Circulating galectin-1 delineates response to bevacizumab in melanoma patients and reprograms endothelial cell biology.

Blockade of vascular endothelial growth factor (VEGF) signaling with bevacizumab, a humanized anti-VEGF monoclonal antibody (mAb), or with receptor tyrosine kinase inhibitors, has improved progression-free survival and, in some indications, overall survival across several types of cancers by interrupting tumor angiogenesis. However, the clinical benefit conferred by these therapies is variable, and tumors from treated patients eventually reinitiate growth. Previously we demonstrated, in mouse tumor models, that galectin-1 (Gal1), an endogenous glycan-binding protein, preserves angiogenesis in anti-VEGF-resistant tumors by co-opting the VEGF receptor (VEGFR)2 signaling pathway in the absence of VEGF. However, the relevance of these findings in clinical settings is uncertain. Here, we explored, in a cohort of melanoma patients from AVAST-M, a multicenter, open-label, randomized controlled phase 3 trial of adjuvant bevacizumab versus standard surveillance, the role of circulating plasma Gal1 as part of a compensatory mechanism that orchestrates endothelial cell programs in bevacizumab-treated melanoma patients. We found that increasing Gal1 levels over time in patients in the bevacizumab arm, but not in the observation arm, significantly increased their risks of recurrence and death. Remarkably, plasma Gal1 was functionally active as it was able to reprogram endothelial cell biology, promoting migration, tubulogenesis, and VEGFR2 phosphorylation. These effects were prevented by blockade of Gal1 using a newly developed fully human anti-Gal1 neutralizing mAb. Thus, using samples from a large-scale clinical trial from stage II and III melanoma patients, we validated the clinical relevance of Gal1 as a potential mechanism of resistance to bevacizumab treatment.

Role of inflammasome activation in tumor immunity triggered by immune checkpoint blockers.

Immune checkpoint blockers improve the overall survival of a limited number of patients among different cancers. Identifying pathways that influence the immunological and clinical response to treatment is critical to improve the therapeutic efficacy and predict clinical responses. Recently, a key role has been assigned to innate immune mechanisms in checkpoint blockade-driven anti-tumor responses. However, inflammatory pathways can both improve and impair anti-tumor immunity. In this review, we discuss how different inflammatory pathways, particularly inflammasome activation, can influence the clinical outcome of immune checkpoint blockers. Inflammasome activation may reinforce anti-tumor immunity by boosting CD8+ T cell priming as well as by enhancing T helper type 17 (Th17) responses. In particular, we focus on the modulation of the cation channel transmembrane protein 176B (TMEM176B) and the ectonucleotidase CD39 as potential targets to unleash inflammasome activation leading to reinforced anti-tumor immunity and improved efficacy of immune checkpoint blockers. Future studies should be aimed at investigating the mechanisms and cell subsets involved in inflammasome-driven anti-tumor responses.

Targeting TMEM176B Enhances Antitumor Immunity and Augments the Efficacy of Immune Checkpoint Blockers by Unleashing Inflammasome Activation.

Although immune checkpoint blockers have yielded significant clinical benefits in patients with different malignancies, the efficacy of these therapies is still limited. Here, we show that disruption of transmembrane protein 176B (TMEM176B) contributes to CD8+ T cell-mediated tumor growth inhibition by unleashing inflammasome activation. Lack of Tmem176b enhances the antitumor activity of anti-CTLA-4 antibodies through mechanisms involving caspase-1/IL-1ß activation. Accordingly, patients responding to checkpoint blockade therapies display an activated inflammasome signature. Finally, we identify BayK8644 as a potent TMEM176B inhibitor that promotes CD8+ T cell-mediated tumor control and reinforces the antitumor activity of both anti-CTLA-4 and anti-PD-1 antibodies. Thus, pharmacologic de-repression of the inflammasome by targeting TMEM176B may enhance the therapeutic efficacy of immune checkpoint blockers.

[Immunotherapy in cancer. Current prospects, challenges and new horizons]. / Inmunoterapia en cáncer. Perspectivas actuales, desafíos y nuevos horizontes.

Recent understanding of the mechanisms that control immune system homeostasis and orchestrate antitumor responses has prompted the development of novel immunotherapeutic modalities. These include antibodies that target immune checkpoints such as PD-1/PD-L1 and CTLA-4, agonistic antibodies of costimulatory molecules such as CD137 and OX-40 and the adoptive transfer of genetically-modified antitumor T cells. However, a large number of patients do not respond to these therapies and develop resistance as a result of activation of compensatory circuits. Rational combination of immunotherapeutic modalities will help overcome resistance and will increase the number of patients who will benefit from these treatments. Moreover, identification of predictive biomarkers will allow selection of patients responding to these treatments. Emerging clinical trials and pre-clinical studies have shown exciting results anticipating new horizons in the design and implementation of cancer immunotherapeutic modalities.

Inmunoterapia en cáncer: Perspectivas actuales, desafíos y nuevos horizontes / Immunotherapy in cancer. Current prospects, challenges and new horizons

La activación del sistema inmunológico en pacientes con cáncer ha sido un objetivo histórico en el campo de la oncología. En las últimas décadas, nuestro entendimiento de la respuesta inmunológica antitumoral ha promovido el desarrollo de novedosas estrategias terapéuticas dando como resultado un cambio de paradigma en el tratamiento del cáncer. La utilización de agentes bloqueantes de puntos de chequeo del sistema inmunológico como PD-1/PD-L1 y CTLA-4, de agonistas de moléculas co-estimuladoras como CD137 y OX-40 y la transferencia adoptiva de células T antitumorales modificadas genéticamente han generado importantes beneficios clínicos, reflejados en respuestas objetivas y durader as, en enfermos sin tratamientos convencionales disponibles. Sin embargo, un gran número de pacientes no responde a dichas terapias generando resistencia o sufriendo recaídas de la enfermedad debido a la aparición de circuitos inhibitorios o compensatorios. La combinación racional de estrategias terapéuticas permite eliminar mecanismos de resistencia, mientras que la identificación de biomarcadores predictivos facilita la selección de pacientes respondedores a dichos tratamientos. Recientes ensayos clínicos y estudios pre-clínicos permiten vislumbrar un escenario optimista con importantes desafíos en la implementación de estrategias de inmunoterapia en cáncer.

Recent under-standing of the mechanisms that control immune system homeostasis and orchestrate antitumor responses has prompted the development of novel immunotherapeutic modalities. These include antibodies that target immune checkpoints such as PD-1/PD-L1 and CTLA-4, agonistic antibodies of costimulatory molecules such as CD137 and OX-40 and the adoptive transfer of genetically-modified antitumor T cells. However, a large number of patients do not respond to these therapies and develop resistance as a result of activation of compensatory circuits. Rational combination of immunotherapeutic modalities will help overcome resistance and will increase the number of patients who will benefit from these treatments. Moreover, identification of predictive biomarkers will allow selection of patients responding to these treatments. Emerging clinical trials and pre-clinical studies have shown exciting results anticipating new horizons in the design and implementation of cancer immunotherapeutic modalities.

Spatial diffusion of surnames by long transhumance routes between highland and lowland: A study in Sardinia.

RIASSUNTO.

Plasma total cell-free DNA (cfDNA) is a surrogate biomarker for tumour burden and a prognostic biomarker for survival in metastatic melanoma patients.

INTRODUCTION: Tumour burden is a prognostic biomarker in metastatic melanoma. However, tumour burden is difficult to measure and there are currently no reliable surrogate biomarkers to easily and reliably determine it. The aim of this study was to assess the potential of plasma total cell free DNA as biomarker of tumour burden and prognosis in metastatic melanoma patients. MATERIALS AND METHODS: A prospective biomarker cohort study for total plasma circulating cell-free DNA (cfDNA) concentration was performed in 43 metastatic melanoma patients. For 38 patients, paired blood collections and scan assessments were available before treatment and at first response evaluation. Tumour burden was calculated as the sum of volumes from three-dimensional radiological measurements of all metastatic lesions in individual patients. RESULTS: Baseline cfDNA concentration correlated with pre-treatment tumour burden (ρ = 0.52, P < 0.001). Baseline cfDNA levels correlated significantly with hazard of death and overall survival, and a cut off value of 89 pg/µl identified two distinct prognostic groups (HR = 2.22 for high cfDNA, P = 0.004). Patients with cfDNA ≥89 pg/µl had shorter OS (10.0 versus 22.7 months, P = 0.009; HR = 2.22 for high cfDNA, P = 0.004) and the significance was maintained when compared with lactic dehydrogenase (LDH) in a multivariate analysis. We also found a correlation between the changes of cfDNA and treatment-related changes in tumour burden (ρ = 0.49, P = 0.002). In addition, the ratio between baseline cfDNA and tumour burden was prognostic (HR = 2.7 for cfDNA/tumour volume ≥8 pg/(µl*cm3), P = 0.024). CONCLUSIONS: We have demonstrated that cfDNA is a surrogate marker of tumour burden in metastatic melanoma patients, and that it is prognostic for overall survival.

Distinct subclonal tumour responses to therapy revealed by circulating cell-free DNA.

BACKGROUND: The application of precision medicine in oncology requires in-depth characterisation of a patient's tumours and the dynamics of their responses to treatment. PATIENTS AND METHODS: We used next-generation sequencing of circulating cell-free DNA (cfDNA) to monitor the response of a KIT p.L576P-mutant metastatic vaginal mucosal melanoma to sequential targeted, immuno- and chemotherapy. RESULTS: Despite a KIT mutation, the response to imatinib was mixed. Unfortunately, tumours were not accessible for molecular analysis. To study the mechanism underlying the mixed clinical response, we carried out whole-exome sequencing and targeted longitudinal analysis of cfDNA. This revealed two tumour subclones; one with a KIT mutation that responded to imatinib and a second KIT-wild-type subclone that did not respond to imatinib. Notably, the subclones also responded differently to immunotherapy. However, both subclones responded to carboplatin/paclitaxel, and although the KIT-wild-type subclone progressed after chemotherapy, it responded to subsequent re-administration of paclitaxel. CONCLUSION: We show that cfDNA can reveal tumour evolution and subclonal responses to therapy even when biopsies are not available.

Demographic structure and microevolution of an Italian alpine isolated population.

The isonymic method has been generally accepted in population genetic studies and surnames have been successfully used to investigate human populations as if they were genetic markers associated to the Y chromosome. In this study we analysed the microevolution dynamics of Postua, a mountain village of North Western Italy, by means of demographic methods. The uniqueness of this community is due to its past geographical and cultural isolation and to the high frequency of marriage between relatives. During the study period considered (1640-1989) the population underwent several fluctuations in size and other demographic parameters such as the endogamy, isonimy and consanguinity rates. Until the first half of the XIX century Postua appears to be a village characterised by a closed and isolated community, with high endogamy (80-90%) and isonimy (up to 34.4%). Only at the beginning of the XX century, when the population started to be subjected to significant immigration fluxes, data show a progressive reduction of the isolation. The population showed two demographic peaks, the first around the second half of the XVIII century (1639 inhabitants) and the second at the end of the XIX century (1464 inhabitants). The S/Nratio was low (0.2-0.3) and relatively constant until the beginning of the last century, and only in the last three decades of the XX century, when the population was subjected to immigration, Postua showed a significant increase in the S/Nratio values (to about 0.9). The surname frequency was constant until the 1850 when almost all surnames were the same as those already present in the XVII century. From the first half of the XIX century, the founder surnames decreased, whereas new surnames started to increase and became persistent in the population.

Surname analysis in biological anthropology: Alpine populations in the 17th and 18th centuries.

As part of an interdisciplinary research program on Alpine populations, we studied the biodemographic evolution of two populations of the Dauphiné in the period 1690-1799. We analyzed several indexes derived from surname analysis to infer the genetic structure of the populations. Although situated in the same area of the Dauphiné, the two communities of Vallouise and Chiomonte had different biodemographic characteristics. Vallouise was heavily populated but genetically homogeneous, whereas Chiomonte was less populated but more heterogeneous. The two districts also differed in geographic position: Vallouise was a glacier-enclosed valley that did not attract new inhabitants; Chiomonte was situated in an open valley served by important roads and thus was able to attract many new inhabitants. The demographic differences between the two populations explain the differences in genetic structure. The index of isonymous relationship (R(i)) being different from 0 is due to the rare marriages between members of the two populations. Because R(i) is based on surnames, which are mostly polyphyletic, it can overestimate the genetic relationships between the populations, as in the case of consanguinity assessed by matrimonial isonymy.

Restraint-induced fra-2 and c-fos expression in the rat forebrain: relationship to stress duration.

The protein product of the fra-2 gene (Fra-2), a fos-family member, can compete with Fos protein for participation in activating protein-1 (AP-1) transcription factor complexes and each protein can contribute different transactivational consequences to an AP-1 complex. To date, there is limited characterization of fra-2 mRNA expression in the rat forebrain. We examined basal and restraint-induced mRNA expression (in situ hybridization) of fra-2 in the rat forebrain and compared its temporal-spatial pattern to c-fos. In contrast to the very low basal expression of c-fos, fra-2 basal expression was moderately high throughout cortex and some subcortical structures, including prominent basal expression in the hypothalamic paraventricular nucleus (PVN). Restraint-induced fra-2 expression was quantified in the prefrontal cortex (PFC), lateral septum (LS) and PVN. Maximal fra-2 gene induction in the PFC and LS was delayed (60 min) after restraint onset with respect to c-fos (15 min), whereas in the PVN, fra-2 mRNA increased within 15 min of restraint. Additionally we compared c-fos and fra-2 gene expression in rats given shorter or longer restraint durations, but equal total time from stress onset to sample collection, to determine the extent to which the kinetics of gene induction matched that of a hypothalamic-pituitary-adrenal axis hormone response. Rats given 45 min recovery after 15 min restraint showed less c-fos expression in the PVN, less fra-2 expression in the prelimbic and infralimbic PFC, and no difference in the LS compared with rats restrained for 60 min. Thus, the expression of both genes was sensitive to stressor duration, but this sensitivity varied with brain region. Differential basal and stress-induced expression patterns of the fra-2 and c-fos genes are likely to have important functional consequences for AP-1 transcription factor dependent regulation of neural plasticity.

Habituation to repeated restraint stress is associated with lack of stress-induced c-fos expression in primary sensory processing areas of the rat brain.

Rats repeatedly exposed to restraint show a reduced hypothalamic-pituitary-adrenal axis response upon restraint re-exposure. This hypothalamic-pituitary-adrenal axis response habituation to restraint does not generalize to other novel stressors and is associated with a decrease in stress-induced c-fos expression in a number of stress-reactive brain regions. We examined whether habituation to repeated restraint is also associated with adaptation of immediate early gene expression in brain regions that process and relay primary sensory information. These brain regions may not be expected to show gene expression adaptation to repeated restraint because of their necessary role in experience discrimination. Rats were divided into a repeated restraint group (five 1-hour daily restraint sessions) and an unstressed group (restraint naïve). On the sixth day rats from each group were either killed with no additional stress experience or at 15, 30 or 60 min during restraint. Immediate early gene expression (corticotrophin-releasing hormone heteronuclear RNA, c-fos mRNA, zif268 mRNA) was determined by in situ hybridization. A reduction in stress-induced hypothalamic-pituitary-adrenal axis hormone secretion (plasma corticosterone and adrenocorticotropic hormone) and immediate early gene expression levels in the paraventricular nucleus of the hypothalamus, the lateral septum and the orbital cortex was observed in repeated restraint as compared with restraint naïve animals. This reduction was already evident at 15 min of restraint. Unexpectedly, we also found in repeated restraint rats a reduction in restraint-induced c-fos expression in primary sensory-processing brain areas (primary somatosensory cortex, and ventroposteriomedial and dorsolateral geniculate nuclei of thalamus). The overall levels of hippocampal mineralocorticoid receptor heteronuclear RNA or glucocorticoid receptor mRNA were not decreased by repeated restraint, as may occur in response to severe chronic stress. We propose that repeated restraint leads to a systems-level adaptation whereby re-exposure to restraint elicits a rapid inhibitory modulation of primary sensory processing (i.e. sensory gating), thereby producing a widespread attenuation of the neural response to restraint.

Blunt abdominal aortic trauma in association with thoracolumbar spine fractures.

All patients with blunt abdominal aortic disruption (BAAD) in the trauma registries at the three Regional Trauma Centres were retrospectively reviewed over the last decade. From the 11465 trauma admissions ISS>16,194 sustained aortic injuries. Eight cases of BAAD were identified, six with concurrent thoracolumbar spine (TLS) fractures (mean ISS 42). Patients with BAAD and TLS were subject to a detailed analysis. Clinically, three injury types were seen, hemodynamically unstable (uncontained full thickness laceration), stable symptomatic (intimal dissection with occlusion), and stable asymptomatic (contained full thickness laceration or intimal dissection without occlusion). All spinal column fractures involved a distractive mechanism, one with both distractive and translational fracture components. We propose that a distractive force, applied to the aorta lying anterior to the anterior longitudinal ligament, results in an aortic injury spectrum ranging from an intimal tear to a full thickness laceration, as a related injury. Computed tomography (CT) was an important imaging modality in the stable asymptomatic patients. All intimal dissections without occlusion were managed non-operatively. With distractive TLS fractures, BAAD needs to be considered.

Intracranial pressure monitoring and outcomes after traumatic brain injury.

OBJECTIVE: Uncontrolled intracranial hypertension after traumatic brain injury (TBI) contributes significantly to the death rate and to poor functional outcome. There is no evidence that intracranial pressure (ICP) monitoring alters the outcome of TBI. The objective of this study was to test the hypothesis that insertion of ICP monitors in patients who have TBI is not associated with a decrease in the death rate. DESIGN: Study of case records. METHODS: The data files from the Ontario Trauma Registry from 1989 to 1995 were examined. Included were all cases with an Injury Severity Score (ISS) greater than 12 from the 14 trauma centres in Ontario. Cases identifying a Maximum Abbreviated Injury Scale score in the head region (MAIS head) greater than 3 were selected for further analysis. Logistic regression analyses were conducted to investigate the relationship between ICP and death. RESULTS: Of 9001 registered cases of TBI, an MAIS head greater than 3 was recorded in 5507. Of these patients, 541 (66.8% male, mean age 34.1 years) had an ICP monitor inserted. Their average ISS was 33.4 and 71.7% survived. There was wide variation among the institutions in the rate of insertion of ICP monitors in these patients (ranging from 0.4% to over 20%). Univariate logistic regression indicated that increased MAIS head, ISS, penetrating trauma and the insertion of an ICP monitor were each associated with an increased death rate. However, multivariate analyses controlling for MAIS head, ISS and injury mechanism indicated that ICP monitoring was associated with significantly improved survival (p < 0.015). CONCLUSIONS: ICP monitor insertion rates vary widely in Ontario's trauma hospitals. The insertion of an ICP monitor is associated with a statistically significant decrease in death rate among patients with severe TBI. This finding strongly supports the need for a prospective randomized trial of management protocols, including ICP monitoring, in patients with severe TBI.

Epidemiology of maxillofacial injuries at trauma hospitals in Ontario, Canada, between 1992 and 1997.

BACKGROUND: The purpose of this study was to review the epidemiology of maxillofacial skeletal injuries in severely injured patients admitted to trauma hospitals in Ontario, Canada, with an Injury Severity Score > 12. METHODS: The Ontario Trauma Registry was accessed to examine the epidemiology of maxillofacial skeletal injuries in severely injured patients treated at 12 trauma hospitals in the province of Ontario, Canada, between 1992 and 1997. Data were collected prospectively, and a descriptive analysis was performed to determine the pattern of maxillofacial injuries, including patient age, sex distribution, etiology of injury, time of injury, and injury profile. RESULTS: There were 2,969 patients that met the inclusion criteria. The median age was 25 years, and men were injured at a 3:1 ratio over women. Most severely injured patients with maxillofacial fractures were injured as a result of motor vehicle collision (70%), with only 33% of the patients restrained with a seat-belt. The temporal distribution of injuries showed that most injuries occurred during evening hours, on weekends, and in the summer. The largest number of fractures was found in the maxilla and orbital bones. The Injury Severity Score of the patients in this study ranged from 13 to 75, with a median of 25. The injury most commonly associated with maxillofacial fractures was injury to the head and neck area. Of patients with injury to the head and neck, most had an altered level of consciousness or injuries to the skull, brain, or cranial vessels. CONCLUSION: Many severely injured patients have maxillofacial injuries. Long-term collection of epidemiologic data regarding maxillofacial fractures is important for the evaluation of existing preventative measures and useful in the development of new methods of injury prevention. Furthermore, insight into the epidemiology of facial fractures and concomitant injuries is an integral component in evaluating the quality of patient care, developing optimal treatment regimens, and making decisions regarding appropriate resource and manpower allocations.

Open or closed diagnostic peritoneal lavage for abdominal trauma? A meta-analysis.

OBJECTIVES: To perform a meta-analysis of prospective, randomized controlled trials comparing the closed and open technique of diagnostic peritoneal lavage (DPL) in trauma patients to determine whether there are any difference in outcomes. METHODS: A search of MEDLINE database of English language articles published from 1977 to 1999 was conducted by using the terms diagnostic peritoneal lavage, trauma, and randomized controlled trials. A manual search and Cochrane Library database search was also conducted. Seven randomized controlled trials, including a total of 1,126 patients were identified that compared closed versus open technique. Two reviewers assessed the trials independently. Trial quality was critically appraised by using the Jadad Instrument, a validated published quality scale. Data extraction of major complications, technical difficulties, procedure times, and false-negative and false-positive rates was carried out. The fixed effects model was used for statistical analysis. The Peto odds ratio (OR), weighted mean differences and 95% confidence intervals (95% CI) were calculated. RESULTS: The overall quality of studies was poor (mean, 2.4/7). Major complications did not differ significantly between closed versus open technique (OR, 0.65; 95% CI, 0.15 to 2.92. Technical failures and difficulties were significantly higher in the closed group, i.e., OR 4.33 (95% CI, 1.96 to 9.56) and OR 4.19 (95% CI, 2.842 to 6.19), respectively. Accuracy of closed and open DPL was comparable with no difference in false-negative or false-positive rates between the two techniques. Procedure time was consistently lower in the closed technique. CONCLUSIONS: The closed DPL technique is comparable to the standard open DPL technique in terms of accuracy and major complications. The advantage of reduced time to perform the closed DPL is offset by the increased technical difficulties and failures of this group. Therefore, any significant benefit of routine closed DPL in improving outcomes can be excluded with more confidence based on pooled data than by the individual trials alone.

Intracranial pressure monitoring in severe traumatic brain injury--results of a Canadian survey.

OBJECTIVE: The purpose of this study was to obtain information from Canadian neurosurgeons regarding their opinions on, and utilization of, intracranial pressure (ICP) monitoring for severe traumatic brain injury (TBI). METHODS: A brief survey was sent to practicing Canadian neurosurgeons questioning them about their utilization of, and confidence in, intracranial pressure monitoring in the management of patients with severe TBI. RESULTS: One hundred and ninety-six surveys were mailed. There were 103 responses for a response rate of 52.6%. The vast majority of responding neurosurgeons (98.1%) utilized ICP monitoring in the management of patients with severe TBI, with most (63.4%) using it in more than 75% of their patients, 14.9% using it in 50-75% of patients, 14.9% in 25-50% of patients, and 6.9% using it in less than 25% of patients. The level of confidence that routine monitoring improves outcome from severe TBI ranged from 23.3% having a low level of confidence, 56.3% having an intermediate level of confidence, to 20.4% having a high level of confidence. Most respondents (78.6%) felt that some form of prospective trial evaluating the role of ICP monitoring in improving outcome from severe TBI was warranted; 17.4% felt such a trial was not warranted and 3.9% were uncertain. CONCLUSIONS: While ICP monitoring has gained almost universal acceptance among responding Canadian neurosurgeons, their level of confidence that routine monitoring improves outcome from severe TBI was quite variable, with only 20.4% of respondents having a high level of confidence. Over 75% of respondents felt that some form of prospective trial evaluating the utility of ICP monitoring is warranted. This information is being used in consideration of a prospective trial addressing this issue.

Autopsies and death certification in deaths due to blunt trauma: what are we missing?

OBJECTIVES: To determine the frequency, body region and severity of injuries missed by the clinical team in patients who die of blunt trauma, and to examine the accuracy of the cause of death as recorded on death certificates. DESIGN: A retrospective review. SETTING: London Health Sciences Centre, London, Ont. PATIENTS: One hundred and eight deaths due to blunt trauma occurring during the period Apr. 1, 1991, to Mar. 31, 1997. Two groups were considered: clinically significant missed injuries were identified by comparing patient charts only (group 1) and more detailed injury lists from the autopsies and charts of the patients (group 2). OUTCOME MEASURES: Chart and autopsy findings. RESULTS: Of the 108 patients, 78 (72%) were male, and they had a median age of 39 years (range from 2 to 90 years). The most common cause of death was neurologic injury (27%), followed by sepsis (17%) and hemorrhage (15%). There was disagreement between the treating physicians and the causes of death listed on the death certificate in 40% of cases and with the coroner in 7% of cases. Seventy-seven clinically significant injuries were missed in 51 (47%) of the 108 patient deaths. Injuries were missed in 29% of inhospital deaths and 100% of emergency department deaths. Abdominal and head injuries accounted for 43% and 34% of the missed injuries, respectively. CONCLUSIONS: The information contained on the death certificate can be misleading. Health care planners utilizing this data may draw inaccurate conclusions regarding causes of death, which may have an impact on trauma system development. Missed injuries continue to be a concern in the management of patients with major blunt trauma.

The creation of strategic alliances: the experience of the London Health Sciences Centre and southwestern Ontario.

This article describes the framework and strategies that the London Health Sciences Centre has developed to foster trusting and collaborative relationships with its regional partners in Southwestern Ontario. A four-phase approach was used to identify, implement and evaluate system-wide opportunities to improve the integration of clinical care in Southwestern Ontario. Specific case studies are illustrated that used this framework to improve both access to patient services and length of stay, while positively affecting operating resources.