Associations between clinical pathway concordance, cost, and survival outcomes for stage II colon cancer: a population-based study.

This study measures patient's concordance between clinical reference pathways with survival or cost among a population-based cohort of colon cancer patients applying a continuous measure of concordance. The primary hypothesis is that a higher concordance score with the clinical pathway is significantly associated with longer survival or lower cost. The study informs whether patient's adherence to a defined clinical pathway is beneficial to patients' outcomes or health system. An externally determined clinical pathway for colon cancer was used to identify treatment nodes in colon cancer care. Using observational data up to 2019, the study generated a continuous measure of pathway concordance. The study measured whether incremental improvements in pathway concordance were associated with survival and treatment costs. Concordance between patients' reference pathways and their observed trajectories of care was highly statistically associated with survivorship [hazard ratio: 0.95 (95% confidence interval, CI, 0.95-0.96)], showing that adherence to the clinical pathway was associated with a lower mortality rate. An increase in concordance was statistically significantly associated with a decrease in health system cost. When patients' care followed the clinical pathway, survival outcomes were better and total health system costs were lower in this cohort. This finding creates a compelling case for further research into understanding the barriers to pathway concordance and developing interventions to improve outcomes and help providers implement best practice care where appropriate.

Estimating the incidence of breast cancer recurrence using administrative data.

BACKGROUND: Breast cancer is the most common cancer among women, but most cancer registries do not capture recurrences. We estimated the incidence of local, regional, and distant recurrences using administrative data. METHODS: Patients diagnosed with stage I-III primary breast cancer in Ontario, Canada from 2013 to 2017 were included. Patients were followed until 31/Dec/2021, death, or a new primary cancer diagnosis. We used hospital administrative data (diagnostic and intervention codes) to identify local recurrence, regional recurrence, and distant metastasis after primary diagnosis. We used logistic regression to explore factors associated with developing a distant metastasis. RESULTS: With a median follow-up 67 months, 5,431/45,857 (11.8%) of patients developed a distant metastasis a median 23 (9, 42) months after diagnosis of the primary tumor. 1086 (2.4%) and 1069 (2.3%) patients developed an isolated regional or a local recurrence, respectively. Patients with distant metastatic disease had a median overall survival of 15.4 months (95% CI 14.4-16.4 months) from the time recurrence/metastasis was identified. In contrast, the median survival for all other patients was not reached. Patients were more likely to develop a distant metastasis if they had more advanced stage, greater comorbidity, and presented with symptoms (p < 0.0001). Trastuzumab halved the risk of recurrence [OR 0.53 (0.45-0.63), p < 0.0001]. CONCLUSION: Distant metastasis is not a rare outcome for patients diagnosed with breast cancer, translating to an annual incidence of 2132 new cases (17.8% of all breast cancer diagnoses). Overall survival remains high for patients with locoregional recurrences, but was poor following a diagnosis of a distant metastasis.

The effect of age on the opportunity to receive cancer treatment.

INTRODUCTION: Older adults with cancer may not receive the same opportunities for treatment as younger patients. In this retrospective population-based cohort study, we explored whether age was an independent predictor of receiving specialist consultation and treatment. METHODS: Patients age 45-99 were identified from the Ontario Cancer Registry having a primary solid tumor diagnosed between 01/Jan/2010 and 31/Dec/2019. We used logistic regression adjusted sociodemographic and clinical characteristics to compare the likelihood of consultation or receipt of treatment using linear splines at critical ages of 65, 80, and 90 years. RESULTS: A total 168,232 (42%), 165,205 (41%), 57,360 (14%), and 7810 (2%) patients were diagnosed age 45-64, 65-79, 80-89, and 90-99, respectively. The likelihood of surgical consultation decreased as patients reached 65 years [adjusted odds ratio (aOR) 0.86 (0.84-0.89)], which decreased further among octogenarians [aOR 0.63 (0.59-0.67)]. Similar results were observed for consultation with a medical oncologist and radiation oncologist. Receipt of surgery also decreased with age. Three-month post-operative mortality was higher among older patients [aRR 1.38 (1.26-1.50) per 10 years, p < 0.0001], an effect that remained similar as patients reached age 65 + years of age (p = 0.09 for change). For stage I patients, 3-month post-operative survival was high across all age groups, ranging from 99.8% in 45-64 year-olds, 99.4% in 65-79 year-olds, and 98.1% among octogenarians and nonagenarians (lung, colorectal, breast, cervical cancer patients). CONCLUSION: Older patients were less likely to have specialist consultations. More comprehensive data collection on clinical factors and referral patterns is needed to improve care for elderly cancer patients.

Identifying Breast Cancer Recurrence in Administrative Data: Algorithm Development and Validation.

Breast cancer recurrence is an important outcome for patients and healthcare systems, but it is not routinely reported in cancer registries. We developed an algorithm to identify patients who experienced recurrence or a second case of primary breast cancer (combined as a "second breast cancer event") using administrative data from the population of Ontario, Canada. A retrospective cohort study design was used including patients diagnosed with stage 0-III breast cancer in the Ontario Cancer Registry between 1 January 2009 and 31 December 2012 and alive six months post-diagnosis. We applied the algorithm to healthcare utilization data from six months post-diagnosis until death or 31 December 2013, whichever came first. We validated the algorithm's diagnostic accuracy against a manual patient record review (n = 2245 patients). The algorithm had a sensitivity of 85%, a specificity of 94%, a positive predictive value of 67%, a negative predictive value of 98%, an accuracy of 93%, a kappa value of 71%, and a prevalence-adjusted bias-adjusted kappa value of 85%. The second breast cancer event rate was 16.5% according to the algorithm and 13.0% according to manual review. Our algorithm's performance was comparable to previously published algorithms and is sufficient for healthcare system monitoring. Administrative data from a population can, therefore, be interpreted using new methods to identify new outcome measures.

Inverse optimization on hierarchical networks: an application to breast cancer clinical pathways.

Clinical pathways are standardized processes that outline the steps required for managing a specific disease. However, patient pathways often deviate from clinical pathways. Measuring the concordance of patient pathways to clinical pathways is important for health system monitoring and informing quality improvement initiatives. In this paper, we develop an inverse optimization-based approach to measuring pathway concordance in breast cancer, a complex disease. We capture this complexity in a hierarchical network that models the patient's journey through the health system. A novel inverse shortest path model is formulated and solved on this hierarchical network to estimate arc costs, which are used to form a concordance metric to measure the distance between patient pathways and shortest paths (i.e., clinical pathways). Using real breast cancer patient data from Ontario, Canada, we demonstrate that our concordance metric has a statistically significant association with survival for all breast cancer patient subgroups. We also use it to quantify the extent of patient pathway discordances across all subgroups, finding that patients undertaking additional clinical activities constitute the primary driver of discordance in the population.

Differences in breast cancer diagnosis by patient presentation in Ontario: a retrospective cohort study.

BACKGROUND: In Ontario, patients with breast cancer typically receive their diagnoses through the Ontario Breast Screening Program (OBSP) after an abnormal screen, through screening initiated by a primary care provider or other referring physician, or through follow-up of symptoms by patients' primary care providers. We sought to explore the association of the route to diagnosis (screening within or outside the OBSP or via symptomatic presentation) with use of OBSP-affiliated breast assessment sites (O-BAS), wait times until diagnosis or treatment, health care use and overall survival for patients with breast cancer. METHODS: In this retrospective cohort study, we used the Ontario Cancer Registry to identify adults (aged 18-105 yr) who received a diagnosis of breast cancer from 2013 to 2017. We excluded patients if they were not Ontario residents or had missing age or sex, or who died before diagnosis. We used logistic regression to evaluate factors associated with categorical variables (whether patients were or were not referred to an OBAS, whether patients were screened or symptomatic) and Cox proportional hazards regression to identify factors associated with all-cause mortality. RESULTS: Of 51 460 patients with breast cancer, 42 598 (83%) received their diagnoses at an O-BAS. Patients whose cancer was first detected through the OBSP were more likely than symptomatic patients to be given a diagnosis at an O-BAS (adjusted odds ratio 1.68, 95% confidence interval [CI] 1.57 to 1.80). Patients screened by the OBSP were given their diagnoses 1 month earlier than symptomatic patients, but diagnosis at an O-BAS did not affect the time until either diagnosis or treatment. Patients referred to an O-BAS had significantly better overall survival than those who were not referred (adjusted hazard ratio 0.73, 95% CI 0.66 to 0.80). INTERPRETATION: Patients screened through the OBSP were given their diagnoses earlier than symptomatic patients and were more likely to be referred to an O-BAS, which was associated with better survival. Our findings suggest that individuals with signs and symptoms of breast cancer would benefit from similar referral processes, oversight and standards to those used by the OBSP.

Development of population-level colon cancer pathway concordance measures and association with survival.

Clinical cancer pathways help standardize healthcare delivery to optimize patient outcomes and health system costs. However, population-level measurement of concordance between standardized pathways and actual care received is lacking. Two measures of pathway concordance were developed for a simplified colon cancer pathway map for Stage II-III colon cancer patients in Ontario, Canada: a cumulative count of concordant events (CCCE) and the Levenshtein algorithm. Associations of concordance with patient survival were estimated using Cox proportional hazards models adjusted for patient characteristics and time-dependent cancer-related activities. Models were compared and the impact of including concordance scores was quantified using the likelihood ratio chi-squared test. The ability of the measures to discriminate between survivors and decedents was compared using the C-index. Normalized concordance scores were significantly associated with patient survival in models for cancer stage-a 10% increase in concordance for Stage II patients resulted in a CCCE score adjusted hazard ratio (aHR) of death of 0.93, 95% CI 0.88-0.98 and a Levenshtein score aHR of 0.64, 95% CI 0.60-0.67. A similar relationship was found for Stage III patients-a 10% increase in concordance resulted in a CCCE aHR of 0.85, 95% CI 0.81-0.88 and a Levenshtein aHR of 0.78, 95% CI, 0.74-0.81. Pathway concordance can be used as a tool for health systems to monitor deviations from established clinical pathways. The Levenshtein score better characterized differences between actual care and clinical pathways in a population, was more strongly associated with survival and demonstrated better patient discrimination.

Variation in Diagnosis, Treatment, and Outcome of Esophageal Cancer in a Regionalized Care System in Ontario, Canada.

Importance: Esophageal cancer remains one of the most deadly cancers, ranking sixth highest among cancers leading to the greatest years of life lost. Objective: To determine how patients with esophageal cancer are diagnosed and treated in Ontario's regionalized thoracic surgery centers. Design, Setting, and Participants: This cohort study included patients diagnosed with esophageal cancer between January 1, 2010, and December 31, 2018, identified from the Ontario Cancer Registry, in a single-payer health care system with regionalization of thoracic surgery in the province of Ontario, Canada. Exposures: Exposures included incidence of esophageal cancer and stage at diagnosis; time from the first health care visit until treatment; and the use of specialist consultations, endoscopic ultrasonography, positron emission tomography and computed tomography, endomucosal resection, esophagectomy, neoadjuvant therapy, adjuvant therapy, radiation alone, and chemotherapy alone or in combination with other treatment. Main Outcomes and Measures: Outcome measures included wait times, health care use, treatment, and overall survival. Data were analyzed from March 2020 to February 2021. Results: There were 10 364 patients (mean [SD] age, 68.3 [11.9] years; 7876 men [76%]) identified during the study period. The incidence of esophageal cancer increased over the study period from 1041 in 2010 to 1309 in 2018, which was driven by a 30% increase in the number of adenocarcinomas. The time from first health care encounter to start of treatment was a median 93 days (interquartile range, 56-159 days). Endoscopic ultrasonography was observed for 12% of patients, and positron emission tomography and computed tomography (CT) in 45%. Use of endoscopic mucosal resection was observed for 8% of patients with stage 0 to I disease. A total of 114 of 547 patients (21%) receiving endoscopic resection had a subsequent esophagectomy. Only 2778 patients (27%) had consultations with a thoracic surgeon, a medical oncologist, and a radiation oncologist, whereas 1514 patients (15%) did not see any of these specialists. Of 3047 patients who had an esophagectomy, those receiving neoadjuvant therapy had better overall survival (median survival, 36 months; 95% CI, 32-39 months) than patients who received esophagectomy alone (median survival, 27 months; 95% CI, 24-30 months) or those who received esophagectomy with adjuvant therapy (median survival, 36 months; 95% CI, 32-44 months) despite significant early mortality (log-rank P < .001). There was significant variation in treatment modality across hospitals: esophagectomy ranged from 5% to 39%; esophagectomy after neoadjuvant therapy ranged from 33% to 93%; and esophagectomy followed by adjuvant therapy ranged from 0 to 34% (P < .001). Perioperative mortality was higher at 30 days for patients receiving esophagectomy at low-volume centers (odds ratio [OR], 3.66; 95% CI, 2.01-6.66) and medium-volume centers (OR, 2.07; 95% CI, 1.33-3.23) compared with high-volume centers (P < .001). A longer wait time until treatment was associated with better overall survival (median overall survival was 15 to 17 days vs 5 to 8 days for patients who received treatment earlier than 30 days vs 30 days or longer after diagnosis; P < .001). Conclusions and Relevance: The results of this cohort study suggest that despite regionalization, there was significant regional variability in volumes at designated centers and in the evaluation and treatment course for patients with esophageal cancer across Ontario.

Restructuring Skin Cancer Care in Ontario: A Provincial Plan.

There is a global rise in skin cancer incidence, resulting in an increase in patient care needs and healthcare costs. To optimize health care planning, costs, and patient care, Ontario Health developed a provincial skin cancer plan to streamline the quality of care. We conducted a systematic review and a grey literature search to evaluate the definitions and management of skin cancer within other jurisdictions, as well as a provincial survey of skin cancer care practices, to identify care gaps. The systematic review did not identify any published comprehensive skin cancer management plans. The grey literature search revealed skin cancer plans in isolated regions of the United Kingdom (U.K.), National Institute for Health and Care Excellence (NICE) guidelines for skin cancer quality indicators and regional skin cancer biopsy clinics, and wait time guidelines in Australia and the U.K. With the input of the Ontario Cancer Advisory Committee (CAC), unique definitions for complex and non-complex skin cancers and the appropriate cancer services were created. A provincial survey of skin cancer care yielded 44 responses and demonstrated gaps in biopsy access. A skin cancer pathway map was created and a recommendation was made for regional skin cancer biopsy clinics. We have created unique definitions for complex and non-complex skin cancer and a skin cancer pathways map, which will allow for the implementation of both process and performance metrics to address identified gaps in care.

The effect of diagnostic assessment programs on the diagnosis and treatment of patients with lung cancer in Ontario, Canada.

INTRODUCTION: Diagnostic assessment programs (DAPs) were implemented in Ontario, Canada, to improve the efficiency of the lung cancer care continuum. We compared the efficiency and effectiveness of care provided to patients in DAPs relative to usual care (non-DAPs). METHODS: Lung cancer patients diagnosed between 2014 and 2016 were identified from the Ontario Cancer Registry. Using administrative databases, we identified various health-care encounters 6 months before diagnosis until the start of treatment and compared utilization patterns, timing, and overall survival between DAP and non-DAP patients. RESULTS: DAP patients were younger (P < 0.0001), had fewer comorbidities (P = 0.0006), and were more likely to have early-stage disease (36% vs. 25%) than non-DAP patients. Although DAP patients had a similar time until diagnosis as non-DAP patients, the time until treatment was 8.5 days shorter for DAP patients. DAP patients were more likely to receive diagnostic tests and specialist consultations and less likely to have duplicate chest imaging. DAP patients were more likely to receive brain imaging. Among early-stage lung cancers, brain imaging was high (74% for DAP and 67% for non-DAP), exceeding guideline recommendations. After adjustment for clinical and demographic factors, DAP patients had better overall survival than non-DAP patients (hazard ratio [HR]: 0.79 [0.76-0.82]), but this benefit was lost after adjusting for emergency presentation (HR: 0.96 [0.92-1.00]). A longer time until treatment was associated with better overall survival. CONCLUSION: DAPs provided earlier treatment and better access to care, potentially improving survival. Quality improvement opportunities include reducing unnecessary or duplicate testing and characterizing patients who are diagnosed emergently.

Incidence and real-world burden of brain metastases from solid tumors and hematologic malignancies in Ontario: a population-based study.

BACKGROUND: Although intracranial metastatic disease (IMD) is a frequent complication of cancer, most cancer registries do not capture these cases. Consequently, a data-gap exists, which thwarts system-level quality improvement efforts. The purpose of this investigation was to determine the real-world burden of IMD. METHODS: Patients diagnosed with a non-CNS cancer between 2010 and 2018 were identified from the Ontario Cancer Registry. IMD was identified by scanning hospital administrative databases for cranial irradiation or coding for a secondary brain malignancy (ICD-10 code C793). RESULTS: 25,478 of 601,678 (4.2%) patients with a diagnosis of primary cancer were found to have IMD. The median time from primary cancer diagnosis to IMD was 5.2 (0.7, 15.4) months and varied across disease sites, for example, 2.1 months for lung, 7.3 months for kidney, and 22.8 months for breast. Median survival following diagnosis with IMD was 3.7 months. Lung cancer accounted for 60% of all brain metastases, followed by breast cancer (11%) and melanoma (6%). More advanced stage at diagnosis and younger age were associated with a higher likelihood of developing IMD (P < .0001). IMD was also associated with triple-negative breast cancers and ductal histology (P < .001), and with small-cell histology in patients with lung cancer (P < .0001). The annual incidence of IMD was 3,520, translating to 24.2 per 100,000 persons. CONCLUSION: IMD represents a significant burden in patients with systemic cancers and is a significant cause of cancer mortality. Our findings support measures to actively capture incidents of brain metastasis in cancer registries.

A novel rat model of stable posttraumatic joint stiffness of the knee.

BACKGROUND: Animal models of posttraumatic joint stiffness (PTJS) are helpful in understanding underlying mechanisms, which is important for developing specific treatments and prophylactic therapies. Existing rat models of PTJS in the knee failed to show that the created contracture does not resolve through subsequent remobilization. Our objective was to establish a rat model of persisting PTJS of the knee and compare it to existing models. METHODS: Thirty skeletally immature male Sprague Dawley rats underwent surgical intervention with knee hyperextension, extracartilaginous femoral condyle defect, and Kirschner (K)-wire transfixation for 4 weeks with the knee joint in 146.7° ± 7.7° of flexion (n = 10 per group, groups I-III). After K-wire removal, group I underwent joint angle measurements and group II and group III were allowed for 4 or 8 weeks of free cage activity, respectively, before joint angles were measured. Eighteen rats (n = 6 per group, groups Ic-IIIc) served as untreated control. RESULTS: Arthrogenic contracture was largest in group I (55.2°). After 4 weeks of remobilization, the contracture decreased to 25.7° in group II (p < 0.05 vs. group I), whereas 8 weeks of remobilization did not reduce the contracture significantly (group III, 26.5°, p = 0.06 vs. group I). Between 4 and 8 weeks of remobilization, no increase in extension (26.5° in group III, p = 0.99 vs. group II) was observed. Interestingly, muscles did not contribute to the development of contracture. CONCLUSION: In our new rat model of PTJS of the knee joint, we were able to create a significant joint contracture with an immobilization time of only 4 weeks after trauma. Remobilization of up to 8 weeks alone did not result in full recovery of the range of motion. This model represents a powerful tool for further investigations on prevention and treatment of PTJS. Future studies of our group will use this new model to analyze medical treatment options for PTJS.

New insights into spinal cord ischaemia after thoracic aortic procedures: the importance of the number of anterior radiculomedullary arteries for surgical outcome.

OBJECTIVES: Anterior radiculomedullary arteries (ARMAs) link dorsal segmental arteries and the intraspinal compartment of the spinal collateral network. The number of thoracic ARMA is highly variable from one person to another. The impact of the number of ARMAs on spinal cord perfusion during thoracic aortic procedures is unknown. We investigated the influence of the number of thoracic ARMAs on spinal cord perfusion in an aortic surgical large animal model. METHODS: Twenty-six pigs were included (20 treatment animals, 6 sham animals, weight 34 ± 3 kg). The animals underwent ligation of the left subclavian artery and the thoracic segmental arteries via a left lateral thoracotomy with normothermia. After sacrifice, complete body perfusion with coloured cast resin was performed and the number of thoracic ARMAs was documented at autopsy. End points were spinal cord perfusion pressure, cerebrospinal fluid pressure, spinal cord blood flow (microspheres) and neurological outcome. Observation time was 3 h post-ligation. RESULTS: The numbers of thoracic ARMAs ranged between 3 (n = 1) and 13 (n = 1). The mean number was 8. Animals were grouped according to number of thoracic ARMA: 6-7 (5 animals), 8-10 (8 animals) and 11-13 (5 animals). A large number of thoracic ARMAs was linked to (i) a lower drop in spinal cord blood flow from baseline to post-clamp, (ii) the presence and increased magnitude of hyperaemia evident 3 h post-clamp (P < 0.001) and (iii) the presence of early hyperaemia starting immediately post-clamp in animals with 11 or more ARMA (P < 0.001). CONCLUSIONS: We showed that a large number of thoracic ARMA protects against spinal cord injury during descending aortic surgical procedures.1.

Spinal ischaemia after thoracic endovascular aortic repair with left subclavian artery sacrifice: is there a critical stent graft length?

OBJECTIVES: Thoracic endovascular aortic repair (TEVAR) is used for treatment of thoracic aortic pathologies, but the covered stent graft can induce spinal ischaemia depending on the length used. The left subclavian artery contributes to spinal cord collateralization and is frequently occluded by the stent graft. Our objective was to investigate the impact of covered stent graft length on the risk of spinal ischaemia in the setting of left subclavian artery sacrifice. METHODS: Twenty-six pigs (German country race, mean body weight 36 ± 4 kg) underwent simulated descending aortic TEVAR via left lateral thoracotomy, with left subclavian artery and thoracic segmental artery occlusion in normothermia. Animals were assigned to treatment groups according to simulated stent graft length: TEVAR to T8 (n = 4), TEVAR to T9 (n = 4), TEVAR to T10 (n = 4), TEVAR to T11 (n = 7) and TEVAR to T12 (n = 1) and a sham group (n = 6). End points included spinal cord perfusion pressure, cerebrospinal fluid pressure and spinal cord blood flow using fluorescent microspheres. RESULTS: There were no group differences in spinal cord perfusion pressure drop or in spinal cord perfusion pressure regeneration potential at 3 h after the procedure: from a baseline average of 75 mmHg (95% confidence interval 71-83 mmHg) to 73 mmHg (67-75 mmHg) at 3 h in Group T10 versus from a baseline average of 67 mmHg (95% CI 50-81 mmHg) to 65 mmHg (95% confidence interval 48-81 mmHg) in Group T8. There were no differences in the spinal cord blood flow courses over time in the different groups nor was there any difference in cerebrospinal fluid pressure levels and cerebrospinal fluid pressure dynamics between groups. However, we did observe local blood flow distribution to the spinal cord that was inhomogeneous depending on the distance between the simulated stent graft end and the first thoracic anterior radiculomedullary artery. CONCLUSIONS: The risk of spinal ischaemia after serial segmental artery occlusion does not depend on the distal extent of the aortic repair alone. Future attempts to allow patient risk stratification for spinal ischaemia need to focus on anterior radiculomedullary artery anatomy together with the extent of planned aortic repair.

Spinal Ischemia in Thoracic Aortic Procedures: Impact of Radiculomedullary Artery Distribution.

BACKGROUND: The aim of this study was to assess the influence of thoracic anterior radiculomedullary artery (tARMA) distribution on spinal cord perfusion in a thoracic aortic surgical model. METHODS: Twenty-six pigs (34 ± 3 kg; study group, n = 20; sham group, n = 6) underwent ligation of the left subclavian artery and thoracic segmental arteries. End points were spinal cord perfusion pressure (SCPP), regional spinal cord blood flow (SCBF), and neurologic outcome with an observation time of 3 hours. tARMA distribution patterns tested for an effect on end points included (1) maximum distance between any 2 tARMAs within the treated aortic segment (0 or 1 segment = small-distance group; >1 segment = large-distance group) and (2) distance between the end of the treated aortic segment and the first distal tARMA (at the level of the distal simulated stent-graft end = group 0; gap of 1 or more segments = group ≥1). RESULTS: The number of tARMA ranged from 3 to 13 (mean, 8). In the large-distance group, SCBF dropped from 0.48 ± 0.16 mL/g/min to 0.3 ± 0.08 mL/g/min (p < 0.001). We observed no detectable SCBF drop in the small-distance group: 0.2 ± 0.05 mL/g/min at baseline to 0.23 ± 0.05 mL/g/min immediately after clamping (p = 0.147). SCBF increased from 0.201 ± 0.055 mL/g/min at baseline to 0.443 ± 0.051 mL/g/min at 3 hours postoperatively (p < 0.001) only in the small-distance group. CONCLUSIONS: We demonstrate experimental data showing that distribution patterns of tARMAs correlate with the degree of SCBF drop and insufficient reactive parenchymal hyperemia in aortic procedures. Individual ARMA distribution patterns along the treated aortic segment could help us predict the individual risk of spinal ischemia.

Immediate Spinal Cord Collateral Blood Flow During Thoracic Aortic Procedures: The Role of Epidural Arcades.

The objective of this study was to investigate the functional differences between paraspinal and intraspinal compartments of the spinal collateral network and the importance of circular epidural arcades in thoracic aortic surgery. N = 33 pigs (mean body weight: 34 ± 3kg) were included. A single-inlet-model of spinal collateral flow was created: paraspinal inflow into the collateral network was isolated by cephalad and caudal interruption of inflow into epidural arcades using laminectomies. Animals were assigned to treatment groups (Treatment "open" [patent epidural arcades, n = 10] and Treatment "closed" [closed epidural arcades, n = 10]) and Sham groups (Sham "open" n = 8 and Sham "closed" n = 5). Treatment was a simulated Frozen Elephant Trunk procedure with occlusion of left subclavian and thoracic segmental arteries under mild permissive hypothermia. Observation time was 3 hours. Endpoints were motor and somatosensory evoked potentials (motor evoked potentials and sensory evoked potentials), spinal cord perfusion pressure, cerebrospinal fluid pressure, regional spinal cord blood flow, and neurologic outcome. Animals with interrupted inflow into epidural arcades (Group Treatment "closed") had higher cerebrospinal fluid pressure levels (P < 0.05), were not able to maintain sufficient spinal cord perfusion pressure during Frozen Elephant Trunk procedure (P < 0.001) and did not generate reactive hyperemia as did group Treatment "open." spinal cord blood flow was strongly decreased in group Treatment "closed" (P < 0.001) at 0 hour, did not recover out to 3 hours of observation and 90% of the animals suffered flaccid paraplegia (P < 0.05). Immediate spinal cord backup blood flow is almost exclusively delivered using the system of epidural arcades in the immediate setting, serving as an immediate backup system. Intraspinal arcades are responsible for generating sufficient intraspinal perfusion pressures, reactive hyperemia, and spinal cord integrity. Paraspinal collaterals might need to undergo arteriogenesis, and thus serve as a long-term backup system.

The Equilibration of PCO2 in Pigs Is Independent of Lung Injury and Hemodynamics.

OBJECTIVES: In mechanical ventilation, normoventilation in terms of PCO2 can be achieved by titration of the respiratory rate and/or tidal volume. Although a linear relationship has been found between changes in respiratory rate and resulting changes in end-tidal cO2 (△PetCO2) as well as between changes in respiratory rate and equilibration time (teq) for mechanically ventilated patients without lung injury, it is unclear whether a similar relationship holds for acute lung injury or altered hemodynamics. DESIGN: We performed a prospective randomized controlled animal study of the change in PetCO2 with changes in respiratory rate in a lung-healthy, lung-injury, lung-healthy + altered hemodynamics, and lung-injury + altered hemodynamics pig model. SETTING: University research laboratory. SUBJECTS: Twenty mechanically ventilated pigs. INTERVENTIONS: Moderate lung injury was induced by injection of oleic acid in 10 randomly assigned pigs, and after the first round of measurements, cardiac output was increased by approximately 30% by constant administration of noradrenalin in both groups. MEASUREMENTS AND MAIN RESULTS: We systematically increased and decreased changes in respiratory rate according to a set protocol: +2, -4, +6, -8, +10, -12, +14 breaths/min and awaited equilibration of Petco2. We found a linear relationship between changes in respiratory rate and △PetCO2 as well as between changes in respiratory rate and teq. A two-sample t test resulted in no significant differences between the lung injury and healthy control group before or after hemodynamic intervention. Furthermore, exponential extrapolation allowed prediction of the new PetCO2 equilibrium and teq after 5.7 ± 5.6 min. CONCLUSIONS: The transition between PetCO2 equilibria after changes in respiratory rate might not be dependent on moderate lung injury or cardiac output but on the metabolic production or capacity of cO2 stores. Linear relationships previously found for lung-healthy patients and early prediction of PetCO2 equilibration could therefore also be used for the titration of respiratory rate on the PetCO2 for a wider range of pathologies by the physician or an automated ventilation system.

Comparison of high-resolution X-ray and micro-CT for experimental evaluation of intracranial stent prototypes: quality evaluation beyond CE mark.

INTRODUCTION: As digital mammography and micro-computed tomography (CT) have been used for evaluation of stents deployed in experimental animal models, we compared the two methods regarding their sensitivity to detect abnormalities in three prototypes of intracranial stents. METHODS: Three different prototypes of intracranial stents (n = 84) were implanted in various animal models. Explanted stents were examined using digital mammography and micro-CT. The images were compared with respect to maintenance of material and form and the stents were compared to one another. Histological analysis was performed as well. RESULTS: In the open-cell stents, expansion of the stent cells was detected in the majority of cases (57.1 %) using micro-CT and less frequently using mammography (42.3 %). The closed-cell stent revealed kink stenoses in mammography as well as in micro-CT (3/7, 42.9 %). Detailed reconstructions of micro-CT images showed high-grade kink stenoses of the flow-diverter stent in two extremely curved vessels. Strut breaks were observed more frequently using micro-CT (6/84, 7.1 %) than by mammography (4/84, 4.8 %). Histology confirmed all changes of stent architecture. CONCLUSION: Significant changes of stent architecture can be observed and assessed even in the two-dimensional mammographic images. The use of micro-CT is recommended to detect subtle changes like single strut breaks and for three-dimensional information.

An oral CD3-specific antibody suppresses T-cell-induced colitis and alters cytokine responses to T-cell activation in mice.

BACKGROUND & AIMS: New therapeutic approaches are needed for inflammatory bowel diseases. A monoclonal antibody against CD3 (anti-CD3) suppresses T-cell-mediated autoimmune diseases such as experimental allergic encephalomyelitis. We explored the effects of anti-CD3 in mice with colitis. METHODS: Severe combined immunodeficient mice were given injections of CD4(+)CD45RB(high) T cells to induce colitis. Four weeks later, the mice were given 2 or 5 µg/day of anti-CD3 or hamster immunoglobulin (Ig)G (control), via gavage, for 5 or 10 days. The effect of oral anti-CD3 on cytokine responses was studied by activating T cells using intraperitoneal injections of anti-CD3 monoclonal antibody 2 days after oral administration of the antibody. We collected intestine samples for histology analysis and cells were analyzed by flow cytometry. Cytokines in sera were analyzed by cytometric bead array. RESULTS: Oral administration of anti-CD3 protected the mice from wasting disease and intestinal inflammation. Analyses of spleen and mesenteric lymph node cells showed no differences in total cell counts, or percentages of CD4(+) and forkhead box P3(+) regulatory T cells, between mice given anti-CD3 or the control immunoglobulin. Colitis therefore was not suppressed by induction of forkhead box P3(+) regulatory T cells, or depletion or limited expansion of T cells. Oral administration of anti-CD3 ameliorated the enteropathy induced by intraperitoneal injection of the antibody. In mice with enteropathy, oral anti-CD3 reduced levels of inflammatory cytokines such as interferon-γ, tumor necrosis factor-α, and interleukin (IL)-6; it also increased levels of the anti-inflammatory cytokines IL-10 and transforming growth factor-ß. The effects of oral anti-CD3 required IL-10. CONCLUSIONS: Oral administration of anti-CD3 to mice induces changes in the mucosal immune response that prevent colitis, independent of specific antigen, and reduce T-cell activation in an IL-10-dependent manner. Oral anti-CD3 therefore might be developed for the treatment of patients with inflammatory bowel disease.

Scaffold-based transplantation of akt1-overexpressing skeletal myoblasts: functional regeneration is associated with angiogenesis and reduced infarction size.

Myoblast-based therapy can improve cardiac function after infarction and is conventionally performed by direct injection. A scaffold-based transfer could overcome injection-associated problems. In upgrading this approach we transplanted skeletal myoblasts (SkM) overexpressing the prosurvival gene Akt1. SkM were transfected with pcDNA3-huda-Akt1 and seeded on polyurethane scaffolds. These scaffolds were transplanted in rats 2 weeks after myocardial infarction. Hemodynamics were analyzed before therapy and 6 weeks later. Infarction size and capillary density were performed thereafter. Additional groups received injections of Akt1-transfected or untransfected myoblasts, scaffolds seeded with untransfected myoblasts, or sham operation. Deterioration of global systolic left ventricular function could be inhibited by all therapeutic approaches. In addition, transplantation of Akt1-transfected cells, either scaffold-based or injected, was superior with regard to systolic properties of the left ventricular wall. This effect was accompanied by smaller infarction sizes and angiogenesis. Scaffolds with untransfected myoblasts yielded also smaller infarctions than injections of untransfected myoblasts. Both Akt groups profited with regard to dP/dt(min). In contrast, other diastolic parameters pointed at impaired relaxation and stiffer myocardium especially in the Akt1-scaffold group. In conclusion, SkM overexpressing Akt1 can maintain myocardial function after infarction, reduce infarction size, and induce neovascularization. Scaffold-based cell transfer does not augment this reverse remodeling capacity.