Patient-reported outcomes in relapsed/refractory multiple myeloma treated with melflufen plus dexamethasone: analyses from the Phase II HORIZON study.

Relapsed/refractory multiple myeloma (RRMM) is known to have a high burden of disease and complications associated with refractoriness to prior lines of therapy. Severe pain and fatigue symptoms and impairments in physical and emotional functioning have been strongly linked to reduced health-related quality of life (HRQoL) in patients with RRMM. Assessment of patient reported-outcome measures from the pivotal, Phase II HORIZON study (OP-106; NCT02963493) in patients with RRMM (n = 64) demonstrated that melphalan flufenamide (melflufen) plus dexamethasone treatment preserved HRQoL. Patients had clinically meaningful improvements, even after eight treatment cycles, in relevant scales such as global health status/QoL, physical functioning, emotional functioning, pain, and fatigue. Patients with triple-class-refractory disease (n = 50) displayed similar improvements. Patient-reported outcome deterioration was delayed for a substantial amount of time in patients who experienced a response to melflufen plus dexamethasone treatment relative to patients who did not experience a response. These findings support the notion that treatment with melflufen plus dexamethasone may sustain or improve HRQoL over time in patients with RRMM, including in patients with triple-class-refractory disease for whom outcomes are generally worse. The clinical benefits observed in patients from the HORIZON trial are encouraging and supportive of translation into real-world practice.

Safety, Tolerability, and Pharmacokinetics of Single Doses of Exidavnemab (BAN0805), an Anti-α-Synuclein Antibody, in Healthy Western, Caucasian, Japanese, and Han Chinese Adults.

Exidavnemab is a monoclonal antibody (mAb) with a high affinity and selectivity for pathological aggregated forms of α-synuclein and a low affinity for physiological monomers, which is in clinical development as a disease-modifying treatment for patients with synucleinopathies such as Parkinson's disease. Safety, tolerability, pharmacokinetics, immunogenicity, and exploratory biomarkers were assessed in two separate Phase 1 single ascending dose studies, including single intravenous (IV) (100 to 6000 mg) or subcutaneous (SC) (300 mg) administration of exidavnemab in healthy volunteers (HVs). Across the two studies, a total of 98 Western, Caucasian, Japanese, and Han Chinese HVs were enrolled, of which 95 completed the study. Exidavnemab was generally well tolerated. There were no serious adverse events or safety issues identified in laboratory analyses. Headache, asymptomatic COVID-19, back pain, and post lumbar puncture syndrome were the most frequently reported treatment-emergent adverse events. Following IV infusion, the pharmacokinetics of exidavnemab was approximately dose linear in the range 100-6000 mg. The terminal half-life was approximately 30 days, and the exposure was comparable across Western, Caucasian, Japanese, and Han Chinese volunteers. The absolute SC bioavailability was ∼71%. Cerebrospinal fluid exposure relative to serum after single dose was within the range expected for mAbs (approximately 0.2%). The anti-drug antibody rates were low and there was no effect of immunogenicity on the pharmacokinetics or safety. Dose-dependent reduction of free α-synuclein in plasma was observed. In summary, exidavnemab was found to have an excellent pharmacokinetic profile and was well tolerated in HVs, supporting the continued clinical development.

Birth weight and attention-deficit/hyperactivity symptoms in childhood and early adolescence: a prospective Swedish twin study.

OBJECTIVE: To determine whether low birth weight increases the risk of attention-deficit/hyperactivity disorder (ADHD) in childhood and early adolescence. METHOD: In a population-based sample of 1,480 twin pairs born in the period 1985-1986 ascertained from the Swedish Twin Registry, birth weight was collected prospectively through the Medical Birth Registry. ADHD symptoms were measured with a 14-item checklist covering DSM-III-R criteria (parental rating) at age 8 to 9 years and 13 to 14 years. We used both a dichotomous approach for birth weight (>400 g or 15% weight difference) and ADHD (eight or more symptoms) and continuous measures to investigate between- and within-twin pair effects. RESULTS: Our results showed that low birth weight was a risk factor for symptoms of ADHD and the associations did not diminish when we controlled for genetic influence. The lighter twin in birth weight-discordant pairs had on average 13% higher ADHD symptom score at age 8 to 9 years (p = .006) and 12% higher ADHD score at age 13 to 14 years (p = .018) compared with the heavier twin. The genetic correlations suggest modest or no genetic overlap between birth weight and ADHD. CONCLUSIONS: The hypothesis that low birth weight is associated with the development of ADHD symptoms was supported in this prospective twin study. Fetal growth restriction seems to represent a modest but fairly consistent environmental influence on the development of ADHD symptoms.

Synergy between cigarette smoking and human papillomavirus type 16 in cervical cancer in situ development.

BACKGROUND: A majority of studies have implicated the involvement of cigarette smoking in cervical cancer development, although its mechanism of action remains unclear. We conducted a large population-based case-control study to address the potential interaction between smoking and human papillomavirus type 16 (HPV-16) in development of cervical cancer in situ (CIS). METHODS: Information on risk factors for CIS was collected via interview, and archival cervical smears were tested for HPV-16 DNA presence in cases (n = 375) and controls (n = 363). Adjusted odds ratios (OR) for the effects of smoking, HPV-16 presence/absence, and load at first smear (taken, on average, 9 years before diagnosis) were calculated. RESULTS: The risk for CIS among current smokers who were HPV-16 positive at time of first smear was >14-fold [adjusted OR, 14.4; confidence interval (95% CI), 5.6-36.8] compared with HPV-16-negative current smokers. In contrast, the risk for CIS among HPV-16-positive nonsmokers was only 6-fold (adjusted OR, 5.6; 95% CI, 2.7-11.5), compared with HPV-16-negative nonsmokers. HPV-16-positive smokers with high viral load at time of first smear exhibited a high risk for CIS (adjusted OR, 27.0; 95% CI, 6.5-114.2) compared with HPV-16-negative smokers. Within nonsmokers, however, high HPV-16 load contributed only a 6-fold increased risk compared with HPV-16-negative nonsmokers (adjusted OR, 5.9; 95% CI, 2.4-14.6). Interaction was observed (P = 0.03) between duration of smoking and HPV-16 presence in CIS development. CONCLUSION: Results suggest a synergistic effect between smoking and both HPV-16 status and HPV-16 viral load, which may occur almost a decade before CIS detection.

Pregnancy characteristics and maternal risk of breast cancer.

CONTEXT: During pregnancy, serum levels of estrogen, progesterone, and other hormones are markedly higher than during other periods of life. Pregnancy hormones primarily are produced in the placenta, and signs of placental impairment may serve as indirect markers of hormone exposures during pregnancy. During pregnancy, these markers have been inconsistently associated with subsequent risk of breast cancer in the mother. OBJECTIVE: To examine associations between indirect markers of hormonal exposures, such as placental weight and other pregnancy characteristics, and maternal risk of developing breast cancer. DESIGN AND SETTING: Population-based cohort study using data from the Swedish Birth Register, the Swedish Cancer Register, the Swedish Cause of Death Register, and the Swedish Register of Population and Population Changes. PARTICIPANTS: Women included in the Sweden Birth Register who delivered singletons between 1982 and 1989, with complete information on date of birth and gestational age. Women were followed up until the occurrence of breast cancer, death, or end of follow-up (December 31, 2001). Cox proportional hazards models were used to estimate associations between hormone exposures and risks of breast cancer. MAIN OUTCOME MEASURE: Incidence of invasive breast cancer. RESULTS: Of 314,019 women in the cohort, 2216 (0.7%) developed breast cancer during the follow-up through 2001, of whom 2100 (95%) were diagnosed before age 50 years. Compared with women who had placentas weighing less than 500 g in 2 consecutive pregnancies, the risk of breast cancer was increased among women whose placentas weighed between 500 and 699 g in their first pregnancy and at least 700 g in their second pregnancy (or vice versa) (adjusted hazard ratio, 1.82; 95% confidence interval [CI], 1.07-3.08), and the corresponding risk was doubled among women whose placentas weighed at least 700 g in both pregnancies (adjusted hazard ratio, 2.05; 95% CI, 1.15-3.64). A high birth weight (> or =4000 g) in 2 successive births was associated with an increased risk of breast cancer before but not after adjusting for placental weight and other covariates (adjusted hazard ratio, 1.10; 95% CI, 0.76-1.59). CONCLUSIONS: Placental weight is positively associated with maternal risk of breast cancer. These results further support the hypothesis that pregnancy hormones are important modifiers of subsequent maternal breast cancer risk.

Testicular cancer incidence in eight northern European countries: secular and recent trends.

OBJECTIVE: Striking geographic variation and marked increasing secular trends characterize the incidence of testicular cancer. However, it is not known whether these patterns have attenuated in recent years and whether they are similar for seminomas and nonseminomas, the two main histologic groups of testicular cancer. METHOD: Cancer registry data, including 27,030 testicular cancer cases, were obtained from Denmark, Estonia, Finland, Latvia, Lithuania, Norway, Poland, and Sweden. Between 57 (Denmark) and 9 (Poland) years of registration were covered. Country-specific temporal trends were estimated, with focus on the last decade and seminomas and nonseminomas. Data from the Nordic countries were further analyzed using an age-period-cohort approach. RESULTS: Age-standardized incidence rates increased annually by 2.6% to 4.9% during the study period, with marginal differences between seminomas and nonseminomas. In the last decade, the increasing trend attenuated only in Denmark (annual change, -0.3%; 95% confidence interval, -1.5 to 0.9). In 1995, the highest and the lowest age-standardized incidence rates (per 10(5)) were 15.2 in Denmark and 2.1 in Lithuania. Incidence rates (i.e., for all cancers and for seminomas and nonseminomas, separately) depended chiefly on birth cohort rather than on calendar period of diagnosis (although both birth cohort and period determined the Danish incidence rates). CONCLUSIONS: Testicular cancer incidence is still increasing, with the exception of Denmark, and a large geographic difference exists. The increasing trend is mainly a birth cohort phenomenon also in recent cohorts. Temporal trends for seminomas and nonseminomas are similar, which suggests that they share important causal factors.

Maternal smoking during pregnancy and school performance at age 15.

BACKGROUND: Smoking during pregnancy has been suggested to have long-term consequences for neuropsychologic development in the offspring, including behavioral problems, attention deficit disorders, and antisocial behavior. Also, findings from several studies indicate an association with impaired cognitive function in the children. METHODS: In a population-based Swedish cohort study, we examined possible associations between maternal smoking in pregnancy and educational achievement in the offspring at age 15 years among more than 400,000 male and female students born 1983 through 1987. Generalized estimating equation models were used to evaluate associations of maternal smoking, other maternal characteristics, and birth characteristics with school performance. Odds ratios (ORs) were used as a measure of risk. RESULTS: In a model adjusted for maternal characteristics, maternal smoking compared with no tobacco use during pregnancy was associated with an increased risk of poor scholastic achievement: for 1-9 cigarettes per day, the OR was 1.59 (95% confidence interval = 1.59-1.63) and for 10 or more cigarettes per day, the OR was 1.92 (1.86-1.98). These risks remained unchanged when we also adjusted for smoking-related pregnancy outcomes such as fetal growth restriction and preterm birth. However, if the mother had smoked in her first pregnancy, but not in her second pregnancy, the younger sibling was also at increased risk of poor school performance. CONCLUSION: Observed associations between maternal smoking during pregnancy and poor cognitive performance in the offspring might not be causal. We suggest that associations reported in earlier studies may instead reflect the influence of unmeasured characteristics that differ between smokers and nonsmokers.

Nutrient intake and risk of non-Hodgkin's lymphoma.

The mechanisms through which diet may influence the development of non-Hodgkin's lymphoma (NHL) are unclear but can be better understood by examining associations between nutrient consumption and NHL risk. Between 2000 and 2002, 591 NHL cases and 460 population-based controls in Sweden completed a semiquantitative food frequency questionnaire. Unconditional logistic regression was performed to estimate odds ratios and 95% confidence intervals for associations with nutrient intake; all statistical tests were two sided. Dietary intake of most macronutrients was not associated with risk of NHL or its common subtypes. Consumption of omega-3 or marine fatty acids was associated with decreased risk of NHL and chronic lymphocytic lymphoma, and dietary fiber was associated with lower risk of all subtypes examined. When the highest and the lowest quartiles of marine fat intake were compared, the odds ratio for NHL risk was 0.6 (95% confidence interval: 0.4, 0.9), ptrend=0.03; for dietary fiber intake, the corresponding odds ratio was 0.5 (95% confidence interval: 0.3, 0.7), ptrend<0.001. Dietary consumption of beta-carotene or alpha-tocopherol was associated with lower NHL risk, whereas intake of calcium or retinol was associated with increased NHL risk. Nutrients that affect inflammation, vitamin D activity, oxidative DNA damage, or DNA methylation may be associated with risk of NHL.

Re-use of case-control data for analysis of new outcome variables.

Case-control studies are usually defined to investigate risk factors for a single disease of interest. However, subsequent to data collection, investigators may wish to examine as an 'outcome' a variable that was an exposure in the original study. A naive analysis that disregards the sampling strategy that gave rise to the data is clearly prone to bias. We present here a simple approach to the analysis of such data using an appropriately weighted regression model. Viewing the problem as a two-stage design provides a unified framework for recognizing and defining the necessary weights when confronted with a variety of real data problems that at first seem unrelated. We provide illustrations that highlight the generality of the approach and demonstrate that the method gives essentially the same results as more specialized methods that require non-standard tools for analysis.

Ultraviolet radiation exposure and risk of malignant lymphomas.

BACKGROUND: The incidence of malignant lymphomas has been increasing rapidly, but the causes of these malignancies remain poorly understood. One hypothesis holds that exposure to ultraviolet (UV) radiation increases lymphoma risk. We tested this hypothesis in a population-based case-control study in Denmark and Sweden. METHODS: A total of 3740 patients diagnosed between October 1, 1999, and August 30, 2002, with incident malignant lymphomas, including non-Hodgkin lymphoma, chronic lymphocytic leukemia, and Hodgkin lymphoma, and 3187 population controls provided detailed information on history of UV exposure and skin cancer and information on other possible risk factors for lymphomas. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by logistic regression. Statistical tests were two-sided. RESULTS: Multivariable-adjusted analyses revealed consistent, statistically significant negative associations between various measures of UV light exposure and risk of non-Hodgkin lymphoma. A high frequency of sun bathing and sunburns at age 20 years and 5-10 years before the interview and sun vacations abroad were associated with 30%-40% reduced risks of non-Hodgkin lymphoma (e.g., for sunbathing four times a week or more at age 20 versus never sunbathing, OR = 0.7, 95% CI = 0.6 to 0.9; for two or more sunburns a year at age 20 versus no sunburns, OR = 0.6, 95% CI = 0.5 to 0.8). These inverse associations increased in strength with increasing levels of exposure (all P(trend)< or =.01). Similar, albeit weaker, associations were observed for Hodgkin lymphoma. There were no clear differences among non-Hodgkin lymphoma subtypes, although associations were stronger for B-cell than for T-cell lymphomas. A history of skin cancer was associated with a doubling in risks of both non-Hodgkin and Hodgkin lymphoma. CONCLUSIONS: A history of high UV exposure was associated with reduced risk of non-Hodgkin lymphoma. The positive association between skin cancer and malignant lymphomas is, therefore, unlikely to be mediated by UV exposure.