An introduction to the special issue

BACKGROUND:  Infantile epileptic spasms syndrome (IESS) is a rare but severe condition affecting children early and is usually secondary to an identifiable brain disorder. It is related to psychomotor deterioration in childhood and epilepsy in adult life. Treatment is challenging as infantile spasms may not respond to most antiseizure medication, and relapse is frequent. OBJECTIVE:  To evaluate the literature regarding treatment of IESS and provide a practical guidance to a healthcare system with limited resources. METHODS:  An expert committee from the Brazilian Society of Child Neurology reviewed and discussed relevant scientific evidence in the treatment of IESS regarding the drugs available in Brazil. RESULTS:  Oral prednisolone and vigabatrin are the most common drugs used as first-line therapy; they are efficient and affordable therapy as both are available in the Brazilian unified health system (SUS, in the Portuguese acronym). Intramuscular adrenocorticotropic hormone (ACTH) presents similar efficacy as oral prednisolone but has a higher cost and is not available in Brazil. Other antiseizure medications such as topiramate, levetiracetam, or benzodiazepines have limited response and are prescribed as adjuvant therapy. If the health service has nutritionists, a ketogenic diet should be implemented for those not responding to hormonal and vigabatrin treatment. Epilepsy surgery is mainly indicated for patients with focal lesions that do not respond to pharmacological therapy. CONCLUSION:  Early treatment of IESS with efficient drugs is feasible in our country. Using standard protocols increases the odds of achieving complete cessation in a shorter time and decreases relapse.

Background

Incidence rates for breast cancer are higher among Mexican-American (MA) women in the United States than women living in Mexico. Studies have shown higher prevalence of breast cancer risk factors in more acculturated than less acculturated Hispanic/Latinas in the United States. We compared the prevalence of behavioral risk factors and family history of breast cancer by level of acculturation and country of residence in women of Mexican descent.

Methods

Data were collected from 1,201 newly diagnosed breast cancer patients living in Mexico (n = 581) and MAs in the United States (n = 620). MA participants were categorized into three acculturation groups (Spanish dominant, bilingual, and English dominant); women living in Mexico were used as the referent group. The prevalence of behavioral risk factors and family history of breast cancer were assessed according to acculturation level, adjusting for age at diagnosis and education.

Results

In the adjusted models, bilingual and English-dominant MAs were significantly more likely to have a body mass index of 30 kg/m(2) or greater, consume more than one alcoholic beverage a week, and report having a family history of breast cancer than women living in Mexico. All three U.S. acculturation groups were significantly more likely to have lower total energy expenditure (≤533 kcal/d) than women in Mexico. English-dominant women were significantly less likely to ever smoke cigarettes than the Mexican group.

Conclusions

Our findings add to the limited scientific literature on the relationships among acculturation, health behavior, and family history of breast cancer in Mexican and MA women.

Familial breast and ovarian cancer prevalence was assessed among 1150 women of Mexican descent enrolled in a case-only, binational breast cancer study. Logistic regression was conducted to compare odds of triple negative breast cancer (TNBC) to non-TNBC according to family history of breast and breast or ovarian cancer among 914 of these women. Prevalence of breast cancer family history in a first- and first- or second-degree relative was 13.1% and 24.1%, respectively; that for breast or ovarian cancer in a first-degree relative was 14.9%. After adjustment for age and country of residence, women with a first-degree relative with breast cancer were more likely to be diagnosed with TNBC than non-TNBC (OR=1.98; 95% CI, 1.26-3.11). The odds of TNBC compared to non-TNBC were 1.93 (95% CI, 1.26-2.97) for women with a first-degree relative with breast or ovarian cancer. There were non-significant stronger associations between family history and TNBC among women diagnosed at age <50 compared to ≥50 years for breast cancer in a first-degree relative (P-interaction = 0.14) and a first- or second-degree relative (P-interaction = 0.07). Findings suggest that familial breast cancers are associated with triple negative subtype, possibly related to BRCA mutations in Hispanic/Latina women, which are strongly associated with TNBC. Family history is an important tool to identify Hispanic/Latina women who may be at increased risk of TNBC, and could benefit from prevention and early detection strategies.

Background

We compared the distribution of breast cancer reproductive and hormonal risk factors by level of acculturation and country of residence in women of Mexican descent.

Methods

To compare the distribution of breast cancer reproductive and hormonal risk factors by level of acculturation and country of residence in women of Mexican descent, taking into account level of education, we analyzed data on 581 Mexican and 620 Mexican American (MA) women with a history of invasive breast cancer from the Ella Binational Breast Cancer Study. An eight-item language-based acculturation measure was used to classify MA women. Multivariate logistic regression was used to test associations between language acculturation, country of residence, and reproductive and hormonal risk factors.

Results

After adjustment for age and education, compared to women residing in Mexico, English-dominant MAs were significantly more likely to have an earlier age at menarche (<12 years; odds ratio [OR]=2.08; 95% confidence interval [CI], 1.30-3.34), less likely to have a late age at first birth (≥30 years; OR=0.49; 95% CI, 0.25-0.97), and less likely to ever breastfeed (OR=0.13; 95% CI, 0.08-0.21).

Conclusions

Differences in reproductive and hormonal risk profile according to language acculturation and country of residence are evident; some of these were explained by education. Results support continued efforts to educate Mexican and MA women on screening and early detection of breast cancer along with promotion of modifiable factors, such as breastfeeding.

Background

Published data support the presence of etiologic heterogeneity by breast tumor subtype, but few studies have assessed this in Hispanic populations.

Methods

We assessed tumor subtype prevalence and associations between reproductive factors and tumor subtypes in 1,041 women of Mexican descent enrolled in a case-only, binational breast cancer study. Multinomial logistic regression comparing HER2(+) tumors and triple-negative breast cancer (TNBC) to luminal A tumors was conducted.

Results

Compared with women with luminal A tumors, those with a later age at first pregnancy were less likely to have TNBC [OR, 0.61; 95% confidence interval (CI), 0.39-0.95], whereas those with three or more full-term pregnancies were more likely to have TNBC (OR, 1.68; 95% CI, 1.10-2.55). A lower odds of TNBC was shown for longer menstruation duration, whether before first pregnancy (OR, 0.78; 95% CI, 0.65-0.93 per 10 years) or menopause (OR, 0.79; 95% CI, 0.69-0.91 per 10 years). Patients who reported breastfeeding for more than 12 months were over twice as likely to have TNBC than luminal A tumors (OR, 2.14; 95% CI, 1.24-3.68). Associations comparing HER2(+) with luminal A tumors were weak or nonexistent except for the interval between last full-term pregnancy and breast cancer diagnosis.

Conclusions

Findings show etiologic heterogeneity by tumor subtype in a population of Hispanic women with unique reproductive profiles.

Impact

Identification of etiologically distinct breast tumor subtypes can further improve our understanding of the disease and help provide personalized prevention and treatment regimens.

The risk of breast cancer transiently increases immediately following pregnancy; peaking between 3-7 years. The biology that underlies this risk window and the effect on the natural history of the disease is unknown. MicroRNAs (miRNAs) are small non-coding RNAs that have been shown to be dysregulated in breast cancer. We conducted miRNA profiling of 56 tumors from a case series of multiparous Hispanic women and assessed the pattern of expression by time since last full-term pregnancy. A data-driven splitting analysis on the pattern of 355 miRNAs separated the case series into two groups: a) an early group representing women diagnosed with breast cancer ≤ 5.2 years postpartum (n = 12), and b) a late group representing women diagnosed with breast cancer ≥ 5.3 years postpartum (n = 44). We identified 15 miRNAs with significant differential expression between the early and late postpartum groups; 60% of these miRNAs are encoded on the X chromosome. Ten miRNAs had a two-fold or higher difference in expression with miR-138, miR-660, miR-31, miR-135b, miR-17, miR-454, and miR-934 overexpressed in the early versus the late group; while miR-892a, miR-199a-5p, and miR-542-5p were underexpressed in the early versus the late postpartum group. The DNA methylation of three out of five tested miRNAs (miR-31, miR-135b, and miR-138) was lower in the early versus late postpartum group, and negatively correlated with miRNA expression. Here we show that miRNAs are differentially expressed and differentially methylated between tumors of the early versus late postpartum, suggesting that potential differences in epigenetic dysfunction may be operative in postpartum breast cancers.

Abstract Background: Gastric cancer is the fourth most common cancer and the second cause of cancer death worldwide. In several Latin American countries, it is the most common cancer and the most common cause of cancer death in men and women combined. Infection with H. pylori (Hp) is associated with the development of gastric carcinoma in many parts of the world including Latin America and is thought to be one of the causative agents. We conducted a clinical trial designed to test the effectiveness of three antibiotic regimens for Hp eradication in seven sites in Latin America while assessing feasibility, and the possibility of identifying a direction for future chemoprevention trials of gastric cancer. Methods: Under a locally IRB approved clinical protocol and signed informed consent requirement, 1852 adults (ages 21-65 years) from the general populations of Chile (Santiago), Colombia (Túquerres), Costa Rica (Guanacaste), Honduras (Copán), México (Obregon and Tapachula), and Nicaragua (León) were screened for the presence of Hp infection with the urea breath test (UBT). 79.4% were positive. 1463 participants consented to be randomized to one of three regimens administered twice a day: 14 days of lansoprazole 30mg, amoxicillin 1,000mg, and clarithromycin 500mg (triple 14d); 5 days of lansoprazole 30mg and amoxicillin 1,000mg followed by 5 days of lansoprazole 30mg, clarithromycin 500mg, and metronidazole 500mg (sequential 10d) or 5 days of lansoprazole 30mg, amoxicillin 1,000mg, and clarithromycin 500mg, and metronidazole 500mg (concomitant 5d). Response was assessed at 6-8 weeks after treatment by UBT. Recurrence at one year was also assessed by UBT. Results are presented by UBT testing and by all participants enrolled (intention-to-treat (ITT)) analysis. 123 (30.8%) patients who did not return for UBT testing were presumed failures at one year. Studies of HP virulence, pepsinogens I and II, as well as inflammatory cytokines, are in progress. Results: Participant characteristics were similar in the three treatment groups. At 6-8 weeks after treatment, UBT was negative in 1133/1414 (80.1%) patients who underwent follow-up UBT and in 1133/1463 (77.4%) of all participants enrolled. The triple 14d regimen was the superior (p 0.008) regimen among all who had repeat UBT and in the ITT group (p 0.005). The estimated fraction remaining free of infection at one year was 79.3% among participants followed by UBT, and 72.7% for all participants enrolled in the study (Table 1). At one year, in those patients with a negative UBT at 6-8 weeks, Hp recurrence was observed in 11.5%. The risk of infection was greater by site - worse in Chile and Colombia- (p <0.0001), age - worse in the younger - (p 0.03), education - worse in the poorly educated - (p 0.02) and household overcrowding - worse in more crowded households - (p 0.007). Gender, prior antibiotic use, water source and sanitation were not significant factors. By multivariate analysis, the most important predictors of Hp recurrence at one year were study site (p <0.0001), younger age (p <0.001) and crowded households (p 0.003). Conclusions: This is the largest, prospective, randomized clinical trial ever conducted to treat Hp. The trial was successful in recruiting participants, as well as conducting and monitoring trial treatments and outcomes in 6 Latin American countries. We demonstrated greater treatment efficacy of the triple 14d antibiotic regimen at 6-8 weeks, but a one year 11.5% recrudescence rate regardless of antibiotic regimen. Study site, younger age and crowded households are important factors associated with Hp recurrence at one year. The recurrence rate at one year is concerning, and points to the necessity of conducting additional studies of the molecular biology and pathogenesis of Hp before launching definitive chemoprevention trials of gastric cancer. Given the unique prevalence of gastric cancer and other infection-related cancers in Latin America, we propose that Latin America investigators consider the formation of an independent Cancer Cooperative Group to facilitate research involving cancer. Just as the United States wisely invested in the development of cancer cooperative groups in Europe (European Organization for Research and Treatment of Cancer - EORTC) and in Canada (National Cancer Institute of Canada Clinical Trials Group - NCIC-CTG), we believe that the time has come for consideration of the creation of a cancer cooperative group in Latin America with financial support from the National Cancer Institute. Support: The Bill & Melinda Gates Foundation grant #43930 and National Cancer Institute grant # CA037429. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY26-02. doi:1538-7445.AM2012-SY26-02

Focal cortical dysplasia is a highly epileptogenic cortical malformation with few treatment options. Here, we generated human cortical organoids from patients with focal cortical dysplasia type II. Using this human model, we mimicked some focal cortical dysplasia hallmarks, such as impaired cell proliferation, the presence of dysmorphic neurons and balloon cells, and neuronal network hyperexcitability. Furthermore, we observed alterations in the adherens junctions zonula occludens-1 and partitioning defective 3, reduced polarization of the actin cytoskeleton, and fewer synaptic puncta. Focal cortical dysplasia cortical organoids showed downregulation of the small GTPase RHOA, a finding that was confirmed in brain tissue resected from these patients. Functionally, both spontaneous and optogenetically-evoked electrical activity revealed hyperexcitability and enhanced network connectivity in focal cortical dysplasia organoids. Taken together, our findings suggest a ventricular zone instability in tissue cohesion of neuroepithelial cells, leading to a maturational arrest of progenitors or newborn neurons, which may predispose to cellular and functional immaturity and compromise the formation of neural networks in focal cortical dysplasia.