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PURPOSE The objective of this review was to address the barriers limiting access to genetic cancer risk assessment and genetic testing for individuals with suspected hereditary breast and ovarian cancer (HBOC) through a review of the diagnosis and management steps of HBOC. METHODS A selected panel of Brazilian experts in fields related to HBOC was provided with a series of relevant questions to address before the multiday conference. During this conference, each narrative was discussed and edited by the entire group, through numerous drafts and rounds of discussion, until a consensus was achieved. RESULTS The authors propose specific and realistic recommendations for improving access to early diagnosis, risk management, and cancer care of HBOC specific to Brazil. Moreover, in creating these recommendations, the authors strived to address all the barriers and impediments mentioned in this article. CONCLUSION There is a great need to expand hereditary cancer testing and counseling in Brazil, and changing current policies is essential to accomplishing this goal. Increased knowledge and awareness, together with regulatory actions to increase access to this technology, have the potential to improve patient care and prevention and treatment efforts for patients with cancer across the country.

Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p 0 center dot 0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and onlyBackground Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence. Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero. Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (pT variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%. Interpretation Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome. Funding National Health and Medical Research Council, Australia. Copyright (c) 2021 Elsevier Ltd. All rights reserved.Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero.

Purpose: To establish a cohort of high-risk women undergoing intensive surveillance for breast cancer. Experimental Design: We performed dynamic contrast-enhanced MRI every 6 months in conjunction with annual mammography (MG). Eligible participants had a cumulative lifetime breast cancer risk ≥20% and/or tested positive for a pathogenic mutation in a known breast cancer susceptibility gene. Results: Between 2004 and 2016, we prospectively enrolled 295 women, including 157 mutation carriers (75 BRCA1, 61 BRCA2); participants' mean age at entry was 43.3 years. Seventeen cancers were later diagnosed: 4 ductal carcinoma in situ (DCIS) and 13 early-stage invasive breast cancers. Fifteen cancers occurred in mutation carriers (11 BRCA1, 3 BRCA2, 1 CDH1). Median size of the invasive cancers was 0.61 cm. No patients had lymph node metastasis at time of diagnosis, and no interval invasive cancers occurred. The sensitivity of biannual MRI alone was 88.2% and annual MG plus biannual MRI was 94.1%. The cancer detection rate of biannual MRI alone was 0.7% per 100 screening episodes, which is similar to the cancer detection rate of 0.7% per 100 screening episodes for annual MG plus biannual MRI. The number of recalls and biopsies needed to detect one cancer by biannual MRI were 2.8 and 1.7 in BRCA1 carriers, 12.0 and 8.0 in BRCA2 carriers, and 11.7 and 5.0 in non-BRCA1/2 carriers, respectively. Conclusions: Biannual MRI performed well for early detection of invasive breast cancer in genomically stratified high-risk women. No benefit was associated with annual MG screening plus biannual MRI screening. See related commentary by Kuhl and Schrading, p. 1693

Colorectal cancer (CRC) is one of the most common cancers in Latin America and the Caribbean, with the highest rates reported for Uruguay, Brazil and Argentina. We provide a global snapshot of the CRC patterns, how screening is performed, and compared/contrasted to the genetic profile of Lynch syndrome (LS) in the region. From the literature, we find that only nine (20%) of the Latin America and the Caribbean countries have developed guidelines for early detection of CRC, and also with a low adherence. We describe a genetic profile of LS, including a total of 2,685 suspected families, where confirmed LS ranged from 8% in Uruguay and Argentina to 60% in Peru. Among confirmed LS, path_MLH1 variants were most commonly identified in Peru (82%), Mexico (80%), Chile (60%), and path_MSH2/EPCAM variants were most frequently identified in Colombia (80%) and Argentina (47%). Path_MSH6 and path_PMS2 variants were less common, but they showed important presence in Brazil (15%) and Chile (10%), respectively. Important differences exist at identifying LS families in Latin American countries, where the spectrum of path_MLH1 and path_MSH2 variants are those most frequently identified. Our findings have an impact on the evaluation of the patients and their relatives at risk for LS, derived from the gene affected. Although the awareness of hereditary cancer and genetic testing has improved in the last decade, it is remains deficient, with 39%–80% of the families not being identified for LS among those who actually met both the clinical criteria for LS and showed MMR deficiency. Radium Hospital Foundation (Oslo, Norway)

Introduction The contribution of CDH1 germline variants to gastric cancer burden among young adults is unknown in Brazil. We aimed to evaluate the frequency of CDH1 germline variants and the diet/lifestyle habits in early age onset gastric cancer (EOGC, ≤ 55 years old) patients. Methodology From 2013 to 2015, a total of 88 unrelated and consecutive patients diagnosed with EOGC were enrolled. All CDH1 exons and intronic boundaries were sequenced, and large genomic rearrangements were screened by MLPA. CDH1 transcription analysis was performed for variants that could potentially induce an effect on splicing. The diet and lifestyle habits of EOGC patients were compared to Brazilian population diet and lifestyle, obtained from governmental databases. Results Of 88 patients, the mean age at EOGC diagnosis was 39 years and 55% fulfilled the criteria for hereditary diffuse gastric cancer. The majority of the tumors were diffuse (74%) and poorly differentiated (80%). In total, 4 novel missense variants of uncertain significance (VUS) were identified: c.313T>A, c.387G>T, c.1676G>A, and c.1806C>A. The MLPA results revealed no rearrangements and CDH1 transcription analysis for variants of interest were inconclusive. EOGC patients had a higher red (OR:2.6, 95%CI:1.4–4.9) and processed (OR:3.1, 95%CI:1.6–6.0) meat intake and higher fruit consumption (OR:0.4, 95%IC:0.3–0.7) compared to eating habits of the Brazilian population. Conclusions No unequivocal pathogenic germline CDH1 variants were identified in Brazilian EOGC patients. Dietary habits may be associated with the EOGC development. Electronic supplementary material The online version of this article (10.1007/s10120-019-00945-9) contains supplementary material, which is available to authorized users.

Germline mutations in hereditary predisposition genes to cancer account for about 5–10% of all diagnosed cases of breast cancer. The loss of function of about 30 different genes presents a clear correlation with patterns of heredity, i.e., individuals with germ mutation in one of these genes are more likely to develop breast cancer, as well as other types of cancer throughout their lives, in comparison with the general population. These mutation-bearing patients have what is called hereditary breast cancer. Currently, the identification of individuals with these genetic alterations is fundamental, as it can not only be extremely useful for guiding the clinical-surgical treatment of patients affected by neoplasias, but it can also guide personalized prevention and risk-reduction strategies for asymptomatic patients who are part of the same family. It is important to note that, once a proband mutation is identified in the test, there is a 50% chance that first-degree relatives (children, siblings, and parents) have this mutation and are at increased risk of developing cancer. Further, distant relatives may also have this genetic variant and therefore, this risk should be evaluated individually.

Background Genetic anticipation, the earlier onset of disease in successive generations, has been reported in hereditary breast and ovarian cancer syndrome (HBOC), but little is known about its underlying mechanisms. Ascertainment bias has been suggested as a reason in previous studies. Likewise, cohort effect, which may be caused by environmental factors, can be misinterpreted as genetic anticipation. Methods The authors reviewed the pedigrees of 176 kindreds, segregating those with deleterious mutations in breast cancer genes 1 and 2 (BRCA1/BRCA2) who had at least 2 consecutive generations of the same cancer (breast or ovarian). By using mutation probabilities as analytical weights in weighted random-effect models, generational differences in the age at onset of breast/ovarian cancer were calculated. The analyses were further controlled for ascertainment bias by excluding probands and adjusting for birth-cohort effect in the anticipation models. Results The mean age at the onset of breast cancer for the probands' generation was 41.9 years, which was 6.8 years and 9.8 years earlier than the parents' and grandparents' generations, respectively. The anticipation effect for breast cancer remained significant after excluding the probands. There was a birth-cohort effect: patients who were born in 1930s and 1940s had breast cancer 5.0 years and 7.6 years earlier than patients who were born before 1920. The difference in breast cancer age of onset across generations was no longer significant after adjusting for birth-cohort effect. Conclusions The observed anticipation effect was driven mainly by a decrease in age of onset across birth cohorts, underscoring the need for risk-reducing interventions that target changing environmental/lifestyle factors in BRCA1/BRCA2 carriers. Cancer 2016;122:1913-20. © 2016 American Cancer Society.

e16749 Background: Pancreatic cancer has the prospect of becoming the second leading cause of cancer death by 2030. The NCCN Guidelines recommend genetic testing for all patients with pancreatic cancer, however, the spectrum of germline mutations has not been extensively evaluated because recent studies with genetic testing have explored only a limited number of genes and have focused predominantly on Caucasian populations. Therefore, our objective is to evaluate the frequency and spectrum of germline mutations in unselected patients with pancreatic cancer in a multiethnic population. Methods: Patients from Instituto do Câncer do Estado de São Paulo (Brazil) with histopathological diagnosis of non-endocrine pancreatic carcinoma were included, regardless of the family history of cancer. These patients answered a life habits and family history of cancer questionnaire and supplied blood for the Next Generation Sequencing (MiSeq platform) with the TruSight Hereditary Cancer panel (Illumina), which includes 115 cancer predisposing genes. Variant analysis was performed with the VarStation, a Brazilian tool that offers post-sequencing computational support and aid for clinical interpretation. Results: To the present moment, 77 patients were evaluated. The mean age of the patients was 62 years (27-83), among whom, 13% with young age (≤50 years) and 47 women (61%). Thirty-eight patients (49%) reported cases of cancer in first-degree relatives. Regarding risk factors, 41 patients (53%) reported smoking, 19 (25%) alcohol ingestion and 20 (26%) had obesity. Seven out of 77 patients presented pathogenic variants in ATM (n = 2) , CHEK2, FANCM (n = 2) or PALB2 (n = 2) genes. Two of these patients ( CHEK2 and FANCM) had early onset pancreatic cancer (≤45 years), both denied smoking habit and family history of cancer in 1st degree relatives. Two patients, who were ATM mutation carriers, reported 1st or 2nd degree relatives with cancer and are alive after 4 and 8 years of diagnosis. Conclusions: In this unselected group of pancreatic cancer patients, 15% were young, almost half reported first-degree relatives with cancer and 9% were carriers of pathogenic variants in genes related with the homologous recombination DNA repair.

Hereditary diffuse gastric cancer (GC) is a syndrome with autosomal dominant inheritance related to germline mutations in the CDH1 gene (CDH1-calcium-dependent adhesion protein) leading to changes in the expression of the E-cadherin protein. This syndrome has a high cumulative lifetime risk of developing diffuse gastric and lobular breast carcinomas. Patients who meet the clinical criteria for the syndrome and their relatives should be tested. When a genetic test is positive for a pathogenic variant, the patient should be strongly advised to consider prophylactic gastrectomy. Total gastrectomy for these patients dramatically reduces their risk of GC development. For mutation carriers for whom surgery is not an option, annual standardized endoscopic surveillance is recommended, but it is not as effective as prophylactic gastrectomy. Breast cancer screening is recommended starting at 30 years of age with annual breast magnetic resonance imaging. Prophylactic mastectomy is not routinely recommended, and surgical management should be discussed on a case-by-case basis depending on family history.

OBJECTIVES: Survival data for young adults (YA) with gastric cancer is conflicting and scarce in Brazil. The aim of this study was to compare the clinicopathological factors and survival rates of younger and older patients with gastric cancer. METHODS: Hospital registries for 294 gastric cancer patients from a reference cancer hospital in São Paulo, Brazil, were consulted for the retrieval of clinicopathological information and follow-up time. Patients were placed into the following groups: YA (≤40 years; N=71), older adult (OA: 41 to 65 years; N=129) and elderly (E: ≥66 years; N=94). Differences were assessed through Pearson’s χ2 test, Kaplan-Meier analysis, Log rank test and Cox regression. RESULTS: More YA were diagnosed with advanced disease (clinical stage III/IV: 86.7% YA, 69.9% OA, and 67% E); however, fewer E patients underwent surgery (64.3% YA, 72.7% OA, and 52.4% E). The median overall survival among all patients was 16 months, and the overall survival rate was not significantly different among the age groups (p=0.129). There were no significant differences in the disease-free survival rate. Metastatic disease at diagnosis (HR=4.84; p

Adenocarcinoma of the seminal vesicle is a rare condition, with fewer than 60 cases described in the literature. Most reports highlight the histopathological characteristics of the tumor; however, the role of chemotherapy, especially in the metastatic setting, is poorly described. In this paper, we describe a patient with metastatic disease, who sustained a response to modified FOLFOX6 as first-line therapy. This platinum-based combination therapy seems effective in this scenario and may provide an opportunity for extended survival and relief of symptoms.

e13610Background: Genetic diversity among populations in the spectrum and frequency of germline variants in BRCA1/2 genes has been well documented. It is unclear whether this extends to other breas...

e16042Background: Gastric cancer is a major health problem worldwide, especially in Brazil, where incidence rate is moderate-high. Although intestinal type of gastric cancer is clearly associated w...

Purpose: To develop a novel approach for early detection of breast cancer and examine molecular features of screen detected cancers in prospectively ascertained high-risk women undergoing semi-annual dynamic contrast-enhanced breast magnetic resonance imaging (DCE-MRI) for women at high genetic risk. Background: Women with a personal or family history of breast cancer and genetic mutation carriers of BRCA1 and BRCA2 have a higher than normal risk of breast cancer. An intensified screening surveillance regimen is an early detection strategy in high-risk women. The American Cancer Society recommends annual DCE-MRI in addition to annual mammogram based off several pivotal screening studies that demonstrated improved sensitivity and cancer detection rates and decreased interval cancer rates with the addition of annual DCE-MRI. Questions remain regarding the optimal screening modality and interval regimen in these high-risk women. Methods: Between 2004 and 2016, we assembled a prospective cohort of high-risk women undergoing semi-annual DCE-MRI and annual mammography. To be eligible, women had a lifetime breast cancer risk >20% and/or tested positive for a pathogenic mutation using a cancer gene panel including BRCA1, BRCA2, CDH1, PALB2, CHEK2 and other cancer susceptibility genes in the DNA repair pathway. Somatic mutation events in screen-detected tumors were investigated using UW-OncoPlex cancer gene panel using DNA extracted from FFPE shavings. Results: 295 women were recruited to the study; 44% of the study participants had pathogenic mutations in BRCA1 or BRCA2 genes. At a median follow-up of 3.3 years (range 0-12 years), 3 DCIS and 13 early stage invasive breast cancers were detected, of which 14 occurred in subjects with identifiable pathogenic mutations (11 BRCA1, 2 BRCA2, 1 CDH1). The incidence rate is 1.3% in all subjects, but 3.5 % per year in BRCA1 carriers. DCE-MRI identified all 13 invasive cancers at a mean size of 0.61 cm (range 0.1-1.0 cm); none had lymph node metastasis. No interval cancers occurred. In addition, 7 of the breast cancers were detected on DCE-MRI imaging obtained at the 6 months screening interval; they would be interval cancers if only annual screening were implemented. There was very little DNA for somatic mutation testing in the majority of cases. However, as expected, there was heterogeneity in the spectrum of mutations but the most commonly somatically mutated gene in the early cancers was TP53. Conclusions: DCE-MRI every 6 months performed well for early detection of invasive breast cancer in high-risk women, accomplishing the ultimate goal of breast cancer screening—detecting node-negative, invasive tumors less than 1 cm. Semi-annual DCE-MRI performed especially well in BRCA1 mutation carriers at risk for the most aggressive subtype of breast cancer. Further interventional studies evaluating this novel screening approach are warranted to personalize breast cancer risk assessment and prevention. Citation Format: Whitaker K, Guindalini R, Abe H, Sheeth D, Huo D, Hong S, Churpek J, Verp M, Obeid E, Zheng Y, Amico A, Yoshimatsu T, Olopade O. Breast cancer surveillance in high-risk women with dynamic contrast-enhanced magnetic resonance imaging every 6 months: Results from a single institution study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-02-10.

Background & Aims African Americans (AAs) have the highest incidence of and mortality resulting from colorectal cancer (CRC) in the United States. Few data are available on genetic and nongenetic risk factors for CRC among AAs. Little is known about cancer risks and mutations in mismatch repair (MMR) genes in AAs with the most common inherited CRC condition, Lynch syndrome. We aimed to characterize phenotype, mutation spectrum, and risk of CRC in AAs with Lynch syndrome. Methods We performed a retrospective study of AAs with mutations in MMR genes ( MLH1 , MSH2 , MSH6 , and PMS2 ) using databases from 13 US referral centers. We analyzed data on personal and family histories of cancer. Modified segregation analysis conditioned on ascertainment criteria was used to estimate age- and sex-specific CRC cumulative risk, studying members of the mutation-carrying families. Results We identified 51 AA families with deleterious mutations that disrupt function of the MMR gene product: 31 in MLH1 (61%), 11 in MSH2 (21%), 3 in MSH6 (6%), and 6 in PMS2 (12%); 8 mutations were detected in more than 1 individual, and 11 have not been previously reported. In the 920 members of the 51 families with deleterious mutations, the cumulative risks of CRC at 80 years of age were estimated to be 36.2% (95% confidence interval [CI], 10.5%–83.9%) for men and 29.7% (95% CI, 8.31%–76.1%) for women. CRC risk was significantly higher among individuals with mutations in MLH1 or MSH2 (hazard ratio, 13.9; 95% CI, 3.44–56.5). Conclusions We estimate the cumulative risk for CRC in AAs with MMR gene mutations to be similar to that of individuals of European descent with Lynch syndrome. Two-thirds of mutations were found in MLH1, some of which were found in multiple individuals and some that have not been previously reported. Differences in mutation spectrum are likely to reflect the genetic diversity of this population.

OBJETIVO: Avaliar provas de posicionamento da agulha de Veress no hipocôndrio esquerdo na criação do pneumoperitônio. MÉTODO: Em cem pacientes puncionados no hipocôndrio esquerdo, provas de posicionamento da agulha foram avaliadas, considerando-as positivas quando, na prova da aspiração (PA), material orgânico era aspirado; na prova da resistência (PRes), exercia-se pequena força no êmbolo da seringa à infusão de líquido; na prova da recuperação (PRec), não se recobrava o líquido infundido; na do gotejamento (PG), as gotas escoavam rapidamente e, na prova da pressão intraperitoneal inicial (PPII), os níveis eram = 8mmHg. PA positiva denunciava iatrogenia, enquanto que PRes, PRec, PG e PPII positivas indicavam que a ponta da agulha estava adequadamente posicionada na cavidade peritoneal. Foram calculadas a sensibilidade (S) e a especificidade (E) das provas, e os seus valores preditivos positivos (VPP) e negativos (VPN), mediante correlação dos resultados verdadeiro-positivos (a), falso-positivos (b), falso negativos (c) e verdadeiro-negativos (d), segundo as fórmulas: S=[a/(a+c)]x100; E=[d/(b+d)]x100; VPP=[a/(a+b)]x100; VPN=[d(c+d)]x100. RESULTADOS: Na PA, constatou-se que S e VPP não puderam ser aplicados, e E=100% e VPN=100%. Na PRes, S=0%, E=100%, VPP=não existiu e VPN=90%. Tanto na PRec quanto na PG, S=50%, E=100%, VPP=100% e VPN=94,7%. Na PPII, obteve-se que S, E, VPP e VPN=100%. CONCLUSÕES: Na punção no hipocôndrio esquerdo, PA negativa garante ausência de lesões; a PRes é insegura quanto ao mau posicionamento da agulha, mas indica corretamente o bom; a PRec e a PG não reconhecem bem o adequado posicionamento, mas detectam com segurança o inadequado; a PPII acusa com segurança tanto o mau quanto o bom posicionamento da agulha, sendo a prova mais confiável dentre as estudadas. BACKGROUND: To evaluate tests for Veress needle tip placement intraperitoneally in the left hypochondrium for creating a pneumoperitoneum. METHODS: Needle tip placement tests were evaluated in one hundred patients using the left hypochondrium area. It was considered positive when: aspiration test (PA) -returned organic material; resistance test (PRes) - a low pressure was pushed on the syringe for the liquid infusion; recovery test (PRec) - no liquid was recovered after infusion; dripping test (PG) - drops drained quickly; test for initial intraperitoneal pressure (PPII) - levels were

PURPOSE: To test the efficacy of the puncture in the left hypochondrium as an alternative method. METHODS: Sixty-two patients randomly distributed into two groups were studied: Group LH, puncture in the left hypochondrium (n=30), and Group ML, puncture in the abdominal midline (n=32). The following were assessed: needle positioning tests, number of failed attempts at needle insertion, and time needed for creation of pneumoperitoneum. Gas flow, volume and intraperitoneal pressure were recorded at every 20 seconds, until a 12 mmHg pressure was reached inside the peritoneal cavity. RESULTS: A similar number of positive results for the needle positioning tests were observed in both groups. Two failed attempts to reach the peritoneal cavity were observed in Group ML and one in Group LH. The time necessary for the creation of pneumoperitoneum was on average 3 minutes and 46 seconds for Group LH, and 4 minutes and 2 seconds for Group ML. Average gas flow, volume and pressure were equivalent for both groups. CONCLUSION: Puncture in the left hypochondrium was as effective as puncture in the abdominal midline for the creation of pneumoperitoneum. OBJETIVO: Avaliar a eficácia e segurança da punção alternativa no hipocôndrio esquerdo. MÉTODOS: Sessenta e dois pacientes distribuídos aleatoriamente em dois grupos foram estudados prospectivamente: grupo HE, punção no hipocôndrio esquerdo (n=30) e grupo LM, punção na linha média do abdome (n=32). Foram avaliados os testes de posicionamento da agulha, o número de tentativas frustradas e a duração da instalação do pneumoperitônio. Os fluxos correntes, as pressões intraperitoneais e os volumes injetados foram registrados a cada 20 segundos, até 12 mmHg. RESULTADOS: O número de resultados positivos aos testes de posicionamento da agulha foi semelhante em ambos os grupos. Ocorreram duas tentativas infrutíferas de punção no grupo LM e uma no grupo HE. O tempo necessário para o estabelecimento do pneumoperitônio foi, em média, 3 minutos e 46 segundos para o Grupo HE e 4 minutos e 2 segundos para o grupo LM. As médias dos fluxos, das pressões e dos volumes foram respectivamente equivalentes entre os grupos.. CONCLUSÃO: A punção no HE foi tão eficaz no estabelecimento do pneumoperitônio quanto a punção na LM do abdome.

1572 Background: The rising global burden of breast cancer (BC) in developing countries demands innovative interventions to accelerate progress in cancer control and prevention. Given the high rates of aggressive young onset breast cancer in Brazil, we sought to examine genetic susceptibility to the disease in the State of Bahia in the Northeast of Brazil, which has the largest population of African descendants. Methods: We screened cases, high-risk breast cancer patients with and without family history of breast cancer, and controls (cancer-free women) for twenty-eight breast cancer susceptibility genes using a validated targeted capture and multiplex sequencing approach – the BROCA panel. Each participant gave informed consent under IRB approved protocols and provided clinical-pathological and epidemiological data. Results: A total of 292 consecutive and unrelated individuals (173 cases and 119 controls) were included. Nearly 2/3rds of the cases (116/173) and about 90% of the controls (108/119) self-reported as African-descendant. Mutations considered pathogenic were identified in 37 (21.4%) cases and in one control (0.84%, RAD51C c.266insA), OR = 27.75 and p = 0.008. The mutated genes in cases were BRCA1 (in 12 patients), BRCA2 (10), ATM (3), PALB2 (3), BRIP1 (3), BRCA2/ BARD1 (1), FAM175A (1), FANCM (1), NBN (1), SLX4 (1) and TP53 (1). Three recurrent mutations accounted for 12.4% (9/37) of the total: 3 BRCA1 c.3331_3334delCAAG (known European mutation), 3 BRCA1 c.211A > G (known Galician mutation), and 3 PALB2c.1671_1674delTATT (novel mutation). Conclusions: Mutations in BRCA1 and BRCA2 (64.85%) or another breast cancer gene (35.15%) occur in one in five high-risk breast cancer patients in the largest study of Northeastern Brazil to date, and a significant proportion were recurrent mutations of European origin, which can be explained by the admixture pattern of the Brazilian population. This result underscores the importance of using multigene panel in cancer genetic epidemiologic research of understudied populations where unexpected findings, such as the recurrent and novel variant in PALB2 c.1671_1674delTATT, can be detected.

Survivin, a member of the inhibitor of apoptosis protein family, is one of the most cancer-specific proteins identified to date. Survivin expression is low or undetectable in most adult tissues, but, alternatively, is overexpressed in a large number of tumors. This multifunctional protein is recognized as a key regulator in apoptosis, proliferation and angiogenesis in the tumor environment. Several studies have shown a correlation between survivin upregulation and poor cancer prognosis, and, as expected, its downregulation or inactivation leads to inhibition of tumor growth. Therefore, survivin has attracted increasing attention both as a potential cancer biomarker and as a new target for anticancer therapies. This review summarizes and discusses survivin expression and its potential as a prognostic and diagnostic biomarker in different types of tumors, as well as provides an overview of the current therapeutic challenges of targeting survivin as a treatment strategy.

Resistance to trastuzumab, either primary/de novo resistance or acquired/treatment-induced resistance, is a major clinical concern facing breast oncologists today.1 Here, we describe two cases of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) with a mucin-producing component that were presumably resistant to trastuzumab.

e12535 Background: Although hereditary diffuse gastric cancer syndrome is a rare condition its contribution to gastric cancer burden in Brazil is unknown. The aim of this study was to examine the f...

OBJETIVO: Avaliar a possibilidade do estabelecimento de parâmetros fidedignos do adequado posicionamento da ponta da agulha de Veress no interior da cavidade peritoneal durante o estabelecimento do pneumoperitônio. MÉTODO: Em 100 pacientes selecionados a ponta da agulha de Veress foi introduzida na cavidade peritoneal e o insuflador foi programado para fluxo de 1,2L/min e pressão máxima final para 12mmHg. No início da insuflação e a cada 20 segundos a pressão intraperitoneal (PI) e o total do volume injetado até aquele momento (TVI) eram registrados. Os dados foram tratados por correlações estatísticas entre momentos e PI, e momentos e TVI. Também foi estabelecida a previsão dos valores de PI e TVI no final de cada um dos quatro primeiros minutos de insulflação, utilizando-se os modelo estimados: PI = 2,3083 + 0,0266 x tempo + 8,3x10-5 x tempo³ - 2,44x10-7 x tempo³ ; TVI = 0,813 + 0,0157 x tempo. RESULTADOS: A PI e o TVI mostraram correlação entre momentos pré-estabelecidos da criação do pneumoperitônio, sendo constatado um ajuste forte: PI = -2E - 07 x tempo³ + 8E - 05 x tempo² + 0,0266 x tempo + 2,3083, com coeficiente de explicação (R2) = 0,8011; TVI = 0,0157 x tempo + 0,1813, com R2 = 0,9604. A previsão de PI e TVI mostrou: PI(mmHg): 1min=4,15; 2min=6,27; 3min=8,36; 4min=10,10 e TVI(L): 1min=1,12; 2min=2,07; 3min=3,01; 4min=3,95. CONCLUSÕES: Parâmetros fidedignos para PI e TVI , quando a ponta da agullha de Veress se encontra na cavidade peritoneal, em dados momentos da insuflação podem ser estabelecidos durante a criação do penumoperitônio.

PURPOSE: Erroneous punctures and insufflations are frequent with the use of the Veress needle. Mistaken injections of gas in the preperitoneal space are not rare. The purpose of this research is to evaluate the correct positioning of the tip of the needle during creation of pneumoperitoneum. METHODS: The needle was inserted into the peritoneal cavity. Tests to assess the positioning of the needle tip were carried out. Pressure, flow rate and volume were periodically recorded and the needle was removed, being immediately reinserted into the right hypochondrium and placed in the preperitoneal space. RESULTS: The liquid flow test was always positive in the peritoneal cavity. No resistance to saline injection into the peritoneal cavity was observed, but increased resistance to saline injection into the preperitoneal space was observed in 45.5% of the cases. Some saline was recovered in 63.5% of the cases in the peritoneal cavity, and in 54.5% in the preperitoneal space. Saline drop test was positive in 66.6% of the cases in the peritoneal cavity and in 45.5% in the preperitoneal space. In the peritoneal cavity, initial pressure lower than 5 mm Hg was observed, and this pressure gradually increased during 123 seconds until reaching 15 mm Hg. In the preperitoneal space, initial pressure was 15 mm Hg. CONCLUSIONS: Aspiration, liquid flow and saline drop tests are important, whereas recovery test is inconclusive. Initial pressure of approximately 5 mm Hg indicates that the tip of the needle is in the peritoneal cavity. The peritoneal cavity should hold ten times as much volume of gas as the preperitoneal space. The increase in pressure and volume in the peritoneal cavity can be predicted by statistics.

OBJETIVO: Estabelecer parâmetros fidedignos do posicionamento adequado da agulha de Veress na cavidade peritoneal durante o estabelecimento do pneumoperitônio pela técnica fechada. MÉTODO: Em 11 porcos a agulha foi introduzida na cavidade peritoneal através do hipocôndrio esquerdo. Provas de posicionamento da ponta do instrumento foram efetuadas. Insuflou-se CO2 e registraram-se periodicamente pressões, fluxos e volumes. A posição intraperitoneal da agulha foi confirmada e esta foi retirada, sendo re-introduzida no hipocôndrio direito e posicionada sob visão direta no espaço pré-peritoneal. Os mesmos parâmetros foram aferidos. RESULTADOS: A prova do escoamento foi sempre positiva no peritônio. Não se encontrou resistência à introdução de soro no peritônio em nenhum caso, mas sim em 45,5% dos casos no pré-peritônio. Soro algum foi recuperado em 63,5% no peritônio e em 54,5% no pré-peritônio. O gotejamento fluiu livremente em 66,6% das vezes no peritônio e em 45,5% dos casos no préperitônio. No peritônio, pressões iniciais de 5,20 mmHg aumentaram progressivamente durante 123 segundos até atingir 15 mmHg. No pré-peritônio a pressão inicial foi de 15,60 mmHg e oscilou entre 12 e 15,60 mmHg. O volume de gás injetado no peritônio foi de 1500 ml e de 100 ml no pré-peritônio. CONCLUSÕES: Aspiração e observação do escoamento e do gotejamento são importantes; recuperar ou não o soro é inconclusivo. Pressão inicial menor ou igual a 5 mmHg é indicativo da ponta da agulha no peritônio, onde devem caber dez vezes mais gás que no pré-peritônio. No peritônio os aumentos das pressões e dos volumes pode ser previstos mediante estatísticas. BACKGROUND: To establish reliable evidence regarding the adequate positioning of the tip of a Veress needle in the interior of the peritoneal sac during the establishment of the pneumoperitoneum by the closed technique. METHODS: In 11 pigs, the needle was introduced in the peritoneal sac through the left hipocondrium. Tests of positioning of the tip of the instrument were carried out. Gas (CO2) was injected, and pressures, flows and volumes were registered periodically. The correct intraperitoneal position of the needle was confirmed and, subsequently, removed, being reintroduced in the right hipocondrium and placed under direct vision in the pre-peritoneal space. The same parameters were surveyed. RESULTS: The test of the draining was always positive in the peritoneum. Resistance to the infusion of serum in the peritoneal sac was not observed, but resistance was detected on 45.5% of cases in the pre-peritoneal space. Some serum was recouped in 63.5% of cases in the peritoneal sac and in 54.5% in the pre-peritoneal space. The dripping flowed freely in 66.6% of cases in the peritoneal sac and in 45.5% in the pre-peritoneal space. In the peritoneal sac, = 5mmHg initial pressure increased gradually during 120 seconds until reaching 15 mmHg. In the pre-peritoneal space, the initial pressure was of 15mmHg and oscillated between 12 and 15mmHg. The volume of gas injected was of 1500 ml in the peritoneal sac and of 100 ml in the pre-peritoneal space. CONCLUSION: Initial pressure of ±5mmHg is indicative of the tip of the needle being placed in the peritoneal sac, inside of which there should fit ten times more gas than in the pre-peritoneal space. When the tip of the Veress needle is placed in the interior of the peritoneal sac, the increase of intraperitoneal pressures and volumes can be predicted by statistics.

1550 Background: Although genetic anticipation has been reported in hereditary breast and ovarian cancer syndrome (HBOCS), little is understood about the underlying genetic and molecular mechanisms for BRCA1/2 families. Two previously unaddressed biases affecting the accuracy of previous studies are ascertainment bias and cohort effect. Methods: We retrospectively reviewed 178 pedigrees of BRCA1/2 families who had at least two consecutive generations of the same cancer (breast or ovarian) in our Cancer Risk Clinic registry. Using paired t-test and BRCAPRO scores as analytical weights in a parametric anticipation model, the calculation of generational differences in breast/ovarian cancer age of onset was performed. This model was then modified to control for ascertainment bias by excluding probands. Multilevel linear regression using breast cancer age of onset, birth year cohort, and generation was applied to study potential cohort effect. Results: Earlier onset of breast cancer and ovarian cancer in succe...

11021 Background: PTK6 gene on chromosome 20q13 encodes the intracellular non-receptor tyrosine kinase. Studies in vivo and in vitro revealed a role for PTK6 in cell proliferation and survival, particularly in HER2+ breast cancer cells suggesting that PTK6 may associate with the HER2 pathway and confer resistance to HER2-targeted therapy. PTK6 protein is frequently overexpressed in breast cancer, however, the mechanism(s) underlying PTK6 overexpression and its role in cancer remains unclear. To address this problem, we analyzed the frequency of PTK6 gene copy number variation (CNV) and expression in association with breast cancer subtypes. Methods: Retrospectiveparaffinsamples of invasive tumor and normal epithelium, and matching DCIS and metastases were mounted on TMA. PTK6 CNV was determined using PTK6:CEP20 FISH assay. Tumor subtypes were defined using the five-marker IHC classifier. The correlation between PTK6 CNV and mRNA expression and association of both with the intrinsic PAM50 tumor subtype were studied using TCGA database (547 cases) and publicly available seven breast cancer data sets (1005 cases). Data were normalized, gene median centered and standardized for the purpose of the study. Results: By FISH, 20% of 41 invasive tumors carried PTK6 CNV: amplification (10%) and gene polysomy (10%). The proportion of PTK6 amplified cases differed by subtype, with the largest proportion in HER2-enriched (17%) and LumB (14%). Strikingly, amplified invasive cases also showed amplification in matching DCIS and metastases. Analysis of the public datasets confirmed the frequent PTK6 amplification in breast cancer. Both low and high levels of amplification were detected with the largest proportion in HER2+ tumors (HER2-enriched and LumB; p=2.05e-26). None of the basal-like tumors showed high levels of PTK6 amplification. A high correlation between PTK6 gene copies and mRNA expression was observed (p=1.13e-08). Conclusions: PTK6 gene is amplified early in breast cancer progression, particularly in HER2+ tumors. Further studies on PTK6 biology may help clinicians to understand its potential role in HER2 resistance. Supported by BREAST CANCER SPORE, NCI K12CA139160 and CTSA-ITM CS UL1 RR024999.

11084 Background: High recall rate and unnecessary biopsies are a concern with screening mammogram (MMG) and magnetic resonance imaging (MRI) in young women at high risk for breast cancer. The aim of this study is to investigate the overall recall rate (ORR) and its consequences in a semi-annual MRI surveillance protocol. Methods: A multi-modality surveillance program for women at high-risk for breast cancer was initiated in 2004. Yearly MMG was supplemented with semi-annual MRI. After 5 years of this protocol, an additional 5 years of follow-up with yearly MMG and MRI were offered only to mutation carriers. Defining positive screening as BIRADS 0, 4 and 5, ORR were analyzed and biopsies findings characterized. Fisher’s exact test was performed to evaluate association between the effect of MMG density, menopausal status, mutation status, age ( 50y), and previous breast cancer with recalls. Results: With a mean follow-up of 3.6 years, 226 patients (pts) underwent 1,467 MRI and 851 MMG. Among 56 abnormal MRI and 18 abnormal MMG, 62 pts (27%) were recalled for further tests (6 recalled at two screening episodes). The MRI and MMG ORR were 3.8% and 2.1%, respectively. Only six cases (8.8%) were abnormal for both tests. Overall, 50 additional breast ultrasound, 10 additional MMG, 8 additional MRI were performed. Of the 40 biopsies in 38 pts (2 pts were biopsied twice), 11 cancers were detected (ductal in situ: 3; invasive: 7 ductal and 1 lobular). Abnormal MRI findings led to 37 biopsies, of which 10 (27%) detected cancers. One high-grade ductal carcinoma in situ was exclusively detected by MMG. The first and second MRI screening rounds together showed 27/56 (66%) abnormal findings which led to 23/40 (58%) of the biopsies, and detected 5/11 (45%) of the tumors. No statistically significant predictors of recall were identified (p < 0.05). Conclusions: Semi-Annual MRI protocol did not show increased ORR when compared to annual MRI/MMG surveillance. Approximately two-thirds of all recalls were in the first two rounds of screening which is consistent with previous results. Ongoing work will evaluate clinical and MRI features associated with recall to improve practice. Clinical trial information: NCT00989638.

1506 Background: Surveillance with mammography (MMG) and magnetic resonance imaging (MRI) is recommended for women at high-risk for breast cancer, but there is no consensus on screening strategy. Aim of this study was to evaluate the efficacy of semi-annual MRI in high-risk women. Methods: A multi-modality surveillance program was initiated in 2004. Yearly MMG was supplemented with semi-annual MRI. After 5 years, an additional 5 years of follow-up with yearly MMG and MRI was offered to mutation carriers. Defining positive screening as BIRADS 0, 4 and 5, sensitivity, specificity, NPV, and PPV of semi-annual MRI were analyzed. Results: From 2004 to 2012, 226 patients underwent 1467 MRI and 851 MMG with a mean follow-up of 3.6 yrs. Median age at entry was 43 yrs (range 21-73), 48% were mutation carriers (105 BRCA1/2, 2 CDH1, 1 P53) and 19% had personal history of breast cancer. Eleven cancers were screen-detected, of which 6 (55%) were detected only by MRI, 1 (9%) only by MMG, and 4 (36%) by both. Of these tumors, 4 were detected in the first round of MMG/MRI screening and 7 (64%) in mutation carriers (5 BRCA1, 1 BRCA2, 1 CDH1), and 3 tumors (27%) were detected due to the additional MRI during semi-annual screening. No interval cancers occurred. Sensitivity, specificity, PPV and NPV of MRI were 91%, 97%, 18%, 99%, respectively. Of the incident cancers, 3 (27%) were stage 0 (ductal) and 8 (73%) were stage 1 (7 ductal and 1 lobular). Mean size of the invasive cancers was 0.78 cm (range 0.1-1.6; only 2 tumors > 1.0 cm), none had lymph node metastasis, and 75% were high grade and hormone receptor positive. The largest tumor detected was invasive lobular in a 73 year old CDH1mutation carrier. Conclusions: To our knowledge, this is the first surveillance protocol with repeated screening rounds that detected mean size of invasive tumors less than 1 cm. Absence of interval cancers, high sensitivity/specificity, and detection of all tumors in early stages (stages 0 or 1) support this screening strategy as a viable alternative to prophylactic mastectomy. Ongoing work will examine quality of life, cost effectiveness and impact on overall survival of this screening approach. Clinical trial information: NCT00989638.

1530 Background: Although African Americans (AA) have the highest colorectal cancer (CRC) incidence and mortality of all populations in the United States, no studies have determined cancer risk and mismatch repair (MMR) genes mutation spectrum in LS patients of AA ancestry and the contribution of this syndrome to cancer disparities. Thus, the aims of this study are: (1) to describe LS cancers in AAs; (2) to investigate the mismatch repair (MMR) gene mutation spectrum in AA families with LS; (3) to determine how Amsterdam II criteria, revised Bethesda guideline, and PREMM(1,2,6) model perform for predicting MMR gene mutations in this population. Methods: Pedigrees of AA families with deleterious mutation or suspected deleterious mutation in MMR genes from five US referral centers were analyzed for personal and familial clinical cancer histories. Results: Twenty-four AA families were identified, of which 22 had deleterious mutations (15 MLH1, 4 MSH2, 2 MSH6, 1 PMS2) and 2 had suspected deleterious mutations (1 MLH1, 1 MSH2). Three recurrent mutation were found in MLH1(677G>A, IVS1-2A>G, IVS4-1G>A), accounting for 25% of all mutations. Of 24 probands, 58% were female and 96% had personal history of cancer. The median age at first primary tumor was 42yrs (range 28-57) and 50% developed more than 1 primary tumor. The majority of probands (79%) had CRC (median age of onset – 42yrs [range 31-61]), of which 26% had at least 2 CRC primaries. Endometrial cancer developed in 50% of the women (median age of onset – 51yrs [range 32-57]). Amsterdam II and Bethesda criteria were met in 63% and 88% of the individuals, respectively. Median score by PREMM(1,2,6) model was 54% (range 12.9-99.8). Conclusions: To our knowledge, this is the largest series of AA families with LS reported to date. Earlier age of onset for CRC at 42yrs (previously reported ~45 yrs) is suggested. The majority of mutations were found in MLH1 (67%), including three recurrent mutations. A 10% cutoff for PREMM(1,2,6) predictive model identified all mutation carriers. Larger studies are warranted to confirm the differences observed in age of CRC onset in this population.

2038 Background: Pilocytic astrocytoma (PA) accounts for up to 25% of all brain tumors in children. A 75% progression-free survival rate at 5 years and overall survival rates of 95.8% at 10 years have been reported after a complete resection. However, the incidence in adults is low and the outcome less well characterized. We conducted a retrospective analysis of adult PAs identified in order to review the clinical characteristics and outcome of this neoplasm in this age group. Methods: A descriptive, cross-sectional study was undertaken in patients over 16 y.o., diagnosed with PA between January 1990 and December 2010 at our center. Clinical characteristics, date and extent of surgery, tumor location, postoperative treatment, complications and recurrences were collected from hospital records. Results: From May, 1990 to December, 2010, 18 eligible adult patients (pts) with the diagnosis of PA were identified. Median age was 25,5 (16-52) years, 72,2% female and 83,3% had an ECOG performance status ≤ 2. The most frequent tumor sites were the cerebellum (44,4%), followed by the cerebral hemispheres (38%). All patients underwent surgery as primary treatment, 72% had a complete macroscopic resection (CMR) and 28% had a partial resection (PR). Two patients received postoperative radiotherapy: one following a PR and the other after tumor relapse following a CMR. Two patients relapsed five months and 44 months after initial complete gross resection. Salvage surgery achieved CMR in both. With a median follow-up of 89 months, all patients are alive, except for one who died in the postoperative period due to fungal meningitis. Of note, none of 5 pts undergoing a partial resection progressed and 3 are alive for more than 10 years. Conclusions: As it occurs in the pediatric population, PA in adults seems to carry a similarly favorable prognosis. It is conceivable that after initial surgical resection a watch and wait type of approach is appropriate, even following partial resection. The role of upfront radiotherapy is uncertain and it should probably be left for progressive tumors.

e12547 Background: Pineal germ cell tumors are very rare, accounting for less than 1% of all intracranial tumors. The peak incidence occurs in the second decade of life. The mainstay of therapy is ...

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.