Survival outcomes in an older US population with advanced melanoma and central nervous system metastases: SEER-Medicare analysis.

BACKGROUND: Central nervous system (CNS) metastasis is common in advanced melanoma patients. New treatment options have improved overall prognosis, but information is lacking for patients with CNS metastases. We investigated treatment patterns and survival outcomes in older melanoma patients with and without CNS metastases. METHODS: A retrospective analysis of SEER-Medicare, a population-based linked database, was undertaken in patients aged > 65 years with advanced melanoma diagnosed from 2004 to 2011 and followed until 2013. RESULTS: A total of 2522 patients were included. CNS metastases were present in 24.8% of patients at initial metastatic diagnosis; 16.5% developed CNS metastases during follow-up. Chemotherapy was the most common treatment regardless of CNS metastases. Overall survival (OS) was better for patients without CNS metastases (median, 9.5 months; 95% confidence interval [CI], 8.8-10.2) vs patients with CNS metastases (3.63 months; 95% CI, 3.4-3.9). Among patients with CNS metastases, median OS for targeted therapy, immunotherapy, and chemotherapy was 6 (95% CI, 2.5-9.6), 5.5 (95% CI, 3.8-7.5), and 4.5 (95% CI, 3.8-5.4) months, respectively, vs 2.4 (95% CI, 2.1-2.7) and 2.1 (95% CI, 1.8-2.7) months for local radiotherapy and no treatment, respectively. Stereotactic radiosurgery demonstrated higher OS vs whole-brain radiation therapy (median, 4.98 [95% CI, 3.5-7.5] vs 2.4 [95% CI, 2.1-2.7] months). CONCLUSION: Patients with CNS metastases from melanoma remain a population with high unmet medical need despite recent advances in treatment. Systemic treatments (eg, BRAF-targeted therapy and immunotherapy) and stereotactic radiosurgery demonstrated meaningful but modest improvements in OS. Further explorations of combinations of radiotherapy, BRAF-targeted therapies, and immunotherapies are needed.

Demographics, deaths and severity indicators in hospitalizations due to drug poisoning among children under age five in Brazil. / Demografia, óbitos e indicadores de agravamento nas internações por intoxicações medicamentosas entre menores de 5 anos no Brasil.

INTRODUCTION: In Brazil, drugs are the main causative agents of poisonings, and children under age five are the group with the highest number of cases. The objective of the present study was to describe hospitalizations due to drug poisoning in this population regarding demographics, deaths and worsening indicators in hospitalizations. METHODS: The frequency of hospitalizations for drug poisoning between 2003 and 2012 was verified using data from the Hospital Information System. The study variables were year, gender, age, place of residence and hospitalization, patient follow-up, main diagnosis, secondary diagnosis, nature of the health establishment and amount related to Intensive Care Unit expenses. RESULTS: There were 17,725 hospitalizations due to drug poisoning in children under five, predominantly two-year-old male children. The hospitalizations outside the city of residence occurred in 25% of the cases, with predominance in the Northeastern region. The proportion of deaths in hospitalizations was 0.4%, with a higher number of deaths in the Southeastern region. CONCLUSION: Despite the decrease in the number of hospitalizations in the period, regional disparities remained, which could be attenuated with the provision of specialized attention to drug poisonings in municipalities, expanding the access to a more complex care.

INTRODUÇÃO: No Brasil, os medicamentos são os principais agentes causadores de intoxicação, e o maior número de casos desse problema envolve menores de 5 anos. Assim, o objetivo deste estudo foi descrever as internações por intoxicação medicamentosa nessa população quanto a sua demografia, óbitos e indicadores de agravamento. MÉTODOS: Verificou-se a frequência das internações por intoxicação medicamentosa entre 2003 e 2012, utilizando os dados do Sistema de Informação Hospitalar. As variáveis utilizadas foram ano, sexo, idade, município de residência e de internação, evolução do paciente, diagnóstico principal, diagnóstico secundário, natureza do estabelecimento de saúde e valor referente aos gastos de unidade de terapia intensiva. RESULTADOS: Ocorreram 17.725 internações por intoxicação medicamentosa em menores de 5 anos de idade, com o predomínio do sexo masculino e de crianças de 2 anos. As internações fora do município de residência deram-se em 25% dos casos, com predomínio da Região Nordeste. A proporção de óbitos nas internações foi de 0,4%, com maior número de óbitos na Região Sudeste. CONCLUSÃO: Apesar da diminuição do número de internações no período, permaneceram disparidades regionais que podem ser atenuadas com a oferta de atenção especializada às intoxicações medicamentosas nos municípios, ampliando o acesso a cuidados de maior complexidade.

Demografia, óbitos e indicadores de agravamento nas internações por intoxicações medicamentosas entre menores de 5 anos no Brasil / Demographics, deaths and severity indicators in hospitalizations due to drug poisoning among children under age five in Brazil

RESUMO: Introdução: No Brasil, os medicamentos são os principais agentes causadores de intoxicação, e o maior número de casos desse problema envolve menores de 5 anos. Assim, o objetivo deste estudo foi descrever as internações por intoxicação medicamentosa nessa população quanto a sua demografia, óbitos e indicadores de agravamento. Métodos: Verificou-se a frequência das internações por intoxicação medicamentosa entre 2003 e 2012, utilizando os dados do Sistema de Informação Hospitalar. As variáveis utilizadas foram ano, sexo, idade, município de residência e de internação, evolução do paciente, diagnóstico principal, diagnóstico secundário, natureza do estabelecimento de saúde e valor referente aos gastos de unidade de terapia intensiva. Resultados: Ocorreram 17.725 internações por intoxicação medicamentosa em menores de 5 anos de idade, com o predomínio do sexo masculino e de crianças de 2 anos. As internações fora do município de residência deram-se em 25% dos casos, com predomínio da Região Nordeste. A proporção de óbitos nas internações foi de 0,4%, com maior número de óbitos na Região Sudeste. Conclusão: Apesar da diminuição do número de internações no período, permaneceram disparidades regionais que podem ser atenuadas com a oferta de atenção especializada às intoxicações medicamentosas nos municípios, ampliando o acesso a cuidados de maior complexidade.

ABSTRACT: Introduction: In Brazil, drugs are the main causative agents of poisonings, and children under age five are the group with the highest number of cases. The objective of the present study was to describe hospitalizations due to drug poisoning in this population regarding demographics, deaths and worsening indicators in hospitalizations. Methods: The frequency of hospitalizations for drug poisoning between 2003 and 2012 was verified using data from the Hospital Information System. The study variables were year, gender, age, place of residence and hospitalization, patient follow-up, main diagnosis, secondary diagnosis, nature of the health establishment and amount related to Intensive Care Unit expenses. Results: There were 17,725 hospitalizations due to drug poisoning in children under five, predominantly two-year-old male children. The hospitalizations outside the city of residence occurred in 25% of the cases, with predominance in the Northeastern region. The proportion of deaths in hospitalizations was 0.4%, with a higher number of deaths in the Southeastern region. Conclusion: Despite the decrease in the number of hospitalizations in the period, regional disparities remained, which could be attenuated with the provision of specialized attention to drug poisonings in municipalities, expanding the access to a more complex care.

Chemoradiation Versus Chemotherapy in Uterine Carcinosarcoma: Patterns of Care and Impact on Overall Survival.

OBJECTIVES: Uterine carcinosarcoma (UCS) is a rare and aggressive cancer with poor survival. Our purpose was to evaluate the patterns-of-care and overall survival (OS) benefit of adjuvant chemoradiation (aCRT) compared with adjuvant chemotherapy (aCT) among UCS patients. METHODS: A query was made in the National Cancer Database to identify patients with UCS diagnosed between 2004 and 2012. Factors predictive of OS were determined using univariate and multivariate Cox regression analysis, as well as Kaplan-Meier and log-rank analysis. Propensity-score matching was employed to decrease the potential influence of selection bias. RESULTS: A total of 3538 patients were identified for analysis, consisting of 1787 patients (50.5%) receiving aCT and 1751 (49.5%) receiving aCRT. The median age of patients was 65 years. The majority of patients in our cohort were white (68.6%), on Medicare insurance (47.9%), with >5 cm tumor size (59.9%), and received a lymph node surgery (87.9%). The following factors were predictive of aCRT use: undergoing lymph node surgery (odds ratio, 1.59, P=0.01), and FIGO stage II (odds ratio, 1.71, P=0.01). Median survival for the aCT and aCRT groups was 24 months and 31.3 months, respectively. When compared with aCT alone, aCRT was associated with a benefit in OS on multivariate analysis (hazard ratio, 0.65, P<0.01). CONCLUSIONS: When compared with aCT alone, the use of aCRT in UCS patients was associated with a significant OS benefit. Multiple demographic and clinical factors significantly influence the choice of adjuvant therapy in this setting.

Mesotelioma Peritoneal Maligno. Presentación de un caso / Malignant Peritoneal Mesothelioma. Case presentation

El mesotelioma es un tumor poco frecuente, sobretodo en localización peritoneal. Originado en las células mesoteliales de superficies serosas. Su etiología es desconocida, aunque en muchos casos se relaciona con exposición a asbestos. Su frecuencia va en aumento en los últimos años, tiene mayor incidencia en varones de edad media. Se presentó un paciente de 73 años diabético e hipertenso que llevaba 21 días con sensación de llenura, aumento de volumen del abdomen, decaimiento marcado, pérdida del apetito. En este período presentó una pérdida de peso corporal de 10 kilos. Por todo lo anterior se decidió su ingreso para estudio y tratamiento (AU).

The mesothelioma is a little frequent tumor, especially in peritoneal location, originated in the mesothelial cells of serous surfaces. Its etiology is unknown, although in many cases it is related with exposition to asbestos. Its frequency increases in the last years, showing higher incidence in medium-age male people. The case of a diabetic, hypertensive patient aged 73 years was presented. He was already 21 days feeling bloating, having increase of the abdominal volume, remarked weakness, appetite loss. In this period he had a body weight loss of 10 kg. For that all, his admission was decided for study and treatment (AU).

Mesotelioma Peritoneal Maligno. Presentación de un caso / Malignant Peritoneal Mesothelioma. Case presentation

El mesotelioma es un tumor poco frecuente, sobretodo en localización peritoneal. Originado en las células mesoteliales de superficies serosas. Su etiología es desconocida, aunque en muchos casos se relaciona con exposición a asbestos. Su frecuencia va en aumento en los últimos años, tiene mayor incidencia en varones de edad media. Se presentó un paciente de 73 años diabético e hipertenso que llevaba 21 días con sensación de llenura, aumento de volumen del abdomen, decaimiento marcado, pérdida del apetito. En este período presentó una pérdida de peso corporal de 10 kilos. Por todo lo anterior se decidió su ingreso para estudio y tratamiento (AU).

The mesothelioma is a little frequent tumor, especially in peritoneal location, originated in the mesothelial cells of serous surfaces. Its etiology is unknown, although in many cases it is related with exposition to asbestos. Its frequency increases in the last years, showing higher incidence in medium-age male people. The case of a diabetic, hypertensive patient aged 73 years was presented. He was already 21 days feeling bloating, having increase of the abdominal volume, remarked weakness, appetite loss. In this period he had a body weight loss of 10 kg. For that all, his admission was decided for study and treatment (AU).

Impact of XRCC1, GSTP1, and GSTM1 Polymorphisms on the Survival of Ovarian Carcinoma Patients Treated with Chemotherapy.

BACKGROUND: Single nucleotide polymorphic variants of DNA repair genes may improve drug efficacy through altering expression levels of the encoded proteins. This study evaluated the influence of genetic polymorphism GSTP1 Ile105Val, GSTM1 (null/non-null) and 2 XRCC1 polymorphisms (Arg194Trp and Arg399Gln) on the survival of ovarian carcinoma patients treated with chemotherapy. METHODS: 106 patients received treatment with a carboplatin-based or alternative chemotherapy. Polymorphisms were genotyped by pyrosequencing. RESULTS: The genotypes XRCC1 194Arg/Trp and XRCC1 194Trp/Trp conferred no significant risk of death when compared to 194Arg/Arg (hazard ratio (HR) 1.01, 95% confidence interval (CI) 0.33-3.09, and HR 0.89, 95% CI 0.31-2.57, respectively). Similarly, those carrying the XRCC1 399Arg/Gln genotype had no increased risk of death compared to the XRCC1 399Arg/Arg (HR 0.85, 95% CI 0.39-1.86); no homozygous carriers of the glutamine allele (XRCC1 399 Gln/Gln) were detected. The GSTP1 105Ile/Val had no increased risk of death compared to the GSTP1 105Ile/Ile (HR = 1.20, 95% CI = 0.55-2.63) and no homozygous carriers of the valine allele (GSTP1 105Val/Val) were detected in the study. Compared to the non-null genotype of GSTM1, the mortality rate was nonsignificantly reduced in patients with the null genotype (HR 1.07, 95% CI 0.48-2.42). However, overall survival of the patients treated with the carboplatin-based regimen was significantly longer than for those treated with alternative chemotherapy (plog-rank = 0.006). CONCLUSIONS: The present findings suggest that there are no correlations between genotypes and survival.

Differential diagnosis of lung lesion in breast carcinoma: a metachronous neoplasm or metastasis?

A 34-year-old woman-a diagnosed case of pT1N1MO, stage IIa, estrogen and progesterone receptor positive (ER, PR) positive, Her2 negative carcinoma of the left breast-was managed with modified radical mastectomy and adjuvant chemotherapy. While planning for radiotherapy, she was found to have a well-defined enhancing lesion with spiculated margins in the superior segment of the right lower lobe along with a heterogeneously enhancing right hilar lymph node on CT. Histopathological evaluation of the lesion was suggestive of adenocarcinoma. The lesion was negative for ER, PR receptors, mammoglobin and gross cystic disease fluid protein. Thyroid transcription factor 1 (TTF-1) was positive, suggesting a primary lung adenocarcinoma rather than metastatic lesion from the breast. This case clearly signifies the importance of histopathological diagnosis of suspicious metastatic lesions in the setting of early breast cancer. We would also like to highlight the importance of TTF-1 in differentiating primary lung malignancy from metastasis.

Comparative effectiveness of exercise and drug interventions on mortality outcomes: metaepidemiological study.

OBJECTIVE: To determine the comparative effectiveness of exercise versus drug interventions on mortality outcomes. DESIGN: Metaepidemiological study. ELIGIBILITY CRITERIA: Meta-analyses of randomised controlled trials with mortality outcomes comparing the effectiveness of exercise and drug interventions with each other or with control (placebo or usual care). DATA SOURCES: Medline and Cochrane Database of Systematic Reviews, May 2013. MAIN OUTCOME MEASURE: Mortality. DATA SYNTHESIS: We combined study level death outcomes from exercise and drug trials using random effects network meta-analysis. RESULTS: We included 16 (four exercise and 12 drug) meta-analyses. Incorporating an additional three recent exercise trials, our review collectively included 305 randomised controlled trials with 339,274 participants. Across all four conditions with evidence on the effectiveness of exercise on mortality outcomes (secondary prevention of coronary heart disease, rehabilitation of stroke, treatment of heart failure, prevention of diabetes), 14,716 participants were randomised to physical activity interventions in 57 trials. No statistically detectable differences were evident between exercise and drug interventions in the secondary prevention of coronary heart disease and prediabetes. Physical activity interventions were more effective than drug treatment among patients with stroke (odds ratios, exercise vanticoagulants 0.09, 95% credible intervals 0.01 to 0.70 and exercise v antiplatelets 0.10, 0.01 to 0.62). Diuretics were more effective than exercise in heart failure (exercise v diuretics 4.11,1.17 to 24.76). Inconsistency between direct and indirect comparisons was not significant. CONCLUSIONS: Although limited in quantity, existing randomised trial evidence on exercise interventions suggests that exercise and many drug interventions are often potentially similar in terms of their mortality benefits in the secondary prevention of coronary heart disease, rehabilitation after stroke, treatment of heart failure, and prevention of diabetes.

Clinical benefit response in pancreatic cancer trials revisited.

OBJECTIVES: Clinical benefit response (CBR), based on changes in pain, Karnofsky performance status, and weight, is an established palliative endpoint in trials for advanced gastrointestinal cancer. We investigated whether CBR is associated with survival, and whether CBR reflects a wide-enough range of domains to adequately capture patients' perception. METHODS: CBR was prospectively evaluated in an international phase III chemotherapy trial in patients with advanced pancreatic cancer (n = 311) in parallel with patient-reported outcomes (PROs). RESULTS: The median time to treatment failure was 3.4 months (range: 0-6). The majority of the CBRs (n = 39) were noted in patients who received chemotherapy for at least 5 months. Patients with CBR (n = 62) had longer survival than non-responders (n = 182) (hazard ratio = 0.69; 95% confidence interval: 0.51-0.94; p = 0.013). CBR was predicted with a sensitivity and specificity of 77-80% by various combinations of 3 mainly physical PROs. A comparison between the duration of CBR (n = 62, median = 8 months, range = 4-31) and clinically meaningful improvements in the PROs (n = 100-116; medians = 9-11 months, range = 4-24) showed similar intervals. CONCLUSION: CBR is associated with survival and mainly reflects physical domains. Within phase III chemotherapy trials for advanced gastrointestinal cancer, CBR can be replaced by a PRO evaluation, without losing substantial information but gaining complementary information.

Intra-arterial infusion chemotherapy for advanced non-small-cell lung cancer: preliminary experience on the safety, efficacy, and clinical outcomes.

PURPOSE: To investigate the effectiveness and toxicity of intra-arterial infusion chemotherapy as a therapeutic modality for advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: In a retrospective study, 40 patients with stage III NSCLC received intra-arterial infusion chemotherapy with gemcitabine and cisplatin. Tumor staining was graded based on angiography, and the number of NSCLC feeding arteries detected was recorded. Toxicity was assessed according to National Cancer Institute Common Toxicity Criteria for Adverse Events. The response to treatment was evaluated per Response Evaluation Criteria In Solid Tumors (RECIST). Efficacy was assessed based on time to tumor progression (TTP), and survival was estimated by Kaplan-Meier analysis. Prognostic factors influencing TTP and overall survival rate were evaluated by Cox regression analysis. RESULTS: The most frequent drug-related adverse events were cough (n = 17; 42.5%), anorexia (n = 14; 35%), and pain (n = 9; 22.5%). Evaluated per RECIST, a total of 47.5% of patients (n = 19) exhibited response to therapy after completion of the first three cycles of intra-arterial infusion chemotherapy. The median TTP was 5 months. Patients had a median life expectancy of 9 months. By Cox regression analysis, tumor staining was shown to be an independent prognostic factor for TTP (relative risk, 0.405; 95% confidence interval, 0.216-0.760) and overall survival (relative risk, 0.348; 95% confidence interval, 0.185-0.656). CONCLUSIONS: Intra-arterial infusion chemotherapy for advanced lung cancer has the potential to reduce the size of tumors and has no severe adverse effects.

Modified DCF (mDCF) regimen seems to be as effective as original DCF in advanced gastric cancer (AGC)

PURPOSE: The aim of this retrospective study (from January 2007 to December 2011) was to investigate the efficacy and tolerability of mDCF schedule for chemotherapy-naïve AGC patients. PATIENTS: Patients (n = 54) with locally inoperable or distant metastasis and performance status of 0-2 were eligible. The triplet combination chemotherapy consisting of docetaxel 60 mg/m(2) on day 1, cisplatin 60 mg/m(2) on day 1, and 5-fluorouracil 600 mg/m(2) for 5 days of continuous infusion were administered every 21 days, up to nine cycles. Prophylactic G-CSF was not allowed. RESULTS: In all, 36 (67 %) patients were male and 18 (33 %) were female; median age was 59 years. The majority of patients (n = 46, 85 %) had metastatic disease and 8 (15 %) of them had locally advanced disease. Liver metastasis and peritonitis carcinomatosa were found in 20 (43 %) and 18 (39 %) of the 46 cases, respectively. The median cycle of chemotherapy was 6. In assessing 50 patients for response evaluation, one had complete response. Partial response was achieved in 27 (54 %) patients. Seventeen patients (34 %) had stable disease and 5 (10 %) had progressive disease, while 4 % (n = 2) and 11 % (n = 6) of the patients developed severe (grade 3-4) neutropenia and anemia, respectively. During the median follow-up time (6.9 months, range 0.4-24), 28 (52 %) patients died. The overall and progression-free survival were 10.7 [95 % CI 8.9-12.4] and 6.8 [95 % CI 5.8-7.8] months, respectively. CONCLUSIONS: Although this was not a prospective comparative study, the mDCF regimen seems to be as effective as the original DCF in AGC with acceptable and manageable side effects (AU)

[Drug-related claims in the Norwegian system of compensation to patients]. / Legemiddelsaker i Norsk pasientskadeerstatning.

BACKGROUND: Patients subjected to drug-related injuries can, in accordance with Norwegian legislation, seek compensation from the Norwegian System of Patient Injury Compensation (NPE). The aim of this study was to examine what drugs and injuries instigate claims against NPE, and how these cases are resolved. MATERIAL AND METHODS: We have assessed anonymised summaries of 992 consecutive indemnity applications received and evaluated by NPE over the period 2003-2009. We recorded the age and gender of applicants, treatment diagnosis, drugs implicated, outcome, and NPE's decision in each case. RESULTS: A total of 964 claims were included. The most commonly implicated drugs were those affecting the nervous system (34.6%) and the musculoskeletal system (26.1%). Rofecoxib at 18.9% was the predominant single drug implicated. In two-thirds of the cases, adverse effects were given as the reason for the claim, whereas the last one-third consisted of claims for medication errors. The most common injuries were related to cardiovascular diseases (28.7%) or non-specific conditions (17.5%). 8.4% of the cases related to fatalities. In all, 26.3% of the claims resulted in compensations. INTERPRETATION: Few patients made use of the NPE. Most of the compensation claims in the years 2003-2009 involved rofecoxib and psychoactive drugs, and the majority of claims were rejected.

Emergency medicine techniques and the forensic autopsy.

Emergency medicine measures often have to be carried out under suboptimal conditions in emergency situations and require invasive patient treatment. In the case of a fatal outcome these measures have to be evaluated at autopsy, regarding indications, correct implementation and possible complications. As well, alongside the more familiar procedures--such as endotracheal intubation, insertion of chest drains, external cardiac massage and cannulation of central and peripheral veins--there are alternative techniques being increasingly applied, that include new tools for the management of hemorrhagic shock, drug delivery and alternative airway management devices. On the one hand, all of these measures are essential for the survival and appropriate treatment of the injured and/or sick patient, but on the other hand they can damage the patient and thus contain a significant risk of both medical and forensic relevance for the patient and the physician. In the following review we provide an overview of established, new and alternative techniques for emergency airway management, administration of drugs and management of hemorrhagic shock. The aim is to facilitate the understanding and autopsy evaluation of current emergency medicine techniques.

The role of toxicology interpretations in prevention of sudden death.

Inappropriate combinations of pharmaceutical drugs are often detected in deaths reported to a coroner. However, the involvement of drug combinations in the cause of death can be overlooked in cases when significant natural disease or external injury is also present. This study examined pathology reports and coroner's findings between January 2002 and December 2008. Cases that included exposure to a selection of serotonergic drugs were examined to determine the role of different death investigators in drug-associated deaths in Victoria, Australia. Of the 326 cases identified, the involvement of drugs in the death was discussed to some degree in 66% of cases. Recommendations by the coroner pertaining to death prevention were made in 12 cases (4%). In 16 cases (5%) the drugs were not mentioned in the findings, including at least 11 cases of probable major adverse drug interactions. Death investigations serve an important public health and safety role, however, the potential involvement of drugs in many cases is not always recognized.

Boca seca, mucositis, problemas dentales y del gusto en la alimentación del niño con cáncer / Dry mouth, mucositis, dental problems and taste power in children with cancer

En niños con cáncer, la quimioterapia y la radioterapia de ciertos tumores de cabeza y cuello, reducen la producción de saliva generando sensación de boca seca, ulceraciones bucales y mucositis. Los problemas dentales se resumen en caries, boca seca y endurecimiento de los músculos de la cara. Así mismo, la quimioterapia, la radiación y el cáncer mismo, ocasionan cambios en el sentido del gusto del niño con cáncer. Todos estas circunstancias se reflejan en el bajo consumo de nutrientes y desarrollo a futuro de desnutrición para lo cual es necesario estar alerta y proponer medidas preventivas.

In children with cáncer, chemotherapy and radiotherapy of ceratin tumors of the head and neck, reduce the production of saliva causing dry mouth, mouth ulcers and mucositis. Dental problems of children with cancer are summarized in caries, dry mouth and tightening of the muscles of the face. Likewise, chemotherapy, radiation and the cancer itself, cause changes in taste of the child with cancer. All these circumstances are reflected in the low nutrient intake and future development of malnutrition for which it is necessary to be vigilant and to suggestpreventive measures.