Common founder BRCA2 pathogenic variants and breast cancer characteristics in Ethiopian Jews.

PURPOSE: BRCA1/2 founder pathogenic variants (PVs) occur in various populations, but data on the mutational spectrum in Africans are limited. We examined BRCA1/2 PVs in breast cancer patients of Ethiopian Jewish (EJ) origin. METHODS: We retrospectively analyzed BRCA1/2 test results and clinical features of EJ breast cancer patients from seven medical institutions. We obtained heterozygote carrier rates in affected individuals from the laboratories of the largest Israeli HMO (Clalit). Population carrier frequency was determined in EJ controls. RESULTS: We identified three recurrent BRCA2 PVs in 11 EJ breast cancer patients (9 females, 2 males): c.7579delG, c.5159C > A, and c.9693delA. Only c.5159C > A was previously reported in Africans. In women, mean age at diagnosis was 35.7y; 8/9 were diagnosed with advanced disease. All tumors were invasive, 4/9 were triple negative. Only 3/11 carriers had relevant family history. Carrier rate in high-risk breast cancer patients was 11% (3/28; 95%CI [2.3%, 28.2%]). Combined carrier rate among controls was 1.8% (5/280; 95%CI [0.6%, 4.1%]). CONCLUSION: EJs harbor 3 recurrent BRCA2 PVs presenting with relatively severe breast cancer morbidity. Combined with the high BRCA2 carrier rate in the EJ population, these findings merit increasing awareness in this community and suggest that a culturally adapted population screening approach may be warranted.

Pazolimus: pazopanib plus sirolimus following progression on pazopanib, a retrospective case series analysis.

BACKGROUND: To explore the activity of pazopanib (P) + sirolimus (S) in patients who progressed after previous clinical benefit on pazopanib. METHODS: Eight patients with progressing metastatic high grade soft tissue sarcoma (STS) whose disease advanced on P following a response duration of at least 4 months were offered re-challenge of P supplemented by off-label S and a single patient with progressing metastatic chondrosarcoma was offered the combination as compassionate treatment. Patients were treated in two centers: Hadassah Medical Center and Tel Aviv Medical Center. Patients received oral P 200-600 mg once a day supplemented by S 3-4 mg taken separately, 12 h after the P dose. RESULTS: Patients received treatment from December 2012 to February 2016. Four progressed on the combination and their treatment was terminated. Two patients were undergoing treatment when data was summarized. Best Response Evaluation Criteria in Solid Tumour (RECIST) responses were: one partial response (PR), four stable disease (SD), and four progressive disease (PD), corresponding to five PR and four PD on the Choi criteria. Median progression free survival was 5.5 months (range 4-17). CONCLUSIONS: Our series showed that the combination of P + S has activity in STS patients selected by previous response to P and in a patient with chondrosarcoma, suggesting this can serve as a mechanism to reverse resistance to P and extend the chemotherapy-free window.

Post-directed-self-assembly membrane fabrication for in situ analysis of block copolymer structures.

Full characterization of the three-dimensional structures resulting from the directed self-assembly (DSA) of block copolymers (BCP) remains a difficult challenge. Transmission electron microscope (TEM) tomography and resonant soft x-ray scattering have emerged as powerful and complementary methods for through-film characterization; both techniques require samples to be prepared on specialized membrane substrates. Here we report a generalizable process to implement BCP DSA with density multiplication on silicon nitride membranes. A key feature of the process developed here is that it does not introduce any artefacts or damage to the polymer assemblies as DSA is performed prior to back-etched membrane formation. Because most research and applications of BCP lithography are based on silicon substrates, process variations introduced by implementing DSA on a silicon nitride/silicon stack versus silicon were identified and mitigated. Using full-wafers, membranes were fabricated with different sizes and layouts to enable both TEM and x-ray characterization. Finally, both techniques were used to characterize structures resulting from the DSA of lamella-forming BCP with density multiplication.

Messenger RNA encoding constitutively active Toll-like receptor 4 enhances effector functions of human T cells.

Adoptive T cell therapy of cancer employs a large number of ex-vivo-propagated T cells which recognize their targets either by virtue of their endogenous T cell receptor (TCR) or via genetic reprogramming. However, both cell-extrinsic and intrinsic mechanisms often diminish the in-vivo potency of these therapeutic T cells, limiting their clinical efficacy and broader use. Direct activation of human T cells by Toll-like receptor (TLR) ligands induces T cell survival and proliferation, boosts the production of proinflammatory cytokines and augments resistance to regulatory T cell (Treg) suppression. Removal of the TLR ligand-binding region results in constitutive signalling triggered by the remaining cytosolic Toll/interleukin-1 receptor (TIR) domain. The use of such TIR domains therefore offers an ideal means for equipping anti-tumour T cells with the arsenal of functional attributes required for improving current clinical protocols. Here we show that constitutively active (ca)TLR-4 can be expressed efficiently in human T cells using mRNA electroporation. The mere expression of caTLR-4 mRNA in polyclonal CD8 and CD4 T cells induced the production of interferon (IFN)-γ, triggered the surface expression of CD25, CD69 and 4-1BB and up-regulated a panel of cytokines and chemokines. In tumour-infiltrating lymphocytes prepared from melanoma patients, caTLR-4 induced robust IFN-γ secretion in all samples tested. Furthermore, caTLR-4 enhanced the anti-melanoma cytolytic activity of tumour-infiltrating lymphocytes and augmented the secretion of IFN-γ, tumour necrosis factor (TNF)-α and granulocyte-macrophage colony-stimulating factor (GM-CSF) for at least 4 days post-transfection. Our results demonstrate that caTLR-4 is capable of exerting multiple T cell-enhancing effects and can potentially be used as a genetic adjuvant in adoptive cell therapy.

Genetic features of Lynch syndrome in the Israeli population.

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.

Informal caregiving to older cancer patients: preliminary research outcomes and implications.

BACKGROUND: The population of the Western world is aging while cancer survival rates are rising. Older patients with cancer will increasingly be taken care of by informal family caregivers. The current study describes levels of psychological distress, social support and coping abilities reported by partners who are caregivers to older patients with cancer (60+ years), comparing them to a control group of spouses of similarly aged people not suffering from life-threatening illness. PATIENTS AND METHODS: Two hundred sixteen partners who are primary caregivers of cancer patients aged 60+ were compared with 76 partners of healthy people aged 60+ and never diagnosed with any terminal illness. Participants completed self-reporting measures on psychological distress, coping ability and social support. RESULTS: Caregivers to cancer patients reported high levels of distress, low levels of social support and low levels of coping abilities which are negatively correlated to distress. Increased patient age was found to accentuate these processes. CONCLUSION: Age and the progression of cancer as a chronic illness present the physician with the reality that focus of care should be on the dyad (patient and caregiver), with high priority given to partners who are informal caregivers.

The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals.

Since BRCA1, the first major gene responsible for inherited breast cancer, was cloned, more than 50 unique mutations have been detected in the germline of individuals with breast and ovarian cancer. In high-risk pedigrees, female carriers of BRCA1 mutations have an 80-90% lifetime risk of breast cancer, and a 40-50% risk of ovarian cancer. However, the mutation stats of individuals unselected for breast or ovarian cancer has not been determined, and it is not known whether mutations in such individuals confer the same risk of cancer as in individuals from the high-risk families studied so far. Following the finding of a 185delAG frameshift mutation in several Ashkenazi Jewish breast/ovarian families, we have determined the frequency of this mutation in 858 Ashkenazim seeking genetic testing for conditions unrelated to cancer, and in 815 reference individuals not selected for ethnic origin. We observed the 185delAG mutation in 0.9% of Ashkenazim (95% confidence limit, 0.4-1.8%) and in none of the reference samples. Our results suggest that one in a hundred women of Ashkenazi descent may be at especially high risk of developing breast and/or ovarian cancer.

A novel founder MSH2 deletion in Ethiopian Jews is mainly associated with early-onset colorectal cancer.

Lynch syndrome is an inherited cancer predisposition syndrome caused by germline defects in any of the mismatch repair (MMR) genes. Diagnosis of carriers makes precision prevention, early detection, and tailored treatment possible. Herein we report a novel founder deletion of 18,758 bp, mediated by Alu repeats on both sides, detected in Ethiopian Jews. The deletion, which encompasses exon 9-10 of the MSH2 coding sequence, is associated mainly with early-onset MSH2/MSH6-deficient colorectal cancer (CRC) and liposarcoma. Testing of 35 members of 5 seemingly unrelated families of Ethiopian origin yielded 10/21 (48%) carriers, of whom 9 had CRC. Age at first tumor diagnosis ranged from 16 to 89 years. Carriers from the oldest generations were diagnosed after age 45 years (mean 57), and carriers from the younger generation were diagnosed before age 45 years (mean 30). Awareness of this founder deletion is important to improve patient diagnosis, institute surveillance from an early age, and refer patients for genetic counseling addressing the risk of bi-allelic constitutional MMR deficiency syndrome.

Understanding and controlling organic-inorganic interfaces in mesostructured hybrid photovoltaic materials.

The chemical compositions and structures of organic-inorganic interfaces in mesostructurally ordered conjugated polymer-titania nanocomposites are shown to have a predominant influence on their photovoltaic properties. Such interfaces can be controlled by using surfactant structure-directing agents (SDAs) with different architectures and molecular weights to promote contact between the highly hydrophobic electron-donating conjugated polymer species and hydrophilic electron-accepting titania frameworks. A combination of small-angle X-ray scattering (SAXS), scanning and transmission electron microscopy (SEM, TEM), and solid-state NMR spectroscopy yields insights on the compositions, structures, and distributions of inorganic and organic species within the materials over multiple length scales. Two-dimensional NMR analyses establish the molecular-level interactions between the different SDA blocks, the conjugated polymer, and the titania framework, which are correlated with steady-state and time-resolved photoluminescence measurements of the photoexcitation dynamics of the conjugated polymer and macroscopic photocurrent generation in photovoltaic devices. Molecular understanding of the compositions and chemical interactions at organic-inorganic interfaces are shown to enable the design, synthesis, and control of the photovoltaic properties of hybrid functional materials.

HLA-B35 correlates with a favorable outcome following adjuvant administration of an HLA-matched allogeneic melanoma vaccine.

This work presents survival data of 42 melanoma patients at high risk for disease recurrence who received an allogeneic melanoma vaccine composed of three cell lines, each matching at least one allele of the recipient's human leukocyte antigen (HLA)-A and -B loci. The 5-year overall survival (OS) rate and disease-free survival (DFS) compared favorably with the standard interferon-α regimen. Interestingly, patients bearing HLA-B35 had significantly better OS and DFS (OS of 100% and DFS of 90% for HLA-B35 vs 56% and 23%, for the non-B35 patients). In contrast, patients expressing HLA-B07 did not fare well with the vaccine. Although the data include a relatively small cohort of patients, it strongly hints toward a correlation between HLA types and potential benefit from anticancer immunotherapy.

Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis.

Heparan sulfate proteoglycans interact with many extracellular matrix constituents, growth factors and enzymes. Degradation of heparan sulfate by endoglycosidic heparanase cleavage affects a variety of biological processes. We have purified a 50-kDa heparanase from human hepatoma and placenta, and now report cloning of the cDNA and gene encoding this enzyme. Expression of the cloned cDNA in insect and mammalian cells yielded 65-kDa and 50-kDa recombinant heparanase proteins. The 50-kDa enzyme represents an N-terminally processed enzyme, at least 100-fold more active than the 65-kDa form. The heparanase mRNA and protein are preferentially expressed in metastatic cell lines and specimens of human breast, colon and liver carcinomas. Low metastatic murine T-lymphoma and melanoma cells transfected with the heparanase cDNA acquired a highly metastatic phenotype in vivo, reflected by a massive liver and lung colonization. This represents the first cloned mammalian heparanase, to our knowledge, and provides direct evidence for its role in tumor metastasis. Cloning of the heparanase gene enables the development of specific molecular probes for early detection and treatment of cancer metastasis and autoimmune disorders.

Preimplantation genetic diagnosis for BRCA1/2--a novel clinical experience.

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 situ hybridization (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.

Glutathione-S-transferase M1, T1 and P1 polymorphisms, and breast cancer risk, in BRCA1/2 mutation carriers.

Variation in penetrance estimates for BRCA1/2 carriers suggests that other environmental and genetic factors may modify cancer risk in carriers. The GSTM1, T1 and P1 isoenzymes are involved in metabolism of environmental carcinogens. The GSTM1 and GSTT1 gene is absent in a substantial proportion of the population. In GSTP1, a single-nucleotide polymorphism that translates to Ile112Val was associated with lower activity. We studied the effect of these polymorphisms on breast cancer (BC) risk in BRCA1/2 carriers. A population of 320 BRCA1/2 carriers were genotyped; of them 262 were carriers of one of the three Ashkenazi founder mutations. Two hundred and eleven were affected with BC (20 also with ovarian cancer (OC)) and 109 were unaffected with BC (39 of them had OC). Risk analyses were conducted using Cox proportional hazard models adjusted for origin (Ashkenazi vs non-Ashkenazi). We found an estimated BC HR of 0.89 (95% CI 0.65-1.12, P=0.25) and 1.11 (95% CI 0.81-1.52, P=0.53) for the null alleles of GSTM1 and GSTT1, respectively. For GSTP1, HR for BC was 1.36 (95% CI 1.02-1.81, P=0.04) for individuals with Ile/Val, and 2.00 (95% CI 1.18-3.38) for carriers of the Val/Val genotype (P=0.01). An HR of 3.20 (95% CI 1.26-8.09, P=0.01), and younger age at BC onset (P=0.2), were found among Val/Val, BRCA2 carriers, but not among BRCA1 carriers. In conclusion, our results indicate significantly elevated risk for BC in carriers of BRCA2 mutations with GSTP1-Val allele with dosage effect, as implicated by higher risk in homozygous Val carriers. The GSTM1- and GSTT1-null allele did not seem to have a major effect.

Determination of Total Biotin by Liquid Chromatography Coupled with Immunoaffinity Column Cleanup Extraction: Multilaboratory Testing, Final Action 2016.02.

Single- and multilaboratory testing data have provided systematic scientific evidence that a simple, selective, accurate, and precise method can be used as a potential candidate reference method for dispute resolution in determining total biotin in all forms of infant, adult, and/or pediatric formula. Using LC coupled with immunoaffinity column cleanup extraction, the method fully meets the intended purpose and applicability statement in AOAC Standard Method Performance Requirement 2014.005. The method was applied to a cross-section of infant formula and adult nutritional matrixes, and acceptable precision and accuracy were established. The analytical platform is inexpensive, and the method can be used in almost any laboratory worldwide with basic facilities. The immunoaffinity column cleanup extraction is the key step to successful analysis.

Tumor suppressor p53 regulates heparanase gene expression.

Mammalian heparanase degrades heparan sulfate, the most prominent polysaccharide of the extracellular matrix. Causal involvement of heparanase in tumor progression is well documented. Little is known, however, about mechanisms that regulate heparanase gene expression. Mutational inactivation of tumor suppressor p53 is the most frequent genetic alteration in human tumors. p53 is a transcription factor that regulates a wide variety of cellular promoters. In this study, we demonstrate that wild-type (wt) p53 binds to heparanase promoter and inhibits its activity, whereas mutant p53 variants failed to exert an inhibitory effect. Moreover, p53-H175R mutant even activated heparanase promoter activity. Elimination or inhibition of p53 in several cell types resulted in a significant increase in heparanase gene expression and enzymatic activity. Trichostatin A abolished the inhibitory effect of wt p53, suggesting the involvement of histone deacetylation in negative regulation of the heparanase promoter. Altogether, our results indicate that the heparanase gene is regulated by p53 under normal conditions, while mutational inactivation of p53 during cancer development leads to induction of heparanase expression, providing a possible explanation for the frequent increase of heparanase levels observed in the course of tumorigenesis.

Rapid development of post-radiotherapy sarcoma and breast cancer in a patient with a novel germline 'de-novo' TP53 mutation.

AIMS: Germline mutations in the TP53 tumour suppressor gene are associated with Li-Fraumeni syndrome, which is characterised by a spectrum of neoplasms occurring in children and young adults that predominantly include early-onset breast cancer, a variety of sarcomas, brain tumours and adrenocortical tumours. The identification of patients carrying TP53 mutations is primarily based on a positive family history of these early-onset characteristic cancer types. The aim of this study is to emphasize the importance of TP53 molecular testing in patients with very early onset breast cancer and no family history of cancer. MATERIALS AND METHODS: A young woman with no family history of cancer presented with bilateral breast cancer at the age of 27 years. Forty months later she developed malignant fibrous histiocytoma of the right clavicle and another primary left breast cancer. Molecular testing of mutations 185delAG, 5382insC in BRCA1 gene and 6174delT in BRCA2 gene was performed using multiplex PCR and separation on a denaturing polyacrylamide gel. TP53 molecular analysis was performed by PCR-SSCP analysis of the whole coding region of the TP53. Exon 8 PCR products were sequenced using an ABI dye terminator kit and examined on an ABI 3100 automated sequencer. RESULTS: Molecular testing of peripheral blood DNA did not reveal mutations in BRCA1 or BRCA2 genes. A novel germline TP53 mutation, c.G841C, p.D281N, was identified. The detected mutation is a missense substitution, c.G841C, resulting in the substitution of the amino acid aspartate to asparagine, p.D281N. Molecular analysis in her parents showed that neither of them carried the mutation. CONCLUSIONS: We describe a novel 'de novo'TP53 mutation and discuss the importance of molecular testing in early-onset breast cancer patients and its effect on the management and outcome of the disease.

Radiocurability of microscopic disease in childhood rhabdomyosarcoma with radiation doses less than 4,000 cGy.

In an attempt to evaluate the radiocurability of microscopic disease in childhood rhabdomyosarcoma (RMS) with total tumor doses of less than 4,000 cGy, we performed a retrospective analysis of all patients with microscopic residual RMS who were treated at the Memorial Sloan-Kettering Cancer Center (MSKCC) during the years 1970 to 1987. There were 32 patients ranging in age from 3 months to 22 years (median, 6 years) with microscopic residual of either (1) a localized primary tumor (MSKCC, stage IB; Intergroup Rhabdomyosarcoma Study [IRS] group IIA), 19 patients; or (2) an involved lymph node region with the primary tumor completely resected (MSKCC stage III; IRS group IIC), 13 patients. Twenty-nine of the 32 patients presented with embryonal histology. All patients were treated with combination chemotherapy (CT) and megavoltage external beam radiotherapy (RT). The RT was delivered in either conventional fractionation of 180 to 200 cGy daily (30 patients) or hyperfractionation of 150 cGy twice daily (two patients). Fifteen patients received RT doses of less than 4,000 cGy with a range of 3,000 to 3,600 cGy and a median value of 3,100 cGy; 17 patients received 4,000 cGy or more with a range of 4,000 to 6,000 cGy and a median value of 4,600 cGy. With a median follow-up of 11 years, the relapse-free survival was 25 of 32 patients (less than 4,000 cGy, 12 of 15; greater than or equal to 4,000 cGy, 13 of 17). The RT local control rate was 30 of 32 (less than 4,000 cGy, 14 of 15; greater than or equal to 4,000 cGy, 16 of 17 [P = .94]). Our results suggest that radiation doses of below 4,000 cGy, when combined with effective multiagent CT, may be sufficient for local control of microscopic disease in childhood embryonal RMS.

Determinants of the use of complementary therapies by patients with cancer.

PURPOSE: We performed a survey of Israeli oncology patients to examine the extent of their use of complementary therapies (CT) and to compare sociodemographic, psychologic, and medical characteristics, attitudes, and quality of life of users and nonusers of CT. PATIENTS AND METHODS: Questionnaires were administered to 1,027 patients attending ambulatory and inpatient hematology or oncology facilities at three hospitals. Medical information was extracted from charts. Univariate and multivariate comparisons of users and nonusers of CT were performed. RESULTS: A total of 526 participants (51.2%) had used CT since their diagnosis, and 357 patients (34.9%) had used CT recently (in the past 3 months). Factors that multivariate analysis found to be significantly associated (P <.05) with recent CT use were as follows: female sex; age 35 to 59 years; more education; coming to the hospital by private car; advanced disease status; having a close friend or a relative with cancer; and attending support groups or individual counseling. After controlling for these factors, individually examined psychosocial variables associated with recent CT use included the following (odds ratios [OR] with 95% confidence intervals [CI]): needs unmet by conventional medicine (OR, 2.76; 95% CI, 1.95 to 3.89); helplessness (OR, 1.39; 95% CI, 1.0 to 1.91); incomplete trust in the doctor (OR, 1.49; 95% CI, 1.08 to 2.06); and changed outlook or beliefs since the diagnosis of cancer (OR, 1.47; 95% CI, 1.07 to 2.02). Functional quality of life (including physical, emotional, social, and role function) and symptom (fatigue and diarrhea) scores were significantly worse for recent CT users compared with nonusers, controlling for age, sex, and current disease status. CONCLUSION: Characteristics associated with CT use include age, sex, education, and advanced disease. Significant associations between CT use and attending supportive psychotherapy, unmet needs, helplessness, and worse emotional and social function indicate considerable distress, suggesting that increased attention to psychosocial needs within oncologic settings is warranted.

PH motifs in PAR1&2 endow breast cancer growth.

Although emerging roles of protease-activated receptor1&2 (PAR1&2) in cancer are recognized, their underlying signalling events are poorly understood. Here we show signal-binding motifs in PAR1&2 that are critical for breast cancer growth. This occurs via the association of the pleckstrin homology (PH) domain with Akt/PKB as a key signalling event of PARs. Other PH-domain signal-proteins such as Etk/Bmx and Vav3 also associate with PAR1 and PAR2 through their PH domains. PAR1 and PAR2 bind with priority to Etk/Bmx. A point mutation in PAR2, H349A, but not in R352A, abrogates PH-protein association and is sufficient to markedly reduce PAR2-instigated breast tumour growth in vivo and placental extravillous trophoblast (EVT) invasion in vitro. Similarly, the PAR1 mutant hPar1-7A, which is unable to bind the PH domain, reduces mammary tumours and EVT invasion, endowing these motifs with physiological significance and underscoring the importance of these previously unknown PAR1 and PAR2 PH-domain-binding motifs in both pathological and physiological invasion processes.

Transmission of response to trauma? Second-generation Holocaust survivors' reaction to cancer.

OBJECTIVE: Opinions differ about the effects of the Holocaust on the adult offspring of survivors. The authors studied cancer patients who were second-generation Holocaust survivors in an attempt to determine whether they react to their illness with the high distress found to be a characteristic of Holocaust survivors. METHOD: In a study population of women with breast cancer, 106 second-generation Holocaust survivors were compared to 102 women whose parents were not in the Holocaust. Background information was obtained by interviews. In addition, all patients completed three self-reports: the Mental Attitude to Cancer Scale, the Brief Symptom Inventory, and the Impact of Event Scale. RESULTS: The two groups had identical mean scores on the Mental Attitude to Cancer Scale. The offspring of Holocaust survivors had scores on the Brief Symptom Inventory and the Impact of Event Scale that were substantially and significantly higher and in the range of psychopathology. Within the group, married women and women whose mothers were still alive were even more distressed. Other independent variables shed little light on why the second-generation Holocaust survivors suffered from extreme distress. CONCLUSIONS: Second-generation Holocaust survivors are particularly vulnerable to psychological distress and, when faced with a trauma such as breast cancer, react with extreme psychological distress.