Aparna K. Mohan

Autologous cultured chondrocytes: adverse events reported to the United States Food and Drug Administration.

BACKGROUND Carticel is an autologous cultured chondrocyte product that has been approved by the United States Food and Drug Administration for the repair of symptomatic cartilaginous defects of the femoral condyle that are caused by acute or repetitive trauma in patients who have been previously managed with arthroscopy or other surgical procedures. The present report describes the adverse events following Carticel implantation as reported to the Food and Drug Administration from 1996 to 2003. METHODS We reviewed adverse event reports that had been submitted to the Food and Drug Administrations MedWatch system for information on demographic characteristics, adverse events, and surgical revisions. Adverse events were categorized into sixteen non-mutually exclusive groups. Five categories were used to classify reoperations. Food and Drug Administration regulations require manufacturers to report adverse events; however, reporting by clinicians and others is voluntary. Therefore, adverse event reporting is likely to underestimate the number of event occurrences. Adverse events may be either causally or coincidentally related to the product. RESULTS A total of 497 adverse events among 294 patients receiving Carticel were reported. The median interval from Carticel implantation to the diagnosis of an adverse event was 240 days (range, one to 2105 days). The median age of the patients was thirty-eight years, and 63% of the patients were male. Of the 270 events for which the anatomic site was noted, 258 (96%) involved the femoral condyles. More than one adverse event was reported for 135 patients (46%). The most commonly reported events were graft failure (seventy-three patients; 25%), delamination (sixty-five patients; 22%), and tissue hypertrophy (fifty-two patients; 18%). In addition, eighteen surgical site infections were reported, including eleven joint and seven soft-tissue infections. Surgical revision subsequent to Carticel implantation was mentioned in the records for 273 patients (93%). The reasons for the 389 revision procedures included graft-related problems (187 procedures; 48.1%), periarticular soft-tissue problems (ninety-seven procedures; 24.9%), and intra-articular problems (sixty-three procedures; 16.2%). Eight patients had a total knee replacement. Based on the manufacturers reported distribution of 7500 Carticel lots between 1995 and 2002, 285 patients (3.8%) had an adverse event that was reported to the Food and Drug Administration. CONCLUSIONS The most common adverse events reported in association with the Carticel technique involved graft failure, delamination, and tissue hypertrophy.

Cancer and other causes of mortality among radiologic technologists in the United States.

Data are limited on the role of chronic exposure to low‐dose ionizing radiation in the etiology of cancer. In a nationwide cohort of 146,022 U.S. radiologic technologists (73% female), we evaluated mortality risks in relation to work characteristics. Standardized mortality ratios (SMRs) were computed to compare mortality in the total cohort vs. the general population of the United States. Mortality risks were low for all causes (SMR = 0.76) and for all cancers (SMR = 0.82) among the radiologic technologists. We also calculated relative risks (RR) for the 90,305 technologists who responded to a baseline mailed questionnaire, using Poisson regression models, adjusted for known risk factors. Risks were higher for all cancers (RR = 1.28, 95% confidence interval [CI] = 0.93–1.69) and breast cancer (RR = 2.92, 95% CI = 1.22–7.00) among radiologic technologists first employed prior to 1940 compared to those first employed in 1960 or later, and risks declined with more recent calendar year of first employment (p‐trend = 0.04 and 0.002, respectively), irrespective of employment duration. Risk for the combined category of acute lymphocytic, acute myeloid and chronic myeloid leukemias was increased among those first employed prior to 1950 (RR = 1.64, 95% CI = 0.42–6.31) compared to those first employed in 1950 or later. Risks rose for breast cancer (p‐trend = 0.018) and for acute lymphocytic, acute myeloid and chronic myeloid leukemias (p‐trend = 0.05) with increasing duration of employment as a radiologic technologist prior to 1950. The elevated mortality risks for breast cancer and for the combined group of acute lymphocytic, acute myeloid and chronic myeloid leukemias are consistent with a radiation etiology given greater occupational exposures to ionizing radiation prior to 1950 than in more recent times.

Infectious complications of biologic treatments of rheumatoid arthritis

&NA; Agents that block the action of tumor necrosis factor‐&agr; and recombinant interleukin‐1 have been shown to be effective biologic treatment modalities in patients with rheumatoid arthritis. Given the immunosuppressive effects of tumor necrosis factor‐&agr; and interleukin‐1 blockers, infections have emerged as possible complications of using these agents, an observation foreshadowed in prelicensure animal studies. At this time, hundreds of thousands of patients have received these drugs, and a wide variety of infectious complications has been reported, among which reactivation tuberculosis is most notable. Case reports alone, however, do not necessarily reflect a causal association between a therapeutic product and an adverse event. The authors review the infectious complications of the use of these agents as reported in the medical literature from November 2001 through October 2002.

Estimating Historical Radiation Doses to a Cohort of U.S. Radiologic Technologists

Abstract Simon, S. L., Weinstock, R. M., Doody, M. M., Neton, J., Wenzel, T., Stewart, P., Mohan, A. K., Yoder, C., Freedman, M., Hauptmann, M., Bouville, A., Cardarelli, J., Feng, H. A. and Linet, M. Estimating Historical Radiation Doses to a Cohort of U.S. Radiologic Technologists. Radiat. Res. 166, 174– 192 (2006). Data have been collected and physical and statistical models have been constructed to estimate unknown occupational radiation doses among 90,000 members of the U.S. Radiologic Technologists cohort who responded to a baseline questionnaire during the mid-1980s. Since the availability of radiation dose data differed by calendar period, different models were developed and applied for years worked before 1960, 1960– 1976 and 1977–1984. The dose estimation used available film-badge measurements (approximately 350,000) for individual cohort members, information provided by the technologists on their work history and protection practices, and measurement and other data derived from the literature. The dosimetry model estimates annual and cumulative occupational badge doses (personal dose equivalent) for each technologist for each year worked from 1916 through 1984 as well as absorbed doses to organs and tissues including bone marrow, female breast, thyroid, ovary, testes, lung and skin. Assumptions have been made about critical variables including average energy of X rays, use of protective aprons, position of film badges, and minimum detectable doses. Uncertainty of badge and organ doses was characterized for each year of each technologists working career. Monte Carlo methods were used to generate estimates of cumulative organ doses for preliminary cancer risk analyses. The models and predictions presented here, while continuing to be modified and improved, represent one of the most comprehensive dose reconstructions undertaken to date for a large cohort of medical radiation workers.

Risk of melanoma among radiologic technologists in the United States.

Our study examines the risk of melanoma among medical radiation workers in the U.S. Radiologic Technologists (USRT) study. We evaluated 68,588 white radiologic technologists (78.8% female), certified during 1926–1982, who responded to a baseline questionnaire (1983–1989) and were free of cancer other than nonmelanoma skin at that time. Participants were followed through completion of a second questionnaire (1994–1998). We identified 207 cases, 193 subjects who reported first primary melanoma and 14 decedents with melanoma listed as an underlying or contributory cause of death. We examined risks of occupational radiation exposures using work history information on practices, procedures, and protective measures reported on the baseline questionnaire. Based on Cox proportional hazards regression, melanoma was significantly associated with established risk factors, including constitutional characteristics (skin tone, eye and hair color), personal history of nonmelanoma skin cancer, family history of melanoma and indicators of residential sunlight exposure. Melanoma risk was increased among those who first worked before 1950 (RR = 1.8, 95% CI = 0.6–5.5), particularly among those who worked 5 or more years before 1950 (RR = 2.4; 0.7–8.7; p (trend) for years worked before 1950 = 0.03), when radiation exposures were likely highest. Risk was also modestly elevated among technologists who did not customarily use a lead apron or shield when they first began working (RR = 1.4; 0.8–2.5). Clarifying the possible role of exposure to chronic ionizing radiation in melanoma is likely to require nested case‐control studies within occupational cohorts, such as this one, which will assess individual radiation doses, and detailed information about sun exposure, sunburn history and skin susceptibility characteristics. Published 2002 Wiley‐Liss, Inc.

Incidence of haematopoietic malignancies in US radiologic technologists

Background: There are limited data on risks of haematopoietic malignancies associated with protracted low-to-moderate dose radiation. Aims: To contribute the first incidence risk estimates for haematopoietic malignancies in relation to work history, procedures, practices, and protective measures in a large population of mostly female medical radiation workers. Methods: The investigators followed up 71 894 (77.9% female) US radiologic technologists, first certified during 1926–80, from completion of a baseline questionnaire (1983–89) to return of a second questionnaire (1994–98), diagnosis of a first cancer, death, or 31 August 1998 (731 306 person-years), whichever occurred first. Cox proportional hazards regression was used to compute risks. Results: Relative risks (RR) for leukaemias other than chronic lymphocytic leukaemia (non-CLL, 41 cases) were increased among technologists working five or more years before 1950 (RR = 6.6, 95% CI 1.0 to 41.9, based on seven cases) or holding patients 50 or more times for x ray examination (RR = 2.6, 95% CI 1.3 to 5.4). Risks of non-CLL leukaemias were not significantly related to the number of years subjects worked in more recent periods, the year or age first worked, the total years worked, specific procedures or equipment used, or personal radiotherapy. Working as a radiologic technologist was not significantly linked with risk of multiple myeloma (28 cases), non-Hodgkin’s lymphoma (118 cases), Hodgkin’s lymphoma (31 cases), or chronic lymphocytic leukaemia (23 cases). Conclusion: Similar to results for single acute dose and fractionated high dose radiation exposures, there was increased risk for non-CLL leukaemias decades after initial protracted radiation exposure that likely cumulated to low-to-moderate doses.

Trends in reproductive, smoking, and other chronic disease risk factors by birth cohort and race in a large occupational study population

PURPOSE To illustrate the value of cohort studies to assess trends in chronic disease risk factors. METHODS In collaboration with the American Registry of Radiologic Technologists and the University of Minnesota, the National Cancer Institute initiated a cohort study of cancer among radiologic technologists. More than 90,000 technologists who responded to a mailed questionnaire were grouped into ten birth cohorts from before 1920 through 1960 and later, and stratified by self-reported racial/ethnic groups. Trends in height, smoking, and reproductive factors were analyzed. RESULTS Among the trends observed were that the proportion of young men (< 18 years) smoking generally fell in each birth cohort after 1925, whereas the proportion of young women smoking rose for those born after 1950. Among women born since 1940, the mean age at menarche for white women has remained at 12.5 years, but has declined among black and Asian/Pacific Islander women. Recent birth cohorts (since 1955) show among the highest mean ages at birth of first child (> 26 years), highest rates of nulliparity at age 25 (>/= 63 %), and lowest mean parity levels (< or = 1.7) compared with earlier cohorts. CONCLUSION Analyses of large cohorts can clarify birth cohort trends in chronic disease risk factors.

Deaths among children less than two years of age receiving palivizumab: an analysis of comorbidities.

Background. Palivizumab (Synagis) is used for prophylaxis against respiratory syncytial virus infection among children at high risk for respiratory syncytial virus disease. A number of deaths after palivizumab use among children <2 years have been reported to the Food and Drug Administration. We assessed available information, including the extent to which preexisting medical conditions may have put these children at higher than normal risk of death. Methods. We reviewed reports of deaths to the Food and Drug Administration (June 1998 to December 2001) among children <2 years of age who received palivizumab. Results. There were 133 deaths reported after palivizumab use. Median age at death was 5 months, and 54% of the children were male. At least one congenital anomaly was reported in 85 cases (64%), and 44% of cases had multiple anomalies. Of the 100 cases with reported gestational age at birth, 36% were severely premature (<28 weeks), 48% were moderately premature (28 to 36 weeks) and 16% had normal gestational age. Only 2% of all cases were full term and were born without congenital anomalies; 50% had both conditions, 34% had prematurity alone and 14% had congenital anomalies alone. A cause of death was reported for 88 (66%) cases; most (38%) died from their congenital anomalies or from respiratory infections (23%). Conclusions. Most children dying after palivizumab treatment were at increased risk of death; many had multiple congenital anomalies and/or premature birth. Patterns of outcomes and the reported medical course did not suggest that palivizumab further elevated the risk of death. Current data do not alter the safety and efficacy assessment that led to the licensure of palivizumab.

Mortality among radiologic technologists in the united states (1926–1997): 2nd Follow up

PURPOSE: To evaluate risk for all-cause and cause-specific mortality in a large, primarily female (73%) cohort of radiologic technologists.METHODS: The study consists of 145,915 radiation technologists, certified in the American Registry of Radiologic Technologists (1926-1982) and followed through 1997. Causes of death were obtained from death certificates or, more recently, through NDI Plus. Standardized Mortality Ratios (SMR) were computed and tests of homogeneity were performed to detect differences in mortality among causes. Poisson models were used to estimate risks using an internal comparison group.RESULTS: Significantly low SMRs were observed for all causes (0.76), all cancers (0.82), and diseases of circulatory system (0.69). Compared to U.S. women, the risk for breast cancer mortality bordered around unity (SMR 1.01, 95% CI 0.94-1.09). However, relative to all other cancers, breast cancer mortality was significantly increased (RSMR 1.24, p < 0.01). Elevated risk for breast cancer was associated with certification before 1940 (SMR 1.55, 95% CI 1.24-1.91), and duration of certification of 20-29 (SMR 1.21, 95% CI 1.06-1.37) and 30+ years (SMR 1.77, 95% CI 1.54-2.02). A 35% increase in leukemia risk was evident for women certified for a duration of 20-29 years and a 36% increase among women certified for 30+ years. Poisson analysis revealed a significant increase in breast cancer risk with increasing number of years certified among women first certified before 1940 (p < 0.001) and during 1940-49 (p = 0.05) compared to women first certified in 1950 or later.CONCLUSIONS: Preliminary findings of this study suggest increased breast cancer risk associated with occupational radiation exposures prior to 1950 and with long-term cumulative exposures. However, potential confounding by reproductive and other risk factors needs to be evaluated.

Trends in reproductive, smoking, and other chronic disease risk factors by birth cohort in a large occupational study

PURPOSE: To illustrate the value of using large cohort studies to identify birth cohort trends in several chronic disease risk factors.METHODS: In collaboration with the American Registry of Radiologic Technologists (ARRT) and the University of Minnesota, the National Cancer Institute (NCI) initiated a cohort study of radiologic technologists who were certified by ARRT for at least two years between 1926 and 1982. Over 90,000 technologists (nearly four-fifths female) from all 50 states responded to a mailed questionnaire on reproductive, medical, work, and lifestyle factors. Ten, mostly five-year, birth cohorts, from before 1920 through 1960 and later, were evaluated.RESULTS: In this population, the mean height of both men and women generally rose in each subsequent birth cohort. The proportion of men who smoked before age 18 fell among those born since the late 1920s. In contrast, the proportion of women smoking before age 18 rose among those born since the early 1950s, reaching 14.2% among those born in 1960 and later. The mean age at menarche fell, until leveling off at 12.5, among those born after 1940. Recent birth cohorts (since 1950) show among the highest mean ages at birth of first child (>26 yeras), highest rates of nulliparity at age 25 (>/=63%), and lowest mean parity levels (</=1.7), compared with earlier birth cohorts. The proportion of women ever using oral contraceptives rose steadily by birth cohort, reaching 86 percent in the most recent birth cohort.CONCLUSIONS: Some of the trends observed may help explain historic chronic disease incidence patterns and predict future disease burdens.