Long term activity of vemurafenib in cancers with BRAF mutations: the ACSE basket study for advanced cancers other than BRAFV600-mutated melanoma.

BACKGROUND: BRAF inhibitors are approved in BRAFV600-mutated metastatic melanoma, non-small-cell lung cancer (NSCLC), Erdheim-Chester disease (ECD), and thyroid cancer. We report here the efficacy, safety, and long-term results of single-agent vemurafenib given in the AcSé vemurafenib basket study to patients with various BRAF-mutated advanced tumours other than BRAFV600-mutated melanoma and NSCLC. PATIENTS AND METHODS: Patients with advanced tumours other than BRAFV600E melanoma and progressing after standard treatment were eligible for inclusion in nine cohorts (including a miscellaneous cohort) and received oral vemurafenib 960 mg two times daily. The primary endpoint was the objective response rate (ORR) estimated with a Bayesian design. The secondary outcomes were disease control rate, duration of response, progression-free survival (PFS), overall survival (OS), and vemurafenib safety. RESULTS: A total of 98 advanced patients with various solid or haematological cancers, 88 with BRAFV600 mutations and 10 with BRAFnonV600 mutations, were included. The median follow-up duration was 47.7 months. The Bayesian estimate of ORR was 89.7% in hairy cell leukaemias (HCLs), 33.3% in the glioblastomas cohort, 18.2% in cholangiocarcinomas, 80.0% in ECD, 50.0% in ovarian cancers, 50.0% in xanthoastrocytomas, 66.7% in gangliogliomas, and 60.0% in sarcomas. The median PFS of the whole series was 8.8 months. The 12-, 24-, and 36-month PFS rates were 42.2%, 23.8%, and 17.9%, respectively. Overall, 54 patients died with a median OS of 25.9 months, with a projected 4-year OS of 40%. Adverse events were similar to those previously reported with vemurafenib. CONCLUSION: Responses and prolonged PFS were observed in many tumours with BRAF mutations, including HCL, ECD, ovarian carcinoma, gliomas, ganglioglioma, and sarcomas. Although not all cancer types responded, vemurafenib is an agnostic oncogene therapy of cancers.

Lack of referral for genetic counseling and testing in BRCA1/2 and Lynch syndromes: a nationwide study based on 240,134 consultations and 134,652 genetic tests.

Based on nationwide data from the French national cancer institute (INCa), we analyzed the evolution of cancer genetics consultations and testing over time, and the uptake of targeted tests in relatives of families with BRCA1/2 or MMR genes mutation. Genetic testing and consultations for familial high-risk individuals are exclusively funded and monitored by the INCa in France. All nationwide cancer genetics centers reported annually standardized parameters of activity from 2003 to 2011. The analysis included a total of 240,134 consultations and 134,652 genetic tests enabling to identify 32,494 mutation carriers. Referral for hereditary breast and ovarian cancer (HBOC) or colorectal cancer predisposition syndromes represented 59 % (141,639) and 23.2 % (55,698) consultations, respectively. From 2003 to 2011, we found a dramatic and steady increase of tests performed for BRCA1/2 (from 2,095 to 7,393 tests/year, P < 0.0001) but not for MMR genes (from 1,144 to 1,635/year, P = NS). The overall percentage of deleterious mutations identified in the probands tested was 13.8 and 20.9 % in HBOC and Lynch syndromes, respectively. Pooled analysis for BRCA1/2 and Lynch syndrome tests showed an inverse relationship between the percentage of mutation detected and the absolute number of tests performed over the time (overall Cochran-Armitage test for trend: P < 0.001). In families with BRCA1/2 or MMR identified mutations, there was an average number of 2.94 and 3.28 relatives performing targeted tests, respectively. This nationwide study shows a lack of referral and genetic testing in Lynch as compared to HBOC syndromes. Only a third of relatives of a proband with a predisposing mutation performed a targeted test. Enhanced information about benefit of genetic testing should be given to clinicians and patients for Lynch syndrome and relatives of a proband carrying an identified predisposing mutation.

[Cancer genetics: estimation of the needs of the population in France for the next ten years]. / Oncogénétique : estimation des besoins de la population en France pour les dix ans à venir.

Organised since 1990 in France, cancer genetics has been strengthened since 2003 by the programme "Plan Cancer" which resulted in an improvement of the organisation of activities. The aim of this review is to present an update of the estimation of the needs of the population in this field for the next ten years, provided by a group of experts mandated by the French National Cancer Institute. Identification and management of major hereditary predispositions to cancer have a major impact on decrease in mortality and incidence. Sensitivity of criteria for the detection of BRCA1/2 mutations could be substantially improved by enlarging the indication for genetic testing to isolated cases of ovarian cancer occurring before 70 years and to familial cases occurring after this age limit. In the Lynch syndrome, the present criteria would have an excellent sensitivity for the detection of mutations in the mismatch repair (MMR) genes if the pre-screening of tumours on microsatellite instability (MSI) phenotype was effective, but these criteria are actually poorly applied. However, genetic testing should not be proposed to all the patients affected by tumours belonging to the spectrum of major predispositions and a fortiori to unaffected persons unless an affected relative has been identified as a carrier. The prescription of tests should continue to be strictly controlled and organised, in patients as well as in at-risk relatives. The enlargement of criteria and the improvement in the spreading of recommendations should result in an increase of genetic counselling activity and of the prescriptions of tests by a factor 2 to 4, and to a lesser extent in the clinical management of at risk persons. In a near future, it appears important to mandate experts on specific issues such as the determinants of the lack of effective application of tumour screening for MSI phenotype, the recommendations for the identification and the management of MYH-associated polyposis, or the predictive value of tumour characteristics for the identification of BRCA1/2 mutations. The expected increase in cancer genetics activity will need an optimal organisation to increase the throughput. Such measures will help in facing up to new predispositions that will probably be identified in common cancers.

[Pulmonary embolism: clinical relevance, requirements for diagnostic and therapeutic strategies]. / Lungenembolie: Klinische Bedeutung, Anforderung an die Diagnostik und Behandlungsoptionen.

In the population the annual incidence of pulmonary embolism amounts to 1.3-2.8 per 1000 at the age of 65-89 years. Mortality reaches about 17% within the first 3 months. Acute pulmonary embolism is characterized by an increase in pulmonary arterial pressure and an impairment of the pulmonary gas exchange. Elevation of the right cardiac pressure up to right heart decompensation may follow. In addition, hypoxemia, hyperventilation, dead space ventilation, right to left shunting, bronchoconstriction, and vasoconstriction may occur. Clinical examination, ECG, laboratory findings such as elevated D-dimer, blood gas analysis, ultrasound examination of the veins of the lower extremities, and transthoracic echocardiography are acutely available diagnostic methods of an emergency department. In addition, extensive diagnostic procedures like pulmonary scintigraphy and pulmonary angiography may be required. The aim is to get a definite diagnosis as quickly as possible to direct therapy. In acute pulmonary embolism with cardiac shock, monitoring and stabilization of the circulatory function as well as an appropriate anticoagulant therapy are essential. In some cases surgery or a local fibrinolytic intervention is indicated.

IPM-FISH, a new M-FISH approach using IRS-PCR painting probes: application to the analysis of seven human prostate cell lines.

We have developed an alternative multicolor karyotyping technique based on multiplex fluorescence in situ hybridization (M-FISH) and our own optical device with a specific filter set. The most innovative part of our development is the use of interspersed polymerase chain reaction (IRS-PCR) painting probes that show an R-band pattern simultaneous to the combinatorial labeling. This allows us not only to recognize the origin of chromosomal fragments, but to identify the breakpoints as well. We have used this technique to analyze seven cell lines: four prostate cancer cell lines (CA-HPV-10, LNCaP, DU145, and PC3), and three normal transformed epithelial prostate cell lines (PNT1B, PNT2, and PZ-HPV-7). In order to validate our IRS-PCR multiplex FISH (IPM-FISH) technique and to complement the results, we applied comparative genomic hybridization (CGH) and FISH analysis, showing good correlation with the IPM-FISH results. To date, molecular and cytogenetic studies have identified several chromosomal regions that are altered in human prostate cancer; several candidate genes have been suggested. However, reliable markers for predicting the aggressiveness of early prostate cancer are not yet available. Our results show several common, unbalanced rearrangements in the cell lines. These rearrangements are similar to regions already implicated in prostate cancer, validating these cell lines as a good model system.

Kinetics of absorbance and anisotropy upon excited state relaxation in the reaction center core complex of a green sulfur bacterium.

Properties of the excited states in reaction center core (RCC) complexes of the green sulfur bacterium Prosthecochloris aestuarii were studied by means of femtosecond time-resolved isotropic and anisotropic absorption difference spectroscopy at 275 K. Selective excitation of the different transitions of the complex resulted in the rapid establishment of a thermal equilibrium. At about 1 ps after excitation, the energy was located at the lowest energy transition, BChl a 835. Time constants varying between 0.26 and 0.46 ps were observed for the energy transfer steps leading to this equilibrium. These transfer steps were also reflected in changes in polarization. Our measurements indicate that downhill energy transfer towards excited BChl a 835 occurs via the energetically higher spectral forms BChl a 809 and BChl a 820. Low values of the anisotropy of about 0.07 were found in the 'two-color' measurements at 820 and 835 nm upon excitation at 800 nm, whereas the 'one-color' kinetics showed much higher anisotropies. Charge separation occurred with a time constant varying between 20 and 30 ps.

Perinatal developmental changes in expression of the neuropeptide genes preoptic regulatory factor-1 and factor-2, neuropeptide Y and GnRH in rat hypothalamus.

The preoptic regulatory factor genes, PORF-1 and PORF-2, are expressed in the rat brain in a regional-, age- and gender-dependent fashion. They are also expressed in the testis, where PORF-2 mRNA localizes to dividing germ cells while PORF-1 mRNA is associated with newly differentiated sperm. This suggests that PORF-1 and PORF-2 may play distinct roles in cell growth and differentiation. Moreover, the two preoptic regulatory factors are also highly expressed in the immature and mature rat hypothalamus, and their expression is modulated by gonadal hormones. Therefore, in the present study we investigated the expression of these two factors in neuroendocrine regions of the developing rat brain by addressing the following questions. First, are PORF-1 and PORF-2 mRNAs expressed during perinatal development in the preoptic area-anterior hypothalamus (POA-AH) and medial basal hypothalamus (MBH), and how do their levels vary? Second, are there gender differences in their expression? We also compared expression of the PORF mRNAs with those of neuropeptide Y (NPY) and gonadotropin-releasing hormone (GnRH), which play critical neuroendocrine roles, in these brain regions. PORF-1, PORF-2, and NPY mRNAs in the POA-AH and MBH, and GnRH mRNA in the POA-AH, were quantified by RNase protection assay at embryonic day (E) 18-19, and postnatal days (P) 0, 5, 10 and 15 in male and female rats. The results show that the four neuropeptide genes are regulated differentially during the perinatal-prepubertal period. PORF-1 mRNA shows age-related increases in expression from E18-E19 to P15 in POA-AH and MBH, without significant gender differences. In contrast, PORF-2 mRNA shows both age and gender differences in expression in these brain regions, with decreases occurring during the same time period in development. NPY mRNA increases similarly in males and females with age in POA-AH and MBH during this period. GnRH mRNA does not change during this period. Taken together with previous studies, the results suggest possible roles for PORF-1 and NPY in the pubertal process, since their expression is maximal from the prepubertal to the early pubertal period. The observation of highest levels of expression of PORF-2 in embryonic neuroendocrine tissues suggests a possible involvement of this neuropeptide in prenatal/neonatal developmental events.

Differential gene expression response to gonadal hormones by preoptic regulatory factors-1 and -2 in the female rat brain.

Steroids and neuropeptides interact in the central nervous system (CNS) to regulate reproductive function and behavior. The preoptic regulatory factors, PORF-1 and PORF-2, are unique neuropeptides for which roles in gender-related brain development and function have been proposed. PORF-1 and PORF-2 expression in rat brain are age, region and gender dependent, and castration or hypophysectomy alter the metabolism of the PORF-1 and PORF-2 mRNAs in male rat brain and testes. If these two peptides have a role in gender-dependent brain function, then gonadal steroids might well affect their expression. The present study was designed to investigate the response of the PORF-1 and PORF-2 mRNAs to sex steroids in the female rat brain and to compare this response to that of two peptides whose roles in the neuroendocrinology of reproduction are well established, gonadotropin-releasing hormone (GnRH) and neuropeptide Y (NPY). Rats were ovariectomized and treated with placebo, estradiol (E2), progesterone (P4) or a combination of the two (E2/P4) and NPY, PORF-2, GnRH and PORF-1 mRNAs were quantified by nuclease protection assays. PORF-1, PORF-2 and GnRH mRNAs were also measured in intact rats during estrus and proestrus. Responses were compared in the preoptic anterior hypothalamus (POA), medial basal hypothalamus (MBH), cerebral cortex (CC) and hippocampus (HIPP). Expression of PORF-1 and PORF-2 was also confirmed in the female rat hypothalamus by in situ hybridization analysis. PORF-1 and PORF-2 mRNAs were detected in the adult female rat brain by both in situ hybridization and ribonuclease protection analyses. In situ hybridization analysis demonstrated that PORF-1 and PORF-2 mRNAs are expressed in hypothalamic neurons. RNase protection analysis showed that PORF-1, PORF-2 and NPY mRNAs were present in all four brain regions examined while GnRH expression was detected only in the MBH and POA. Estradiol alone upregulated expression of the PORF-1 and PORF-2 mRNAs in the ovariectomized rat in the POA and HIPP, and of NPY mRNA in the MBH and HIPP. Progesterone alone had a stimulatory effect on NPY mRNA in the MBH and HIPP. Treatment with a combination of E2/P4 downregulated PORF-2 mRNA in the POA as well as PORF-1, PORF-2 and NPY mRNAs in the CC. In contrast, E2/P4 upregulated the PORF-2 and NPY mRNAs in the HIPP and NPY mRNA in the MBH. In the cycling rat, PORF-1 mRNA levels were higher during proestrus than estrus in both the MBH and POA, while PORF-2 mRNA levels did not change. In contrast GnRH mRNA was lower in the POA and higher in the MBH during proestrus compared with estrus. Thus, intrinsic factors, most likely both ovarian and neuroendocrine, regulate PORF-1 and GnRH expression in the intact cycling rat CNS in a region-dependent manner. In the ovariectomized rat, PORF-1, PORF-2, NPY and GnRH mRNAs all respond in a region-specific manner to sex steroid treatment. These data support the role of PORF-1 and PORF-2 in gender-dependent brain function in the adult female rat.

Upregulation of CD40 and CD40 ligand expression in IgE-associated cutaneous diseases.

In order to better understand the immunological processes connected with IgE-associated cutaneous disease, we have examined the expression of CD40 and its ligand CD40L, required for the induction of IgE synthesis in B-cells, as well as of IgE and its receptors in various dermatoses (atopic dermatitis (AD), scabies, chronic recurrent urticaria) versus normal skin, and in one dermopathic lymph node versus normal lymphatic tissue by immunohistochemistry. Compared to normal skin, cells expressing IgE, Fc epsilon RI, Fc epsilon RII, CD40, CD40L and L26 were increased in the dermis, partly also in the epidermis, from patients with AD and scabies, but not in chronic urticaria. CD40 and CD40L were detected on numerous cells in lymphatic tissue from both normal donors and a patient with AD, whereas large numbers of IgE- and Fc epsilon RI-positive cells were only found in the dermopathic lymph node from the AD patient, in contrast to very few in normal lymphatic tissue. These results with selectively increased IgE/Fc epsilon RI and associated CD40/CD40L expression in the skin of AD and scabies suggest that cutaneous tissue, in addition to dermopathic lymphatic tissue, might contribute to IgE synthesis.

Expression of the activated p185erbB2 tyrosine kinase in human epithelial cells leads to MAP kinase activation but does not confer oncogenicity.

Amplification of the c-erbB2 gene and overexpression of p185erbB2 is found in approximately one-third of primary breast and ovarian cancers and also in some colon carcinomas. Moreover, a single point mutation in erbB2(V 664 E) confers transforming potential to erbB2 in NIH3T3 cells, even when expressed at low levels. To examine the transformation potential of erbB2 or erbB2(V-E) in colon epithelial cells, we have transfected a nontumorigenic clone of SW 613-S cells with either wild-type p185erbB2 or mutated p185erbB2(V-E). In contrast to p185erbB2, p185erbB2(V-E) associated constitutively with members of the Shc protein family, leading to phosphorylation of Shc and to stimulation of mitogen-activated protein kinase (MAP kinase). However, constitutive activation of MAP kinase activation in p185erbB2(V-E) expressing cells did not result in a tumorigenic phenotype. In addition, p185erbB2(V-E) expressing cells displayed a reduced ability to grow in soft agar compared to the parental cell line. In contrast these transfected cells were able to grow in three-dimensional collagen gels, whereas parental cells were not. Thus, expression of erbB2(V-E) in SW 613-S cells induced multiple changes in intracellular signaling and in growth requirement phenotype, particularly in response to the extracellular environment.

Modulation of preoptic regulatory factor-2 (porf-2) mRNAs by castration and hypophysectomy.

Neuropeptides are central to the regulation of mammalian gender-dependent development and reproduction. Preoptic regulatory factor-2 is a neuropeptide gene that is known to be expressed in rat brain and testis. In the brain, expression is gender-dependent and age-dependent. Tissue-specific transcripts are found in the preoptic area (POA) of the hypothalamus and in the testis. In order to investigate the effects of reproductive hormone status on expression of porf-2 in the male rat, porf-2 transcripts were studied by Northern blot analysis in intact, hypophysectomized, and castrated rat POA, medial basal hypothalamus (MBH), cerebral cortex (CC), testis, and liver. Castration of hypophysectomy increased levels of the brain-specific 0.84 kb 5' porf-2 transcript in the POA, but did not affect levels of this transcript in the CC. There was a small decrease in the MBH following castration. Hypophysectomy also resulted in a fourfold increase in the 5' 1.1 kb testis-specific transcript. The affected transcripts are localized to the cytoplasm. A nontissue specific 3' transcript was also detected. Interestingly, this 0.6 kb transcript became non-detectable in all tissues examined following hypophysectomy. Porf-2 mRNA was also detected in human hypothalamus, testis, adrenal, placenta, and prostate with unique transcripts in each tissue examined . It has been shown elsewhere that porf-2 is a unique single copy gene in the rat genome. These data demonstrate that expression of the porf-2 gene is differentially regulated at the pretranslational level by intrinsic tissue-specific, as well as extrinsic pituitary and gonadal factors. The selected responses to reproductive hormonal status suggest that porf-2 may play a role in hypothalamic pituitary-gonadal interactions.

Expression of the preoptic regulatory factor-1 and -2 genes in rat testis. Developmental and hormonal regulation.

Hormone-responsive peptides play a vital role in development and regulation of testicular function. The preoptic regulatory factors, porf-1 and porf-2, were originally discovered in the rat brain, but are also expressed in the rat and human testis. In the brain expression is age-related, hormone-responsive, region- specific, and gender-related, suggesting that porf-1 and porf-2 are involved in gender-specific brain development and function. Tissue-specific porf-1 and porf-2 mRNAs are also found in the testis and hypophysectomy may alter testicular porf-2 expression. It was thus of interest to further examine porf-1 and porf-2 expression in the testis to evaluate their potential as hormone-responsive peptides that regulate testicular development and function. Testicular expression of both porf-1 and -2 was analyzed as a function of maturational stage, aging and hypophysectomy by the solution hybridization/nuclease protection assay, and cellular location determined by in situ hybridization histochemistry. Expression was quantitatively compared in normal male rats at 15, 30 and 60 d (n = 4) and at 2, 6, 12, and 24 mo of age (n = 5). During development porf-1 is expressed at a constant level at 15, 30 and 60 d, then declines significantly with advancing age; levels at 24 mo are only 20% of those seen at 2 mo (p < 0.05). In contrast, porf-2 expression is highest at 15 d of age and steadily declines at 30 and 60 d, plateaus in the mature adult (6 and 12 mo), then exhibits an additional significant decline in the aged 24 mo animals (6 vs 24 mo, p < 0.05). Hypophysectomy of young adult rats at day 42 results in increased testicular expression 12 d later of both porf-1 (p < 0.05) and porf-2(p < 0.005) compared to intact 54-d-old rats (n = 5). In situ hybridization histochemistry confirms that both porf-1 and porf-2 are expressed in the mature testis at 60 d of age. Porf-2 mRNA is localized to immature germ cells including spermatogonia and primary spermatocytes. Porf-1 mRNA is associated with mature sperm and at low levels in the Sertoli cell cytoplasm surrounding spermatocytes. These data suggest that porf-2 is a pituitary hormone-responsive factor in the developing testis and that both porf-1 and porf-2 have cell-type specific functions in the germ cell compartment of the mature testis

Epidermal growth factor receptor signaling cascade as target for tyrphostin (RG 50864) in epithelial cells. Paradoxical effects on mitogen-activated protein kinase kinase and mitogen-activated protein kinase activities.

Tyrphostins are synthetic compounds that have been described as in vitro inhibitors of epidermal growth factor receptor (EGF-R) tyrosine kinase activity. The inhibitory effect of tyrphostins in intact cells has been shown only after prolonged treatment. However, these compounds appear to be readily incorporated, which suggests that tyrphostin acts indirectly on EGF-R. We studied the effects of a tyrphostin derivative, RG 50864, without preincubation in intact epithelial cells. We selected two human cell lines differing in degree of expression of the p185erbB2 protein, which is closely related to EGF-R. We showed that tyrphostin (RG 50864) had no effect on EGF-dependent EGF-R tyrosine phosphorylation in the parental cell line. On the contrary, it prolonged the EGF-dependent EGF-R and p185erbB2(V-E) tyrosine phosphorylation in p185erbB2(V-E)-expressing cells. Because tyrphostin has been shown to be an inhibitor of p185erbB2 and EGF-R in vitro, this finding indicates that the tyrphostin effect on p185erbB2(V-E) and EGF-R was the result of an indirect mechanism in transfected cells. Tyrphostin treatment alone led to the activation of mitogen-activated protein (MAP) kinase kinase or MAP kinase or extracellular signal-regulated kinase kinase (MEK), suggesting that one of the tyrphostin targets was upstream of MEK1. MAP kinase, however, was not activated after tyrphostin treatment. This finding indicates that tyrphostin had another target in intact cells because MEK1 activation by tyrphostin alone did not correlate with MAP kinase activation. In the two cell lines, tyrphostin modified the time course of EGF-dependent MEK and MAP kinase activation. We conclude that whereas tyrphostins were designed to inhibit EGF-R tyrosine kinase activity, under our conditions EGF-R is not a physiological target for tyrphostin, nor is one of its related protein tyrosine kinases, p185erbB2(V-E). On the contrary, our results show that tyrphostin targets are multiple, leading to complex effects on receptor signaling in these epithelial cells.

[Comparison of treatment outcome for non-variceal upper gastrointestinal hemorrhage using endoscopic obliteration methods and traditional methods in patients over 60]. / Porównanie wyników leczenia niezylakowych krwawien z górnego odcinka przewodu pokarmowego metoda obliteracji endoskopowej oraz metoda tradycyjna u chorych po 60 roku zycia.

UNLABELLED: Authors present results of therapy of patients over 60 treated because of nonvariceal upper gastrointestinal bleeding in General Surgery Department in Oswiecim. In 1991-1993 47 patients underwent non-endoscopic therapy. In 1994-1996 endoscopic obliteration with 0.01% epinephrine or 1% polidocanol in patients over 60 was applied. In the group over 60 more often concomitant diseases (cardiovascular, diabetes, atherosclerosis) were noted. Similar endoscopic obliteration efficacy (90% vs. 91%) in patients aged under and over 60 was observed. Patients treated with endoscopic obliteration underwent urgent operation twice rarely then conservative management (6.7% vs. 13%). They obtained less quantity of blood (2.23 vs. 3.4 unit). Their hospital stay was shorter (9 vs. 13 days). In both kind of therapy, mortality in patients over 60 was higher then under 60, but less often in group undergone endoscopic obliteration (traditional treatment 28% vs. 6%, endoscopic 15% vs. 2%). CONCLUSIONS: 1. Reason of worse therapy results of upper gastrointestinal bleeding among patients aged over 60 was great number of concomitant diseases. 2. Efficacy of endoscopic obliteration 0.01% epinephrine and 1% polidocanol was independent from age. 3. Application of endoscopic obliteration improved results of therapy in patients aged over 60.

[Form fruste of long QT syndrome]. / Forme fruste eines langen QT-Syndroms.

The long QT syndrome (LQTS) is an inherited disorder associated with recurrent syncope and sudden death from ventricular arrhythmias. It is characterized by a prolonged QT interval on the ECG. A case is discussed in which a patient presented with recurrent syncopal episodes on exertion associated with a slightly prolonged QT interval. Family history revealed an increased incidence of sudden deaths in two generations. Some reports on similar patients suggest that there may be a forme fruste of the long QT syndrome. The additional diagnostic values of exercise stress test, Valsalva maneuver and genetic testing are evaluated. After analysis of the patient's and mother's ECGs the diagnosis of a forme fruste of LQTS is made. This case is presented to emphasize the importance of diagnosis of borderline cases of LQTS because of the high risk of sudden death for untreated patients.