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Cannabis is one of the most widely used plant drugs in the world today. In spite of the large number of scientific reports on medical marijuana, there still exists much controversy surroun...

Background Fragile X premutation (Amplification of CGG number 55–200) is associated with increased risk for fragile X-Associated Premature Ovarian Insufficiency (FXPOI) in females and fragile X-associated tremor/ataxia syndrome (FXTAS) predominantly in males. Recently, it has been shown that CGG repeats trigger repeat associated non-AUG initiated translation (RAN) of a cryptic polyglycine-containing protein, FMRpolyG. This protein accumulates in ubiquitin-positive inclusions in neuronal brain cells of FXTAS patients and may lead to protein-mediated neurodegeneration. FMRpolyG inclusions were also found in ovary stromal cells of a FXPOI patient. The role of FMRpolyG expression has not been thoroughly examined in folliculogenesis related cells. The main goal of this study is to evaluate whether FMRpolyG accumulates in mural granulosa cells of FMR1 premutation carriers. Following FMRpolyG detection, we aim to examine premutation transfected COV434 as a suitable model used to identify RAN translation functions in FXPOI pathogenesis. Results FMRpolyG and ubiquitin immunostained mural granulosa cells from six FMR1 premutation carriers demonstrated FMRpolyG aggregates. However, co-localization of FMRpolyG and ubiquitin appeared to vary within the FMR1 premutation carriers’ group as three exhibited partial ubiquitin and FMRpolyG double staining and three premutation carriers demonstrated FMRpolyG single staining. None of the granulosa cells from the five control women expressed FMRpolyG. Additionally, human ovarian granulosa tumor, COV434, were transfected with two plasmids; both expressing 99CGG repeats but only one enables FMRpolyG expression. Like in granulosa cells from FMR1 premutation carriers, FMRpolyG aggregates were found only in COV434 transfected with expended CGG repeats and the ability to express FMRpolyG. Conclusions Corresponding with previous studies in FXTAS, we demonstrated accumulation of FMRpolyG in mural granulosa cells of FMR1 premutation carriers. We also suggest that following further investigation, the premutation transfected COV434 might be an appropriate model for RAN translation studies. Detecting FMRpolyG accumulation in folliculogenesis related cells supports previous observations and imply a possible common protein-mediated toxic mechanism for both FXPOI and FXTAS.

PURPOSE: To detect which factors influence decision-making among pregnant FMR1 premutation carriers regarding the preferred mode of genetic diagnosis: IVF-PGT-M (in vitro fertilization with preimplantation genetic testing for monogenic gene diseases), or CVS (chorionic villus sampling), or AC (amniocentesis) after spontaneous conception. METHODS: In Israel FMR1 premutation preconception genetic screening is offered, free of charge, to every woman in her reproductive years. FMR1 premutation carriers with ≥ 70 CGG repeats, or a history of FXS offspring, are offered IVF-PGT-M. This is a historical cohort study including all pregnant FMR1 premutation carriers who underwent prenatal diagnosis between the years 2011 and 2016 at a tertiary medical center. Data were collected from electronic charts and through phone interviews. RESULTS: One hundred seventy-five women with high-risk pregnancies who were offered IVF-PGT-M were evaluated. In 37 pregnancies (21%), the women decided to undergo IVF-PGT-M. Using the generalized estimating equations (GEE) statistical method including seven parameters, we found that previous termination of pregnancy due to FXS and advanced woman’s age were significantly associated with making the decision to undergo IVF-PGT-M. Previously failed IVF was the most significant parameter in a woman’s decision not to undergo IVF-PGT-M. CONCLUSION: The most dominant factor affecting the decision of FMR1 premutation carriers to choose spontaneous conception with prenatal diagnosis versus IVF-PGT-M is a previous experience of failed IVF treatments. Women whose IVF treatments failed in the past tended to try to conceive naturally and later, during the course of the pregnancy, perform CVS or AC. Conversely, women who previously experienced a termination of pregnancy (TOP) due to an affected fetus, and older women, preferred to undergo IVF-PGT-M procedures.

Purpose: To test the frequency of single-nucleotide polymorphisms in the IL-10, IL23R-IL12RB2 genes in patients with Behcet's uveitis. Methods: Blood samples were collected from 89 Israeli and Turkish patients, and from healthy control subjects of different origins. Genomic DNA was extracted from peripheral blood leukocytes and genotyped. Results: The risk allele, A, in rs1800871, of IL-10 gene was highly prevalent in Behcet's uveitis and healthy control samples alike; highest among the Turkish groups. Prevalence of G allele, in rs1495965, in the IL23R-IL12RB2 gene was high in Behcet's uveitis patients, and among healthy Turkish and Israelis of Middle Eastern origin, while lower among the other Israeli control group (77.9%, 78.9%, 27.8%, respectively, P < 0.001). Conclusion: Our findings highlight the differences between populations and may account for the increased prevalence of the disease among Turkish and Israelis of Middle Eastern origin. Further studies are required to map other healthy and affected populations.

Fragile X syndrome (FXS) is the most prevalent known genetically inherited cause for autism and intellectual disability. Premutation state can cause several clinical disorders as well. We aimed to perform a nesting approach to acquire data with regard to first degree relatives of index fragile X cases at the largest child development center in Israel in order to map characteristics of Israeli FXS permutation women carriers. Seventy-nine women were referred due to a related fragile X syndrome patient, mainly an offspring or sibling. General information regarding demographics, ethnicity, and associated medical conditions were collected using interviews and structured questionnaires. Thirteen (17 %) of the women who were referred as "carrier" were proven to be actually full mutation. The mean years of education were 14 (±1.51, range 12-17). Twenty-one women (27 %) originated from Tunisia (mainly from the island of Djerba). Ten women (13 %) reported delivery of their affected offspring beyond 41 gestational weeks. Twenty-two percent of women with premutation reported symptoms consistent with learning difficulties, mainly dyscalculia, and 14 % reported ADHD symptoms. Awareness about clinical disorders of the carriers was existent only in 25 % of the patients. Increased awareness and knowledge dissemination concerning premutation symptomatology and associated medical conditions are warranted. We suggest a national registry to be installed in different countries in order to identify fragile X premutation carriers at increased risk for various medical complications.

The phosphoinositide 3-kinase (PIK3)/v-akt murine thymoma (AKT) oncogene pathway and the RAS/RAF pathway are involved in regulating the signalling of multiple biological processes, including apoptosis, metabolism, cell proliferation, and cell growth. Mutations in the genes within these pathways are frequently found in several tumours. The aim of this study was to investigate the frequency of mutations in the PIK3CA, BRAF, and KRAS genes in cases of malignant salivary gland tumours. Mutational analysis of the PIK3CA, KRAS, and BRAF genes was performed by direct sequencing of material from 21 patients with malignant salivary gland tumours who underwent surgery between 1992 and 2001. No mutations were found in the KRAS exon 2, BRAF exon 15, or PIK3CA exon 9 genes. However, an unpublished mutation of the PIK3CA gene in exon 20 (W1051 stop mutation) was found in one case of adenocarcinoma NOS. The impact of this mutation on the biological behaviour of the tumour has yet to be explored, however the patient with adenocarcinoma NOS harbouring this mutation has survived for over 20 years following surgery despite a high stage at presentation. Further studies with more homogeneous patient cohorts are needed to address whether this mutation reflects a different clinical presentation and may benefit from targeted treatment strategies.

Introduction: Fragile X syndrome (FXS) is a common form of X-linked intellectual and developmental disability with a prevalence of 1/4000–5000 in males and 1/6000–8000 in females. Most cases of the syndrome result from expansion of a premutation (55–200 CGGs) to a full mutation (>200 CGGs) repeat located in the 5′ untranslated region of the fragile X mental retardation (FMR1) gene. The risk for full mutation expansions increases dramatically with increasing numbers of CGG repeats. Recent studies, however, revealed AGG interruptions within the repeat area function as a “protective factor” decreasing the risk of intergenerational expansion. Materials and Methods: This study was conducted to validate the relevance of AGG analysis for the ethnically diverse Israeli population. To increase the accuracy of our results, we combined results from Israel with those from the New York State Institute for Basic Research in Developmental Disabilities (IBR). To the best of our knowledge this is the largest cohort of different ethnicities to examine risks of unstable transmissions and full mutation expansions among FMR1 premutation carriers. Results: The combined data included 1471 transmissions of maternal premutation alleles: 369 (25.1%) stable and 1,102 (74.9%) unstable transmissions. Full mutation expansions were identified in 20.6% (303/1471) of transmissions. A total of 97.4% (388/397) of transmissions from alleles with no AGGs were unstable, 79.6% (513/644) in alleles with 1 AGG and 46.7% (201/430) in alleles with 2 or more AGGs. The same trend was seen with full mutation expansions where 40% (159/397) of alleles with no AGGs expanded to a full mutation, 20.2% (130/644) for alleles with 1 AGG and only 3.2% (14/430) in alleles with 2 AGGs or more. None of the alleles with 3 or more AGGs expanded to full mutations. Conclusion: We recommend that risk estimates for FMR1 premutation carriers be based on AGG interruptions as well as repeat size in Israel and worldwide.

Abnormalities in the X-linked FMR1 gene are associated with a constellation of disorders, which have broad and profound implications for the person first diagnosed, and extended family members of all ages. The rare and pleiotropic nature of the associated disorders, both common and not, place great burdens on (1) the affected families, (2) their care providers and clinicians, and (3) investigators striving to conduct research on the conditions. Fragile X syndrome, occurring more severely in males, is the leading genetic cause of intellectual disability. Fragile X associated tremor and ataxia syndrome (FXTAS) is a neurodegenerative disorder seen more often in older men. Fragile X associated primary ovarian insufficiency (FXPOI) is a chronic disorder characterized by oligo/amenorrhea and hypergonadotropic hypogonadism before age 40 years. There may be significant morbidity due to: (1) depression and anxiety related to the loss of reproductive hormones and infertility; (2) reduced bone mineral density; and (3) increased risk of cardiovascular disease related to estrogen deficiency. Here we report the case of a young woman who never established regular menses and yet experienced a 5-year diagnostic odyssey before establishing a diagnosis of FXPOI despite a known family history of fragile X syndrome and early menopause. Also, despite having clearly documented FXPOI the woman conceived spontaneously and delivered two healthy children. We review the pathophysiology and management of FXPOI. As a rare disease, the diagnosis of FXPOI presents special challenges. Connecting patients and community health providers with investigators who have the requisite knowledge and expertise about the FMR1 gene and FXPOI would facilitate both patient care and research. There is a need for an international natural history study on FXPOI. The effort should be coordinated by a global virtual center, which takes full advantage of mobile device communication systems.

Introduction Magnetic resonance (MR) imaging is a sensitive modality for demonstrating in vivo alterations in brain structure and function after acute organophosphate (OP) poisoning. The goals of this study were to explore early imaging findings in organophosphate-poisoned animals, to assess the efficacy of centrally acting antidotes and to find whether early MR findings can predict post-poisoning cognitive dysfunction. Methods Sprague–Dawley rats were poisoned with the agricultural OP paraoxon and were treated with immediate atropine and obidoxime (ATOX) to reduce acute mortality caused by peripheral inhibition of acetylcholinesterase. Animals were randomly divided into three groups based on the protocol of centrally acting antidotal treatment: group 1 – no central antidotal treatment (n = 10); group 2 – treated with midazolam (MID) at 30 min after poisoning (n = 9), group 3 – treated with a combination of MID and scopolamine (SCOP) at 30 min after poisoning (n = 9) and controls (n = 6). Each animal had a brain MR examination 3 and 24 h after poisoning. Each MR examination included the acquisition of a T2 map and a single-voxel 1H MR spectroscopy (localized on the thalami, to measure total creatine [Cr], N-acetyl-aspartate [NAA] and cholines [Cho] levels). Eleven days after poisoning each animal underwent a Morris water maze to assess hippocampal learning. Eighteen days after poisoning, animals were euthanized, and their brains were dissected, fixed and processed for histology. Results All paraoxon poisoned animals developed generalized convulsions, starting within a few minutes following paraoxon injection. Brain edema was maximal on MR imaging 3 h after poisoning. Both MID and MID + SCOP prevented most of the cortical edema, with equivalent efficacy. Brain metabolic dysfunction, manifested as decreased NAA/Cr, appeared in all poisoned animals as early as 3 h after exposure (1.1 ± 0.07 and 1.42 ± 0.05 in ATOX and control groups, respectively) and remained lower compared to non-poisoned animals even 24 h after poisoning. MID and MID + SCOP prevented much of the 3 h NAA/Cr decrease (1.22 ± 0.05 and 1.32 ± 0.1, respectively). Significant correlations were found between imaging findings (brain edema and spectroscopic changes) and clinical outcomes (poor learning, weight loss and pathological score) with correlation coefficients of 0.4–0.75 (p Conclusions MR imaging is a sensitive modality to explore organophosphate-induced brain damage. Delayed treatment with midazolam with or without scopolamine provides only transient neuroprotection with some advantage in adding scopolamine. Early imaging findings were found to correlate with clinical consequences of organophosphate poisoning and could be potentially used in the future to predict long-term prognosis of poisoned casualties.

Testing for genetic abnormalities in epithelial growth factor receptor (EGFR), anaplastic lymphoma receptor tyrosine kinase (ALK), and potentially additional genes is a critical tool in the care of advanced NSCLC. There is conflicting evidence for the role of such tests in early NSCLC. We report a single-institute Sequenom testing for a wide range of mutations and their clinical correlations in early-resected NSCLC specimens.Early NSCLC paraffin-embedded, formalin-fixed (FFPE) specimens were collected, DNA extracted, and using Sequenom-based matrix-assisted laser desorption/ionization-time of flight analysis, mutations in 22 oncogenes and tumor suppressor genes were evaluated. Clinical data was collected retrospectively.The technique was found to be feasible. Thirty-six of 96 patients (37.5%) had any genetic abnormality identified, and 8 (8.3%) had 2 or more mutations. Kirsten rat sarcoma viral oncogene homolog (KRAS) and EGFR were the most common genes to appear mutated (15.6%); phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) was the gene to be found most commonly in tumors with co-mutations. Transversions were found mostly in KRAS gene mutations and to be nonprognostic. No difference in the spectrum of mutations was found between squamous-cell and non-squamous-cell lung cancers. Ever-smokers showed a trend for worse prognosis, with a similar spectrum of mutations.Sequenom-based mutation screen is feasible using FFPE samples. More than a third of the patients were found to harbor some genetic abnormality, and 8% were found to have more than a single mutated gene. Wide-range gene screens using large sample depositories are required for further insight into the important genes at play in early NSCLC.

Identification of non-small cell lung carcinoma (NSCLC) patients at high-risk for recurrence after complete resection would potentially direct surveillance frequency and administration of adjuvant treatments. Genetic profiling of tumors could provide clinicians with information regarding recurrence risk. Conflicting evidence exists regarding EGFR, KRAS, and TP53 mutations as prognostic for recurrence. We aimed to test such mutations for prognostic significance in a cohort of early-resected NSCLC specimens. Formalin-fixed paraffin-embedded stage I NSCLC specimens resected in our institute during 1988–2008 were sampled. DNA was extracted and a panel of common EGFR, KRAS, and TP53 mutations was tested using a mass-spectrometry-based technique. Clinical data were extracted from patients’ files. A total of 96 NSCLC stage I patients were included in this study. EGFR mutation frequency of 15.6 %, KRAS mutation frequency of 15.6 %, and a TP53 mutation frequency of 6.2 % were found. A nonsignificant trend for longer relapse-free survival (RFS) was seen for patients with an EGFR mutation, and a nonsignificant trend for worse RFS was found for patients with a KRAS mutation. EGFR mutation and KRAS mutation were not found to be prognostic for RFS in our cohort of early NSCLC. Larger cohorts and a broader genetic screen for mutations are required.

The main aim was to develop recommendations on eMental health interventions for the treatment of psychotic disorders. A systematic literature search on eMental health interventions was performed, and 24 articles about interventions in psychotic disorders were retrieved and systematically assessed for their quality. Studies were characterized by a large heterogeneity with regard to study type, sample sizes, interventions and outcome measures. Five graded recommendations were developed dealing with the feasibility of eMental health interventions, beneficial effects of psychoeducation, preliminary results of clinical efficacy, the need of moderation in peer support eMental health groups and the need to develop quality standards.

The JAK2V617F mutation has emerged in recent years as a diagnostic as well as treatment target in patients with polycythemia vera (PV). We analyzed JAK2V617F allele burden (JAK2(V617F)) in a Jewish population with PV. Results were correlated with disease symptoms and complications. Median JAK2(V617F) was 48% and 54% in patients of Ashkenazi and non-Ashkenazi origin, respectively (p =0.75). Higher JAK2(V617F) was seen in patients with imaging-proven splenomegaly (p =0.01). A correlation between JAK2(V617F) and the weekly hydoxyurea dose needed for disease control was found (p =0.043). In addition, a trend for higher allele burden in patients with longer disease duration (p =0.064) and those treated with cytoreductive drugs other than hydroxyurea (p =0.056) was noted. Higher JAK2(V617F) was seen in patients with transformation to myelofibosis (p =0.0001), but not in patients with vascular complications. JAK2(V617F) may assist in prognostic stratification of patients with PV.

Summary The phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma (AKT) viral oncogene pathway is involved in regulating the signaling of multiple biological processes such as apoptosis, metabolism, cell proliferation, and cell growth. Mutations in the genes associated with the PI3K/AKT pathway including PI3K , AKT , RAS and PTEN , are infrequently found within head and neck squamous cell carcinoma and more specifically are rarely reported in oral squamous cell carcinoma (OSCC) cases. We aimed to investigate the frequency of mutations in AKT1 , PTEN , PIK3CA , and RAS ( K-RAS , N-RAS , H-RAS ) genes in 37 cases of oral squamous cell carcinoma (OSCC). Mutational analysis of PTEN , RAS , PIK3CA and AKT genes was performed using chip-based matrix-assisted laser desorption time-of-flight (MALDI-TOF) mass spectrometry and by direct sequencing. The only gene mutated in our series was the PIK3CA . Missense mutations of the PIK3CA gene were found in 4 of our cases (10.8%); no correlation has been found with oral location, stage and survival. The absence of mutations in AKT1 , PTEN , and RAS genes in the present study is in accordance with previous studies confirming that these genes are rarely mutated in OSCC. Our data confirm that PIK3CA is important to OSCC tumorigenesis and can contribute to oncogene activation of the PIK3CA / AKT pathway in OSCC. The knowledge of the PIK3CA’s involvement in OSCC is important because a specific kinase inhibitor could be considered as a future therapeutic option for OSCC patients with PIK3CA mutations.

Quinolinic acid (QA) induced striatal lesion is an important model for excitotoxicity that is also used for efficacy studies. To date, the morphological and spectroscopic indices of this model have not been studied longitudinally by MRI; therefore the objectives of this study were aimed at following the lesion progression and changes in N-acetyl aspartate (NAA) as viewed by MRI and MRSI, respectively, in-vivo over a period of 49 days. We found that the affected areas exhibited both high and low apparent diffusion coefficients (ADC) even 49 days post QA injection in three of the six tested animals. MRI-guided histological analysis correlated areas characterized by high ADCs on day 49 with cellular loss, while areas characterized by lower ADCs were correlated with macrophage infiltration (CD68 positive stain). Our MRSI study revealed an initial reduction of NAA levels in the lesioned striatum, which significantly recovered with time, although not to control levels. Total-striatum normalized NAA levels recovered from 0.67 +/- 0.15 (of the contralateral row) on day 1 to 0.90 +/- 0.12 on day 49. Our findings suggest that NAA should be considered as a marker for neuronal dysfunction, in addition to neuronal viability. Some behavioral indices could be correlated to permanent neuronal damage while others demonstrated a spontaneous recovery parallel to the NAA recovery. Our findings may have implications in efficacy-oriented studies performed on the QA model.

Purpose: To investigate the neuroprotective effect of brimonidine following induction of ischaemic optic neuropathy in rodents (rAION). Methods: Mice were treated with an intraperitoneal injection of brimonidine 48, 24 or 0 h before rAION induction or eye drops for 5 days after rAION induction. Retinal ganglion cell (RGC) loss and expression of genes involved in the angiogenesis (vascular endothelial growth factor [VEGF], pigment epithelium-derived factor [PEDF], The epidermal growth factor homology domains-2 [Tie-2]), ischaemia (haem oxygense-1 [HO-1], hypoxia-inducible factor 1α[HIF-1α], endothelial nitric oxide synthase [eNOS]) and oxidative stress (superoxide dismutase-1 [SOD-1], glutathione peroxidase-1 [GPX-1]) response to ischaemic damage were compared with sham or rAION-untreated mice. Results: No RGC loss was detected in the brimonidine-treated mice. Effect of post-rAION eye drops: day 1 – no decrease in retinal mRNA levels of angiogenesis-related genes, increase in ischaemia- and oxidative stress-related genes except HIF-1α; day 3 – baseline or higher levels of oxidative and ischaemia-related genes except HIF-1α, increase in VEGF, decrease in PEDF; day 21 – no change in angiogenesis-related genes. Effect of pre-rAION injection: baseline levels of angiogenesis-related genes with all injection schedules; increase in ischaemia-related genes with 48-h and 0-h pretreatment; decrease in HO-1 and eNOS with 24-h pretreatment; increase in oxidative-related genes except GPX-1. In optic nerve tissue, HO-1, HIF-1α and SOD-1 decreased on day 1 after topical administration and were still below baseline on day 3. Conclusions: The increase in HO-1 associated with rAION is mitigated with brimonidine treatment, especially when administered intraperitoneally. Topical brimonidine apparently reduces VEGF, Tie-2, HIF-1α and GPX-1 expression on day 21. These results agree with published data and may have therapeutic implications for patients diagnosed with AION in the acute phase.

The PI3 K/AKT pathway is frequently activated in human cancer. Recently, a G to A point mutation (E17 K) was found in the pleckstrin homology domain of AKT1. We aimed to explore this mutation in cases of urothelial carcinoma. Using chip-based matrix-assisted laser desorption-time-of-flight (MALDI-TOF) mass spectrometer, AKT1 E17 K mutation was searched in 26 total RNA samples obtained from 26 patients known to have urothelial carcinoma. Mutation was found in one out of 26 (3.8%) patients – a 46 year old female with a low grade transitional cell carcinoma located to the lamina propria (Ta disease). Our finding is in line with previous studies showing AKT1 E17 K mutation to be rare. Yet, further studies are required to determine whether this mutation is indeed related to less aggressive disease and carries better prognosis.

BRCA1/BRCA2 germline mutations substantially increase breast and ovarian cancer risk, yet penetrance is incomplete. We hypothesized that germline epigenetic gene silencing may affect mutant BRCA1/2 penetrance. To test this notion, we determined the methylation status, using methylation-specific quantitative PCR of the promoter in putative modifier genes: BRCA1, BRCA2, ATM, ATR and P53 in Jewish BRCA1/BRCA2 mutation carriers with (n = 41) or without (n = 48) breast cancer, in sporadic breast cancer (n = 52), and healthy controls (n = 89). Promoter hypermethylation was detected only in the BRCA1 promotor in 5.6-7.3% in each of the four subsets of participants, regardless of health and BRCA1/2 status.Germline promoter hypermethylation in the BRCA1 gene can be detected in about 5% of the female Israeli Jewish population, regardless of the BRCA1/2 status. The significance of this observation is yet to be determined.

Alzheimer's disease (AD) and Vascular Dementia (VaD) are the most common types of dementia and are progressive diseases affecting millions of people. Despite the high sensitivity of MRI to neurological disorders it has not thus far been found to be specific for the detection of either of these pathologies. In the present study high b-value q-space diffusion-weighted MRI (DWI) was applied to VaD and AD. Controls (N=4), VaD patients (N=8) and AD patients (N=6) were scanned with high b-value DWI, which emphasizes the water component which exhibits restricted diffusion. VaD patients were found to present major WM loss while, in AD, the major pathology found was GM changes, as expected. Also, WM changes in VaD and AD were of a different pattern, more specific to frontal and temporal areas in AD and more widespread in VaD. This pattern of WM changes may be utilized as a diagnosis criterion. Conventional diffusion tensor imaging did not show significant changes between either of the groups and controls. These results demonstrate the potential of high b-value DWI in the diagnosis of dementia.

Importance The risk for herpes zoster (HZ) in patients with psoriasis treated with biologic medications or other systemic treatments has been given little attention to date. Objective To describe the risk for HZ in patients with psoriasis and its relation to treatment. Design, Setting, and Participants A cohort study was performed using the administrative database of Clalit Health Services, the largest public health care provider organization in Israel, in the setting of general community clinics, primary care and referral centers, and ambulatory and hospitalized care. We extracted information for all patients who received a psoriasis diagnosis from January 2002 to June 2013. Follow-up was conducted until the end of July 2013. The study included 95 941 patients with psoriasis in the analysis, with 522 616 person-years of follow-up. Incidence of HZ events was calculated for each systemic antipsoriatic medication provided, during a follow-up period of 11 years and 7 months. We used a generalized estimating equation Poisson regression model to examine the effect of each systemic treatment for psoriasis on HZ incidence, adjusting for age, sex, psoriasis severity, Charlson comorbidity index, steroid treatment, and socioeconomic status. Main Outcomes and Measures Incidence of HZ associated with systemic therapies. Results In a multivariate analysis, it was observed that treatment with phototherapy (rate ratio [RR], 1.09 [95% CI, 0.62-1.93]; P = .99), methotrexate (RR, 0.98 [95% CI, 0.78-1.23]; P = .83), cyclosporine (RR, 1.16 [95% CI, 0.48-2.80]; P = .49), and biologic medications as a single agent (RR, 2.67 [95% CI, 0.69-10.3]; P = .14) was not associated with HZ. The use of combination treatment with biologic medications and methotrexate was significantly associated with an increased incidence of HZ (RR, 1.66 [95% CI, 1.08-2.57]; P = .02). The use of acitritin was associated with decreased incidence of HZ (RR, 0.69 [95% CI, 0.49-0.97]; P = .004). Conclusions and Relevance Physicians may need to consider offering an HZ preventive vaccine to patients receiving combination treatment with biologic medications and methotrexate, particularly if they have additional risk factors for HZ.

Experimental allergic encephalomyelitis (EAE) is the primary experimental model of multiple sclerosis (MS), which involves both inflammation and demyelination and is known to be species-dependent. Spinal cord abnormalities were found in more than 80% of postmortem specimens of MS patients. In the present study, T1, T2 and high b-value q-space diffusion-weighted magnetic resonance imaging (MRI) were used, for the first time, to characterize the EAE model in excised swine spinal cords. The MR images were compared with histological staining and clinical scoring. Although all spinal cords were excised from swine with severe or very severe (clinical score between 3 to 5 on a scale of 5) motor impairments, T1- and T2-weighted MRI revealed white matter (WM) abnormalities in only five of the ten EAE diseased spinal cords studied, while high b-value q-space diffusion weighted MRI (q-space DWI) detected WM abnormalities in all diseased spinal cords studied. Interestingly, high b-value q-space DWI was able to detect abnormalities in the normal appearing white matter (NAWM) even in spinal cords where no plaques were identified by the T1- and T2-weighted MR images. Good anatomical correlation was observed between the high b-value q-space MR images and histology. The extent of DWI abnormalities paralleled the clinical scoring and correlated with histology. In addition, areas classified as NAWM by the T1- and T2-weighted MR images that showed abnormalities in the q-space DWI were also found to have abnormal histology. This improved detection level of the EAE model by high b-value q-space DWI over conventional T1-, and T2-weighted MRI is briefly discussed.

Papillary thyroid carcinoma may encompass a mixed group of neoplasms where divergence in clinical behavior may reflect distinct genetic alterations. For example, young patients with papillary thyroid carcinoma have a better prognosis than affected adults, and their carcinomas are much more likely to harbor chromosomal rearrangements involving the RET proto-oncogene. Mutational activation of the BRAF oncogene has recently been identified as the most common genetic alteration in papillary thyroid carcinoma, but little is known about its frequency as a function of patient age. We tested 20 papillary thyroid carcinomas from young patients ranging from 10 to 17 years of age for the thymine (T) --adenine (A) missense mutation at nucleotide 1796 in the BRAF gene using a newly developed assay that employs a novel primer extension method (Mutector assay). The prevalence of BRAF mutation was compared with a larger group of papillary thyroid carcinomas from previously tested adult patients (20 years). BRAF mutations were not common in papillary thyroid carcinomas from young patients compared to their counterparts in adults (20 vs 77%; OR=13.3, 95% confidence interval (CI)=3.4-56.5; P0.0001), but they become increasingly prevalent with advancing patient age (OR as a function of age at 10-year intervals=1.80 CI=1.33-2.44; P0.001). Unlike papillary thyroid carcinomas that arise in adults, mutational activation of BRAF is not a major genetic alteration in papillary thyroid carcinomas that arise in young patients. The increasing frequency of BRAF mutations as a function of age could help account for the well documented but poorly understood observation that age is a relevant prognostic indicator for patients with papillary thyroid carcinoma.

Objectives/Hypothesis: Epstein-Barr virus (EBV) has classically been associated with nasopharyngeal carcinoma and Burkitt's lymphoma. Recently, multiple studies have been published linking EBV with oral squamous cell carcinoma and, to a lesser extent, hypopharyngeal and laryngeal tumors. Using a sensitive method of detection, the authors sought to analyze the presence and quantity of EBV DNA in a large cohort of head and neck cancers. Study Design: Retrospective cohort study. Methods: Three hundred head and neck cancer samples exclusive of nasopharyngeal carcinoma were examined for the presence of EBV using quantitative polymerase chain reaction. Eighty-four tumor samples from the larynx, 30 from the hypopharynx, 73 from the oropharynx, and 113 from the oral cavity were analyzed for EBV quantity, which was expressed as the number of viral copies per cell genome. Representative samples, which contained the highest EBV DNA levels, were examined using in situ hybridization. Results were correlated with tumor grade and site and tobacco and alcohol exposure. Results: Three of 300 (1%) tumor samples were overtly positive for EBV DNA (defined as >0.1 copies of viral DNA/cell genome). Five of 300 (2%) tumor samples showed low levels (defined as >0.01 and

BACKGROUND: The number of (trinucleotide) CAG repeats within the androgen receptor (AR) gene is inversely correlated with transcriptional activity of testosterone-target genes. Although abnormally long CAG repeats are strongly associated with male infertility, it is unclear whether CAG repeat length polymorphism can affect androgen receptor activity and sperm parameters. To explore the previously suggested association between CAG repeats and male fertility, we conducted this prospective cohort study. METHODS: We enrolled 172 men attending the IVF unit in Shaare-Zedek Medical Center. Sperm concentration, motility and morphology and the number of CAG repeats in the AR gene were measured. RESULTS: Mean CAG repeat length was greater in teratozoospermia (

Objective . Our recent study determined the possible effects and incidence of BRCA1 and BRCA2 germline mutations in uterine serous papillary carcinoma (USPC). The purpose of this study was to determine the incidence of these mutations in an enlarged series of USPC. Methods . We screened DNA from 27 women with USPC for BRCA1 and BRCA2 germline mutations common in the Jewish population ( BRCA1 -185delAG and 5382 insC, BRCA2 -6174delT). In women with germline mutations, tumor DNA was screened for loss of heterozygosity (LOH) at the appropriate loci. Results . Women (20) were of Jewish Ashkenazi origin and seven were non-Ashkenazi. Four of 20 (20%) Ashkenazi women were carriers of germline mutations: three 185delAG mutation and one 5382insC mutation. All carriers had strong family histories of breast–ovarian carcinoma. Seven out of 20 (35%) women had been diagnosed for breast carcinoma before diagnosis of USPC. Family histories of 12 women (60%) showed at least one first-degree relative with breast, ovarian, or colon carcinoma. Loss of heterozygosity analysis found a loss of the wild-type BRCA1 allele in three of the four primary uterine tumors that were examined. Conclusions . Our findings further support our previous published data suggesting a high incidence of BRCA carriers among USPC Ashkenazi Jewish patients. The loss of heterozygosity in the tumor tissue of carriers coupled with the high frequency of patient and family history of breast and ovarian malignancies suggest that USPC might be part of the manifestation of familial breast–ovarian cancer in Ashkenazi Jewish patients.

Despite the many studies of the middle cerebral artery occlusion (MCAO) model, efficient therapy for stroke is still lacking, emphasizing the need for further development and characterization of experimental stroke models. In the present study, the rather unexplored multifocal microsphere-induced stroke model in rats was characterized by multiparametric MRI. We induced microembolic infarction in a group of Sprague-Dawley rats by injecting a dose of about 1000 50-m polyethylene microspheres intracranially from the external carotid artery. Diffusion-, perfusion-, and T2-weighted MRI were used to evaluate the infarct development during and following the first 3 hr after microsphere injection (N 20). The animals were also imaged at 12-hr (N 8), 24-hr (N 17), and 48-hr (N 5) time points. After the final imaging time point, the brains were removed and sectioned into 2-mm-thick slices, and infarct volumes were measured by 2,3,4-triphenyltetrazolium chloride (TTC) staining. From calculated apparent diffusion coefficient (ADC) maps, a volume of reduced ADC appeared 0.5–1.0 hr postinjection, and by the 3-hr time point the volume of ADC reduction had increased to a size of 5% 1% (mean SEM) of the brain hemisphere. The lesion volume increased significantly (P < 0.01) to 16% 2% of the hemisphere volume at the 12-hr time point, while at 24 hr the lesion (15% 2% of the hemisphere) was also significantly larger (P < 0.001) than at 3 hr. The perfusion deficit resulting from the microsphere injection was immediate, going from a cerebral blood flow index (CBFi )o f 74% 3% at the time of microsphere injection to 68% 2% of the contralateral mean at 3 hr (P < 0.05), to 55% 4% of the contralateral values at 12 hr (P < 0.05), and to 57% 2% of the contralateral mean at 24 hr (P < 0.001). The lesion development in the microsphere-induced stroke model was found to be slower than in the MCAO model, and continued up to the 24 – 48-hr time point. Magn Reson Med 51:1232–1238, 2004.

Hypertension is one of the major risk factors of stroke and vascular dementia (VaD). We used stroke prone spontaneous hypertensive rats (SPSHRs) as a model for neuronal degeneration frequently occurring in humans with vascular disease. Recently, high b value q-space diffusion-weighted imaging (DWI) was shown to be very sensitive to the pathophysiological state of the white matter. We studied the spinal cords of SPSHR rats ex vivo after the appearance of motor impairments using diffusion anisotropy and q-space diffusion imaging (measured at a high b value of up to 1 × 105 s/mm2). The diffusion anisotropy images computed from low b value data set (bmax approximately 2500 s/mm2) showed a small but statistically significant decrease (approximately 12%, P < 0.05) in the diffusion anisotropy in the spinal cords of the SPSHR group as compared to control rats. However, more significant changes were found in the high b value q-space diffusion images. The q-space displacement values in the white matter of the SPSHR group were found to be higher by more than 70% (P < 0.002) than that of the control group. These observations concurred with electron microscopy (EM) that showed significant demyelination in the spinal cords of the SPSHR group. These results seem to indicate that high b value q-space DWI might be a sensitive method for following demyelination and axonal loss associated with vascular insults.

Summary The aim of this study was to assess portal imaging for quality assurance of patient positioning in external beam radiotherapy. We present a retrospective study of the variability of patient position in the treatment of 34 prostate cancer patients who were treated with whole pelvic irradiation followed by arc therapy or boost field (Series I) and 25 patients treated by ‘small’ pelvic 4-field box technique (Series II). Weekly anteroposterior-posteranterior (AP-PA) and left-lateral portal images were compared to simulation films by using a fiducial point-pair registration technique based on the computer-assisted portal imaging quality assurance program PIPSpro, developed specifically for the verification of treatment positioning in radiation therapy. Series I consisted of 34 patients and 194 portal films (97 AP-PA and 97 left-lateral). Overirradiated (OA) and underirradiated (UA) areas were computed in terms of percentage of the reference field size. For the AP-PA portals, the average OA was 2.75% and average UA was 2.74%. For left-lateral portals, an average OA of 2.49% and UA of 2.78% were measured. Series II consisted of 25 patients and 194 portal films (98 AP-PA and 96 left-lateral). The average OA was 0.88% and average UA was 0.86% in AP-PA portals, and 1.03 and 0.82% for left-lateral portals, respectively. The accuracy of patient positioning in irradiation of prostate cancer in our institution is in the range of 2.69% for whole pelvic fields and 1.0% for small fields. We conclude that PIPSpro is an effective and useful tool for quality assurance in radiotherapy.

High b value diffusion weighted magnetic resonance imaging (high-b DWI) was used to characterize white matter changes in the brain of patients with vascular dementia (VaD). Hyperintense white matter areas detected by T2-weighted magnetic resonance imaging (MRI) represent lesions, also termed leukoaraiosis that are very common in VaD as well as in other types of dementia. Therefore, the role of white matter changes in the cognitive and memory decline that occurs in VaD patients is still under debate. High-b DWI, analyzed using the q-space approach, is a more sensitive MRI method for detection of white matter changes. High-b DWI revealed massive white matter loss in VaD patients that surpassed the boundaries of T2 hyperintensities. This technique, therefore, might serve as a better indication for the extensive nerve fiber loss in the white matter that is caused by vascular disease.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) which affects nearly one million people worldwide, leading to a progressive decline of motor and sensory functions, and permanent disability. High b-value diffusion-weighted MR images (b of up to 14000 s/mm 2 ) were acquired from the brains of controls and MS patients. These diffusion MR images, in which signal decay is not monoexponential, were analyzed using the q-space approach that emphasizes the diffusion characteristics of the slow-diffusing component. From this analysis, displacement and probability maps were constructed. The computed q-space analyzed MR images that were compared with conventional T1, T2 (fluid attenuated inversion recovery (FLAIR)), and diffusion tensor imaging (DTI) images were found to be sensitive to the pathophysiological state of white matter. The indices used to construct this qspace analyzed MR maps, provided a pronounced differentiation between normal tissue and tissues classified as MS plaques by the FLAIR images. More importantly, a pronounced differentiation was also observed between tissues classified by the FLAIR MR images as normal-appearing white matter (NAWM) in the MS brains, which are known to be abnormal, and the respective control tissues. The potential diagnostic capacity of high b-value diffusion q-space analyzed MR images is discussed, and experimental data that explains the consequences of using the q-space approach once the short pulse gradient approximation is violated are presented. Magn Reson Med 47:115‐126, 2002. © 2002 Wiley-Liss, Inc.

Uterine papillary serous carcinoma (UPSC) is an uncommon highly malignant variant of endometrial carcinoma that histologically and clinically resembles ovarian papillary serous carcinoma. The purpose of this study was to present the conjoined experience of two regional hospitals in the south of Israel (Soroka Medical Center, Beer-Sheva and Kaplan Hospital, Rehovot) of handling this tumour.Data from the files of 19 patients with UPSC who were managed at these hospitals between July 1991 and June 1997 were evaluated.The three-year survival rate was 57.3% overall; 83.3% for Stage I and 21.2% for Stages II, III, and IV combined (P0.02). Eighteen patients had primary surgery which included total abdominal hysterectomy and bilateral salpingo-oophorectomy and 15 (83.3%) of them received postoperative adjuvant therapy which included radiotherapy and/or systemic chemotherapy.The prognosis of patients with UPSC is worse than that of patients with other forms of endometrial carcinoma. Primary surgery comprised of total abdominal hysterectomy, bilateral salpingo-oophorectomy and staging is the mainstay of treatment. The type of postoperative treatment is not consistent. By and large, adjuvant pelvic radiotherapy is usually given in early-stage disease and adjuvant systemic chemotherapy is usually prescribed in advanced-stage disease.

Diffusion- and T2-weighted MRI were used to evaluate changes in brain water characteristics following closed-head injury in rats. Images were collected within the first 2 h and at 24 h and 7 days following the traumatic event and then compared with histology. The ratios between the apparent diffusion coefficients (ADCs) of the traumatized tissues and normal brain tissues were significantly different from unity and were found to be 0.79 +/- 0.25 (p0.01), 0.49 +/- 0.33 (p0.0002), and 3.47 +/- 1.36 (p10(-6)) at 1-2 h, 24 h, and 1 week after the trauma, respectively. In severe trauma, areas of hyperintensity which were not apparent on the T2-weighted images could be detected on the diffusion-weighted images within 1-2 h after the trauma. At 24 h following the traumatic event, large areas of hyperintensity are observed in both types of images. One week following the trauma, the ADCs of the traumatized tissues (1.84 +/- 0.69 x 10(-5) cm2/s) are much larger than those of normal brain (0.57 +/- 0.19 x 10(-5) cm2/s) and approach the value of free water. At 7 days, the areas of hyperintensity in the T2-weighted images seem to underestimate the injured areas found by histology. At this time point a good correlation is obtained between the areas of hypointensity observed on the diffusion-weighted images and the infarct areas obtained by histology (r = 0.88).

Background Uterine sarcomas are rare, characterized by rapid clinical progression and poor prognosis, and their management has been a challenge. The purpose of this study was to investigate the clinical and histologic findings, treatment, and outcome of patients with uterine sarcoma in the south of Israel. Methods Data from the files of 36 patients with uterine sarcoma who were managed at the Soroka Medical Center between January 1961 and December 1994 were evaluated. Results The 5-year survival rate was 32% overall; 63% for 9 patients with endometrial stromal sarcoma (ESS), 30% for 14 patients with mixed mesodermal sarcoma (MMS) and 18% for 13 patients with leiomyosarcoma (LMS); 41% for 22 patients with Stage I and 19% for 14 patients with Stages II, III, and IV. Only the difference in the 5-year survival rate between ESS and LMS was statistically significant (P < 0.05). Eleven patients (30.6%) were treated with surgery alone, 4 (11.1%) with surgery followed by pelvic radiotherapy, 11 (30.6%) with surgery followed by chemotherapy, 8 (22.2%) with surgery followed by pelvic radiotherapy and chemotherapy, one (2.8%) with chemotherapy alone, and one (2.8%) had no treatment. Conclusions Uterine sarcomas are aggressive tumors with a poor prognosis. The treatment is surgery generally followed by adjuvant pelvic radiotherapy and/or systemic chemotherapy. J. Surg. Oncol. 64:55–62 © 1997 Wiley-Liss, Inc.

Background. Recently, a high incidence of BRCA1 cancer predisposing mutation was described among patients with Uterine Serous Papillary Carcinoma (USPC). A BRCA2 germline mutation in a USPC patient has never been reported. Case. A 65-year-old Ashkenazi Jewish woman was diagnosed with USPC Stage III A. The patient family history included a mother with ovarian carcinoma, a maternal aunt who had breast carcinoma that was diagnosed at an early age, an additional maternal aunt who suffered from gastric carcinoma, and the patient's sister who had duodenal carcinoma. The patient was found to be a carrier of the germline BRCA2 cancer predisposing mutation (6174delT). Conclusions. We report the first case of a BRCA2 mutation in a USPC patient. A strong family history of breast and ovarian cancer with the presence of the BRCA2 germline mutation is an additional hint for the possible association between BRCA cancer predisposing mutations and USPC.

Endometriosis is associated with an increased risk of ovarian cancer. Few studies have also shown increased risk of breast cancer. BRCA1/2 mutations are linked to an increased risk of breast and ovarian cancers but their relation to endometriosis is unknown. The objective of this study was to examine the mutation rate of BRCA1/2 among women with surgically treated ovarian endometriosis. We collected 126 specimens from Jewish Ashkenazi women with endometriotic (76) and control non-endometriotic (50) ovarian cysts, reviewed the pathological diagnoses and extracted DNA from all samples. Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), samples were examined for the founder germline mutations of BRCA1/2, most common among Ashkenazi Jews. The rate of mutations in each group was calculated and compared. BRCA1/2 mutation rate was 1/76 (1.3%) in the endometriotic cyst study group and 1/50 (2%) in the control non-endometriotic cysts, showing no statistically significant difference between the groups (p=0.84). BRCA1/2 mutation rate was similar to the previously reported rate among Jewish Ashkenazi women. BRCA1/2 mutation rates in patients with endometriotic ovarian cysts and with non-endometriotic ovarian cysts are similar. A larger cohort is required to completely exclude the possibility of an association between BRCA1/2 mutations and surgically treated endometriosis.

In a study of 37 patients diagnosed with cervical adenocarcinoma between 1961 and 1994, clinical and pathologic findings were evaluated. Of the 37 patients, 27 (73%) had a pure adenocarcinoma, five (13.5%) had a collision tumor and five (13.5%) had an adenosquamous carcinoma. Twenty-six patients (70.3%) were diagnosed in Stage I, and 11 (29.7%) patients in Stage II, III, and IV. Two patients (5.4%) were treated with simple hysterectomy alone, nine (24.3%) with simple hysterectomy followed by radiotherapy, eight (21.6%) with radical hysterectomy alone, five (13.5%) with radical hysterectomy followed by radiotherapy, nine (24.3%) with radiotherapy alone, one (2.7%) with radiotherapy followed by simple hysterectomy, and three (8.1%) received no treatment. The actuarial 5-year survival rate was 69%. It is suggested that for patients with small early-stage disease, radical hysterectomy should be primary treatment and postoperative adjuvant radiotherapy would be advocated if high-risk features are histologically demonstrated. For all other patients, radiotherapy should be primary treatment.

Our objective was to determine the pregnancy outcome in women who underwent a Shirodkar cerclage following a failed McDonald procedure in previous pregnancy. The study included 62 women who underwent an elective Shirodkar procedure between week 9 and week 15 of their singleton pregnancies. They had all failed to complete 34 weeks of gestation in their previous pregnancy despite the use of a McDonald cerclage. Complications observed included premature contractions in 18 patients (29.0%), preterm premature rupture of the membranes (PROM) in 7 (11.3%), vaginal bleeding in 6 (9.7%), chorioamnionitis in 2 (3.2%), cervical laceration in 1 (1.6%), and a single case (1.6%) of rupture of the uterus. Spontaneous abortion ( 37 weeks gestation) in 41 (66.1%) of the women. The fetal survival rate was 88.7% (55 viable newborns). I...

Diffusion MRI is extensively used to study brain microarchitecture and pathologies, and water diffusion appears highly anisotropic in the white matter (WM) of the spinal cord (SC). Despite these facts, the use of diffusion MRI to study the SC, which has increased in recent years, is much less common than that in the brain. In the present review, after a brief outline of early studies of diffusion MRI (DWI) and diffusion tensor MRI (DTI) of the SC, we provide a short survey on DTI and on diffusion MRI methods beyond the tensor that have been used to study SC microstructure and pathologies. After introducing the porous view of WM and describing the q-space approach and q-space diffusion MRI (QSI), we describe other methodologies that can be applied to study the SC. Selected applications of the use of DTI, QSI, and other more advanced diffusion MRI methods to study SC microstructure and pathologies are presented, with some emphasis on the use of less conventional diffusion methodologies. Because of length constraints, we concentrate on structural studies and on a few selected pathologies. Examples of the use of diffusion MRI to study dysmyelination, demyelination as in experimental autoimmune encephalomyelitis and multiple sclerosis, amyotrophic lateral sclerosis, and traumatic SC injury are presented. We conclude with a brief summary and a discussion of challenges and future directions for diffusion MRI of the SC. Copyright © 2016 John Wiley & Sons, Ltd.

In a study of 20 patients diagnosed with malignant ovarian germ cell tumors between 1961 and 1993, clinical and pathologic findings were evaluated. Of the 20 patients, seven (35%) had dysgerminoma, two (10%) endodermal sinus tumor, three (15%) malignant teratoma, one (5%) malignant struma ovarii, one (5%) primary ovarian carcinoid, two (10%) benign teratoma with malignant transformation, and four (20%) combination germ cell tumor. Twelve patients (60%) had stage IA, five (25%) stage IC, and three (15%) stage IIIC. Twelve patients (60%) underwent conservative surgery and eight (40%) had at least bilateral salpingo-oophorectomy. At follow-up, 18 patients (90%) were alive free of disease, one (5%) had died of disease, and one (5%) had died of intercurrent disease. The actuarial 5-year survival rate was 93.3%. It is concluded that for young women who wish to preserve child-bearing capacity, regardless of the stage of the tumor, fertility-preserving surgery with complete surgical staging followed, if necessary by cisplatin-based combination chemotherapy is an appropriate and definitive treatment in the absence of involvement of the contralateral ovary and uterus. For patients in whom child-bearing capacity is not an issue, surgery should include total abdominal hysterectomy and bilateral salpingo-oophorectomy with complete staging, followed if necessary by chemotherapy.

The BRAF gene has been found to be activated by mutation in human cancers, predominantly in malignant melanoma. We tested 476 primary tumors, including 214 lung, 126 head and neck, 54 thyroid, 27 bladder, 38 cervical, and 17 prostate cancers, for the BRAF T1796A mutation by polymerase chain reaction (PCR)-restriction enzyme analysis of BRAF exon 15. In 24 (69%) of the 35 papillary thyroid carcinomas examined, we found a missense thymine (T)-->adenine (A) transversion at nucleotide 1796 in the BRAF gene (T1796A). The T1796A mutation was detected in four lung cancers and in six head and neck cancers but not in bladder, cervical, or prostate cancers. Our data suggest that activating BRAF mutations may be an important event in the development of papillary thyroid cancer.

Objective To evaluate the safety and efficacy of tamoxifen co-administration during conventional controlled ovarian hyperstimulation (COH) protocols for a fertility-preservation IVF cycle in breast cancer patients. Design Two groups: retrospective descriptive cohort study and prospective study. Setting Breast cancer oncology and fertility-preservation centers in a tertiary hospital. Patient(s) Two groups of breast cancer patients: premenopausal patients treated with adjuvant tamoxifen; and patients undergoing in vitro fertilization (IVF) for fertility preservation. Intervention(s) Fertility-preservation cycles, tamoxifen co-administration during conventional IVF. Main Outcome Measure(s) Endocrine records, and IVF results. Result(s) Estradiol (E 2 ) levels were chronically high (mean 2663 pmol/L, maximum: 10,000 pmol/L) in 38 of 46 breast cancer patients treated with adjuvant tamoxifen. Co-administration of tamoxifen (48 cycles) during conventional IVF or without tamoxifen (26 cycles), using either the long gonadotropin-releasing hormone–agonist or–antagonist protocols, resulted, respectively, in a mean of 12.65 and 10.2 oocytes retrieved, and 8.5 and 6.4 embryos cryopreserved. Average peak E 2 levels were 6,924 pmol/L and 5,093 pmol/L, respectively, but long-term recurrence risk (up to 10 years) was not increased. Conclusion(s) In breast cancer patients, co-administration of tamoxifen during conventional COH for fertility preservation does not interfere with IVF results. The high serum E 2 levels during COH should be considered safe, as it simulates the high prevalence of persistently high serum E 2 levels in premenopausal breast cancer patients safely treated with adjuvant tamoxifen.

This study investigated the correlation between in vivo serial T2-weighted magnetic resonance (MR) imaging and changes in superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, and water, sodium ion (Na+), and potassium ion (K+) contents measured in vitro using rat brain following right middle cerebral artery occlusion in conjunction with bilateral common carotid artery (CCA) occlusion. One hour later the left CCA was released. Serial MR images showed edema developed from the outer cortex towards the center. The T2 signal intensity of the injured right cortex increased with time compared to that of the contralateral cortex. Increased Na+ and water and decreased K+ contents occurred in the injured cortex, indicating that serial T2-weighted MR imaging reflects the changes in water content and Na+ and K+ concentrations determined by biochemical techniques. GSH-Px activity was little changed. Total SOD in the injured cortex decreased 1 hour after ischemia and remained low throughout the experiment. In contrast, SOD activity in the noninfarcted left cortex also decreased after 1 hour but returned to normal after 2 hours of ischemia. Our results suggest that oxygen free radicals are important in developing ischemic brain edema and cerebral infarction.

Immunosuppressive acidic protein (IAP) has been described as a tumor marker in a number of malignant diseases. To evaluate the clinical importance of IAP in breast cancer patients, IAP serum level was determined in 75 breast cancer patients, using single radial immunodiffusion. Serum samples were also tested for CA 15-3. Cut off value for IAP was determined according to IAP serum level in 50 patients with benign, non inflammatory, diseases, and was set as 725 microgram/ml. Mean IAP serum level (623 mcg/ml) and positivity rate (20%) in 24 breast cancer patients with active disease were similar to those in 51 breast cancer patients with no evidence of disease (590 mcg/ml and 18%). The mean CA 15-3 serum level and positivity rate were significantly higher in patients with active disease (200 units/ml, 67%), compared to patients with no evidence of disease (18.3 units/ml, 6%). In our experience IAP was not found to be an effective tumor marker in breast cancer.

Mutations in the LMNA gene encoding lamins A/C are responsible for Hutchinson-Gilford syndrome (HGS), a disorder of premature aging. Cataract is 1 of the main manifestations. The most prevalent mutation in Hutchinson-Gilford syndrome is C1824T, which activates a cryptic splice donor site to produce an abnormal lamin A protein. The purpose of this study was to investigate a possible association of the C1824T mutation with age-related cataract. Anterior lens capsule material was collected during cataract extraction surgery from 178 patients with senile cataract during 2007-2008. DNA and mRNA were extracted and sequenced for the LMNA gene. DNA and cDNA were screened for the C1824T mutation, which was not detected. Messenger RNA (mRNA) expression was normal, with no truncation. We found that human age-related nuclear cataract is not associated with LMNA gene mutations or truncation of lamin A.

Objective To develop a rapid, sensitive and reliable method to detect FOXL2 C402G mutation in granulosa cell tumor (GCT) and to investigate the prevalence of FOXL2 mutation in granulose cell tumors among Israeli patients. Methods We designed and optimized a matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) genotyping assay to detect FOXL2 C402G mutation in DNA isolated from formalin-fixed paraffin-embedded tissue samples. We examined 20 tumor samples obtained from Israeli patients diagnosed with granulose cell tumor. Results Eighteen out of 20 samples were found to harbor FOXL2 C402G mutation. Pathological review of the two tumors harboring wild type FOXL2 (C402) concluded that they were adenocarcinomas and has been misclassified at initial diagnosis. We found that the prevalence of FOXL2 mutations among Israeli patients with GCT (100%) is similar to previous reports. Conclusions Our results indicate that the FOXL2 mutations can be reliably detected by MALDI-TOF-MS genotyping. MALDI-TOF-MS genotyping is a simple, robust and highly sensitive method to detect FOXL2 C402G mutation. Our results confirm previous studies reporting over 95% prevalence of FOXL2 mutation in GCT. Furthermore, we suggest that testing for the presence of the FOXL2 C402G mutation may improve diagnostic accuracy.

Open liver biopsy in a 34-year-old woman with hepatosplenomegaly showed small noncleaved cell lymphoma. Except for an enlarged spleen, there was no evidence of other sites of involvement. She was treated with combination chemotherapy and is alive and free of disease > 5 years after diagnosis. We believe this to be the first reported case in an adult of primary hepatic or hepatosplenic lymphoma of the small cleaved cell type with long-term disease-free survival.

Primary adrenal lymphoma is extremely rare. Only 75 cases have been reported in the medical literature. A case of non-Hodgkin's lymphoma originating in both adrenal glands is presented. Combination chemotherapy apparently produced complete disappearance of the primary lymphomatous lesions, but subsequently a cerebral relapse was discovered 6 months later, in the form of a solid brain mass. Cranial extension of primary adrenal lymphoma is extremely unusual, and the presentation as a solid mass seems to be unique.

Specific mutations leading to the development of various histological grades of intraductal papillary mucinous neoplasm (IPMN) have been partially characterized.Analysis of 323 oncogenic mutations in 22 tumor-related genes was conducted, using a chip-based matrix-assisted laser desorption time-of-flight mass spectrometer of DNA extracted from microdissected cells of low-grade (n = 14), borderline (n = 6), and invasive IPMN (n = 7). Additional assays were performed on the DNA extracted from dyplastic cells found in the background of the adenocarcinoma.We identified 9 K-ras mutations (low grade, 2/14; borderline, 1/6; invasive, 6/7), 3 p53 mutations (low grade, 1/14; invasive 2/7), and 2 PIK3CA mutations (low grade, 1/14; invasive, 1/7). K-ras, p53, and PIK3CA mutations present in the invasive cancer were absent in the adjacent precursor cells in 50% of the cases. In one patient, K-ras mutation was present in the precursor lesion and absent in the adjacent invasive lesion.Of the 22 screened tumor-related genes, only K-ras, p53, and PIK3CA mutations were found in IPMN. K-ras mutations are more prevalent in invasive than premalignant IPMN. The variable coexistence of mutations in the invasive cancer and in the adjacent precursor cells may point to the heterogeneous nature of this tumor.

A 39-year-old male developed primary brain lymphoma 33 years after receiving scalp irradiation for tinea capitis. This is the first reported association between cranial irradiation during childhood and subsequent development of primary brain lymphoma. © 1992 Wiley-Liss, Inc.