Surrogate markers predicting overall survival for lung cancer: ELCWP recommendations.

The present systematic review was performed under the auspices of the European Lung Cancer Working Party (ELCWP) in order to determine the role of early intermediate criteria (surrogate markers), instead of survival, in determining treatment efficacy in patients with lung cancer. Initially, the level of evidence for the use of overall survival to evaluate treatment efficacy was reviewed. Nine questions were then formulated by the ELCWP. After reviewing the literature with experts on these questions, it can be concluded that overall survival is still the best criterion for predicting treatment efficacy in lung cancer. Some intermediate criteria can be early predictors, if not surrogates, for survival, despite limitations in their potential application: these include time to progression, progression-free survival, objective response, local control after radiotherapy, downstaging in locally advanced nonsmall cell lung cancer (NSCLC), complete resection and pathological TNM in resected NSCLC, and a few circulating markers. Other criteria assessed in these recommendations are not currently adequate surrogates of survival in lung cancer.

Invasive mechanical ventilation in cancer patients. Prior non invasive ventilation is a poor prognostic factor.

PURPOSE: Prior non invasive ventilation (NIV) is associated with an increased mortality in patients with haematological malignancies and acute respiratory failure treated by invasive mechanical ventilation (IMV). We have assessed whether NIV failure is an independent prognostic factor for hospital discharge in a general cancer population treated by IMV. METHODS: 106 patients with solid tumors and 58 patients with haematological malignancies were eligible for this retrospective study; 41 were treated by NIV before IMV. RESULTS: The main indications for mechanical ventilation were sepsis/shock (35%), acute respiratory failure (33%), cardiopulmonary resuscitation (16%) and neurologic disease (10%). Respectively, 35%, 28% and 24% of the patients were extubated, discharged from the intensive care unit (ICU) and from the hospital. For patients treated with NIV prior to IMV, the rates were 22%, 17% and 10%, respectively. In multivariate analysis, 3 variables were independently associated with a decreased probability of being discharged from the hospital: NIV use before IMV (odds ratio/OR=0.30, 95% confidence interval/CI: 0.09-0.95; p=0.04); leukopenia (OR=0.21, 95% CI: 0.06-0.77; p=0.02) and serum bilirubin >1.1 mg/dl (OR=0.38, 95% CI: 0.16-0.94; p=0.04). CONCLUSION: NIV failure before IMV is an independent poor prognostic factor in cancer patients treated by IMV.

Proton conductivity and proton dynamics in nanocrystalline cellulose functionalized with imidazole.

In the present study, we report the synthesis, electrical and dynamic properties of a new generation bio-based nanocomposite, that is a proton-exchange membrane based on nanocrystalline cellulose (CNC) and imidazole (Im). CNC serves as supporting material and imidazole acts as a proton donor and proton acceptor at the same time. The nanocomposite (1.3 CNC-Im) was synthesized as a film and shows proton conductivity equal to 4.0 × 10-1 S/m at 160 °C in anhydrous conditions. Analysis of impedance measurements and NMR spectra provided some insight into the macroscopic and microscopic processes involved in proton transport in 1.3 CNC-Im. Local processes such as reorientation of imidazole rings and breaking of hydrogen bonds are identified and their activation energies are calculated. The energies of the macroscopic and microscopic proton transport in CNC-Im film are correlated. The percolation model used confirmed the percolation nature of conductivity in cellulose composites with imidazole.

A three-dimensional geometric quantification of human cortical canals using an innovative method with micro-computed tomographic data.

The complex architecture of bone has been investigated for several decades. Some pioneer works proved an existing link between microstructure and external mechanical loading applied on bone. Due to sinuous network of canals and limitations of experimental acquisition technique, there has been little quantitative analysis of three-dimensional description of cortical network. The aim of this study is to provide an algorithmic process, using Python 3.5, in order to identify 3D geometrical characteristics of voids considered as canals. This script is based on micro-computed tomographic slices of two bone samples harvested from the humerus and femur of male cadaveric subject. Slice images are obtained from 2.94 µm isotropic resolution. This study provides a generic method of image processing which considers beam hardening artefact so as to avoid heuristic choice of global threshold value. The novelty of this work is the quantification of numerous three-dimensional canals features, such as orientation or canal length, but also connectivity features, such as opening angle, and the accurate definition of canals as voids which ranges from connectivity to possibly another intersection. The script was applied to one humeral and one femoral samples in order to analyse the difference in architecture between bearing and non-bearing cortical bones. This preliminary study reveals that the femoral specimen is more porous than the humeral one whereas the canal network is denser and more connected.

Modification of the apoptotic-like effects of MBP protein overexpression in E. coli by fusion with 14-3-3 derived polypeptides.

Overexpression of even non-toxic proteins in bacteria causes a starvation-like response: the arrest of bacterial proliferation and apoptotic-like suicidal cell death. We have shown here that, as in the cells of higher organisms, these effects are accompanied by DNA degradation. The fusion with the bacterial MBP of a polypeptide, belonging to the 14-3-3 family and normally expressed in pumpkin (C. pepo), modifies the apoptotic-like effects of overexpression of this protein in E. coli. Fusion of the full length 14-3-3 protein with the MBP considerably slows down the DNA degradation caused by overexpression of the unmodified MBP. Overexpression of the construct containing a truncated version of the 14-3-3 polypeptide causes immediate arrest of bacterial growth and rapid degradation of the chromosomal DNA. This result suggests that the DNA degradation in bacteria is an active process which can be modified to some extent by an endogenous protein.

The lens of the eye: exposures in the UK medical sector and mechanistic studies of radiation effects.

The recommendation from the International Commission on Radiological Protection that the occupational equivalent dose limit for the lens of the eye should be reduced to 20 mSv year(-1), averaged over 5 years with no year exceeding 50 mSv, has stimulated a discussion on the practicalities of implementation of this revised dose limit, and the most appropriate risk and protection framework to adopt. This brief paper provides an overview of some of the drivers behind the move to a lower recommended dose limit. The issue of implementation in the medical sector in the UK has been addressed through a small-scale survey of doses to the lens of the eye amongst interventional cardiologists and radiologists. In addition, a mechanistic study of early and late post-irradiation changes in the lens of the eye in in-vivo-exposed mice is outlined. Surveys and studies such as those described can contribute to a deeper understanding of fundamental and practical issues, and therefore contribute to a robust evidence base for ensuring adequate protection of the eye while avoiding undesirable restrictions to working practices.

Identification of the proteins responsible for SAR DNA binding in nuclear matrix of Cucurbita pepo.

The nuclear matrices from White bush (Cucurbita pepo var. patisonina) cell nuclei have been isolated using three methods: I, standard procedure involving extraction of cell nuclei with 2 M NaCl and 1% Triton X-100; II, the same with pre-treatment of cell nuclei with 0.5 mM CuSO4 (stabilisation step); and III, method with extraction by lithium diiodosalicylate (LIS), and compared the polypeptide pattern. The isolated matrices specifically bind SAR DNA derived from human beta-interferon gene in the exogenous SAR binding assay and in the gel mobility shift assay. Using IgG against the 32 kDa endonuclease we have found in the DNA-protein blot assay that this protein is one of the proteins binding SAR DNA. We have identified three proteins with molecular mass of 65 kDa, 60 kDa and 32 kDa which are responsible for SAR DNA binding in the gel mobility shift assay experiments.

Interaction of the Pisum sativum nuclear matrix proteins with SAR DNA.

We have isolated the nuclear matrices from Pisum sativum cell nuclei using three methods: i. standard procedure involving extraction of cell nuclei with 2 M NaCl and 1% Triton X-100; ii. the same with pretreatment of cell nuclei with 0.5 mM CuSO4 (stabilisation step); and iii. method including lithium diiodosalicylate extraction. We compared the polypeptide pattern and residual DNA content of the nuclear matrices isolated. The nuclear matrices displayed a specific endonuclease activity which was due to the presence of a 32 kDa protein. The isolated nuclear matrices bound specifically the scaffold-attached (SAR) DNA derived from human beta interferon gene, in the exogenous SAR binding assay. Using the DNA-protein binding blot assay we demonstrated the presence of two nuclear matrix proteins of 66 kDa and 62 kDa which bound specifically SAR DNA.

Medical cancer patients and intensive care.

Between November 1985 and October 1989, 1413 patients were admitted to the medical intensive care unit (ICU) of our cancer hospital. Data collected at admission and during the ICU stay were analysed for: 1) medical problems and treatment modalities requiring the admission; 2) types of underlying disease; 3) mortality during intensive care; 4) nursing requirements. Of the 1413 admissions, 1220 were for solid tumors (mainly ovarian cancer, breast cancer and lung cancer) and 144 for hematological malignancies. Overall mortality during the ICU stay was 10%. There was a relative lack of nurses, as shown by the evaluation of the nursing activity with the TISS. 621 admissions were because of a medical emergency such as hypercalcemia or respiratory failure. Overall mortality was 22%. Of 64 patients treated by artificial ventilation, 46 (72%) died during their ICU stay. 732 admissions were made in order for administration and monitoring of special treatment or new therapeutic modalities including phase I drug infusion, intraperitoneal chemotherapy, intensive (megadosage) chemotherapy, lipophilic drug containing liposomes and coadministration of platinum derivatives. Our experience emphasizes the role of ICU facilities in modern oncology for both optimal supportive care in emergency cases and the safe development of new anticancer modalities.

Cisplatin-carboplatin-gemcitabine or ifosfamide-gemcitabine in advanced non-small cell lung carcinoma: two pilot studies.

Gemcitabine has been demonstrated active in non-small cell lung cancer (NSCLC). The objective of this trial was to evaluate the feasibility of combinations of gemcitabine (1 g/m2 dl,8,15) with cisplatin (60 mg/m2 dl) and carboplatin (200 mg/m2 dl) (CCG; n = 12) or ifosfamide (4.5 g/m2 dl) (IG;n = 4) in patients with advanced NSCLC, in order to prepare a phase III randomised trial. Toxicity, mainly haematological, was tolerable. It consisted in neutropenia (IG) and both thrombopenia and neutropenia (CCG). The administration of carboplatin according to the AUC (AUC = 3) resulted in a significant reduction of haematological toxicity. A good number of responses were documented. These acceptable results urged our group to compare these regimens to the combination of cisplatin, carboplatin and if osfamide.

[Cardiopulmonary resuscitation in cancer patients: experience of an intensive care unit in a cancer center]. / Ressuscitation cardiorespiratoire chez le patient cancéreux: expérience d'une unité de réanimation médicale dans un centre anticancéreux.

The goal of this study was to determine the effectiveness and potential indications of cardiopulmonary resuscitation (CPR) in medical cancer patients. A retrospective analysis of the records of patients admitted between November 1985 and January 1992 in the medical ICU of a cancer hospital and having had cardiac arrest was performed. Cardiac arrest occurred in 49 cancer patients. CPR was successful in 19 (39%), but only 5 (10%) were discharged alive from the hospital. CPR was successful in all eight patients in which cardiac arrest was the consequence of an acute cardiovascular drug toxicity, even if cancer was metastatic and treatment intent not curative, while it was effective in only 25% of those in which cardiac arrest was an ultimate complication of various problems, like septic shock or respiratory failure complicating the neoplastic disease. In cancer as in other types of disease, CPR is mainly indicated when cardiac arrest is the consequence of and acute insult.

Monitoring anti-angiogenic therapy in colorectal cancer murine model using dynamic contrast-enhanced MRI: comparing pixel-by-pixel with region of interest analysis.

Sorafenib is a multi-kinase inhibitor that blocks cell proliferation and angiogenesis. It is currently approved for advanced hepatocellular and renal cell carcinomas in humans, where its major mechanism of action is thought to be through inhibition of vascular endothelial growth factor and platelet-derived growth factor receptors. The purpose of this study was to determine whether pixel-by-pixel analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is better able to capture the heterogeneous response of Sorafenib in a murine model of colorectal tumor xenografts (as compared with region of interest analysis). MRI was performed on a 9.4 T pre-clinical scanner on the initial treatment day. Then either vehicle or drug were gavaged daily (3 days) up to the final image. Four days later, the mice were again imaged. The two-compartment model and reference tissue method of DCE-MRI were used to analyze the data. The results demonstrated that the contrast agent distribution rate constant (K(trans)) were significantly reduced (p < 0.005) at day-4 of Sorafenib treatment. In addition, the K(trans) of nearby muscle was also reduced after Sorafenib treatment. The pixel-by-pixel analysis (compared to region of interest analysis) was better able to capture the heterogeneity of the tumor and the decrease in K(trans) four days after treatment. For both methods, the volume of the extravascular extracellular space did not change significantly after treatment. These results confirm that parameters such as K(trans), could provide a non-invasive biomarker to assess the response to anti-angiogenic therapies such as Sorafenib, but that the heterogeneity of response across a tumor requires a more detailed analysis than has typically been undertaken.

On the effect of marrow in the mechanical behavior and crush response of trabecular bone.

The present paper focuses on the mechanical behavior analysis of bones at mesoscopic scale, paying a special attention to the trabecular bone and the bone marrow filling the porosities. Uni-axial quasi-static compression tests under unconfined conditions have been performed to identify the mechanical behavior of 46 trabecular bone samples. The bone marrow for 22 samples has been preserved to analyze the fluid flow effects on the crushing response. Although deformation patterns do not differ significantly, the average crush behavior of the trabecular bone shows an unexpected decrease of the mechanical properties when the marrow is kept in the sample (26% for the elastic modulus (E(a)), 38% for the maximum compressive stress (σ(max)) and 33% for the average stress (σ(mean))). An explanation is given by analyzing the contribution of the bone marrow viscosity which smooths the mechanical response. A numerical analysis on an idealized trabecula confirms that the marrow induces transverse pressure and extra local stress on trabeculae during its flow, causing the premature collapse of the trabecular network.

Intensive care in anticancer centres: an international inquiry.

Intensive care is increasingly frequently used in the management of cancer patients. In order to determine whether and how critical-care facilities are used specifically for these patients, we performed a world-wide inquiry in anticancer centres. We mailed a questionnaire to 141 centres and received 84 responses (57.5%). There was at least one oncological intensive care-unit (ICU) in 59 hospitals (70%). The majority of the ICU were found in the European institutions. Data were obtained concerning the ICU organisation, the medical team, the nursing staff, the critical-care techniques and the anticancer treatments performed. Medical ICU appeared to be managed by physicians and nurses often qualified in both intensive care and oncology. These data suggest that oncological intensive care should be part of the training of oncologists and intensivists.

Cardiopulmonary resuscitation in medical cancer patients: the experience of a medical intensive-care unit of a cancer centre.

This study aimed to determine the effectiveness and potential indications of cardiopulmonary resuscitation (CPR) in medical cancer patients, by retrospective analysis of the records of the patients admitted between November 1985 and January 1992 in the medical intensive-care unit of a cancer hospital following cardiac arrest. Cardiac arrest occurred in 49 cancer patients. CPR was successful in 19 (39%) but only 5 (10%) were discharged alive from the hospital. CPR was successful in all 8 patients in which cardiac arrest was the consequence of an acute cardiovascular drug toxicity, even if the cancer was metastatic and the purpose of treatment not curative, while it was effective in only 25% of those where cardiac arrest was an ultimate complication of various problems such as septic shock or respiratory failure complicating the neoplastic disease. The results suggest that in cancer, as in other types of disease, CPR is mainly indicated when cardiac arrest is the consequence of an acute insult.