Extent of surgery in cancer of the colon:Is more better?

Since the introduction of total mesorectal excision as the standard approach in mid and low rectal cancer,the incidence of local recurrence has sharply declined.Similar attention to surgical technique in colon cancer(CC) has resulted in the concept of complete mesocolic excision(CME),which consists of complete removal of the intact mesentery and high ligation of the vascular supply at its origin.Although renewed attention to meticulous surgical technique certainly has its merits,routine implementation of CME is currently unfounded.Firstly,in contrast to rectal cancer,local recurrence originating from an incompletely removed mesenteryis rare in CC and usually a manifestation of systemic disease.Secondly,although CME may increase nodal counts and therefore staging accuracy,this is unlikely to affect survival since the observed relationship between nodal counts and outcome in CC is most probably not causal but confounded by a range of clinical variables.Thirdly,several lines of evidence suggest that metastasis to locoregional nodes occurs early and is a stochastic rather than a stepwise phenomenon in CC,in essence reflecting the tumor-host-metastasis relationship.Unsurprisingly,therefore,comparative studies in CC as well as in other digestive cancers have failed to demonstrate any survival benefit associated with extensive,additional or extra-mesenteric lymphadenectomy.Finally,routine implementation of CME may cause patient harm by longer operating times,major vascular damage and autonomic nerve injury.Therefore,data from randomized trials reporting relevant endpoints are required before CME can be recommended as a standard approach in CC surgery.     

Identification of angular naphthopyrones from the Philippine echinoderm Comanthus species as inhibitors of the NF-κB signaling pathway

In the past few years heat shock protein 90 (Hsp90) inhibitors have been reported to possess significant antitumor activity. We investigated, for the first time, the antitumor activity of a novel Hsp90 inhibitor 2-(4-acetyloxycyclohexylamino)-4-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydro-1H-indazol-1-yl)-benzamide (BJ-B11) and the molecular mechanism underlying the apoptosis it induces in human chronic myeloid leukemia K562 cells. The results revealed that BJ-B11 triggered growth inhibition in K562 cells and other malignant cell lines in vitro with only minor toxicity in a normal human cell line. BJ-B11 inhibited the proliferation of K562 cells in a concentration- and time-dependent manner, with IC(50) values of 1.1 ± 0.2 μM and 0.4 ± 0.1 μM after 48 and 72 h incubations respectively. This most likely results from cell cycle arrest at the G(0)/G(1) phase and the induction of apoptosis. In addition, BJ-B11 degraded the Hsp90 client proteins Bcr-Abl and Akt, induced activation of caspase-9 and caspase-3, and subsequent cleavage of PARP. The caspase signals may originate from mitochondrial dysfunction, which is supported by the finding of cytochrome c release. In addition, inactivation of the Akt signaling pathway may be involved in the process of BJ-B11-induced apoptosis. Taken together, our data provide a putative molecular mechanism for the anticancer effect of BJ-B11 on K562 cells, and suggest a potential application for BJ-B11 in chronic myeloid leukemia therapy.     

Inhibition of inositol monophosphatase by lithium chloride induces selective macrophage apoptosis in atherosclerotic plaques

BACKGROUND AND PURPOSE

Lithium chloride (LiCl) inhibits inositol monophosphatase (IMPase) at therapeutic concentrations. Given that LiCl induces death in cultured macrophages and that macrophages play an active role in atherosclerotic plaque destabilization, we investigated whether LiCl would induce selective macrophage death to stabilize the structure of the plaque.

EXPERIMENTAL APPROACH

The effect of LiCl was assessed on macrophages and smooth muscle cells (SMCs) in culture, in isolated atherosclerotic carotid arteries from rabbits and after local in vivo treatment via osmotic minipumps to rabbits with collared atherosclerotic carotid arteries. In addition, in vitro experiments were performed to elucidate the mechanism of LiCl-induced macrophage death.

KEY RESULTS

In vitro, whereas SMCs were highly resistant, LiCl induced macrophage death characterized by externalization of phosphatidylserine, caspase-3 cleavage and DNA fragmentation, all indicative of apoptosis. LiCl reduced inositol-1,4,5-trisphosphate levels in macrophages. Moreover, the IMPase inhibitor L-690 330 as well as IMPase gene silencing induced macrophage apoptosis. Both in vitro treatment of rabbit atherosclerotic carotid arteries with LiCl and local in vivo administration of LiCl to the plaques decreased plaque macrophages through apoptosis, as shown by terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labelling (TUNEL), without affecting SMCs. Vasomotor studies in vitro showed that LiCl did not affect the functionality of SMCs and endothelial cells.

CONCLUSIONS AND IMPLICATIONS

LiCl selectively decreased the macrophage load in rabbit atherosclerotic plaques via IMPase inhibition without affecting the viability or functionality of SMCs and endothelial cells. These data provide evidence for local administration of an IMPase inhibitor to stabilize atherosclerotic plaques.     

Angiotensin II type 1 receptor blockade does not enhance apoptotic cell death during ischemia and reperfusion in humans in vivo

Despite the theoretical benefits, angiotensin II type 1 receptor antagonists seem to enhance rather than reduce morbidity and mortality after myocardial infarction compared with angiotensin-converting enzyme inhibitors. This may result from unopposed angiotensin II type 2 receptor stimulation, which is associated with enhanced apoptotic cell death and increased infarct size. We studied whether the clinical effectiveness of irbesartan is hampered by enhanced apoptotic activity, detected by exposition of phosphatidylserines, during ischemia and reperfusion in humans in vivo. Twenty healthy male volunteers were randomized to a 1-week treatment with irbesartan (300 mg/d) or placebo in a double-blind fashion. After treatment, all participants underwent 10 minutes of ischemic exercise of the nondominant forearm. Upon reperfusion, Tc-99m-labeled Annexin A5 was administered, and 1 and 4 hours afterward, both hands were scanned using a gamma camera. Targeting of annexin A5, expressed as the percentage difference in radioactivity in the area of interest (thenar muscle) between experimental and control hand, did not differ between participants treated with irbesartan or placebo. Therefore, irbesartan does not enhance phosphatidylserine exposition in humans in vivo. The results of this study do not support enhanced apoptotic activity after treatment with irbesartan in a setting of ischemia and reperfusion.     

The role of [18F]-2-fluoro-2-deoxy-d-glucose-positron emission tomography in thyroid nodules with indeterminate fine-needle aspiration biopsy: systematic review and meta-analysis of the literature

Indeterminate results at fine-needle aspiration biopsy (FNAB) of thyroid nodules pose a clinical dilemma, because only 20% to 30% of patients suffer from malignancy. Previous studies suggested that the false-negative ratio of [(18)F]-2-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) is very low; therefore, it may help identify patients who would benefit from (hemi)thyroidectomy. A systematic literature search was performed in 5 databases. After assessment, the identified studies were analyzed for heterogeneity, and the extracted data of test characteristics were pooled using a random-effects model. Threshold effects were examined, and publication bias was assessed. The query resulted in 239 records, of which 6 studies met predefined inclusion criteria. Data from 225 of the 241 described patients could be extracted. There was mild to moderate heterogeneity in study results (inconsistency index [I(2)] = 0.390-0.867). The pooled prevalence of malignancy was 26%. Pooled sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 95% (95% confidence interval [95% CI], 86%-99%), 48% (95% CI, 40%-56%), 39% (95% CI, 31%-47%), 96% (95% CI, 90%-99%), and 60% (95% CI, 53%-67%), respectively. Sensitivity increased to 100% for the 164 lesions that measured >15 mm in greatest dimension. There was no evidence of threshold effects or publication bias. A negative FDG-PET scan in patients who had thyroid nodules >15 mm with indeterminate FNAB results excluded thyroid cancer in a pooled population of 225 patients. Conversely, a positive FDG-PET result did not identify cancer, because approximately 50% of these patients had benign nodules. The authors concluded that the incorporation of FDG-PET into the initial workup of such patients before surgery deserves further investigation.     

Effectiveness of case management among older adults with early symptoms of dementia and their primary informal caregivers: a randomized clinical trial

Background

It is believed that timely recognition and diagnosis of dementia is a pre-condition for improving care for both older adults with dementia and their informal caregivers. However, diagnosing dementia often occurs late in the disease. This means that a significant number of patients with early symptoms of dementia and their informal caregivers may lack appropriate care.

Objectives

To compare the effects of case management and usual care among community-dwelling older adults with early symptoms of dementia and their primary informal caregivers.

Design

Randomized controlled trial with measurements at baseline and after 6 and 12 months.

Setting

Primary care in West-Friesland, the Netherlands.

Participants

99 pairs of community-dwelling older adults with dementia symptoms (defined as abnormal screening for symptoms of dementia) and their primary informal caregivers.

Intervention

12 months of case management by district nurses for both older adults and informal caregivers versus usual care.

Measurements

Primary outcome: informal caregiver's sense of competence. Secondary outcomes: caregiver's quality of life, depressive symptoms, and burden, and patient's quality of life. Process measurements: intervention fidelity and caregiver's satisfaction with the quality of case management.

Results

Linear mixed model analyses showed no statistically significant and clinically relevant differences over time between the two groups. The process evaluation revealed that intervention fidelity could have been better. Meanwhile, informal caregivers were satisfied with the quality of case management.

Conclusion

This study shows no benefits of case management for older adults with dementia symptoms and their primary informal caregivers. One possible explanation is that case management, which has been recommended among diagnosed dementia patients, may not be beneficial if offered too early. However, on the other hand, it is possible that: (1) case management will be effective in this group if more fully implemented and adapted or aimed at informal caregivers who experience more severe distress and problems; (2) case management is beneficial but that it is not seen in the timeframe studied; (3) case management might have undetected small benefits. This has to be established.Trial registration ISCRTN83135728.