Association between COVID-19 vaccination and myasthenia gravis: A population-based, nested case-control study.

BACKGROUND: Existing data regarding the link between COVID-19 vaccine and myasthenia gravis (MG) are scarce. We aimed to assess the association between Pfizer-BioNTech vaccine with both new-onset MG and MG exacerbation. METHODS: For the first aim, we conducted a nested case-control study in a cohort of 3,052,467 adults, without a diagnosis of MG, from the largest healthcare provider in Israel. Subjects were followed from January 1, 2021 until June 30, 2022 for the occurrence of MG. Ten randomly selected controls were matched to each case of new-onset MG on age and sex. For the second aim, a nested case-control study was conducted in a cohort of 1446 MG patients. Four randomly selected MG patients (controls) were matched to each case of MG exacerbation. Exposure to COVID-19 vaccine in the prior 4 weeks was assessed in cases and controls. RESULTS: Overall, 332 patients had new-onset MG and were matched with 3320 controls. Multivariable conditional logistic regression models showed that the odds ratio (OR) for new-onset MG, associated with COVID-19 vaccine, was 1.14 (95% CI 0.73-1.78). The results were consistent in sensitivity analysis that used more stringent criteria to define MG. Overall, 62 patients with MG exacerbation were matched to 248 MG controls. The multivariable OR for MG exacerbation, associated with COVID-19 vaccine, was 1.35 (95% CI 0.37-4.89). All results were similar when the prior exposure to COVID-19 vaccine was extended to 8 weeks. CONCLUSION: This study suggests that Pfizer-BioNTech vaccine is not associated with increased risk of new-onset nor exacerbation of MG.

Breast cancer polygenic risk scores derived in White European populations are not calibrated for women of Ashkenazi Jewish descent.

PURPOSE: Polygenic risk scores (PRSs) are a major component of accurate breast cancer (BC) risk prediction but require ethnicity-specific calibration. Ashkenazi Jewish (AJ) population is assumed to be of White European (WE) origin in some commercially available PRSs despite differing effect allele frequencies (EAFs). We conducted a case-control study of WE and AJ women from the Predicting Risk of Cancer at Screening Study. The Breast Cancer in Northern Israel Study provided a separate AJ population-based case-control validation series. METHODS: All women underwent Illumina OncoArray single-nucleotide variation (SNV; formerly single-nucleotide polymorphism [SNP]) analysis. Two PRSs were assessed, SNV142 and SNV78. A total of 221 of 2243 WE women (discovery: cases = 111; controls = 110; validation: cases = 651; controls = 1772) and 221 AJ women (cases = 121; controls = 110) were included from the UK study; the Israeli series consisted of 2045 AJ women (cases = 1331; controls = 714). EAFs were obtained from the Genome Aggregation Database. RESULTS: In the UK study, the mean SNV142 PRS demonstrated good calibration and discrimination in WE population, with mean PRS of 1.33 (95% CI 1.18-1.48) in cases and 1.01 (95% CI 0.89-1.13) in controls. In AJ women from Manchester, the mean PRS of 1.54 (1.38-1.70) in cases and 1.20 (1.08-1.32) in controls demonstrated good discrimination but overestimation of BC relative risk. After adjusting for EAFs for the AJ population, mean risk was corrected (mean SNV142 PRS cases = 1.30 [95% CI 1.16-1.44] and controls = 1.02 [95% CI 0.92-1.12]). This was recapitulated in the larger Israeli data set with good discrimination (area under the curve = 0.632 [95% CI 0.607-0.657] for SNV142). CONCLUSION: AJ women should not be given BC relative risk predictions based on PRSs calibrated to EAFs from the WE population. PRSs need to be recalibrated using AJ-derived EAFs. A simple recalibration using the mean PRS adjustment ratio likely performs well.

Association Between ABCG2, ABCB1, ABCC2 Efflux Transporter Single-Nucleotide Variants and Irinotecan Adverse Effects in Patients With Colorectal Cancer: A Real-Life Study.

Among patients treated with irinotecan, homozygous carriers of the UGT1A1*28 allele are at increased risk for neutropenia, but UGT1A1 genotype alone does not account for irinotecan-induced toxicity. Our aim was to study the association between single-nucleotide variants in genes encoding for efflux transporters of irinotecan (ABCG2, ABCB1, and ABCC2) and toxicity in real life. The source population was a cohort of patients with colorectal cancer (CRC) in Northern Israel, who had undergone genome-wide association study. From the source population we chose the patients with CRC prescribed irinotecan, and a comparative cohort of patients with CRC treated with other anticancer systemic therapies. Using Clalit Health Services electronic medical records (including laboratory results) we ascertained hematological and gastrointestinal adverse effects and mortality, within 90 days of the first dose, as a composite outcome. There were 601 patients with CRC who received irinotecan, and 756 patients with CRC treated with other anticancer regimens. The minor allele in rs2231142 (ABCG2) was associated with lower incidence of the composite outcome (odds ratio (OR) = 0.54 (0.33, 0.91); P = 0.02) in irinotecan-treated patients with CRC, but not in patients with CRC treated with other regimens. ABCB1 rs1045642 and ABCC2 rs3740066 were not associated with the composite outcome. In a sensitivity analysis, adjusted for UGT1A1 status and for possible demographic and clinical confounders, adjusted OR was 0.56 (0.33, 0.94) for the association between rs2231142 (ABCG2) and the composite outcome. In conclusion, we describe a novel association between the minor allele of rs2231142 in the efflux transporter gene ABCG2 and protection against severe side effects in CRC patients treating with irinotecan.

Culprit Medications and Risk Factors Associated with Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Population-Based Nested Case-Control Study.

OBJECTIVE: Our objective was to describe the incidence of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in a large unselected cohort, to validate the culprit drugs involved and the frequency of SJS/TEN for each drug, and to analyze the clinical risk factors for SJS/TEN. METHODS: Using the computerized database of Clalit Health Services, we identified all adult patients with a new SJS/TEN diagnosis between 1 January, 2008 and 30 June, 2019 and validated each case. Cumulative incidence of SJS/TEN for each culprit drug was calculated by dividing the number of valid cases by the total number of new users of the drug in the study period. Using risk-set sampling, 20 controls were matched to each case by sex and age on the index date for a nested case-control analysis. Multivariable conditional logistic regression was used to estimate the odds ratio and 95% confidence interval for the association of incident SJS/TEN with chronic diseases. RESULTS: We identified 87 adult cases of true/probable SJS/TEN between 1 January, 2008 and 30 June, 2019. Culprit drugs [with ALDEN scores ascertained as at least probable (≥ 4)] associated with the highest absolute risks were phenytoin, lamotrigine, and allopurinol with 3.56, 2.82, and 1.10 SJS/TEN cases/10,000 new users, respectively. Additional drugs with mean ALDEN scores ≥ 4 were sunitinib, sulfasalazine, carbamazepine, etoricoxib, etodolac, and cefuroxime, cumulative incidence: 13.57, 0.72, 0.32, 0.05, 0.02, and 0.02/10,000 new users, respectively. Previous diagnosis of systemic lupus erythematosus, psoriasis, previous drug allergies, epilepsy, malignancy, history of cerebrovascular accident, and history of diabetes mellitus were associated with an increased risk for SJS/TEN, odds ratios (95% confidence interval):17.41 (1.31-230.72), 10.28 (3.61-29.31), 5.21 (2.95-9.19), 4.92 (1.88-12.85), 3.17 (1.77-5.66), 2.61 (1.26-5.41), and 1.98 (1.12-3.53), respectively. CONCLUSIONS: Attention should be drawn to drugs assessed by high ALDEN scores that were associated with high absolute risks for SJS/TEN. Psoriasis, former drug allergies, in addition to systemic lupus erythematosus, malignancy, history of cerebrovascular accident, and diabetes mellitus were associated with increased SJS/TEN risk in our analysis.

Association of CYP2C19 Polymorphism With Proton Pump Inhibitors Effectiveness and With Fractures in Real-Life: Retrospective Cohort Study.

Symptom refractoriness of patients treated with proton pump inhibitors (PPIs) might be explained by polymorphism in CYP2C19. This is a retrospective cohort study in which we used the computerized database of Clalit Health Services to compose a cohort from cancer case-control studies' participants that had been genotyped, and that have been dispensed PPI (January 1, 2002 to November 10, 2020). We retrieved demographic and clinical variables on date of PPI initiation (cohort entry), and studies' questionnaires-reported consumption of foods/beverages known to increase peptic-related symptoms. Primary outcome was an abdominal pain diagnosis; secondary outcome was a composite of abdominal pain, visit to a gastroenterology clinic, change to another PPI, PPI dose increase, or metoclopramide prescription, reflecting symptoms persistence/recurrence; in a 2-year follow-up. We also evaluated the association between genetic groups and hip/wrist/spine fractures, in a long-term follow-up. Of 3,326 PPI initiators, there were 66 (2.0%), 739 (22.2%), 1394 (41.9%), 947 (28.5%), and 180 (5.4%) CYP2C19 poor, intermediate, normal, rapid, and ultra-rapid metabolizers, respectively. Being a poor metabolizer was associated with lower risk for the primary outcome, hazard ratio (HR) = 0.50 (95% confidence interval (CI) 0.27-0.91), HR = 0.52 (95% CI 0.28-0.94); and for the secondary outcome, HR = 0.57 (95% CI 0.38-0.86), HR = 0.58 (95% CI 0.39-0.87), in univariate and multivariable cox regression analyses, respectively. In long-term follow-up with 20,142 person-years of follow-up: 7.6% (5 cases) within the poor metabolizers group, and 11.6%, 12.9%, 12.8%, and 11.1% in the normal, intermediate, rapid, and ultra-rapid metabolizers groups, respectively, had a new fracture (nonsignificant). We conclude that CYP2C19 poor metabolizer status is associated with higher effectiveness of PPIs, and is not associated with higher risk for fractures.

Long term follow-up of EGFR mutated NSCLC cases.

PURPOSE: A substantial fraction of all non-small cell lung cancers(NSCLC) carry a mutation in the EGFR gene for which an effective treatment with anti-tyrosine kinases(TKIs) is available. We studied the long term survival of these patients following the introduction of TKIs. EXPERIMENTAL DESIGN: All consecutive cases of NSCLC newly diagnosed with advanced disease were referred for free tumor EGFR mutation testing at Clalit's national personalized medicine laboratory. Mutations and deletions in target codons 18-21 of EGFR were sought using RT-PCR and fragment analysis. Comprehensive EMRs were used to collect full data on treatments and clinical status. RESULTS: A cohort of 3,062 advanced NSCLC cases, included 481(15.7%) somatic EGFR mutation carriers (17.5% of all adenocarcinomas, 26.7% of females with adenocarcinomas). TKIs treatment to EGFR mutation carriers was provided to 85% of all eligible. After a median follow up period of 15.9 months for EGFR mutated cases the hazard ratio for overall survival of EGFR-mutated NSCLC treated with TKIs was 0.55(0.49-0.63, p<0.0001) when compared with EGFR wild-type(WT) tumors under usual care. After adjusting for age, sex, ethnicity, smoking history and tumor histology, all of which had an independently significant effect on survival, the HR for TKI-treated, EGFR-mutated tumors, was 0.63 (0.55-0.71, p<0.0001). Treating EGFR-WT cases with TKIs yielded a high HR=1.32 (1.19-1.48). CONCLUSIONS: TKIs given to EGFR mutated advanced NSCLC demonstrated a substantial survival benefit for at least five years. Squamous histology, smoking, male sex and Arab ethnicity were associated with higher NSCLC mortality hazard. Treating non-EGFR-mutated NSCLC with TKIs seems detrimental. Statement of Significance: • TKIs given to EGFR mutated advanced NSCLC demonstrated a substantial survival benefit for at least five years but not much longer. • Treating non-EGFR-mutated NSCLC with TKIs seems detrimental and should probably be avoided. • Squamous histology of non-small cell lung cancer, smoking history, male sex and Arab ethnicity were associated with altogether higher NSCLC mortality hazard.

Use of metformin and risk of breast and colorectal cancer.

BACKGROUND: Diabetes has been associated with increased risk of cancer, including breast cancer and colorectal cancer. Metformin, an oral hypoglycemic drug, but not other anti-diabetic drugs, has been associated with reduced risk of breast and of colon cancers in some, but not in other, studies. METHODS: Data from two large-scale, population-based, case-control studies of breast and colorectal cancers etiology, conducted in Northern Israel since 1998 were analyzed to evaluate the association between regular use (>3 times) of metformin prior to diagnosis and risk of developing cancer. The multivariate analyses for both cancer sites included age, family history of breast/colorectal cancer, history of diabetes, sports participation, fruits/vegetables consumption, aspirin and statins use, and for breast cancer, also included use of oral contraceptives and postmenopausal hormones and number of pregnancies. Use of metformin and diabetes status were determined based on valid electronic medical records of the participants. RESULTS: Metformin use prior to diagnosis of cancer was associated with a decrease in risk of both breast cancer (OR = 0.821, 0.726-0.928, p = 0.002) and colorectal cancer (OR = 0.754, 0.623-0.912, p = 0.004). An inverse association was not identified with use of other anti-diabetic medications. Diabetes was found to be associated with risk of colorectal cancer (OR = 1.204, 1.014-1.431, p = 0.034) but not of breast cancer. No dose response by years of use of metformin was found. CONCLUSION: These analyses of large population-based studies provide evidence of a strong inverse association of metformin with breast and, even more so, with colorectal cancer risk.

Cancer Risk After Radioactive Iodine Treatment for Hyperthyroidism: A Cohort Study.

Background: Radioactive iodine (131I) is in widespread use for the treatment of hyperthyroidism. Data on long-term safety outcome are limited and conflicting. The objectives of this study were to evaluate the association of radioiodine treatment for hyperthyroidism with overall cancer and with specific cancer types. Methods: This is a historical cohort study, using the Clalit health care database. Participants were all adults with a new diagnosis of hyperthyroidism in 2002-2015, newly treated with 131I, or with thionamides (propylthiouracil/thiamazole), excluding patients with previous malignancies. Age, sex, smoking history, body mass index, Clalit district, socioeconomic status, history of diabetes mellitus and of hypertension, use of aspirin and of statins, and adherence to cancer screening procedures were used to calculate propensity score to receive radioiodine. Incidence rates and 95% confidence intervals (CIs) were calculated for overall cancer occurrence, and for each cancer type using Poisson distribution. Association between study variables and time to cancer event was evaluated using cause-specific hazard ratios (HR) and CIs, estimated by univariate and propensity score adjusted multivariate Cox proportional hazards models. For sensitivity analysis we stratified the cohort by calendar year at cohort entry and by length of follow-up. Results: A total of 16,637 patients formed the study cohort, with 123,166 person-years of follow-up. There was no association between radioiodine treatment and increased risk of overall cancer (HR = 0.99 [CI 0.83-1.19], p = 0.91; HR = 1.01 [CI 0.83-1.21], p = 0.95) in univariate and multivariate analyses, respectively. However, in a sensitivity analysis, we found an association with overall cancer risk in the first period of follow-up (up to 4.2 years) (HR = 2.11 [CI 1.59-2.80], p < 0.0001), and no association with increased risk in a longer follow-up period. An association was found between radioiodine exposure and an increased risk for non-Hodgkin's lymphoma (NHL) in univariate but a nonsignificant increased risk in multivariate analysis: HR = 2.89 [CI 1.12-7.46], p = 0.03; HR = 2.32 [CI 0.88-6.13], p = 0.09, respectively. Conclusions: No association was found between radioiodine treatment for hyperthyroidism and risk for incident cancer in long-term follow-up. In an analysis of specific cancer types, a statistically significant association was found with NHL only in univariate analysis.

Red meat and processed meat intake and risk of colorectal cancer: a population-based case-control study.

To examine the association between red meat subtypes intake and risk of colorectal cancer (CRC) among Jewish and Arabs populations in a unique Mediterranean environment. The Molecular Epidemiology of Colorectal Cancer study (n=10 026) is a prospective population-based case-control study in northern Israel. Participants were interviewed in-person about their dietary intake and lifestyle using a questionnaire that included a food-frequency questionnaire. Red meat consumption in Israel was found to be especially low in the Jewish population (1.29±1.45 servings/week), but higher in Arabs (3.0±1.98 servings/week) (P<0.001). Beef was the most commonly consumed red meat by Jews (1.15/1.29 servings/week, 89%) and proportionally less so by Arabs (2.00/3.00, 67%). Processed meat consumption (mostly pork free) was lower among Arabs (0.9±1.56 servings/week) compared with Jews (1.97±2.97 servings/week) (P<0.001). The adjusted odds of CRC per one serving/week of red meat were 1.05 (95% confidence interval: 1.01-1.08) in Jews and 0.94 (0.88-1.01) in Arabs. Compared with no consumption, beef consumption was associated with odds ratio (OR)=0.96 (0.86-1.07) in Jews and 0.94 (0.61-1.45) in Arabs, lamb consumption with OR=1.28 (1.10-1.5) and 1.01 (0.75-1.37), pork consumption with OR=1.44 (1.24-1.67) and 1.07 (0.73-1.56), and processed meat consumption with OR=1.22 (1.10-1.35) and 1.04 (0.82-1.33) in Jews and Arabs, respectively. Overall red meat consumption was associated weakly with CRC risk, significant only for lamb and pork, but not for beef, irrespective of tumor location. Processed meat was associated with mild CRC risk.

Increased Risk of Antithyroid Drug Agranulocytosis Associated with Amiodarone-Induced Thyrotoxicosis: A Population-Based Cohort Study.

BACKGROUND: Agranulocytosis occurs in 0.2-0.5% of patients treated with the antithyroid drugs (ATDs) methimazole and propylthiouracil. The objectives of this study were to evaluate the risk of ATD-related agranulocytosis in patients with amiodarone-induced thyrotoxicosis (AIT), and to compare it with the agranulocytosis risk in patients with thyrotoxicosis due to other etiologies treated with ATDs. METHODS: This was a retrospective cohort study. Participants were 14,781 adult patients with thyrotoxicosis, newly treated with an ATD between January 1, 2002, and December 31, 2015. Among them were 593 patients treated by ATDs due to AIT. The main outcome measures were incidence rates and crude and adjusted hazard ratios using univariate and multivariable Cox regression models for ATD-related agranulocytosis within one year of treatment initiation, in association with AIT. RESULTS: Agranulocytosis occurred in 28 (0.19%) of patients newly treated with methimazole or propylthiouracil during the first year of follow-up. Of these 28 patients, 8/593 (1.35%) were AIT patients and 20/14,188 (0.14%) were thyrotoxic patients that was not AIT related (p < 0.001). Incidence rates were 22 (9.47-43.36) cases/1000 person-years of follow-up in AIT, and 1.79 (1.09-2.76)/1000 person-years of follow-up in non-AIT thyrotoxicosis (p < 0.0001). In univariate Cox regression analysis, risk for ATD agranulocytosis associated with AIT was 9.71 (4.28-22.05) compared to the risk in non-AIT thyrotoxicosis. In a multivariable model, adjusting for age, sex, body mass index, smoking history, year of cohort entry, diabetes mellitus, hypertension, renal failure, beta blockers, calcium channel blockers, anti-aggregants, and dose of ATDs, the risk associated with AIT was 5.70 (2.14-15.21). In a model adjusted for a propensity score to receive amiodarone, risk for ATD agranulocytosis associated with AIT was 6.32 (1.22-32.70). CONCLUSIONS: ATD use is associated with a higher risk for agranulocytosis in patients with AIT.

Association of atrial fibrillation and cancer: Analysis from two large population-based case-control studies.

BACKGROUND: An association between atrial fibrillation (AF) and risk of cancer has been suggested in several studies, including prospective cohort studies. However, the magnitude and the temporal nature of this association remain unclear. METHODS: Data from two large prospective population-based case-control studies, the Molecular Epidemiology of Colorectal Cancer (MECC, n = 8,383) and the Breast Cancer in Northern Israel Study (BCINIS, n = 11,608), were used to better understand the nature and temporality of a possible association between cancer diagnosis and AF events before and after cancer diagnosis. A case-control study approach was employed to study prior AF as a risk factor for cancer, and a cohort study approach was employed to study incident cancer as a risk factor for AF. RESULTS: AF was associated with a significant reduced odds of cancer as reflected in the case-control approach, with an adjusted OR = 0.77 (95% CI, 0.65-0.91), while cancer was not found to be significantly associated with elevated risk of AF in the cohort approach, with an adjusted HR = 1.10 (0.98-1.23). The immediate period (90 days) after an AF event was associated with a 1.85 times increased risk of cancer, and the immediate period after the diagnosis of cancer was associated with a 3.4 fold increased risk of AF. These findings probably reflect both the effect of acute transient conditions associated with new cancer diagnosis and detection bias. Similar results were identified with colorectal and breast cancer cases. CONCLUSIONS: Atrial fibrillation of longer than 90 days duration is associated with reduced odds of new cancer diagnosis. The results of this study suggest that an association observed in prior research may be due to instances related to cancer diagnosis and detection bias rather than a causal relationship. However, there may be bias in the sampling and residual confounding that distort the associations.

Oral Bisphosphonates and Improved Survival of Breast Cancer.

Purpose: Bisphosphonates are used for treatment or prevention of osteoporosis and of bone metastases. The use of oral bisphosphonates was suggested to be associated with reduced risk of developing breast cancer, and their positive influence on breast cancer survival was only demonstrated with third-generation bisphosphonates. We studied the association of use of oral bisphosphonates after breast cancer diagnosis on overall and breast cancer survival.Experimental Design: A nested case-control analysis was performed using data from the population-based Breast Cancer in Northern Israel Study (BCINIS). Participants were postmenopausal women with newly diagnosed breast cancer insured by Clalit. Use of second-generation bisphosphonates (alendronate and/or risedronate) was identified using computerized prescription records. The analysis was restricted to women who did not use bisphosphonates prior to diagnosis.Results: In a cohort of 3,731 postmenopausal women with breast cancer, followed up for an average of 70 months, there were 799 cases of death which were matched to 15,915 control periods of living breast cancer cases. Use of bisphosphonates after diagnosis for at least 18 months was significantly more common among survivors than among their matched controls who died, adjusted for tumor stage/grade (overall survival: OR = 0.63, 0.41-0.96, P = 0.03; breast cancer-specific survival: OR = 0.28, 0.09-0.91, P = 0.035). A similar advantageous effect, but statistically underpowered, was found in estrogen receptor (ER)-positive, ER-negative, and HER2neu-positive tumors.Conclusions: The use of oral bisphosphonates, by postmenopausal, probably osteoporotic, women initiated after diagnosis of breast cancer was associated with a significant improvement in overall and breast-specific odds of survival. Clin Cancer Res; 23(7); 1684-9. ©2016 AACR.

Beyond aspirin-cancer prevention with statins, metformin and bisphosphonates.

Cancer risk reduction using pharmacological means is an attractive modern preventive approach that supplements the classical behavioural prevention recommendations. Medications that are commonly used by large populations to treat a variety of common, non-cancer-related, medical situations are an attractive candidate pool. This Review discusses three pharmacological agents with the most evidence for their potential as cancer chemopreventive agents: anti-hypercholesterolaemia medications (statins), an antidiabetic agent (metformin) and antiosteoporosis drugs (bisphosphonates). Data are accumulating to support a significant negative association of certain statins with cancer occurrence or survival in several major tumour sites (mostly gastrointestinal tumours and breast cancer), with an augmented combined effect with aspirin or other non-steroidal anti-inflammatory drugs. Metformin, but not other hypoglycaemic drugs, also seems to have some antitumour growth activity, but the amount of evidence in human studies, mainly in breast cancer, is still limited. Experimental and observational data have identified bisphosphonates as a pharmacological group that could have significant impact on incidence and mortality of more than one subsite of malignancy. At the current level of evidence these potential chemopreventive drugs should be considered in high-risk situations or using the personalized approach of maximizing individual benefits and minimizing the potential for adverse effects with the aid of pharmacogenetic indicators.

Simvastatin induces death of multiple myeloma cell lines.

BACKGROUND: Accumulating reports indicate that statins widely prescribed for hypercholesteromia have antineoplastic activity. We hypothesized that because statins inhibit farnesylation of Ras that is often mutated in multiple myeloma (MM), as well as the production of interleukin (IL)-6, a key cytokine in MM, they may have antiproliferative and/or proapoptotic effects in this malignancy. METHODS: U266, RPMI 8226, and ARH77 were treated with simvastatin (0-30 microM) for 5 days. The following aspects were evaluated: viability (IC50), cell cycle, cell death, cytoplasmic calcium ion levels, supernatant IL-6 levels, and tyrosine kinase activity. RESULTS: Exposure of all cell lines to simvastatin resulted in reduced viability with IC50s of 4.5 microM for ARH77, 8 microM for RPMI 8226, and 13 microM for U266. The decreased viability is attributed to cell-cycle arrest (U266, G1; RPMI 8226, G2M) and cell death. ARH77 underwent apoptosis, whereas U266 and RPMI 8226 displayed a more necrotic form of death. Cytoplasmic calcium levels decreased significantly in all treated cell lines. IL-6 secretion from U266 cells was abrogated on treatment with simvastatin, whereas total tyrosine phosphorylation was unaffected. CONCLUSIONS: Simvastatin displays significant antimyeloma activity in vitro. Further research is warranted for elucidation of the modulated molecular pathways and clinical relevance.