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The standard treatment approach for stage II/III rectal cancer is neoadjuvant chemoradiation therapy (nCRT) followed by surgery. In recent years, new treatment approaches have led to higher rates of complete tumor eradication combined with organ-preservation strategies. However, better tools are still needed to personalize therapy for the individual patient. In this prospective observational study, we analyzed colon-derived cell-free (cf)DNA (c-cfDNA) using a tissue-specific DNA methylation signature, and its association with therapy outcomes. Analyzing plasma samples (n = 303) collected during nCRT from 37 patients with locally advanced rectal cancer (LARC), we identified colon-specific methylation markers that discriminated healthy individuals from patients with untreated LARC (area under the curve, 0.81; 95% confidence interval, 0.70-0.92; P 0.0001). Baseline c-cfDNA predicted tumor response, with increased levels linked to larger residual cancer. c-cfDNA measured after the first week of therapy identified patients with maximal response and complete cancer eradication, who had significantly lower c-cfDNA compared with those who had residual disease (8.6 vs 57.7 average copies/mL, respectively; P = 0.013). Increased c-cfDNA after one week of therapy was also associated with disease recurrence. Methylation-based liquid biopsy can predict nCRT outcomes and facilitate patient selection for escalation and de-escalation strategies.

Summary Inhibition of histone deacetylases (HDACs) and subsequent hyperacetylation of histone proteins lead to altered gene expression associated with therapeutic drug effects, but also with teratogenicity. The only US Food and Drug Administration (FDA)–approved antiepileptic drug that has been consistently shown to induce histone hyperacetylation is valproic acid. More recently, lacosamide was reported to interfere with histone modifications, but histone hyperacetylation was not demonstrated. In the current study we evaluated the effects of lacosamide on histone acetylation in vitro. MDA‐MB‐231 (triple‐negative breast cancer) cells and human placental BeWo cells were exposed for 16 hours to 5‐20 μg/ml (20‐80 μm) lacosamide. Histone acetylation was evaluated by western blot analysis. We additionally measured HDAC1 activity in the presence of lacosamide. At 5, 10, and 20 μg/ml, lacosamide enhanced histone acetylation in BeWo cells by 1.7‐fold (p > 0.05), 3.4‐fold (p 0.05), respectively. Histone H3 acetylation and total histones H3 and H4 levels were not significantly modified (p > 0.05). The magnitude of change in histone acetylation in MDA‐MB‐231 cells was smaller (p > 0.05). In contrast to valproic acid, lacosamide did not inhibit HDAC1. Our findings suggest that the effects of lacosamide on gene expression, and the related potential antitumor activity and teratogenicity, may differ from those of valproic acid.

Gene expression assays are widely used to predict risk of recurrence in early breast cancer (BC). We report the 21-gene expression assay (Oncotype Dx) recurrence score (RS) distribution of 27 BRCA carriers with estrogen receptor (ER) positive BCs, identified at Hadassah Medical Center, combined with 2 previous studies. Treatment decision and outcomes of the 27 BRCA carriers were compared with an Israeli cohort of 1594 patients published recently. We found Oncotype Dx RS low ( 30) among 12 (21.4%), 23 (41.1%) and 21 (37.5%) of 56 BRCA1 carriers compared with 15 (17.2%), 49 (56.3%) and 23 (26.4%) of 87 BRCA2 carriers (p=0.2). The corresponding distribution in a population of 82,434 women published by Genomic Health was 53.4%, 36.3% and 10.3% for low, intermediate and high RS (p< 0.001 for BRCA1 and BRCA2). Treatment decision regarding chemotherapy according to RS was similar in BRCA1, BRCA2 and the control group. Two of 27 carriers had distant recurrence: a BRCA1 carrier with RS of 18 and a BRCA2 carrier with RS of 22; both have an excellent response to chemotherapy. We found an approximately 3 fold increased rate of high RS among BRCA1 and 2 carriers with ER positive BC compared with the general BC population. These data might indicate that hormone positive BC in BRCA carriers are molecularly unique. The surprisingly good response to chemotherapy in the metastatic setting in 2 patients may suggest that the predictive value of low-intermediate RS in carriers merits further studies. This article is protected by copyright. All rights reserved.

Background Heterozygous germline mutations in any of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2, cause Lynch syndrome (LS), an autosomal dominant cancer predisposition syndrome conferring a high risk of colorectal, endometrial, and other cancers in adulthood. Offspring of couples where both spouses have LS have a 1:4 risk of inheriting biallelic MMR gene mutations. These cause constitutional MMR deficiency (CMMRD) syndrome, a severe recessively inherited cancer syndrome with a broad tumor spectrum including mainly hematological malignancies, brain tumors, and colon cancer in childhood and adolescence. Many CMMRD children also present with cafe au lait spots and axillary freckling mimicking neurofibromatosis type 1. Procedure We describe our experience in seven CMMRD families demonstrating the role and importance of founder mutations and consanguinity on its prevalence. Clinical presentations included brain tumors, colon cancer, lymphoma, and small bowel cancer. Results In children from two nonconsanguineous Ashkenazi Jewish (AJ) families, the common Ashkenazi founder mutations were detected; these were homozygous in one family and compound heterozygous in the other. In four consanguineous families of various ancestries, different homozygous mutations were identified. In a nonconsanguineous Caucasus/AJ family, lack of PMS2 was demonstrated in tumor and normal tissues; however, mutations were not identified. Conclusions CMMRD is rare, but, especially in areas where founder mutations for LS and consanguinity are common, pediatricians should be aware of it since they are the first to encounter these children. Early diagnosis will enable tailored cancer surveillance in the entire family and a discussion regarding prenatal genetic diagnosis.

Diagnosis of Lynch syndrome (LS) may be complex. Knowledge of mutation spectrum and founder mutations in specific populations facilitates the diagnostic process. Aim of the study is to describe genetic features of LS in the Israeli population and report novel and founder mutations. Patients were studied at high-risk clinics. Diagnostics followed a multi-step process, including tumor testing, gene analysis and testing for founder mutations. LS was defined by positive mutation testing. We diagnosed LS in 242 subjects from 113 families coming from different ethnicities. We identified 54 different mutations; 13 of them are novel. Sixty-seven (59%) families had mutations in MSH2, 20 (18%) in MSH6, 19 (17%) in MLH1 and 7 (6%) in PMS2; 27% of the MSH2 mutations were large deletions. Seven founder mutations were detected in 61/113 (54%) families. Constitutional mismatch repair deficiency (CMMR-D) was identified in five families. Gene distribution in the Israeli population is unique, with relatively high incidence of mutations in MSH2 and MSH6. The mutation spectrum is wide; however, 54% of cases are caused by one of seven founder mutations. CMMR-D occurs in the context of founder mutations and consanguinity. These features should guide the diagnostic process, risk estimation, and genetic counseling.

Objective To describe our 2-year experience with preimplantation genetic diagnosis (PGD) for carriers of mutations in the genes BRCA1 and BRCA2, the dilemmas incurred and the lessons learned. Methods We collected data on those carriers of BRCA1/2 mutations who applied for PGD counseling and who decided to proceed. We describe the PGD procedures that were conducted and their outcome. Results Ten carriers of BRCA1/2 mutations applied for PGD counseling, seven were healthy, and three were BC survivors. Eight women needed in vitro fertilization (IVF) because of coexisting infertility. After counseling, six opted for the procedure and five of them underwent PGD for the BRCA mutation. In one of these PGD, fluorescence in situhybridization (FISH) analysis for chromosomes 21, X and Y was also performed. Three women conceived, each in the first treatment attempt. One of them gave birth to twins, the second to a singleton and the third is currently pregnant. During the pregnancies, dilemmas concerning PGD confirmation were discussed. Conclusions PGD is an acceptable reproductive option for BRCA mutation carriers, especially for those who require IVF due to fertility problems. Discussion of this option should be carried out with sensitivity, taking into account the age of the woman, her health, fertility status and emotional state. Confirmatory prenatal diagnosis may not always be encouraged. Copyright © 2009 John Wiley & Sons, Ltd.

In 1994, a clinic for cancer risk counseling was opened at Hadassah University Hospital in Jerusalem. Most of the counselees have been women who had breast cancer and/or a relative with breast cancer. In order to evaluate the effect of this counseling on women's knowledge and perceptions regarding the risks for breast cancer, a questionnaire was given before and after the counseling session to 60 healthy women who came to the clinic because they have relatives with breast cancer. According to the genetic counselors' estimations, most of these women had a significantly increased risk (compared to the general population) of developing cancer. Before counseling, the women overestimated the population risk for breast cancer, the contribution of heredity to morbidity of cancer, and their own risks to get cancer. After counseling session, they gave reduced estimates, closer to the "real" ones. The subjective perceptions regarding these risks were reduced after counseling, except for the perceptions regarding their relativerisks which have not changed after the counseling. About 90% of the women who came to the clinic wanted to be tested for genetic predisposition to cancer. For most of these women, the expectations that the test can rule out a genetic predisposition to cancer became more realistic after the counseling. The option to first test an affected relative was offered to all families, and a test was actually conducted in 75% of the families.

Mediastinal and hilar lymphadenopathy secondary to gastrointestinal metastases rarely have been reported and have been considered to occur only in conjunction with lymphangitic lung spread. The current report is of 15 cases of hilar and mediastinal metastases secondary to pancreatic, gastric, and colonic primary tumors. In only three of these cases was lymphangitic lung involvement noted. Possible pathways of spread of these tumors to the mediastinal lymph nodes are discussed.