Lidocaine induces a reversible decrease in alveolar epithelial fluid clearance in rats

BACKGROUND: Lidocaine is widely used in patients with acute cardiac disorders and has also been recently implicated as a possible cause of pulmonary edema after liposuction. The objective of this study was to assess the effect of lidocaine on alveolar fluid clearance, the primary mechanism responsible for the resolution of alveolar edema. METHODS: Alveolar fluid clearance was measured in 29 ventilated rats using our well-validated method over 1 h using a 5% albumin solution instilled into the distal air spaces of the lung. Lidocaine was added to the instilled albumin solution (10(-5) M) or administered intravenously at a dose estimated to achieve a clinically relevant plasma concentration of 10(-5) M. Standard agonists and antagonists were used to determine the effect of lidocaine on alveolar fluid clearance. To determine whether lidocaine acted predominantly on the apical or basal surface, we also used QX314, lidocaine n-ethyl bromide quaternary salt, an analog of lidocaine, which is unable to cross the alveolar epithelium. The effect of lidocaine on the apical epithelial sodium channel transfected in Xenopus oocytes was also studied. RESULTS: Alveolar or intravenous lidocaine decreased alveolar fluid clearance by 50%, an effect that was reversible with the beta2 agonist, terbutaline. Lidocaine acted predominantly on the basal surface of the epithelium because n-ethyl bromide quaternary salt decreased alveolar fluid clearance only when it was given intravenously and because lidocaine did not inhibit the apical epithelial sodium channel when expressed in oocytes. CONCLUSIONS: Lidocaine decreased alveolar fluid clearance by 50%, an effect that may have major clinical implications in the care of patients with cardiac disease or during the perioperative period in some patients. Importantly, the effect of lidocaine was completely reversible with beta2-adrenergic therapy.     

Neurosteroids and glutamate toxicity in fibroblasts expressing human NMDA receptors

We charactrized glutamate receptor-mediated toxicity in mouse fibroblasts expressing the human NR1a/2A or NR1a/2B NMDA receptor. After induction of NMDA receptor, cells in both lines died over a 24 h time period. This toxicity was associated with a progressive increase in the glutamate content of the media. Cell death could be prevented by including either the non-competitive NMDA receptor antagonist ketamine or the competitive antagonist, d,l-AP-5. Cells expressing NR1a/2A receptors were maximally protected by 0.5 mM d,l-AP-5, while those expressing NR1a/2B receptors required 2 mM d,l-AP-5 for maximal protection. The neurosteroid pregnanolone sulfate, which negatively modulates NMDA receptor function, partially protected fibroblasts containing NR1a/2A or NR1a/2B NMDA receptor constructs. However, the neurosteroid pregnenolone sulfate, which has been reported to act as a positive allosteric modulator of the NMDA receptor, had no effect on the toxicity caused by endogenous glutamate. Our results on cells expressing human NMDA receptors suggest that certain neurosteriods may protect against NMDA induced toxicity while having low neurotoxic liabilities of their own.     

Prothrombin index decrease: a useful and reliable marker of extensive fibrosis?

Non-invasive serum markers of extensive liver fibrosis are required in clinical practice for several reasons: (1) although histological analysis is considered to be the gold standard for the diagnosis of extensive fibrosis and cirrhosis, the rate of false-negative results is approximately 15-20%; (2) liver biopsy is an invasive method with a 1/10 000 mortality rate, even though occurrence of death is exceptional in patients with diffuse liver disease; (3) patients with chronic viral hepatitis have to undergo multiple liver biopsies during follow-up to assess the progression of tissue injury. In this leading article, we briefly overview the recent progress in non-invasive serum markers for the prediction of the extent of liver fibrosis. Among those serum markers, we focused on prothrombin index, which seems to be a reliable and non-expansive marker for the diagnosis of extensive fibrosis.     

Chemoembolization for hepatocellular carcinoma: where does the truth lie?

Hepatocellular carcinoma (HCC) remains one of the most highly lethal cancers in the world. It continues to be plagued by a shortage of effective therapeutic options and consequently is a major cause of death, especially in eastern Asia and sub-Saharan Africa. In the United States, the incidence of HCC has been rapidly and steadily increasing in the past 20 years because of the concomitant epidemic rise in hepatitis C virus infection. Surgical resection and liver transplantation offer the only chance for a cure, but, unfortunately, tumors in most patients are found to be unresectable at presentation and the patients are therefore left with palliative options only. Of those, transcatheter arterial chemoembolization has been the most widely used over the years and has become the mainstay of therapy for patients with unresectable HCC. Yet, controversy has surrounded its efficacy and impact on patient survival. After a period of initial enthusiasm followed by encouraging results from retrospective and prospective studies, several randomized trials failed to show any survival advantage of chemoembolization over supportive care. So where does the truth lie? The publication this year of two separate high-quality randomized trials, one in Hepatology from Hong Kong and the other in Lancet from Spain, should help answer this question and finally establish the usefulness of chemoembolization as an effective palliative therapy against HCC.     

Chemoembolization of hepatocellular carcinoma--what to tell the skeptics: review and meta-analysis

Transcatheter arterial chemoembolization (TACE) has become the standard treatment for patients with unresectable hepatocellular carcinoma (HCC). When untreated, patients with inoperable HCC have a median survival of three months. Given the widespread use of chemoembolization, accurate evidence of the impact of TACE on patient survival is critical. Several review articles have examined randomized controlled trials (RCTs) of TACE; however, these analyses are inherently flawed by including trials in which control groups were treated. There have been only four RCTs comparing TACE to untreated controls to date. None has demonstrated a significant impact of TACE on patient survival. However, in addition to severe methodological flaws, these RCTs were limited by low patient enrollment, precluding any meaningful conclusions. In contrast, several non-randomized trials have clearly demonstrated a significant benefit of TACE on patient survival. New RCTs examining the impact of chemoembolization on survival are urgently needed to provide definitive evidence for the increasing number of patients treated with TACE. A new, well-designed RCT would provide significant insight on the impact of chemoembolization on patient survival.     

Impact of the type of imaging modality on target volumes delineation and dose distribution in pharyngo-laryngeal squamous cell carcinoma: comparison between pre- and per-treatment studies.

BACKGROUND AND PURPOSE: It has been shown that the use of pre-treatment FDG-PET impacted on the GTV delineation of pharyngo-laryngeal tumors. The goals of this study were to evaluate (1) the impact of FDG-PET GTV on dose distribution, and (2) the impact of per-treatment re-imaging on target volume delineation and dose distribution. MATERIALS AND METHODS: Eighteen patients with squamous cell carcinoma of the oropharynx or larynx/hypopharynx were treated with curative intent by forward planning IMRT. Prior to treatment and on average after a dose of 46 Gy, all patients underwent contrast-enhanced CT, MRI and FDG-PET. After coregistration, GTVs were delineated manually on CT and MRI and automatically on FDG-PET. From these volumes, CTVs and PTVs were derived using consistent guidelines. Planning was performed using conformal radiotherapy. RESULTS: GTVs, CTVs and PTVs based on pre-treatment FDG-PET were significantly smaller than those based on pre-treatment CT. Such difference in target volumes (TV) translated into a significant reduction in the irradiated volumes (reduction of 13 and 18% of the V50 and V95, respectively), Dmean to ipsilateral parotids (30.7 and 38.6% for FDG-PET and CT based plans, respectively) and to controlateral parotids (11.2 and 14.4% for FDG-PET and CT based plans, respectively). TVs based on per-treatment CT or MRI were also significantly smaller compared to those delineated from pre-treatment CT. Volumes delineated with MRI were significantly smaller than those delineated with CT. Due to radiotherapy-induced peri-tumoral inflammation, automatic delineation of FDG-PET GTV could not be performed. Such reductions in TVs translated into a reduction of the irradiated volumes compared to pre-treatment CT planning (reduction for V50 of 19 and 32%, and for V95 of 22 and 40%, for CT and MRI, respectively); Dmean to the ipsilateral parotids were also reduced (ipsilateral parotid Dmean of 20.4% for CT and of 20.1% for MRI compared to 24.7% for pre-treatment CT). CONCLUSIONS: The use of pre-treatment FDG-PET and per-treatment CT or MRI significantly impacts on the delineation of TVs in pharyngo-laryngeal SCC, translating into more normal tissue sparing after conformal radiotherapy planning.     

Deprived areas and attendance to screening of cervix uteri cancer in a French region

Objectives: To examine the relationship between deprivation and attendance to cervical cancer screening. Methods: Three deprivation indices (Carstairs, UnderPrivileged Area, Department of Environment) were calculated for women aged 25–65 attending a 1993–95 cervical cancer screening program (Doubs département, France), with 594 municipalities as statistical units. Weighted multivariate linear regressions were performed, with attendance rate as the dependent variable, and the three deprivation indices in turn as independent variables along with women's mean age, average net income, density of (para)medical amenities, density of population and proportion of women. Results: Per municipality women were numbered 1–29,822 (mean 210). In multivariate models, the three deprivation indices were negatively linked to attendance rate, and so were mean age of women and density of population. Average net income, proportion of women, and density of (para)medical amenities (nurses, laboratories, ambulances, physicians, dentists) were positively associated with attendance rate. Conclusions: In early stages, cervical cancer screening programs should account for populations living in deprived areas, through focused health promotion efforts and easier access to screening facilities.     

Are inflammatory cytokines the common link between cancer-associated cachexia and depression?

The prevalence of depression among patients diagnosed with cancer is higher than among the general medical population and is associated with faster tumor progression and shortened survival time. Cancer-related depression often occurs in association with anorexia and cachexia, although until recently the relationship between these conditions has not been well understood. Cachexia is associated with poorer quality of life and survival outcomes and is theeventual cause of death in approximately 30% of all patients with cancer. Recent evidence has linked elevated levels of inflammatory cytokines with both depression and cachexia, and experiments have shown that introducing cytokines induces depression and cachectic symptoms in both humans and rodents, suggesting that there may be a common etiology at the molecular level. Therapeutic agents targeting specific cytokine molecules, such as interleukin-6 or tumor necrosis factor-alpha, are currently being evaluated for their potential to simultaneously treat both depression and cachexia pharmacologically. This review summarizes the available data suggesting a dual role for cytokines in the development of cancer-related depression and cachexia and describes how biologic therapies targeting specific cytokines may improve outcomes beyond depression and cachexia, such as survival and quality of life.     

Three-dimensional rotational angiography: introduction of an adjunctive tool for successful transarterial chemoembolization

Transcatheter arterial embolization (TACE) is a minimally invasive procedure that requires precise visualization of the feeding vessels to liver tumors for proper catheter placement and effective therapy. The use of three-dimensional (3D) rotational angiography (RA) can be extremely useful to the interventional radiologist during TACE while the patient is on the catheterization table. This report demonstrates the role of 3D RA in interventional oncology by presenting two cases of hepatocellular carcinoma with complex vascular anatomy successfully treated because of the information provided by this new technology.     

Transcatheter arterial chemoembolization in unresectable cholangiocarcinoma: initial experience in a single institution

PURPOSE: Unresectable cholangiocarcinoma carries a dismal prognosis, with median survival times ranging from 6 to 12 months from the time of diagnosis. Palliative therapies have been disappointing and have not been shown to significantly prolong survival. Conversely, transcatheter arterial chemoembolization (TACE) has been effective in prolonging the lives of patients with hepatocellular carcinoma but has not been used against cholangiocarcinoma. Therefore, the purpose of the present study was to assess the safety and efficacy (ie, survival) of TACE in patients with unresectable intrahepatic cholangiocarcinoma. MATERIALS AND METHODS: Seventeen patients with unresectable cholangiocarcinoma were treated with one or more cycles of TACE between 1995 and 2004 at our institution. Follow-up imaging was performed on all patients 4-6 weeks after each TACE procedure to determine tumor response and need for further treatment. Survival was calculated with use of the Kaplan-Meier survival curve. RESULTS: The median survival for 17 patients treated with TACE was 23 months. Two patients with previously unresectable disease underwent successful resection after TACE. The procedure was well tolerated by 82% of the patients, who experienced no side effects or mild side effects that quickly resolved with conservative therapy alone. Two patients had minor complications (12%), which were managed successfully, and one had a major complication that resulted in a fatal outcome. This patient had a rapidly declining course from the time of diagnosis and died shortly after TACE. CONCLUSIONS: The results suggest that TACE was effective at prolonging survival of patients with unresectable cholangiocarcinoma. Therefore, for these patients, TACE may be an appropriate palliative therapy.