Biosimilars and cancer treatment of older patients

AbstractBiosimilar monoclonal antibodies are being developed globally to meet clinical demand in oncology and potentially provide greater access to biologic therapies for patients with cancer, including older patients. In this supplement, we present an overview of the development, approval requirements, and characteristics of biosimilar monoclonal antibodies that may help practicing oncologists and other healthcare providers to acquire familiarity with this new group of therapeutic biologic agents. Furthermore, we review and discuss some of the challenges and potential strategies for the management of older patients with cancer, who represent an increasing population in many countries

An evaluation of food as a potential source for clostridium difficile acquisition in hospitalized patients

OBJECTIVETo determine whetherClostridium difficileis present in the food of hospitalized patients and to estimate the risk of subsequent colonization associated withC. difficilein food.METHODSThis was a prospective cohort study of inpatients at a university-affiliated tertiary care center, May 9, 2011–July 12, 2012. Enrolled patients submitted a portion of food from each meal. Patient stool specimens and/or rectal swabs were collected at enrollment, every 3 days thereafter, and at discharge, and were cultured forC. difficile. Clinical data were reviewed for evidence of infection due toC. difficile.A stochastic, discrete event model was developed to predict exposure toC. difficilefrom food, and the estimated number of new colonization events from food exposures per 1,000 admissions was determined.RESULTSA total of 149 patients were enrolled and 910 food specimens were obtained. Two food specimens from 2 patients were positive forC. difficile(0.2% of food samples; 1.3% of patients). Neither of the 2 patients was colonized at baseline withC. difficile. Discharge colonization status was available for 1 of the 2 patients and was negative. Neither was diagnosed withC. difficileinfection while hospitalized or during the year before or after study enrollment. Stochastic modeling indicated contaminated hospital food would be responsible for less than 1 newly colonized patient per 1,000 hospital admissions.CONCLUSIONSThe recovery ofC. difficilefrom the food of hospitalized patients was rare. Modeling suggests hospital food is unlikely to be a source ofC. difficileacquisition.Infect Control Hosp Epidemiol2016;1401–1407</jats:sec

Risk for Clostridium difficile infection after allogeneic hematopoietic cell transplant remains elevated in the postengraftment period

BACKGROUND: Clostridium difficile infection (CDI) is a frequent cause of diarrhea among allogeneic hematopoietic cell transplant (HCT) recipients. It is unknown whether risk factors for CDI vary by time posttransplant. METHODS: We performed a 3-year prospective cohort study of CDI in allogeneic HCT recipients. Participants were enrolled during their transplant hospitalizations. Clinical assessments were performed weekly during hospitalizations and for 12 weeks posttransplant, and monthly for 30 months thereafter. Data were collected through patient interviews and chart review, and included CDI diagnosis, demographics, transplant characteristics, medications, infections, and outcomes. CDI cases were included if they occurred within 1 year of HCT and were stratified by time from transplant. Multivariable logistic regression was used to determine risk factors for CDI. RESULTS: One hundred eighty-seven allogeneic HCT recipients were enrolled, including 63 (34%) patients who developed CDI. 38 (60%) CDI cases occurred during the preengraftment period (days 0-30 post-HCT) and 25 (40%) postengraftment (day >30). Lack of any preexisting comorbid disease was significantly associated with lower risk of CDI preengraftment (odds ratio [OR], 0.3; 95% confidence interval [CI], 0.1-0.9). Relapsed underlying disease (OR, 6.7; 95% CI, 1.3-33.1), receipt of any high-risk antimicrobials (OR, 11.8; 95% CI, 2.9-47.8), and graft-versus-host disease (OR, 7.8; 95% CI, 2.0-30.2) were significant independent risk factors for CDI postengraftment. CONCLUSIONS: A large portion of CDI cases occurred during the postengraftment period in allogeneic HCT recipients, suggesting that surveillance for CDI should continue beyond the transplant hospitalization and preengraftment period. Patients with continued high underlying severity of illness were at increased risk of CDI postengraftment

Randomized controlled trial to determine the impact of probiotic administration on colonization with multidrug-resistant organisms in critically ill patients

This was a randomized controlled pilot study of Lactobacillus rhamnosus GG versus standard of care to prevent gastrointestinal multidrug-resistant organism (MDRO) colonization in ICU patients. Seventy subjects were included in analyses. There were no significant differences in acquisition or loss of any MDROs (p>0.05). There were no probiotic-associated adverse events

a randomized controlled study

Background Uncertainty persists regarding the optimal ventilatory strategy in trauma patients developing acute respiratory distress syndrome (ARDS). This work aims to assess the effects of two mechanical ventilation strategies with high positive end-expiratory pressure (PEEP) in experimental ARDS following blunt chest trauma. Methods Twenty-six juvenile pigs were anesthetized, tracheotomized and mechanically ventilated. A contusion was applied to the right chest using a bolt-shot device. Ninety minutes after contusion, animals were randomized to two different ventilation modes, applied for 24 h: Twelve pigs received conventional pressure-controlled ventilation with moderately low tidal volumes (VT, 8 ml/kg) and empirically chosen high external PEEP (16cmH2O) and are referred to as the HP-CMV-group. The other group (n = 14) underwent high-frequency inverse-ratio pressure-controlled ventilation (HFPPV) involving respiratory rate of 65breaths · min−1, inspiratory-to-expiratory- ratio 2:1, development of intrinsic PEEP and recruitment maneuvers, compatible with the rationale of the Open Lung Concept. Hemodynamics, gas exchange and respiratory mechanics were monitored during 24 h. Computed tomography and histology were analyzed in subgroups. Results Comparing changes which occurred from randomization (90 min after chest trauma) over the 24-h treatment period, groups differed statistically significantly (all P values for group effect <0.001, General Linear Model analysis) for the following parameters (values are mean ± SD for randomization vs. 24-h): PaO2 (100 % O2) (HFPPV 186 ± 82 vs. 450 ± 59 mmHg; HP-CMV 249 ± 73 vs. 243 ± 81 mmHg), venous admixture (HFPPV 34 ± 9.8 vs. 11.2 ± 3.7 %; HP-CMV 33.9 ± 10.5 vs. 21.8 ± 7.2 %), PaCO2 (HFPPV 46.9 ± 6.8 vs. 33.1 ± 2.4 mmHg; HP-CMV 46.3 ± 11.9 vs. 59.7 ± 18.3 mmHg) and normally aerated lung mass (HFPPV 42.8 ± 11.8 vs. 74.6 ± 10.0 %; HP-CMV 40.7 ± 8.6 vs. 53.4 ± 11.6 %). Improvements occurring after recruitment in the HFPPV- group persisted throughout the study. Peak airway pressure and VT did not differ significantly. HFPPV animals had lower atelectasis and inflammation scores in gravity-dependent lung areas. Conclusions In this model of ARDS following unilateral blunt chest trauma, HFPPV ventilation improved respiratory function and fulfilled relevant ventilation endpoints for trauma patients, i.e. restoration of oxygenation and lung aeration while avoiding hypercapnia and respiratory acidosis

Correlation of lung collapse and gas exchange

Background: Atelectasis can provoke pulmonary and non-pulmonary complications after general anaesthesia. Unfortunately, there is no instrument to estimate atelectasis and prompt changes of mechanical ventilation during general anaesthesia. Although arterial partial pressure of oxygen (PaO2) and intrapulmonary shunt have both been suggested to correlate with atelectasis, studies yielded inconsistent results. Therefore, we investigated these correlations. Methods: Shunt, PaO2 and atelectasis were measured in 11 sheep and 23 pigs with otherwise normal lungs. In pigs, contrasting measurements were available 12 hours after induction of acute respiratory distress syndrome (ARDS). Atelectasis was calculated by computed tomography relative to total lung mass (Mtotal). We logarithmically transformed PaO2 (lnPaO2) to linearize its relationships with shunt and atelectasis. Data are given as median (interquartile range). Results: Mtotal was 768 (715–884) g in sheep and 543 (503–583) g in pigs. Atelectasis was 26 (16–47)% in sheep and 18 (13–23) % in pigs. PaO2 (FiO2 = 1.0) was 242 (106–414) mmHg in sheep and 480 (437–514) mmHg in pigs. Shunt was 39 (29–51)% in sheep and 15 (11–20) % in pigs. Atelectasis correlated closely with lnPaO2 (R2 = 0.78) and shunt (R2 = 0.79) in sheep (P-values<0.0001). The correlation of atelectasis with lnPaO2 (R2 = 0.63) and shunt (R2 = 0.34) was weaker in pigs, but R2 increased to 0.71 for lnPaO2 and 0.72 for shunt 12 hours after induction of ARDS. In both, sheep and pigs, changes in atelectasis correlated strongly with corresponding changes in lnPaO2 and shunt. Discussion and Conclusion: In lung-healthy sheep, atelectasis correlates closely with lnPaO2 and shunt, when blood gases are measured during ventilation with pure oxygen. In lung-healthy pigs, these correlations were significantly weaker, likely because pigs have stronger hypoxic pulmonary vasoconstriction (HPV) than sheep and humans. Nevertheless, correlations improved also in pigs after blunting of HPV during ARDS. In humans, the observed relationships may aid in assessing anaesthesia-related atelectasis

Computed tomographic assessment of lung weights in trauma patients with early posttraumatic lung dysfunction

Introduction: Quantitative computed tomography (qCT)-based assessment of total lung weight (M(lung)) has the potential to differentiate atelectasis from consolidation and could thus provide valuable information for managing trauma patients fulfilling commonly used criteria for acute lung injury (ALI). We hypothesized that qCT would identify atelectasis as a frequent mimic of early posttraumatic ALI. Methods: In this prospective observational study, M(lung) was calculated by qCT in 78 mechanically ventilated trauma patients fulfilling the ALI criteria at admission. A reference interval for M(lung) was derived from 74 trauma patients with morphologically and functionally normal lungs (reference). Results are given as medians with interquartile ranges. Results: The ratio of arterial partial pressure of oxygen to the fraction of inspired oxygen was 560 (506 to 616) mmHg in reference patients and 169 (95 to 240) mmHg in ALI patients. The median reference M(lung) value was 885 (771 to 973) g, and the reference interval for M(lung) was 584 to 1164 g, which matched that of previous reports. Despite the significantly greater median M(lung) value (1088 (862 to 1,342) g) in the ALI group, 46 (59%) ALI patients had M(lung) values within the reference interval and thus most likely had atelectasis. In only 17 patients (22%), Mlung was increased to the range previously reported for ALI patients and compatible with lung consolidation. Statistically significant differences between atelectasis and consolidation patients were found for age, Lung Injury Score, Glasgow Coma Scale score, total lung volume, mass of the nonaerated lung compartment, ventilator-free days and intensive care unit-free days. Conclusions: Atelectasis is a frequent cause of early posttraumatic lung dysfunction. Differentiation between atelectasis and consolidation from other causes of lung damage by using qCT may help to identify patients who could benefit from management strategies such as damage control surgery and lung-protective mechanical ventilation that focus on the prevention of pulmonary complications.Leipzig University Hospita

Development and validation of a Clostridium difficile infection risk prediction model

OBJECTIVE: The purpose of this study was to develop and validate a risk prediction model that could identify patients at high risk for Clostridium difficile infection (CDI) before they develop disease. DESIGN: Retrospective cohort. SETTING: Tertiary care medical center. PATIENTS: Patients admitted to the hospital for ≥48 hours from 1-1-2003 through 12-31-2003. METHODS: Data were collected electronically from the hospital’s Medical Informatics database and analyzed with logistic regression to determine variables that best predicted patients’ risk for development of CDI. Model discrimination and calibration were calculated. The model was bootstrapped 500 times to validate the predictive accuracy. A receiver operating characteristic (ROC) curve was calculated to evaluate potential risk cut-offs. RESULTS: 35,350 admissions with 329 CDI cases were included. Variables in the risk prediction model were age, CDI pressure, admissions in previous 60 days, modified Acute Physiology Score, days on high risk antibiotics, low albumin, admission to an ICU, and receipt of laxatives, gastric acid suppressors, or antimotility drugs. The calibration and discrimination of the model were very good to excellent (C index=0.88; Brier score 0.009). CONCLUSIONS: The CDI risk prediction model performed well. Further study is needed to determine if it could be used in a clinical setting to prevent CDI-associated outcomes and reduce costs

Implanted Reuptake-deficient or Wild-type Dopaminergic Neurons Improve ON L-dopa Dyskinesias Without OFF-dyskinesias in a Rat Model of Parkinson's Disease

OFF-L-dopa dyskinesias have been a surprising side-effect of intrastriatal foetal ventral mesencephalic transplantation in patients with Parkinson's disease. It has been proposed that excessive and unregulated dopaminergic stimulation of host post-synaptic striatal neurons by the grafts could be responsible for these dyskinesias. To address this issue we transplanted foetal dopaminergic neurons from mice lacking the dopamine transporter (DATKO) or from wild-type mice, into a rat model of Parkinson's disease and L-dopa-induced dyskinesias. Both wild-type and DATKO grafts reinnervated the host striatum to a similar extent, but DATKO grafts produced a greater and more diffuse increase in extra-cellular striatal dopamine levels. Interestingly, grafts containing wild-type dopaminergic neurons improved parkinsonian signs to a similar extent as DATKO grafts, but provided a more complete reduction of L-dopa induced dyskinesias. Neither DATKO nor wild-type grafts induced OFF-L-dopa dyskinesias. Behavioural and receptor autoradiography analyses demonstrated that DATKO grafts induced a greater normalization of striatal dopaminergic receptor supersensitivity than wild-type grafts. Both graft types induced a similar downregulation and normalization of PEnk and fosb/Δfosb in striatal neurons. In summary, DATKO grafts causing high and diffuse extra-cellular dompamine levels do not per se alter graft-induced recovery or produce OFF-L-dopa dyskinesias. Wild-type dopaminergic neurons appear to be the most effective neuronal type to restore function and reduce L-dopa-induced dyskinesias