Clinical significance of nuclear factor (NF)-κB levels in urothelial carcinoma of the urinary bladder

Nuclear factor (NF)-kappaB has been reported to be constitutively activated in various human neoplasms. However, its clinical significance in bladder urothelial carcinoma (UC) remains an unresolved issue. We conducted this study trying to elucidate the role of NFkappaB in bladder UC and its potential prognostic significance, by quantifying immunohistochemically the levels of p65/RelA expression in paraffin-embedded tissue from 116 patients. Some of the cases had previously been stained for cellular FLICE-like inhibitory protein (c-FLIP) and bcl-2. Seventy-four cases displayed concurrent cytoplasmic and nuclear immunoreactivity, whereas 18 only nuclear immunoexpression and 21 only cytoplasmic immunoexpression, and the remaining three cases were negative for p65/RelA. Nuclear p65/RelA expression was positively associated with tumour grade and T-category (p=0.0001 in both cases). In addition, cytoplasmic p65/RelA expression was lower in advanced T-category (p=0.0030). Moreover, p65/RelA nuclear expression was positively correlated with c-FLIP (p=0.0109) and bcl-2 (p=0.0452). p65/RelA nuclear expression adversely affected survival in both univariate and multivariate analysis in superficial (Ta-T1; p=0.0010 and p=0.0008) as well as in muscle-invasive carcinomas (T2-T4; p=0.0004 and p=0.0003). Our results demonstrate that NF-kappaB nuclear expression is correlated with histologic grade and T category in bladder UC. Moreover, NF-kappaB nuclear expression emerges as an independent prognosticator of adverse significance, conveying information beyond that obtained by standard clinicopathological prognosticators.     

Predictors of hepatitis B surface antigen loss,relapse and retreatment after discontinuation of effective oral antiviral therapy in noncirrhotic HBeAg‐negative chronic hepatitis B

Reliable predictors of outcomes after treatment discontinuation in HBeAg‐negative chronic hepatitis B (CHB) patients have not been established. We investigated the role of hepatitis B surface antigen (HBsAg), interferon‐inducible protein‐10 (IP10) and hepatitis B core‐related antigen (HBcrAg) serum levels as predictors of HBsAg loss, relapse and retreatment in noncirrhotic HBeAg‐negative CHB patients who discontinued long‐term antiviral therapy. All HBsAg‐positive (n = 57) patients of the prospective DARING‐B study were included and followed monthly for 3 months, every 2/3 months until month‐12 and every 3/6 months thereafter. HBsAg, IP10 and HBcrAg levels were measured by enzyme immunoassays, and SCALE‐B score was calculated. Twelve patients achieved HBsAg loss before retreatment with 18‐month cumulative incidence of 25%. Independent predictors of HBsAg loss were baseline HBsAg and month‐1 IP10 levels. Of 10 patients with baseline HBsAg ≤100 IU/mL, 70% cleared HBsAg and 10% required retreatment. Of 23 patients with baseline HBsAg >1000 IU/mL, 4% cleared HBsAg and 43% required retreatment. Of 24 patients with intermediate baseline HBsAg (100‐1000 IU/mL), 17% cleared HBsAg and 21% required retreatment; in this subgroup, month‐1 IP10 was significantly associated with HBsAg loss, which occurred in 30% and 7% of cases with IP10 >150 and ≤150 pg/mL, respectively. Baseline HBcrAg was undetectable in all patients who cleared HBsAg and was associated with retreatment. SCALE‐B was associated with HBsAg loss but not with relapse or retreatment. In conclusion, HBsAg, IP10 and HBcrAg serum levels can be useful for the decisions and management of treatment discontinuation in noncirrhotic Caucasian patients with HBeAg‐negative CHB.     

Epidemiology,pathophysiology and contemporary management of cardiogenic shock – a position statement from the Heart Failure Association of the European Society of Cardiology

Cardiogenic shock (CS) is a complex multifactorial clinical syndrome with extremely high mortality, developing as a continuum, and progressing from the initial insult (underlying cause) to the subsequent occurrence of organ failure and death. There is a large spectrum of CS presentations resulting from the interaction between an acute cardiac insult and a patient's underlying cardiac and overall medical condition. Phenotyping patients with CS may have clinical impact on management because classification would support initiation of appropriate therapies. CS management should consider appropriate organization of the health care services, and therapies must be given to the appropriately selected patients, in a timely manner, whilst avoiding iatrogenic harm. Although several consensus‐driven algorithms have been proposed, CS management remains challenging and substantial investments in research and development have not yielded proof of efficacy and safety for most of the therapies tested, and outcome in this condition remains poor. Future studies should consider the identification of the new pathophysiological targets, and high‐quality translational research should facilitate incorporation of more targeted interventions in clinical research protocols, aimed to improve individual patient outcomes. Designing outcome clinical trials in CS remains particularly challenging in this critical and very costly scenario in cardiology, but information from these trials is imperiously needed to better inform the guidelines and clinical practice. The goal of this review is to summarize the current knowledge concerning the definition, epidemiology, underlying causes, pathophysiology and management of CS based on important lessons from clinical trials and registries, with a focus on improving in‐hospital management.     

Expression of functional CXCR4 chemokine receptors on human colonic epithelial cells

In addition to their role as regulators of leukocyte migration and activation, chemokines and their receptors also function in angiogenesis, growth regulation, and HIV-1 pathogenesis--effects that involve the action of chemokines on nonhematopoietic cells. To determine whether chemokine receptors are expressed in human colonic epithelium, HT-29 cells were examined by RT-PCR for the expression of the chemokine receptors for lymphotactin, fractalkine, CCR1-10, and CXCR1-5. The only receptor consistently detected was CXCR4 (fusin/LESTR), although HT-29 cells did not express mRNA for its ligand, stromal cell-derived factor (SDF-1alpha). Flow cytometric analysis with anti-CXCR4 antibody indicated that the CXCR4 protein was expressed on the surface of roughly half of HT-29 cells. CXCR4 was also expressed in colonic epithelial cells in vivo as shown by immunohistochemistry on biopsies from normal and inflamed human colonic mucosa. The mRNA for SDF-1alpha and other CC and CXC chemokines was present in normal colonic biopsies. The CXCR4 receptor in HT-29 cells was functionally coupled, as demonstrated by the elevation in [Ca2+]i, which occurred in response to 25 nM SDF-1alpha and by the SDF-1alpha-induced upregulation of ICAM-1 mRNA. Sodium butyrate downregulated CXCR4 expression and induced differentiation of HT-29 cells, suggesting a role for CXCR4 in maintenance and renewal of the colonic epithelium. This receptor, which also serves as a coreceptor for HIV, may mediate viral infection of colonic epithelial cells.     

Intermittent therapy with high-dose 5-aminosalicylic acid enemas maintains remission in ulcerative proctitis and proctosigmoiditis

PURPOSE: The aim of this study was to compare the efficacy of intermittent therapy with mesalazine enemas and continuous oral mesalazine to maintain remission of distal ulcerative colitis or proctitis. METHODS: Thirt-yeight patients with distal ulcerative colitis (n=17) or ulcerative proctitis (n=21) in clinical, endoscopic, and histologic remission were randomly assigned to receive either oral mesalazine (0.5 g three times/day, Eudragit L coating, n=19) or intermittent therapy with mesalazine enemas (4 g of 5-aminosalicylic acid enema every third night, n=19). Both groups were comparable in regard to sex, age, age at disease onset, extent and duration of disease, number and mode of treatment of previous attacks, and time in remission. Patients were reviewed at the beginning of the study and, subsequently, at two-month intervals for 24 months or until a relapse occurred. At each visit, diaries were reviewed and clinical and laboratory assessments were performed. Sigmoidoscopy was carried out and biopsies were obtained by a blinded observer. Histology was assessed without knowledge of the patient's clinical state or treatment category. RESULTS: At the end of the study, 6 of 19 patients on oral mesalazine (32 percent) and 14 of 19 patients on mesalazine enemas (74 percent) were still in full remission (log rank test: 15.280,P <0.001). Differences in relapse rates between groups were significant even when data were stratified by extent of disease (P <0.01). In the oral group, six and seven patients relapsed at 12 and 24 months, respectively. In the enema group, three and two relapses occurred in the first and second year of the study, respectively. All patients complied with the treatment satisfactorily and there were no dropouts. CONCLUSION: These results suggest that intermittent therapy with mesalazine enemas is more effective than continuous oral mesalazine in maintaining remission in patients with distal ulcerative colitis and proctitis.Read at the meeting of the First United European Gastroenterology Week, Athens, Greece, September 25 to 30, 1992.     

Modulation of peripheral immune responses by paclitaxel–ifosfamide–cisplatin chemotherapy in advanced non-small-cell lung cancer

Purpose

The aim of this study was to assess systemic immunological responses in non-small-cell lung cancer (NSCLC) patients with stage III/IV disease during treatment with paclitaxel–ifosfamide–cisplatin (TIP) chemotherapy.

Methods

Peripheral blood mononuclear cells (PBMCs) collected from healthy donors (HD) (n = 20) and chemotherapy-naive NSCLC patients treated with TIP (n = 32) were tested for production of IL-1, TNF-α, TNF-β, IL-6, IL-8, IL-10, IL-12 and IL-2 upon polyclonal stimulation with anti-CD3 mAb. They were further assessed over a treatment period of twelve weeks (i.e., four treatment cycles).

Results

PBMCs from NSCLC patients produced higher IL-1, TNF-α, TNF-β, IL-6, IL-8, IL-10 and IL-12 levels, whereas IL-2 exhibited lower values compared to HD (p < 0.001 for all parameters). Of interest, patients who responded to treatment had significantly higher increases in IL-2 (p < 0.001) and significantly higher decreases in IL-1 (p < 0.001), TNF-α (p < 0.001), TNF-β (p < 0.001), IL-6 (p = 0.02), IL-8 (p < 0.001), IL-10 (p < 0.001) and IL-12 (p < 0.001) levels. Non-responders revealed post-therapeutically a significantly higher increase in IL-1, TNF-α, TNF-β, IL-6, IL-8, IL-10 and IL-12 secretion and a significantly higher decrease in IL-2 levels (p < 0.001 for all parameters). Patients who responded to treatment and had a significantly higher increase in IL-2 showed a significantly longer median survival (p value < 0.001, 26 vs. 7.5 months).

Conclusion

Our study indicates that monitoring cytokine dynamics in patients with advanced NSCLC and especially those of IL-2 in peripheral blood components in vitro could be used as a predictor of treatment-related outcome and overall survival in NSCLC.     

CASE REPORT: Light Chain Deposition Disease of the Liver Without Renal Involvement in a Patient with Multiple Myeloma Related to Liver Failure and Rapid Fatal Outcome

We describe a 36-year-old man with advanced multiple myeloma (Salmon and Durie stage III) who developed jaundice and severe cholestasis after a first cure with systemic chemotherapy of vincristine, doxorubicin, and oral dexamethasone (VAD). Serology for hepatitis A, B, and C and for CMV was negative. A liver ultrasound and CT scan showed mild hepatomegaly without evidence of extrahepatic or intrahepatic biliary tree dilatation. A percutaneous liver biopsy revealed perisinusoidal deposits of an abundant slightly eosinophilic, PAS-positive amorphous substance. Immunohistochemistry showed positivity for kappa-light chains and was negative for lambda-light chains, for IgA, IgG, IgM, and IgD immunoglobulins as well as for AA and AL proteins and for amyloid P component. A diagnosis of light chain deposition disease (LCDD) of the liver was made. The patient developed rapid deterioration of liver function, leading to a multisystem dysfunction and death. The occurrence of LCDD in multiple myeloma is close to 5% and myeloma is the underlying disease in two thirds of patients with LCDD. The kidneys are involved in almost all cases of LCDD and renal dysfunction usually reveals the disease. Only three patients with LCDD of the liver without overt renal involvement have been reported so far. This is the first observation of LCDD presenting with jaundice and severe cholestasis shortly after the diagnosis of high tumor mass myeloma, without overt renal involvement, leading rapidly to the patient's death.     

Budesonide versus mesalamine for maintaining remission in patients refusing other immunomodulators for steroid-dependent Crohn's disease.

BACKGROUND & AIMS: To compare the efficacy of controlled-release budesonide capsules with that of mesalamine for maintaining remission and improving quality of life (QOL) in patients with steroid-dependent Crohn's disease. METHODS: Fifty-seven patients (25 men; mean age, 32 +/- 10.1 yr) with quiescent steroid-dependent Crohn's ileitis, ileocolitis, or colitis (Crohn's disease activity index <150) entered a prospective, investigator-blind trial. Patients were eligible for treatment with azathioprine but had not consented or had developed side effects. Patients were randomized to receive budesonide 6 mg/day (n = 29) or mesalamine 1 g 3 times/day (n = 28). Follow-up assessments were made every 2 months for up to 1 year or until relapse. At each visit, quality of life (QOL) was assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ). RESULTS: There were no significant differences in baseline clinical characteristics between the study groups. The 1-year relapse rate was significantly lower in the budesonide group than in the mesalamine group (55% vs. 82%; 95% confidence interval, 12.4%-41%; P = 0.045). Patients assigned to budesonide also remained in remission longer (241 +/- 114 days vs. 147 +/- 117 days; 95% confidence interval, 32.7-155.3 days; P = 0.003). Compared with mesalamine, budesonide treatment also was associated with a better QOL throughout the study (mean total IBDQ scores 165 +/- 36 vs. 182 +/- 28, respectively; 95% confidence interval, -0.4 to 34.4, P = 0.0001). This advantage was confirmed in patients' self-assessed QOL scores. CONCLUSIONS: Over a 1-year period, controlled-release budesonide was significantly more effective than mesalamine for maintaining remission and improving the QOL of patients with steroid-dependent Crohn's disease.