D-dimer from central and peripheral blood samples in asymptomatic central venous catheter-related thrombosis in patients with cancer.

OBJECTIVES: To evaluate the usefulness of a negative D-dimer in peripheral or central venous blood to screen for asymptomatic catheter-related thrombosis in cancer patients. METHODS: D-dimer was measured in blood from central venous catheter and peripheral venous samples in 48 patients with cancer. Asymptomatic catheter-related thrombosis was identified via Doppler ultrasound. Bland and Altman's limits of agreement analysis was used to compare sample sites. Sensitivity and specificity of D-dimer was calculated. RESULTS: Overall, 33 of the central samples and 32 of the peripheral samples had D-dimer levels below the cutoff (≥0.3 mg/l). Mean central D-dimer was 0.31 ± 0.35 mg/l; peripheral 0.24 ± 0.22 mg/l (p = 0.5). Bland-Altman plot showed that the two sample sites were not equivalent. Catheter-related thrombosis was demonstrated in five patients, and there were three false negatives. Peripheral D-dimer had a negative predictive value of 90.9%. CONCLUSIONS: A negative D-dimer may be useful for screening asymptomatic catheter-related thrombosis in patients with cancer, but the central and peripheral sample sites are not equivalent.

Epidermal growth factor receptor overexpression and outcomes in early breast cancer: A systematic review and a meta-analysis.

BACKGROUND: The epidermal growth factor receptor (EGFR) is a member of the ErbB family of membrane tyrosine-kinase receptors. Studies exploring the prognostic role of EGFR-overexpression in early breast cancer have shown variable results, and the true prognostic value of EGFR is unknown. METHODS: A systematic review of identified publications exploring the association between EGFR-overexpression (as defined from different techniques and cut-offs) and outcomes [disease-free (DFS) and, overall survival (OS)] in women with early breast cancer. The hazard ratios (HR) for DFS and OS were weighted and pooled in a meta-analysis using generic inverse variance and random effects modeling. RESULTS: Fifty-three studies comprising 21,418 women were included. EGFR-overexpression was found in 27% of the patients. Primary analysis included studies reporting HRs from multivariable analyses (10 studies including 4857 patients with HRs for OS and 17 studies comprising 8747 patients with HRs for DFS), EGFR-overexpression was associated with worse OS (HR 1.98, 95% CI: 1.59-2.47, p < .001) and DFS (HR 1.59, 95% CI 1.30-1.95, p < .001). The influence of EGFR overexpression on DFS was greater in women with triple negative tumors compared to women with non-triple negative tumors (HR 2.35 versus HR 1.45, respectively; p = .01). Analysis looking at odd ratios for both 5-year and 10-year for DFS and OS showed similar results. CONCLUSION: EGFR-overexpression appears to be associated with reduced OS and DFS in women with early breast cancer. Patients with triple negative and EGFR-overexpression have poorer OS and DFS than those with triple negative tumors and normal EGFR expression.

Thymidylate synthase gene variants as predictors of clinical response and toxicity to fluoropyrimidine-based chemotherapy for colorectal cancer.

BACKGROUND: Fluoropyrimidines form the chemotherapy backbone of advanced and metastatic colorectal cancer (CRC). These drugs are frequently associated with toxicity events that result in dose adjustments and even suspension of the treatment. The thymidylate synthase (TYMS) gene is a potential marker of response and toxicity to fluoropyirimidines as this enzyme is the molecular target of these drugs. Our aim was to assess the association between variants of TYMS with response and toxicity to fluoropyrimidines in patients with CRC in independent retrospective and prospective studies. METHODS: Variants namely rs45445694, rs183205964, rs2853542 and rs151264360 of TYMS were genotyped in 105 CRC patients and were evaluated to define their association with clinical response and toxicity to fluoropyrimidines. Additionally, the relationship between genotypes and tumor gene expression was analyzed by quantitative polymerase chain reaction. RESULTS: The 2R/2R (rs45445694) was associated with clinical response (p=0.05, odds ratio (OR)=3.45) and severe toxicity (p=0.0014, OR=5.21, from pooled data). Expression analysis in tumor tissues suggested a correlation between the 2R/2R genotype and low TYMS expression. CONCLUSIONS: The allele 2R (rs45445694) predicts severe toxicity and objective response in advanced CRC patients. In addition, the alleles G(rs2853542) and 6bp-(rs151264360) are independent predictors of response failure to chemotherapy. This is the first study made on a Latin American population that points out TYMS gene variants have predictive values for response and toxicity in patients with CRC treated with fluoropyrimidine-based chemotherapy.

Remarkably higher efficacy and a wider safety window for nonfrontline over first-line drug combinations in the adenocarcinoma Colo 320DM cell line.

PURPOSE: To determine in vitro, the efficacy and safety window of not-front-line and first-line anti-colorectal (CRC) drug combinations. METHODS: The adenocarcinoma cell line Colo 320DM and normal human mesenchymal stem cells derived from adipose tissue were used respectively to determine the anti-CRC efficacy (% of Colo 320DM cell death [CD]) and safety window [SW] - % Colo 320DM percent cancer death (PCD)/% of mesenchymal stem cell's death) of drug combinations, using the adenosine triphosphate-based chemotherapy response assay (ATP-CRA). RESULTS: First-line anti-CRC drug combinations (5-fluorouracil [5FU]/oxaliplatin [oxa] and 5-FU/Oxa /leucovorin [Leuco]) produced 57.7% and 52.4% CD, and 1.38 and 2.44 SW, respectively. Combinations of 5-FU/Oxa and 1 to 3 non-front line drugs led to 56.3-99.8% CD and to 0.96-2.2 SW. The highest safety window corresponded to 5FU/Oxa/ carboplatin [Carbo] (93% CD and 1.4 SW) and to 5-FU/ Oxa/cisplatin [Cispl] (93.5% CD and 1.4 SW). In contrast, non-front line drugs led to 89.8-97.4% CD and to 1.1-78.2 SW. Outstandingly, those combinations containing Carbo/ Cispl/3,3'-diindolylmethane (DIM), aspirin (Asp), or 3,3'- DIM/ Asp showed a very high CD (91.9-96.9% [39.2-39.5 times higher than first-line-combined drugs]) and very wide SW (57.8-81.56 [66.6-40 times higher than the first-line drug combinations]). CONCLUSIONS: Human mesenchymal stem cells could be an excellent alternative to laboratory animals, when testing the safety profiles of drugs. The most promising combinations of non-frontline drugs to treat CRC are Carbo/Cispl/ Asp and Carbo/Cispl/DIM.

Prognostic role of Ki-67 score in localized prostate cancer: A systematic review and meta-analysis.

BACKGROUND: Ki-67 for quantifying tumor proliferation is widely used. In localized prostate cancer (PCa), despite a suggested predictive role of Ki-67 for outcomes after therapies, it has not been incorporated into clinical practice. Herein, we conduct a systematic review and meta-analysis of the literature reporting the association of Ki-67 and disease outcomes in PCa treated radically. METHODS: Medline and EMBASE databases were searched without date or language restrictions, using "KI67" and "prostate cancer" MeSH terms. Studies reporting Ki-67 association with clinical outcomes (disease-free survival [DFS], biochemical failure-free survival, rate of distant metastases [DM], disease-specific survival [DSS], or overall survival [OS], or all of these) in patients with PCa managed actively were included, and relevant data extracted by 2 independent reviewers. Odds ratios (OR) were weighted and pooled in a meta-analysis using Mantel-Haenszel random-effect modeling. RESULTS: Twenty-one studies comprising 5,419 patients met eligibility for analysis, and 67.6% of patients had low Ki-67. Mean Ki-67 was 6.14%. High Ki-67 was strongly associated with worse clinical outcomes. DFS was better in those patients with low Ki-67 at 5 and 10 years (OR = 0.32, 95% CI: 0.23-0.44, P<0.00001; OR = 0.31, 95% CI: 0.20-0.48, P<0.00001). Similarly, low Ki-67 was related to improved DSS at 5 and 10 years (OR = 0.15, 95% CI: 0.10-0.21, P<0.00001; OR = 0.16, 95% CI: 0.06-0.40, P<0.00001). Association between low Ki-67 scores with improved OS (OR = 0.47; 95% CI: 0.37-0.61; P<0.00001) and high Ki-67 scores with DM at 5 years (OR = 4.07; 95% CI: 2.52-6.58; P<0.00001) was consistently observed. CONCLUSIONS: High Ki-67 expression in localized PCa is a factor of poor prognosis for DSS, biochemical failure-free survival, DFS, DM, and OS after curative-intent treatments. Incorporation into clinical routine of this widely available and standardized biomarker should be strongly considered.

Prevalence and 3-year persistence of human papillomavirus serotypes in asymptomatic patients in Northern Mexico.

OBJECTIVE: To investigate clinical outcomes and 3-year persistence of human papillomavirus (HPV) infections among women in Mexico. METHODS: A prospective study enrolled sexually active women attending primary healthcare clinics in metropolitan Monterrey, Mexico, between June 3 and August 30, 2002. Baseline data were collected and participants underwent HPV screening. Patients with HPV infections were asked to attend a repeat screening appointment after 3 years, when the same screening data were gathered. Descriptive analyses were performed and the prevalence of cervical lesions and viral infections were examined. RESULTS: In total, 1188 patients who underwent initial HPV screening were included. Cervical lesions were detected in 5 (0.4%) patients and 239 (20.1%) patients had HPV infections; 129 (54.0%) of these patients attended 3-year follow-up. Among the 357 HPV serotypes identified, the most prevalent serotypes were HPV-59, HPV-52, HPV-16, and HPV-56, detected 62 (17.4%), 38 (10.6%), 27 (7.6%), and 18 (5.0%) times, respectively. Of the 129 patients attending 3-year follow-up, 104 (80.6%) were clear from HPV infections, 13 (10.1%) patients had persistent HPV infections, and 12 (9.3%) had HPV infections with different HPV types. CONCLUSIONS: The HPV prevalence was 20.1% in the present study; the most prevalent infections were HPV-59, HPV-52, HPV-16, and HPV-56. At 3-year follow-up, 25 (19.4%) patients had HPV infections.

Validación de la escala de empatía médica de Jefferson en estudiantes de medicina mexicanos

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Summary Introduction A meaningful doctor-patient relationship is a key factor in medical practice and in the art of curing. In the past, several institutions have recommended the addition of humanistic education among medical doctors not only for enhancing the doctor-patient relationship, but also for improving the quality of medical care. In fact, an empathic physician-patient relationship has been associated with better clinic outcomes. In spite of recommendations, medical empathy is still an unexplored research area in medical education for two reasons. One of these is that theoretical research on empathy is not easy because of a lack of clarity in its conceptualization. Another reason for the dearth of empirical research is the absence of a valid and reliable operational tool by which to measure empathy in patient care situations. A team from the Center for Research in Medical Education and Health Care at the Medical College of Thomas Jefferson University, developed the Jefferson Scale of Physician Empathy (JSPE). The English version factor structure is consistent with conceptual aspects of a multidimensional scale that measures the perspective taking, compassionate care and "standing in the patient's shoes" factors. The JSPE has shown satisfactory psychometric properties; construct, discriminant, and criterion validity has been confirmed among medical students with an internal consistency of 0.89. Empathy may vary among individuals depending on social, educational, and personal experiences, and it corresponds to an interpersonal ability and a clinical competence component. Hence, the availability of a valid and reliable instrument for measuring empathy among medical doctors is a critical issue. However, the instrument should be culturally adapted for the population of interest. Therefore, the present study was designed for evaluating the validity and reliability of the Spanish version of the JPES among Mexican medical students. Material and methods Subjects: 1022 medical students (mean age 21±2.7 years) from the School of Medicine at the Autonomous University of Nuevo Leon, in Monterrey, Mexico (494 women and 528 men). Instrument: The students' version of the JSPE was used to measure the orientation of medical students towards empathy in patient care situations. The JSPE consists of 20 items on a seven-point Likert scale (1=strongly disagree, 7= strongly agree). Procedures: The JSPE was translated into Spanish and back translated following the guidelines to adaptate psychological evaluation instruments. The questionnaire was answered by first (n=687), third (n=183) and fifth grade (n=152) medical students. They were assured of the strict confidentiality of the test and of the individual responses. Plan of analysis: Dimensionality of 20 items was assessed with factors analysis using the principal components extraction method and orthogonal rotation. Cronbach's alpha was calculated for evaluating the internal consistency. Results The exploratory factor analysis allowed the identification of three factors with eigen values greater or equal to one. All the items with coefficients greater than 0.30 of the first factor were positive and corresponded to the perspective taking domain. On the other hand, seven out of ten negative questions loaded to the second factor with coefficients greater than 0.40; all of them were related to compassionate care. Finally, there were other two questions with high loading on the third factor, which matched to "standing in the patient's shoes" domain. The internal consistency was 0.74. The mean of empathy scores was 110 and the standard deviation, 14. The observed range was 44-140 compared to the possible range of 20-140. The mean empathy score was higher for women than men (111.9 ±13.9 vs. 109.08± 14.1, p=.002). Age was not significantly correlated with empathy scores, even after controlling for sex (women: r=-0.01; men: r=0.02). Conclusions The results of study supported the validity of the JSPE among medical students in Mexico. The first factor (perspective taking) corresponded to the main component of empathy. The other two factors, compassionate care and "standing in the patient's shoes", were related to specific components of the doctor-patient relationship. The observed internal consistency was satisfactory for personality tests. The findings showed significantly higher empathy scores for women than men, suggesting that female doctors might render a different type of medical care. These findings are consistent with those reported for U.S.A. medical students. It has been informed that women are more receptive to emotional signs than men and that they devote more time and offer more preventive care to their patients. More scientific evidence is needed to explain these sex differences which represents different implications for the selection of medical training. Interpersonal relationships are especially critical between physicians and patients. Failures in understanding a patient's perspective may result in communication problems, which in turn contribute to the patient's dissatisfaction with care. As soon as the doctor understands what his/her patient thinks and feels, he/she can offer a better care. This is how empathy translates into the vehicle of a meaningful doctor-patient relationship. Finally, empathy measurement is meaningful because it constitutes the first step for examining permanence from the first years of the medical career up to specialty training years. It also allows for the analysis of the impact of educational strategies designed to improve empathy and achieve potential benefits not only for the doctors' professional development but also for their patients' health.

Genomic diversity of human papillomavirus-16, 18, 31, and 35 isolates in a Mexican population and relationship to European, African, and Native American variants.

Cervical cancer, mainly caused by infection with human papillomaviruses (HPVs), is a major public health problem in Mexico. During a study of the prevalence of HPV types in northeastern Mexico, we identified, as expected from worldwide comparisons, HPV-16, 18, 31, and 35 as highly prevalent. It is well known that the genomes of HPV types differ geographically because of evolution linked to ethnic groups separated in prehistoric times. As HPV intra-type variation results in pathogenic differences, we analyzed genomic sequences of Mexican variants of these four HPV types. Among 112 HPV-16 samples, 14 contained European and 98 American Indian (AA) variants. This ratio is unexpected as people of European ethnicity predominate in this part of Mexico. Among 15 HPV-18 samples, 13 contained European and 2 African variants, the latter possibly due to migration of Africans to the Caribbean coast of Mexico. We constructed phylogenetic trees of HPV-31 and 35 variants, which have never been studied. Forty-six HPV-31 isolates from Mexico, Europe, Africa, and the United States (US) contained a total of 35 nucleotide exchanges in a 428-bp segment, with maximal distances between any two variants of 16 bp (3.7%), similar to those between HPV-16 variants. The HPV-31 variants formed two branches, one apparently the European, the other one an African branch. The European branch contained 13 of 29 Mexican isolates, the African branch 16 Mexican isolates. These may represent the HPV-31 variants of American Indians, as a 55% prevalence of African variants in Mexico seems incomprehensible. Twenty-seven HPV-35 samples from Mexico, Europe, Africa, and the US contained 11 mutations in a 893-bp segment with maximal distances between any two variants of only 5 mutations (0.6%), including a characteristic 16-bp insertion/deletion. These HPV-35 variants formed several phylogenetic clusters rather than two- or three-branched trees as HPV-16, 18, and 31. An HPV-35 variant typical for American Indians was not identifiable. Our research suggests type specific patterns of evolution and spread of HPV-16, 18, 31, and 35 both before and after the worldwide migrations of the last four centuries. The high prevalence of highly carcinogenic HPV-16 AA variants, and the extensive diversity of HPV-18, 31, and 35 variants with unknown pathogenic properties raise the possibility that HPV intra-type variation contributes to the high cervical cancer burden in Mexico.

Tratamiento de la enfermedad neoplásica del trofoblasto gestacional: análisis de 20 casos / Treatment of gestational trophoblastic tumor: analysis of 20 cases

Se presenta el análisis de 20 casos de Enfermedad Neoplásica del Trofoblasto Gestacional (ENTG) vistos y tratados en el Instituto Nacional de Cancerología de México y se recalca la importancia pronóstica determinante de la clasificación clínica de Alto y Bajo riesgo de éstas enfermas. Seis pacientes con mola invasora tratadas con methotrexate estan curadas y viven sin evidencia de enfermedad. Catorce casos de coriocarcinoma con actividad tumoral en útero, vagina, pulmones, hígado y sistema nervioso central (11 de alto riesgo y 3 de bajo riesgo), fueron tratadas con methotrexate solo o en combinación con actinomicina D; 5 mostraron respuesta completa y están curadas; 5 con respuesta parcial tuvieron una sobrevida máxima calculada mayor de 12 meses (2 casos actualmente tratadas en el IMSS); en cuatro no hubo respuesta y el tiempo máximo de sobrevida en un caso fué de ocho meses. Se exponen además algunos datos y criterios para el uso de la quimioterapia antineoplásica