Inclusion Of Such Patients Research Articles

Colorectal Cancer Screening and Surveillance in the Geriatric Population.

Our national guidelines regarding screening and surveillance for colorectal cancer recommend individualized discussions with patients 75-85 years of age. This review explores the complex decision-making that surrounds these discussions. Despite updated guidelines for colorectal cancer screening and surveillance, the guidance for patients 75 years of age or older remains unchanged. Studies exploring the risks to colonoscopy in this population, patient preferences, life expectancy calculators and additional studies in the subpopulation of inflammatory bowel disease patients provide points of consideration to aid in individualized discussions. The benefit-risk discussion for colorectal cancer screening in patients over 75 years old warrants further guidance to develop best practice. To craft more comprehensive recommendations, additional research with inclusion of such patients is needed.

Translational modeling for patients with RAS mutant tumors: Profiling the dual-MEK inhibitor IMM-1-104 in a humanized 3D assay.

e15084 Background: Elevated RAS-RAF-MEK-ERK (MAPK pathway) signaling is observed in over half of all solid human tumors, and mutations in RAS or RAF account for a large fraction. Given MEK’s unique position in the MAPK cascade, it remains an attractive target in cancer. However, FDA-registered MEK inhibitors are susceptible to pathway reactivation events that limit their use to RAF mutant disease and cause on-target toxicities stemming from chronic target engagement. IMM-1-104 is a novel, allosteric dual-MEK inhibitor designed for better applicability to RAS mutant tumors by preventing MEK reactivation. Endowed with a short plasma half-life, IMM-1-104 promotes deep cyclic inhibition with a near-zero drug trough, affording normal cells a chance to recover between doses. Methods: We characterized IMM-1-104’s pharmacologic activity across 52 tumor cell lines that spanned 11 distinct tumor types in a humanized, ECM-based 3D tumor growth assay (3D-TGA). The 3D-TGA has better predicted in vivo tumor responses versus 2D culture and more accurately reflects human tumor biology. Tumor models were categorized based on in vivo drug PK limits as sensitive to IMM-1-104 (EC50 < 1uM), intermediate (1uM≤EC50≤10uM and ≥25% inhibition at 10uM) or resistant otherwise. Models were evaluated by whole exome sequencing, along with RNA sequencing in the 3D context, to profile determinants of sensitivity and resistance and to prioritize patient populations most likely to respond to IMM-1-104. Results: Models sensitive to IMM-1-104 were enriched for MAPK driver mutations, consistent with pathway addiction. We reasoned that activation of parallel compensatory pathways that can reduce reliance on MAPK signaling may increase the likelihood of resistance to IMM-1-104. Pathways and genes suspected of contributing to resistance helped refine signatures based on 3D-TGA outcome data. Models with a MAPK driver mutation and compensatory mutations such as PIK3CA or PTEN deletion were more likely to show intermediate response than those with a greater addiction to MAPK drivers. Models lacking a clear MAPK driver mutation but harboring other putative resistance alterations were more likely to be resistant in the 3D-TGA. Conclusions: To better understand the relevance of tumor model responses in the 3D-TGA relative to RAS mutant patient populations, we computationally compared tumor model data to patient somatic alterations, identified in the public resource GENIE, which has cataloged the molecular profiles of over 100,000 cancer patients. Based on model-to-patient molecular mapping, we identified biomarker-defined subsets of sensitive KRAS mutant lung and colorectal models. The most broadly sensitive patient-aligned models in the 3D assay were KRAS mutant pancreatic cancer and NRAS mutant melanoma patients, supporting the inclusion of such patients in planned clinical studies of IMM-1-104.

COVID-19 Vaccination Imperatives in People on Maintenance Dialysis: An International Perspective.

COVID-19 Vaccination Imperatives in People on Maintenance Dialysis: An International Perspective.

Exclusion of Patients Living with Chronic Viral Infections and Underrepresentation of Ethnic Minorities in Diffuse Large B-Cell Lymphoma Clinical Trials

Introduction There is a substantial underrepresentation of ethnic minorities within oncology studies. Specifically, Black, Asian and Hispanic patients have a low participation rate in US based randomized clinical trials (RCT). Furthermore, patients living with HIV (PLWH) or chronic viral hepatitis are often systematically excluded from these studies. Diffuse large B-cell lymphoma (DLBCL) is one of the most common malignancies associated with HIV and viral hepatitis. Given these characteristics, it is imperative that studies reporting on safety and efficacy of new treatments mirror real-world populations. Objective: The primary objective of our study was to describe the demographic characteristics of patients who have participated in DLBCL phase II and III randomized US clinical trials; evaluating each group's enrollment fraction compared to US DLBCL prevalence. The secondary objective was analyzing the inclusion of PLWH and chronic viral hepatitis in US based DLBCL RCT. Methods and Measures: We queried PubMed, ClinicalTrials.gov, as well as ASCO and ASH meeting abstracts for phase II and III RCTs on DLBCL from 2000 to 2020, including chimeric antigen receptor T cells (CAR-T) therapy studies. Trials that did not report race and ethnicity or recruited outside of the US were excluded. We analyzed enrollment data and compared to DLBCL prevalence demographics obtained from the SEER 18 Registries. Enrollment fraction (EF) is defined as the number of trial enrollees divided by the estimated US prevalence of DLBCL. Results: We identified 51 trials between 2000 and 2020 with only 25 (49%) studies reporting race and ethnicity. Only 9 trials enrolled solely in the US which comprised of 763 patients. Compared with an EF of 1.88% among Non-Hispanic whites, lower EF was noted in Blacks (1.08%; P=0.0009), Hispanics (0.71; P=<0.0001) and Asian patients (0.71%; P=<0.0001). The EF of patients < 65 years old was significantly higher than those aged 65 or more (1.2 vs 0.79%, P=<0.0001). The EF of males and females was 1.8 vs 1.4%, respectively (P=0.001). PLWH and/or chronic viral hepatitis were excluded in 89% and 67% of the clinical trials analyzed (Table 1). Conclusions: US based clinical trials for DLBCL have significant underrepresentation of Hispanic, Black and Asian patients. Moreover, despite being commonly associated with HIV and chronic viral hepatitis, patients with these comorbidities are typically excluded from clinical trials. Pharmacoethnicity, ethnic differences in susceptibility to the effects of therapy, remains a challenge in oncology because clinical trials have significant underrepresentation of minorities. Efforts are needed to address the ascertainment bias and improve external validity of RCTs in DLCBL. Reasons for clinical trial underrepresentation are complex and multifactorial including lack of access, cultural differences and healthcare system mistrust. Healthcare professionals must address the inequalities through awareness and education with the objective of increasing enrollment of minorities in clinical trials. Although there have been efforts to increase enrollment of patients with HIV and chronic viral hepatitis in clinical trials, it remains inadequate. In accordance to recent recommendations by the FDA, investigators should consider having a predefined plan for inclusion of such patients. Disclosures Sandoval-Sus: Massive Bio: Consultancy; Janssen: Consultancy; MorphoSys US: Consultancy; Celgene: Speakers Bureau.

Adjuvant Treatment of Residual Disease Following Neoadjuvant Chemotherapy and Radical Cystectomy for Muscle Invasive Bladder Cancer

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) has shown overall survival benefit for patients with muscle invasive bladder cancer (MIBC). In contrast, there is limited data for adjuvant treatment options in patients with residual muscle invasive disease after NAC followed by radical cystectomy (RC). OBJECTIVE: This systematic review aims to give an overview of studies examining adjuvant treatment options for patients with residual MIBC at RC despite NAC. METHODS: We systematically searched the PubMed database and Clinicaltrials.gov (end point August 2019) for publications and registered trials combining NAC, RC, and adjuvant treatment options. RESULTS: After removal of duplicates, 659 articles and registered trials were further analyzed. Finally, 10 studies and 7 registered clinical trials met inclusion criteria. While 5 publications did not further characterize NAC and adjuvant regimens, the remaining 5 studies reported mainly platinum-based regimens. Altogether, the selected studies showed conflicting results regarding the potential role of adjuvant treatment strategies in the setting of residual disease after NAC and RC. CONCLUSION: Although there is an urgent need for adjuvant treatment options for patients with MIBC after NAC and residual muscle invasive disease at RC, there has been very limited evidence available. Inclusion of such patients into ongoing adjuvant clinical trials is urgently needed; active surveillance is strongly recommended in the absence of trials.

Cognitive fluctuations in Lewy body dementia: towards a pathophysiological framework.

Fluctuating cognition is a complex and disabling symptom that is seen most frequently in the context of Lewy body dementias encompassing dementia with Lewy bodies and Parkinson's disease dementia. In fact, since their description over three decades ago, cognitive fluctuations have remained a core diagnostic feature of dementia with Lewy bodies, the second most common dementia in the elderly. In the absence of reliable biomarkers for Lewy body pathology, the inclusion of such patients in therapeutic trials depends on the accurate identification of such core clinical features. Yet despite their diagnostic relevance, cognitive fluctuations remain poorly understood, in part due to the lack of a cohesive clinical and scientific explanation of the phenomenon itself. Motivated by this challenge, the present review examines the history, clinical phenomenology and assessment of cognitive fluctuations in the Lewy body dementias. Based on these data, the key neuropsychological, neurophysiological and neuroimaging correlates of cognitive fluctuations are described and integrated into a novel testable heuristic framework from which new insights may be gained.

Targeted Intraoperative Radiotherapy Tumour Bed Boost during Breast-Conserving Surgery after Neoadjuvant Chemotherapy - a Subgroup Analysis of Hormone Receptor-Positive HER2-Negative Breast Cancer

Introduction: In a previous study our group showed a beneficial effect of targeted intraoperative radiotherapy (TARGIT-IORT) as an intraoperative boost on overall survival after neoadjuvant chemotherapy (NACT) compared to an external boost (EBRT). In this study we present the results of a detailed subgroup analysis of the hormone receptor (HR)-positive HER2-negative patients. Methods: In this cohort study involving 46 patients with HR-positive HER2-negative breast cancer after NACT, we compared the outcomes of 21 patients who received an IORT boost to those of 25 patients treated with an EBRT boost. All patients received whole breast radiotherapy. Results: Median follow-up was 49 months. Whereas disease-free-survival and breast cancer-specific mortality were not significantly different between the groups, the 5-year Kaplan-Meier estimate of overall mortality was significantly lower by 21% with IORT, p = 0.028. Non-breast cancer-specific mortality was significantly lower by 16% with IORT, p = 0.047. Conclusion: Although our results have to be interpreted with caution, we have shown that the improved overall survival demonstrated previously could be reproduced in the HR-positive HER2-negative subgroup. These data give further support to the inclusion of such patients in the TARGIT-B (Boost) randomised trial that is testing whether IORT boost is superior to EBRT boost.

Targeted intraoperative radiotherapy tumor bed boost during breast conserving surgery after neoadjuvant chemotherapy in hormone receptor positive HER2 negative breast cancer.

e12090 Background: Targeted intraoperative radiotherapy (TARGIT – IORT) as a tumor bed boost during breast conserving surgery is an established option for women with early breast cancer. In a previous study our group could show a beneficial effect of TARGIT-IORT on overall survival after neoadjuvant chemotherapy compared to an external boost in an unselected cohort. In this study we present an analysis of the hormone receptor positive HER2 negative subgroup. Methods: In this non-randomized cohort study involving 46 hormone receptor positive HER2 negative patients after NACT we compared outcomes of 21 patients who received a tumour bed boost with IORT (TARGIT-IORT) during lumpectomy versus 25 patients treated in the previous 13 months with external (EBRT) boost. All patients received whole breast radiotherapy. Disease free survival (DFS) and overall survival (OS) were compared. Results: There were no statistical differences between the two groups regarding tumor size, grading, nodal status and pCR rates. Median follow up was 49 months. Whereas DFS was not significantly different between the groups the 5-year Kaplan-Meier estimate of OS was significantly better by 21% with IORT: TARGIT-IORT 0 events 100%, EBRT 5 events 79%, log rank p = 0.028. Conclusions: Although our results have to be interpreted with caution due to a possible selection bias and the small numbers, we could show that the improved OS as previously demonstrated in our dataset for TARGIT-IORT during lumpectomy after neoadjuvant chemotherapy as a tumor bed boost compared to an external beam radiotherapy boost is driven by the hormone receptor positive HER2 negative subgroup. These data give further support to the inclusion of such patients in the TARGIT-B (Boost) randomised trial that is testing whether IORT boost is superior to EBRT boost and to the analysis of subgroups based on tumor biology in this trial.

Early rise in postoperative creatinine for identification of acute kidney injury after cardiac surgery.

Acute kidney injury (AKI) is a potentially serious complication of cardiac surgery. Treatment strategies are unlikely to prove efficacious unless patients are identified and treated soon after the onset of injury. In this observational study, we determined and validated the ability of an early rise in postoperative serum creatinine to identify patients who suffer AKI during cardiac surgery. The relationship between an early rise in creatinine (immediate postoperative / preoperative creatinine) and AKI (> 50% increase in creatinine by postoperative calendar days 1or 2) was determined by logistic regression modelling. Existing databases were used for model development (n = 4,820; one institution) and validation (n = 6,553; 12 institutions). Acute kidney injury occurred in 9.1% (n = 437) and 9.8% (n = 645) of patients in the development and validation sets, respectively. An early rise in creatinine was related to AKI (P < 0.001), with an area under the receiver operating characteristic curve of 0.78 (95% confidence interval [CI], 0.75 to 0.80) in the development set and 0.77 (95% CI, 0.75 to 0.79) in the validation set. Using a threshold ratio of > 1.30 (n = 127), the sensitivity, specificity, positive, and negative predictive values for AKI in the development set were 20% (95% CI, 16 to 24), 99% (95% CI, 99 to 99), 68% (95% CI, 59 to 76), and 93% (95% CI, 92 to 93), respectively. In patients undergoing cardiac surgery with cardiopulmonary bypass, an early rise in postoperative creatinine is a useful marker for the early identification of AKI patients. This could allow inclusion of such patients in clinical trials of promising therapeutic strategies that need to be initiated soon after the onset of injury.

Targeted intraoperative radiotherapy tumour bed boost during breast-conserving surgery after neoadjuvant chemotherapy.

The use of targeted intraoperative radiotherapy (TARGIT-IORT) as atumour bed boost during breast-conserving surgery (BCS) for breast cancer has been reported since 1998. We present its use in patients undergoing breast conservation following neoadjuvant therapy (NACT). In this retrospective study involving 116 patients after NACT we compared outcomes of 61patients who received atumour bed boost with IORT during lumpectomy versus 55patients treated in the previous 13months with external (EBRT) boost. All patients received whole breast radiotherapy. Local recurrence-free survival (LRFS), disease-free survival (DFS), distant disease-free survival (DDFS), breast cancer mortality (BCM), non-breast cancer mortality (NBCM) and overall mortality (OS) were compared. Median follow up was 49months. The differences in LRFS, DFS and BCM were not statistically significant. The 5‑year Kaplan-Meier estimate of OS was significantly better by 15% with IORT: IORT 2events (96.7%, 95%CI 87.5-99.2), EBRT 9events (81.7%, 95%CI 67.6-90.1), hazard ratio (HR) 0.19 (0.04-0.87), log rank p= 0.016, mainly due to areduction of 10.1% in NBCM: IORT 100%, EBRT 89.9% (77.3-95.7), HR (not calculable), log rank p= 0.015. The DDFS was as follows: IORT 3events (95.1%, 85.5-98.4), EBRT 12 events (69.0%, 49.1-82.4), HR 0.23 (0.06-0.80), log rank p= 0.012. IORT during lumpectomy after neoadjuvant chemotherapy as atumour bed boost appears to give results that are not worse than external beam radiotherapy boost. These data give further support to the inclusion of such patients in the TARGIT-B (boost) randomised trial that is testing whether IORT boost is superior to EBRT boost.

Abstract TMP24: Duration of Asymptomatic Status and Outcomes Following Endarterectomy and Stenting in the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST)

Introduction: Inclusion of asymptomatic patients in randomized trials comparing revascularization to medical therapy has been questioned if they have been previously symptomatic. Hypothesis: Duration of asymptomatic status is not associated with better outcomes following endarterectomy (CEA) or stenting (CAS). Methods: Patients in CREST were classified as asymptomatic if they had not had a TIA or stroke ipsilateral to the study artery within 6 months prior to randomization. We compared those patients who had always been asymptomatic (AA) to those who had been previously symptomatic (PS) ≥ 6 months prior to randomization. Proportional hazards models adjusting for age and treatment were used to assess risk of 30-day stroke or death (S+D), and risk of any 30-day S+D plus ipsilateral stroke at 4 years by asymptomatic status Results: Among the 1056 asymptomatic patients who received the assigned procedure within 30 days of randomization, 977 (93%) were AA and 79 (7%) were PS. There was no difference in the 30-day and 4 year outcomes (Table). Conclusion: In CREST, 93% of the asymptomatic patients were always asymptomatic. Similar outcomes for the previously symptomatic patients (7%) supports the inclusion of such patients in randomized trials comparing CEA and CAS to medical treatment.

Risk of bias from inclusion of patients who already have diagnosis of or are undergoing treatment for depression in diagnostic accuracy studies of screening tools for depression: systematic review

Objectives To investigate the proportion of original studies included in systematic reviews and meta-analyses on the diagnostic accuracy of screening tools for depression that appropriately exclude patients who already have...

Stereotactic radiosurgery eligibility and selection bias in the treatment of glioblastoma multiforme

Several single institution studies have shown a survival advantage when a stereotactic radiosurgery (SRS) boost followed fractionated external beam radiation (FracRT) in the treatment of glioblastoma (GBM). RTOG 93-05 employed SRS before FracRT and demonstrated no survival benefit. We examined the effect of SRS eligibility before and after FracRT on patient outcome in a group of patients treated with conventional therapy without SRS. From 1998 to 2008, 106 patients with GBM treated definitively at the University of Utah were divided into groups based on eligibility for SRS: ineligible ("Never"), eligible before FracRT ("All Pre"), eligible before FracRT only ("Pre Only"), or eligible before and after FracRT ("Always"). Overall (OS) and progression-free survival (PFS) based on SRS eligibility was assessed. Eleven patients were alive at the time of analysis with a median follow-up of 42.3 months. Median OS for groups "All Pre" (n = 29), "Always" (n = 17), "Pre Only" (n = 12), and "Never" (n = 77) were 13.6, 13.6, 12.4, and 9.2 months, respectively. Of the 29 patients in group "All Pre," 12 (41.4%) were ineligible for SRS following FracRT. PFS did not significantly differ between groups. SRS for GBM can only be of benefit to selected patients with minimal focal postoperative disease. Following FracRT, over a third of initially SRS-eligible patients demonstrated more extensive disease in our experience. It is possible inclusion of such patients in a series of SRS for GBM could mask a benefit in remaining patients. No significant difference in OS or PFS based on SRS-eligibility status was found.

Hyperlactatemia in critical illness and cardiac surgery

We read with interest the article by Nichol and colleagues [1] in a recent issue of Critical Care. Their study of more than 7,000 medical and surgical patients supports the claim that an admission plasma lactate level in the upper normal range is associated with increased mortality. However, we are concerned about the lack of data regarding patient baseline characteristics. Specifically, although 3,166 and 1,614 patients had diagnoses of 'surgery' and 'cardiac/vascular', respectively, it is likely, but not stated, that numerous patients were admitted following cardiac surgery. This is of great importance as changes in lactate in this patient group are not homogenous in nature. In post-cardiac surgery patients, early hyperlactatemia and late hyperlactatemia (LHL) differ in both risk profile and physiological rationale. Early hyperlactatemia (on intensive care unit arrival) is associated with adverse outcome. This association is not seen in the 10% to 20% of patients who develop LHL (pooled odds ratio [OR] of death with LHL in two published trials 1.39, 95% confidence interval [CI] 0.28 to 7.04) [2-4]. Moreover, in our recent single-center review of prospectively collated data from 529 post-cardiac surgical patients in a tertiary Australian cardiac surgical intensive care unit, 25% developed LHL (>2.53 mmol/L). When compared with patients with a normal lactate profile, patients with LHL showed no increase in hospital mortality (OR 0.57, 95% CI 0.07 to 5.05) (unpublished data). Therefore, we believe that inclusion of such patients in studies of lactate in critical illness should be avoided and, as in the study by Nichol and colleagues, may actually weaken any association demonstrated between lactate levels and hospital mortality.

Antiphospholipid antibody associated thrombocytopenia and the paradoxical risk of thrombosis

The pathogenesis of thrombocytopenia in patients with antiphospholipid syndrome (APS) is heterogeneous. Patients with antiphospholipid antibodies (aPL) and thrombocytopenia in the absence of clinical manifestations of APS will be diagnosed and treated as idiopathic thrombocytopenic purpura. However, the presence of aPL places those individuals at particular risk for developing both bleeding and thrombotic complications. Therefore, we propose the inclusion of such patients in the subgroup 'aPL-associated thrombocytopenia'. More attention should be devoted to this subgroup of patients to elucidate the role of aPL in the development of thrombocytopenia and to facilitate the adequate monitoring of its potential thrombotic risk.

Radiation Therapy Alone for Spinal Cord Compression: Time to Improve Upon a Relatively Ineffective Status Quo

Metastatic spinal cord compression (MSCC) is a common problem afflicting cancer patients. It affects 5% to 14% of all patients with cancer, and more than 20,000 cases are diagnosed annually in the United States. Once diagnosed, it is considered to be a medical emergency, and immediate intervention is required with high-dose corticosteroids and radiotherapy, with or without decompressive surgery. Without therapy, MSCC is a source of significant morbidity and mortality, causing pain, paralysis, incontinence, and an overall decline in quality of life. Even with aggressive therapy, results can often be unsatisfactory. Although most patients will die as a result of their underlying cancer within the first year of the diagnosis of MSCC, up to one third will survive beyond 1 year. Therefore, optimal therapy is required to maintain quality of life. Palliative radiotherapy has long been standard in the management of patients with MSCC, but the radiation oncologist is often faced with multiple competing and complex issues. The need to deliver a meaningful radiation dose to the tumor for adequate palliation must be balanced with the necessity of avoiding undue toxicity, the most serious of which is radiation myelopathy. Furthermore, the fractionation scheme must be weighed against the performance status and expected survival of the patient. These issues may explain the wide range of fractionation schemes reported in multiple retrospective analyses, with a total of 30 Gy in 3-Gy daily fractions for 10 days most frequently prescribed. In this issue of the Journal of Clinical Oncology, Maranzano et al report on a phase III, randomized, multicenter trial of two hypofractionation schemes, short course compared with split course, for patients with MSCC. Although there are multiple randomized trials on fractionation schemes for brain and bone metastases, to our knowledge this report is the first such trial for MSCC. The authors should be commended for completing such a difficult trial. Unfortunately, multiple problems are inherent in this study, and readers should be cautious before implementing the results in clinical practice. The explanation of the selection criteria for short life expectancy ( 6 months) of the study patients is incomplete. One can form the interpretation that the main criterion for inclusion was unfavorable histology alone, or favorable histology with neurologic dysfunction or poor performance status. However, this study has included groups of patients who might be anticipated to live significantly longer than 6 months. For example, one of the most significant predictors of short survival for patients with metastatic cancer is poor performance status; yet, 17% of patients in this study had Karnofsky performance status of 80 to 100. Furthermore, patients with radiosensitive tumors (such as lymphoma, seminoma, and myeloma) were included, as were those with histologies that have relatively long survivals after development of metastasis (such as breast and prostate cancer). Although patients with these favorable factors may have been equally distributed between the two treatments, the inclusion of such patients needs to be taken into account to estimate the true efficacy of radiation in the trial. Although only five patients experienced in-field recurrence, 18 patients (10%) lost the ability to walk after therapy. Is it possible that the inclusion of patients with favorable histology and good Karnofsky performance status allowed for longer survivals, and offered just enough time for the late toxicities of hypofractionated radiotherapy to occur? One of the most controversial aspects of this study was the choice of the two treatment arms. The most common JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 15 MAY 2

Thrombolysis for Intraventricular Hemorrhage After Endovascular Aneurysmal Coiling

Current applications of lytic therapy for intraventricular hemorrhage (IVH) rely on exclusion of vascular abnormalities as etiology. Its use in patients with recently coiled aneurysms remains far from considered safe. We report a patient with subarachnoid hemorrhage (SAH) and massive IVH from aneurysmal rupture, which was safely treated with intraventricular recombinant tissue plasminogen activator (rt-PA) after endovascular coiling. We also review two other similar cases reported in the literature. A 61-year-old man presented with a ruptured anterior communicating artery aneurysm causing SAH and IVH (Hunt & Hess grade IV, Fisher grade III with IVH). During coiling of the aneurysm, extravasation of contrast was noted on fluoroscopy. Follow-up head computed tomography (CT) scan showed casted ventricles. Once in the intensive care unit, the patient progressed to coma, which did not improve with external ventricular drainage alone. After endovascular coiling of the aneurysm, intraventricular rt-PA was administered. Isovolemic injections of 2 mg rt-PA every 12 hours were performed for a total of four doses. No clinical or radiological evidence of worsening SAH/IVH was documented. At the time of discharge, the patient was awake but requiring assistance with activities of daily living. We report the safe administration of intraventricular rt-PA after endovascular coiling of a ruptured cerebral aneurysm. Two other similar cases were found in the literature and are reviewed. Hindrance of aneurysmal cavity thrombosis by early administration of rt-PA (increasing the risk of rerupture) remains a widespread concern. The lack of such instances should therefore be acknowledged. We propose that inclusion of such patients in trials assessing safety/efficacy of thrombolytic therapy in the treatment of patients with intracranial hemorrhage should be carefully considered.

Increased iron-related MRI contrast in the substantia nigra in Parkinson's disease.

Elevated iron levels in the substantia nigra (SN) of the brain in Parkinson's disease (PD) may mediate lipid peroxidative reactions, promoting SN neuronal death. To assess SN iron accumulation in living PD patients and its relation to motor performance, we measured, in 13 nondemented PD patients and 10 normal control subjects, simple reaction time (SRT) and simple movement time (SMT), followed by head MRI in a 3-tesla system. We measured T2 and T2* in the right and left SN of all subjects and calculated R2', the relaxation rate due to local magnetic field in-homogeneities, from these values. Asymmetries of 1/T2 (R2), 1/T2* (R2*), or R2' versus asymmetries of SRT and SMT were assessed in eight PD subjects who had not taken anti-PD medication(s) for 12 hours. The average of right and left SN values for R2 was lower, and R2* and R2' were higher, in PD patients than in controls (R2, p = 0.046; R2*, p = 0.001; R2', p < 0.001). R2' best predicted group differences. The asymmetry of SRT performance was highly correlated with asymmetries of SN R2* (0.91; p = 0.001) and R2' (0.72; p = 0.03). These results strongly suggest that the increases in iron levels seen postmortem in the SN in PD are reflected in increased iron-related MRI contrast at 3 tesla in living PD patients. Correlations with motor performance in PD suggest that the clinical severity of PD may be related to SN iron accumulation.

Medication use and the elderly: current status and opportunities.

The crucial role played by medication use in the elderly is common knowledge in the worlds of health services research, clinical epidemiology, and geriatrics. It is now widely known that although persons over age sixty-five represent only about 13 percent of the population, they consume nearly one-third of all medications in the United States; that medications probably are the single most important health care technology in preventing illness, disability, and death in the geriatric population; that drugs represent one of the largest and fastest-rising out-of-pocket health care expenditures for the elderly; and that the old, because of their high drug usage rate, greater frequency of coexisting illnesses, and diminished physiological reserves, are at greater risk of experiencing adverse drug effects. Yet despite this knowledge, the use of drugs by the elderly and their clinical outcomes have not been prominent research or programmatic priorities for federal government, philanthropic, or corporate grantmakers. Beginning in the mid-1980s, The John A. Hartford Foundation began a grant-making program in the area of medication use and aging, out of an interest in enhancing the therapeutic effect of drugs used by this age group and in reducing the frequency and consequences of adverse drug events. After a number of years of active support in this area, the foundation convened its Expert Panel on Medications and Aging. This panel brought together authorities in the disciplines of geriatrics, gerontology, epidemiology, health services research, public policy, and pharmacology. Its mandate was to provide a consensus report that would critically define the further work needed to make the use of medications by the elderly more effective. This essay represents a synthesis of the work of that panel. The positions and opinions expressed below are extracted from transcripts of the expert panel’s deliberations, a structured survey administered to panel members,

On the possibility of incorporating patients from non-randomising centres into a randomised clinical trial

The implications of incorporating patients from non-randomising centres into the design of a 2 arm randomised multicentre clinical trial are investigated from the point of view of Bayesian statistics. It is concluded that although the inclusion of such patients may contribute to the reduction in recruitment time to a trial in the special circumstances when any biases introduced by such centres can be assumed very small, this is offset by a larger number of patients to be followed than in the corresponding fully randomised trial.