clinical Trial to Assess the Safety and Efficacy of Umbilical Cord-Derived Mesenchymal Stromal Cells in Knee Osteoarthritis.

Osteoarthritis (OA) is the most common degenerative joint disease. Mesenchymal stromal cells (MSC) are promising cell-based therapy for OA. However, there is still a need for additional randomized, dose-dependent studies to determine the optimal dose and tissue source of MSC for improved clinical outcomes. Here, we performed a dose-dependant evaluation of umbilical cord (UC)-derived MSC (Celllistem) in a murine model and in knee OA patients. For the preclinical study, a classical dose (200.000 cells) and a lower dose (50.000 cells) of Cellistem were intra-articularly injected into the mice knee joints. The results showed a dose efficacy response effect of Cellistem associated with a decreased inflammatory and degenerative response according to the Pritzker OARSI score. Following the same approach, the dose-escalation phase I clinical trial design included 3 sequential cohorts: low-dose group (2 × 106 cells), medium-dose group (20 × 106), and high-dose group (80 × 106). All the doses were safe, and no serious adverse events were reported. Nonetheless, 100% of the patients injected with the high-dose experienced injection-related swelling in the knee joint. According to WOMAC total outcomes, patients treated with all doses reported significant improvements in pain and function compared with baseline after 3 and 6 months. However, the improvements were higher in patients treated with both medium and low dose as compared to high dose. Therefore, our data demonstrate that the intra-articular injection of different doses of Cellistem is both safe and efficient, making it an interesting therapeutic alternative to treat mild and symptomatic knee OA patients. Trial registration ClinicalTrials.gov NCT03810521.

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.

Are we overcoming our inability to have pediatric patients properly use inhaled corticosteroids by inappropriately escalating their therapy?

OBJECTIVE: To perform a narrative review to describe and discuss potential methods and strategies for effectively assessing and dealing with poor adherence and/or misuse of inhalers in difficult-to-treat pediatric asthmatic patients. DATA SOURCES: Articles available in electronic databases, published from inception to April 2021. STUDY SELECTIONS: Relevant articles in the literature that discuss and analyze potential methods and strategies for effectively assessing and dealing with poor adherence and/or misuse of inhalers in difficult-to-treat pediatric asthmatic patients. RESULTS: Validated self-reported questionnaires, weighing inhaler canisters, and pharmacy records might be the most suitable methods for assessing adherence to inhaled controller therapy in clinical practice. Additionally, validated instruments could be used as an objective measurement of the adequacy of inhaler technique. Finally, empathy and a true and strong physician-parent/patient partnership have a more powerful influence on adherence than almost any other factor, and they are probably the most cost-effective methods not only for detecting poor adherence to controller therapy but also for dealing with and improving it. CONCLUSIONS: Failure to detect or effectively handle nonadherence and/or inhaler misuse in a patient with uncontrolled asthma can mislead clinicians into thinking that the patient is nonresponsive to the original less-intensive therapy, resulting in unneeded dosage increases and/or escalation of controller therapy to more costly medications, in some cases reaching the level of biologic therapy.

Modeling synergism in early phase cancer trials with drug combination with continuous dose levels: is there an added value?

In parametric Bayesian designs of early phase cancer clinical trials with drug combinations exploring a discrete set of partially ordered doses, several authors claimed that there is no added value in including an interaction term to model synergism between the two drugs. In this paper, we investigate these claims in the setting of continuous dose levels of the two agents. Parametric models will be used to describe the relationship between the doses of the two agents and the probability of dose limiting toxicity and efficacy. Trial design proceeds by treating cohorts of two patients simultaneously receiving different dose combinations and response adaptive randomization. We compare trial safety and efficiency of the estimated maximum tolerated dose (MTD) curve between models that include an interaction term with models without the synergism parameter with extensive simulations. Under a selected class of dose-toxicity models and dose escalation algorithm, we found that not including an interaction term in the model can compromise the safety of the trial and reduce the pointwise reliability of the estimated MTD curve.

Contemporary dose-escalation methods for early phase studies in the immunotherapeutics era.

Phase 1 dose-escalation trials are crucial to drug development by providing a framework to assess the toxicity of novel agents in a stepwise and monitored fashion. Despite widely adopted, rule-based dose-escalation methods (such as 3 + 3) are limited in finding the maximum tolerated dose (MTD) and tend to treat a significant number of patients at subtherapeutic doses. Newer methods of dose escalation, such as model-based and model-assisted designs, have emerged and are more accurate in finding MTD. However, these designs have not yet been broadly embraced by investigators. In this review, we summarise the advantages and disadvantages of contemporary dose-escalation methods, with emphasis on model-assisted designs, including time-to-event designs and hybrid methods involving optimal biological dose (OBD). The methods reviewed include mTPI, keyboard, BOIN, and their variations. In addition, the challenges of drug development (and dose-escalation) in the era of immunotherapeutics are discussed, where many of these agents typically have a wide therapeutic window. Fictional examples of how the dose-escalation method chosen can alter the outcomes of a phase 1 study are described, including the number of patients enrolled, the trial's timeframe, and the dose level chosen as MTD. Finally, the recent trends in dose-escalation methods applied in phase 1 trials in the immunotherapeutics era are reviewed. Among 856 phase I trials from 2014 to 2019, a trend towards the increased use of model-based and model-assisted designs over time (OR = 1.24) was detected. However, only 8% of the studies used non-rule-based dose-escalation methods. Increasing familiarity with such dose-escalation methods will likely facilitate their uptake in clinical trials.

When adherence and inhalation technique matter: Difficult-to-control pediatric asthma in low- to middle-income countries.

Despite relatively recent advances in our understanding of the physiopathology of asthma and the availability of highly effective controller medications, such as inhaled corticosteroids (ICS), currently many pediatric patients fail to control their asthma, especially in low- and middle-income countries (LMICs). Although some of these difficult-to-control asthmatic children have severe therapy-resistant asthma, most of them experience poor asthma control due to various modifiable factors, among which poor adherence to inhaled controller therapy and inadequate inhaler technique are the most common. Although electronic monitoring devices have been considered to be essential tools in identifying patients with severe therapy-resistant asthma, their high cost and low availability have currently limited their use in clinical practice. For these reasons, clinicians might consider using validated self-reported questionnaires and the weight of inhaler canisters and as alternative and valid options for assessing adherence to inhaled controller therapy. Furthermore, clinicians might consider adopting validated instruments as an objective measurement of the adequacy of inhaler technique. Although recognizing poor adherence does not automatically lead to improved adherence, it is usually an essential first step in effectively targeting adherence behavior, especially if the reasons for low or erratic compliance are explored by means of non-judgmental doctor-patient communication. These recommendations could assist in overcoming our inability to have pediatric asthmatic patients use ICS and in avoiding escalating their controller therapy toward more expensive medications, eventually reaching the use biologics. Promoting the rational and cost-effective use of asthma controller therapy could help to optimize the limited health resources in many LMICs.

Autologous fat as a rectal-prostate spacer for prostate brachytherapy: Results at 6 months.

PURPOSE: Implanted rectal spacers (IRS) have been developed to increase the distance between the prostate and the rectum, thus optimizing dose escalation. Cost is a disadvantage and there are still uncertainties as to their durability. We have developed an autologous fat transfer (AFT) technique to use as an IRS. We aim to present the feasibility and durability at 6 months of AFT placed immediately after the implant of the seeds in low-dose-rate brachytherapy (BT). METHODS AND MATERIALS: Thirty-five patients underwent AFT (12 were treated with primary BT, 7 with a combined primary treatment of external beam radiotherapy + BT, 16 with salvage BT). The isodose used for primary BT was 14400 cGy, 11,000 cGy after 4600 cGy of external beam radiotherapy in the combined group, and 14400 cGy for the salvage group. Patients underwent a CT scan at 1, 3, and 6 months to measure the distance between the rectum and the prostate. RESULTS: An average of 32.7 cc (20-40) of fat was transferred successfully in 100% of cases. The mean distance to the rectum at the level of the base, middle, and apex at 1 and 6 months were 11.2, 9.7, and 7.6 mm; 8.3, 8.1, and 5.9 mm, respectively. No rectal toxicity or major complications were reported. CONCLUSIONS: The use of fat as an IRS seems to be a valid alternative to reduce rectal toxicity after BT, achieving equivalent distances to synthetic IRS. It is feasible, safe, and the loss of distance at 6 months is small. Cost is lower than other alternatives.

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.

Declining brachytherapy utilization for high-risk prostate cancer-Can clinical pathways reverse the trend?

PURPOSE: Although external beam radiation therapy (EBRT) plus a brachytherapy boost (BB) offers a 20% improvement in biochemical progression-free survival compared with dose-escalated EBRT alone for men with intermediate and high-risk prostate cancer, population studies show a concerning decline in BB utilization. METHODS: We modified our clinical pathway (CP) in January 2016 to indicate EBRT with BB as first-choice modality for high-risk prostate cancer, based on preliminary findings of Androgen Suppression Combined with Elective Nodal and Dose-Escalated Radiation Therapy. A retrospective review was performed on 659 patients with high-risk prostate cancer treated with definitive intent EBRT ± BB within a network of 19 sites between December 2011 and July 2017. χ2 test was used to determine changes in practice pattern before vs. after CP modification. RESULTS: Before CP modification, 25.2% of patients were planned for BB, compared with 45.4% afterward (p < 0.001). Among 23 nonbrachytherapist physicians, utilization of BB increased from 3.4% to 14.8% (p < 0.001) after CP modification. Among nine brachytherapists, utilization increased from 46.4% to 55.6% (p = 0.120). Among patients treated by a nonbrachytherapist who did not receive BB, the reason was physician preference in 59.7%, patient preference in 19.9%, and other in 20.4%. CONCLUSION: Based on recent evidence suggesting improved biochemical progression-free survival with use of BB for high-risk prostate cancer, we modified our CP, after which we observed increased use of a BB across a network, especially among physicians who do not perform brachytherapy. However, physician preference remains the most significant factor in the nonutilization of BB. New mechanisms are needed to overcome this barrier.

The effect of dose escalation for large squamous cell carcinomas of the anal canal.

PURPOSE: Chemoradiation allows for organ preservation in patients with anal cancer, but patients with large tumors (> 5 cm) have elevated rates of locoregional recurrence. With conformal radiation techniques, there is interest in dose escalation to decrease local recurrence in patients with large tumor size. METHODS/PATIENTS: The National Cancer Database (NCDB) was used to identify patients with anal cancer from 2004 to 2013 with tumors > 5 cm. Adult patients who received definitive chemoradiation were included. Patients with prior resection were excluded. High dose was defined as greater than or equal to 5940 cGy. Statistical analyses were performed using logistic regression, Kaplan-Meier, and Cox proportional hazards for overall survival (OS). RESULTS: In total, 1349 patients were analyzed with 412 (30.5%) receiving high-dose radiation therapy (RT). 5-year OS was 58 and 60% for high and standard dose RT, respectively (p = 0.9887). On univariate analysis, high-dose RT was not associated with improved OS (HR = 0.998, CI 0.805-1.239, p = 0.9887). On multivariate analysis, high-dose RT (HR = 0.948, CI 0.757-1.187, p = 0.6420) was not associated with improved OS but older age (HR = 1.535, CI 1.233-1.911, p = 0.0001), male sex (HR = 1.695, CI 1.382-2.080, p < 0.0001), comorbidities (HR = 1.389, CI 1.097-1.759, p = 0.0064), and long RT (HR = 1.299, CI 1.047-1.611, p = 0.0173) were significantly associated with decreased OS. CONCLUSIONS: There was no observed difference in OS for dose escalation of anal cancers > 5 cm in this population-based analysis. Differences in local control and salvage therapy cannot be assessed through the NCDB. Whether dose escalation of large tumors may improve local control and colostomy-free survival remains an important question and is the subject of ongoing trials.

Adjuvant Dose-Dense Chemotherapy for Breast Cancer: Available Evidence and Recent Updates.

Adjuvant chemotherapy has greatly improved the prognosis of early breast cancer. Dose-dense chemotherapy seeks to increase efficacy by changing the interval between cycles of treatment without the need of increasing doses and toxicity. According to the Gompertzian model, the smaller tumors are and the more rapid they grow, the more benefit could be expected from dose-dense therapy. Some clinical trials showed reduced mortality when adjuvant chemotherapy is administered in shorter intervals, while others had discordant results. Interpreting results is difficult due to a great variability in doses and schemes used in different trials. Dose-dense chemotherapy does not seem to increase adverse events and appears to be the most efficacious in higher-risk individuals and in hormone receptor-negative tumors. This review intends to summarize the available evidence and recent research about this subject.

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)

Violências no ambiente de trabalho: ponderações teóricas / Violencias en el ambiente de trabajo: ponderaciones teóricas / Violence in the workplace: theoretical considerations

Resumo Neste artigo teórico, tem-se como objetivo analisar as diferenças e possíveis sobreposições conceituais a respeito de tipologias de violências no trabalho, as quais são cada vez mais sutis. A reflexão crítica sobre o trabalho de Hershcovis (2011) nos instigou a pensar nas diferenciações entre as tipologias de violência, visando sua compreensão a partir de modelos que se aproximam de uma visão mais complexa e realística das interações sociais (Andersson & Pearson, 1999; Cortina, Kabat-Farr, Magley, & Nelson, 2017; Leymann, 1996; Vasconcelos, 2015). Os principais resultados consistem na identificação de dois riscos potenciais para a compreensão do tema: (a) a aglutinação dos conceitos, o que prejudica avanços teóricos e tratamentos específicos no trabalho; e (b) o isolamento dos tipos em silos, o que contribui para a perda de avanços alcançados em outros domínios. Ainda, postula-se a necessidade de vislumbrar as diversas tipologias de violências em um continuum conforme o contexto social.

Resumen En este artículo teórico, el objetivo es analizar las diferencias y posibles superposiciones conceptuales respecto a tipologías de violencias en el trabajo, las cuales son cada vez más sutiles. La reflexión crítica sobre el trabajo de Hershcovis (2011) nos instigó a pensar en las diferenciaciones entre las tipologías de violencia, apuntando a su comprensión a partir de modelos que se aproximan a una visión más compleja y realista de las interacciones sociales (Andersson & Pearson, 1999; Cortina, Kabat-Farr, Magley, & Nelson, 2017; Leymann, 1996; Vasconcelos, 2015). Los principales resultados consisten en la identificación de dos riesgos potenciales para la comprensión del tema: (a) la aglutinación de conceptos, que perjudica avances teóricos y tratamientos específicos en el trabajo; y (b) el aislamiento de los tipos en silos, lo que contribuye a la pérdida de avances en otros ámbitos. Además, se postula la necesidad de vislumbrar las diversas tipologías de violencias en un continuo, según el contexto social.

Abstract In this theoretical article, the objective is to analyze the differences and possible conceptual overlaps regarding typologies of violence at work, which are increasingly subtle. The critical reflection on the work of Hershcovis (2011) instigated us to think about the differences between the typologies of violence, aiming at their understanding from models that approach a more complex and realistic view of social interactions (Andersson & Pearson, 1999; Cortina, Kabat-Farr, Magley, & Nelson, 2017; Leymann, 1996; Vasconcelos, 2015). The main results are the identification of two potential risks to the understanding of the theme: (a) the agglutination of concepts, which harms theoretical advances and specific treatments at work; and (b) the isolation of types in silos, which contributes to the loss of progressions that reached other domains. Still, it postulates the need to glimpse the different typologies of violence in a continuum according to the social context.

Identifying demographic and psychosocial factors related to the escalation of smoking behavior among Mexican American adolescents.

Cigarette smoking is the leading preventable cause of death in the United States; smoking in Mexican American adolescents, a rapidly growing population, remains a major concern. Factors associated with escalation or progression along the smoking trajectory have not been studied in adolescent Mexican Americans. A better understanding of escalation is needed for cancer prevention and overall health. N=1,328 Mexican American adolescents joined a cohort in 2005-06. At baseline participants provided demographic, acculturation and psychosocial data, and reported their smoking status using the Minnesota Smoking Index. Those that never tried a cigarette or only had a few puffs in their life were included in this study. The primary outcome of interest, escalation in smoking status, was defined as moving up the Minnesota Smoking Index by 2010-2011. The current analysis is based on 973 participants of whom 48.2% were male, mean age=11.8 (SD=0.8), and 26.0% were born in Mexico. By 2010-2011, 283 (29%) escalated their smoking status and 690 (71%) remained the same. Being older (OR=1.30; CI=1.07-1.57), male (OR=1.88, CI=1.40-2.53), having higher levels of anxiety (OR=1.03, CI=1.02-1.05), intending to smoke (OR=1.70, CI=1.18-2.46), having friends who smoke (OR=1.73, CI=1.12-2.70) and having parents' friends who smoke (OR=1.38, CI=1.02-1.88) increased risk for smoking escalation. Higher levels of subjective social status (OR=0.91, CI=0.83-0.99) were protective against smoking escalation. Contrasting previous work in smoking experimentation, parents' friends influence was a stronger predictor than the family household influence. Preventative interventions for Mexican American youth could address this risk factor to reduce smoking escalation.

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.