Alejandro Mohar

Involvement of chemokine receptors in breast cancer metastasis

Breast cancer is characterized by a distinct metastatic pattern involving the regional lymph nodes, bone marrow, lung and liver. Tumour cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. Here we report that the chemokine receptors CXCR4 and CCR7 are highly expressed in human breast cancer cells, malignant breast tumours and metastases. Their respective ligands CXCL12/SDF-1α and CCL21/6Ckine exhibit peak levels of expression in organs representing the first destinations of breast cancer metastasis. In breast cancer cells, signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia formation, and subsequently induces chemotactic and invasive responses. In vivo, neutralizing the interactions of CXCL12/CXCR4 significantly impairs metastasis of breast cancer cells to regional lymph nodes and lung. Malignant melanoma, which has a similar metastatic pattern as breast cancer but also a high incidence of skin metastases, shows high expression levels of CCR10 in addition to CXCR4 and CCR7. Our findings indicate that chemokines and their receptors have a critical role in determining the metastatic destination of tumour cells.

Helicobacter pylori eradication and gastric preneoplastic conditions: a randomized, double-blind, placebo-controlled trial.

Helicobacter pylori causes gastric adenocarcinoma; whether treatment of H. pylori infection prevents this cancer remains unknown. In a randomized, double-blind, placebo-controlled trial of H. pylori eradication, we determined whether treatment for H. pylori decreases gastric cancer risk, using preneoplastic conditions as surrogate markers. A total of 248 healthy volunteers (age >40 years) randomly received H. pylori treatment (omeprazole, amoxicillin, clarythromycin; n = 122) or matched placebo (n = 126) for 1 week. Endoscopy was performed at baseline and at 6 weeks and 1 year. Seven biopsies from each endoscopy were reviewed by two pathologists using the revised Sydney classification. Outcome measures were both a consensus “worst biopsy” diagnosis and a weighted index score that incorporated degrees of severity of preneoplasia from all biopsies. We compared change in these outcomes over time between the two treatment groups. H. pylori cure rates for compliant subjects in the treatment arm were 79.2% and 75.7% at 6 weeks and 1 year, respectively. No statistically significant change in the worst biopsy diagnosis was observed from 6 weeks to 1 year between placebo and treated subjects (for improvement/worsening, placebo, 19.4%/10.5%; treatment, 22.5%/8.3%; P = 0.74). Change in index score was favorably greater in treatment compared with placebo subjects (intention-to-treat analysis, P = 0.03); this finding was particularly evident in the antrum. H. pylori eradication gave more favorable gastric histopathologies over 1 year than no treatment. Such incomplete regression suggests but does not prove that eradication of H. pylori decreases cancer risk.

Use of and barriers to access to opioid analgesics: a worldwide, regional, and national study

BACKGROUND Despite opioid analgesics being essential for pain relief, use has been inadequate in many countries. We aim to provide up-to-date worldwide, regional, and national data for changes in opioid analgesic use, and to analyse the relation of impediments to use of these medicines. METHODS We calculated defined daily doses for statistical purposes (S-DDD) per million inhabitants per day of opioid analgesics worldwide and for regions and countries from 2001 to 2013, and we used generalised estimating equation analysis to assess longitudinal change in use. We compared use data against the prevalence of some health disorders needing opioid use. We surveyed 214 countries or territories about impediments to availability of these medicines, and used regression analyses to establish the strength of associations between impediments and use. FINDINGS The S-DDD of opioid analgesic use more than doubled worldwide between 2001-03 and 2011-13, from 1417 S-DDD (95% CI -732 to 3565; totalling about 3.01 billion defined daily doses per annum) to 3027 S-DDD (-1162 to 7215; totalling about 7.35 billion defined daily doses per annum). Substantial increases occurred in North America (16,046 S-DDD [95% CI 4032-28,061] to 31,453 S-DDD [8121-54,785]), western and central Europe (3079 S-DDD [1274-4883] to 9320 S-DDD [3969-14,672]), and Oceania (2275 S-DDD [763-3787] to 9136 S-DDD [2508-15,765]). Countries in other regions have shown no substantial increase in use. Impediments to use included an absence of training and awareness in medical professionals, fear of dependence, restricted financial resources, issues in sourcing, cultural attitudes, fear of diversion, international trade controls, and onerous regulation. Higher number of impediments reported was significantly associated with lower use (unadjusted incidence rate ratio 0.39 [95% CI 0.29-0.52]; p<0.0001), but not when adjusted for gross domestic product and human development index (0.91 [0.73-1.14]; p=0.4271). INTERPRETATION Use of opioid analgesics has increased, but remains low in Africa, Asia, Central America, the Caribbean, South America, and eastern and southeastern Europe. Identified impediments to use urgently need to be addressed by governments and international agencies. FUNDING International Narcotics Control Board, UN.

p53 Mutations in Nasal Natural Killer/T-Cell Lymphoma from Mexico: Association with Large Cell Morphology and Advanced Disease

Nasal NK/T-cell lymphoma is a unique form of lymphoma highly associated with Epstein-Barr virus, and with a characteristic geographic distribution. Recently, we showed that p53 is overexpressed in a high percentage of nasal NK/T-cell lymphomas. The aim of this study was to analyze the status of the p53 gene, and correlate it with the expression of p53 protein and its downstream target, the cyclin-dependent kinase inhibitor p21, in a series of 25 cases of well-characterized nasal NK/T-cell lymphoma from Mexico. The highly conserved exons 5 to 8 of the p53 gene were amplified by polymerase chain reaction and screened for mutations by denaturing high-pressure liquid chromatography. Abnormal polymerase chain reaction products detected by denaturing high-pressure liquid chromatography and additional selected cases were sequenced. In addition, the incidence of loss of heterozygosity at the p53 locus was analyzed in 12 cases. Of the 25 patients, 17 were male and 8 female (M:F ratio, 2.1:1), with a median age of 43 years (range, 21 to 93 years). Morphologically, most of the cases were composed of a mixture of medium-sized cells and large transformed cells (21 cases), and four cases were composed exclusively of large transformed cells. Three different groups determined by p53 gene status and expression of p53 protein were identified: group 1 was p53 +/p53 mutated (five cases, all with p53 missense mutations). Morphologically, three of the five cases were composed of large cells. All five cases revealed overexpression of p53 in the majority of the tumor cells with a mean of 86%. Unexpectedly, three of these cases also showed overexpression of p21. Four of the five patients presented with clinical stage IVB and died with disease. Group 2 was p53+/p53 wild-type (10 cases). Histologically, nine cases were of the mixed type, and one of the large cell type. The percentage of p53 overexpressing cells was lower than in the previous group with a mean of 23%. p21 was positive in 7 of the 10 cases. Six patients in this group presented with clinical stages I to II and four patients with advanced disease (stage III and IV). Five patients are alive 12 to 120 months later (mean, 24 months), three with no evidence of disease. Group 3 was p53-/p53 wild-type (10 cases). All cases showed mixed cell morphology. p21 was positive in 5 of 10 cases. Four patients presented with clinical stage I to II and six patients with advanced disease. Four patients are alive with no evidence of disease 9 to 60 months later (mean, 10 months). Overall, p53 mutations were present in 24% (5 of 21) of the evaluable cases, all of them overexpressing p53 in the majority of tumor cells. Cases with p53 mutations were associated with large cell morphology (P = 0.0162) and presented more often with advanced stage disease. Loss of heterozygosity at chromosome 17p was found only in 2 of the 12 (17%) cases investigated, both cases showed p53 mutations of the remaining allele. P21 overexpression (60% of cases) is frequent in nasal NK/T-cell lymphoma and seems to be independent of p53 gene status. The overexpression of p53 and p21, independent of p53 mutations, although as yet not clear, might be the result of Epstein-Barr virus infection, and warrants further investigation.

Epidemiology of Cervical Cancer

Abstract In 1985, 7.6 million cases of cancer were diagnosed in 24 different regions all over the world (1). Globally, cervical cancer is the fifth most frequent malignancy and second among women, with an annual estimate of 471,000 new cases and 213,000 deaths. The age-adjusted incidence rates for developed countries are 7.6 to 11.8 per 105 and for developing countries, 17.6 to 46.8 per 105 (1,2). This variation in the incidence of cervical cancer is also present within countries, where rural and poor areas have the highest rates.

Breast cancer in Mexico: a growing challenge to health and the health system

Breast cancer is a major public health issue in low-income and middle-income countries. In Mexico, incidence and mortality of breast cancer have risen in the past few decades. Changes in health-care policies in Mexico have incorporated programmes for access to early diagnosis and treatment of this disease. This Review outlines the status of breast cancer in Mexico, regarding demographics, access to care, and strategies to improve clinical outcomes. We identify factors that contribute to the existing disease burden, such as low mammography coverage, poor quality control, limited access to diagnosis and treatment, and insufficient physical and human resources for clinical care.

Interobserver variability in application of the revised sydney classification for gastritis

The Sydney classification for gastritis provides guidelines for histological grading of gastric biopsies. In an ongoing study of gastric preneoplastic lesions in Chiapas, Mexico, 7 biopsies from 150 patients (4 from the antrum and 3 from the body) were obtained during endoscopy and studied histologically. The first 74 endoscopy specimens were read independently by 2 general surgical pathologists. We assessed diagnostic concordance using kappa statistics. The 2 pathologists then jointly reviewed biopsies about which they had disagreed to reach a final diagnosis. A second group of 76 endoscopies was subsequently evaluated independently by the 2 pathologists, and concordance was again assessed. In the first group of biopsies, we found low concordance rates (Heliobacter pylori 0.59, acute inflammation 0.22, intestinal metaplasia 0.60, and atrophy 0.04). In the second group, of independently reviewed cases, there was better concordance (H pylori 0.77, acute inflammation 0.50, intestinal metaplasia 0.70, and atrophy 0.64). We presumed that use of the Sydney classification would result in minimal interpretational differences achieving ideal kappas greater than 0.80. Because pathology results are based on subjective interpretation of this classification, complete diagnostic agreement is practically impossible. Concordance by general surgical pathologists after joint review of cases was similar to that obtained by gastrointestinal pathologists.

Surgical site infections at the National Cancer Institute in Mexico: A case-control study***

OBJECTIVES To quantify the surgical infection rate and to identify risk factors associated with surgical site infection. METHODS We conducted a case-control study of all surgical patients between January 1, 1993, and June 30, 1994. The frequency of surgical site infection per 100 surgeries was calculated. The odds ratio (OR) was estimated by using logistic regression analysis. SETTING A 130-bed tertiary-care teaching hospital for adult patients with cancer. RESULTS The study followed 3372 surgeries. Three hundred thirteen patients had a surgical site infection (rate per 100 surgeries: 9. 30). The risk factors associated with surgical site infection were diabetes mellitus (OR = 2.5, 95% confidence interval [CI] = 1.27-4. 91), obesity (OR = 1.76, 95% CI = 1.14-2.7), presence of surgical drains for >5 and <16 days (OR = 1.84, 95% CI = 1.02-3.31), and presence of surgical drains for >/=16 days (OR = 2.14, 95% CI = 1. 0-4.6). The bacteria most frequently isolated were Escherichia coli 38 (21.8% of the total of microorganisms found), Pseudomonas sp 22 (12.6%), Staphylococcus aureus 16 (9.2%), and coagulase-negative Staphylococcus 25 (13.6%). The coexistence of other nosocomial infections was greater among the cases (OR = 1.8, 95% CI = 1.1-3.1) than in the control group. CONCLUSIONS The surgical site infection rate in our hospital is slightly higher than the rates reported for general hospitals. The risk factors associated with surgical site infection are similar to those previously reported. Diabetes mellitus, obesity, and prolonged presence of a surgical drain increased the risk of infection.

A phase II study of gemcitabine and cisplatin combination as induction chemotherapy for untreated locally advanced cervical carcinoma

BACKGROUND Cisplatin-based chemoradiation for locally advanced cervical carcinoma is now the standard of care for most patients with cervical carcinoma. However, induction chemotherapy followed by surgery, particularly with newer agents or combinations remains to be explored. This study was undertaken to evaluate the antitumor activity and toxicity of gemcitabine in combination with cisplatin for untreated locally advanced cervical carcinoma. PATIENTS AND METHODS Open-label, single center, phase II, non-randomized study of neoadjuvant gemcitabine plus cisplatin. Forty-one patients with histologic diagnosis of cervical carcinoma, with no previous treatment and staged as IB2 to IIIB, were treated with three 21-day courses of cisplatin 100 mg/m2 day I and gemcitabine 1000 mg/m2 days 1 and 8, followed by locoregional treatment with either surgery or concomitant chemoradiation. Response and toxicity were evaluated before each course and at the end of chemotherapy. RESULTS All patients were evaluated for toxicity and 40 for response. The overall objective response rate was 95% (95% confidence interval (CI): 88%-100%) being complete in 3 patients (7.5%) and partial in 35 (87.5%). A complete pathological response was found in 6 (26%) of the 23 patients that underwent surgery. Granulocytopenia grades 3-4 occurred in 13.8% and 3.4% of the courses, respectively, whereas non-hematological toxicity was mild. CONCLUSIONS Induction chemotherapy with the combination of gemcitabine and cisplatin is highly active for untreated cervical cancer patients and has an acceptable toxicity profile.

Impact of diabetes and hyperglycemia on survival in advanced breast cancer patients

Purpose. We examined the impact of diabetes and hyperglycemia on cancer-specific survival of patients with metastatic or recurrent breast cancer (BC). Methods. We performed a retrospective analysis of 265 patients with advanced BC receiving palliative chemotherapy. BC-specific mortality was compared for diabetic and nondiabetic patients as well as for patients that presented hyperglycemia during treatment. Results. No difference was observed between the diabetic and nondiabetic patients in terms of overall survival (OS). A difference in OS was observed between nondiabetic patients and diabetic patients who had hyperglycemia. The OS was greater in diabetic patients with proper metabolic control than diabetic patients with hyperglycemia. The risk of death was higher in patients with mean glucose levels >130 mg/dL during treatment. Several factors were associated with poor OS: tumor stage, hormone-receptor-negative tumors, HER2 negative disease, multiple metastatic sites, presence of visceral metastases, and mean glucose >130 mg/dL. Conclusion. Elevated glucose levels are associated with a poor outcome in diabetic and nondiabetic patients in contrast to patients with normoglycemic levels, conferring an elevated risk of death. According to these results, clinicians should monitor glucose levels during treatment for advanced breast cancer disease and take action to maintain normal glucose levels.