The safety profile of anti-tumour necrosis factor therapy in inflammatory bowel disease in clinical practice: analysis of 620 patient-years follow-up

Background  Anti-TNF agents are now widely used in Crohn's disease (CD), and in ulcerative colitis (UC).
Aim  To review the safety profile of anti-TNF agents in all patients treated with infliximab in Edinburgh from 1999 to 2007.
Methods  Complete data were available on 202/207 patients comprising 157 CD, 42 UC and three coeliac disease. Median follow-up was 2.4 years (1.0–4.9) with a total of 620 patient-years follow-up. About 19.1% of CD patients were subsequently treated with adalimumab.
Results  Seven deaths (3.3%) occurred in follow-up; only one death was <1 year post-infliximab (at day 72, from lung cancer). A total of six malignancies (three haematological, three bronchogenic) and six cases of suspected demyelination (three with confirmed neurological disease) were reported. In the 90 days following infliximab, 95 adverse events (36 serious) occurred in 58/202 (28.7%) patients. In all, 42/202 (20.8%) had an infectious event (22 serious) and 27/202 (13.4%) of patients had an infusion reaction: 19 acute (four serious) and eight delayed (three serious).
Conclusions  Serious infections, malignancies and neurological disease complicate anti-TNF use in clinical practice. Although evidence for causality is unclear, potential mechanisms and predisposing factors need to be explored. In individual patients, the risk/benefit analysis needs to be carefully assessed and discussed prior to commencement of therapy.     

Diagnostic labeling of COPD in five Latin American cities

Background:COPD is a major worldwide problem with a rising prevalence. Despite its importance, there is a lack of information regarding underdiagnosis and misdiagnosis of COPD in different countries. As part of the Proyecto Latinoamericano de Investigación en Obstrucción Pulmonar study, we examined the relationship between prior diagnostic label and airway obstruction in the metropolitan areas of five Latin American cities (São Paulo, Santiago, Mexico City, Montevideo, and Caracas).Methods:A two-stage sampling strategy was used in each of the five areas to obtain probability samples of adults aged ≥ 40 years. Participants completed a questionnaire that included questions on prior diagnoses, and prebronchodilator and postbronchodilator spirometry. A study diagnosis of COPD was based on airway obstruction, defined as a postbronchodilator FEV₁/FVC < 0.70.Results:Valid spirometry and prior diagnosis information was obtained for 5,303 participants; 758 subjects had a study diagnosis of COPD, of which 672 cases (88.7%) had not been previously diagnosed. The prevalence of undiagnosed COPD was 12.7%, ranging from 6.9% in Mexico City to 18.2% in Montevideo. Among 237 subjects with a prior COPD diagnosis, only 86 subjects (36.3%) had postbronchodilator FEV₁/FVC < 0.7, while 151 subjects (63.7%) had normal spirometric values. In the same group of 237 subjects, only 34% reported ever undergoing spirometry prior to our study.Conclusions:Inaccurate diagnostic labeling of COPD represents an important health problem in Latin America. One possible explanation is the low rate of spirometry for COPD diagnosis.     

Results of a pilot trial of immunotherapy with dendritic cells pulsed with autologous tumor lysates in patients with advanced cancer

AIMS AND BACKGROUND: The purpose of the study was to test the immunological and clinical effects of infusions of dendritic cells pulsed with autologous tumor lysate in patients with advanced cancer. PATIENTS AND METHODS: Peripheral blood mononuclear cells from 15 patients with metastatic cancer (melanoma in 10, lung cancer in 2, renal cell carcinoma in 1, sarcoma in 1, breast cancer in 1) were harvested by leukapheresis after mobilization with GM-CSF (5 microg/kg/day s.c. for 4 days). Mononuclear cells were separated and cultured in GM-CSF (1000 U/ml) and interleukin-4 (1000 U/ml) for 7 days. Phenotype was assessed by 2-color flow cytometry and immunocytochemistry. On day 6, dendritic cells were pulsed with 1 g of fresh autologous tumor lysate for 24 h and infused intravenously. Interleukin-2 (6 million IU), interferon a (4 million IU) and GM-CSF (400 microg) were injected s.c. daily for 10 days beginning on the day of dendritic cell infusion. Treatment was repeated every 21 days for 3 courses. RESULTS: The morphology, immunocytochemistry and phenotype of cultured cells was consistent with dendritic cells: intense positivity for HLA-DR and CD86, with negativity for markers of other lineages, including CD3, CD4, CD8 and CD14. More than 5 x 10(7) dendritic cells were injected in all patients. Nine patients developed >5 mm delayed type cutaneous hypersensitivity reactions to tumor lysate+/-GM-CSF after the first immunization (larger than GM-CSF in all cases). Median delayed type cutaneous hypersensitivity to lysate +/- GM-CSF was 3 cm after the third immunization. One melanoma patient with skin, liver, lung and bone metastases had a partial response lasting 8 months (followed by progression in the brain). Seven patients had stable disease for >3 months, and 7 had progression. CONCLUSIONS: Infusion of tumor lysate-pulsed dendritic cells induces a strong cell-mediated antitumor immune reaction in patients with advanced cancer and has some clinical activity.     

Ovarian tumors of borderline malignancy: a review of 247 patients from 1991 to 2004

Borderline ovarian tumors account for 15% of epithelial ovarian cancers and are different from invasive malignant carcinoma. Majority are early stage, occurring in women in the reproductive age group, where fertility is important. We reviewed retrospectively 247 such cases treated at the Gynaecological-Oncology Unit, KK Women's and Children's Hospital, between January 1991 and December 2004. The mean age was 38 years (16-89 years). Majority of the cases (92%) were FIGO stage I (Ia, 75%; Ib, 1%; and Ic, 16%). Seven (3.5%) patients were diagnosed as having stage II disease, six (2.5%) as stage IIIa, two (1%) as stage IIIb, and four (2%) as stage IIIc. Histological origin was as follows: mucinous (68%), serous (26%), endometrioid (2.6%), and clear cell (1.2%). Primary surgical procedures undertaken were as follows: hysterectomy with bilateral salpingo-oophorectomy (52%), unilateral salpingo-oophorectomy (33%), or ovarian cystectomy (15%). Adjuvant chemotherapy was administered in 13 patients (5.2% of cases), of which 4 patients were given chemotherapy only because of synchronous malignancies. There were six recurrences (2.4% of cases). Overall mean time to recurrence was 59 months. Recurrence rate for patients who underwent a primary pelvic clearance was 1.6% compared to fertility-sparing conservative surgery (3.3%; although P= 0.683). No significant difference was noted in recurrence and mortality between staged versus unstaged procedures. The overall survival rate was 98.0%. There were a total of five deaths (2.8%): three (1.5%) from invasive ovarian/peritoneal carcinoma and two from synchronous uterine malignancies. It appears that surgical resection is the mainstay of treatment, with conservative surgery where fertility is desired or pelvic clearance if the family is complete. Surgical staging is important to identify invasive extraovarian implants that portend an adverse prognosis. The role of adjuvant chemotherapy is not established.