The second Mexican consensus on hepatocellular carcinoma. Part II: Treatment.

Hepatocellular carcinoma (HCC) is more frequently manifesting as one of the main complications of cirrhosis of the liver, its principal risk factor. There have been modifications in its incidence over the past decade, related to an epidemiologic transition in the etiology of cirrhosis, with a decrease in the prevalence of hepatitis C and an increase in nonalcoholic fatty liver disease (NAFLD) as a cause, as well as the development of HCC in the non-cirrhotic liver due to NAFLD. Genetic markers associated with the disease have been identified, and surveillance and diagnosis have improved. Regarding treatment, surgical techniques, in both resection and transplantation, have advanced and radiologic techniques, at the curative stage of the disease, have enhanced survival in those patients. And finally, there have been radical changes in the systemic approach, with much more optimistic expectations, when compared with the options available a decade ago. Therefore, the Asociación Mexicana de Hepatología decided to carry out the Second Mexican Consensus on Hepatocellular Carcinoma, which is an updated review of the available national and international evidence on the epidemiology, risk factors, surveillance, diagnosis, and treatment of the disease, to offer the Mexican physician current information on the different topics regarding hepatocellular carcinoma. In this second part of the document, the topics related to the treatment of HCC are presented.

The second Mexican consensus on hepatocellular carcinoma. Part I: Epidemiology and diagnosis.

Hepatocellular carcinoma (HCC) is more frequently manifesting as one of the main complications of cirrhosis of the liver, its principal risk factor. There have been modifications in its incidence over the past decade, related to an epidemiologic transition in the etiology of cirrhosis, with a decrease in the prevalence of hepatitis C and an increase in nonalcoholic fatty liver disease (NAFLD) as a cause, as well as the development of HCC in the non-cirrhotic liver due to NAFLD. Genetic markers associated with the disease have been identified, and surveillance and diagnosis have improved. Regarding treatment, surgical techniques, in both resection and transplantation, have advanced and radiologic techniques, at the curative stage of the disease, have enhanced survival in those patients. And finally, there have been radical changes in the systemic approach, with much more optimistic expectations, when compared with the options available a decade ago. Therefore, the Asociación Mexicana de Hepatología decided to carry out the Second Mexican Consensus on Hepatocellular Carcinoma, which is an updated review of the available national and international evidence on the epidemiology, risk factors, surveillance, diagnosis, and treatment of the disease, to offer the Mexican physician current information on the different topics regarding hepatocellular carcinoma. In this first part of the document, the topics related to epidemiology and diagnosis are presented.

Assessing the genotoxicities of sparteine and compounds isolated from Lupinus mexicanus and L. montanus seeds by using comet assay.

The genus Lupinus is widely distributed. Its seeds are used for animal and human food, and Lupinus possesses pharmacological potential because of its high content of quinolizidine alkaloids and flavonoids; however, there is little available information about its genotoxicity. We used the comet assay and staminal nuclei of Tradescantia (clone 4430) to evaluate the in vitro genotoxicity of 4 concentrations (0.01, 0.1, 0.5, and 1.0 mM) of alkaloid extracts of Lupinus mexicanus and Lupinus montanus, flavonoids of L. mexicanus, and commercial sparteine; nitrosodiethylamine was used as a positive control and untreated nuclei were used as a negative control. All concentrations of L. mexicanus and L. montanus showed significant genotoxic activity (P ≤ 0.05). A similar behavior was observed for flavonoid extracts of L. montanus except the 1.0 mM concentration. Sparteine showed genotoxic activity only at 0.5 mM. The order of genotoxicity of the compounds studied was as follows: L. mexicanus > L. montanus > flavonoids of L. montanus > sparteine. There is evident genotoxic activity in the compounds that were studied, particularly at lower concentrations (0.01 and 0.1 mM). Given the limited information about the genotoxicity of the compounds of L. mexicanus and L. montanus, further studies are necessary.

Highly pathogenic avian influenza A/H7N3 in great-tailed grackles (Quiscalus mexicanus) in the Altos de Jalisco region of Mexico.

INTRODUCTION: In June 2012, the presence of a severe highly pathogenic avian influenza (HPAI) outbreak produced by an influenza type A, subtype H7N3 (A/H7N3) virus was reported in Mexico, which significantly affected the region of Los Altos de Jalisco, the most important table-egg production zone in Mexico. CASE PRESENTATION: To the best of our knowledge, this is the first report describing the occurrence of infection in wild endemic birds, and particularly in the great-tailed grackle (Quiscalus mexicanus), by an HPAI A/H7N3 orthomyxovirus, during the avian influenza epizootic, which occurred in June-October 2012, in the Los Altos region of Jalisco, Mexico, a highly significant poultry area. The great-tailed grackle population has increased significantly due to intense agricultural and livestock farming expansion throughout North and Central America and northern South America, in diverse ecological systems. The great-tailed grackle's infectious/epidemiological role is unknown, as is its role as the avian influenza virus reservoir and as disseminator of other infectious diseases. CONCLUSION: Because of the huge impact that avian influenza virus has on food production, on the economic activity of the affected areas and on the public health of animal and human populations, it is necessary to further investigate the significance of a wild population existing in the vicinity of industrial poultry farms and backyard poultry operations.

The NPY intergeniculate leaflet projections to the suprachiasmatic nucleus transmit metabolic conditions.

The intergeniculate leaflet (IGL) is classically known as the area of the Thalamic Lateral Geniculate Complex providing the suprachiasmatic nucleus (SCN) non-photic information. In the present study we investigated whether this information might be related to the metabolic state of the animal. The following groups of male Wistar rats were used for analysis of neuropeptide Y (NPY) and c-Fos in the IGL and SCN. (1) Fed ad libitum. (2) Fasted for 48 h. (3) Fasted for 48 h followed by refeeding for 3 h. (4) Monosodium glutamate-lesioned and 48 h fasted. (5) Electrolytic lesion in the IGL and 48 h fasted. The results were quantified by optical densitometry. Neuronal tracers were injected in two brain areas that receive metabolic information from the periphery, the arcuate nucleus (ARC) and Nucleus of the Tractus Solitarius to investigate whether there is an anatomical relationship with the IGL. Lesion studies showed the IGL, and not the ARC, as origin of most NPY projections to the SCN. Fasting induced important changes in the NPY expression in the IGL, coinciding with similar changes of NPY/glutamate decarboxylase projections of the IGL to the SCN. These changes revealed that the IGL is involved in the transmission of metabolic information to the SCN. In fasted animals IGL lesion resulted in a significant increase of c-Fos in the SCN as compared to intact fasted animals demonstrating the inhibitory influence of the IGL to the SCN in fasting conditions. When the animal after fasting was refed, an increase of c-Fos in the SCN indicated a removal of this inhibitory input. Together these observations show that in addition to increased inhibitory IGL input during fasting, the negative metabolic condition also results in increased excitatory input to the SCN via other pathways. Consequently the present observations show that at least part of the non-photic input to the SCN, arising from the IGL contains information about metabolic conditions.

Frequencies of -308G/A (TNFA) and -509C/T (TGFB1) polymorphisms in sickle cell anemia patients from Brazil.

Sickle cell anemia is an affection that causes chronic inflammation, with consequences for vaso-occlusion, oxidative stress and cytokine production. Genetic polymorphisms in markers involved in this process can modulate the inflammatory response, including polymorphisms -308G/A of TNFA (tumor necrosis factor alpha) and -509C/T of TGFB1 (transforming growth factor beta 1), reported to increase TNF-α and TGF-ß1 production, respectively. Changes in the cytokine balance are important risk factors for clinical events; consequently, we examined the frequencies of these polymorphisms in 240 Brazilian sickle cell anemia patients from southeast Brazil. PCR-RFLP was used to detect these polymorphisms. The -509C/T (TGFB1) polymorphism was more frequent than -308G/A (TNFA), with allelic frequency of 0.3 for the mutant allele T (TGFB) agaist 0.1 for the mutant allele A (TNFA). These allelic frequencies are similar to those known from populations with ethnicity similar to the Brazilian population. Inheritance of these polymorphisms does not seem to be associated with that of the Hb S mutation; however, this information could be useful in analyses of specific clinical characteristics of sickle cell anemia.

Inflammatory myofibroblastic tumor of the esophagus treated by endoscopy.

Inflammatory myofibroblastic tumors are rare lesions that have been described in virtually every organ including the gastrointestinal tract. The esophagus is an extremely unusual site for these tumors, with only a few cases described in the literature. Surgery has been the most common therapeutic approach used for the resection of these lesions. In the present case, a patient diagnosed with an inflammatory myofibroblastic tumor of the upper esophagus was reported, and it was successfully removed by endoscopy with no complications.

[Combined hormonal contraception in cycles artificially extended]. / Anticoncepción con hormonales combinados en ciclos extendidos artificialmente.

OBJECTIVE: To compare the bleeding patterns, satisfaction and tolerability of 3 different contraceptive in an extended regimens in the service of Family Planning of the North Central Hospital of PEMEX. MATERIAL AND METHODS: Healthy, adult women with desire of contraception for one year (N 120) were randomly assigned to receive oral contraceptive drospirenone/ethinyl E2 (group1), the norelgestromin/ethinyl E2 transdermal patch (group 2) and vaginal ring etonogestrel/ ethinyl E2 (group 3) in an extended regimen (42 consecutive days, 1 hormone-free week). Study assessments were conducted at scheduled visits at the time of initial screening, at baseline after 1, 3, 6, and 12 months. Subjects recorded menstrual associated symptoms bleeding data and completed satisfaction questionnaires. Subjects and investigators provided overall assessments of the regimens. RESULTS: Extended use of 3 different contraceptive resulted in fewer bleeding days in every group (66.6%, 55% and 58.3% P 0.0024), and less mastalgia and menstrual pain. Subjects were highly satisfied with three regimens (93.3%, 96.6% and 91.6% P 0.00421). Although not mayor adverse events were reported with this regimen, there was an increase in spotting days; it decreased with each successive cycle of therapy. Efficacy and safety were similar to those reported for traditional cycle. CONCLUSION: Extended-contraceptive regimen delays menses and reduces bleeding, a profile that may be preferred by women who seek flexibility with their contraceptive method.

p63 protein expression in high risk diffuse large B-cell lymphoma.

BACKGROUND: p63 gene is a p53 homologue that encodes proteins with transactivation, DNA-binding and tetramerisation domains. The isoforms TAp63 and TAp73 transactivate p53 target genes and induce apoptosis, whereas the isoforms DeltaNp63 and DeltaNp73 lack transactivation and might have dominant-negative effects in p53 family members. p63 is expressed in germinal centre lymphocytes and can be related to the development of the lymphoma, but the prognostic significance of its expression in the survival of patients with diffuse large B-cell lymphoma (DLBCL) remains unclear. AIMS: To determine whether quantitative immunohistochemical (IHC) analysis of p63 protein expression correlates with CD10 antigen, Bcl-6 antigen and IRF4 antigen expression and to determine whether p63 is a surrogate predictor of overall survival in high-intermediate and high risk DLBCL populations. METHODS: CD10, Bcl-6 and IRF4 expression were retrospectively evaluated by IHC in 73 samples of high-intermediate and high risk DLBCL and were used to divide the lymphomas into subgroups of germinal centre B-cell-like (GCB) and activate B-cell-like (ABC) DLBCL. Similarly, p63 expression was evaluated by IHC and the results were compared with subgroups of DLBCL origin and with the survival rates for these patients. RESULTS: p63 was expressed in more than 50% of malignant cells in 11 patients and did not show correlation with subgroups of GCB-like DLBCL or ABC-like DLBCL, but p63(+) patients had better disease-free survival (DFS) than those who were negative (p = 0.01). CONCLUSIONS: p63(+) high-intermediate and high risk DLBCL patients have a better DFS than negative cases.

Clinical outcome in chronic myeloid leukemia after allogeneic hematopoietic stem cell transplantation: the experience of the Bone Marrow Transplantation Unit of FUNFARME/BRAZIL using FISH.

Investigation of the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in chronic myeloid leukemia patients is essential to predict prognosis and survival. In 20 patients treated at the Bone Marrow Transplantation Unit of São José do Rio Preto (São Paulo, Brazil), we used fluorescence in situ hybridization (FISH) to investigate the frequency of cells with BCR/ABL rearrangement at diagnosis and at distinct intervals after allo-HSCT until complete cytogenetic remission (CCR). We investigated the disease-free survival, overall survival in 3 years and transplant-related mortality rates, too. Bone marrow samples were collected at 1, 2, 3, 4, 6, 12, and 24 months after transplantation and additional intervals as necessary. Success rate of the FISH analyses was 100%. CCR was achieved in 75% of the patients, within on average of 3.9 months; 45% patients showed CCR within 60 days after HSCT. After 3 years of the allo-HSCT, overall survival rate was 60%, disease-free survival was 50% and the transplant-related mortality rate was 40%. The study demonstrated that the BCR-ABL FISH assay is useful for follow-up of chronic myeloid leukemia patients after HSCT and that the clinical outcome parameters in our patient cohort were similar to those described for other bone marrow transplantation units.

[Acute abdominal pain and mesenteric cyst: Presentation of a case.]. / Abdomen agudo y quiste de mesenterio: Presentación de un caso.

The cysts of mesentery (QM) are organizations whose embryological origin is multiple and the clinical presentation is not clear, in most of the times it is diagnosed of incidental form or by exclusion of other organizations.At least the third part is diagnosed before the 15 years of age, and tends to be of benign nature, but the recurrence she is high when no parched the surgical treatment the totality of the injury.Little series exist reported in Literature in the last years that try to classify and to know the behavior clinical the organization as well as the surgical findings and the histological types without being able to group series greater to 4 patients.The present work tries to inform on the findings ofa pediatric patient of 4 years of age that enter our hospital by a picture of acute abdomen whose diagnosis of certainty was of a QM and to make are vision of Literature in special in our country.

[Dysphagia: Forestier and Rotes Querol disease]. / Disfagia: enfermedad de Forestier y Rotes Querol.

Inside of the study of Dysphagia, until 38% of the greater patients of 50 years, they present/display cervical Osteophytes like cause of Dysphagia; frequently I diagnose passes for the methods of radiology and endoscopy unnoticed. The disease of Forestier and Rotes better well known Querol or like skeletal hiperostosis diffuse idiophatic it is characterized by the formation of spinal and cervical Osteophytes, ossification of ligaments and muscles for vetebrates of the cervical column. Frequently it produces affectation to medullar that it can pronounce like Dysphagia and crosstalk. We presented/displayed the case of a patient of 78 years with chronic pneumopathy, that presents/displays Dysphagia and progressive crosstalk with pondered loss, in where radiology of the cervical column they show cervical osteofitos with espondilolistesis, rectification of the cervical lordosis and diminution of the intersomatic spaces that they compress the trachea and column of air and an extrinsic compression below the cricopharyngeal is documented by endoscopy.

Clinical outcome in chronic myeloid leukemia after allogeneic hematopoietic stem cell transplantation: the experience of the Bone Marrow Transplantation Unit of FUNFARME/BRAZIL using FISH

Investigation of the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in chronic myeloid leukemia patients is essential to predict prognosis and survival. In 20 patients treated at the Bone Marrow Transplantation Unit of São José do Rio Preto (São Paulo, Brazil), we used fluorescence in situ hybridization (FISH) to investigate the frequency of cells with BCR/ABL rearrangement at diagnosis and at distinct intervals after allo-HSCT until complete cytogenetic remission (CCR). We investigated the disease-free survival, overall survival in 3 years and transplant-related mortality rates, too. Bone marrow samples were collected at 1, 2, 3, 4, 6, 12, and 24 months after transplantation and additional intervals as necessary. Success rate of the FISH analyses was 100%. CCR was achieved in 75% of the patients, within on average of 3.9 months; 45% patients showed CCR within 60 days after HSCT. After 3 years of the allo-HSCT, overall survival rate was 60%, disease-free survival was 50% and the transplant-related mortality rate was 40%. The study demonstrated that the BCR-ABL FISH assay is useful for follow-up of chronic myeloid leukemia patients after HSCT and that the clinical outcome parameters in our patient cohort were similar to those described for other bone marrow transplantation units.

A protocol for the calibration of gamma cameras to estimate internal contamination in emergency situations.

The concern about accidents involving radioactive materials has led to the search of alternative methods to quickly identify and quantify radionuclides in workers and in the population. One of the options to face up an eventual demand for mass monitoring of internal contamination is the use of a nuclear medicine diagnostic equipment known as gamma camera, a device used to scan patients who have been administered specific amounts of radioactive materials for medical purposes. Although the gamma camera is used for image diagnosis, it can be calibrated with anthropomorphic phantoms or point sources for the quantification of radionuclide activities in the human body. This work presents a protocol for the calibration of gamma cameras for such application. In order to evaluate the suitability of this type of equipment, a gamma camera available in a public hospital located in Rio de Janeiro was calibrated for the in vivo measurement of 131I. The calibration includes the determination of detection efficiencies and minimum detectable activities for each radionuclide. The results show that the gamma camera presents enough sensitivity to detect activity levels corresponding to effective doses below 1 mSv. The protocol is the basis to establish a network of Nuclear Medicine Centres, located in public hospitals in eight countries of Latin America (Argentina, Brazil, Colombia, Cuba, Chile, Mexico, Peru and Uruguay) and in Spain that could be requested to collaborate in remediation actions in the event of an accident involving incorporation of radioactive materials. This protocol is one of the most significant outputs of the IAEA-ARCAL Project (RLA/9/049-LXXVIII) aimed to the Harmonization of Internal Dosimetry Procedures.

Epidemiology of bacteremia and factors associated with multi-drug-resistant gram-negative bacteremia in hematopoietic stem cell transplant recipients.

The incidence of Gram-negative bacteremia has increased in hematopoietic stem cell transplant (HSCT) recipients. We prospectively collected data from 13 Brazilian HSCT centers to characterize the epidemiology of bacteremia occurring early post transplant, and to identify factors associated with infection due to multi-drug-resistant (MDR) Gram-negative isolates. MDR was defined as an isolate with resistance to at least two of the following: third- or fourth-generation cephalosporins, carbapenems or piperacillin-tazobactam. Among 411 HSCT, fever occurred in 333, and 91 developed bacteremia (118 isolates): 47% owing to Gram-positive, 37% owing to Gram-negative, and 16% caused by Gram-positive and Gram-negative bacteria. Pseudomonas aeruginosa (22%), Klebsiella pneumoniae (19%) and Escherichia coli (17%) accounted for the majority of Gram-negative isolates, and 37% were MDR. These isolates were recovered from 20 patients, representing 5% of all 411 HSCT and 22% of the episodes with bacteremia. By multivariate analysis, treatment with third-generation cephalosporins (odds ratio (OR) 10.65, 95% confidence interval (CI) 3.75-30.27) and being at one of the hospitals (OR 9.47, 95% CI 2.60-34.40) were associated with infection due to MDR Gram-negative isolates. These findings may have important clinical implications in the decision of giving prophylaxis and selecting the empiric antibiotic regimen.

Frontline therapy with early intensification and autologous stem cell transplantation versus conventional chemotherapy in unselected high-risk, aggressive non-Hodgkin's lymphoma patients: a prospective randomized GEMOH report.

This prospective multicenter randomized trial compares conventional with early intensification with high-dose sequential chemotherapy (HDS) and autologous stem cell transplantation (ASCT) as frontline therapy in high-risk non-Hodgkin lymphomas (NHL). Newly diagnosed patients with aggressive high-risk [intermediate-high (HI) and high-risk (HR)] NHL according to the international prognosis index (IPI) were randomized to receive 12-week VACOP-B (arm A, 27 patients) or 6-week VACOP-B followed by HDS and ASCT (arm B, 29 patients). Complete remission rate was 52% in arm A and 55% in B. Nine patients (16%) died early due to progression. According to intention-to-treat, with a median follow-up of 23 months, the 5-year actuarial overall survival, progression-free survival and disease-free survival in arms A and B were 47 and 40% (p = nonsignificant), 47 and 30% (p = nonsignificant), and 97 and 47% (p = 0.02), respectively. Abbreviated chemotherapy followed by intensification with HDS-ASCT does not seem to be superior to conventional chemotherapy in HI/HR aggressive NHL.

Addition of low-dose busulfan to cyclophosphamide in aplastic anemia patients prior to allogeneic bone marrow transplantation to reduce rejection.

Busulfan was added at the dose of 4 mg/kg to 200 mg/kg cyclophosphamide in 81 patients (3-53 years, median 24) with aplastic anemia to reduce graft rejection. Graft-versus-host disease (GVHD) prophylaxis comprised cyclosporine-methotrexate. The number of prior transfusions was 0-276 (median 26), and 48% had received prior immunosuppressive therapy. Two patients experienced primary graft failure, and 10 secondary rejection at 28-1001 days (median 317 days). The cumulative incidence of rejection was 22%; for heavily transfused patients (>/=50 U) it was 43% compared to 16% for the rest (P=0.06). Overall survival rate at 8 years was 56%; patients who received 15 transfusions was 78 and 50%, respectively (P=0.01), whereas it was 67 and 28% for 50 transfusions, respectively (P=0.002). In multivariate analysis, higher number of prior transfusions, shorter period of immunosuppression with cyclosporine and GVHD were associated with inferior survival; moreover, a higher risk of graft rejection were associated with a higher number of prior transfusions and a trend was observed for a shorter cyclosporine administration. Low-dose busulfan is feasible and may be helpful in patients exposed to <50 transfusions. However, rejection remains a significant problem, mainly in heavily transfused patients.

Chemical composition, nutritive value, and toxicology evaluation of Mexican wild lupins.

The nutrient composition, toxic factors content, and nutritional and toxicological value of Lupinus splendens, L. rotundiflorus, L. elegans, L. simulans, L. exaltatus, L. reflexus, and L. madrensis species from Mexico were analyzed. The seeds of these species were a good source of protein. All the species showed a high lysine and tryptophan content, though sulfur amino acids were limiting. Cyanogenic glycosides were absent, and lectins, trypsin inhibitors, and tannins were present in low concentrations. Lupanine was the major alkaloid in almost all the samples, although sparteine was the major alkaloid in Lupinus reflexus (26.63 mg/g of sample). Cytisine was not found in any of the studied lupins. L. reflexus showed the highest acute toxicity, and L. elegans exhibited no toxicity as evaluated using a mice model. The alkaloid was reduced by hot-water extraction. The protein efficiency ratio in water-debittered seeds was relatively poor (1.1-1.5). These results suggest that the wild lupins studied represent a potential protein supply, and they could be domesticated and used for animal feed if the alkaloids were eliminated and the protein was supplemented with methionine, or if the lupins were used in mixture with cereals.