Erlotinib in patients with previously irradiated, recurrent brain metastases from non-small cell lung cancer: Two case reports

Background: With the current improvements in primary lung care, the long-term control of brain metastases becomes a clinical challenge. No established therapeutic approaches exist for cranial relapse after response to previous radiotherapy and systemic therapy. Tyrosine kinase inhibitors like erlotinib with its proven activity in non-small cell lung cancer may provide clinical benefits in such patients. Patients and Methods: Two case reports are presented illustrating the efficacy of erlotinib in patients with recurrent brain metastases and parallel thoracic progression. Results: Both patients showed lasting partial remissions in the brain and lung, and clinical symptom improvement. Conclusion: The observed survival times of above 18 and 15 months, respectively, since occurrence of cranial disease manifestation in line with the achieved progression-free survival times of 9 and 6 months by the erlotinib third-line therapy are remarkable. The use of targeted therapies after whole-brain irradiation should be investigated more systematically in prospective clinical trials

Lung Cancer in a U.S. Population with Low to Moderate Arsenic Exposure

BackgroundLittle is known about the carcinogenic potential of arsenic in areas with low to moderate concentrations of arsenic (< 100 microg/L) in drinking water.ObjectivesWe examined associations between arsenic and lung cancer.MethodsA population-based case-control study of primary incident lung cancer was conducted in 10 counties in two U.S. states, New Hampshire and Vermont. The study included 223 lung cancer cases and 238 controls, each of whom provided toenail clippings for arsenic exposure measurement by inductively coupled-plasma mass spectrometry. We estimated odds ratios (ORs) of the association between arsenic exposure and lung cancer using unconditional logistic regression with adjustment for potential confounders (age, sex, race/ethnicity, smoking pack-years, education, body mass index, fish servings per week, and toenail selenium level).ResultsArsenic exposure was associated with small-cell and squamous-cell carcinoma of the lung [OR = 2.75; 95% confidence interval (CI), 1.00-7.57] for toenail arsenic concentration > or = 0.114 microg/g, versus < 0.05 microg/g. A history of lung disease (bronchitis, chronic obstructive pulmonary disease, or fibrosis) was positively associated with lung cancer (OR = 2.86; 95% CI, 1.39-5.91). We also observed an elevated risk of lung cancer among participants with a history of lung disease and toenail arsenic > or = 0.05 microg/g (OR = 4.78; 95% CI, 1.87-12.2) than among individuals with low toenail arsenic and no history of lung disease.ConclusionAlthough this study supports the possibility of an increased risk of specific lung cancer histologic types at lower levels of arsenic exposure, we recommend large-scale population-based studies

Pancreatitis-diabetes-pancreatic cancer: summary of an NIDDK-NCI workshop

A workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Cancer Institute (NCI) on "Pancreatitis-Diabetes-Pancreatic Cancer" focused on the risk factors of chronic pancreatitis (CP) and diabetes mellitus (DM) on the development of pancreatic ductal adenocarcinoma (PDAC). Sessions were held on (a) an overview of the problem of PDAC; (b) CP as a risk factor of PDAC; (c) DM as a risk factor of PDAC; (d) pancreatogenic, or type 3c, DM; (e) genomic associations of CP, DM, and PDAC; (f) surveillance of high-risk populations and early detection of PDAC; and (g) effects of DM treatment on PDAC. Recent data and current understandings of the mechanisms of CP- and DM-associated factors on PDAC development were discussed, and a detailed review of the possible risks of DM treatment on the development of PDAC was provided by representatives from academia, industry, and the Food and Drug Administration. The current status of possible biomarkers of PDAC and surveillance strategies for high-risk populations were discussed, and the gaps in knowledge and opportunities for further research were elucidated. A broad spectrum of expertise of the speakers and the discussants provided an unusually productive workshop, the highlights of which are summarized in the accompanying article

Profiling Sterols in Cerebrotendinous Xanthomatosis: Utility of Girard Derivatization and High Resolution Exact Mass LC-ESI-MSn Analysis

In this study we profile free 3-oxo sterols present in plasma from patients affected with the neurodegenerative disorder of sterol and bile acid metabolism cerebrotendinous xanthomatosis (CTX), utilizing a combination of charge-tagging and LC-ESI-MSn performed with an LTQ-Orbitrap Discovery instrument. In addition, we profile sterols in plasma from 24-month-old cyp27A1 gene knockout mice lacking the enzyme defective in CTX. Charge-tagging was accomplished by reaction with cationic Girard\u27s P (GP) reagent 1-(carboxymethyl) pyridinium chloride hydrazide, an approach uniquely suited to studying the 3-oxo sterols that accumulate in CTX, as Girard\u27s reagent reacts with the sterol oxo moiety to form charged hydrazone derivatives. The ability to selectively generate GP-tagged 3-oxo-4-ene and 3-oxo-5(H) saturated plasma sterols enabled ESI-MSn analysis of these sterols in the presence of a large excess (3 orders of magnitude) of cholesterol. Often cholesterol detected in biological samples makes it challenging to quantify minor sterols, with cholesterol frequently removed prior to analysis. We derivatized plasma (10μl) without SPE removal of cholesterol to ensure detection of all sterols present in plasma. We were able to measure 4-cholesten-3-one in plasma from untreated CTX patients (1207±302ng/ml, mean±SD, n=4), as well as other intermediates in a proposed pathway to 5α-cholestanol. In addition, a number of bile acid precursors were identified in plasma using this technique. GP-tagged sterols were identified utilizing high resolution exact mass spectra (±5ppm), as well as MS2 ([M]+→) spectra that possessed characteristic neutral loss of 79Da (pyridine) fragment ions, and MS3 ([M]+→[M-79]+→) spectra that provided additional structurally informative fragment ions. © 2010 Elsevier B.V

Pancreatitis and pancreatic cancer in two large pooled case–control studies

The association between duration of pancreatitis and pancreatic cancer has not been well characterized in large population-based studies. We conducted detailed analyses to determine the association between pancreatitis onset and pancreatic cancer risk. Data from two case–control studies of pancreatic cancer (n = 4515) in the San Francisco Bay Area and the M.D. Anderson Cancer Center were pooled for analysis (1,663 cases, 2,852 frequency-matched controls). Adjusted odds ratios (OR) were estimated using a random-effects model. In the pooled multivariable model, history of pancreatitis was associated with a 7.2-fold increased risk estimate for pancreatic cancer [95% confidence interval (CI): 4.0, 13]. The risk estimate was nearly 10-fold in participants aged <55 years (OR = 9.9, 95% CI: 3.5, 28). A shorter temporal history of pancreatitis was more closely associated with pancreatic cancer than was a longer temporal history: <3 years (OR = 29, 95% CI: 12, 71), 3–10 years (OR = 2.6, 95% CI: 1.5, 5.6), and >10 years (OR = 1.8, 95% CI: 0.7, 4.5, p trend < 0.001). A short temporal history of pancreatitis was highly associated with pancreatic cancer, suggesting that pancreatitis may be an early manifestation of pancreatic cancer in some individuals. Pancreatic cancer should be considered in the differential diagnosis of individuals with an episode of pancreatitis

Clonal karyotype evolution involving ring chromosome 1 with myelodysplastic syndrome subtype RAEB-t progressing into acute leukemia

s Karyotypic evolution is a well-known phenomenon in patients with malignant hernatological disorders during disease progression. We describe a 50-year-old male patient who had originally presented with pancytopenia in October 1992. The diagnosis of a myelodysplastic syndrome (MDS) FAB subtype RAEB-t was established in April 1993 by histological bone marrow (BM) examination, and therapy with low-dose cytosine arabinoside was initiated. In a phase of partial hernatological remission, cytogenetic assessment in August 1993 revealed a ring chromosome 1 in 13 of 21 metaphases beside BM cells with normal karyotypes {[}46,XY,r(1)(p35q31)/46,XY]. One month later, the patient progressed to an acute myeloid leukemia (AML), subtype M4 with 40% BM blasts and cytogenetic examination showed clonal evolution by the appearance of additional numerical aberrations in addition to the ring chromosome{[}46,XY,r(1),+8,-21/45,XY,r(1),+8,-21,-22/46, XY]. Intensive chemotherapy and radiotherapy was applied to induce remission in preparation for allogeneic bone marrow transplantation (BMT) from the patient's HLA-compatible son. After BMT, complete remission was clinically, hematologically and cytogenetically (normal male karyotype) confirmed. A complete hematopoietic chimerism was demonstrated. A relapse in January 1997 was successfully treated using donor lymphocyte infusion and donor peripheral blood stem cells (PB-SC) in combination with GM-CSF as immunostimulating agent in April 1997, and the patient's clinical condition remained stable as of January 2005. This is an interesting case of a patient with AML secondary to MDS. With the ring chromosome 1 we also describe a rare cytogenetic abnormality that predicted the poor prognosis of the patient, but the patient could be cured by adoptive immunotherapy and the application of donor's PB-SC. This case confirms the value of cytogenetic analysis in characterizing the malignant clone in hernatological neoplasias, the importance of controlling the quality of an induced remission and of the detection of a progress of the disease. Copyright (c) 2006 S. Karger AG, Basel

Efficacy and safety of bempedoic acid in patients not receiving statins in phase 3 clinical trials

BACKGROUND: Despite the high incidence of patients with statin tolerance problems, randomized evaluations of nonstatin oral treatment options for lowering of low-density lipoprotein cholesterol (LDL-C) in this population are sparse. OBJECTIVE: To assess the LDL-C lowering effect of bempedoic acid in patients not taking statins. METHODS: This was a pooled analysis of data from patients enrolled in four phase 3 bempedoic acid studies (12 to 52 weeks in duration) who were not taking concomitant statins (Phase 3 No Statin Cohort) and a phase 3 bempedoic acid plus ezetimibe fixed-dose combination study (BA+EZE FDC No Statin Cohort). The primary endpoint for all studies was the percent change from baseline to week 12 in LDL-C levels. Safety and tolerability were assessed by laboratory values and adverse events. RESULTS: In the Phase 3 No Statin Cohort, bempedoic acid (n = 394) lowered LDL-C levels at week 12 significantly more than placebo (n = 192; -26.5% [95% CI, -29.7%, -23.2%]; P\u3c0.001). The fixed-dose combination of bempedoic acid with ezetimibe lowered LDL-C by 39.2% (95% CI, -51.7% to -26.7%; P\u3c0.001). Muscle-related disorders occurred at a rate of 26.4 and 28.6 per 100 person-years with bempedoic acid and placebo, respectively. CONCLUSIONS: In patients with hypercholesterolemia unable to take statins, bempedoic acid lowered LDL-C levels by a mean of 26.5% vs placebo and bempedoic acid + ezetimibe fixed-dose combination lowered LDL-C by 39.2%. The treatments were generally well tolerated, suggesting that bempedoic acid may be efficacious and well tolerated in this challenging-to-treat patient population

A prospective study of XRCC1 (X-ray cross-complementing group 1) polymorphisms and breast cancer risk

INTRODUCTION: The gene XRCC1 (X-ray repair cross-complementing group 1) encodes a protein involved in DNA base excision repair. Two non-synonymous polymorphisms in XRCC1 (Arg194Trp and Arg399Gln) have been shown to alter DNA repair capacity in some studies in vitro. However, results of previous association studies of these two XRCC1 variants and breast cancer have been inconsistent. We examined the association between polymorphisms in XRCC1 and breast cancer in the American Cancer Society Cancer Prevention Study II (CPS-II) Nutrition Cohort, a large prospective study of cancer incidence in the USA. METHODS: Among the 21,965 women who were cancer-free in 1992 and gave blood between 1998 and 2001, 502 postmenopausal breast cancer cases were diagnosed between 1992 and 2001; 502 controls were matched to cases on age, race/ethnicity, and date of blood collection. Genotyping on DNA extracted from buffy coat was performed with Taqman. Conditional logistic regression was used to examine the association between each polymorphism and breast cancer risk controlling for breast cancer risk factors. We also examined whether factors associated with DNA damage, such as smoking and antioxidant intake, modified the association between XRCC1 polymorphisms and breast cancer. RESULTS: We observed a significant inverse association between Trp194 carriers (Trp/Trp and Trp/Arg) compared with Trp194 non-carriers in relation to breast cancer (Arg/Arg) (odds ratio (OR) 0.62, 95% confidence interval (CI) 0.40 to 0.95). The inverse association between breast cancer and Trp194 carriers compared with non-carriers was slightly stronger among smokers (OR 0.47, 95% CI 0.24 to 0.94) than never smokers (OR 0.78, 95% CI 0.43 to 1.40). An increased risk associated with the Arg399Gln polymorphism (Gln/Gln versus Arg/Arg) was observed only among women who reported ever smoking cigarettes (OR 2.76, 95% CI 1.36 to 5.63), and not in women who were lifelong non-smokers (OR 0.64, 95% CI 0.33 to 1.26). No other factor examined modified the association between XRCC1 polymorphisms and breast cancer risk. CONCLUSION: Our results support the hypothesis that genetic variation in XRCC1, particularly in Arg194Trp, may influence postmenopausal breast cancer risk. In our study, genetic variation in XRCC1 Arg399Gln was associated with breast cancer risk only among women with a history of smoking cigarettes

Bempedoic acid safety analysis: Pooled data from four phase 3 clinical trials

Background An ongoing need exists for safe and effective lipid-lowering therapies (LLTs) for patients unable to achieve desired lipid levels with current treatment options. Objective The objective of this study was to describe the safety profile of bempedoic acid, an oral, first-in-class, adenosine triphosphate (ATP)–citrate lyase inhibitor that significantly reduces low-density lipoprotein cholesterol (LDL-C) levels by 17.4%–28.5% vs placebo. Methods This was a pooled analysis of four phase 3, randomized (2:1), double-blind, placebo-controlled studies in patients with hypercholesterolemia who required additional LDL-C lowering, despite stable maximally-tolerated LLT. Patients received 180 mg of bempedoic acid (n = 2424) or placebo (n = 1197) once daily for 12 to 52 weeks. Assessments included treatment-emergent adverse events (TEAEs) and clinical laboratory tests. Results Of 3621 patients (the median drug exposure: 363 days), exposure-adjusted TEAE rates were 87.1/100 and 82.9/100 person-years (PY) for bempedoic acid and placebo, respectively. No single TEAE influenced the difference in rates. TEAEs leading to discontinuation occurred at rates of 13.4/100 and 8.9/100 PY for bempedoic acid vs placebo, with the most common cause being myalgia, which occurred less frequently with bempedoic acid vs placebo (1.5/100 vs 2.0/100 PY). Rates of myalgia and muscle weakness were comparable vs placebo. Bempedoic acid was associated with mild increases in blood urea nitrogen, creatinine, and uric acid and decreases in hemoglobin. These laboratory abnormalities were apparent by week 4, stable over time, and reversible after treatment cessation. Gout incidence was 1.6/100 vs 0.5/100 PY in the bempedoic acid vs placebo groups. New-onset diabetes/hyperglycemia occurred less frequently with bempedoic acid vs placebo (4.7/100 vs 6.4/100 PY). The safety profile was consistent across subgroups. Conclusions Bempedoic acid is generally safe and well tolerated among patients with hypercholesterolemia who require additional LLT

1973

Skunks Shoot Back by William Stewart (page 1) The Daily Plan: A Management Factor by Rob McIntyre (2) Teed Off by Samuel Pavadore (3) A Responsible Neighbor by Gerald Moscato (4) Drainage by David Clement (A-1) Fairway Renovation at Baltusrol Golf Club by Joseph R. Flaherty (A-4) Converting to Kentucky Bluegrass Fairways by Thomas Rewinski (A-10) Grooming the Golf Course by Melvin B. Lucas, Jr. (A-12) Turf Diseases of 1972, Controls and Prevention for 1973 by Stanley J. Zontek (A-13) Noncropland Weed Control by John E. Gallagher (A-16) Soil Factors Affecting Arsenic Toxicity by Robert N. Carrow (A-24) The Necessity of Cart Paths and Traffic Regulations by William G. Buchanan (A-27) Herbicides for Turfgrass Areas by John A. Jagschitz (A-29) Perspectives on Lawn Making and Keeping by Robert Schery (A-33) Stadium Turf Maintenance by George P. Toma (A-39) Highway Turfgrass by Robert W. Duell (A-44) Cemetery Maintenance by Martin Stolpe (A-50) Keeping Records by Al Barauskas (A-54) Planning Capital Expenditures by Sherwood A. Moore (A-59) British Golf Course Architecture -Historical Influences- Current Trends by F.W. Hawtree (A-64) Golf Course Architecture in North America By Geoffrey S. Cornish (A-70