Importance of non-affine viscoelastic response in disordered fibre networks.

Disordered fibre networks are ubiquitous in nature and have a wide range of industrial applications as novel biomaterials. Predicting their viscoelastic response is straightforward for affine deformations that are uniform over all length scales, but when affinity fails, as has been observed experimentally, modelling becomes challenging. Here we present a numerical methodology, related to an existing framework for amorphous packings, to predict the steady-state viscoelastic spectra and degree of affinity for disordered fibre networks driven at arbitrary frequencies. Applying this method to a peptide gel model reveals a monotonic increase of the shear modulus as the soft, non-affine normal modes are successively suppressed as the driving frequency increases. In addition to being dominated by fibril bending, these low frequency network modes are also shown to be delocalised. The presented methodology provides insights into the importance of non-affinity in the viscoelastic response of peptide gels, and is easily extendible to all types of fibre networks.

Universality in the morphology and mechanics of coarsening amyloid fibril networks.

Peptide hydrogels have important applications as biomaterials and in nanotechnology, but utilization often depends on their mechanical properties for which we currently have no predictive capability. Here we use a peptide model to simulate the formation of percolating amyloid fibril networks and couple these to the elastic network theory to determine their mechanical properties. We find that the time variation of network length scales can be collapsed onto master curves by using a time scaling function that depends on the peptide interaction anisotropy. The same scaling applies to network mechanics, revealing a nonmonotonic dependence of the shear modulus with time. Our structure-function relationship between the peptide building blocks, network morphology, and network mechanical properties can aid in the design of amyloid fibril networks with tailored mechanical properties.

Prefrontal gray matter volume mediates age effects on memory strategies.

Age differences in the strategies that individuals spontaneously use to learn new information have been shown to contribute to age differences in episodic memory. We investigated the role of prefrontal structure in observed age effects on self-initiated use of memory strategies. The relationships among age, prefrontal regional gray matter volumes, and semantic and serial clustering during free recall on the California Verbal Learning Test-II were examined across the adult lifespan. Semantic clustering was negatively correlated with age and positively correlated with gray matter volumes in bilateral middle and left inferior frontal regions across the adult lifespan. Gray matter volumes in these regions mediated the effects of age on semantic clustering. Forward serial clustering was also negatively correlated with age. However, forward serial clustering was not significantly positively correlated with gray matter volumes in any region of lateral prefrontal cortex. These results suggest that bilateral middle and left inferior frontal regions support self-initiated semantic memory strategy use across the adult lifespan. They also suggest that age differences in prefrontal gray matter volume are a significant contributor to age differences in self-initiated use of elaborative memory strategies.

Vitamin D deficiency in anesthesia department caregivers at the end of winter.

BACKGROUND: To test whether the vitamin D status of anesthesia department caregivers practicing at high Northern latitudes is compatible with current recommendations, the 25-hydroxyvitamin D (25(OH)D) levels of caregivers at hospitals in Iceland (64°08' N) and in Wisconsin (43°07' N) were compared at the end of winter. METHODS: Anesthesia department faculty and resident physicians, non-physician anesthetists, and critical care nurses completed a questionnaire, and provided blood samples for analysis of 25(OH)D by reverse-phase high performance liquid chromatography. RESULTS: One hundred and six participants in Iceland and 124 participants in Wisconsin were enrolled. No difference in mean serum 25(OH)D levels between Iceland [70.53 nmol/l, standard deviation (SD) 30.87 nmol/l] and Wisconsin (70.0 nmol/l, SD 30.0 nmol/l) was observed. In Iceland and Wisconsin, 25(OH)D levels below 25 nmol/l were observed in 4.7% and 4.0%, below 50 nmol/l in 34.9% and 25.0%, and below 75 nmol/l in 56.6% and 61.3% of caregivers, respectively. CONCLUSIONS: 25(OH)D levels below the 50 nmol/l (20 ng/ml) threshold recommended by the Institute of Medicine and the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, and below the 75 nmol/l (30 ng/ml) threshold recommended by The Endocrine Society, are highly prevalent among anesthesia caregivers working at two Northern hospitals at the end of winter who may otherwise not meet criteria to be tested. Anesthesia and critical care providers may wish to determine their 25(OH)D levels and use effective, safe, and low cost supplementation to target a 25(OH)D level compatible with optimal health.

A technique for recording polycrystalline structure and orientation during in situ deformation cycles of rock analogues using an automated fabric analyser.

Two in situ plane-strain deformation experiments on norcamphor and natural ice using synchronous recording of crystal c-axis orientations have been performed with an automated fabric analyser and a newly developed sample press and deformation stage. Without interrupting the deformation experiment, c-axis orientations are determined for each pixel in a 5 × 5 mm sample area at a spatial resolution of 5 µm/pixel. In the case of norcamphor, changes in microstructures and associated crystallographic information, at a strain rate of ∼2 × 10(-5) s(-1), were recorded for the first time during a complete in situ deformation-cycle experiment that consisted of an annealing, deformation and post-deformation annealing path. In the case of natural ice, slower external strain rates (∼1 × 10(-6) s(-1)) enabled the investigation of small changes in the polycrystal aggregate's crystallography and microstructure for small amounts of strain. The technical setup and first results from the experiments are presented.

In Silico Modeling of Hyposalivation and Biofilm Dysbiosis in Root Caries.

Root caries progression is aggravated by hyposalivation, which can accelerate the conversion of a dental biofilm from having a symbiotic microbial relationship with the host (predominance of nonaciduric species) to a dysbiotic one (dominated by aciduric species). Using a mathematical model previously employed to investigate factors associated with biofilm dysbiosis, we systematically explored the deleterious effect of hyposalivation on the composition of the biofilm and the risk of root dentin demineralization. By varying the clearance half-times of sugar (i.e., readily fermented dietary carbohydrates), we simulated hyposalivation and investigated its effect on 1) the time that the biofilm pH spends below the minimum for dentin or enamel demineralization and 2) the conversion of the biofilm from a symbiotic to dysbiotic composition. The effect of increasing sugar clearance half-times on the time that the biofilm pH is below the threshold for demineralization was more pronounced for dentin than for enamel (e.g., increasing the clearance half-time from 2 to 6 min doubled the time that the biofilm pH was below the threshold for dentin demineralization). The effect on biofilm composition assessed at 50 d showed that the conversion from a symbiotic to a dysbiotic biofilm happened around a frequency of 6 sugar intakes per day when the clearance half-time was 2 min but only 3 sugar intakes per day when the clearance half-time was 6 min. Taken together, the results confirm the profound effect that prolonged sugar clearance has on the dynamics of dental biofilm composition and the subsequent risk of root caries. This in silico model should be applied to study how interventions that alter salivary clearance rates or modify biofilm pH can affect clinical conditions such as root caries.

Anisotropic mechanical response of layered disordered fibrous materials.

Mechanically bonded fabrics account for a significant portion of nonwoven products, and serve many niche areas of nonwoven manufacturing. Such fabrics are characterized by layers of disordered fibrous webs, but we lack an understanding of how such microstructures determine bulk material response. Here we numerically determine the linear shear response of needle-punched fabrics modeled as cross-linked sheets of two-dimensional (2D) Mikado networks. We systematically vary the intra-sheet fiber density, inter-sheet separation distance, and direction of shear, and quantify the macroscopic shear modulus alongside the degree of affinity and energy partition. For shear parallel to the sheets, the response is dominated by intrasheet fibers and follows known trends for 2D Mikado networks. By contrast, shears perpendicular to the sheets induce a softer response dominated by either intrasheet or intersheet fibers depending on a quadratic relation between sheet separation and fiber density. These basic trends are reproduced and elucidated by a simple scaling argument that we provide. We discuss the implications of our findings in the context of real nonwoven fabrics.

Effects of superheated steam on Geobacillus stearothermophilus spore viability.

AIMS: To examine the effect of processing with superheated steam (SS) on Geobacillus stearothermophilus ATCC 10149 spores. METHODS AND RESULTS: Two inoculum levels of spores of G. stearothermophilus were mixed with sterile sand and exposed to SS at 105-175 degrees C. The decimal reduction time (D-value) and the thermal resistance constant (z-value) were calculated. The effect of cooling of spores between periods of exposure to SS was also examined. A mean z-value of 25.4 degrees C was calculated for both inoculum levels for SS processing temperatures between 130 degrees C and 175 degrees C. CONCLUSIONS: Spore response to SS treatment depends on inoculum size. SS treatment may be effective for reduction in viability of thermally resistant bacterial spores provided treatments are separated by intermittent cooling periods. SIGNIFICANCE AND IMPACT OF THE STUDY: There is a need for technologies that require short thermal processing times to eliminate bacterial spores in foods. The SS processing technique has the potential to reduce microbial load and to modify food texture with less energy in comparison to commonly used hot air treatment. This work provides information on the effect of SS processing parameters on the viability of G. stearothermophilus spores.

The impact of electrode resistance on the biogalvanic characterisation technique.

Measurement of a tissue-specific electrical resistance may offer a discriminatory metric for evaluation of tissue health during cancer surgery. With a move toward minimally-invasive procedures, applicable contact sensing modalities must be scalable, fast and robust. A passive resistance characterisation method utilising a biogalvanic cell as an intrinsic power source has been proposed as a potentially suitable solution. Previous work has evaluated this system with results showing effective discrimination of tissue type and damage (through electroporation). However, aspects of the biogalvanic cell have been found to influence the characterisation performance, and are not currently accounted for within the system model. In particular, the electrode and salt-bridge resistance are not independently determined, leading to over-predictions of tissue resistivity. This paper describes a more comprehensive model and characterisation scheme, with electrode parameters and salt-bridge resistivity being evaluated independently. In a generalised form, the presented model illustrates how the relative resistive contributions from the electrodes and medium relate to the existing characterisation method efficacy. We also describe experiments with physiologically relevant salt solutions (1.71, 17.1, 154 mM), used for validation and comparison. The presented model shows improved performance over the current biogalvanic measurement technique at the median conductivity. Both the proposed and extant system models become unable to predict conductivity accurately at high conductivity due to the dominance of the electrodes. The characterisation techniques have also been applied to data collected on freshly excised human colon tissue (healthy and cancerous). The findings suggest that the resistance of the cell under the test conditions is electrode dominated, leading to erroneous tissue resistance determination. Measurement optimisation strategies and the surgical applicability of the biogalvanic technique are discussed in light of these findings.

Cyclophosphamide followed by fludarabine for untreated chronic lymphocytic leukemia: a phase II SWOG TRIAL 9706.

B-cell chronic lymphocytic leukemia (CLL) accounts for 95% of chronic leukemia cases and 25% of all leukemia. Despite the prevalence of CLL, progress in its treatment has been only modest over the past three decades. Based upon the ability of fludarabine to produce high-grade remissions especially among patients with low initial tumor mass, and the ability of alkylators to reduce tumor mass, we hypothesized that sequential administration of a limited number of cycles of intermediate-dose cyclophosphamide followed by fludarabine could result in a larger percentage of patients with complete remissions (CRs). In all, 27 of the 49 eligible patients achieved overall responses of CR, unconfirmed complete remission (UCR), or PR, for a total response rate of 55% (95% confidence interval (CI) 40-69%). Considering the confounding medical issues of this patient population with advanced aggressive disease, the regimen was generally well tolerated. This study demonstrates that high-dose cyclophosphamide followed by fludarabine was relatively well tolerated in this group of advanced CLL patients. The study's criterion for testing whether the regimen is sufficiently effective to warrant further investigation was met: 14 (32%) of the first 44 eligible patients achieved CR or UCR.

Modeling the elastic deformation of polymer crusts formed by sessile droplet evaporation.

Evaporating droplets of polymer or colloid solution may produce a glassy crust at the liquid-vapor interface, which subsequently deforms as an elastic shell. For sessile droplets, the known radial outward flow of solvent is expected to generate crusts that are thicker near the pinned contact line than the apex. Here we investigate, by nonlinear quasistatic simulation and scaling analysis, the deformation mode and stability properties of elastic caps with a nonuniform thickness profile. By suitably scaling the mean thickness and the contact angle between crust and substrate, we find that data collapse onto a master curve for both buckling pressure and deformation mode, thus allowing us to predict when the deformed shape is a dimple, Mexican hat, and so on. This master curve is parameterized by a dimensionless measure of the nonuniformity of the shell. We also speculate on how overlapping time scales for gelation and deformation may alter our findings.

Overexpression of p21(WAF1/CIP1) is an early event in the development of pancreatic intraepithelial neoplasia.

Pancreatic cancer (PC) is thought to develop through a series of duct lesions termed pancreatic intraepithelial neoplasia (PanIN). Characterization of the molecular pathology of these lesions may lead to additional understanding of pancreatic ductal carcinogenesis. We examined the protein expression of four functionally related genes, p21(WAF1/CIP1) (CDKN1A), p53, cyclin D1 (CCND1), and DPC4/Smad4 (MADH4), aberrations of which are associated with PC, within 451 PanIN lesions present in the pancreata of 60 patients. p21(WAF1/CIP1) overexpression was present in the normal ducts of 9% of patients and increased progressively to 16% of patients with PanIN-1A lesions, to 32% of patients with PanIN-1B lesions, 56% of patients with PanIN-2 lesions, 80% of patients with PanIN-3 lesions, and 85% of patients with invasive carcinomas (P < 0.01). p53 and cyclin D1 overexpression occurred predominantly in PanIN-3 lesions (P < 0.01), and loss of DPC4/Smad4 expression occurred predominantly in PanIN-3 lesions and invasive carcinoma (P < 0.01). In addition, p21(WAF1/CIP1) overexpression occurred independently of p53 and DPC4/Smad4 expression within invasive carcinoma and PanIN-3 lesions. Cyclin D1 overexpression or loss of DPC4/Smad4 expression was apparent in 85% of invasive carcinomas but in only 14% of PanIN-2 lesions. These data demonstrate that overexpression of p21(WAF1/CIP1) occurs early in the development of PanIN, before aberrations in p53, cyclin D1, and DPC4/Smad4 expression. p21(WAF1/CIP1) overexpression, independent of p53 and/or DPC4/Smad4 expression, may reflect increased Ras activity, either directly through activating K-ras mutations or as a consequence of HER-2/neu (ERBB2) overexpression, both of which are common in PC and in early events in the development of PanIN. These data support further the current progression model for PC and demonstrate that aberrant expression of key cell cycle regulatory genes may be important in the early development and progression of PanIN.

Altered expression of androgen receptor in the malignant epithelium and adjacent stroma is associated with early relapse in prostate cancer.

The molecular basis of androgen-independent prostate cancer is unknown; however, functional androgen receptor (AR) signaling is maintained after the acquisition of hormone-refractory disease. Because normal and malignant prostate epithelial cell proliferation is regulated by androgen stimulation via both the AR-positive stroma and epithelium, we sought to evaluate patterns of AR expression in these cells and to determine any relationships with prostate cancer progression. AR expression in the malignant epithelium and associated periepithelial and nonperiepithelial stroma was measured in a cohort of 96 patients with clinically localized prostate cancer treated with radical prostatectomy. Data were evaluated for disease relapse using the Kaplan-Meier method and in a Cox proportional hazards model with other variables of known clinical relevance, including Gleason score, pathological stage, clinical stage, and pretreatment prostate-specific antigen concentration. Concurrent overexpression of AR (> or = 70% positive nuclei) in the malignant epithelium and loss of AR immunoreactivity in the adjacent periepithelial stroma (< or = 30%) was associated with higher clinical stage (P = 0.01), higher pretreatment prostate-specific antigen level (P = 0.03), and earlier relapse after radical prostatectomy (log-rank P = 0.009). These data identify a pattern of AR expression in malignant epithelium and adjacent stroma that is associated with a poor clinical outcome in prostate cancer. Equally important, they identify the need to further investigate the mechanistic basis of loss of AR expression in the malignant stroma and its potential role in deregulation of prostate epithelial cell proliferation.

Prognostic significance of p53 nuclear accumulation in localized prostate cancer treated with radical prostatectomy.

The role of p53 in the pathogenesis of, and as a predictive biomarker for, localized prostate cancer (PCa) is contested. Recent work has suggested that patterns of p53 nuclear accumulation determined by immunohistochemistry are prognostic, whereas studies using other methods question the role of p53 mutations in predicting outcome. We studied 263 men with localized PCa treated with radical prostatectomy to determine whether p53 nuclear accumulation predicts relapse and disease-specific mortality. We combined two p53 immunohistochemistry scoring systems: (a) percentage of p53-positive tumor nuclei in all major foci of cancer within the prostate; and (b) clustering, where the presence of 12 or more p53-positive cells within a x 200 power field was deemed "cluster positive." Analysis was undertaken using chi2, Kruskal-Wallis, and Mann-Whitney tests for clinicopathological variables and the Kaplan-Meier method, log-rank test, and univariate and multivariate Cox regression modeling for evaluation of contribution to relapse and disease-specific survival. At mean follow-up of 55.1 months (range, 4.9-123.0 months), 39% (102 of 263) of patients had relapsed and 2.3% (6 of 253) had died of PCa. Pretreatment serum prostate-specific antigen concentration, pathological tumor stage, lymph node involvement, Gleason score, and p53 nuclear accumulation, as determined by either percentage score or cluster status, were independent predictors of relapse in multivariate analysis. Clustering of p53-positive cells distinguished between favorable and poor prognosis patients within the lowest p53-positive stratum (>0 to <2%) and was the most discriminatory threshold for predicting relapse in the entire cohort. p53 status predicted outcome in patients with a Gleason score of 5 and above but not those with a score of 4 and below. In patients treated with neoadjuvant hormonal therapy, p53 cluster positivity carried a 90% (19 of 21) risk of relapse by 36 months. All six patients who died from PCa in the period of the study exhibited p53 nuclear accumulation in 20% or more tumor nuclei. This study demonstrates strong relationships between p53 nuclear accumulation and relapse and disease-specific mortality in a large series of localized PCas. Furthermore, the presence of clusters of p53-positive nuclei delineates a group of patients with poor prognosis not identified by traditional scoring methods and supports the hypothesis that p53 dysfunction within PCa may exist in foci of tumor cells that are clonally expanded in metastases.

Frequent loss of estrogen receptor-beta expression in prostate cancer.

The role of estrogen and its receptors in the etiology and progression of prostate cancer (PC) is poorly understood. In normal and malignant human prostate, estrogen receptor-alpha is expressed only in the stroma, whereas estrogen receptor-beta (ERbeta) is present in both normal stroma and epithelium. Because loss of ERbeta expression is associated with prostate hyperplasia in ERbeta-null mice, this study determined patterns of ERbeta expression in normal, hyperplastic, and malignant human prostate and associations with clinical outcome. Five normal prostates from organ donors and 159 radical prostatectomy specimens from patients with clinically localized PC were assessed for ERbeta expression using immunohistochemistry. ERbeta-positivity was defined as > or =5% of cells demonstrating nuclear immunoreactivity. All of the five normal prostates showed strong ERbeta-nuclear staining in >95% of the epithelium and 35% of the stromal cells. The number of ERbeta-positive cases declined to 24.2% (38/157) in hyperplasia adjacent to carcinoma and 11.3% (18/159) in PCs. ERbeta-positivity was related to decreased relapse-free survival (log-rank P = 0.04). Thus, loss of ERbeta expression is associated with progression from normal prostate epithelium to PC, whereas those cancers that retained ERbeta expression were associated with a higher rate of recurrence. These data identify the need to further investigate the potential role of ERbeta in the regulation of prostate epithelial cell proliferation and the functional consequences of decreased ERbeta expression in the evolution of PC.

Methods to detect P-glycoprotein-associated multidrug resistance in patients' tumors: consensus recommendations.

Multidrug resistance (MDR), especially that associated with overexpression of MDR1 and its product, P-glycoprotein (Pgp), is thought to play a role in the outcome of therapy for some human tumors; however, a consensus conclusion has been difficult to reach, owing to the variable results published by different laboratories. Many factors appear to influence the detection of Pgp in clinical specimens, including its low and heterogeneous expression; conflicting definitions of detection end points; differences in methods of sample preparation, fixation, and analysis; use of immunological reagents with variable Pgp specificity and avidity and with different recognition epitopes; use of secondary reagents and chromogens; and differences in clinical end points. Also, mechanisms other than Pgp overexpression may contribute to clinical MDR. The combined effect of these factors is clearly important, especially among tumors with low expression of Pgp. Thus, a workshop was organized in Memphis, Tennessee, to promote the standardization of approaches to MDR1 and Pgp detection in clinical specimens. The 15 North American and European institutions that agreed to participate conducted three preworkshop trials with well-characterized MDR myeloma and carcinoma cell lines that expressed increasing amounts of Pgp. The intent was to establish standard materials and methods for a fourth trial, assays of Pgp and MDR1 in clinical specimens. The general conclusions emerging from these efforts led to a number of recommendations for future studies: (a) although detection of Pgp and MDR1 is at present likely to be more reliable in leukemias and lymphomas than in solid tumors, accurate measurement of low levels of Pgp expression under most conditions remains an elusive goal; (b) tissue-specific controls, antibody controls, and standardized MDR cell lines are essential for calibrating any detection method and for subsequent analyses of clinical samples; (c) use of two or more vendor-standardized anti-Pgp antibody reagents that recognize different epitopes improves the reliability of immunological detection of Pgp; (d) sample fixation and antigen preservation must be carefully controlled; (e) multiparameter analysis is useful in clinical assays of MDR1/Pgp expression; (f) immunostaining data are best reported as staining intensity and the percentage of positive cells; and (g) arbitrary minimal cutoff points for analysis compromise the reliability of conclusions. The recommendations made by workshop participants should enhance the quality of research on the role of Pgp in clinical MDR development and provide a paradigm for investigations of other drug resistance-associated proteins.

Secondary acute myeloid leukemia in children previously treated with alkylating agents, intercalating topoisomerase II inhibitors, and irradiation.

PURPOSE: Patient records were reviewed to identify cases of secondary acute myeloid leukemia (AML) with clinical and cytogenetic features characteristic of classic epipodophyllotoxin-related AML in patients whose prior treatment for cancer did not include these agents. PATIENTS AND METHODS: Four cases of secondary AML with chromosomal abnormalities involving bands 11q23 and 21q22, in the absence of prior treatment with etoposide or teniposide, were identified among patients treated at St Jude Children's Research Hospital between January 1980 and April 1992. RESULTS: The four identified patients were initially treated for rhabdomyosarcoma, non-Hodgkin's lymphoma (n = 2), and Hodgkins' disease. Prior chemotherapy included relatively low cumulative doses of doxorubicin (median, 150 mg/m2; range, 120 to 375 mg/m2) and cyclophosphamide (median, 3,100 mg/m2; range, 2,250 to 11,400 mg/m2). All four patients had received radiation therapy: 59.4 Gy to the right middle ear for rhabdomyosarcoma; 15 Gy and 12 Gy to the abdomen and right lower quadrant, respectively, for non-Hodgkin's lymphoma; 27 Gy to the right orbit for non-Hodgkin's lymphoma; and 36.6 Gy to the mantle-paraaortic-spleen regions plus 20.4 Gy inverted-Y radiation at relapse for Hodgkin's disease. Secondary AML was diagnosed a median of 38 months after initial diagnosis (range, 14 to 55). Leukemic cell translocations involved band 11q23 in two cases and band 21q22 in two. Although all patients obtained a complete remission (CR), only one remains disease-free (at 34 months), following an allogeneic bone marrow transplant. CONCLUSION: Intercalating topoisomerase II inhibitors (doxorubicin, dactinomycin), when combined with alkylating agents and irradiation, may cause secondary AML.

Randomized comparison of pentostatin versus interferon alfa-2a in previously untreated patients with hairy cell leukemia: an intergroup study.

PURPOSE: Therapy of hairy cell leukemia has markedly improved. Interferon alfa-2a and pentostatin are active agents. The National Cancer Institute organized an intergroup trial to compare these agents prospectively in untreated patients. METHODS: Patients were randomized to receive either interferon alfa-2a (3 x 10(6) U subcutaneously three times per week) or pentostatin (4 mg/m2 intravenously every 2 weeks). Patients who did not respond to initial treatment were crossed over. RESULTS: Of 356 patients on study, 313 were eligible. Among interferon patients, 17 of 159 (11%) achieved a confirmed complete remission and 60 of 159 (38%) had a confirmed complete or partial remission. Among pentostatin patients, 117 of 154 (76%) achieved a confirmed complete remission and 121 of 154 (79%) had a confirmed complete or partial remission. Additional patients achieved criteria for complete remission, but lacked confirmatory follow-up evaluation. Response rates were significantly higher (P < .0001) and relapse-free survival was significantly longer with pentostatin than interferon (P < .0001). The median follow-up duration is 57 months (range, 19 to 82). Myelosuppression was more frequent with pentostatin (P = .013). A multivariate logistic regression analysis of the confirmed complete remissions on pentostatin showed the following factors to be important for achieving a complete remission: high hemoglobin level (two-tailed P = .024), young age (P = .0085), and no or little splenomegaly (P = .0029). CONCLUSION: Both agents were well tolerated. Pentostatin produced higher response rates, and the responses were durable. Patient age and clinical status had an impact on outcome with pentostatin. Pentostatin is effective therapy for hairy cell leukemia.

Improved survival for children with B-cell acute lymphoblastic leukemia and stage IV small noncleaved-cell lymphoma: a pediatric oncology group study.

PURPOSE: In an effort to improve outcome for children with advanced B-cell malignancies, a treatment plan based on a published regimen that consists of four courses of fractionated cyclophosphamide (cyclo) given with doxorubicin (doxo) and vincristine (VCR) was intensified by alternating with sequential high-dose methotrexate (MTX) and cytarabine (Ara-C), given in conjunction with intrathecal (IT) MTX and Ara-C. PATIENTS AND METHODS: From October 1986 to October 1992, 133 eligible patients were enrolled: 74 with B-cell (surface immunoglobulin-positive [Slg+] acute lymphoblastic leukemia (B-ALL) and 59 with stage IV small noncleaved-cell lymphoma (SNCCL). The median age was 8 years; there were 103 males and 30 females. Abdominal tumor masses were prominent in 63 cases (33 B-ALL and 30 stage IV SNCCL). RESULTS: Complete remission (CR) was achieved in 66 B-ALL and 57 stage IV patients (93% overall). At 4 years, the estimated event-free survival (EFS) rate is 65% +/- 8% for patients with B-ALL and 79% +/- 9% for those with stage IV SNCCL. Among patients with CNS involvement, 23 of 36 remain in CR (4-year EFS rate, 64% +/- 13%). Relapses occurred early; only 3 patients relapsed after completion of therapy. Thirteen relapses occurred in the marrow, three in the CNS, and six in other sites. Of 11 CNS-positive patients who relapsed, only two recurred primarily in the CNS. CONCLUSION: The results of this study indicate that with intensified chemotherapy an increasing potential for cure exists for patients with B-ALL and stage IV SNCCL.

Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia.

The National Cancer Institute (NCI) sponsored a workshop to develop a set of standardized diagnostic and response criteria for acute myeloid leukemia (AML) clinical trials. The French-American-British (FAB) classification was retained for diagnosing AML, with the addition of patients with bone marrow morphologic features of a myelodysplastic syndrome and less than 30% bone marrow blasts, but with greater than or equal to 30% blasts in the peripheral blood. In this report, there are four important subgroups of AML not defined in the FAB classification that are discussed: undifferentiated acute leukemia, MO (AML lacking definitive myeloid differentiation by morphology or conventional cytochemistry but with ultrastructural or immunophenotypic evidence for AML), mixed lineage leukemia, and hypocellular AML. Definitions of response for clinical trials are presented to facilitate comparisons among different studies. Complete remission is considered the only response worth reporting in phase III trials, since lesser responses do not improve survival. Partial remissions may be of interest to identify active new agents in phase I and II studies. Monoclonal antibodies and cytogenetic studies are not part of the routine assessment of remission or reassessment at relapse, and their role in the evaluation of patients with AML is currently being evaluated in clinical trials. Although we recognize that some of the definitions in this report are arbitrary, generalized use of these guidelines will make results of clinical trials more comparable and interpretable.