Activation of the glmS Ribozyme Confers Bacterial Growth Inhibition.

The ever-growing number of pathogenic bacteria resistant to treatment with antibiotics call for the development of novel compounds with as-yet unexplored modes of action. Here, we demonstrate the in vivo antibacterial activity of carba-α-d-glucosamine (CGlcN). In this mode of action study, we provide evidence that CGlcN-mediated growth inhibition is due to glmS ribozyme activation, and we demonstrate that CGlcN hijacks an endogenous activation pathway, hence utilizing a prodrug mechanism. This is the first report describing antibacterial activity mediated by activating the self-cleaving properties of a ribozyme. Our results open the path towards a compound class with an entirely novel and distinct molecular mechanism.

Surgery Is an Effective Option after Failure of Chemoradiation in Cancers of the Anal Canal and Anal Margin.

BACKGROUND: Surgery for anal canal cancer (ACC) and anal margin cancer (AMC) is the only curative option after failure of chemoradiotherapy (CRT). This study aimed to determine the efficacy of surgery for ACC or AMC after failed CRT. METHODS: This was a single-centre, retrospective study of 161 patients initially treated with CRT. We compared the survival rates of patients successfully treated by CRT with those of patients whose CRT failed (both surgically salvaged and treated palliatively). RESULTS: Thirty-one patients underwent surgery with curative intent, 20 received palliative treatment after failure of CRT, and 110 had effective CRT. The 5-year overall survival (OS) rate was significantly higher among patients with successful CRT than among patients who underwent surgery with curative intent (86 vs. 66%, p < 0.001). On the other hand, the 5-year OS of patients treated with curative surgery was significantly better than that of patients who underwent palliative treatment (66 vs. 13.5%, p < 0.001). The postoperative morbidity and mortality rates were 32 and 3%, respectively. Considering patients with failed CRT, curative surgery was the only factor prognostic of favourable OS in the multivariate analysis. CONCLUSION: Curative surgery after failure of CRT for ACC or AMC remains an effective treatment to improve survival in two-thirds of cases, resulting in high but manageable morbidity.

Small cationic antimicrobial peptides delocalize peripheral membrane proteins.

Short antimicrobial peptides rich in arginine (R) and tryptophan (W) interact with membranes. To learn how this interaction leads to bacterial death, we characterized the effects of the minimal pharmacophore RWRWRW-NH2. A ruthenium-substituted derivative of this peptide localized to the membrane in vivo, and the peptide also integrated readily into mixed phospholipid bilayers that resemble Gram-positive membranes. Proteome and Western blot analyses showed that integration of the peptide caused delocalization of peripheral membrane proteins essential for respiration and cell-wall biosynthesis, limiting cellular energy and undermining cell-wall integrity. This delocalization phenomenon also was observed with the cyclic peptide gramicidin S, indicating the generality of the mechanism. Exogenous glutamate increases tolerance to the peptide, indicating that osmotic destabilization also contributes to antibacterial efficacy. Bacillus subtilis responds to peptide stress by releasing osmoprotective amino acids, in part via mechanosensitive channels. This response is triggered by membrane-targeting bacteriolytic peptides of different structural classes as well as by hypoosmotic conditions.

Superior sulcus non-small cell lung carcinoma: A comparison of IMRT and 3D-RT dosimetry.

AIM: A dosimetric study comparing intensity modulated radiotherapy (IMRT) by TomoTherapy to conformational 3D radiotherapy (3D-RT) in patients with superior sulcus non-small cell lung cancer (NSCLC). BACKGROUND: IMRT became the main technique in modern radiotherapy. However it was not currently used for lung cancers. Because of the need to increase the dose to control lung cancers but because of the critical organs surrounding the tumors, the gains obtainable with IMRT is not still demonstrated. MATERIAL AND METHODS: A dosimetric comparison of the planned target and organs at risk parameters between IMRT and 3D-RT in eight patients who received preoperative or curative intent irradiation. RESULTS: In the patients who received at least 66 Gy, the mean V95% was significantly better with IMRT than 3D-RT (p = 0.043). IMRT delivered a lower D2% compared to 3D-RT (p = 0.043). The IH was significantly better with IMRT (p = 0.043). The lung V 5 Gy and V 13 Gy were significantly higher in IMRT than 3D-RT (p = 0.043), while the maximal dose (D max) to the spinal cord was significantly lower in IMRT (p = 0.043). The brachial plexus D max was significantly lower in IMRT than 3D-RT (p = 0.048). For patients treated with 46 Gy, no significant differences were found. CONCLUSION: Our study showed that IMRT is relevant for SS-NSCLC. In patients treated with a curative dose, it led to a reduction of the exposure of critical organs, allowing a better dose distribution in the tumor. For the patients treated with a preoperative schedule, our results provide a basis for future controlled trials to improve the histological complete response by increasing the radiation dose.

Age impacts the pattern of care for elderly patients with rectal cancer.

PURPOSE: This study analyzed the current approaches for rectal cancer treatment in elderly patients. METHODS: We retrospectively studied 240 rectal cancer patients who had undergone radiotherapy from 2000 to 2008. The ages of the patients ranged from 65 and 75 years (group A, n = 127) and older than 75 years (group B, n = 113). The distribution of the Charlson comorbidity index was similar between the two groups, but the ECOG performance status (PS) differed between the groups (66 % of the patients of group A were PS 0, and 40 % were PS 0 in group B (p < 0.0001)). The tumor stages were comparable between groups. RESULTS: The median age of the patients was 74.3 years (range 65-90.6). Treatment was discussed during a multidisciplinary cancer team meeting before treatment for 55 % of the cases in group A and 73 % of the cases in group B (p < 0.001), and treatment proposals were in accordance with guidelines in 96 % of the cases in group A and 76 % of the cases in group B (p < 0.001). Group B patients received slightly less concurrent chemotherapy (35 vs. 30 % for group A; p = 0.54), more hypofractionated radiotherapy (41 vs. 54 % for group A; p = 0.064), less surgery (92 vs. 80 % for group A; p = 0.014), and less adjuvant chemotherapy (34 vs. 10 % for group A; p < 0.001). Finally, 80 % of the patients in group A and 60 % of the patients in group B received treatment in accordance with guidelines (p = 0.007) and in the logistic regression model. Non-metastatic patients who were aged below 75 years were predicted for conformal management (HR = 0.323; 95 % CI = 0.152-0.684) irrespective of their performance status, comorbidity, or disease stage. CONCLUSIONS: Treatment proposals and administered therapy differed according to age.

3D radiation therapy boost improves the outcome of whole brain radiation therapy treated RPA II patients with one or two brain metastases.

PURPOSE: to evaluate the role of whole brain radiotherapy (WBRT) and radiation boost (RB) for 208 patients recursive partitioning analysis (RPA) II with 1 or 2 brain metastases (BM) at a single institution. METHODS AND MATERIALS: the dose of WBRT was 30 Gy (10 fractions of 3 Gy). One hundred thirty-two patients (63.5%) benefited from RB of 9 Gy in 3 fractions of 3 Gy at the metastatic site. Patients had 1 or 2 BM in 122 (58.7%) and 86 cases (41.3%), respectively. RESULTS: patients with one or two metastases had similar survival (4.6 and 5.1 months, respectively) (p = 0.4). Median overall survival (OS) for patients treated with WBRT and RB, and with WBRT alone was 5.9 and 3.7 months, respectively (p = 0.03). The 6-, 12- and 24-month OS rates after WBRT and RB were 48.5%, 25% and 10.6%, respectively, while WBRT alone resulted in OS rates of 34%, 22.4% and 3.2%, respectively (p = 0.03). After WBRT and RB, the 6-, 12- and 24-month local control rates were 92%, 82% and 67%, respectively, while they were 81.2%, 75% and 37.5%, respectively, after WBRT alone (p = 0.03). The 6-, 12- and 24-month brain control rates after WBRT and RB were 88.7%, 75.8% and 62%, respectively, and after WBRT alone they were 78.5%, 59% and 37.7%, respectively (p = 0.03). CONCLUSION: additional boost delivered with 3D conformal radiotherapy improves local and brain control rates significantly as well as overall survival for RPA II patients with 1 or 2 unresectable BM.

Early evaluation predicts pain relief of irradiated bone metastases: a single-center prospective study.

BACKGROUND: Radiation therapy is a well-recognized, effective modality used for palliative care. Most studies completed to date have endpoints of one month or greater after treatment completion. This study analyzed the response rates at different time points during the first month after treatment. METHODS: From May 2010 to November 2011, 61 patients treated for 74 metastases were included in the study. The end points were defined as the completion of treatment (CT) and d8, d15 and d30 after the completion of treatment. The response rate was measured by the worst pain in the last 24 hours and the administered opioid dose. Patient assessment was performed during consultations and phone appointments. RESULTS: The overall response rate significantly improved from the CT (38%) to d8 (53.8%), d15 (53.8%) and d30 (57.1%) (respectively p < 0.001; p < 0.001 and p = 0.001). The improvement peaked at d8. Patients responding to the treatment at d8 had a significative longer pain relapse free survival (PRFS) compared to patients not responding (3.38 weeks vs 0.3 weeks; p < 0.001). From the beginning of treatment to the CT and at d8 , d15 and d30, oral morphine equivalent dose (OMED) did not significantly differ. However, the pain decrease did not result in a performance status improvement, which declined over time (p < 0.001). CONCLUSION: Radiation therapy is an efficient treatment method for providing pain relief. This relief peaked at d8 after treatment, and the response at d8 is predictive of the response at 4 weeks. Pain management alone is not enough to improve performance status; further studies are needed to evaluate a more global supportive care approach.

Treatment that follows guidelines closely dramatically improves overall survival of patients with anal canal and margin cancers.

BACKGROUND: To assess relevance of ESMO-ESSO-ESTRO treatment guidelines in a retrospective analysis of patients with anal canal or anal margin cancers. MATERIAL AND METHODS: 155 patients were separated into standard treatment group (STG), treated according to or closely the guidelines, and an altered treatment group (ATG). RESULTS: The median follow-up time was 50.7 months. In the STG, the 5- and 10-year LR-DFS rates were 75.2% and 72.7%; in the ATG, they were 66.8% and 61.2%, respectively. In the STG, the 5- and 10-year OS rates were 81.8% and 68%; in the ATG, they were 63.3% and 49.5%, respectively (p=0.037). In the multivariate analysis, favorable prognostic factors for OS included the standard treatment, age <60, tumor 50.4Gy. CONCLUSION: This study identifies the superiority of treatment according to standard guidelines compared to altered treatment. Our results corroborate the guidelines.

Cardiovascular disease among Alaska Natives: a review of the literature.

BACKGROUND: We reviewed the literature of population-based studies regarding heart disease and stroke occurrence among Alaska Natives. The existing literature suggests that differences in cardiovascular mortality rates and risk factors exist in Alaska Natives by ethnicity and residence. However, data sources are largely limited to mortality data and small community-based studies. OBJECTIVES: Because cardiovascular disease occurrence has not been well studied among Alaska Natives, it is important to avoid sweeping generalizations about the increasing or decreasing prevalences of cardiovascular disease and risk factors. RESULTS: Recent mortality rates from heart disease (of all types) among Alaska Natives are similar to rates for U.S. whites, and mortality rates from stroke among Alaska Natives are higher than rates for U.S. whites. Mortality rates from ischemic heart disease have been relatively constant among Alaska Natives over the past 20 years, while over the same time period, rates declined dramatically among U.S. Whites. The ischemic heart disease mortality rates among Alaska Native males are now comparable to rates among U.S. White males. CONCLUSIONS: Although available data indicate no increase in mortality from ischemic heart disease in Alaska Natives, the relatively constant death rates over the recent 20 years, compared with declining rates elsewhere in the U.S, and the high prevalence of risk factors for ischemic heart disease calls for increased descriptive epidemiologic studies of the incidence and prevalence of cardiovascular disease outcomes. In addition, analytic epidemiologic studies are needed to examine the relationship between lifestyle, especially subsistence and traditional lifestyles, and cardiovascular disease outcomes.

Superior sulcus non small cell lung carcinoma: retrospective analysis of 42 patients.

AIMS: Retrospective, monocentric analysis of localized superior sulcus non-small cell cancer (SS-NSCLC), article management. MATERIALS AND METHODS: Between 2000 and 2010, 42 patients have been treated for a SS-NSCLC. Median age was 54.7 years (34.5-86.8). Nineteen tumors (45.2%) were stage IIB, 18 were stage IIIA (42.9%) and 5 were stage IIIB (11.9%). Twenty-two patients were treated by pre-operative radiotherapy or chemoradiotherapy, 20 received exclusive radiotherapy or chemoradiotherapy. Preoperative and exclusive median radiotherapy doses were 46 Gy (40-47 Gy) and 51.8 Gy (40-70 Gy), respectively. All patients treated with chemotherapy received at least platinum. Mean follow up was 44.1 months (0-128 months). RESULTS: Local, loco-regional and metastatic relapses occurred in 11 (26.2%), 2 (4.8%) and 15 patients (35.7%), respectively. Most common metastatic site was cerebral (7 patients, 46.7%). Median disease-free survival (DFS) was 9.7 months (8.9-10.4). One-, 2- and 5- years DFS rates were 44%, 33% and 26.5%, respectively. No prognostic factor was identified. Median overall survival (OS) was 22.6 months (10.4-34.8). One-, 2- and 5- years OS rates were 61.9%, 44.9% and 30.1%, respectively. Univariate prognostic factors for OS were WHO (p = 0.027) and tumoral response (p = 0.05). In multivariate analysis, independent favorable prognostic factors were WHO 0-1 (p = 0.017; OR = 0.316 [CI95% 0.123-0.81) and complete response to treatment (p = 0.035; OR = 0.312 [IC95% 0.106-0.919]). CONCLUSION: This study highlighted that a good performans status and complete response to treatment are independent factors of OS, whatever the delivered treatment. Brain was the most common metastatic relapse site.

Institutional, retrospective analysis of 777 patients with brain metastases: treatment outcomes and diagnosis-specific prognostic factors.

PURPOSE: To retrospectively evaluate the prognostic factors and survival of a series of 777 patients with brain metastases (BM) from a single institution. METHODS AND MATERIALS: Patients were treated with surgery followed by whole-brain radiation therapy (WBRT) or with WBRT alone in 16.3% and 83.7% of the cases, respectively. The patients were RPA (recursive partitioning analysis) class I, II, and III in 11.2%, 69.6%, and 18.4% of the cases, respectively; RPA class II-a, II-b, and II-c in 8.3%, 24.8%, and 66.9% of the cases, respectively; and with GPA (graded prognostic assessment) scores of 0-1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0 in 35%, 27.5%, 18.2%, and 8.6% of the cases, respectively. RESULTS: The median overall survival (OS) times according to RPA class I, II, and III were 20.1, 5.1, and 1.3 months, respectively (P<.0001); according to RPA class II-a, II-b, II-c: 9.1, 8.9, and 4.0 months, respectively (P<.0001); and according to GPA score 0-1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0: 2.5, 4.4, 9.0, and 19.1 months, respectively (P<.0001). By multivariate analysis, the favorable independent prognostic factors for survival were as follows: for gastrointestinal tumor, a high Karnofsky performance status (KPS) (P=.0003) and an absence of extracranial metastases (ECM) (P=.003); for kidney cancer, few BM (P=.002); for melanoma, few BM (P=.01), an absence of ECM (P=.002), and few ECM (P=.0002); for lung cancer, age (P=.007), a high KPS (P<.0001), an absence of ECM (P<.0001), few ECM and BM (P<.0001 and P=.0006, respectively), and control of the primary tumor (P=.004); and for breast cancer, age (P=.001), a high KPS (P=.007), control of the primary tumor (P=.05), and few ECM and BM (P=.01 and P=.0002, respectively). The triple-negative subtype was a significant unfavorable factor (P=.007). CONCLUSION: Prognostic factors varied by pathology. Our analysis confirms the strength of prognostic factors used to determine the GPA score, including the genetic subtype for breast cancer.

Can exhaled NO fraction predict radiotherapy-induced lung toxicity in lung cancer patients?

BACKGROUND: A large increase in nitric oxide fraction (FeNO) after radiotherapy (RT) for lung cancer may predict RT-induced lung toxicity. METHODS: In this study, we assessed the relationships between FeNO variations and respiratory symptoms, CT scan changes or dose volume histogram (DVH) parameters after RT. We measured FeNO before RT, 4, 5, 6, 10 weeks, 4 and 7.5 months after RT in 65 lung cancer patients. RESULTS: Eleven lung cancer patients (17%) complained of significant respiratory symptoms and 21 (31%) had radiation pneumonitis images in > 1/3 of the irradiated lung after RT. Thirteen patients (20%) showed increases in FeNO > 10 ppb. The sensitivity and specificity of a > 10 ppb FeNO increase for the diagnosis of RT-associated respiratory symptoms were 18% and 83%, respectively. There was no correlation between DVH parameters or CT scan changes after RT and FeNO variations. Three patients (5%) showed intriguingly strong (2 or 3-fold, up to 55 ppb) and sustained increases in FeNO at 4 and 5 weeks, followed by significant respiratory symptoms and/or radiation-pneumonitis images. CONCLUSION: Serial FeNO measurements during RT had a low ability to identify lung cancer patients who developed symptoms or images of radiation pneumonitis. However, three patients presented with a particular pattern which deserves to be investigated.

Metabolic syndrome: prevalence among American Indian and Alaska native people living in the southwestern United States and in Alaska.

BACKGROUND: Metabolic syndrome occurs commonly in the United States. The purpose of this study was to measure the prevalence of metabolic syndrome among American Indian and Alaska Native people. METHODS: We measured the prevalence rates of metabolic syndrome, as defined by the National Cholesterol Education Program, among four groups of American Indian and Alaska Native people aged 20 years and older. One group was from the southwestern United States (Navajo Nation), and three groups resided within Alaska. Prevalence rates were age-adjusted to the U.S. adult 2000 population and compared to rates for U.S. whites (National Health and Nutrition Examination Survey [NHANES] 1988-1994). RESULTS: Among participants from the southwestern United States, metabolic syndrome was found among 43.2% of men and 47.3% of women. Among Alaska Native people, metabolic syndrome was found among 26.5% of men and 31.2% of women. In Alaska, the prevalence rate varied by region, ranging among men from 18.9% (western Alaska) to 35.1% (southeast), and among women from 22.0% (western Alaska) to 38.4 % (southeast). Compared to U.S. whites, American Indian/Alaska Native men and women from all regions except western Alaska were more likely to have metabolic syndrome; men in western Alaska were less likely to have metabolic syndrome than U.S. whites, and the prevalence among women in western Alaska was similar to that of U.S. whites. CONCLUSION: The prevalence rate of metabolic syndrome varies widely among different American Indian and Alaska Native populations. Differences paralleled differences in the prevalence rates of diabetes.