Timothy R. Coté

Spectrum of AIDS-associated malignant disorders

BACKGROUND To clarify which types of cancer result from AIDS, we compared the cancer experiences of people with AIDS with those of the general population by matching population-based cancer and AIDS registries in the USA and Puerto Rico. METHODS We used a probabilistic matching algorithm to compare names, birth dates, and, where available, social-security numbers of 98,336 people with AIDS and 1,125,098 people with cancer aged less than 70 years. We defined AIDS-related cancers as those with both significantly raised incidence post-AIDS and increasing prevalence from 5 years pre-AIDS to 2 years post-AIDS. FINDINGS Among people with AIDS, we found 7028 cases of Kaposis sarcoma (KS), 1793 of non-Hodgkin lymphoma (NHL), and 712 other cases of histologically defined cancer. Incidence rates among people with AIDS were increased 310-fold for KS, 113-fold for NHL, and 1.9-fold (95% CI 1.5-2.3) for other cancers. Of 38 malignant disorders other than KS and NHL, only angiosarcoma (36.7-fold), Hodgkins disease (7.6-fold), multiple myeloma (4.5-fold), brain cancer (3.5-fold), and seminoma (2.9-fold) were raised and increasing significantly (p<0.02) from the pre-AIDS to the post-AIDS period. INTERPRETATION Interpretation is complicated by screening and shared risk factors, such as sexual behaviour and cigarette smoking. However, our data indicate that AIDS leads to a significantly increased risk of Hodgkins disease, multiple myeloma, brain cancer, and seminoma. Immunological failure to control herpes or other viral infections may contribute to these malignant diseases.

Non‐Hodgkin's lymphoma among people with AIDS: Incidence, presentation and public health burden

We describe the anatomic and histologic presentation and prognosis of non‐Hodgkins lymphoma (NHL) among people with AIDS (PWA) and determine their contribution to the NHL burden. We linked AIDS and cancer registries in selected areas of the United States and compared NHL sites and histologies in PWA and non‐PWA, after adjusting for age, sex and ethnicity. Among 51,033 PWA, we found 2,156 cases of NHL (4.3%). Half of NHL cases occurring post‐AIDS were not reported to AIDS registries. NHL was part of an AIDS‐defining condition for 3.2% of all PWA; the relative risk of NHL with 3.5 years of another AIDS diagnosis was 165‐fold compared to non‐PWA within the cancer surveillance system. Of NHLs, 39% were high grade (vs. 12% among non‐PWA), 60% were nodal (vs. 74% among non‐PWA) and 15% had brain primaries (vs. 1% among non‐PWA). Excluding brain sites, extranodal sites were still 20% more common than expected. Relative risk was elevated for all histologic types, with the risk ranging from 652‐fold for high‐grade diffuse immunoblastic tumors and 261‐fold for Burkitts lymphomas to 113 for intermediate‐grade lymphoma to 14‐fold for low‐grade lymphoma. Survival among PWA with NHL was poor, and tumor grade had little impact. In high‐risk AIDS areas, AIDS‐related NHLs constitute a major share of the NHL burden. We conclude that NHL risk is considerably under‐estimated in AIDS registry data. The major differences between PWA and non‐PWA were the high frequency of brain lymphoma and the increase in high‐grade lymphomas in PWA. However, the grade of NHL did not influence the prognosis among PWA with lymphoma. The increasing risk of NHL in PWA has contributed substantially to the general increase in NHL rates in the United States since 1981. Int. J. Cancer 73:645–650, 1997.

High incidence of anal cancer among AIDS patients

Until now, the only cancers that have been strongly associated with AIDS are Kaposis sarcoma and non-Hodgkin lymphoma. We used a linkage between AIDS (50,050 reports) and cancer (859,398 reports) registries in seven health departments in the USA to investigate the association between HIV infection and epidermoid anal cancer. We compared the numbers of observed cases and expected cases, calculated from general population rates with adjustment for age, sex, and race. The relative risk of anal cancer at and after AIDS diagnosis was 84.1 (95% CI 46.4-152) among homosexual patients (11 cases) and 37.7 (9.4-151) among non-homosexual patients (2 cases). The relative risk of anal cancer up to 5 years before the AIDS diagnosis (23 cases) was also increased; it was 13.9 (6.6-29.2) in the period 2-5 years before AIDS and 27.4 (15.9-47.2) during the 2 years before AIDS diagnosis (p for trend = 0.004). Among homosexual men, the relative risk of anal cancer was inversely related to age at AIDS onset (p for trend < 0.001). Excess risks were found in all geographical areas. This study establishes a strikingly increased risk of anal cancer among people with AIDS. These data are consistent with a previously hypothesized association between HIV-induced immunodeficiency and anal cancer development, but because homosexual men were at increased risk of anal cancer even before the AIDS epidemic, we cannot say how much of the increased risk is attributable to HIV infection. Nevertheless, clinicians should be aware that AIDS patients have an increased risk of anal cancer.

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.

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.

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.

Typhoid fever in the park: Epidemiology of an outbreak at a cultural interface

The number of reported outbreaks of typhoid fever in the United States has recently increased. Only six were reported from 1980–1989, but seven outbreaks were reported in 1990. In August 1990, health officials in Montgomery County, Maryland, were notified of two cases of typhoid fever among persons who had attended both a family picnic attended by 60 persons and a Latin Food Festival attended by 100,000 people. We obtained interviews, blood and stool cultures, and Vi serologies from attendees at and food handlers for the picnic. We defined cases as culture-confirmed or probable. Of the 60 picnic attendees, 24 (40%) had cases, of which 16 were culture confirmed. Those who ate potato salad were at increased risk of disease (17/32vs. 6/28, relative risk [RR]=2.5,95% confidence interval [CI] 1.1–5.4). Picnic attendees who also attended the Latin Food Festival were not at significantly greater risk of disease than those who did not, (11/22vs. 13/38, RR=1.5, CI=0.8–2.7) and we found no evidence of disease among other festival attendees. The potato salad was prepared with intensive handling and without adequate temperature control by a recent immigrant from El Salvador who was asymptomatic, did not attend the picnic, hadSalmonella typhi (S. typhi) in her stool, and had elevated Vi antibodies, strongly suggestive of the carrier state. Outbreaks of typhoid fever are a threat for cosmopolitan communities. While currently available control measures are unlikely to prevent all outbreaks, thorough investigation can identify previously unrecognized carriers.