Immune Markers Are Associated With Asymptomatic Intracranial Large Artery Stenosis and Future Vascular Events in NOMAS.

BACKGROUND: Inflammation contributes to atherosclerosis but is incompletely characterized in intracranial large artery stenosis (ICAS). We hypothesized that immune markers would be associated with ICAS and modify the risk ICAS confers on future vascular events. METHODS: This study included a subsample of stroke-free participants in the prospective NOMAS (Northern Manhattan Study), who had blood samples analyzed with a 60-plex immunoassay (collected from 1993 to 2001) and ICAS assessment with time-of-flight magnetic resonance angiography (obtained from 2003 to 2008). We dichotomized ICAS as either ≥50% stenosis or not (including no ICAS). We ascertained post-magnetic resonance imaging vascular events. We used least absolute shrinkage and selection operator procedures to select immune markers independently associated with ICAS. Then, we grouped selected immune markers into a derived composite Z score. Using proportional odds regression, we quantified the association of the composite immune marker Z score, ICAS, and risk of vascular events. RESULTS: Among 1211 participants (mean age, 71±9 years; 59% women; 65% Hispanic participants), 8% had ≥50% ICAS. Using least absolute shrinkage and selection operator regression, we identified CXCL9 (C-X-C motif chemokine ligand 9), HGF (hepatocyte growth factor), resistin, SCF (stem cell factor), and VEGF-A(vascular endothelial growth factor A) to have the strongest positive relationships with ≥50% ICAS in fully adjusted models. Selected markers were used to derive a composite immune marker Z score. Over an average follow-up of 12 years, we found that each unit increase in immune marker Z scores was associated with an 8% (95% CI, 1.05-1.11), 11% (95% CI, 1.06-1.16), and 5% (95% CI, 1.01-1.09) increased hazard of death, vascular death, and any vascular event, respectively, in adjusted models. We did not find a significant interaction between immune marker Z scores and ICAS in their relationship with any longitudinal outcome. CONCLUSIONS: Among a diverse stroke-free population, selected serum immune markers were associated with ICAS and future vascular events. Further study is needed to better understand their role in the pathogenesis of ICAS and as a potential therapeutic target in stroke prevention.

Sleep Duration Is Associated With Subclinical Carotid Plaque Burden.

BACKGROUND: Sleep duration is associated with stroke risk and is 1 of 8 essential components of cardiovascular health according to the American Heart Association. As stroke disproportionately burdens Black and Hispanic populations in the United States, we hypothesized that long and short sleep duration would be associated with greater subclinical carotid atherosclerosis, a precursor of stroke, in the racially and ethnically diverse NOMAS (Northern Manhattan Study). METHODS: NOMAS is a study of community-dwelling adults. Self-reported nightly sleep duration and daytime sleepiness were collected between 2006 and 2011. Carotid plaque presence, total plaque area, and intima-media thickness were measured by ultrasound between 1999 and 2008. Linear and logistic regression models examined the cross-sectional associations of sleep duration groups (primary exposure) or daytime sleepiness (secondary exposure) with measures of carotid atherosclerosis. Models adjusted for age, time between ultrasound and sleep data collection, sex, race and ethnicity, education, health insurance, smoking, alcohol use, physical activity, body mass index, hypertension, diabetes, hypercholesterolemia, and cardiac disease. RESULTS: The sample (n=1553) had a mean age of 64.7±8.5 years and was 61.9% female, 64.8% Hispanic, and 18.2% non-Hispanic Black. Of the sample, 55.6% had carotid plaque, 22.3% reported nightly short sleep (<7 hours), 66.6% intermediate sleep (≥7 and <9 hours), and 11.1% had long sleep (≥9 hours). Compared with intermediate sleep, long sleep was associated with greater odds of carotid plaque presence relative to plaque absence (odds ratio, 1.6 [95% CI, 1.1-2.4]) and larger total plaque area (odds ratio, 1.4 [95% CI, 1.0-1.9]) after full covariate adjustment. Short sleep and daytime sleepiness were not significantly associated with any carotid measures. CONCLUSIONS: The association between long sleep and subclinical carotid atherosclerosis may explain prior associations between long sleep and stroke.

Combining Transoral Nasopharyngeal Brush and Plasma Epstein-Barr Virus DNA in Detecting Locally Recurrent Nasopharyngeal Carcinoma.

OBJECTIVE: To evaluate the sensitivities and specificities of Epstein-Barr virus (EBV) DNA in the detection of locally recurrent or persistent nasopharyngeal carcinoma (NPC) through nasopharyngeal (NP) brush biopsy and plasma, respectively, and whether a combination of both would be superior to the individual tests. STUDY DESIGN: A case-control study was conducted from September 2016 to June 2022. SETTING: A multicentre study at 3 tertiary referral centers in Hong Kong was conducted by the Department of Otorhinolaryngology, Head and Neck Surgery, The Chinese University of Hong Kong. METHODS: Twenty-seven patients with biopsy-confirmed locally recurrent NPC were recruited as study subjects. Magnetic resonance imaging was performed to rule out regional recurrence. The control group consisted of 58 patients with a prior history of NPC who were now disease-free based on endoscopic and imaging findings. Patients underwent both the transoral NP brush (NP Screen®) and blood for plasma Epstein-Barr DNA levels. RESULTS: The sensitivity and specificity of the combined modalities were 84.62% and 85.19%, respectively. The positive predictive value was 73.33% and the negative predictive value was 92.0%. CONCLUSION: The combination of NP brush biopsy and plasma EBV DNA is potentially an additional surveillance modality in detecting the local recurrence of NPC. Further study with a larger sample size would be required to validate the cutoff values.

Creatinine versus cystatin C for renal function-based mortality prediction in an elderly cohort: The Northern Manhattan Study.

BACKGROUND: Estimated glomerular filtration rate (eGFR) is routinely utilized as a measure of renal function. While creatinine-based eGFR (eGFRcr) is widely used in clinical practice, the use of cystatin-C to estimate GFR (eGFRcys) has demonstrated superior risk prediction in various populations. Prior studies that derived eGFR formulas have infrequently included high proportions of elderly, African-Americans, and Hispanics. OBJECTIVE: Our objective as to compare mortality risk prediction using eGFRcr and eGFRcys in an elderly, race/ethnically diverse population. DESIGN: The Northern Manhattan Study (NOMAS) is a multiethnic prospective cohort of elderly stroke-free individuals consisting of a total of 3,298 participants recruited between 1993 and 2001, with a median follow-up of 18 years. PARTICIPANTS: We included all Northern Manhattan Study (NOMAS) participants with concurrent measured creatinine and cystatin-C. MAIN MEASURES: The eGFRcr was calculated using the CKD-EPI 2009 equation. eGFRcys was calculated using the CKD-EPI 2012 equations. The performance of each eGFR formula in predicting mortality risk was tested using receiver-operating characteristics, calibration and reclassification. Net reclassification improvement (NRI) was calculated based on the Reynolds 10 year risk score from adjusted Cox models with mortality as an outcome. The primary hypothesis was that eGFRcys would better predict mortality than eGFRcr. RESULTS: Participants (n = 2988) had a mean age of 69±10.2 years and were predominantly Hispanic (53%), overweight (69%), and current or former smokers (53% combined). The mean eGFRcr (74.68±18.8 ml/min/1.73m2) was higher than eGFRcys (51.72±17.2 ml/min/1.73m2). During a mean of 13.0±5.6 years of follow-up, 53% of the cohort had died. The AUC of eGFRcys (0.73) was greater than for eGFRcr (0.67, p for difference<0.0001). The proportions of correct reclassification (NRI) based on 10 year mortality for the model with eGFRcys compared to the model with eGFRcr were 4.2% (p = 0.002). CONCLUSIONS: In an elderly, race/ethnically diverse cohort low eGFR is associated with risk of all-cause mortality. Estimated GFR based on serum cystatin-C, in comparison to serum creatinine, was a better predictor of all-cause mortality.

A comparison of nurses' and physicians' perception of cancer treatment burden based on reported adverse events.

BACKGROUND: Cancer treatments are associated with a multitude of adverse events (AEs). While both nurses and physicians are involved in patient care delivery and AE assessment, very few studies have examined the differences between nurses' and physicians' reporting and perception of AEs. An approach was recently proposed to assess treatment burden based on reported AEs from the physician's perspective. In this paper, we use this approach to evaluate nurses' perception of burden, and compare nurses' and physicians' assessment of the overall and relative burden of AEs. METHODS: AE records for 334 cancer patients from a randomized clinical trial conducted by the SWOG Cancer Research Network were evaluated by 14 nurses at Columbia University Medical Center. Two nurses were randomly selected to assign a burden score from 0 to 10 based on their impression of the global burden of the captured AEs. These nurses did not interact directly with the patients. Scores were compared to previously obtained physicians scores using paired T-test and Kappa statistic. Severity scores for individual AEs were obtained using mixed-effects models with nurses assessments, and were qualitatively compared to physicians'. RESULTS: Given the same AEs, nurses' and physicians' perception of the burden of AEs differed. While nurses generally perceived the overall burden of AEs to be only slightly worse compared to physicians (mean average VAS score of 5.44 versus 5.14), there was poor agreement in the perception of AEs that were in mild to severe range. The percent agreement for a moderate or worse AE was 64% with a Kappa of 0.34. Nurses also assigned higher severity scores to symptomatic AEs compared to physicians (p < 0.05), such as gastrointestinal (4.77 versus 4.14), hemorrhage (5.07 versus 4.14), and pain (5.17 versus 4.14). CONCLUSIONS: These differences in the perception of burden of AEs can lead to different treatment decisions and symptom management strategies. Thus, having provider consistency, training, or a collaborative approach in follow-up care between nurses and physicians is important to ensure continuity in care delivery. Moreover, estimating overall burden from both physicians' and nurses' perspective, and comparing them may be useful for deciding when collaborations are warranted.

Creatinine- versus cystatin C-based renal function assessment in the Northern Manhattan Study.

BACKGROUND: Accurate glomerular filtration rate estimation informs drug dosing and risk stratification. Body composition heterogeneity influences creatinine production and the precision of creatinine-based estimated glomerular filtration rate (eGFRcr) in the elderly. We compared chronic kidney disease (CKD) categorization using eGFRcr and cystatin C-based estimated GFR (eGFRcys) in an elderly, racially/ethnically diverse cohort to determine their concordance. METHODS: The Northern Manhattan Study (NOMAS) is a predominantly elderly, multi-ethnic cohort with a primary aim to study cardiovascular disease epidemiology. We included participants with concurrently measured creatinine and cystatin C. eGFRcr was calculated using the CKD-EPI 2009 equation. eGFRcys was calculated using the CKD-EPI 2012 equation. Logistic regression was used to estimate odds ratios and 95% confidence intervals of factors associated with reclassification from eGFRcr≥60ml/min/1.73m2 to eGFRcys<60ml/min/1.73m2. RESULTS: Participants (n = 2988, mean age 69±10yrs) were predominantly Hispanic, female, and overweight/obese. eGFRcys was lower than eGFRcr by mean 23mL/min/1.73m2. 51% of participants' CKD status was discordant, and only 28% maintained the same CKD stage by both measures. Most participants (78%) had eGFRcr≥60mL/min/1.73m2; among these, 64% had eGFRcys<60mL/min/1.73m2. Among participants with eGFRcr≥60mL/min/1.73m2, eGFRcys-based reclassification was more likely in those with age >65 years, obesity, current smoking, white race, and female sex. CONCLUSIONS: In a large, multiethnic, elderly cohort, we found a highly discrepant prevalence of CKD with eGFRcys versus eGFRcr. Determining the optimal method to estimate GFR in elderly populations needs urgent further study to improve risk stratification and drug dosing.

Long-Term Outcomes in Patients Aged ≤70 Years With Intravenous Glyburide From the Phase II GAMES-RP Study of Large Hemispheric Infarction: An Exploratory Analysis.

BACKGROUND AND PURPOSE: We aimed to determine whether subjects aged ≤70 years who were treated with intravenous glyburide (RP-1127; BIIB093; glibenclamide) would have better long-term outcomes than those who received placebo. METHODS: GAMES-RP (Glyburide Advantage in Malignant Edema and Stroke-Remedy Pharmaceuticals) was a prospective, double-blind, randomized, placebo-controlled phase 2 clinical trial. Eighty-six participants, aged 18 to 80 years, who presented to 18 centers with large hemispheric infarction (baseline diffusion-weighted imaging volumes, 82-300 cm3) randomized within 10 hours of symptom onset were enrolled. In the current exploratory analysis, we included participants aged ≤70 years treated with intravenous glyburide (n=35) or placebo (n=30) who met per-protocol criteria. Intravenous glyburide or placebo was administered in a 1:1 ratio. We analyzed 90-day and 12-month mortality, functional outcome (modified Rankin Scale, Barthel Index), and quality of life (EuroQol group 5-dimension). Additional outcomes assessed included blood-brain barrier injury (MMP-9 [matrix metalloproteinase 9]) and cerebral edema (brain midline shift). RESULTS: Participants ≤70 years of age treated with intravenous glyburide had lower mortality at all time points (log-rank for survival hazards ratio, 0.34; P=0.04). After adjustment for age, the difference in functional outcome (modified Rankin Scale) demonstrated a trend toward benefit for intravenous glyburide-treated subjects at 90 days (odds ratio, 2.31; P=0.07). Repeated measures analysis at 90 days, 6 months, and 12 months using generalized estimating equations showed a significant treatment effect of intravenous glyburide on the Barthel Index (P=0.03) and EuroQol group 5-dimension (P=0.05). Participants treated with intravenous glyburide had lower plasma levels of MMP-9 (189 versus 376 ng/mL; P<0.001) and decreased midline shift (4.7 versus 9 mm; P<0.001) compared with participants who received placebo. CONCLUSIONS: In this exploratory analysis, participants ≤70 years of age with large hemispheric infarction have improved survival after acute therapy with intravenous glyburide. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01794182.

Ideal Cardiovascular Health and Cognitive Aging in the Northern Manhattan Study.

BACKGROUND: The American Heart Association defined target levels for 7 cardiovascular health (CVH) factors: smoking, body mass index, physical activity, diet, blood pressure, cholesterol, and glucose. We hypothesized that a greater number of American Heart Association ideal CVH metrics would be associated with less decline in cognitive performance in our multiethnic population. METHODS AND RESULTS: A subsample from the population-based Northern Manhattan Study underwent repeated neuropsychological testing (mean interval 6±2 years). Domain-specific Z scores were derived by using factor analysis for the domains of Episodic Memory, Semantic Memory, Executive Function, and Processing Speed, based on initial performance and decline over time. Linear regression models were constructed to examine the relationship between the number of ideal CVH metrics at enrollment with later cognitive performance and decline, adjusting for sociodemographics and magnetic resonance imaging brain markers. Among 1033 participants (mean age at initial cognitive assessment 72±8 years, 39% male, 19% black, 16% white, 65% Hispanic; n=722 with repeat testing), 3% had 0 ideal factors, 15% had 1 factor, 33% had 2 factors, 30% had 3 factors, 14% had 4 factors, 4% had 5 factors, 1% had 6 factors, and 0% had 7 factors. An increasing number of ideal CVH factors was associated with better processing speed at initial assessment and less decline. The association was driven by nonsmoking and glucose. Among those with better cognitive performance at initial assessment, positive associations were observed between the number of ideal CVH factors and less decline in the domains of Executive Function and Episodic Memory. CONCLUSIONS: The number of ideal CVH metrics was associated with less decline in the domains of Processing Speed and, to a lesser extent, of Executive Function and Episodic Memory. Ideal CVH promotion benefits brain health and cognitive aging.

Racial-ethnic disparities in the association between risk factors and diabetes: The Northern Manhattan Study.

PURPOSE: To identify risk factors (RF) for diabetes within a multiethnic cohort and to examine whether race-ethnicity modified their effects. METHODS: Participants in the Northern Manhattan Study without diabetes at baseline were studied from 1993 to 2014 (n=2430). Weibull regression models with interval censoring data were fit to calculate hazard ratios and 95% confidence intervals for incident diabetes. We tested for interactions between RF and race-ethnicity. RESULTS: During a mean follow-up period of 11years, there were 449 diagnoses of diabetes. Being non-Hispanic black (HR 1.69 95% CI 1.11-2.59) or Hispanic (HR 2.25 95% CI 1.48-3.40) versus non-Hispanic white, and body mass index (BMI; HR 1.34 per SD 95% CI 1.21-1.49) were associated with greater risk of diabetes; high-density lipoprotein cholesterol (HR 0.75 95% CI 0.66-0.86) was protective. There were interactions by race-ethnicity. In stratified models, the effects of BMI, current smoking, and C-reactive protein (CRP) on risk of diabetes differed by race-ethnicity (p for interaction <0.05). The effects were greater among non-Hispanic whites than non-Hispanic blacks and Hispanics. CONCLUSIONS: Although Hispanics and non-Hispanic blacks had a greater risk of diabetes than whites, there were variations by race-ethnicity in the association of BMI, smoking, and CRP with risk of diabetes. Unique approaches should be considered to reduce diabetes as traditional RF may not be as influential in minority populations.

Phase Ib Randomized, Double-Blinded, Placebo-Controlled, Dose Escalation Study of Polyphenon E in Patients with Barrett's Esophagus.

This study was conducted to determine the safety and efficacy of the green tea-derived Polyphenon E (Poly E) in patients with Barrett's Esophagus (BE). Subjects were randomized to a 6-month, twice daily (BID) oral treatment of placebo or Poly E (200, 400, or 600 mg). Endoscopic evaluation, including biopsies, was performed before and after treatment. The primary objective was to demonstrate safety; secondary objectives investigated catechin accumulation and effects in clinical specimens. Of the 44 enrolled subjects, 11 received placebo, and 33 received Poly E. No dose-limiting toxicities were encountered, and a maximum tolerated dose (MTD) was not reached. The recommended phase II dose was 600 mg twice daily. The most common treatment-related adverse events (AE) in Poly E-treated subjects were grade I and II nausea, grade I belching, and grade I lactate dehydrogenase (LDH) elevation. No treatment-related AEs were reported in placebo-treated subjects, aside from grade I laboratory abnormalities. Pill counts and subject diaries were not consistently collected, and compliance was difficult to determine. However, on the basis of an intention-to-treat analysis, there was a significant relationship between Poly E dose and esophageal EGCG level--mean changes (pmol/g) of 0.79 (placebo), 6.06 (200 mg), 35.67 (400 mg), and 34.95 (600 mg); P = 0.005. There was a possible relationship between Poly E dose and urine PGE-M concentration. In conclusion, Poly E was well-tolerated, and treatment with Poly E (400 and 600 mg) but not Poly E (200 mg) or placebo resulted in clinically relevant and detectable EGCG accumulation in the target organ, esophageal mucosa.

Electrocardiographic Left Atrial Abnormality and Risk of Stroke: Northern Manhattan Study.

BACKGROUND AND PURPOSE: Electrocardiographic left atrial abnormality has been associated with stroke independently of atrial fibrillation (AF), suggesting that atrial thromboembolism may occur in the absence of AF. If true, we would expect an association with cryptogenic or cardioembolic stroke rather than noncardioembolic stroke. METHODS: We conducted a case-cohort analysis in the Northern Manhattan Study, a prospective cohort study of stroke risk factors. P-wave terminal force in lead V1 was manually measured from baseline ECGs of participants in sinus rhythm who subsequently had ischemic stroke (n=241) and a randomly selected subcohort without stroke (n=798). Weighted Cox proportional hazard models were used to examine the association between P-wave terminal force in lead V1 and stroke etiologic subtypes while adjusting for baseline demographic characteristics, history of AF, heart failure, diabetes mellitus, hypertension, tobacco use, and lipid levels. RESULTS: Mean P-wave terminal force in lead V1 was 4452 (±3368) µV*ms among stroke cases and 3934 (±2541) µV*ms in the subcohort. P-wave terminal force in lead V1 was associated with ischemic stroke (adjusted hazard ratio per SD, 1.20; 95% confidence interval, 1.03-1.39) and the composite of cryptogenic or cardioembolic stroke (adjusted hazard ratio per SD, 1.31; 95% confidence interval, 1.08-1.58). There was no definite association with noncardioembolic stroke subtypes (adjusted hazard ratio per SD, 1.14; 95% confidence interval, 0.92-1.40). Results were similar after excluding participants with a history of AF at baseline or new AF during follow-up. CONCLUSIONS: ECG-defined left atrial abnormality was associated with incident cryptogenic or cardioembolic stroke independently of the presence of AF, suggesting atrial thromboembolism may occur without recognized AF.

Cigarette Smoking and Carotid Plaque Echodensity in the Northern Manhattan Study.

BACKGROUND: We sought to determine the association between cigarette smoking and carotid plaque ultrasound morphology in a multiethnic cohort. METHODS: We analyzed 1,743 stroke-free participants (mean age 65.5 ± 8.9 years; 60% women; 18% white, 63% Hispanic, 19% black; 14% current and 38% former smokers, 48% never smoked) from the Northern Manhattan Study using an ultrasound index of plaque echodensity, the Gray-Scale Median (GSM). Echolucent plaque (low GSM) represents soft plaque and echodense (high GSM) more calcified plaque. The mean GSM weighted by plaque area for each plaque was calculated for those with multiple plaques. Quintiles of GSM were compared to no plaque. Multinomial logistic regression models were used to assess associations of cigarette smoking with GSM, adjusting for demographics and vascular risk factors. RESULTS: Among subjects with carotid plaque (58%), the mean GSM scores for quintiles 1-5 were 48, 72, 90, 105, and 128, respectively. Current smokers had over a two fold increased risk of having GSM in quintile 1 (odds ratio (OR) = 2.17; 95% confidence interval (CI), 1.34-3.52), quintile 2 (OR = 2.33; 95% CI, 1.42-3.83), quintile 4 (OR = 2.05; 95% CI, 1.19-3.51), and quintile 5 (OR = 2.13; 95% CI, 1.27-3.56) but not in quintile 3 (OR = 1.18; 95% CI, 0.67-2.10) as compared to never smokers in fully adjusted models. Former smokers had increased risk in quintile 2 (OR = 1.46; 95% CI, 1.00-2.12), quintile 3 (OR = 1.56; 95% CI, 1.09-2.24), quintile 4 (OR = 1.66; 95% CI, 1.13-2.42), and quintile 5 (OR = 1.73; 95% CI, 1.19-2.51), but not in quintile 1 (OR = 1.05; 95% CI, 0.72-1.55). CONCLUSIONS: A nonlinear, V-shaped-like relationship between current cigarette smoking and plaque echodensity was observed. Former smokers were at the highest risk for plaques in high GSM quintiles. Thus, current smokers were more likely to have either soft or calcified plaques and former smokers were at greater risk of having only echodense plaques when compared to those who have never smoked. Further research is needed to determine if plaque morphology mediates an association between smoking and clinical vascular events.

Mediterranean diet and carotid atherosclerosis in the Northern Manhattan Study.

OBJECTIVE: Adherence to a Mediterranean-style diet (MeDi) may protect against clinical vascular events by reducing atherosclerosis, but data is limited. This is the first observational study of the association between MeDi adherence and carotid plaque thickness and area. METHODS: The study included 1374 participants of the population-based Northern Manhattan Study with diet assessed and carotid intima-media thickness (cIMT) and plaque measured using B-mode ultrasound (mean age 66 ± 9 years, 60% female, 60% Hispanic, 18% White, 19% Black). A MeDi adherence score (range = 0-9, 9 representing maximal adherence) was examined continuously and in quintiles (3/4/5/6-9 vs. 0-2). RESULTS: Mean cIMT = 0.9 ± 0.1 mm and 57% had plaque (median plaque thickness = 1.5 mm, 75th percentile = 2.2; median plaque area = 4.2 mm(2), 75th percentile = 15.8). There was no association between MeDi and cIMT or plaque presence. MeDi adherence was inversely associated with the 75th percentile of plaque thickness and median of plaque area in quantile regression analyses. These associations persisted after controlling for demographics, smoking, physical activity, and total energy consumption (effect of a 1-point increase in MeDi score on the 75th percentile of plaque thickness = -0.049 mm, p = 0.03; median of plaque area = -0.371 mm(2), p = 0.03), and when additionally controlling for vascular disease biomarkers, medication use, BMI, and previous cardiac disease. The protective associations appeared strongest for those with a MeDi score of 5 (4th quintile) vs. 0-2 (bottom quintile). Differential effects of a MeDi on plaque thickness and area across race/ethnic groups was suggested. CONCLUSIONS: Moderate and strict adherence to a MeDi may protect against a higher burden of carotid atherosclerotic plaque, which may mediate the protection against clinical vascular events. Efforts to improve adherence to a MeDi are critical to reducing the burden of atherosclerotic disease.

Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma.

PURPOSE: The proteasome inhibitor bortezomib may enhance activity of chemoimmunotherapy in lymphoma. We evaluated dose-escalated bortezomib plus standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus rituximab (R) in patients with diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). PATIENTS AND METHODS: Seventy-six subjects with untreated DLBCL (n = 40) and MCL (n = 36) received standard CHOP every 21 days (CHOP-21) with R plus bortezomib at 0.7 mg/m(2) (n = 4), 1.0 mg/m(2) (n = 9), or 1.3 mg/m(2) (n = 63) on days 1 and 4 for six cycles. RESULTS: Median age was 63 years (range, 20 to 87), and International Prognostic Index (IPI) scores were generally unfavorable (39% with IPI of 2, and 49% with IPI of 3 to 5), as were Mantle Cell Lymphoma International Prognostic Index scores in patients with MCL (28% intermediate risk and 39% high risk). Toxicity was manageable, including neuropathy in 49 subjects (8% grade 2 and 4% grade 3) and grade 3/4 anemia (13%), neutropenia (41%), and thrombocytopenia (25%). For DLBCL, the evaluable overall response rate (ORR) was 100% with 86% complete response (CR)/CR unconfirmed (CRu; n = 35). Intent-to-treat (ITT, n = 40) ORR was 88% with 75% CR/CRu, 2-year progression-free survival (PFS) of 64% (95% CI, 47% to 77%) and 2-year overall survival (OS) of 70% (95% CI, 53% to 82%). For MCL, the evaluable ORR was 91% with 72% CR/CRu (n = 32). The ITT (n = 36) ORR was 81% with 64% CR/CRu, 2-year PFS 44% (95% CI, 27% to 60%) and 2-year OS 86% (95% CI, 70% to 94%). IPI and MIPI correlated with survival in DLBCL and MCL, respectively. Unlike in DLBCL treated with R-CHOP alone, nongerminal center B cell (non-GCB) and GCB subtypes had similar outcomes. CONCLUSION: Bortezomib with R-CHOP-21 can be safely administered and may enhance outcomes, particularly in non-GCB DLBCL, justifying randomized studies.

Durable responses with the metronomic rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide regimen in elderly patients with recurrent mantle cell lymphoma.

BACKGROUND: Targeting the tumor microenvironment and angiogenesis is a novel lymphoma therapeutic strategy. The authors report safety, activity, and angiogenic profiling results with the rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide (RT-PEPC) regimen in patients with recurrent mantle cell lymphoma (MCL). METHODS: RT-PEPC included induction (Months 1-3) of rituximab 4 times weekly, daily thalidomide (50 mg), and PEPC followed by maintenance thalidomide (100 mg), oral PEPC titrated to the neutrophil count, and rituximab every 4 months. Endpoints included safety, efficacy, quality of life (QoL), and translational studies, including tumor angiogenic phenotyping, plasma vascular endothelial growth factor (VEGF), and circulating endothelial cells. RESULTS: Twenty-five patients were enrolled, and 22 were evaluable. The median age was 68 years (range, 52-81 years), 24 patients (96%) had stage III or IV disease, 18 patients (72%) had an International Prognostic Index (IPI) score of 3 to 5, and 20 patients (80%) had high-risk Mantle Cell International Prognostic Index (MIPI) scores. Patients had received a median of 2 previous therapies (range, 1-7 previous therapies), and 15 patients (60%) had progressed on bortezomib. At a median follow-up of 38 months, the overall response rate was 73% (complete response [CR]/unconfirmed CR rate, 32%; partial response [PR] rate, 41%; n = 22 patients), and the median progression-free survival was 10 months. Four CRs were ongoing (> or =6 months, > or =31 months, > or =48 months, and > or =50 months). Toxicities included grade 1 and 2 fatigue, rash, neuropathy, and cytopenias, including grade 1 and 2 thrombocytopenia (64%) and grade 3 and 4 neutropenia (64%). Two thromboses and 5 episodes of grade 3 or 4 infections occurred. QoL was maintained or improved. Correlative studies demonstrated tumor autocrine angiogenic loop (expression of VEGF A and VEGF receptor 1) and heightened angiogenesis and lymphangiogenesis in stroma. Plasma VEGF levels and circulating endothelial cells trended down with treatment. CONCLUSIONS: RT-PEPC had significant and durable activity in MCL with manageable toxicity and maintained QoL. Novel, low-intensity approaches warrant further evaluation, potentially as initial therapy in elderly patients.

On health sustenance and surgical innovation: an inquiry into linear and circular causality.

Innovative surgery teeters on the horns of a dilemma. Although a surgical innovation may offer substantial improvement over conventional treatment strategies on one hand, it may on the other be perceived as involving significant risk by both the surgeon and the patient. Based on primary data collected from field research in the operating rooms of a local hospital and from in-depth interviews with a consultant surgeon of orthopedics and traumatology, this article looks into 2 real-life spine surgery cases: an exploration of the possibilities for cervical spine fusion surgery and the creative use of a computerized surgical navigation tool. The discussion centers on how a surgeon thinks and acts when presented with such scenarios. It is argued that surgical innovation as well as the responses to it develop through a process of "nested" circular causalities that arise from a linearly directed intention-that is, the intention to cure illness. In relation to how a surgeon thinks, it is argued that if the causes for intervention were different-that is, the surgeon's desire to cure an illness and, at the same time, allow the patient to live a better and happier life-then the effect would be the decision to carry out an alternate procedure, thus, presenting a new choice. In relation to how a surgeon acts, it is argued that rigid, unquestioning adherence to prevailing assumptions and practices can serve to stifle originality. Surprise and novelty emerge only when the surgeon challenges existing assumptions as well as the validity of their constituent elements.

High-dose lovastatin for acute ischemic stroke: results of the phase I dose escalation neuroprotection with statin therapy for acute recovery trial (NeuSTART).

BACKGROUND: Hydroxymethylglutaryl coenzyme A reductase inhibitors ('statins') reduce the neuronal injury in dose-dependent fashion in rodent stroke models. We sought to determine whether lovastatin at doses above those currently approved can be administered safely within 24 h after an acute ischemic stroke. METHODS: We conducted a phase 1B dose-finding study using an adaptive design novel to stroke trials, the continual reassessment method, to find the highest tolerated dose of lovastatin. Planned doses were 1, 3, 6, 8 and 10 mg/kg/day for 3 days. The primary safety outcomes were myotoxicity and hepatotoxicity. The model was calibrated to select a dose causing 7-13% toxicity. RESULTS: We enrolled 33 patients (16 men/17 women, age range 23-82 years). Three patients were treated at 1 mg/kg, 10 at 3 mg/kg, 12 at 6 mg/kg, and 8 at 8 mg/kg. Thirty of the 33 patients (90.9%) completed at least 11 of 12 doses. Two patients at the 6-mg/kg dose level experienced transient mild elevations in transaminases without clinical sequelae. After an initial dose reduction, the dose was re-escalated to 8 mg/kg, and no further patients reached safety outcomes. No clinical liver disease, myopathy, or creatine phosphokinase elevations occurred. The final model-based toxicity at 8 mg/kg was 13%; no patient was treated at 10 mg/kg. CONCLUSIONS: Lovastatin at doses above those currently approved by the Food and Drug Administration is feasible for 3 days after an acute ischemic stroke and the maximum tolerated dose is estimated to be 8 mg/kg/day. Further randomized studies are warranted to confirm its safety and to demonstrate its efficacy in improving functional outcomes after stroke.

The use of air in the inspired gas mixture during two-lung ventilation delays lung collapse during one-lung ventilation.

BACKGROUND: Collapse of the ipsilateral lung facilitates surgical exposure during thoracic procedures. The use of different gas mixtures during two-lung ventilation (2LV) may improve or impede surgical conditions during subsequent one-lung ventilation (OLV) by increasing or delaying lung collapse. We investigated the effects of three different gas mixtures during 2LV on lung collapse and oxygenation during subsequent OLV: Air/Oxygen (fraction of inspired oxygen [FIO(2)] = 0.4), Nitrous Oxide/Oxygen ("N(2)O," FIO(2) = 0.4) and Oxygen ("O(2)," FIO(2) = 1.0). METHODS: Subjects were randomized into three groups: Air/Oxygen (n = 33), N(2)O (n = 34) or O(2) (n = 33) and received the designated gas mixture during induction and until the start of OLV. Subjects' lungs in all groups were then ventilated with FIO(2) = 1.0 during OLV. The surgeons, who were blinded to the randomization, evaluated the lung deflation using a verbal rating scale at 10 and 20 min after the start of OLV. Serial arterial blood gases were performed before anesthesia induction, during 2LV, and every 5 min, for 30 min, after initiation of OLV. RESULTS: The use of air in the inspired gas mixture during 2LV led to delayed lung deflation during OLV, whereas N(2)O improved lung collapse. Arterial oxygenation was significantly improved in the O(2) group only for the first 10 min of OLV, after which there were no differences in mean Pao(2) values among groups. CONCLUSIONS: De-nitrogenation of the lung during 2LV is a useful strategy to improve surgical conditions during OLV. The use of FIO(2) 1.0 or N(2)O/O(2) (FIO(2) 0.4) during 2LV did not have an adverse effect on subsequent oxygenation during OLV.

Quality assessment of phase I dose-finding cancer trials: proposal of a checklist.

BACKGROUND: Qualitative checklists for phase III trials have been proposed, to improve the reporting of such trials and to assess the validity of their results. PURPOSE: Our objective was to develop such a scale for phase I cancer trials. METHODS: From a review of existing guidelines and checklists for phase III clinical trials, a staff team was responsible for the first selection of items and the construction of the questionnaire. The proposed quality assessment measures were rated by the survey respondents comprised of phase I research clinicians and statisticians on a 4-point Likert scale. Selected items from the quantitative analysis of the questionnaires were reviewed by an expert team who was responsible for providing the final items list. This was then applied to 103 recently published cancer phase I trials. RESULTS: Of the 48 initial items proposed by the staff team, 17 were selected from the quantitative analysis of the 99 participants' ratings. After qualitative analysis by the expert team, a 15-item checklist was derived, with 5 items related to trial objective, 5 to design, and 5 to analysis. The application to 103 recent journal articles on phase I cancer trials evaluating cytotoxic drugs showed on average the report of 10 items (range: 6-13) with 4 items reported in more than 95% of papers, while 2 were poorly reported. LIMITATIONS: The response rate of participants was 20.7%. CONCLUSIONS: A quality assessment checklist was developed for improved critical appraisal of the reporting of cytotoxic, dose-finding phase I oncology trials. This may be a first step toward a minimum standard of quality measures for all phase I clinical trial reports.