Rapid Tumor DNA Analysis of Cerebrospinal Fluid Accelerates Treatment of Central Nervous System Lymphoma.

Delays and risks associated with neurosurgical biopsies preclude timely diagnosis and treatment of central nervous system (CNS) lymphoma and other CNS neoplasms. We prospectively integrated targeted rapid genotyping of cerebrospinal fluid (CSF) into the evaluation of 70 patients with CNS lesions of unknown etiology. Participants underwent genotyping of CSF-derived DNA using a qPCR-based approach for parallel detection of single-nucleotide variants in the MYD88, TERT promoter, IDH1, IDH2, BRAF and H3F3A genes within 80 minutes of sample acquisition. Canonical mutations were detected in 42% of patients with neoplasms, including cases of primary and secondary CNS lymphoma, glioblastoma, IDH-mutant brainstem glioma and H3K27M-mutant diffuse midline glioma. Genotyping results eliminated the need for surgical biopsies in 7/33 (21.2%) cases of newly diagnosed neoplasms, resulting in significantly accelerated initiation of disease-directed treatment (median 3 vs 12 days; p = 0.027). This assay was then implemented in a Clinical Laboratory Improvement Amendments (CLIA) environment, with 2-day median turnaround for diagnosis of central nervous system lymphoma from 66 patients across 4 clinical sites. Our study prospectively demonstrates that targeted rapid CSF genotyping influences oncologic management for suspected CNS tumors.

The impact of in-house pathology services on downstaging cervical cancer in Tanzania over an 18-year period.

PURPOSE: Reducing time between cancer screening, diagnosis, and initiation of treatment is best achieved when services are available in the same hospital. Yet, comprehensive cancer centers are typically unavailable in low- and middle-income countries (LMICs), where resources are limited and services scattered. This study explored the impact of establishing an in-house pathology laboratory at the largest public cancer hospital in Tanzania on the downstaging of cervical cancer. METHODS: We examined clinical datasets of 8,322 cervical cancer patients treated at the Ocean Road Cancer Institute (ORCI). The first period included patients treated from 2002 to 2016, before establishment of the pathology laboratory at ORCI; the second period (post-pathology establishment) included data from 2017 to 2020. Logistic regression analysis evaluated the impact of the pathology laboratory on stage of cervical cancer diagnosis. RESULTS: Patients treated during the post-pathology period were more likely to be clinically diagnosed at earlier disease stages compared to patients in the pre-pathology period (pre-pathology population diagnosed at early disease stage: 44.08%; post-pathology population diagnosed at early disease stage: 59.38%, p < 0.001). After adjustment for age, region of residence, and place of biopsy, regression results showed patients diagnosed during the post-pathology period had higher odds of early stage cervical cancer diagnosis than patients in the pre-pathology period (OR 1.35, 95% CI (1.16, 1.57), p < 0.001). CONCLUSIONS: Integrated and comprehensive cancer centers can overcome challenges in delivering expedited cervical cancer diagnosis and treatment. In-house pathology laboratories play an important role in facilitating timely diagnosis and rapid treatment of cervical and possibly other cancers in LMICs.

The Effects of Creatine Monohydrate Loading on Exercise Recovery in Active Women throughout the Menstrual Cycle.

Creatine supplementation improves anaerobic performance and recovery; however, to date, these outcomes have not been well explored in females. This study evaluated the effect of creatine monohydrate loading on exercise recovery, measured by heart rate variability (HRV) and repeated sprint performance, in women across the menstrual cycle. In this randomized, double-blind, cross-over study, 39 women (mean ± standard deviation: age: 24.6 ± 5.9 years, height: 172.5 ± 42.3 cm, weight: 65.1 ± 8.1 kg, BF: 27.4 ± 5.8%) were randomized to a creatine monohydrate (n = 19; 20 g per day in 4 × 5 g doses) or non-caloric PL group (n = 20). HRV was measured at rest and after participants completed a repeated sprint cycling test (10 × 6 s maximal sprints). Measurements were conducted before and after supplementation in the follicular/low hormone and luteal/high hormone phases. Creatine monohydrate supplementation did not influence HRV values, as no significant differences were seen in HRV values at rest or postexercise. For repeated sprint outcomes, there was a significant phase × supplement interaction (p = 0.048) for fatigue index, with the greatest improvement seen in high hormone in the creatine monohydrate group (-5.8 ± 19.0%) compared to changes in the PL group (0.1 ± 8.1%). Sprint performance and recovery were reduced by the high hormone for both groups. Though not statistically significant, the data suggests that creatine monohydrate could help counteract performance decrements caused by the high hormone. This data can help inform creatine monohydrate loading strategies for females, demonstrating potential benefits in the high hormone phase.

Association of MTHFR Polymorphisms With Leukoencephalopathy Risk in Patients With Primary CNS Lymphoma Treated With Methotrexate-Based Regimens.

OBJECTIVES: The folate antagonist high-dose methotrexate (HD-MTX) is integral to induction chemotherapy for primary CNS lymphoma (PCNSL); however, it can be associated with leukoencephalopathy. Methylenetetrahydrofolate reductase (MTHFR) is involved in intracellular folate depletion. We assessed whether MTHFR polymorphisms affect the risk of leukoencephalopathy. METHODS: We retrospectively searched our database at the Massachusetts General Hospital for newly diagnosed PCNSL treated with HD-MTX (without radiotherapy nor intrathecal chemotherapy). RESULTS: Among 68 patients with PCNSL, MTHFR polymorphisms were found in 60 individuals (88.2%) including a 677C→T genotype, a 1298A→C genotype, or a combined 677C→T/1298A→C genotype. Neither MTX clearance nor response to induction therapy was affected by specific genotypes, and complete response was achieved in 72.1% of patients by HD-MTX-based induction. However, the 1298A→C genotype was associated with increased frequency and severity of leukoencephalopathy over time (odds ratio 4.0, CI 1.5-11.4). Such genotype predicted treatment-induced leukoencephalopathy with a sensitivity of 71.0% and a specificity of 62.2% (area under the curve 0.67, CI 0.5-0.8; p = 0.019). While progression-free survival did not differ in genotype-based subgroups, overall survival was lower for the 1298A→C genotype. DISCUSSION: The MTHFR 1298A→C genotype may serve to identify patients with PCNSL at elevated risk of HD-MTX-induced leukoencephalopathy. This seems to translate into reduced survival, potentially due to decreased functional status.

Women who pre-game: A study of stress and alcohol use in female collegiate predrinkers.

Introduction: This study examined the relationship between stress and pre-gaming (i.e., drinking prior to going out to an event) in female college students. Methods: Thirty-four female college students were grouped as pre-gamers or non-pre-gamers based on self-reported drinking patterns. They completed surveys about alcohol use and mental health and provided a set of salivary cortisol samples upon waking, 30 min later, and at 10am on the same day. Results: Pre-gamers and non-pre-gamers did not differ on demographics or psychosocial variables. Pre-gamers reported riskier drinking overall and had greater endorsement of social, coping, and enhancement drinking motives. Pre-gamers also had lower cortisol levels 30 min after waking and exhibited attenuated CAR. Conclusions: Female collegiate pre-gamers may differ from their peers not only in terms of alcohol consumption and drinking motives, but also on attenuated CAR, a physiological biomarker associated with stress dysregulation and vulnerability to addictive behaviors.

Menopause Transition: A Cross-Sectional Evaluation on Muscle Size and Quality.

INTRODUCTION: The menopause transition yields significant physiological alterations. The purpose was to characterize lean soft tissue (LST), muscle size (muscle cross-sectional area (mCSA)), muscle quality (echo intensity (EI)), and strength across the menopause transition. A secondary aim was to evaluate whole-body protein turnover in a subsample of women. METHODS: Seventy-two healthy women were enrolled in this cross-sectional study based on menopause stage (PRE: n = 24; PERI: n = 24; POST: n = 24). Whole-body LST was measured via dual-energy x-ray absorptiometry, and muscle characteristics (mCSA and EI) were measured via B-mode ultrasound of the vastus lateralis. Maximal voluntary contractions (N·m) of the knee extensors were evaluated. Physical activity (in minutes per day) was accounted for using the International Physical Activity Questionnaire. A subsample of women ( n = 27) ingested 2.0 g of 15 N-alanine to determine whole-body net protein balance (NB; in grams per kilogram of body mass per day). RESULTS: Significant differences were evident in LST ( P = 0.022), leg LST ( P = 0.05), and EI ( P = 0.018) between menopause stages. Bonferroni post-hoc comparisons revealed greater LST in PRE versus PERI (mean difference (MD) ± SE, 3.8 ± 1.5 kg; P = 0.048) and POST (3.9 ± 1.5 lb; P = 0.049). Similarly, EI was significantly higher in PERI PRE (MD, 18.3 ± 7.1 a.u.; P = 0.036). There was no significant difference in mCSA ( P = 0.082) or in maximal voluntary contraction ( P = 0.167). NB was significantly different across groups ( P = 0.026); NB was greater in PRE compared with PERI (MD, 0.39 ± 0.17 g·kg -1 ; P = 0.090), and from PRE to POST (MD, 0.46 ± 0.17 g·kg -1 ; P = 0.042). Physical activity was not significantly different across groups but demonstrated a linear increase from PRE to POST. CONCLUSIONS: The current findings suggest that LST, muscle quality, and protein balance may be negatively influenced by the menopause transition.

A Randomized Controlled Trial of Changes in Fluid Distribution across Menstrual Phases with Creatine Supplementation.

This study examined the effects of creatine (Cr) loading on body mass (BM) and fluid markers of total body water (TBW), extra-cellular fluid (ECF), and intra-cellular fluid (ICF) across the menstrual cycle (MC). Thirty moderately active females, either naturally-menstruating (NM) or using hormonal contraceptives (HC), were randomized to Cr (Cr; 4 × 5 g/day of creatine monohydrate for 5 days; n = 15) or a non-caloric placebo (PL; n = 15) using a double-blind, placebo-controlled design, with a menstrual phase crossover. BM, TBW, ECF, and ICF were measured at pre- and post-supplementation in randomized order of follicular phase (FP; NM: MC days 0−8, HC: inactive pill days) or luteal phase (LP; NM: ≤15 days from next projected cycle start date, HC: active pill days) using bioelectrical impedance spectroscopy. Acute hydration status and salivary estrogen were used as covariates. Change in BM was not different between groups across MC ([PL-Cr] Δ 0.40 ± 0.50 kg; p = 0.427) or between MC phase across groups ([FP-LP] Δ 0.31 ± 0.48 kg; p = 0.528). TBW (p = 0.802), ECF (p = 0.373), and ICF (p = 0.795) were not different between supplement groups at pre-supplementation/FP time points. There were no significant differences between the NM and HC subjects at any time point, for any outcome (p > 0.05). Following LP supplementation, significant changes were observed in TBW (Cr: Δ 0.83 ± 0.38 L, PL: Δ −0.62 ± 0.38 L; p = 0.021), ECF (Cr: Δ 0.46 ± 0.15 L, PL: Δ −0.19 ± 0.15 L; p = 0.013), and ICF (Cr: Δ 0.74 ± 0.23 L, PL: Δ −0.02 ± 0.23 L; p = 0.041). These data demonstrate an increase in all fluid compartments in the LP following Cr loading, without observed alterations in body weight for females.

Evaluation of pre-workout and recovery formulations on body composition and performance after a 6-week high-intensity training program.

Introduction: Activities such as high-intensity resistance training (HIRT) and high-intensity interval training (HIIT) may be more time-efficient modes to stimulate rapid changes in performance and body composition. There is little research evaluating the combined effects of HIRT and HIIT on body composition and strength, particularly when paired with nutritional supplementation. Purpose: To evaluate the chronic effects of pre- and post-workout supplementation on body composition and strength, and to understand sex-specific responses. Materials and methods: 64 untrained males (n = 23) and females (n = 41) (mean ± standard deviation; age: 33.2 ± 10.0 years; %fat: 31.6 ± 7.4%) were randomized to either (1) pre-post supplementation [SUP (n = 25); pre = multi-ingredient caffeine/HMB/vit D; post = whey protein/carbohydrates/glucosamine/vitamins], (2) placebo [PL (n = 24); non-caloric], or (3) control [CON (n = 15)]. All participants completed one repetition max (1RM) strength testing for leg press and bench press at baseline and week 6. Estimates of fat mass (FM) and lean mass (LM) were measured via dual energy x-ray absorptiometry. Participants in the SUP or PL group completed a 6-week supervised exercise intervention consisting of a full-body HIRT workout (3 × 6-8 reps) followed by a HIIT treadmill run (6 × 1 min run: 1 min rest) twice per week. Outcomes were evaluated by separate repeated measure ANOVAs (2 × 3). Results: There were no differences in FM between groups or sex (p = 0.133-0.851). LM increased from baseline to post-testing for all groups [Mean difference [MD(Post-Pre) ± Standard Error (SE) = 0.78 ± 0.12 kg; p < 0.001]. While not significant (p = 0.081), SUP gained more LM compared to PL [MD(SUP-PL) ± SE = 3.5 ± 3.3 kg] and CON [MD(SUP-CON) ± SE = 5.2 ± 3.8 kg]. LM increased over time for both males (0.84 ± 0.24 kg; p = 0.003) and females (0.73 ± 0.14 kg; p < 0.001). The SUP group resulted in a significant increase in 1RM leg press compared to the CON group (89.9 ± 30.8 kg; p = 0.015), with no significant differences compared to PL (p = 0.409). The SUP group had greater increases in 1RM bench press compared to the CON group (9.8 ± 1.8 kg; p < 0.001), with no significant differences compared to PL (p = 0.99). Both sexes increased upper- (5.5 ± 0.7 kg; p < 0.001) and lower-body strength (69.8 ± 4.5 kg p < 0.001) with training. Conclusion: Nutrient supplementation timing appears to augment body composition changes and strength compared to control. Pre-/post-nutrient timing may support greater increases in LM and lower- and upper-body strength in both men and women. Clinical trial registration: [https://clinicaltrials.gov/ct2/show/NCT04230824?cond=NCT04230824&draw=2&rank=1], identifier [NCT04230824].

Conduction System Pacing in Pediatrics and Congenital Heart Disease, a Single Center Series of 24 Patients.

His-bundle pacing has demonstrated feasibility in numerous adult studies to reverse and prevent pacing-induced cardiomyopathy, however, is met with higher capture thresholds with deployment sheaths designed for adults with his-bundles in the typical location. To describe 24 pediatric and adult congenital patients post-physiologic pacing. Patients at the University of Minnesota Masonic Children's Hospital with congenital complete heart block or congenital heart disease and atrioventricular block presented for pacemaker placement between November 2019 and January 2021. Twenty-four patients had attempted his-bundle placement using either Medtronic's C315 or C308 sheaths and 3830 leads except for 3 patients who had Boston Scientific's His system with the Shape 3 sheath and 7842 leads. Twenty-four total patients underwent physiologic pacing (23 his-bundle, 13 female, 11 male) with median age of 14 years (range 8-39 years) with median weight of 51 kg (range 21.2-81 kg) with five right-sided implants performed. Twelve patients had congenital heart disease including atrioventricular canal defects, tetralogy of Fallot, and ventricular septal defect repairs (nine patients with ventricular septal defect repairs). Twelve patients had selective His-bundle pacing (six with congenital heart disease). Median threshold to capture was 0.5 V at 0.4 ms (range 0.4 to 1.1 V at 0.4 ms), impedance 570 ohms (range 456-1140 ohms), and sensing median of 9.7 mV (range 1.5-13.8 mV if present). The median follow-up time was 610 days (range 240-760 days). No complications occurred peri-procedurally or during follow-up. His-bundle pacing is feasible in pediatric and congenital heart disease patients.

Differences in strength, leg lean mass, and lifestyle factors between premenopausal and perimenopausal women.

BACKGROUND: Menopausal changes coupled with age-related reductions in muscle strength can impact functionality. AIM: To evaluate the differences in muscle strength, dominant leg lean mass (DLMleg ), relative protein intake (r_PRO) and physical activity (PA) between premenopausal (PRE) and perimenopausal (PERI) women. METHODS: Twenty-four PRE- (age = 39.8 ± 3.3 years; BMI: 25.3 ± 5.0 kg/m2 ) and 24 PERI-women (age = 50.0 ± 3.3 years; BMI: 26.5 ± 5.4 kg/m2 ) participated in leg extensor isometric peak force (PF), DLMleg , r_PRO and PA. Independent samples t-tests and one-way analyses of covariance covaried for age and DLMleg were used to compare groups. RESULTS: The PRE group had significantly higher PF (mean difference ± standard error: 57.8 ± 28.0 N; p = 0.045) and DLMleg (0.7 ± 0.3 kg; p = 0.031) when compared to the PERI group. There were no significant differences in r_PRO, or PA between groups (p = 0.173-0.423). When covaried for age and DLMleg , there was no significant difference in PF (p = 0.982 and 0.405, respectively). CONCLUSIONS: Age and DLMleg may be important contributors to menopause-phase related differences in strength.

Body composition of NCAA division I football players pre- and post-COVID-19 stay-at-home advisory.

BACKGROUND: The COVID-19 pandemic forced collegiate athletes to train at home, without access to facilities. The purpose of this study was to evaluate the effect of the COVID-19 stay-at-home order on body composition of Division I Football Players, with a secondary aim to evaluate these changes between players with "higher" (>25 kg/m2) and "lower" (<25 kg/m2) Fat-Free Mass Index (kg/m2). METHODS: Body composition of 29 NCAA Division I Football Players (age=21.0±10 yr, Ht=186.7±5.6 cm, body mass=110.5±22.8 kg) were measured spring season (February) and prior to preseason (June). Whole body dual-energy X-ray absorptiometry scans were used to determine regional (arms, legs, trunk) and total body fat mass (FM), lean mass (LM), and fat-free mass (FFM). Fat-Free Mass Index (FFMI) was calculated as (LM+bone mineral content [BMC])/height2); participants were stratified by FFMI higher (N.=16) and lower (N.=13). RESULTS: Total LM (mean difference±standard error: 0.80±1.65 kg, P=0.016) increased from pre- to post-COVID stay-at-home. No significant changes in total FM were seen. Players with lower FFMI showed a significant decrease in trunk FM (-0.55±0.19 kg, P=0.016). Players with higher FFMI showed a significant increase in total LM (0.96±0.42 kg, P=0.038). CONCLUSIONS: These results suggest no detrimental effect on body composition.

Metabolic effects of menopause: a cross-sectional characterization of body composition and exercise metabolism.

OBJECTIVES: To evaluate body composition, fat distribution, and metabolism at rest and during exercise in premenopausal, perimenopausal, and postmenopausal women. METHODS: This cross-sectional study in 72 women ages 35 to 60 years evaluated body composition via a fourcompartment model, fat distribution using dual-energy x-ray absorptiometry-derived android to gynoid ratio, metabolic measures via indirect calorimetry, and lifestyle factors using surveys. One-way analyses of variance and one-way analyses of covariance covaried for age and hormone levels (estrogen and progesterone) were used to compare groups. RESULTS: Body fat percent was significantly lower in premenopausal than perimenopausal women (mean difference ± standard error: - 10.29 ± 2.73%, P = 0.026) despite similarities in fat mass and fat-free mass between groups (P≥0.217). Android to gynoid ratio was significantly lower in premenopausal than perimenopausal women (MD ± SE: -0.16 ± 0.05 a.u., P = 0.031). Resting energy expenditure was similar between groups (P = 0.999). Fat oxidation during moderate intensity cycle ergometer exercise was significantly greater in premenopausal than postmenopausal women (MD ± SE: 0.09 ± 0.03 g/min, P = 0.045). The change in respiratory exchange ratio between rest and moderate intensity exercise was significantly lower in premenopausal women than peri- (MD ± SE: -0.05 ± 0.03 a.u., P = 0.035) and postmenopausal women (MD ± SE: -0.06 ± 0.03 a.u., P = 0.040). Premenopausal women reported significantly fewer menopause symptoms than peri- (MD ± SE: -6.58 ± 1.52 symptoms, P = 0.002) and postmenopausal participants (MD ± SE: -4.63 ± 1.52 symptoms, P = 0.044), while similarities between groups were observed for lifestyle factors including diet and physical activity (P>0.999). CONCLUSIONS: Perimenopause may be the most opportune window for lifestyle intervention, as this group experienced the onset of unfavorable body composition and metabolic characteristics. VIDEO SUMMARY: http://links.lww.com/MENO/A932.

A rapid genotyping panel for detection of primary central nervous system lymphoma.

Diagnosing primary central nervous system lymphoma (PCNSL) frequently requires neurosurgical biopsy due to nonspecific radiologic features and the low yield of cerebrospinal fluid (CSF) studies. We characterized the clinical evaluation of suspected PCNSL (N = 1007 patients) and designed a rapid multiplexed genotyping assay for MYD88, TERT promoter, IDH1/2, H3F3A, and BRAF mutations to facilitate the diagnosis of PCNSL from CSF and detect other neoplasms in the differential diagnosis. Among 159 patients with confirmed PCNSL, the median time to secure a diagnosis of PCNSL was 10 days, with a range of 0 to 617 days. Permanent histopathology confirmed PCNSL in 142 of 152 biopsies (93.4%), whereas CSF analyses were diagnostic in only 15/113 samplings (13.3%). Among 86 archived clinical specimens, our targeted genotyping assay accurately detected hematologic malignancies with 57.6% sensitivity and 100% specificity (95% confidence interval [CI]: 44.1% to 70.4% and 87.2% to 100%, respectively). MYD88 and TERT promoter mutations were prospectively identified in DNA extracts of CSF obtained from patients with PCNSL and glioblastoma, respectively, within 80 minutes. Across 132 specimens, hallmark mutations indicating the presence of malignancy were detected with 65.8% sensitivity and 100% specificity (95% CI: 56.2%-74.5% and 83.9%-100%, respectively). This targeted genotyping approach offers a rapid, scalable adjunct to reduce diagnostic and treatment delays in PCNSL.

Pemetrexed in Recurrent or Progressive Central Nervous System Lymphoma: A Phase I Multicenter Clinical Trial.

LESSONS LEARNED: The findings from this study using monotherapy with pemetrexed in a pretreated patient population are, overall, encouraging. Unlike high-dose methotrexate, which requires several days of inpatient hospitalization, pemetrexed is relatively easy to administer in the outpatient setting and remains a viable treatment option in this patient population. The maximum tolerated dose of pemetrexed administered (900 mg/m2 every 2 weeks) was generally well tolerated and showed activity in patients with relapsed or refractory CNSL. BACKGROUND: There is currently no standard salvage treatment for patients with relapsed/refractory central nervous system (CNS) lymphoma (CNSL). We report the results of a phase I study of pemetrexed, an antifolate drug with broader activity than methotrexate (MTX). We provide the safety, tolerability, and maximum tolerated dose (MTD) of pemetrexed in patients with recurrent CNSL. METHODS: Through October 2015, 17 patients with relapsed/refractory CNSL received pemetrexed every 2 weeks with the first cohort receiving 600 mg/m2 and dose escalation in increments of 300 mg/m2 to a maximum of 1,200 mg/m2 . Three patients were to enroll at each dose level with expansion to six patients in the event of dose-limiting toxicity. Patients with both primary CNS lymphoma (PCNSL) and secondary CNS lymphoma (SCNSL) could be enrolled. RESULTS: Seventeen patients were evaluable with a median age of 63.7 years. Main adverse events included fatigue (82.4%), anemia (82.4%), and neutropenia (70.6%). The MTD was established at 900 mg/m2 . Dose-limiting toxicities were recorded in one patient in the 600 mg/m2 cohort and in two patients in the 1,200 mg/m2 cohort. Fourteen patients were evaluable for response assessment; 21.4% achieved a complete response, 35.7% had a partial response, 14.3% had stable disease, and 28.6% had progressive disease. The median progression-free survival was 4.2 months. The median overall survival was 44.5 months. In the original study protocol, the plan was to add an expansion cohort of six patients at MTD level. However, the first phase of the study was characterized by slow recruitment. Therefore, after achieving the primary objective of the study and establishing the MTD, the investigators decided to amend the protocol and to close the study. CONCLUSION: Pemetrexed administered at 900 mg/m2 every 2 weeks exhibits single-agent activity in patients with recurrent CNSL; it is well tolerated, and side effects are manageable.

Combined lenalidomide, low-dose dexamethasone, and rituximab achieves durable responses in rituximab-resistant indolent and mantle cell lymphomas.

BACKGROUND: Lenalidomide is an immunomodulatory drug with effects on the immune system that may enhance antibody-dependent cell-mediated cytotoxicity and reverse tumor-induced immune suppression. Furthermore, single-agent lenalidomide has therapeutic activity in relapsed/refractory B-cell lymphomas. These immunologic effects potentially may enhance the action of rituximab. METHODS: To test the efficacy of lenalidomide combined with rituximab, the authors conducted a phase 2 trial of lenalidomide, low-dose dexamethasone, and rituximab in patients who had rituximab-resistant, relapsed/refractory, indolent B-cell or mantle cell lymphomas. Patients received two 28-day treatment cycles of lenalidomide 10 mg daily and dexamethasone 8 mg once weekly (part I). During cycle 3, 4 weekly doses of rituximab 375 mg/m2 were administered with lenalidomide-dexamethasone (part II). After the part II response assessment, stable or responding patients continued to receive lenalidomide-dexamethasone. RESULTS: Twenty-seven patients with follicular (n=18), mantle cell (n=5), small lymphocytic (n=3), and marginal zone (n=1) lymphomas started therapy; 3 of 27 patients discontinued therapy because of adverse events and were not evaluable for response. For 24 patients, the overall response rate after part I was 29% (4 patients had a complete response [CR] or CR unconfirmed, and 3 patients had a partial response), and the overall response rate after part II was 58% (8 patients had a CR, and 6 patients had a partial response). For 27 patients, at a median follow-up of 12.2 months, the median progression-free survival was 23.7 months. CONCLUSIONS: The combination of lenalidomide, low-dose dexamethasone, and rituximab achieved high response rates with durable responses in patients with rituximab-resistant, indolent B-cell and mantle cell lymphomas. Overall response rate increased from 29% after two 28-day cycles of lenalidomide and low-dose dexamethasone to 58% after the addition of rituximab, suggesting that lenalidomide can overcome resistance to rituximab.

Synthesis, cytotoxicity and DNA-binding of novel bisnaphthalimidopropyl derivatives in breast cancer MDA-MB-231 cells.

New naphthalimidopropyl, bisphthalimidopropyl and bisnaphthalimidopropyl (BNIP) derivatives were synthesised and characterised. Their interactions with Calf Thymus DNA were studied by UV spectrophotometric analysis and a competitive Ethidium bromide displacement assay. Cytotoxicity was determined by MTT assay in a breast cell system (MDA-MB-231 and MCF-10A cells). All BNIPs exhibited strong DNA-binding properties and cytotoxic activity with IC(50) values in the range of 0.83-12.68 microM (24 and 48 h treatment). In addition, the uptake of BNIP derivatives within cancer cells was not via utilisation of the MGBG polyamine transporter. Put together the results confirm that the presence of the bisnaphthalimidopropyl and alkyl linker functionality are crucial for exerting DNA-binding and cytotoxic properties, hence demonstrating promise in their further development as potential anti cancer agents.

A prospective, blinded analysis of A-PROTEIN (recoverin or CAR protein) levels in pediatric patients with central nervous system tumors.

BACKGROUND: Abnormal expression of A-PROTEIN has been identified in a number of tumors including carcinoma of the lung, breast, colon, prostate, and cervix. Brain tumors have been reported to express high plasma levels of A-PROTEIN, suggesting that it may be of significant diagnostic and prognostic value. PROCEDURE: This prospective study evaluated the sensitivity and specificity of A-PROTEIN levels in pediatric brain tumor patients. Patients included those with newly diagnosed disease pre- and post-surgery, during treatment, during routine follow-up, and at recurrence or progression. A total of 154 A-PROTEIN levels from 54 patients were evaluated. RESULTS: For patients without evidence of disease, 42% had normal A-PROTEIN levels, 35% were elevated, and 23% were equivocal. For patients with stable disease, 53% demonstrated normal A-PROTEIN levels, 19% were elevated, and 28% were equivocal. For patients with progressive disease, 53% had normal A-PROTEIN levels, 35% were elevated, and 12% were equivocal. The sensitivity was 35% and the specificity was 50%. A correlation of increased A-PROTEIN levels in patients with increased disease in glial tumors was also identified. CONCLUSIONS: A-PROTEIN levels were not predictive of disease status in children with most brain tumors. However, in patients with glial tumors there was a correlation with increased disease and elevated A-PROTEIN levels. This could represent variability of A-PROTEIN during growth, development, or tumor cell origin and needs further evaluation.

Analysis of condom lubricants for forensic casework.

The detection of DNA is inhibited in cases of sexual assault involving condom use. Trace evidence, including condom lubricant residues, provides crucial associative evidence in such cases. The existing Fourier transform infrared spectroscopy (FTIR) methods for lubricant analysis and detection are limited with regard to sensitivity and discrimination. The aim of this research was to establish a new method as an alternative to FTIR for the analysis of condom lubricant residues. Pyrolysis gas chromatography-mass spectrometry (PyGC-MS) and GC-MS are highly sensitive methods of analysis for a wide range of chemical substances. PyGC-MS and GC-MS were used to analyze condom lubricants in standard solution, from clean swabs and from postcoital swabs. Pyrolysis of polydimethylsiloxane (PDMS) lubricant forms cyclic products known as cyclic dimethyl siloxanes (DMS), which are separated and detected by the GC-MS. The polyethylene glycol (PEG) lubricant can be analyzed by GC-MS directly from solution. The methods of extraction and analysis presented in this paper were shown to be significantly more sensitive than FTIR for the analysis of PDMS and PEG condom lubricants. PDMS was detected as low as 1 mug in standard solution and from clean swabs using the PyGC-MS method. PEG was detected as low as 0.5 microg from standard solution and 50 mug from clean swabs using the GC-MS method. Unfortunately, we were unable to provide further discrimination between condom brands and subbrands. The methods established throughout the research were used successfully to detect condom lubricants from donated postcoital swabs. Lubricants were detected in abundance on swabs 12 h postcoitus. Recommendations are made regarding implementation of new methods for routine analysis of casework samples along with strict pyrolysis interpretation criteria to minimize the possibility of misinterpretation of false positives.