Nandita Mitra

Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial.

BACKGROUND The issue of whether regular use of an inhaled beta2-adrenergic agonist worsens airflow and clinical outcomes in asthma is controversial. Retrospective studies have suggested that adverse effects occur in patients with a genetic polymorphism that results in homozygosity for arginine (Arg/Arg), rather than glycine (Gly/Gly), at aminoacid residue 16 of the beta2-adrenergic receptor. However, the existence of any genotype-dependent difference has not been tested in a prospective clinical trial. METHODS Patients with mild asthma, not using a controller medication, were enrolled in pairs matched for forced expiratory volume in 1 s (FEV1) according to whether they had the Arg/Arg (n=37; four of 41 matches withdrew before randomisation) or Gly/Gly (n=41) genotype. Regularly scheduled treatment with albuterol or placebo was given in a masked, cross-over design, for 16-week periods. During the study, as-needed albuterol use was discontinued and ipratropium bromide was used as needed. Morning peak expiratory flow rate (PEFR) was the primary outcome variable. The primary comparisons were between treatment period for each genotype; the secondary outcome was a treatment by genotype effect. Analyses were by intention to treat. FINDINGS During the run-in period, when albuterol use was kept to a minimum, patients with the Arg/Arg genotype had an increase in morning PEFR of 23 L/min (p=0.0162); the change in patients with the Gly/Gly genotype was not significant (2 L/min; p=0.8399). During randomised treatment, patients with the Gly/Gly genotype had an increase in morning PEFR during treatment with regularly scheduled albuterol compared with placebo (14 L/min [95% CI 3 to 25]; p=0.0175). By contrast, patients with the Arg/Arg genotype had lower morning PEFR during treatment with albuterol than during the placebo period, when albuterol use was limited (-10 L/min [-19 to -2]; p=0.0209). The genotype-attributable treatment difference was therefore -24 L/min (-37 to -12; p=0.0003). There were similar genotype-specific effects in FEV1, symptoms, and use of supplementary reliever medication. INTERPRETATION Genotype at the 16th aminoacid residue of the beta2-adrenergic receptor affects the long-term response to albuterol use. Bronchodilator treatments avoiding albuterol may be appropriate for patients with the Arg/Arg genotype.

Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer

Testicular germ cell tumors (TGCT) have been expected to have a strong underlying genetic component. We conducted a genome-wide scan among 277 TGCT cases and 919 controls and found that seven markers at 12p22 within KITLG (c-KIT ligand) reached genome-wide significance (P < 5.0 × 10−8 in discovery). In independent replication, TGCT risk was increased threefold per copy of the major allele at rs3782179 and rs4474514 (OR = 3.08, 95% CI = 2.29–4.13; OR = 3.07, 95% CI = 2.29–4.13, respectively). We found associations with rs4324715 and rs6897876 at 5q31.3 near SPRY4 (sprouty 4; P < 5.0 × 10−6 in discovery). In independent replication, risk of TGCT was increased nearly 40% per copy of the major allele (OR = 1.37, 95% CI = 1.14–1.64; OR = 1.39, 95% CI = 1.16–1.66, respectively). All of the genotypes were associated with both seminoma and nonseminoma TGCT subtypes. These results demonstrate that common genetic variants affect TGCT risk and implicate KITLG and SPRY4 as genes involved in TGCT susceptibility.

Incidence of treated cardiac arrest in hospitalized patients in the United States.

Objective:The incidence and incidence over time of cardiac arrest in hospitalized patients is unknown. We sought to estimate the event rate and temporal trends of adult inhospital cardiac arrest treated with a resuscitation response. Design:Three approaches were used to estimate the inhospital cardiac arrest event rate. First approach: calculate the inhospital cardiac arrest event rate at hospitals (n = 433) in the Get With The Guidelines-Resuscitation registry, years 2003–2007, and multiply this by U.S. annual bed days. Second approach: use the Get With The Guidelines-Resuscitation inhospital cardiac arrest event rate to develop a regression model (including hospital demographic, geographic, and organizational factors), and use the model coefficients to calculate predicted event rates for acute care hospitals (n = 5445) responding to the American Hospital Association survey. Third approach: classify acute care hospitals into groups based on academic, urban, and bed size characteristics, and determine the average event rate for Get With The Guidelines-Resuscitation hospitals in each group, and use weighted averages to calculate the national inhospital cardiac arrest rate. Annual event rates were calculated to estimate temporal trends. Setting:Get With The Guidelines-Resuscitation registry. Patients:Adult inhospital cardiac arrest with a resuscitation response. Measurements and Main Results:The mean adult treated inhospital cardiac arrest event rate at Get With The Guidelines-Resuscitation hospitals was 0.92/1000 bed days (interquartile range 0.58 to 1.2/1000). In hospitals (n = 150) contributing data for all years of the study period, the event rate increased from 2003 to 2007. With 2.09 million annual U.S. bed days, we estimated 192,000 inhospital cardiac arrests throughout the United States annually. Based on the regression model, extrapolating Get With The Guidelines-Resuscitation hospitals to hospitals participating in the American Hospital Association survey projected 211,000 annual inhospital cardiac arrests. Using weighted averages projected 209,000 annual U.S. inhospital cardiac arrests. Conclusions:There are approximately 200,000 treated cardiac arrests among U.S. hospitalized patients annually, and this rate may be increasing. This is important for understanding the burden of inhospital cardiac arrest and developing strategies to improve care for hospitalized patients.

Patient Online Self-Reporting of Toxicity Symptoms During Chemotherapy

PURPOSE Tracking symptoms related to treatment toxicity is standard practice in routine care and during clinical trials. Currently, clinicians collect symptom information via complex and often inefficient mechanisms, but there is growing interest in collecting outcome information directly from patients. PATIENTS AND METHODS The National Cancer Institute Common Terminology Criteria for Adverse Events schema for seven common symptoms was adapted into a Web-based patient-reporting system, accessible from desktop computers in outpatient clinics and from home computers. Eighty patients with gynecologic malignancies beginning standard chemotherapy regimens were enrolled between April and September 2004. During an 8-week observation period, participants were encouraged to log in and report symptoms at each follow-up visit, or alternatively, to access the system from home. RESULTS All patients completed an initial log in. At each subsequent appointment, most enrollees (80% to 85%) reported symptoms using the online system, with a mean of three follow-up visits per patient during the observation period (range, one to six). Sixty of 80 patients (75%) logged in at least once from home. Use was significantly associated with prior Internet experience. Forty-two severe toxicities (grade 3 to 4) entered from home prompted seven clinician interventions. Most patients (96%) found the system useful and would recommend it to others. CONCLUSION Patients are capable of reporting symptoms experienced during chemotherapy using a Web-based interface. Assessment in the clinical trial setting and comparison of direct patient- versus clinician-based approaches for reporting symptoms and their severity are warranted.

Adjuvant Chemotherapy and Survival in Older Women With Hormone Receptor–Negative Breast Cancer: Assessing Outcome in a Population-Based, Observational Cohort

PURPOSE For older breast cancer patients, there is limited evidence of the efficacy of adjuvant chemotherapy from randomized clinical trials. Our goal was to assess the relationship between adjuvant chemotherapy use and survival in a large, population-based cohort of older women with hormone receptor (HR) -negative breast cancer. METHODS We identified women age 66 and older diagnosed with HR-negative, nonmetastatic breast cancer from 1992 to 1999 in the Surveillance, Epidemiology and End Results (SEER) cancer registries. Chemotherapy use was identified in Medicare claims linked to SEER records. Clinical and sociodemographic predictors of chemotherapy use were identified using logistic regression. The effect of chemotherapy on survival was evaluated using propensity score methods and multivariable proportional hazards regression. RESULTS A total of 1,711 (34%) of 5,081 women with HR-negative breast cancer received chemotherapy within 6 months of cancer diagnosis. Chemotherapy use decreased with increasing age and comorbidity, and increased with year of diagnosis, tumor size, number of positive lymph nodes, and higher tumor grade. Adjuvant chemotherapy was associated with a mortality reduction of approximately 15% whether analyzed using propensity scores or standard multivariable methods. The greatest overall survival benefit was observed in patients with node-positive disease and in the node-negative patients most likely to receive chemotherapy. CONCLUSION This analysis suggests a survival benefit from adjuvant chemotherapy in older women with HR-negative breast cancer. The benefit of chemotherapy is most pronounced in the patients most likely to be selected for treatment, including those with involved lymph nodes or other high-risk disease characteristics.

Use of Adjuvant Chemotherapy and Radiation Therapy for Rectal Cancer Among the Elderly: A Population-Based Study

PURPOSE Combined adjuvant fluorouracil (5-FU)-based chemotherapy with radiation is now the standard of care for locally advanced rectal cancer in the United States. We investigated the use of these treatments for stages II and III rectal cancer among the elderly and the effectiveness of these treatments on a population-based scale. PATIENTS AND METHODS The linked Surveillance, Epidemiology, and End-Results-Medicare database was used to identify 1,807 Medicare beneficiaries > or = 65 years of age with stage II or III rectal cancer who underwent surgical resection between 1992 and 1996. We excluded members of a health maintenance organization in the 12 months before or 4 months after their diagnosis and those who died within 4 months of diagnosis. We used multivariate analysis to identify factors associated with combined 5-FU and radiation therapy, and propensity score methodology to determine survival benefit for those treated. RESULTS We found that 37% of patients received both adjuvant 5-FU and radiation therapy, 11% 5-FU alone, and 14% radiation alone. Decreasing age, increasing lymph node positivity, comorbid conditions, and nonblack race were associated with increased probability of treatment with 5-FU and radiation. Combined chemotherapy/radiation therapy was associated with improved survival for stage III (relative risk, 0.71; 95% confidence interval, 0.56 to 0.90), but not for stage II rectal cancer (relative risk, 0.89; 95% confidence interval, 0.70 to 1.14). CONCLUSION The association of combined treatment with improved survival in node-positive disease was similar to that observed in other studies. In the absence of data from well-designed randomized controlled trials, our observational data support efforts on the part of clinicians to make appropriate referrals and provide combined treatment for elderly patients with stage III rectal cancer.

Association between Albuminuria, Kidney Function, and Inflammatory Biomarker Profile in CKD in CRIC

BACKGROUND AND OBJECTIVES Increased risk of mortality in patients with CKD has been attributed to inflammation. However, the association between kidney function, albuminuria, and biomarkers of inflammation has not been examined in a large cohort of CKD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This study measured the plasma levels of IL-1β, IL-1 receptor antagonist (IL-1RA), IL-6, TNF-α, TGF-β, high-sensitivity C-reactive protein (hs-CRP), fibrinogen, and serum albumin in 3939 participants enrolled in the Chronic Renal Insufficiency Cohort study between June 2003 and September 2008. An inflammation score was established based on plasma levels of IL-1β, IL-6, TNF-α, hs-CRP, and fibrinogen. Estimated GFR (eGFR) and serum cystatin C were used as measures of kidney function. Albuminuria was quantitated by urine albumin to creatinine ratio (UACR). RESULTS Plasma levels of IL-1β, IL-1RA, IL-6, TNF-α, hs-CRP, and fibrinogen were higher among participants with lower levels of eGFR. Inflammation score was higher among those with lower eGFR and higher UACR. In regression analysis adjusted for multiple covariates, eGFR, cystatin C, and UACR were strongly associated with fibrinogen, serum albumin, IL-6, and TNF-α. Each unit increase in eGFR, cystatin C, and UACR was associated with a -1.2% (95% confidence interval, -1.4, -1), 64.9% (56.8, 73.3) and 0.6% (0.4, 0.8) change in IL-6, respectively (P<0.001). CONCLUSIONS Biomarkers of inflammation were inversely associated with measures of kidney function and positively with albuminuria.

Exisulind (sulindac sulfone) suppresses growth of human prostate cancer in a nude mouse xenograft model by increasing apoptosis

OBJECTIVES Recent studies have shown that Exisulind, a sulfone metabolite of the nonsteroidal anti-inflammatory drug (NSAID) sulindac, has inhibitory activity in vitro with cultured human prostate cancer cells. To determine whether this effect might be pharmacologically relevant in vivo, we tested whether Exisulind therapy could suppress the growth of human prostate cancer cells in a nude mouse xenograft model. METHODS Thirty athymic nude mice were injected subcutaneously in the flank with 1 x 10(7) LNCaP human prostate tumor cells. All mice received a control diet for 21 days. One group of mice was continued on this control diet for an additional 4 weeks, a second group was switched to a diet supplemented with 0.05% Exisulind (40% of maximal tolerated dose [MTD]), and a third group was switched to a diet supplemented with 0.1% Exisulind (80% MTD) for the additional 4 weeks. Tumor growth was measured through the 4-week test period, and subsequently tissue sections from the various groups were tested for apoptotic and dividing cells by quantified use of the TUNEL assay and a bromodeoxyuridine (BrdU) incorporation immunoassay. RESULTS Tumors grew by 158%, 24%, and 18% for the control and 0.05% and 0.1% Exisulind groups, respectively (P = 0.02) during the 4-week test period. Immunohistochemical studies on excised tumors showed an increased number of apoptotic bodies in the treated groups versus the control group (P<0.0001) but no change in the number of BrdU positive cells. CONCLUSIONS This is the first study to show a direct in vivo effect of an NSAID-derived drug, lacking cyclooxygenase inhibitory activity, in a xenograft model of prostate cancer. Clinical studies to evaluate the effects of Exisulind against prostate cancer in humans are warranted.

BRCA Mutations and Risk of Prostate Cancer in Ashkenazi Jews

Purpose: The Breast Cancer Linkage Consortium and other family-based ascertainments have suggested that male carriers of BRCA mutations are at increased risk of prostate cancer. Several series looking at the frequency of BRCA mutations in unselected patients with prostate cancer have not confirmed this finding. To clarify this issue, we conducted a large case-control study. Experimental Design: Blood specimens from 251 unselected Ashkenazi men with prostate cancer were screened for the presence of one of the three common Ashkenazi founder mutations in BRCA1 and BRCA2. The incidence of founder mutations was compared with the incidence of founder mutations in 1472 male Ashkenazi volunteers without prostate cancer using logistic regression analysis after adjusting for age. Results: Thirteen (5.2%) cases had a deleterious mutation in BRCA1 or BRCA2 compared with 28 (1.9%) controls. After adjusting for age, the presence of a BRCA1 or BRCA2 mutation was associated with the development of prostate cancer (odds ratio, 3.41; 95% confidence interval, 1.64–7.06; P = 0.001). When results were stratified by gene, BRCA2 mutation carriers demonstrated an increased risk of prostate cancer (odds ratio, 4.78; 95% confidence interval, 1.87–12.25; P = 0.001), whereas the risk in BRCA1 mutation carriers was not significantly increased. Conclusions: BRCA2 mutations are more likely to be found in unselected individuals with prostate cancer than age-matched controls. These results support the hypothesis that deleterious mutations in BRCA2 are associated with an increased risk of prostate cancer.

A moving target: Image guidance for stereotactic body radiation therapy for early-stage non-small cell lung cancer

PURPOSE Precise patient positioning is critical due to the large fractional doses and small treatment margins employed for thoracic stereotactic body radiation therapy (SBRT). The goals of this study were to evaluate the following: (1) the accuracy of kilovoltage x-ray (kV x-ray) matching to bony anatomy for pretreatment positioning; (2) the magnitude of intrafraction tumor motion; and (3) whether treatment or patient characteristics correlate with intrafraction motion. METHODS AND MATERIALS Eighty-seven patients with lung cancer were treated with SBRT. Patients were positioned with orthogonal kV x-rays matched to bony anatomy followed by cone-beam computed tomography (CBCT), with matching of the CBCT-visualized tumor to the internal gross target volume obtained from a 4-dimensional CT simulation data set. Patients underwent a posttreatment CBCT to assess the magnitude of intrafraction motion. RESULTS The mean CBCT-based shifts after initial patient positioning using kV x-rays were 2.2 mm in the vertical axis, 1.8 mm in the longitudinal axis, and 1.6 mm in the lateral axis (n = 335). The percentage of shifts greater than 3 mm and 5 mm represented 39% and 17%, respectively, of all fractions delivered. The mean CBCT-based shifts after treatment were 1.6 mm vertically, 1.5 mm longitudinally, and 1.1 mm laterally (n = 343). Twenty-seven percent and 10% of shifts were greater than 3 mm and 5 mm, respectively. Univariate and multivariable analysis demonstrated a significant association between intrafraction motion with weight and pulmonary function. CONCLUSIONS Kilovoltage x-ray matching to bony anatomy is inadequate for accurate positioning when a conventional 3-5 mm margin is employed prior to lung SBRT. Given the treatment techniques used in this study, CBCT image guidance with a 5-mm planning target volume margin is recommended. Further work is required to find determinants of interfraction and intrafraction motion that may help guide the individualized application of planning target volume margins.