Role of chromosomal instability and clonal heterogeneity in the therapy response of breast cancer cell lines.

Objective: Chromosomal instability (CIN) is a hallmark of cancer characterized by cell-to-cell variability in the number or structure of chromosomes, frequently observed in cancer cell populations and is associated with poor prognosis, metastasis, and therapeutic resistance. Breast cancer (BC) is characterized by unstable karyotypes and recent reports have indicated that CIN may influence the response of BC to chemotherapy regimens. However, paradoxical associations between extreme CIN and improved outcome have been observed. Methods: This study aimed to 1) evaluate CIN levels and clonal heterogeneity (CH) in MCF7, ZR-751, MDA-MB468, BT474, and KPL4 BC cells treated with low doses of tamoxifen (TAM), docetaxel (DOC), doxorubicin (DOX), Herceptin (HT), and combined treatments (TAM/DOC, TAM/DOX, TAM/HT, HT/DOC, and HT/DOX) by using fluorescence in situ hybridization (FISH), and 2) examine the association with response to treatments by comparing FISH results with cell proliferation. Results: Intermediate CIN was linked to drug sensitivity according to three characteristics: estrogen receptor α (ERα) and HER2 status, pre-existing CIN level in cancer cells, and the CIN induced by the treatments. ERα+/HER2- cells with intermediate CIN were sensitive to treatment with taxanes (DOC) and anthracyclines (DOX), while ERα-/HER2-, ERα+/HER2+, and ERα-/HER2+ cells with intermediate CIN were resistant to these treatments. Conclusions: A greater understanding of CIN and CH in BC could assist in the optimization of existing therapeutic regimens and/or in supporting new strategies to improve cancer outcomes.

Resistance and Overcoming Resistance in Breast Cancer.

The incidence and mortality of breast cancer (BC) have increased in recent years, and BC is the main cause of cancer-related death in women worldwide. One of the most significant clinical problems in the treatment of patients with BC is the development of therapeutic resistance. Therefore, elucidating the molecular mechanisms involved in drug resistance is critical. The therapeutic decision for the management of patients with BC is based not only on the assessment of prognostic factors but also on the evaluation of clinical and pathological parameters. Although this has been a successful approach, some patients relapse and/or eventually develop resistance to treatment. This review is focused on recent studies on the possible biological and molecular mechanisms involved in both response and resistance to treatment in BC. Additionally, emerging treatments that seek to overcome resistance and reduce side effects are also described. A greater understanding of the mechanisms of action of treatments used in BC might contribute not only to the enhancement of our understanding of the mechanisms involved in the development of resistance but also to the optimization of the existing treatment regimens.

Protective behavioral strategies and alcohol-related regretted sex among college students.

Regretted sexual experiences are reported at higher rates among sexually active female college students than by their male counterparts. Moreover, alcohol is involved in approximately one third of regretted sex experienced by college students. Previous research has shown that students who implement protective behavioral strategies (PBS) while drinking are able to reduce alcohol-related negative consequences, including regretted sex. In order to compare differences in associations among alcohol use, PBS, and regretted sex, the current study examined these associations as a function of gender. Results were analyzed for each of the 3 subtypes of PBS: Manner of Drinking (MD); Stopping/Limiting Drinking (SLD) and Serious Harm Reduction (SHR). The current study included 371 college students (64.15% female) from a moderate-sized Midwest university. Participants completed a series of online surveys that assessed drinking habits, alcohol-related consequences (i.e., regretted sex), and PBS use. A multigroup path analysis found that alcohol use was positively associated with regretted sex, however, 2 of the 3 PBS subtypes (MD and SLD) were negatively associated with alcohol use. The third PBS subtype (SHR) yielded a direct negative relationship with regretted sex for women, but not for men. Lastly, the interaction of SHR and alcohol use was significantly associated with regretted sex, which was moderated by gender. These results suggest an among PBS use, decreased alcohol use, and fewer instances of regretted sex. Further examination of the differences in relationships among PBS subtypes, alcohol use, and regretted sex for men and women is warranted. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Making Improvements in the ED: Does ED Busyness Affect Time to Antibiotics in Febrile Pediatric Oncology Patients Presenting to the Emergency Department?

OBJECTIVES: Febrile neutropenic pediatric patients are at heightened risk for serious bacterial infections, and rapid antibiotic administration (in <60 minutes) improves survival. Our objectives were to reduce the time-to-antibiotic (TTA) administration and to evaluate the effect of overall emergency department (ED) busyness on TTA. METHODS: This study was a quality improvement initiative with retrospective chart review to reduce TTA in febrile children with underlying diagnosis of cancer or hematologic immunodeficiency who visited the pediatric ED. A multidisciplinary clinical practice guideline (CPG) was implemented to improve TTA. The CPG's main focus was delivery of antibiotics before availability of laboratory data. We collected data on TTA during baseline and intervention periods. Concurrent patient arrivals to the ED per hour served as a proxy of busyness. Time to antibiotic was compared with the number of concurrent arrivals per hour. Analyses included scatter plot and regression analysis. RESULTS: There were 253 visits from October 1, 2010 to March 30, 2012. Median TTA administration dropped from 207 to 89 minutes (P < 0.001). Eight months after completing all intervention periods, the median had dropped again to 44 minutes with 70% of patients receiving antibiotics within 60 minutes of ED arrival. There was no correlation between concurrent patient arrivals and TTA administration during the historical or intervention periods. CONCLUSIONS: Implementation of a CPG and process improvements significantly reduced median TTA administration. Total patient arrivals per hour as a proxy of ED crowding did not affect TTA administration. Our data suggest that positive improvements in clinical care can be successful despite fluctuations in ED patient volume.

Integration of Germline Pharmacogenetics Into a Tumor Sequencing Program.

PURPOSE: Evidence-based guidelines inform treatment decisions for patients for whom germline genetic information is available. Our real-time tumor sequencing program, which makes precision treatment decisions for patients with cancer, produces matched germline information, providing a unique opportunity to efficiently implement pharmacogenetics and benefit patients. METHODS: The germline genetic database from the Michigan Oncology Sequencing (MI-Oncoseq) program was searched for 21 clinically actionable polymorphisms in five cancer-relevant genes: TPMT, DPYD, CYP2C19, CYP3A5, and UGT1A1. Residual germ line DNA was sent to an external Clinical Laboratory Improvement Amendments-approved laboratory for confirmatory genotyping. The medical records of MI-Oncoseq patients with actionable phenotypes were searched for receipt of relevant drugs and to determine whether having genetic information at the time of treatment would have led to a treatment recommendation. RESULTS: All nine variants in TPMT, DPYD, and CYP2C19 that were detected in MI-Oncoseq were confirmed by external genotyping. Genotype determinations could not be made for CYP3A5*3, UGT1A1*28, or UGT1A1*80. On the basis of retrospective assessment of 115 adult and pediatric patient records, 4.3% (n = 5) had a potentially clinically actionable phenotype for TPMT, DPYD, or CYP2C19 and received a relevant medication. After accounting for differences in adult and pediatric recommendations, three of these patients could have received a treatment recommendation at the time of prescribing. CONCLUSION: Germline genotype determinations for TPMT, DPYD, and CYP2C19 can be used to make evidence-based treatment recommendations in MI-Oncoseq patients. Although the proportion of patients for whom recommendations can be made is small, this added value to MI-Oncoseq and patient care comes at no additional genotyping cost. Pharmacogenetic assessment should be integrated into tumor sequencing programs that genotype matched germline DNA; however, the complexity and additional cost of implementing pharmacogenetics remain challenging.

Clofarabine Dosing in a Patient With Acute Myeloid Leukemia on Intermittent Hemodialysis: Case Report and Review of the Literature.

Clofarabine containing chemotherapeutic regimens have demonstrated efficacy in the treatment of relapsed refractory acute myeloid leukemia. Nonetheless, there are limited data on the use of clofarabine in patients with renal failure. The present report describes the use of clofarabine in a patient with renal failure undergoing intermittent dialysis. We describe our rationale for dosing, clofarabine plasma levels obtained, and discuss our findings in the context of other available literature. Consistent with previous findings, intermittent hemodialysis was not found to be a reliable method of removing clofarabine in patients with renal insufficiency.

Vincristine-induced peripheral neuropathy in pediatric cancer patients.

Vincristine is a chemotherapeutic agent that is a component of many combination regimens for a variety of malignancies, including several common pediatric tumors. Vincristine treatment is limited by a progressive sensorimotor peripheral neuropathy. Vincristine-induced peripheral neuropathy (VIPN) is particularly challenging to detect and monitor in pediatric patients, in whom the side effect can diminish long term quality of life. This review summarizes the current state of knowledge regarding VIPN, focusing on its description, assessment, prediction, prevention, and treatment. Significant progress has been made in our knowledge about VIPN incidence and progression, and tools have been developed that enable clinicians to reliably measure VIPN in pediatric patients. Despite these successes, little progress has been made in identifying clinically useful predictors of VIPN or in developing effective approaches for VIPN prevention or treatment in either pediatric or adult patients. Further research is needed to predict, prevent, and treat VIPN to maximize therapeutic benefit and avoid unnecessary toxicity from vincristine treatment.

Características de la prueba piloto: revisión de artículos publicados en enfermería / Characteristics of the pilot test: a review of articles published in nursing

Objetivo: Conocer y describir las características de las pruebas piloto que se mencionan en los artículos de investigación en enfermería publicados en un periodo de tres años en un grupo de revistas indizadas. Metodología: Estudio descriptivo, retrospectivo y transversal. La muestra correspondió a 271 artí- culos de investigación, fueron seleccionados 42. Se elaboró un instrumento de 18 ítems; sometido al análisis de expertos y piloteado previo a la revisión final para valorar características de los artículos publicados en cuatro revistas Latinoamericanas. Resultados: El 15.7% indicaron haber realizado el pilotaje previo y el resto no menciona prueba piloto. Con respecto a las investigaciones que utilizaron procedimientos técnicos, solo el 45% mencionó capacitación previa de los aplicadores. Discusión: Identificar previamente que el instrumento es confuso para el sujeto de investigación puede ayudar a que éste pueda ser modificado antes de ser aplicado a una muestra final, y así disminuir el error susceptible. Conclusión: Sin el reporte de haber realizado previamente una PP, la veracidad y confiabilidad de los instrumentos psicométricos y de los procedimientos técnicos de una investigación disminuyen.

Objective. To know and describe the characteristics of pilot-tests mentioned in nursing research papers published within a three-year period in a group of indexed journals. Method. Descriptive, retrospective and transversal study, with a 271 research articles sample, they were selected 42. An 18-items instrument was elaborated and submitted to experts analysis and then pilot-tested previous to the final review, aiming to evaluate the characteristics of the articles published in four Latin-American journals. Results. 15.7% indicated a previous pilot-testing, and the rest did not mention a pilot-test. Regarding researches that used technical procedures, only 45% mentioned previous training for those in charge of application. Discussion. Identifying previously that the instrument is confusing for the research subject might help in modifying it before it can be applied on a final sample, decreasing, thus, the susceptible error. Conclusion. Without reporting the previous PT application, the research psychometric instruments and technical procedures reliability and truthfulness decrease.

[Consent and confidentiality in occupational health practice: balance between legal requirements and ethical values]. / Consenso e confidenzialità nella pratica professionale del medico competente tra requisiti normativi e valori etici.

INTRODUCTION: The recently introduced Italian law on the protection of workers' health states that the occupational health physician (competent physician) is required to act according to the Code of Ethics of the International Commission on Occupational Health (ICOH). AIM: This paper aims at examining the articles of legislative decree 81/2008 dealing with informed consent and confidentiality compared with the corresponding points of the ICOH Ethics Code. RESULTS: Analysis of the relationship between articles 25 and 39 (informed consent) and 18, 20 and 39 (confidentiality) of the decree shows that there are some points of disagreement between the legal requirements and the Code of Ethics, in particular concerning prescribed health surveillance, consent based on appropriate information (points 8, 10 and 12 of the Code) and some aspects of confidentiality (points 10, 20, 21, 22 and 23 of the Code). CONCLUSION: Although the competent physician is required to act according to the law, the decisional process could lead to a violation of workers' autonomy.

Focusing ethical dilemmas of evidence-based practice in SMF-exposed MRI-workers: a qualitative analysis.

PURPOSE: To analyze ethical dilemmas for occupational health physicians and other stakeholders involved in the implementation of a surveillance program in workers exposed to static magnetic fields (SMF) used in magnetic resonance imaging. METHODS: The ethical analysis was carried out according to the model proposed by Westerholm and others, which takes into account two elements: (i) the stakeholders involved in the decision process and (ii) the ethical principles of beneficence, autonomy and justice. The analysis is based on the assessment of ethical costs (violating the consistent principle) and ethical benefits (fulfillment of the consistent principle) for workers, employers, occupational health physicians, community, workers' representatives and medical inspectors. RESULTS: According to the European Directive 2004/40/EC (Official Journal of the European Union, Luxemburg), employers must ensure that health surveillance is carried out to prevent adverse health effects in SMF-exposed workers. However, limited scientific evidence on health effects from SMF influences the decision of undertaking appropriate health surveillance. The uncertainties entail a number of ethical conflicts, such as the choice of reliable indicators, the interpretation of abnormal data, the complexity of the decision-making process resulting in a fitness judgment and the diversion of funds for more effective practices. CONCLUSIONS: The analysis shows that the decision-making process aiming at the provision of evidence-based health surveillance to SMF-exposed workers is characterized by controversial ethical costs and ethical benefits for workers and the other stakeholders.

[Occupational medicine: practice and ethical requirements of the new law on health and safety in the workplace (legislative decree 81/2008)]. / Attività del medico competente e obblighi etici secondo il nuovo testo unico sulla sicurezza sul lavoro (decreto legislativo 81/2008).

Decisions in occupational health may involve ethical conflicts arising from conflicts between stakeholders' interests. Codes of ethics can provide a practical guide to solve dilemmas. The new law on health and safety in the workplace in Italy (decree 81/2008) states that occupational health practice must comply with the code of ethics of the International Commission on Occupational Health. The universally acknowledged ethical principles of beneficience/nonmaleficience, autonomy and justice, which are the basis of the Charter of fundamental rights of the European Union, inspired this code. Although the code is not a systematic textbook of occupational health ethics and does not cover all possible aspects arising from the practice, making decisions based on it will assure their effectiveness and compliance with ethical principles, besides the formal respect of the law.

[Comparative analysis of occupational health physician's duties based upon legislative decree 81/2008 art. 25 and upon the Ethics Code of the International Commission on Occupational Health]. / Analisi comparativa degli obblighi del medico competente alla luce dell'art. 25 del Decreto legislativo 81/2008 e del codice etico della Commissione Internazionale di Medicina del Lavoro (ICOH).

INTRODUCTION: Ethical behaviour consists ofindividual choices inspired by knowledge and professional experience derived from the universally acknowledged ethical principles of beneficience/nonmaleficience, autonomy and justice. However, in spite of the unanimous consent on their universal importance, such principles do not usually have the strength of a law. AIM: The recently introduced Italian law on the protection of workers' health represents a novelty because it gives the Ethics Code of the International Commission on Occupational Health legal strength. This paper aims at examining article 25 of legislative decree 81/2008 by comparing the points of the Ethics Code and the Deontology Code of the Italian medical profession. RESULTS: The relationships between the 12 points of paragraph 1 of article 25, the 26 points ofthe Code ofEthics and the 75 articles of the Deontology Code are described with regard to the occupational health physician's duties (i) of collaboration with other occupational health professionals, (ii) of organization and execution of health surveillance, (iii) of recording, securing, transmitting of medical files on workers' health and (iv) of employee and employer information on the importance and meaning of health surveillance.

Myeloperoxidase-positive cell infiltration in colorectal carcinogenesis as indicator of colorectal cancer risk.

Colorectal mucosa is targeted by toxic agents, which can initiate or promote colon cancer. The mechanism of damage might be a focal irritation with loss of normal epithelial cell barrier function. Genetic alterations in tumors may also affect host inflammatory response. The aim of this study was to define the extent of inflammation in colorectal mucosa, along colorectal carcinogenesis, and in microsatellite stable and unstable colorectal carcinomas. We collected 103 samples of normal colorectal mucosa from 65 patients (35 with colorectal cancer or adenoma, 8 with inflammatory bowel diseases, and 22 controls with normal colonoscopy). We also examined 24 aberrant crypt foci, 14 hyperplastic polyps, 16 adenomas, and 67 samples of colorectal carcinoma. Immunohistochemistry was used to count myeloperoxidase (MPO)-positive cells (neutrophils and monocytes) in x100 optical fields under a light microscope. Patients with colorectal tumors had a higher mean number of MPO-positive cells in normal mucosa than controls (mean +/- SD, 2.7 +/- 2.0 versus 1.4 +/- 1.4; P = 0.017). MPO-positive cell number was tightly linked to dysplasia in aberrant crypt foci and adenomas, and it was higher in carcinomas microsatellite unstable than those microsatellite stable (21.6 +/- 15.5 versus 11.9 +/- 8.0; P < 0.01). MPO immunohistochemistry is a simple and reliable technique for the quantification of inflammation in colorectal mucosa., and it may be a potential marker of colorectal cancer risk. Microsatellite instability seems to influence host immune responses to colorectal carcinoma. These observations strongly support a key role of inflammation in colorectal carcinogenesis.