Mutational spectrum of breast cancer susceptibility genes among women ascertained in a cancer risk clinic in Northeast Brazil.

PURPOSE: There is a paucity of data on the spectrum and prevalence of pathogenic variants among women of African ancestry in the Northeast region of Brazil. METHODS: We performed BROCA panel sequencing to identify inherited loss-of-function variants in breast cancer susceptibility genes among 292 Brazilian women referred to a single institution cancer risk assessment program. RESULTS: The study included a convenient cohort of 173 women with invasive breast cancer (cases) and 119 women who were cancer-free at the time of ascertainment. The majority of the women self-reported as African-descended (67% for cases and 90.8% for unaffected volunteers). Thirty-seven pathogenic variants were found in 36 (20.8%) patients. While the spectrum of pathogenic variants was heterogeneous, the majority (70.3%) of the pathogenic variants were detected in high-risk genes BRCA1, BRCA2, PALB2, and TP53. Pathogenic variants were also found in the ATM, BARD1, BRIP1, FAM175A, FANCM, NBN, and SLX4 genes in 6.4% of the affected women. Four recurrent pathogenic variants were detected in 11 patients of African ancestry. Only one unaffected woman had a pathogenic variant in the RAD51C gene. Different risk assessment models examined performed well in predicting risk of carrying germline loss-of-function variants in BRCA1 and/or BRCA2 in breast cancer cases. CONCLUSION: The high prevalence and heterogenous spectrum of pathogenic variants identified among self-reported African descendants in Northeast Brazil is consistent with studies in other African ancestry populations with a high burden of aggressive young onset breast cancer. It underscores the need to integrate comprehensive cancer risk assessment and genomic testing in the management of newly diagnosed Black women with breast cancer across the African Diaspora, enabling improved cancer control in admixed underserved and understudied populations.

BRCA1 and BRCA2 rearrangements in Brazilian individuals with Hereditary Breast and Ovarian Cancer Syndrome.

Approximately 5-10% of breast cancers are caused by germline mutations in high penetrance predisposition genes. Among these, BRCA1 and BRCA2, which are associated with the Hereditary Breast and Ovarian Cancer (HBOC) syndrome, are the most frequently affected genes. Recent studies confirm that gene rearrangements, especially in BRCA1, are responsible for a significant proportion of mutations in certain populations. In this study we determined the prevalence of BRCA rearrangements in 145 unrelated Brazilian individuals at risk for HBOC syndrome who had not been previously tested for BRCA mutations. Using Multiplex Ligation-dependent Probe Amplification (MLPA) and a specific PCR-based protocol to identify a Portuguese founder BRCA2 mutation, we identified two (1,4%) individuals with germline BRCA1 rearrangements (c.547+240_5193+178del and c.4675+467_5075-990del) and three probands with the c.156_157insAlu founder BRCA2 rearrangement. Furthermore, two families with false positive MLPA results were shown to carry a deleterious point mutation at the probe binding site. This study comprises the largest Brazilian series of HBOC families tested for BRCA1 and BRCA2 rearrangements to date and includes patients from three regions of the country. The overall observed rearrangement frequency of 3.44% indicates that rearrangements are relatively uncommon in the admixed population of Brazil.

Resveratrol abrogates the temozolomide-induced G2 arrest leading to mitotic catastrophe and reinforces the temozolomide-induced senescence in glioma cells.

BACKGROUND: Temozolomide (TMZ) is the most widely used drug to treat glioblastoma (GBM), which is the most common and aggressive primary tumor of the Central Nervous System and one of the hardest challenges in oncotherapy. TMZ is an alkylating agent that induces autophagy, apoptosis and senescence in GBM cells. However, therapy with TMZ increases survival after diagnosis only from 12 to 14.4 months, making the development of combined therapies to treat GBM fundamental. One candidate for GBM therapy is Resveratrol (Rsv), which has additive toxicity with TMZ in several glioma cells in vitro and in vivo. However, the mechanism of Rsv and TMZ additive toxicity, which is the aim of the present work, is not clear, especially concerning cell cycle dynamics and long term effects. METHODS: Glioma cell lines were treated with Rsv and TMZ, alone or in combinations, and the induction and the role of autophagy, apoptosis, cell cycle dynamics, protein expression and phosphorylation status were measured. We further evaluated the long term senescence induction and clonogenic capacity. RESULTS: As expected, temozolomide caused a G2 cell cycle arrest and extensive DNA damage response. Rsv did not reduced this response, even increasing pATM, pChk2 and gammaH2Ax levels, but abrogated the temozolomide-induced G2 arrest, increasing levels of cyclin B and pRb(S807/811) and reducing levels of pWee1(S642) and pCdk1(Y15). This suggests a cellular state of forced passage through G2 checkpoint despite large DNA damage, a scenario that may produce mitotic catastrophe. Indeed, the proportion of cells with high nuclear irregularity increased from 6 to 26% in 48 h after cotreatment. At a long term, a reduction in clonogenic capacity was observed, accompanied by a large induction of senescence. CONCLUSION: The presence of Rsv forces cells treated with TMZ through mitosis leading to mitotic catastrophe and senescence, reducing the clonogenic capacity of glioma cells and increasing the chronic effects of temozolomide.

Should extragonadal germ cell tumors be included in studies of families with testicular germ cell tumors?

BACKGROUND: Family history is among the few established risk factors for testicular germ cell tumor (TGCT). Approximately 1.4% of newly diagnosed TGCT patients report a positive family history of TGCT. Sons and siblings of TGCT patients have four- to six fold and eight- to tenfold increase in TGCT risk, respectively. In twins of men with TGCT the relative risk of testicular cancer is 37.5 (12.3-115.6). Nevertheless, information about the occurrence of TGCT in relatives of patients with extragonadal germ cell tumor is limited. CASE REPORT: A 24 year-old male patient was diagnosed with a mediastinum tumor and was submitted to image-guided biopsy, which revealed a seminoma. Two months later, his non-identical asymptomatic twin brother was submitted to an elective ultrasound of the testes, which showed a left testicular mass of 4.2 cm. This patient underwent orchiectomy revealing a seminoma of the left testis. There are no other cases of seminoma or other types of cancers reported in first-degree relatives in this family. CONCLUSIONS: Although familial aggregations of TGCT have been well described, to the best of our knowledge, no data concerning the association of gonadal and extragonadal germ cell tumor in relatives has been previously reported. Further investigation on this association is warranted and may help in improving our knowledge of familial pattern inheritance.

PD-L1 testing in advanced gastric cancer-what physicians who treat this disease must know-a literature review.

Background and Objective: Immune checkpoint inhibition has shed light on a new era in cancer therapy, and randomized clinical trials have demonstrated that a meaningful portion of the overall population of metastatic gastric cancer (GC) patients may derive clinical benefit from immunotherapy, which raises the relevance in identifying predictive biomarkers. Programmed cell death-ligand 1 (PD-L1) expression has demonstrated a significant association between level of expression and the magnitude of benefit derived from immune checkpoint inhibition in GC. Nevertheless, this biomarker shows several pitfalls that must be considered in the therapeutic decision to incorporate immune checkpoint inhibition as the standard of care of GC, such as spatial and temporal heterogeneity, interobserver variability, immunohistochemistry (IHC) assay, and influence by chemotherapy or radiation therapy. Methods: In the present comprehensive review, we revised the main studies regarding PD-L1 evaluation in GC. Key Content and Findings: Here we describe the molecular characteristics of the tumor microenvironment in GC, the obstacles in the interpretation of PD-L1 expression and present the data of the clinical trials that have evaluated the efficacy and safety of immune checkpoint inhibition and the association with the biomarker expression, both in first-line and later lines of therapy. Conclusions: From the emerging predictive biomarkers for immune checkpoint inhibition, PD-L1 has demonstrated a meaningful association between level of expression in tumor microenvironment and the magnitude of benefit derived from immune checkpoint inhibition in GC.

Vitamin D and colorectal cancer - A practical review of the literature.

Colorectal cancer (CRC) is the third leading cause of cancer-related mortality in the United States and the second cause worldwide. Its incidence rates have been decreasing in the overall population in the US in the past few decades, but with increasing rates in the population younger than 50 years old. Environmental factors are supposed to be involved in the development of the disease, with strong evidence favoring an influence of the diet and lifestyle. A diet high in red meat and calories, and low in fiber, fruits and vegetables increases the risk of CRC, as well as physical inactivity. The influence of low calcium intake and low levels of vitamin D on the risk of the disease and on the clinical outcomes of CRC patients has also been investigated. Hypovitaminosis D has been highly prevalent worldwide and associated with several chronic diseases, including malignancies. Vitamin D is a steroid hormone with the main function of regulating bone metabolism, but with many other physiological functions, such as anti-inflammatory, immunomodulatory, and antiangiogenic effects, potentially acting as a carcinogenesis inhibitor. In this review, we aim to describe the relation of vitamin D with malignant diseases, mainly CRC, as well as to highlight the results of the studies which addressed the potential role of vitamin D in the development and progression of the disease. In addition, we will present the results of the pivotal randomized clinical trials that evaluated the impact of vitamin D supplementation on the clinical outcomes of patients with CRC.

Novel Insights From the Germline Landscape of Breast Cancer in Brazil.

INTRODUCTION: Breast cancer patients with germline pathogenic variants may benefit from risk-reducing surgeries, intensive screening, and targeted cancer therapies. There is a paucity of data regarding prevalence and distribution of germline pathogenic variants in the Brazilian population. Our primary endpoint was the description of prevalence and distribution of germline pathogenic variants among breast cancer patients who underwent next-generation sequencing (NGS) panel testing. Secondary endpoint was the assessment of predictive factors of a positive test. METHODS: We analyzed NGS results, personal, and family history data from a prospectively collected cohort of breast cancer patients from August 2013 to May 2019. Exact logistic regression was used to perform multivariable analysis. RESULTS: Of 370 breast cancer patients, we found 59 pathogenic variants in 57 (15%) patients. Pathogenic variants were identified in BRCA1 (24%), ATM (14%), BRCA2 (10%), TP53 (8%), PALB2 (8%), CHEK2 (7%), CDH1 (3%), RAD51C (3%), MITF (2%), PMS2 (2%), RAD51D (2%), and TERT (2%). Monoallelic MUTYH pathogenic variants were found in 15%. After multivariable analysis, age of diagnosis (OR 0.89, 95% CI: 0.81-0.95, for each year increase), triple-negative subtype (OR 17.2, 95% CI: 3.74-114.72), and number of breast cancers in the family (OR 2.46, 95% CI 1.57-4.03, for each additional case) were associated with BRCA1 pathogenic variants. In the present study, a quarter of triple-negative breast cancer patients harbored a germline pathogenic variant and two-thirds of those were BRCA1 carriers. CONCLUSIONS: Prevalence and distribution of germline pathogenic variants in this Brazilian sample of breast cancer patients are mostly similar to other populations. However, there is a trend to an overrepresentation of TP53 pathogenic variants that merits confirmation in further studies. Early-onset breast cancer patients should be offered genetic counseling, particularly those with triple-negative subtype.

Efficacy and Safety Associated With Immune Checkpoint Inhibitors in Unresectable Hepatocellular Carcinoma: A Meta-analysis.

Importance: Immune checkpoint inhibitors (ICIs) have yielded conflicting results in hepatocellular carcinoma (HCC). The overall effect of ICIs compared with standard therapies in unresectable HCC requires more research. Objective: To estimate the efficacy and safety associated with ICIs compared with standard therapies in patients with unresectable HCC. Data Sources: PubMed, Cochrane Library, Web of Science, Latin American and Caribbean Health Sciences Literature, and American Society of Clinical Oncology and European Society of Medical Oncology meeting proceedings were systematically searched. Reference lists from studies selected by electronic searching were manually searched to identify additional relevant studies. The search included literature published or presented from February 2010 to February 2020. Study Selection: From December 2019 to February 2020, independent reviewers evaluated each database, scanning the title, abstract, and keywords of every record retrieved. Full articles were further assessed if the information given suggested that the study was a randomized clinical trial (RCT) comparing ICIs vs standard therapies in the treatment of unresectable HCC. Data Extraction and Synthesis: The full text of the resulting studies and extracted data were reviewed independently according to PRISMA guidelines. Summary hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS) were calculated by a random-effects model. The likelihood of ICIs being associated with overall response rate (ORR) and treatment-related adverse events (TRAEs) was expressed by odds ratios (ORs) using a random-effects model. Main Outcomes and Measures: The main outcomes were OS, PFS, ORR, and TRAEs. Results: Of 1836 studies yielded by the search, 3 were retained, totaling 1657 patients (985 treated with ICIs vs 672 receiving standard treatment). Two studies evaluated ICIs as monotherapy, and 1 study investigated the combination of ICIs with bevacizumab. Compared with standard therapies (sorafenib in first-line therapy or placebo in second-line therapy), ICIs were associated with significantly improved OS (HR, 0.75; 95% CI, 0.62-0.92; P = .006), PFS (HR, 0.74; 95% CI, 0.56-0.97; P = .03), and ORR (OR, 2.82; 95% CI 2.02-3.93; P < .001). The probability of grade 3 or 4 TRAEs was lower with ICIs than with sorafenib (OR, 0.44; 95% CI, 0.20-0.96; P = .04). Conclusions and Relevance: This meta-analysis found superior efficacy and safety associated with ICIs compared with standard therapies and highlights the survival benefit associated with the combination of antiangiogenic therapy with ICIs in first-line systemic therapy of unresectable HCC.

Basal-like immunophenotype markers and prognosis in early breast cancer.

AIMS AND BACKGROUND: Basal-like breast cancer is a distinct group of tumors with heterogeneous behavior, and not all have a poor prognosis. The present study analyzed the prevalence and prognosis of early basal-like breast cancer. METHODS AND STUDY DESIGN: A total of 112 patients with stage I and II breast cancer were retrospectively analyzed using immunohistochemical stains for estrogen receptor, progesterone receptor, HER2, cytokeratin 5/6 and epidermal growth factor receptor. Basal-like tumors were defined as being estrogen receptor, progesterone receptor and HER2 negative and cytokeratin 5/6 and/or epidermal growth factor receptor positive. RESULTS: Of the 112 cases, respectively 13 (11.6%) were basal-like, 77 (68.8%) luminal A or B, 13 (11.6%) HER2 positive and 9 (8%) undefined. In basal-like tumors, epidermal growth factor receptor and cytokeratin 5/6 expression was positive in 5 patients (38.5%) and 12 patients (92%), respectively. There was no significant correlation between basal-like breast cancer and age (P = 0.207), lymph node status (P = 1.0) or clinical stage (P = 0.53). Among all tested biomarkers, positivity was found in 81 (72.3%) for estrogen receptor, 13 (11.6%) for HER2, 11 (9.8%) for epidermal growth factor receptor and 36 (32.1%) for cytokeratin 5/6. Epidermal growth factor receptor expression was significantly correlated with estrogen receptor-negative (P = 0.01) and HER2-positive (P = 0.02) tumors. During a median follow-up of 81 months, there were 26 (23%) disease relapses and 12 (10.7%) deaths. No significant difference relating to disease-free survival and overall survival was noted between basal-like breast cancer and subtypes luminal A and B, HER2 positive and undefined. CONCLUSIONS: The addition of cytokeratin 5/6 and epidermal growth factor receptor defines a small subgroup of patients with basal-like tumors. In a population with early breast cancer, basal-like tumors did not have a prognosis different from the other subtypes. Neither was there a significant association with clinicopathological features. The high frequency of epidermal growth factor receptor positivity in estrogen receptor-negative and HER2-positive tumors represents a potential target in clinical trials.

Increased tissue factor expression and poor nephroblastoma prognosis.

PURPOSE: There is potential interaction between malignant cell growth and the coagulation pathway. Recent studies suggest that tissue factor, a primary initiator of the extrinsic coagulation pathway, is expressed in various solid tumors in association with increased angiogenesis. To our knowledge we report for the first time the detection of tissue factor expression by immunohistochemistry in Wilms tumors and its correlation with clinical outcomes. MATERIAL AND METHODS: Tissue factor expression detected by immunohistochemistry was assessed in 41 formalin fixed, paraffin embedded Wilms tumor cases treated at university hospitals. We correlated findings with tumor recurrence and cancer specific survival. RESULTS: Positive immunohistochemistry detection of tissue factor was observed in 88.3% of the tumors analyzed. Tissue factor on immunohistochemistry was associated with tumor recurrence and survival (p = 0.01 and 0.02, respectively). Increased immunohistochemical detection of tissue factor was the most important risk factor for recurrence and mortality in our population on bivariate and multivariate analysis. CONCLUSIONS: Tissue factor is a promising research subject as a prognostic factor for Wilms tumor. More studies are needed to clarify the mechanisms by which tissue factor affects cancer progression and outcome, and its potential role as a therapeutic target.

Safety and seizure control in patients with mesial temporal lobe epilepsy treated with regional superselective intra-arterial injection of autologous bone marrow mononuclear cells.

Temporal lobe epilepsy (TLE) is a highly prevalent syndrome among people with epilepsy, and is usually refractory to drug treatment. Structural and physiological changes, such as hippocampal sclerosis, are often present in TLE patients. The objective of this study is to evaluate the feasibility and safety of intra-arterial infusion of autologous bone marrow mononuclear cells (BMMC) in adults with medically refractory mesial TLE (MTLE) and unilateral hippocampal sclerosis (HS). We enrolled 20 patients who had been diagnosed with MTLE-HS and were refractory to medical treatment. All patients underwent a neurological evaluation, magnetic resonance imaging with hippocampal volumetry, video-electroencephalography (EEG) with ictal recording, and a neuropsychological test battery focusing on verbal and nonverbal memory domains. After bone marrow aspiration and subsequent cell preparation, the BMMC were infused by selective posterior cerebral artery catheterization. Patients were followed for 6 months. Safety of the procedure, seizure frequency, neuropsychological evaluation, EEG variables, routine brain magnetic resonance imaging and hippocampal volumetry were considered measurements of outcome. Any serious intercurrent clinical event or adverse effects related to the procedure were reported. No additional lesions and no significant hippocampal volumetric changes were observed. EEG recordings showed a decrease in theta activity and spike density. At 6 months, eight patients (40%) were seizure free. A significant increase in the memory scores over time was observed. The BMMC autologous transplant for the treatment of temporal lobe epilepsy is feasible and safe. The seizure control achieved in this novel study supports the therapeutic potential of stem cell transplants in MTLE-HS patients. Copyright © 2016 John Wiley & Sons, Ltd.

The germline mutational landscape of BRCA1 and BRCA2 in Brazil.

The detection of germline mutations in BRCA1 and BRCA2 is essential to the formulation of clinical management strategies, and in Brazil, there is limited access to these services, mainly due to the costs/availability of genetic testing. Aiming at the identification of recurrent mutations that could be included in a low-cost mutation panel, used as a first screening approach, we compiled the testing reports of 649 probands with pathogenic/likely pathogenic variants referred to 28 public and private health care centers distributed across 11 Brazilian States. Overall, 126 and 103 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-six novel variants were reported from both genes, and BRCA2 showed higher mutational heterogeneity. Some recurrent mutations were reported exclusively in certain geographic regions, suggesting a founder effect. Our findings confirm that there is significant molecular heterogeneity in these genes among Brazilian carriers, while also suggesting that this heterogeneity precludes the use of screening protocols that include recurrent mutation testing only. This is the first study to show that profiles of recurrent mutations may be unique to different Brazilian regions. These data should be explored in larger regional cohorts to determine if screening with a panel of recurrent mutations would be effective.

Preoperative embolization of the splenic artery in patients that underwent splenectomy for immune thrombocytopenic purpura.

UNLABELLED: Transfusion of platelets, red blood cells, or both is usually necessary immediately after splenic artery ligature in patients with immune thrombocytopenic purpura who undergo splenectomy. PURPOSE: To investigate whether preoperative embolization of the splenic artery reduced the need for transfusion of platelets, red blood cells, or both. METHODS: Twenty- seven consecutive patients that underwent splenectomy for purpura between October 1999 and March 2006 performed by the same surgical team were enrolled. The first 17 patients did not undergo embolization and were compared with the next 10 patients, who composed the embolization group. RESULTS: The platelet count in the embolization group rose from a mean 7000 u/microl before to 75000 u/microl after the procedure. There was no need for platelet or red blood cell transfusion in the embolization group; in the group without preoperative embolization, 11 patients (p=0.001) required platelet transfusion and 8 (p=0.01), red blood cell transfusion. CONCLUSION: Embolization of the splenic artery before splenectomy is a safe method to avoid blood transfusions in patients with ITP.

Cancer immunology and melanoma immunotherapy.

The stimulation of the immune system, in order to generate an attack against cancer cells, similarly to that which occurs in infectious disease, has long been matter of interest in oncology; however, only limited success has been achieved, with different treatment strategies tested in recent years. The development of new immune checkpoint inhibitors is currently changing this scenario, and immunotherapy is becoming a real choice among traditional cytotoxic treatments to fight cancer. Recent reports have shown efficacy and safety with the use of pembrolizumab, nivolumab, and ipilimumab for the treatment of different neoplasms, especially melanoma. In this article, we propose a review of the mechanisms of action involved in cancer immunology, the response evaluation of immunotherapies, and its toxicity profile, as well as a summary of the main clinical trials that led to the adoption of these new drugs for melanoma treatment.

Treatment of advanced melanoma - A changing landscape.

Following decades of relative ostracism, advances in the treatment of melanoma have brought a new reality for patients, physicians and researchers. While antibodies targeting molecules involved in the modulation of the interaction between melanoma and immune cells changed the meaning of the term "cancer immunotherapy," a better characterization of the molecular aberrations involved in melanoma carcinogenesis prompted the development of inhibitors of the mitogen-activated protein kinase pathway (MAPK) that also led to significant improvements both in response rates and survival. As a result, new drugs have been approved for clinical use in the United States and Europe, including the immune-checkpoint blockers ipilmumab, pembrolizumab and nivolumab, the oncolytic herpesvirus talimogene laherparepvec, and the targeted-agents vemurafenib, dabrafenib, cobimetinib and trametinib. In this article, we review the results of studies that brought new approaches to the bedside and discuss how these developments are being incorporated into the care of patients in Brazil.

Long-term outcomes of dose-escalated intensity modulated radiation therapy alone without androgen deprivation therapy for patients with intermediate and high-risk prostate cancer.

OBJECTIVE: The addition of androgen deprivation therapy (ADT) to conventional radiation therapy improves overall survival (OS) in intermediate- and high-risk prostate cancer. The benefit of ADT to added to dose-escalated radiotherapy is less clear. The aim of this study was to report disease control outcomes and to identify prognostic variables associated with favorable outcomes in patients with intermediate- and high-risk prostate cancer treated with dose-escalated radiation therapy without ADT. METHODS AND MATERIALS: From September 2001 to March 2010, 127 patients with intermediate- or high-risk prostate cancer were treated with dose-escalated radiation otherapy without ADT. Biochemical recurrence-free survival (bRFS), distant metastases-free survival (DMFS), prostate cancer-specific mortality, and OS were assessed. Univariate and multivariate analyses using Cox regression modeling were performed. RESULTS: The median follow-up was 6.5 years, and the 5-year estimated bRFS, DMFS, prostate cancer-specific mortality, and OS for all patients was 89%, 96.1%, 98.4%, and 96.9% respectively. On multivariate analysis, factors that predict bRFS include risk group and PSA nadir, and factors that predict DMFS include perineural invasion, risk group, and PSA nadir. CONCLUSIONS: Patients with favorable intermediate-risk cancer could likely be treated with dose-escalated radiation therapy without ADT. Patients with high-risk and unfavorable intermediate-risk cancer, perineural invasion, and PSA nadir ≥1ng/dL had worse outcomes and likely need distinct therapeutic approaches.

Hereditary nonpolyposis colorectal cancer identification and surveillance of high-risk families.

Hereditary nonpolyposis colorectal cancer is an autosomal dominant condition caused by highly penetrant gene mutations. It is characterized by increased susceptibility for a specific group of cancer, mainly colorectal cancer. The syndrome originates from the inheritance of mutations in DNA mismatch repair genes. The most commonly affected genes in hereditary nonpolyposis colorectal cancer are hMLH1 and hMSH2. Their deficient expression renders the cell susceptible to the accumulation of many molecular defects, a condition which can be evaluated by the instability in sections of base repeats in the genoma known as microsatellite instability. The molecular detection of hereditary nonpolyposis colorectal cancer is possible in most of the highly suspicious cases. Genetic tests for hereditary nonpolyposis colorectal cancer also allow characterization of the individual that bears the mutation within a family. The high cost and restricted availability of these tests hamper their use for every person presenting colorectal cancer. Due to this fact, some clinical criteria have been developed by a hereditary nonpolyposis colorectal cancer international organization to select families with a high probability of carrying the mutation. Once families at risk are identified, they are encouraged to join a screening program that aims at early detection of hereditary nonpolyposis colorectal cancer-related cancers, increasing the possibility of its prevention and early detection.

MicroRNAs, cancer and ionizing radiation: Where are we?

The aim of this study is to describe the biogenesis of microRNA, its relations with carcinogenesis, and the correlation between microRNA and ionizing radiation (IR), focusing on radioresponsiveness. It is known that microRNA biogenesis is well established and involves different enzymatic cleavages, resulting in the production of mature microRNA. MicroRNAs are involved in carcinogenesis. Their interaction is related to the genetic and epigenetic changes associated with activation of proto-oncogenes or inactivation of tumor suppressor genes. Several studies have shown that the levels of expression of some microRNAs vary significantly after irradiation. There are evidences that microRNAs can influence cellular response after IR. In addition, microRNAs are related to modulation of the expression of several post-transcriptional targets in DNA damage response pathways, and to the DNA damage repair regulation mechanism. Future studies can clarify a possible clinical use of microRNAs as a new class of radiosensitive agents.

[Immunosuppression with cyclophosphamide and fudarabine, with support of autologous CD-34+ stem cells, in the treatment of severe scleroderma]. / Imunossupressão com ciclofosfamida e fludarabina, com suporte de células tronco hematopoéticas autólogas CD-34+, para tratamento de esclerose sistêmica severa.

Immune ablation of T lymphocytes, key players in the physiopathogenic processes leading to autoimmune diseases, may arrest scleroderma progression even in some severely ill patients. High-dose chemotherapy followed by autologous stem cell reinfusion - sometimes named peripheral blood stem cell transplantation - has been an effective therapy for some autoimmune diseases, including scleroderma. In this paper the authors present a patient with the diffuse form of scleroderma who received immunosuppression with cyclophosphamide 0.5 g/m² and fludarabine followed by infusion of autologous CD-34+ cells without T lymphocyte purging. This patient was followed up with cutaneous score measures, imaging and laboratory tests, as well as a well-being questionnaire. After transplantation there were major positive responses on skin and gastrointestinal tract, with cessation of diarrhea and malabsorption syndrome. These clinical improvements did not last past 6 months. We observed transitory stem cell transfusion reaction and localized herpes zoster. The patient died 12 months after the procedure due to aspirative pneumonia and gastrointestinal complications. The immunosuppressive regimen, and not the autologous stem cell transplantation, could have been responsible for the observed transitory patient improvement.

Familial Lymphoproliferative Malignancies and Tandem Duplication of NF1 Gene.

Background. Neurofibromatosis type 1 is a genetic disorder caused by loss-of-function mutations in a tumor suppressor gene (NF1) which codifies the protein neurofibromin. The frequent genetic alterations that modify neurofibromin function are deletions and insertions. Duplications are rare and phenotype in patients bearing duplication of NF1 gene is thought to be restricted to developmental abnormalities, with no reference to cancer susceptibility in these patients. We evaluated a patient who presented with few clinical signs of neurofibromatosis type 1 and a conspicuous personal and familiar history of different types of cancer, especially lymphoproliferative malignancies. The coding region of the NF-1 gene was analyzed by real-time polymerase chain reaction and direct sequencing. Multiplex ligation-dependent probe amplification was performed to detect the number of mutant copies. The NF1 gene analysis showed the following alterations: mosaic duplication of NF1, TRAF4, and MYO1D. Fluorescence in situ hybridization using probes (RP5-1002G3 and RP5-92689) flanking NF1 gene in 17q11.2 and CEP17 for 17q11.11.1 was performed. There were three signals (RP5-1002G3conRP5-92689) in the interphases analyzed and two signals (RP5-1002G3conRP5-92689) in 93% of cells. These findings show a tandem duplication of 17q11.2. Conclusion. The case suggests the possibility that NF1 gene duplication may be associated with a phenotype characterized by lymphoproliferative disorders.