Induced sputum for the diagnosis of pulmonary tuberculosis: Is it useful in clinical practice?

BACKGROUND:

Diagnosing pulmonary tuberculosis (PTB) is challenging in patients who are unable to spontaneously expectorate. Published evidence suggests that induced sputum (IS) is the least invasive and most cost-effective method of diagnosis, and should be used before fibre-optic bronchoscopy (FOB).

METHODS:

The medical records of 337 adults treated for PTB in northern Alberta between 1997 and 2007 were reviewed to determine whether local practice patterns reflect the evidence. Microbiological data were collected from the Provincial Laboratory for Public Health. Demographic information was collected from the patients’ charts.

RESULTS:

A total of 8.5% (26 of 307) of PTB patients had IS collected, whereas 35.8% (110 of 307) underwent FOB. Among FOB patients, 56.4% (62 of 110) had no sputum sent before the procedure and 29% (18 of 62) of these patients were smear positive. Only five patients referred for FOB had IS sent previously. There were no demographic factors predictive of IS use, whereas being an inpatient at a teaching facility or having a nodule or mass on chest x-ray was predictive of FOB referral. Because so few IS samples were available, not all patients had spontaneously expectorated sputum, IS and FOB tests performed; thus, the calculated yields were not comparable with one another.

CONCLUSIONS:

Despite published evidence recommending IS collection before FOB referral in suspected PTB patients, clinicians in our health region appeared to prefer early FOB over IS by a large margin. This practice pattern is less cost effective and exposes patients and health care workers to greater risk. Further research is needed to identify the reasons for the underuse of sputum induction.     

Bladder Tumor Infiltrating Mature Dendritic Cells and Macrophages as Predictors of Response to Bacillus Calmette-Guérin Immunotherapy

Background

The clinical significance of tumor-infiltrating dendritic cells (TIDCs) and tumor-associated macrophages (TAMs) as markers of immune response has been reported for many cancers.

Objective

To measure tumor infiltration by CD83⁺ dendritic cells (DCs) and CD68⁺ macrophages in non–muscle-invasive urothelial cancer (NMIUC) prior to bacillus Calmette-Guérin (BCG) immunotherapy and to evaluate their significance in the response to immunotherapy.

Design, setting, and participants

Patients with NMIUC at high risk of recurrence and progression were recruited for a study on markers of the response to BCG.

Intervention

Patients were treated by transurethral resection followed by maintenance BCG.

Measurements

Immunohistochemical staining with anti-CD83 and anti-CD68 monoclonal antibodies on 53 and 46 NMIUC tumors, respectively, prior to BCG treatment. A scoring index was calculated based on the average density of positive cells within the papillary axis, the stroma, lymphoid aggregates, and infiltration into tumors.

Results and limitations

CD83⁺ TIDCs were observed mostly within lymphoid aggregates. Multivariate Cox regression analysis showed that maintenance BCG (more than one maintenance cycle) was highly effective in patients with a low level of CD83⁺ TIDCs at time of resection (hazard ratio [HR]: 0.035; p = 0.002) but showed reduced efficacy in patients with a high level of CD83⁺ TIDCs (HR: 0.87; p = 0.810). A high level of infiltration by CD83⁺ TIDCs slightly decreased the risk of recurrence in patients treated with one or no maintenance BCG cycle (HR: 0.4; p = 0.117). In the same population, a strong infiltration of CD68⁺ TAMs was associated with an increased risk of recurrence (HR: 3.8; p = 0.013).

Conclusions

These results suggest that patients with a high level of infiltration by CD83⁺ TIDCs or CD68⁺ TAMs do not respond as well to BCG immunotherapy. If confirmed in larger cohorts, the pretreatment level of infiltration by these cells may be useful to influence the choice of treatment strategy.     

Submovements during pointing movements in Parkinson’s disease

Velocity irregularities frequently observed during deceleration of arm movements have usually been interpreted as corrective submovements that improve motion accuracy. This hypothesis is re-examined here in application to movements of Parkinson’s disease (PD) patients in which submovements are specifically frequent. Pointing movements in patients and age-matched controls to large and small targets in three movement modes were studied. The modes were discrete (stop on the target), continuous (reverse on the target), and passing (stop after crossing the target). Two types of submovements were distinguished, gross and fine. In both groups, gross submovements were more frequent during the discrete and passing than continuous mode, specifically for large targets. This suggested that gross submovements were fluctuations accompanying motion termination (stabilization at the target) that was included in discrete and passing but not continuous movements. Gross submovements were specifically frequent in patients, suggesting that PD causes deficiency in smooth motion termination. Although in both groups fine submovements were more frequent for small than large targets, this relation was also observed in passing movements after crossing the target, i.e., when no corrections were needed. This result, together with higher jerk of the entire trajectory found for smaller targets, indicates that fine submovements may also be not corrective adjustments but rather velocity fluctuations emerging due to low speed of movements to small targets. This interpretation is consistent with the recognized inability of PD patients to promptly change generated force as well as to quickly re-plan current motion. The results suggest a need to re-examine the traditional interpretation of submovements in PD and the related theory that the production of iterative submovements is a strategy used by patients to compensate for a decreased initial force pulse.     

3��,4��-Dihydroxyflavonol down-regulates monocyte chemoattractant protein-1 in smooth muscle: role of focal adhesion kinase and PDGF receptor signalling

Background and purpose:

We investigated the effects of a synthetic flavonol, 3′,4′-dihydroxyflavonol (DiOHF) on the expression of monocyte chemoattractant protein-1 (MCP-1) in rat vascular smooth muscle cells.

Experimental approach:

MCP-1 expression was assessed by quantitative real-time PCR and protein phosphorylation by immunoprecipitation and Western blots.

Key results:

DiOHF (1–30 µmol·L⁻¹) concentration-dependently reduced MCP-1 expression in both quiescent cells and cells stimulated with platelet-derived growth factor (PDGF) or interleukin 1-β. The effect of DiOHF was associated with a suppression of focal adhesion kinase (FAK)-mediated signalling. In vitro kinase assays demonstrated that DiOHF is a potent inhibitor of FAK kinase activity (EC₅₀= 2.4 µmol·L⁻¹). Expression of FAK-related non-kinase reduced basal MCP-1 expression, but not that induced by PDGF or interleukin 1-β. DiOHF also inhibited autophosphorylation of PDGF receptors. The PDGF receptor inhibitor AG-1296 potently suppressed basal and PDGF-induced MCP-1 expression. Inhibition of extracellular signal-regulated kinase activation by DiOHF, either directly or indirectly, may also be involved in its effects on MCP-1 expression. DiOHF had no inhibitory effect on either p38 or nuclear factor-κB activation. Moreover, DiOHF inhibited smooth muscle cell spreading (a FAK-mediated response) and proliferation.

Conclusions and implications:

This is the first report on a flavonoid compound (DiOHF) that is a potent FAK inhibitor. DiOHF also inhibits PDGF receptor autophosphorylation. These effects underlie the inhibitory action of DiOHF on MCP-1 expression in smooth muscle cells. Our results suggest that DiOHF might be a useful tool for dissection of the (patho)physiological roles of FAK signalling.British Journal of Pharmacology (2009) 157, 597–606; doi:10.1111/j.1476-5381.2009.00199.x; published online 9 April 2009     

A comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of carcinoma in situ in patients with bladder cancer: a phase III, multicenter study

PURPOSE: We compared hexaminolevulinate (Hexvix) fluorescence cystoscopy with white light cystoscopy for detecting carcinoma in situ. MATERIALS AND METHODS: In this multicenter study 298 patients with known or suspected bladder cancer underwent bladder instillation with 50 ml 8 mM hexaminolevulinate for 1 hour. Cystoscopy was then performed, first using standard white light and then hexaminolevulinate fluorescence cystoscopy. Lesions or suspicious areas identified under the 2 illumination conditions were mapped and biopsied for histological examination. In addition, 1 directed biopsy was obtained from an area appearing to be normal. RESULTS: Of 196 evaluable patients 29.6% (58 of 196) had carcinoma in situ, including 18 with carcinoma in situ alone, and 35 with carcinoma in situ and concomitant papillary disease, which was only detected on random biopsy in 5. Of the 18 patients with no concomitant papillary disease carcinoma in situ was detected only by hexaminolevulinate fluorescence in 4 and only by white light in 4. In the group with concomitant papillary disease carcinoma in situ was found only by hexaminolevulinate fluorescence in 5 patients and only by white light in 3. The proportion of patients in whom 1 or more carcinoma in situ lesions were found only by hexaminolevulinate cystoscopy was greater than the hypothesized 5% (p=0.0022). Overall more carcinoma in situ lesions were found by hexaminolevulinate than by white light cystoscopy in 22 of 58 patients (41.5%), while the converse occurred in 8 of 58 (15.1%). Biopsy results confirmed cystoscopy findings. Of a total of 113 carcinoma in situ lesions in 58 patients 104 (92%) were detected by hexaminolevulinate cystoscopy and 77 (68%) were detected by white light cystoscopy, while 5 were detected only on directed visually normal mucosal biopsy. Hexaminolevulinate instillation was well tolerated with no local or systemic side effects. CONCLUSIONS: In patients with bladder cancer hexaminolevulinate fluorescence cystoscopy with blue light can diagnose carcinoma in situ that may be missed with white light cystoscopy. Hexaminolevulinate fluorescence cystoscopy can be used in conjunction with white light cystoscopy to aid in the diagnosis of this form of bladder cancer.     

Substratification of high-risk localised prostate cancer treated by radical prostatectomy

AIM: To evaluate the clinical outcome of high-risk prostate cancer (PC) treated by radical prostatectomy (RP) according to risk factors. METHODS: Patients with stage cT1-T3 PC were stratified in high and low/intermediate risk groups using D'Amico's criteria: PSA>or=20 ng/ml or Gleason score>or=8 or clinical stage>or=T2c. The Kaplan Meier and Log rank test were used to generate estimates of biochemical free-survival (BFS) and PC specific mortality (PCSM). RESULTS: We analysed 1,109 patients with a median age of 64.1 years, a mean PSA of 12.8 and a median follow-up of 8.18 years (max. 17.5 years). Overall PSA failures (PSAF) were observed in 23.4%, mortality by all causes in 11.4% and PCSM in 2.9%. The 10-year BFS of the 290 high-risk was 45 versus 75.5% for low/intermediate risk patients and the 10-year PCSM was 10.3 versus 1.4%, respectively. Of the 290 high-risk PC, 25% had organ-confined disease at surgery with 28% PSAF compared to 55% PSAF for non-organ-confined PC irrespective of nodal status. High-risk patients with 1 or>or=2 high risk criteria had 2.6 and 3.86 times increased risk of PSAF compared to low/intermediate risk. Ten-year PCSM for PC individual risk criteria was 4.5% for PSA>or=20, 9.2% for stage>or=T2c and 18.2% for Gleason>or=8. CONCLUSION: Patients with high-risk PC treated by RP by experienced surgeons can have a favourable long-term survival. Further substratification should take into account the variable prognostic implication of the different individual risk factors.     

PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression

BACKGROUND: PD-L1 (programmed death ligand 1, B7-H1) is a cell surface glycoprotein that can impair T-cell function. PD-L1 is aberrantly expressed by multiple human malignancies and has been shown to carry a highly unfavorable prognosis in patients with kidney cancer. The role of PD-L1 was evaluated as a mechanism for local stage progression in urothelial carcinoma (UC) of the bladder. METHODS: Using immunohistochemistry, PD-L1 expression was evaluated in a cohort of 280 high-risk UCs of the bladder. PD-L1 was modeled as a predictor of bladder cancer stage using ordinal logistic regression. Other covariates evaluated as potential confounders included age, gender, tumor grade, and lymphocytic infiltration. Further, PD-L1 was evaluated as a potential mechanism of bacillus Calmette-Guerin (BCG) failure in the subset of high-risk nonmuscle-invasive tumors that received this treatment. RESULTS: PD-L1 expression was observed in 7% of pTa, 16% of pT1, 23% of pT2, 30% of pT3/4, and 45% of carcinoma in situ (CIS) tumors. PD-L1 expression was associated with high-grade tumors (odds ratio [OR] = 2.4, P = .009) and tumor infiltration by mononuclear cells (OR = 5.5, P = .004). We observed that the key determinants of stage progression in this cohort were World Health Organization/International Society of Urologic Pathology (WHO/ISUP) high-grade tumor pathology (OR = 4.77, 95% confidence interval [CI]: 2.73-8.34; P < .001) and PD-L1 expression (OR = 2.20, P = .012). PD-L1 expression was found to be extremely abundant in the BCG-induced bladder granulomata in 11 of 12 patients failing BCG treatment. CONCLUSIONS: Collectively, these data indicate that tumor PD-L1 may facilitate localized stage-advancement of UC and attenuate responses to BCG immunotherapy by neutralizing T cells that normally guard against cancer invasion from the epithelium into the bladder musculature.