Framework for the Use of External Controls to Evaluate Treatment Outcomes in Precision Oncology Trials.

Advances in genomics have enabled anticancer therapies to be tailored to target specific genomic alterations. Single-arm trials (SATs), including those incorporated within umbrella, basket, and platform trials, are widely adopted when it is not feasible to conduct randomized controlled trials in rare biomarker-defined subpopulations. External controls (ECs), defined as control arm data derived outside the clinical trial, have gained renewed interest as a strategy to supplement evidence generated from SATs to allow comparative analysis. There are increasing examples demonstrating the application of EC in precision oncology trials. The prospective application of EC in conducting comparative studies is associated with distinct methodological challenges, the specific considerations for EC use in biomarker-defined subpopulations have not been adequately discussed, and a formal framework is yet to be established. In this review, we present a framework for conducting a prospective comparative analysis using EC. Key steps are (1) defining the purpose of using EC to address the study question, (2) determining if the external data are fit for purpose, (3) developing a transparent study protocol and a statistical analysis plan, and (iv) interpreting results and drawing conclusions on the basis of a prespecified hypothesis. We specify the considerations required for the biomarker-defined subpopulations, which include (1) specifying the comparator and biomarker status of the comparator group, (2) defining lines of treatment, (3) assessment of the biomarker testing panels used, and (4) assessment of cohort stratification in tumor-agnostic studies. We further discuss novel clinical trial designs and statistical techniques leveraging EC to propose future directions to advance evidence generation and facilitate drug development in precision oncology.

Recursive Partitioning to Determine Order of Significance of Regional Metastasis Characteristics in Head and Neck Cutaneous Squamous Cell Carcinoma.

BACKGROUND: The order of significance of clinicopathologic characteristics for the prognosis of patients with regional metastases from head and neck cutaneous squamous cell carcinoma (HNcSCC) is not well characterized. This study aimed to understand the impact of the known characteristics, including the presence of immunosuppression, number of deposits, largest deposit size, location and laterality of deposits, and presence of extranodal extension (ENE) on overall survival (OS) and disease-specific survival (DSS). METHODS: A retrospective study of 366 patients treated with curative intent for HNcSCC with regional metastatic disease was undertaken using recursive partitioning analysis (RPA). RESULTS: Using RPA modeling, the study determined that number of metastatic deposits carried the highest impact for both OS and DSS, followed by largest deposit size. The presence of ENE and immunosuppression was less significant. CONCLUSIONS: The results from this study provide new evidence for identifying and stratifying high-risk patients with metastatic HNcSCC. This information will be valuable in determining future HNcSCC staging systems.

High-dose chemotherapy for relapsed germ cell tumours: outcomes in low-volume specialized centres.

OBJECTIVE: To report treatment patterns and survival outcomes of patients with relapsed and refractory metastatic germ cell tumours (GCTs) treated with high-dose chemotherapy (HDCT) and autologous stem-cell transplantation in low-volume specialized centres within the widely dispersed populations of Australia and New Zealand between 1999 and 2019. PATIENTS AND METHODS: We conducted a retrospective analysis of 111 patients across 13 institutions. Patients were identified from the Australasian Bone Marrow Transplant Recipient Registry. We reviewed treatment regimens, survival outcomes, deliverability and toxicities. Primary endpoints included overall (OS) and progression-free survival (PFS). Cox proportional hazards models were used to test the association of survival outcomes with patient and treatment factors. RESULTS: The median (range) age was 30 (14-68) years and GCT histology was non-seminomatous in 84% of patients. International Prognostic Factors Study Group (IPFSG) prognostic risk category was very low/low, intermediate, high and very high in 18%, 36%, 25% and 21% of patients, respectively. Salvage conventional-dose chemotherapy (CDCT) was administered prior to HDCT in 59% of patients. Regimens included paclitaxel, ifosfamide, carboplatin and etoposide (50%), carboplatin and etoposide (CE; 28%), carboplatin, etoposide and ifosfamide (CEI; 6%), carboplatin, etoposide and cyclophosphamide (CEC; 5%), CEC-paclitaxel (6%) and other (5%). With a median follow-up of 4.4 years, the 1-, 2- and 5-year PFS rates were 62%, 57% and 52%, respectively, and OS rates were 73%, 65% and 61%, respectively. There were five treatment-related deaths. Progression on treatment occurred in 17%. In a univariable analysis, worse International Germ Cell Cancer Collaborative Group (IGCCCG) and IPFSG prognostic groups were associated with inferior survival outcomes. An association of inferior survival was not found with the number of high-dose cycles received nor when HDCT was delivered after salvage CDCT. CONCLUSION: This large dual-national registry-based study reinforces the efficacy and deliverability of HDCT for relapsed and refractory metastatic GCT in low-volume specialized centres in Australia and New Zealand, with survival outcomes comparable to those found in international practice.

Remodeling of the Feeding Arterial System After Surgery for Resection of Brain Arteriovenous Malformations: An Observational Study.

BACKGROUND: Avoiding the risk of postoperative hemorrhage after brain arteriovenous malformation (AVM) resection involves aggressive blood pressure control. Remodeling of the feeding arterial system is critical in reducing this risk. OBJECTIVE: To investigate factors predicting time to return to normal on digital subtraction angiography (DSA) after AVM resection. METHODS: For AVM in which the largest feeding artery (FA) on DSA was in the anterior circulation, the preoperative and postoperative diameter of the FA were compared with the diameter of the internal carotid artery (IC) immediately proximal to the posterior communicating artery. The preoperative FA/IC ratio (FA/IC preAVM) was compared with the first postoperative FA/IC ratio (FA/IC postAVM). Normal FA/IC ratio (FA/IC normal) was established from matched arteries in the contralateral hemisphere to the AVM. RESULTS: Eighty-six patients were analyzed for postoperative DSA performed a median 4 d after resection. From the interval-censored proportional hazards regression analysis, FA/IC preAVM (hazard ratio of 0.0006; 95% confidence interval: 0.00-0.21; P = .013) and maximum AVM diameter (hazard ratio of 0.47; 95% confidence interval: 0.23-0.95; P = .036) were significant in time to return to normal. These 2 factors were poorly correlated with each other (r = 0.41). AVMs with FA/IC preAVMs <0.57 combined with a diameter <3.0 cm normalize within 7 d in more than 50% of cases. Any other combination of ratio and size has fewer than 20% normalizing within 7 d (log rank P < .001). CONCLUSION: FA/IC preAVM and AVM size are both important in predicting the time taken for return to normal feeding arterial system on DSA after AVM resection.

Comparing outcome scales for unruptured intracranial aneurysms: A prospective cohort study.

Outcomes on the modified Rankin Scale (mRS) are commonly used to guide and evaluate the management of unruptured intracranial aneurysms (uIA). However, the mRS is unlikely to measure all the relevant aspects of the clinical health of a patient. The current study therefore investigated the relationship between the mRS and additional measures of outcome. Between January 2011 and January 2016 patients with a new diagnosis of uIA were prospectively examined at referral and 12-month follow-up. Assessment included the Physical and Mental Component Scores of the Short Form 36 (SF-36), the computerized driver screening instrument DriveSafe (DS), and the mRS. Minimally Important Change (MIC) for each outcome measure was used to identify adverse outcomes for individual patients. A total of 128 patients (98 surgery; 30 untreated) completed the minimal dataset for analysis. In the surgical group, 6% (95% CI 3-14%) experienced morbidity at 12-months, as defined by the MIC for mRS. This risk rate increased to 51% (95% CI 41-61%) when defined as an MIC on any outcome. A combined MIC also identified a downgrade in outcomes, not detectable on the mRS, in 42% (95% CI 26-61%) of untreated patients. Correlation and regression analyses were unable to identify any significant relationships between the different outcomes instruments. In sum, there were considerably more adverse outcomes reported by quality of life (SF-36) and functional (DS) instruments than by the mRS for either treated or untreated uIA. To obtain a more complete representation of patient outcomes requires administration of a multi-dimensional assessment.

The role of embolization before surgery for Spetzler-Ponce Class B and C brain AVMs: a prospective cohort series.

BACKGROUND: There is uncertainty of the benefit of preoperative embolization for Spetzler-Ponce Class (SPC) B and C arteriovenous malformations of the brain (bAVM). We examined whether or not preoperative embolization reduces the risk of permanent neurological deficits in SPC B and C bAVM surgery. METHODS: A prospective bAVM database (between1989 and 2015) was analyzed by regression for factors associated with a new permanent neurological deficit arising as a consequence of surgery or preoperative embolization with a modified Rankin Scale (mRS) score >1 at 12 months after surgery (adverse outcome). RESULTS: From a cohort of 785 patients with bAVM, 277 patients with SPC B or C bAVM were planned for treatment by surgery with (N.=67) or without (N.=210) preoperative embolization. There were significant differences (embolization versus no embolization) in: permanent neurological deficits leading to a mRS>1 (45% versus 20%, P<0.01); permanent neurological deficits leading to a mRS>2 (22% versus 8.1%, P=0.04); perioperative transfusion of 2.5 liters of blood or more (31% versus 16%, P<0.01); and, delayed postoperative hemorrhage (19% versus 8.1%, P=0.01). Regression analysis identified the following factors to be associated with increased likelihood of an adverse outcome: infratentorial location (odds ratio 0.441, P=0.045); SPC C bAVM (OR=0.501, P=0.034); earlier rank order of surgery (OR=0.994, P<0.01); and, preoperative embolization (OR=0.313, P<0.01). CONCLUSIONS: The use of preoperative embolization does not reduce adverse outcomes in SPC B and C bAVM. The role of embolization in the preoperative management of complex bAVM by surgery deserves further study.

The Risk of Seizure Following Surgery for Brain Arteriovenous Malformation: A Prospective Cohort Study.

BACKGROUND: The evidence for the risk of seizures following surgery for brain arteriovenous malformations (bAVM) is limited. OBJECTIVE: To determine the risk of seizures after discharge from surgery for supratentorial bAVM. METHODS: A prospectively collected cohort database of 559 supratentorial bAVM patients (excluding patients where surgery was not performed with the primary intention of treating the bAVM) was analyzed. Cox proportional hazards regression models (Cox regression) were generated assessing risk factors, a Receiver Operator Characteristic curve was generated to identify a cut-point for size and Kaplan-Meier life table curves created to identify the cumulative freedom from postoperative seizure. RESULTS: Preoperative histories of more than 2 seizures and increasing maximum diameter (size, cm) of bAVM were found to be significantly (P < .01) associated with the development of postoperative seizures and remained significant in the Cox regression (size as continuous variable: P = .01; hazard ratio: 1.2; 95% confidence interval: 1.0-1.3; more than 2 seizures: P = .02; hazard ratio: 2.1; 95% confidence interval: 1.1-3.8). The cumulative risk of first seizure after discharge from hospital following resection surgery for all patients with bAVM was 5.8% and 18% at 12 mo and 7 yr, respectively. The 7-yr risk of developing postoperative seizures ranged from 11% for patients with bAVM ≤4 cm and with 0 to 2 preoperative seizures, to 59% for patients with bAVM >4 cm and with >2 preoperative. CONCLUSION: The risk of seizures after discharge from hospital following surgery for bAVM increases with the maximum diameter of the bAVM and a patient history of more than 2 preoperative seizures.

Deliberate employment of postoperative hypotension for brain arteriovenous malformation surgery and the incidence of delayed postoperative hemorrhage: a prospective cohort study.

OBJECTIVE The aim of this study was to examine the impact of deliberate employment of postoperative hypotension on delayed postoperative hemorrhage (DPH) for all Spetzler-Ponce Class (SPC) C brain arteriovenous malformations (bAVMs) and SPC B bAVMs ≥ 3.5 cm in diameter (SPC B 3.5+). METHODS A protocol of deliberate employment of postoperative hypotension was introduced in June 1997 for all SPC C and SPC B 3.5+ bAVMs. The aim was to achieve a maximum mean arterial blood pressure (BP) ≤ 70 mm Hg (with cerebral perfusion pressure > 50 mm Hg) for a minimum of 7 days after resection of bAVMs (BP protocol). The authors compared patients who experienced DPH (defined as brain hemorrhage into the resection bed that resulted in a new neurological deficit or that resulted in reoperation during the hospitalization for microsurgical bAVM resection) between 2 periods (prior to adopting the BP protocol and after introduction of the BP protocol) and 4 bAVM categories (SPC A, SPC B 3.5- [that is, SPC B < 3.5 cm maximum diameter], SPC B 3.5+, and SPC C). Patients excluded from treatment by the BP protocol were managed in the intensive care unit to avoid moderate hypertensive episodes. The pooled cases of all bAVM treated by surgery were analyzed to identify characteristics associated with the risk of DPH. These identified characteristics were then examined by multiple logistic regression analysis in both SPC B 3.5+ and SPC C cases. RESULTS From a cohort of 641 bAVMs treated by microsurgery, 32 patients with DPH were identified. Of those, 66% (95% CI 48-80) had a permanent new neurological deficit with a modified Rankin Scale score of 2-6. This included a mortality rate of 13% (95% CI 4.4-29). The BP protocol was used to treat 162 patients with either SPC B 3.5+ or SPC C. For SPC B 3.5+, there was no significant reduction in DPH with the introduction of the BP protocol (p = 0.77). For SPC C, there was a significant (p = 0.035) reduction of DPH from 29% (95% CI 13%-53%) to 8.2% (95% CI 3.2%-18%) associated with the introduction of the BP protocol. Multiple logistic regression analysis found that the absence of the BP protocol (p = 0.011, odds ratio 7.5, 95% CI 1.6-36) remained significant for the development of DPH in patients with SPC C bAVMs. CONCLUSIONS Treating patients with SPC C bAVMs with a protocol that lowers BP immediately after resection seems to reduce the risk of DPH. For SPC A and SPC B 3.5- bAVMs, there is unlikely to be a need to do more than avoid postoperative hypertension. For SPC B 3.5+ bAVMs, a larger number of patients would be required to test the absence of benefit of the BP protocol.

Microsurgery for Spetzler-Ponce Class A and B arteriovenous malformations utilizing an outcome score adopted from Gamma Knife radiosurgery: a prospective cohort study.

OBJECTIVE The purpose of this study was to adapt and apply the extended definition of favorable outcome established for Gamma Knife radiosurgery (GKRS) to surgery for brain arteriovenous malformations (bAVMs). The aim was to derive both an error around the point estimate and a model incorporating angioarchitectural features in order to facilitate comparison among different treatments. METHODS A prospective microsurgical cohort was analyzed. This cohort included patients undergoing embolization who did not proceed to microsurgery and patients denied surgery because of perceived risk of treatment. Data on bAVM residual and recurrence during long-term follow-up as well as complications of surgery and preoperative embolization were analyzed. Patients with Spetzler-Ponce Class C bAVMs were excluded because of extreme selection bias. First, patients with a favorable outcome were identified for both Class A and Class B lesions. Patients were considered to have a favorable outcome if they were free of bAVM recurrence or residual at last follow-up, with no complication of surgery or preoperative embolization, and a modified Rankin Scale score of more than 1 at 12 months after treatment. Patients who were denied surgery because of perceived risk, but would otherwise have been candidates for surgery, were included as not having a favorable outcome. Second, the authors analyzed favorable outcome from microsurgery by means of regression analysis, using as predictors characteristics previously identified to be associated with complications. Third, they created a prediction model of favorable outcome for microsurgery dependent upon angioarchitectural variables derived from the regression analysis. RESULTS From a cohort of 675 patients who were either treated or denied surgery because of perceived risk of surgery, 562 had Spetzler-Ponce Class A or B bAVMs and were included in the analysis. Logistic regression for favorable outcome found decreasing maximum diameter (continuous, OR 0.62, 95% CI 0.51-0.76), the absence of eloquent location (OR 0.23, 95% CI 0.12-0.43), and the absence of deep venous drainage (OR 0.19, 95% CI 0.10-0.36) to be significant predictors of favorable outcome. These variables are in agreement with previous analyses of microsurgery leading to complications, and the findings support the use of favorable outcome for microsurgery. The model developed for angioarchitectural features predicts a range of favorable outcome at 8 years following microsurgery for Class A bAVMs to be 88%-99%. The same model for Class B bAVMs predicts a range of favorable outcome of 62%-90%. CONCLUSIONS Favorable outcome, derived from GKRS, can be successfully used for microsurgical cohort series to assist in treatment recommendations. A favorable outcome can be achieved by microsurgery in at least 90% of cases at 8 years following microsurgery for patients with bAVMs smaller than 2.5 cm in maximum diameter and, in the absence of either deep venous drainage or eloquent location, patients with Spetzler-Ponce Class A bAVMs of all diameters. For patients with Class B bAVMs, this rate of favorable outcome can only be approached for lesions with a maximum diameter just above 6 cm or smaller and without deep venous drainage or eloquent location.

The Risk of Seizure After Surgery for Unruptured Intracranial Aneurysms: A Prospective Cohort Study.

BACKGROUND: We aimed to identify a group of patients with a low risk of seizure after surgery for unruptured intracranial aneurysms (UIA). OBJECTIVE: To determine the risk of seizure after discharge from surgery for UIA. METHODS: A consecutive prospectively collected cohort database was interrogated for all surgical UIA cases. There were 726 cases of UIA (excluding cases proximal to the superior cerebellar artery on the vertebrobasilar system) identified and analyzed. Cox proportional hazards regression models and Kaplan-Meier life table analyses were generated assessing risk factors. RESULTS: Preoperative seizure history and complication of aneurysm repair were the only risk factors found to be significant. The risk of first seizure after discharge from hospital following surgery for patients with neither preoperative seizure, treated middle cerebral artery aneurysm, nor postoperative complications (leading to a modified Rankin Scale score >1) was <0.1% and 1.1% at 12 months and 7 years, respectively. The risk for those with preoperative seizures was 17.3% and 66% at 12 months and 7 years, respectively. The risk for seizures with either complications (leading to a modified Rankin Scale score >1) from surgery or treated middle cerebral artery aneurysm was 1.4% and 6.8% at 12 months and 7 years, respectively. These differences in the 3 Kaplan-Meier curves were significant (log-rank P < .001). CONCLUSION: The risk of seizures after discharge from hospital following surgery for UIA is very low when there is no preexisting history of seizures. If this result can be supported by other series, guidelines that restrict returning to driving because of the risk of postoperative seizures should be reconsidered. ABBREVIATIONS: MCA, middle cerebral arterymRS, modified Rankin ScaleUIA, unruptured intracranial aneurysms.

Complication-Effectiveness Analysis for Brain Arteriovenous Malformation Surgery: A Prospective Cohort Study.

BACKGROUND: Intervention for brain arteriovenous malformations (bAVMs) should aim at treatment that is safe and effective. OBJECTIVE: To analyze a prospective database to derive the probability of neurological deficit and adjust this risk for effectively treated bAVMs (complication-effectiveness analysis [CEA]). METHODS: First, we calculated the percentage of surgical complications leading to a modified Rankin Scale >1 at 12 months after surgery for each Spetzler-Ponce class (SPC). Second, we performed a sensitivity analysis of these results by including bAVMs not undergoing surgery, to correct for bias. Third, we established the long-term cumulative incidence of freedom from recurrence from Kaplan-Meier analysis. Finally, we combined the results to calculate the risk of surgery per effective treatment in a complication-effectiveness analysis. RESULTS: Seven hundred seventy-nine patients underwent 641 microsurgical resections. Complications of surgery leading to a modified Rankin Scale >1 at 12 months occurred in 1.4% (95% confidence interval [CI]: 0.5-3.3), 20% (95% CI: 15-26), and 41% (95% CI: 30-52) of SPC A, SPC B, and SPC C, respectively. The cumulative 9-year freedom from recurrence was 97% for SPC A and 92% for other bAVMs. The 9-year CEA risk was 1.4% (credible range: 0.5%-3.4%) for SPC A, 22% to 24% (credible range: 16%-31%) for SPC B, and 45% to 63% (credible range: 33%-73%) for SPC C bAVM. CONCLUSION: CEA presents the treatment outcome in the context of efficacy and provides a basis for comparing outcomes from techniques with different times to elimination of the bAVM. ABBREVIATIONS: bAVM, brain arteriovenous malformationCEA, complication-effectiveness analysisCI, confidence intervalCTA, computerized tomographic angiographyDSA, digital subtraction angiographyMRA, magnetic resonance angiographymRS, modified Rankin ScaleSMG, Spetzler-Martin gradeSPC, Spetzler-Ponce class.

Complication-Effectiveness Analysis for Unruptured Intracranial Aneurysm Surgery: A Prospective Cohort Study.

BACKGROUND: The aim of intervention for unruptured intracranial aneurysms (UIAs) is safe, effective treatment. OBJECTIVE: To analyze a prospective database for variables influencing the risk of surgery to produce a risk model adjusting this risk for effectively treated aneurysms. METHODS: First, we identified variables to create a model from multiple logistic regression for complications of surgery leading to a 12-month modified Rankin Scale score >1. Second, we established the long-term cumulative incidence of freedom from retreatment or rupture (treated aneurysm) from Kaplan-Meier analysis. Third, we combined these analyses to establish a model of risk of surgery per effective treatment. RESULTS: One thousand twelve patients with 1440 UIA underwent 1080 craniotomies. We found that 10.1% (95% confidence interval [CI], 8.4-12.0) of craniotomies resulted in a complication leading to a modified Rankin Scale score >1 at 12 months. Logistic regression found age (odds ratio, 1.04; 95% CI, 1.02-1.06), size (odds ratio, 1.12; 95% CI, 1.09-1.15), and posterior circulation location (odds ratio, 2.95; 95% CI, 1.82-4.78) to be significant. Cumulative 10-year risk of retreatment or rupture was 3.0% (95% CI, 1.3-7.0). The complication-effectiveness model was derived by dividing the complication risk by the 10-year cumulative freedom from retreatment or rupture proportion. Risk per effective treatment ranged from 1% for a 5-mm anterior circulation UIA in a 20-year-old patient to 70% for a giant posterior circulation UIA in a 70-year-old patient. CONCLUSION: Complication-effectiveness analyses increase the information available with regard to outcome for the management of UIAs.

Validity of European position paper on rhinosinusitis disease control assessment and modifications in chronic rhinosinusitis.

OBJECTIVES: To develop a chronic rhinosinusitis (CRS) disease control staging system that predicts patient and physician opinion. This involved exploring the predictive capacity of the proposed European Position Paper on Rhinosinusitis (EPOS) 2012 staging system and other potential scoring systems based on patient symptoms and objective criteria. STUDY DESIGN: Prospective study. SETTING: Tertiary hospitals. SUBJECTS AND METHODS: Adults CRS patients undergoing sinus surgery were prospectively enrolled from a tertiary clinic. The Sino-Nasal Outcome Test 22, endoscopy score, and systemic medication were recorded at 6 and 12 months. A physician and patient report of their condition as either "controlled,""partly controlled," or "uncontrolled" was also recorded. Ordinal regression was used for modeling a staging system. The EPOS criteria and various combinations were assessed. Kappa agreements between the staging systems and patient/physician reports were analyzed. RESULTS: One hundred six patients were assessed. Nasal obstruction (P = .02), endoscopic mucosal inflammation (P < .001), and thick and/or purulent discharge (P = .01) associated with progress reports. A modified staging system of Nasal Obstruction, Systemic medication used, and Endoscopic inflammation (NOSE) was selected on predictive strengths. The EPOS and NOSE had significant agreement with physician's (k = 0.29, P < .01, and k = 0.45, P < .01) and patient's report (k = 0.18, P = .01, and k = 0.32, P < .01). CONCLUSIONS: The disease control assessment by EPOS has slight agreement with patients and a physician. A simpler NOSE system using nasal obstruction, mucosa, and discharge is proposed.

Influence of the combination of patient age and deep venous drainage on brain arteriovenous malformation recurrence after surgery.

OBJECT: Case reports suggest that young age is a critical factor in determining recurrence of brain arteriovenous malformations (AVMs) after surgery. However, other factors that may contribute to the increased risk of recurrence have not been considered. In this study, the authors' goal was to ascertain the risk and risk factors of recurrence after resection of AVMs of the brain. METHODS: A consecutive case series (prospectively collected data) of 600 cases of resection of brain AVMs was retrospectively analyzed. Radiological evidence of recurrence or nonrecurrence, as well as clinical evidence of recurrence, could be established in 427 of these cases that underwent follow-up for more than 350 days after initial surgery. These cases were analyzed using Kaplan-Meier curves and Cox regression with respect to age and the presence of deep venous drainage. RESULTS: Nine recurrent AVMs were found in 8 patients. By analysis of the Kaplan-Meier curves, the 10-year recurrence rate was 14% for those with deep venous drainage, compared with 4% for those without deep venous drainage. Stratifying by age, in the 0- to 20-year age group, the 10-year recurrence rates were 63% and 13% for those with and without deep venous drainage, respectively. In the 20- to 39-year age group, the rates were 5% and 0% respectively, and in the 40-year and older age group they were 0% and 3%, respectively. The hazard ratio for deep venous drainage, adjusted for age, was 5.97 (95% CI 1.20-29.69, p = 0.029). CONCLUSIONS: The risk of recurrence after AVM resection is significant for young patients with deep venous drainage.

A modelling approach for blood units transfused after stem cell transplantation.

Patients undergoing stem cell transplantation may require transfusion of units (bags) of packed red blood cells (PRBCs). Modelling of PRBC usage is important not only for prediction of transfusion requirements in future patients but also for its use as an inverse surrogate for engraftment, that is transplantation success. Inspection of PRBC unit usage reveals a strong preference for even numbers, which is caused by behavioural preference on the part of prescribing physicians. Digit preference is a phenomenon observed more commonly with self-reported data: typically survey respondents round recalled quantities such as the age at which a life event occurred to multiples of 5 or 10. In all cases, we can conceive of a latent variable, which has a smooth distribution, which is transformed via stochastic rules to a discrete variable with probability spikes at preferred digits. We propose a modelling framework based on a latent variable specification and stochastic transformation to the spiked distribution. Loglinear models for the mean of the process are implemented. Specification of the stochastic rules is important to success in accurate modelling of the process.

Multilevel latent variable models for global health-related quality of life assessment.

Quality of life (QOL) assessment is a key component of many clinical studies and frequently requires the use of single global summary measures that capture the overall balance of findings from a potentially wide-ranging assessment of QOL issues. We propose and evaluate an irregular multilevel latent variable model suitable for use as a global summary tool for health-related QOL assessments. The proposed model is a multiple indicator and multiple cause style of model with a two-level latent variable structure. We approach the modeling from a general multilevel modeling perspective, using a combination of random and nonrandom cluster types to accommodate the mixture of issues commonly evaluated in health-related QOL assessments--overall perceptions of QOL and health, along with specific psychological, physical, social, and functional issues. Using clinical trial data, we evaluate the merits and application of this approach in detail, both for mean global QOL and for change from baseline. We show that the proposed model generally performs well in comparing global patterns of treatment effect and provides more precise and reliable estimates than several common alternatives such as selecting from or averaging observed global item measures. A variety of computational methods could be used for estimation. We derived a closed-form expression for the marginal likelihood that can be used to obtain maximum likelihood parameter estimates when normality assumptions are reasonable. Our approach is useful for QOL evaluations aimed at pharmacoeconomic or individual clinical decision making and in obtaining summary QOL measures for use in quality-adjusted survival analyses.

Relationship of CD34+ cells infused and red blood cell transfusion requirements after autologous peripheral blood stem cell transplants: a novel method of analysis.

BACKGROUND: CD34+ cells infused predicts myeloid and platelet engraftment at the time of autologous stem cell transplantation. An association between the number of CD34+ cells infused and erythroid engraftment has yet to be established. STUDY DESIGN AND METHODS: Red blood cells transfused after autologous transplantation were compared with the number of CD34+ cells infused. Myeloid engraftment was assessed to confirm that normal engraftment kinetics occurred. RESULTS: Logistic regression established that the logarithm of the number of CD34+ cells infused (p = 0.0498) and admission hemoglobin (Hb; p < 0.001) predicted the need for transfusion. In those patients who required transfusion, standard regression methods were not valid. A novel model demonstrated that the initial Hb (p < 0.001) and diagnosis (p = 0.047) were significant predictors of transfusion requirements in patients needing transfusion. However, the number of CD34+ cells infused did not predict transfusion requirements in this group (p = 0.226). As myeloid engraftment demonstrated kinetics that have been previously described, it can be inferred that erythroid engraftment was not atypical. CONCLUSION: The number of CD34+ cells infused predicted the need for transfusion, although it did not predict the number of RBCs transfused in those patients having transfusion during their admission for autologous stem cell transplant.

Ordinal regression models for continuous scales.

Ordinal regression analysis is a convenient tool for analyzing ordinal response variables in the presence of covariates. In this paper we extend this methodology to the case of continuous self-rating scales such as the Visual Analog Scale (VAS) used in pain assessment, or the Linear Analog Self-Assessment (LASA) scales in quality of life studies. These scales measure subjects' perception of an intangible quantity, and cannot be handled as ratio variables because of their inherent nonlinearity. We express the likelihood in terms of a function connecting the scale with an underlying continuous latent variable and approximate this function either parametrically or non-parametrically. Then a general semi-parametric regression framework for continuous scales is developed. Two data sets have been analyzed to compare our method to the standard discrete ordinal regression model, and the parametric to the non-parametric versions of the model. The first data set uses VAS data from a study on the efficacy of low-level laser therapy in the treatment of chronic neck pain; the second comes from a study on chemotherapy treatments in advanced breast cancer and looks at the impact of different drugs on patients' quality of life. The continuous formulation of the ordinal regression model has the advantage of no loss of precision due to categorization of the scores and no arbitrary choice of the number and boundaries of categories. The semi-parametric form of the model makes it a flexible method for analysis of continuous ordinal scales.

Hormone replacement therapy after a diagnosis of breast cancer: cancer recurrence and mortality.

OBJECTIVE: To determine whether hormone replacement therapy (HRT) after treatment for breast cancer is associated with increased risk of recurrence and mortality. DESIGN: Retrospective observational study. PARTICIPANTS AND SETTING: Postmenopausal women diagnosed with breast cancer and treated by five Sydney doctors between 1964 and 1999. OUTCOME MEASURES: Times from diagnosis to cancer recurrence or new breast cancer, to death from all causes and to death from primary tumour were compared between women who used HRT for menopausal symptoms after diagnosis and those who did not. Relative risks (RRs) were determined from Cox regression analyses, adjusted for patient and tumour characteristics. RESULTS: 1122 women were followed up for 0-36 years (median, 6.08 years); 154 were lost to follow-up. 286 women used HRT for menopausal symptoms for up to 26 years (median, 1.75 years). Compared with non-users, HRT users had reduced risk of cancer recurrence (adjusted relative risk [RR], 0.62; 95% CI, 0.43-0.87), all-cause mortality (RR, 0.34; 95% CI, 0.19-0.59) and death from primary tumour (RR, 0.40; 95% CI, 0.22-0.72). Continuous combined HRT was associated with a reduced risk of death from primary tumour (RR, 0.32; 95% CI, 0.12-0.88) and all-cause mortality (RR, 0.27; 95% CI, 0.10-0.73). CONCLUSION: HRT use for menopausal symptoms by women treated for primary invasive breast cancer is not associated with an increased risk of breast cancer recurrence or shortened life expectancy.