Inflammation in coronary artery disease: potential role for immunomodulatory therapy

Understanding of the mechanisms underlying atherosclerotic disorders has evolved beyond the view of a progressive collection of lipids and cellular debris in the vascular wall. Current evidence has implicated inflammatory pathways as an important pathogenic mechanism in atherogenesis and plaque destabilization. Although not necessarily the primary event, inflammation and cytokine activation during plaque formation and destabilization may represent a common final pathway to various stimuli. Thus, it seems that not only 'new' risk factors, such as infections with various microorganisms, but also classic risk factors for cardiovascular disease, such as hyperlipidemia, hypertension and diabetes, may promote their atherogenic effects through inflammatory responses. Indeed, recent reports have suggested that traditional cardiovascular medications may attenuate atherogenesis and enhance plaque stability, at least partly through anti-inflammatory mechanisms. However, uncovering the inflammatory pathways in atherosclerosis has raised the possibility that newer treatment modalities should be more directly targeted against inflammatory mediators. Recently, a series of experimental studies have reported reduction of atherosclerosis by immunomodulatory therapy, such as chemokine blockade, interleukin-10 and immunization/vaccination against oxidized low-density lipoprotein and heat-shock protein. It is conceivable that some of these approaches will be tested clinically and, if successful, they could provide novel treatment strategies in coronary artery disease in humans.     

Prediction of pelvic lymph node metastases by a prostate-specific antigen and prostatic acid phosphatase in clinical T3/T4M0 prostatic cancer.

Prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) were determined in the serum of 69 patients with clinical T3/T4M0 prostatic cancer before staging lymphadenectomy. In principle, high-dose radiotherapy was given only to patients of pathological N0 category. Seventeen patients had a prelymphadenectomy PSA level below the normal upper reference limit (10 micrograms/l) and only 3 of them had pelvic lymph node metastases. Fifteen of 52 patients with a preoperative PSA level > or = 10 micrograms/l were of N0 category. Only 8 of the 41 evaluable patients had PAP values above the normal range, and 6 of these 8 patients had pelvic lymph node metastases. Preoperative PSA values, but not preoperative PAP levels, assist the clinician in predicting regional lymph node metastases in patients with clinical T3/T4M0 prostatic cancer. Two-thirds of the patients with T3/T4 tumours and PSA values between 10 and 50 micrograms/l have regional lymph node metastases. About 80% of the patients with PSA levels < 10 micrograms/l belong to the N0 category. About 75% of the patients with PSA > 50 micrograms/l have N+ disease. Taking into account the individual preoperative PSA values, the indication for preradiotherapy staging lymphadenectomy should be balanced between the chance of demonstrating N+ disease, the expected postoperative morbidity and the benefit for the patient found to be of N0 category.     

Total pelvic exenteration with preoperative irradiation for advanced primary and recurrent rectal cancer.

OBJECTIVE: To study the complication rate, local recurrence rate, and survival after total pelvic exenteration for primary advanced and recurrent rectal cancer. DESIGN: Prospective study. SETTING: Tertiary referral university hospital, Norway. SUBJECTS: 25 patients who were operated on for primary advanced and 22 for recurrent rectal cancer since 1991; 42 men and 5 women, mean age 64 years (range 44-78). All had preoperative irradiation of 46-50 Gy. MAIN OUTCOME MEASURES: Incidence of major complications, and actuarial 5-year survival and local recurrence rate. RESULTS: Twenty patients had RO resection in the primary group versus seven in the recurrent group. No R2 resections were done in the primary group compared with four in the recurrent group. Half the primary cases (n = 13) had abdominoperineal resections. Hartmann's procedures were common in both groups (n = 8 in each). Postoperative mortality at 30 days was 4% (n = 2) and in-hospital 13% (n = 6). 18 patients had major complications and 12 were reoperated on. Overall 5-year actuarial survival for 43 patients without distant metastases was 28%-those with primary tumours 36%, and those with recurrent tumours 18%-similar to the figures for RO and R1 resections. Actuarial local recurrence at 5 years for primary cancers was 18% compared with 68% for recurrent cancers, again nearly identical to the figures for R0/R1 operations (p = 0.008 and p = 0.03). CONCLUSION: Some patients with advanced rectal cancer either primary or recurrent may benefit from simultaneous en-bloc cystectomy. The higher postoperative morbidity and mortality indicate the need for well-defined indications for this procedure and the necessity for thorough preoperative staging.     

Excessive innate immune response and mutant D222G/N in severe A (H1N1) pandemic influenza

Aim

Explore the role of viral factors and immune response in patients with severe pandemic pdmH1N1 illness without significant co-morbidity.

Materials

Seven patients with pdmH1N1 influenza, bilateral chest X-rays infiltrates, requiring mechanical ventilator support were consecutively recruited. Seven age- and gender-matched healthy individuals served as controls.

Results

Four patients were viremic, two with the mutant D222G/N pdmH1N1.Microarray analyses of peripheral blood leukocytes suggested a marked granulocytes activation, but no up-regulation of inflammatory cytokine mRNA. Patients with severe pdmH1NI had a marked systemic complement activation, and in contrast to the lack of cytokine mRNA up-regulation in blood leukocytes, plasma levels of a broad range of inflammatory mediators, including IP-10, and mediators involved in pulmonary remodelling were markedly elevated. Patients with mutant virus had particularly high IP-10 levels, and the most pronounced complement activation.

Conclusions

In severe pdmH1N1, viremia was common and the D222G/N mutant was found in half of the viremic patients. Host immune response was characterized by strong activation of the innate immune system, including complement and granulocytes activation, increased serum levels of inflammation and pulmonary remodelling markers, possibly contributing to the observed tissue damage. However, few patients were included and further studies are needed to characterize the immune response in severe pdmH1N1 infection.     

DNA ploidy in primary testicular cancer

The DNA stemline ploidy was measured by flow cytometry (FCM) in 129 samples from paraffin-embedded primary testicular tumours (61 seminomas, 68 non-seminomas). Only one DNA stemline was found in 38 seminomas and 44 non-seminomas. Two seminomas and one non-seminoma were DNA diploid, the other tumours being non-diploid. Twenty-three seminomas and 24 non-seminomas displayed two or three DNA stemlines. The median minimal DNA index (DI) of all seminomas was significantly higher than that of all non-seminomas (1.58 vs 1.43; P: 0.008). Three seminomas removed from two monozygotic twins within 1 week had DIs of 1.66, 1.56 and 1.59. In this limited series there was no association between DNA ploidy of the primary tumour and the metastatic status for either seminomas or non-seminomas. The results support the pathogenetic model stating that at least some (if not all) non-seminomas develop from a seminoma by additional chromosomal aberration. The clinical relevance of DNA stemline ploidy has to be further evaluated in larger series.