Use of photodynamic therapy in the palliation of massive advanced rectal cancer

Photodynamic therapy (PDT) is a relatively new form of cancer therapy utilizing a photosensitizer such as hematoporphyrin derivative. We conducted a pilot study to determine the efficacy of its use in palliating advanced rectal cancer, to determine toxicity, and to establish objective outcome criteria. Six patients with very advanced, usually recurrent rectal cancer were treated with PDT after being photosensitized with Photofrin II^®. A protocol was established to measure clinical and radiologic response to therapy. A new intraluminal delivery system was incorporated. Five patients had both clinical and radiologic responses to therapy. In two patients we observed such significant responses that they cannot be accounted for on a photobiologic basis alone. One patient developed a significant sunburn after discharge. There was no major toxicity of bleeding or sepsis even at maximum doses (200 J/cm²). We are confident that PDT has a role to play in rectal cancer and speculate as to future applications.     

Chronic α1-Na/K-ATPase inhibition reverses the elongation of the axon initial segment of the hippocampal CA1 pyramidal neurons in Angelman syndrome model mice

Angelman syndrome (AS) is a neurodevelopmental disorder caused by the loss of function of the maternal UBE3A gene. The hippocampus is one of the most prominently affected brain regions in AS model mice, manifesting in severe hippocampal-dependent memory and plasticity deficits. Previous studies in AS mice reported an elongated axon initial segment (AIS) in pyramidal neurons (PNs) of the hippocampal CA1 region. These were the first reports in mammals to show AIS elongation in vivo. Correspondingly, this AIS elongation was linked to enhanced expression of the α1 subunit of Na⁺/K⁺-ATPase (α1-NaKA). Recently, it was shown that selective pharmacological inhibition of α1-NaKA by marinobufagenin (MBG) in adult AS mice rescued the hippocampal-dependent deficits via normalizing their compromised activity-dependent calcium (Ca⁺²) dynamics. In the herein study, we showed that a chronic selective α1-NaKA inhibition reversed the AIS elongation in hippocampal CA1 PNs of adult AS mice, and differentially altered their excitability and intrinsic properties. Taken together, our study is the first to demonstrate in vivo structural plasticity of the AIS in a mammalian model, and further elaborates on the modulatory effects of elevated α1-NaKA levels in the hippocampus of AS mice.Subject terms: Cellular neuroscience, Autism spectrum disorders, Developmental disorders     

Influence of conduction disturbances on clinical outcome in patients with acute myocardial infarction receiving thrombolysis (results from the ARGAMI-2 study)

Right bundle branch block and complete atrioventricular (AV) block are conduction disorders (CDs) that have been observed in 14% of patients admitted with ST-elevation acute myocardial infarction. CDs carry a poor prognosis, with a threefold increase in the mortality rate, mainly due to cardiogenic shock and recurrent fatal myocardial infarction at 1-year follow-up. According to multivariable analysis, CD was the second strongest predictor of death, after high Killip class. Compared with patients without CD, the 1-year outcome of patients with CD was identically worse, irrespective of whether CD appeared during admission, disappeared, or remained constant. Similar adverse outcomes were seen in patients with complete AV block and right bundle branch block.     

Platinum-resistance in ovarian cancer cells is mediated by IL-6 secretion via the increased expression of its target cIAP-2

Ovarian carcinoma patients are initially responsive to platinum-based therapy, but eventually become refractory to treatment due to the development of platinum chemoresistance. Elevated levels of interleukin-6 (IL-6) in the sera and ascites of these patients predict poor clinical outcome. Our goal was to analyze the interaction between cisplatin and cisplatin-resistant ovarian cancer cells, and to identify means of circumventing platinum resistance. We studied ovarian carcinoma cell lines and cells drawn from ovarian carcinoma patients. Gene array analyses were performed on ovarian carcinoma cells upon treatment with cisplatin, and the results were validated by ELISA and Western blotting (WB). Cytotoxicity assays were performed on anti-IL-6 Ab-, IL-6-, and cellular inhibitor of apoptosis 2 (cIAP-2) siRNA-treated cells, following cisplatin addition. Our results revealed a highly significant increase in IL-6 and cIAP-2 mRNA and protein levels upon treatment with cisplatin. WB analysis of cisplatin-treated cells exhibited decreased cIAP-2 expression level following anti-IL-6 Ab addition. Furthermore, IL-6 by itself, significantly increased cIAP-2 levels in ovarian carcinoma cells. Finally, cytotoxicity assays showed sensitization to cisplatin following the addition of IL-6 and cIAP-2 inhibitors. In conclusion, cisplatin treatment of ovarian carcinoma cells upregulates IL-6 and cIAP-2 levels while their inhibition significantly sensitizes them to cisplatin. Here, we present cIAP-2 as a novel inducer of platinum resistance in ovarian carcinoma cells, and suggest an axis beginning with an encounter between cisplatin and these cells, mediated sequentially by IL-6 and cIAP-2, resulting in cisplatin resistance. Consequently, we propose that combining IL-6/cIAP-2 inhibitors with cisplatin will provide new hope for ovarian carcinoma patients by improving the current treatment.     

Management and outcomes of elderly women and men with acute coronary syndromes in 2000 and 2002

BACKGROUND: Previous studies have suggested that women with myocardial infarction are treated less aggressively and have worse outcomes compared with men. The objective of this study was to evaluate sex differences in the management and outcomes of elderly (age > or = 70 years) women and men with acute coronary syndromes (ACSs) in the new millennium. METHODS: This study includes 1331 consecutive elderly patients with ACSs admitted to all intensive coronary care units and cardiology departments in Israel from 2 prospective nationwide ACS surveys conducted in 2000 and 2002. RESULTS: The mean age of women vs men was comparable (79 vs 78 years). Comorbidities were more frequent in women, whereas previous coronary disease and typical anginal pain on admission were more frequent in men. Medical treatments and revascularization procedures during the index hospitalization were comparable in both groups. Crude and covariate-adjusted mortality rates were higher in women at 7 days (12% vs 7%; P = .007; adjusted odds ratio [OR], 1.83; 95% confidence interval [CI], 1.15-2.91) but not at 6 months (21% vs 19%; adjusted OR, 1.10; 95% CI, 0.79-1.52). This difference was attributed to ST elevation (STE)-ACS in women vs men (19% vs 12%; P = .007; adjusted OR, 1.97; 95% CI, 1.14-3.46). Seven-day mortality rates were highest in patients with STE-ACS denied coronary angiography, especially women (23% vs 15%; P = .06). CONCLUSIONS: In the 2000s, elderly women and men with ACSs are receiving similar medical and invasive management during the index hospitalization; however, women with STE-ACS have higher mortality rates at 7 days but not at 6 months. Mortality rates are highest in patients with STE-ACS denied coronary angiography. The benefit of invasive procedures on mortality rates in elderly patients with STE-ACS needs further investigation.     

Primary angioplasty with routine stenting compared with thrombolytic therapy in elderly patients with acute myocardial infarction

Background

Prior studies have yielded conflicting data on the advantage of primary angioplasty compared with thrombolysis in elderly patients with acute myocardial infarction (AMI). These studies, however, were performed before the contemporary widespread use of intracoronary stents and glycoprotien IIb/IIIa antagonists.

Methods

We prospectively compared the outcome of 130 consecutive elderly patients (aged ≥70 years) with ST-elevation AMI who were admitted to 2 similar neighboring medical centers. Patients were assigned to receive either thrombolytic therapy with accelerated tissue-type plasminogen activator (center I) or primary angioplasty with routine stenting (center II).

Results

Of the patients assigned to receive primary angioplasty, 91% underwent stenting. At 6 months, patients treated with primary angioplasty, compared with those treated with thrombolytic therapy, had a lower incidence of reinfarction (2% vs 14%, P = .053) and revascularization for recurrent ischemia (9% vs 61%, P < .001) and a significant reduction in the prespecified combined end point of death, reinfarction, or revascularization for recurrent ischemia (29% vs 93%, P < .01). Primary angioplasty remained an independent predictor of the triple combined end point after controlling for potential covariables (relative risk 0.63, 95% CI 0.38-0.84). Major bleeding complications were also significantly reduced in the primary angioplasty group (0% vs 17%, P = .03).

Conclusions

Compared with thrombolysis, primary angioplasty with routine stenting in elderly patients with AMI is associated with better clinical outcomes and a lower risk of bleeding complications.     

Outcome of myocardial infarction in patients treated with aspirin is enhanced by pre-hospital administration

OBJECTIVE: Reducing time to reperfusion therapy is one of the goals in the management of acute myocardial infarction (AMI). We assessed the association between timing of aspirin administration and outcome of patients with AMI. PATIENTS: We studied 922 consecutive AMI patients with ST-segment elevation in Killip class I-III on admission. Patients were divided into two groups based upon the timing of emergency aspirin administration: before (early aspirin users) or after (late aspirin users) hospital admission. RESULTS: Early aspirin users (n = 338; 37%) were younger, less likely to be women, and more likely to smoke (p < 0.006) than late users (n = 584; 63%). Other baseline and clinical characteristics were similar. Early aspirin users were more likely to be treated with thrombolysis or primary percutaneous transluminal coronary angioplasty. Compared with late users, early aspirin users had significantly lower in-hospital complications and lower mortality rates at 7 (2.4 vs. 7.3%, p = 0.002) and 30 days (4.9 vs. 11.1%, p = 0.001). By multivariate adjustment, pre-hospital aspirin was an independent determinant of survival at 7 (odds ratio 0.43; 95% confidence interval 0.18-0.92) and at 30 days (odds ratio, 0.60; 95% confidence interval 0.32-1.08). Survival benefit associated with aspirin persisted for subgroups treated or not with reperfusion therapy. CONCLUSIONS: Outcome of AMI patients treated with aspirin is improved by pre-hospital administration. Our findings suggest that emergency pre-hospital aspirin might facilitate early reperfusion.     

Photodynamic therapy of colorectal cancer using a new light source

PURPOSE: Photodynamic therapy (PDT) is a relatively new alternative modality for palliation of rectal cancer. Current source of light for PDT are laser systems that are expensive and not necessarily needed for PDT. We evaluated a new nonlaser light source for PDT, Versa-Light ^® .METHODS AND RESULTS: In vitro PDT—CT26 murine colon carcinoma cells were incubated with aluminum phthalocyanine (AlPcS ₄ ) for 48 hours and subjected to photoradiation using Versa-Light ^® ,and viability was assessed. There was a significant decrease in viability of treated cells compared with controls. In vivo PDT—BALB/c mice were injected either subcutaneously or intrarectally with CT26 cancer cells. IP AlPcS ₄ (2.5 mg/kg) was injected when tumors were visible. After 24 hours, mice were subjected to photoradiation. Massive tumor necrosis in response to PDT was observed. PDT also prolonged survival of treated mice. Patient treatment—A 70-year-old woman with recurrent local rectal carcinoma received intravenous Photofrin II ^® (2 mg/kg). After 48 and 96 hours, she was subjected to direct photoradiation. After the first light session, there was complete macroscopic disappearance of the tumor. Biopsies up to 10 weeks after the treatment showed no cancer cells in the treated area. Sixteen weeks later, a randomized biopsy from previous tumor site showed carcinoma cells. CONCLUSIONS: We believe that Versa-Light ^® ,is a good light source for PDT. It was effective in both in vitro and animal studies. It can also be safely used for clinical PDT.Supported by the Roni Udassin Memorial Fund of the Israel Cancer Society.     

Improved posterobasal segment function after thrombolysis is associated with decreased incidence of significant mitral regurgitation in a first inferior myocardial infarction

Objectives. This study was designed to investigate the association between wall motion abnormalities and the occurrence of ischemic mitral regurgitation in patients with a first inferior or posterior myocardial infarction and to reassess the role of thrombolytic treatment in these patients.

Background. We previously demonstrated that thrombolytic therapy reduces the incidence of significant mitral regurgitation in patients with a first inferior myocardial infarction, but the mechanisms responsible for this decrease were not clear.

Methods. Wall motion score on two-dimensional echocardiography (16 segments) and mitral regurgitation grade (0 to 3) on Doppler color flow imaging were assessed in 95 patients (in 47 after thrombolysis) at 24 h, 7 to 10 days and 1 month after myocardial infarction. Significant mitral regurgitation was defined as moderate or severe (grade 2 or 3).

Results. Multivariate analysis revealed that the presence of an advanced wall motion abnormality of the posterobasal segment of the left ventricle was the most significant independent variable associated with significant mitral regurgitation: odds ratio (OR) 15.0, 90% confidence interval (CI) 1.4 to 165.6 at 24 h; OR 2.8, CI 0.9 to 9.3 at 7 to 10 days; OR 4.2, CI 1.2 to 11.4 at 1 month. Thrombolysis reduced the prevalence of advanced wall motion abnormalities in the posterobasal segment at 24 h (55% vs. 75%, OR 0.5, CI 0.2 to 0.99), 7 to 10 days (44% vs. 73%, OR 0.3, CI 0.1 to 0.7) and 1 month (36% vs. 56%, OR 0.4, CI 0.2 to 0.9).

Conclusions. There is a strong association between advanced wall motion abnormalities in the posterobasal segment and significant mitral regurgitation. In this study group, thrombolysis reduced the prevalence of advanced wall motion abnormalities in the posterobasal segment and thereby reduced the incidence of significant mitral regurgitation.