Hodgkin and Reed-Sternberg cells harbor alterations in the major tumor suppressor pathways and cell-cycle checkpoints: analyses using tissue microarrays

Tumoral cells in Hodgkin lymphoma (HL) display an increased growth fraction and diminished apoptosis, implying a profound disturbance of the cell cycle and apoptosis regulation. However, limitations of molecular techniques have prevented the analysis of the tumor suppressor pathways and cell-cycle checkpoints. Tissue microarray (TMA) is a powerful tool for analyzing a large number of molecular variables in a large series of tumors, although the feasibility of this technique has not yet been demonstrated in heterogeneous tumors. The expression of 29 genes regulating the cell cycle and apoptosis were analyzed by immunohistochemistry and in situ hybridization in 288 HL biopsies using TMA. The sensitivity of the technique was validated by comparing the results with those obtained in standard tissue sections. The results revealed multiple alterations in different pathways and checkpoints, including G1/S and G2/M transition and apoptosis. Striking findings were the overexpression of cyclin E, CDK2, CDK6, STAT3, Hdm2, Bcl2, Bcl-X(L), survivin, and NF-kappaB proteins. A multiparametric analysis identified proteins associated with increased growth fraction (Hdm2, p53, p21, Rb, cyclins A, B1, D3, and E, CDK2, CDK6, SKP2, Bcl-X(L), survivin, STAT1, and STAT3), and proteins associated with apoptosis (NF-kappaB, STAT1, and RB). The analysis also demonstrated that Epstein-Barr virus (EBV)-positive cases displayed a characteristic profile, confirming the pathogenic role of EBV in HL. Survival probability depends on multiple biologic factors, including overexpression of Bcl2, p53, Bax, Bcl-X(L), MIB1, and apoptotic index. In conclusion, Hodgkin and Reed-Sternberg cells harbor concurrent and overlapping alterations in the major tumor suppressor pathways and cell-cycle checkpoints. This appears to determine the viability of the tumoral cells and the clinical outcome.     

Ileal pouch-anal anastomosis: Is preoperative anal manometry predictive of postoperative functional outcome?

PURPOSE: The aim of this study was to determine the value of preoperative anal manometry in predicting postoperative continence. METHODS: Anal manometry was performed in 73 consecutive patients before ileal pouch-anal anastomosis (IPAA) surgery (m1), before loop ileostomy closure (m2), and at a follow-up of one (m3) and two (m4) years. Mean and maximum resting and squeezing pressures were documented at each occasion. One year after surgery, pressures were correlated (r)with an incontinence score. RESULTS: A significant (P < 0.05) decrease in mean resting pressures was observed after IPAA (m1=66 mmHg; m2=42.8 mmHg), followed by a significant (P < 0.05) improvement of mean resting pressure after loop ileostomy closure (m3 = 538 mmHg; m4 = 54.7 mmHg). Mean squeezing pressures did not change (P > 0.05) at any time during the study (m1 =114 mmHg; m2 = 102.9 mmHg; m3 = 103.4 mmHg; m4 = 95.8 mmHg). There was no correlation between preoperative mean resting pressure and postoperative (mI) incontinence score. CONCLUSION: Anal manometry showed a characteristic trend in internal anal sphincter injury after IPAA followed by recovery after ileostomy closure. However, it failed to prove helpful in the prediction of clinical outcome. Thus, although this study supports the continued use of manometry in a research setting, it challenges the value of routine manometry in a clinical context.Poster presentation at the meeting of The American Society of Colon and Rectal Surgeons, Chicago, Illinois, May 2 to 7, 1993.Dr. Morgado was a visiting surgeon from Centro Medico, Caracas, Venezuela. He was funded, in part, by a grant from The American Society of Colon and Rectal Surgeons Research Foundation.     

Immune reconstitution syndrome in patients treated for HIV and tuberculosis in Rio de Janeiro.

We made a retrospective longitudinal study from January 2000 to January 2003 to examine cases of immune reconstitution syndrome (IRS) and its incidence rate in tuberculosis (TB)-human immunodeficiency virus (HIV) co-infected patients. The incidence rate (IR) was calculated using a Poisson regression. The confidence interval (CI) that was stipulated was 95%. IRS occurred in 10/84 HIV and TB-positive patients; nine of them were on highly active anti-retroviral therapy (HAART) during a mean of 61.7 (+/- 59) days following the introduction of antiretrovirals. Lymph-node enlargement was the sole clinical manifestation. CD4 counts were <100 cells/mm(3)in 50% of the patients, at the time of TB diagnosis. All but two patients were treated with prednisone, and recovered from TB within a mean of 91 days (+/- 30 days). One relapse of TB was observed, but there were no IRS-related deaths. The incidence rate was higher (IR=11.18; CI, 1.41-88.76) in patients that had superficial lymph node enlargement at the moment of TB diagnosis (not associated with TB), extrapulmonary TB (IR=1.97; CI, 0.44-8.79), were antiretroviral naive (IR=1.85; CI, 0.48-7.16), and CD4 counts <100 cells/mm(3) (IR=1.50; CI, 0.40-5.59), although with a wide CI. IRS was frequent in our sample, occurred more frequently in HIV-naive patients with lymph-node enlargement and extrapulmonary TB. No cases of new pulmonary lesions or worsening of pulmonary infiltrates were observed.     

Virtual chromoendoscopy in small bowel capsule endoscopy: New light or a cast of shadow?

AIM: To evaluate whether virtual chromoendoscopy can improve the delineation of small bowel lesions previously detected by conventional white light small bowel capsule endoscopy(SBCE). METHODS: Retrospective single center study. One hundred lesions selected from forty-nine consecutive conventional white light SBCE(SBCE-WL) examinations were included. Lesions were reviewed at three Flexible Spectral Imaging Color Enhancement(FICE) settings and Blue Filter(BF) by two gastroenterologists with ex-perience in SBCE, blinded to each other's findings, whoranked the quality of delineation as better, equivalent or worse than conventional SBCE-WL. Inter-observer percentage of agreement was determined and analyzed with Fleiss Kappa(k) coefficient. Lesions selected for the study included angioectasias(n = 39), ulcers/ero-sions(n = 49) and villous edema/atrophy(n = 12). RESULTS: Overall, the delineation of lesions was im-proved in 77% of cases with FICE 1, 74% with FICE 2, 41% with FICE 3 and 39% with the BF, with a percent-age of agreement between investigators of 89%(k = 0.833), 85%(k = 0.764), 66%(k = 0.486) and 79%(k = 0.593), respectively. FICE 1 improved the delineation of 97.4% of angioectasias, 63.3% of ulcers/erosions and 66.7% of villous edema/atrophy with a percentage of agreement of 97.4%(k = 0.910), 81.6%(k = 0.714) and 91.7%(k = 0.815), respectively. FICE 2 improved the delineation of 97.4% of angioectasias, 57.1% of ulcers/erosions and 66.7% of villous edema/atrophy, with a percentage of agreement of 89.7%(k = 0.802), 79,6%(k = 0.703) and 91.7%(k = 0.815), respectively. FICE 3 improved the delineation of 46.2% of angioecta-sias, 24.5% of ulcers/erosions and none of the cases of villous edema/atrophy, with a percentage of agreement of 53.8% [k = not available(NA)], 75.5%(k = NA) and 66.7%(k = 0.304), respectively. The BF improved the delineation of 15.4% of angioectasias, 61.2% of ulcers/erosions and 25% of villous edema/atrophy, with a per-centage of agreement of 76.9%(k = 0.558), 81.6%(k = 0.570) and 25.0%(k = NA), respectively.CONCLUSION: Virtual chromoendoscopy can improve the delineation of angioectasias, ulcers/erosions and villous edema/atrophy detected by SBCE, with almost perfect interobserver agreement for FICE 1.     

Metastatic Crohn's disease. Response to adalimumab dose intensification

Inflammatory bowel disease is accompanied by extraintestinal manifestations in a high percentage of patients. Cutaneous lesions are the second most prevalent of these manifestations, and within these, metastatic Crohn's disease is one of the least common, being the least frequent specific cutaneous manifestation of Crohn's disease. This entity includes cutaneous and subcutaneous lesions with a non-caseating granulomatous appearance on histological analysis identical to that of Crohn's disease. These lesions are not found adjacent to the digestive tract. Due to the low prevalence of these manifestations, conclusive trials on the treatment of choice have not been performed and there is no well-defined therapeutic strategy. Distinct therapies with varying results have been reported. We report the case of a female patient with longstanding and complex Crohn's disease who developed metastatic cutaneous manifestations while receiving adalimumab. The cutaneous manifestations responded well to dose intensification of this drug. A review of the literature is provided.