International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia.

Most patients with chronic lymphocytic leukemia (CLL) are diagnosed with early-stage disease and managed with active surveillance. The individual course of patients with early-stage CLL is heterogeneous, and their probability of needing treatment is hardly anticipated at diagnosis. We aimed at developing an international prognostic score to predict time to first treatment (TTFT) in patients with CLL with early, asymptomatic disease (International Prognostic Score for Early-stage CLL [IPS-E]). Individual patient data from 11 international cohorts of patients with early-stage CLL (n = 4933) were analyzed to build and validate the prognostic score. Three covariates were consistently and independently correlated with TTFT: unmutated immunoglobulin heavy variable gene (IGHV), absolute lymphocyte count higher than 15 × 109/L, and presence of palpable lymph nodes. The IPS-E was the sum of the covariates (1 point each), and separated low-risk (score 0), intermediate-risk (score 1), and high-risk (score 2-3) patients showing a distinct TTFT. The score accuracy was validated in 9 cohorts staged by the Binet system and 1 cohort staged by the Rai system. The C-index was 0.74 in the training series and 0.70 in the aggregate of validation series. By meta-analysis of the training and validation cohorts, the 5-year cumulative risk for treatment start was 8.4%, 28.4%, and 61.2% among low-risk, intermediate-risk, and high-risk patients, respectively. The IPS-E is a simple and robust prognostic model that predicts the likelihood of treatment requirement in patients with early-stage CLL. The IPS-E can be useful in clinical management and in the design of early intervention clinical trials.

Common single nucleotide polymorphisms in transient receptor potential melastatin type 6 increase the risk for proton pump inhibitor-induced hypomagnesemia: a case-control study.

OBJECTIVE: Proton pump inhibitors (PPIs) are effective drugs for the treatment of gastric acid-related disorders. Serious adverse events are rare for PPIs, but recent data suggest that PPIs cause hypomagnesemia. The aim of this study was to estimate the frequency of PPI-induced hypomagnesemia and to define the risk factors for its development. MATERIALS AND METHODS: A total of 133 chronic users of PPIs were enrolled and patients were distinguished on the basis of their serum Mg concentrations. Common single nucleotide polymorphisms (SNPs) in the candidate gene, transient receptor potential melastatin type 6 (TRPM6), were screened. RESULTS: Seventeen out of 133 patients had PPI-induced hypomagnesemia. The duration of PPI use was longer in those with hypomagnesemia (7.7 vs. 5.2 years). Two common SNPs in TRPM6 (rs3750425 and rs2274924) increased the risk for PPI-induced hypomagnesemia by 5.8-fold. CONCLUSION: We found hypomagnesemia in 13% of PPI users. SNPs in TRPM6 drive the risk of developing hypomagnesemia during chronic PPI use.

Aerial remote sensing of sub-sea dispersant injection effects during the Deepwater Horizon (MC-252) oil spill.

During the Deepwater Horizon oil spill in 2010, subsea dispersant injection (SSDI) was utilized for the first time in an effort to reduce the amount of oil reaching the sea surface and thus potentially decrease its environmental impact and enhance responders' safety. Since then, controversy has developed about SSDI's effectiveness. Most of the analysis is based on modeling, with some models concluding SSDI significantly reduced surfacing oil volumes, and others predicting that processes unrelated to the dispersant caused most of the subsurface oil retention. This study utilized a multispectral aerial sensor image time series to correlate the surface area covered by freshly upwelled oil with changes in SSDI rates, accounting for an approximate 4 hour oil rise time lag. A significant negative correlation was found between oil-covered surface area and SSDI rates, providing direct observation support that the technique did reduce the amount of surfacing oil around the wellhead.

Correlation of the combined symptom and medication score with quality of life, symptom severity and symptom control in allergic rhinoconjunctivitis.

Background: The European Academy of Allergy and Clinical Immunology recommended the Combined Symptom and Medication Score (CSMS) as primary endpoint in clinical trials on allergen-specific immunotherapy (AIT) in allergic rhinoconjunctivitis. Here, the correlation between the CSMS and the validated standardised Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ(S)), Rhinitis Control Assessment Test (RCAT) and Visual Analogue Scale (VAS) was analysed. Methods: Two prospective, multicentre, non-interventional studies on tree pollen, grass pollen and house dust mite allergic patients were performed. The first study comprised 167 patients receiving AIT (AIT population), and the second included 56 patients treated with symptomatic medication only (control population). For up to two seasons (pollen)/exposure periods (house dust mites), participants documented their symptoms and medication intake in a CSMS diary, including VAS. In addition, the standardised RQLQ(S) and the RCAT were completed during study visits. Results: Comparison between CSMS and RQLQ(S) revealed a positive correlation in the AIT population (r = 0.426) and in the control population (r = 0.569). For CSMS and RCAT, a negative correlation with r = -0.409 (AIT) and r = -0.547 (control) was shown. Positive correlation between CSMS and VAS was also demonstrated with r = 0.585 (AIT) and r = 0.563 (control). Conclusion: These results support the assumption that the CSMS correlates with quality of life, symptom severity and symptom control on the one hand, while the moderate strength of correlations on the other hand mirrors distinctions of the CSMS compared to the assessments used here.

Brain-derived neurotrophic factor stimulates growth of pituitary melanotrope cells in an autocrine way.

Brain-derived neurotrophic factor (BDNF) is expressed in the mammalian pituitary gland, in both the anterior and intermediate lobes, where its functional significance is unknown. Melanotrope cells in the intermediate pituitary lobe of the amphibian Xenopus laevis also produce BDNF, which co-exists in secretory granules with α-melanophore-stimulating hormone (α-MSH), a peptide that causes pigment dispersion in dermal melanophores during adaptation of the toad to a dark background. Xenopus melanotropes are highly plastic, undergoing very strong growth to support the high biosynthesis and release of α-MSH in black-adapted animals. In this study we have tested our hypothesis that this enhanced growth of the melanotrope is maintained by autocrine release of BDNF. Furthermore, since the extracellular-regulated kinase (ERK) pathway is a major component of BDNF signaling in neuronal plasticity, we investigated its involvement in melanotrope cell growth. For these purposes melanotropes were treated for 3 days in vitro, with either an anti-BDNF serum or a recombinant tropomyosin-receptor kinase B (TrkB) receptor fragment to eliminate released BDNF, or with the ERK inhibitor U0126. We also applied a novel inhibitor of the TrkB receptor, cyclotraxin-B, to test this receptor's involvement in melanotrope cell growth regulation. All treatments markedly reduced melanotrope cell growth. Therefore, we conclude that autocrine release of BDNF and subsequent TrkB-dependent ERK-mediated signaling is important for melanotrope cell growth during its physiologically induced activation.

Shortened up-dosing with sublingual immunotherapy drops containing tree allergens is well tolerated and elicits dose-dependent clinical effects during the first pollen season.

BACKGROUND: This study compared a rapid home-based up-dosing schedule for sublingual immunotherapy (SLIT) drops containing tree pollen allergens with two previously established schedules. Furthermore, the clinical effect of the SLIT was investigated with respect to patients' first pollen season under treatment. METHODS: In this open-label, prospective, patient-preference, non-interventional study, local and systemic reactions were compared between three up-dosing groups using a SLIT formulation containing birch, alder, and hazel pollen extracts (ORALVAC® Compact Bäume). Clinical improvement after patients' first season under treatment was analysed using symptom scores, ARIA classification, symptom control, and the use of symptomatic medication and was compared with data from the previous, pre-treatment pollen season. As the real-life study design allowed no placebo group, the late-treated patients (co-seasonal) served as a control, and crowd-sourced symptom data from persons with hay fever were used from a free web-based online diary. RESULTS: In 33 study centres in Germany and Austria, 164 patients were included. The treatment was well tolerated, without difference between the groups during the up-dosing phase. At the end of the assessment, 96.1% rated the tolerability of the treatment as good or very good. Local reactions were mostly mild in severity and no serious adverse events occurred. Symptom scores decreased from the 2016 pollen season to the 2017 pollen season. As for the ARIA classification, 79.0% of patients had persistent, moderate-to-severe rhinitis before treatment, but only 18.6% had the same classification after treatment. In all, 62.4% of patients achieved symptom control, and 34.3% of patients required no symptomatic medication after treatment. The rhinoconjunctivitis score was 34.4% lower for pre-seasonal treatment initiation than for the control group. Crowd-sourced symptom load indices showed that the 2016 season caused slightly more symptoms; however, it is assumed that this difference of 0.3-0.5 (score range 0-10) was of less clinical relevance. CONCLUSION: The treatment administered using the rapid home-based up-dosing schedule was safe and well tolerated. Symptom relief and reduction in medication use were observed during the first pollen season with SLIT. TRIAL REGISTRATION NUMBER: NCT03097432 (clinicaltrials.gov).

Design and synthesis of 3-pyrrol-3-yl-3H-isobenzofuran-1-ones as inhibitors of human cytosolic phospholipase A2alpha.

A series of 3-pyrrol-3-yl-3H-isobenzofuran-1-ones was synthesized and assessed for the ability to inhibit cytosolic phospholipase A(2)alpha (cPLA(2)alpha). Several of these compounds were found to be active in both a cell based assay and an isolated enzyme assay. The most potent inhibitor was the thiazolidine-2,4-dione substituted derivative 35. With IC(50)-values of 0.7 muM and 7.3 muM in the cellular and isolated enzyme assay, respectively, it possesses similar inhibitory potency as the known cPLA(2)alpha inhibitor arachidonyltrifluoromethyl ketone (AACOCF(3)). Structure-activity relationship studies revealed that the evaluated isobenzofuran-1-ones seem to exert their cellular activities not only by a direct interaction with the enzyme but also by other as yet unknown mechanisms.

Characterization of surface oil thickness distribution patterns observed during the Deepwater Horizon (MC-252) oil spill with aerial and satellite remote sensing.

Knowledge of the spatial distribution of oil thickness patterns within an on-water spill is of obvious importance for immediate spill response activities as well as for subsequent evaluation of the spill impacts. For long-lasting continuous spills like the 2010 3-month Deepwater Horizon (DWH) event in the Gulf of Mexico, it is also important to identify changes in the dominant oil features through time. This study utilized very high resolution (≤5m) aerial and satellite imagery acquired during the DWH spill to evaluate the shape, size and thickness of surface oil features that dominated the DWH slick. Results indicate that outside of the immediate spill source region, oil distributions did not encompass a broad, varied range of thicknesses. Instead, the oil separated into four primary, distinct characterizations: 1) invisible surface films detectable only with Synthetic Aperture Radar imaging because of the decreased surface backscatter, 2) thicker sheen & rainbow areas (<0.005mm), 3) large regional areas of relatively thin, "metallic appearance" films (0.005-0.08mm), and 4) strands of thick, emulsified oil (>1mm) that were consistently hundreds of meters long but most commonly only 10-50m wide. Where present within the slick footprint, each of the three distinct visible oil thickness classes maintained its shape characteristics both spatially (at different distances from the source and in different portions of the slick), and temporally (from mid-May through July 2010). The region over the source site tended to contain a more continuous range of oil thicknesses, however, our results indicate that the continuous injection of subsurface dispersants starting in late May significantly altered (lowered) that range. In addition to characterizing the oil thickness distribution patterns through the timeline of one of the world's largest oil spills, this paper also details the extension of using high resolution aerial imagery to calibrate medium resolution satellite data sources such as USA's Thematic Mapper (30m) to provide larger-scale spatial views of major spills, and discusses implications for utilizing such data for oil spill characterizations and spill response.

Long-term follow-up of a prospective study of combined modality therapy for stage I-II indolent non-Hodgkin's lymphoma.

PURPOSE: Standard therapy for patients with stage I-II indolent lymphoma has been involved-field radiation therapy (IF-XRT), which achieves 10-year disease-free survival in 40% to 50% of patients, with many of these patients cured. We investigated the potential for combined-modality therapy to increase the disease-free survival for such patients. PATIENTS AND METHODS: A total of 102 eligible patients with stage I-II low grade lymphoma (International Working Formulation criteria) were enrolled from 1984 to 1992. Treatment comprised 10 cycles of risk-adapted chemotherapy (cyclophosphamide, vincristine, prednisone, bleomycin [COP-Bleo], and with doxorubicin added for some [CHOP-Bleo]) and 30 to 40 Gy IF-XRT. RESULTS: The patients' median age was 56 years (range, 28 to 77), with follicular histology in 83%, bulky disease (>/= 5 cm) in 24%, and stage II in 52%. There were no treatment-related deaths and 99% of patients attained complete remission. With a median follow-up of 10 years, the 10-year time to treatment failure and overall survival were 76% and 82%, respectively. For patients with follicular lymphoma, these figures were 72% and 80%, respectively. The only factor associated with treatment failure, for follicular lymphoma patients, was stage-modified International Prognostic Factors Index score (P =.02). None of 17 patients with diffuse small lymphocytic or mucosa-associated lymphoid tissue histology have relapsed. Elevated serum beta2-microglobulin was associated with shorter survival (P <.0001). The 10-year survival after relapse was 46%. There have been two cases of myelodysplasia and 12 other new malignancies, including four arising within radiation fields. CONCLUSION: With prolonged follow-up, combined-modality therapy with risk-adapted COP-/CHOP-Bleo and IF radiation has attained higher rates of disease control and survival than previously reported with IF-XRT alone. This apparent improvement is being further explored in an ongoing randomized trial.

Time- and frequency-domain models for Smith-Purcell radiation from a two-dimensional charge moving above a finite length grating.

Smith-Purcell radiation (SPR), formed by an electron beam traveling above a grating, is a very promising source of coherent radiation from the THz to the optical regime. We present two theoretical calculations of the SPR from a two-dimensional bunch of relativistic electrons passing above a grating of finite length. The first calculation uses the finite-difference time-domain approach with the total-field/scattered-field procedure for fields incident on the grating. This calculation allows good physical insight into the radiation process and also allows arbitrary geometries to be treated. The second calculation uses an electric-field integral equation method. Good agreement is obtained between these two calculations. The results of these theoretical calculations are then compared with a theoretical formalism based on an infinite-length grating. The latter formalism allows periodic boundary conditions to be rigorously applied. For gratings with less than approximately 50 periods, a significant error in the strength of the radiated field is introduced by the infinite-grating approximation. It is shown that this error disappears asymptotically as the number of periods increases. The Wood-Rayleigh anomalies, predicted in the infinite-grating approximation, were not seen in our finite-grating calculations. The SPR resonance condition is the same in all three formalisms. Numerical examples are presented for an approximately 18 MeV, 50 nC/m, 200 microm bunch traveling 0.6 mm above a ten-period echelle grating having a 2.-mm periodicity.

Dietary Inulin Fibers Prevent Proton-Pump Inhibitor (PPI)-Induced Hypocalcemia in Mice.

BACKGROUND: Proton-pump inhibitor-induced hypomagnesemia (PPIH) is the most recognized side effect of proton-pump inhibitors (PPIs). Additionally, PPIH is associated with hypocalcemia and hypokalemia. It is hypothesized that PPIs reduce epithelial proton secretion and thereby increase the pH in the colon, which may explain the reduced absorption of and Mg2+ and Ca2+. Fermentation of dietary oligofructose-enriched inulin fibers by the microflora leads to acidification of the intestinal lumen and by this enhances mineral uptake. This study aimed, therefore, to improve mineral absorption by application of dietary inulin to counteract PPIH. METHODS: Here, C57BL/J6 mice were supplemented with omeprazole and/or inulin. Subsequently, Mg2+ and Ca2+ homeostasis was assessed by means of serum, urine and fecal electrolyte measurements. Moreover, the mRNA levels of magnesiotropic and calciotropic genes were examined in the large intestine and kidney by real-time PCR. RESULTS: Treatment with omeprazole significantly reduced serum Mg2+ and Ca2+ levels. However, concomitant addition of dietary inulin fibers normalized serum Ca2+ but not serum Mg2+ concentrations. Inulin abolished enhanced expression of Trpv6 and S100g in the colon by omeprazole. Additionally, intestinal and renal mRNA levels of the Trpm6 gene were reduced after inulin intake. CONCLUSIONS: This study suggests that dietary inulin counteracts reduced intestinal Ca2+ absorption upon PPI treatment. In contrast, inulin did not increase intestinal absorption of Mg2+ sufficiently to recover serum Mg2+. The clinical potential of dietary inulin treatment should be the subject of future studies.

Stage III follicular lymphoma: long-term follow-up and patterns of failure.

PURPOSE: To analyze the long-term outcomes and pattern of failures for Stage III follicular lymphomas. METHODS AND MATERIALS: A retrospective review of all patients with Stage III follicular lymphoma presented to our institution between 1978 and 1993 was performed. One hundred ten patients were eligible and form the basis of this analysis. Fifty-seven patients were male. The median age was 57 years (range: 21-82 years). The treatments were as follows: chemotherapy alone (CTX), 39 patients; combined modality with chemotherapy and radiation therapy (CMT), 69; radiation therapy alone, 2. Radiation therapy fields were as follows: regional, 13 patients; extended, 6; subtotal, 44; and central lymphatic, 8. The median number of chemotherapy cycles was 8, and 98 patients received doxorubicin-containing regimens. Enough information was available to calculate the International Prognostic Index for 107 patients. The following prognostic factors were examined for predictive value in overall survival (OS) and freedom from progression (FFP) by univariate and multivariate analyses: International Prognostic Index, gender, lactate dehydrogenase (LDH) (normal vs. elevated), B symptoms, performance status, beta-2 microglobulin, presence or absence of a bulky disease, age (60 years), number of sites of involvement, treatment (CTX vs. CMT), and pathology. To minimize patient selection biases given the nature of the retrospective analysis, the patterns of relapse were analyzed only for the patients who achieved a complete response. RESULTS: The median follow-up for the alive patients was 9.5 years (range: 1.1-19.5 years). Complete response was achieved in 80 patients: 24 of 39 patients in the CTX group (62%), 54 of 69 patients in the CMT group (78%), and 2 of 2 patients in the radiation therapy alone group. The actuarial 5- and 10-year OS rates were 65% and 42%, respectively. The 5- and 10-year FFP was 42% and 26%, respectively. Significant prognostic factors by multivariate analyses were age and LDH for OS and LDH for FFP. For complete responders, 5-year freedom from recurrence in the original sites of involvement (with or without recurrence in the new sites) was 43% for CTX and 60% for CMT patients (p = 0.03, Wilcoxon). Five-year freedom from isolated recurrence in the original sites of involvement was 60% for CTX and 69% for CMT patients (p = 0.17). The 5-year overall FFP was 43% for CTX patients and 56% for CMT patients (p = 0.06). CONCLUSION: Combined modality treatment seems to give an advantage in terms of disease control in the primary sites compared to chemotherapy alone, though the advantages in OS and FFP were not statistically significant in our patient population. By multivariate analyses, LDH was a significant prognostic indicator for OS and FFP, whereas age was for OS.

Central lymphatic irradiation for stage I-III follicular lymphoma: report from a single-institutional prospective study.

PURPOSE: This study was undertaken to update our experience with follicular lymphoma treated with central lymphatic irradiation (CLI). METHODS AND MATERIALS: A total of 47 patients were treated with CLI between January 1993 and March 2000 in a prospective manner. CLI consisted of mantle, whole abdomen, and pelvic radiation fields with a 1-month break after each field. Each field was treated to 3000-3060 cGy at 150-180 cGy per fraction followed by a boost dose of 900 cGy to the areas with gross disease. The median age was 52 years (range: 29-73 years). There were 29 males. The diagnoses were as follows: follicular small cleaved-cell lymphoma, 23 patients; follicular mixed-cell lymphoma, 19 patients; follicular large-cell lymphoma, 5 patients. Ann Arbor stages were as follows: I, 5 patients; II, 14 patients; and III, 28 patients. The International Prognostic Index (IPI) categories were as follows: 0, 14 patients; 1, 24 patients; and 2, 9 patients. M. D. Anderson Tumor Score was as follows: 0, 14 patients; 1, 18 patients; 2, 9 patients; 3, 4 patients; 4, 1 patient; and unknown, 1 patient. Two patients had abnormal LDH levels, and 11 patients had beta2M levels >2 mg/dL. Gender, pathology, stage, IPI, Anderson Tumor Score, beta2M, and number of disease sites were examined for significance in freedom from progression (FFP) by univariate analyses. RESULTS: The median follow-up was 54 months (range: 8-93 months) for the 45 surviving patients. Every patient achieved a complete response, except for 1 patient whose lymphoma progressed to diffuse large-cell lymphoma during treatment. The 5-year overall survival and FFP were 94% and 53%, respectively. No failure has yet been observed beyond 55 months of follow-up with 13 patients at risk. Patterns of failure were as follows: within the radiation field, 10; outside the fields, 4; and both, 2. Of the seven variables investigated, beta2M >2 mg/dL and IPI >1 were the only significant adverse prognostic factors for FFP (p = 0.023 and 0.046, respectively). CONCLUSIONS: CLI is well tolerated and seems to achieve durable FFP in about half of the patients with Stage I-III follicular lymphoma. Most of the experiences with CLI come from the treatment of Stage III disease and are very similar to our previous experience with combined modality treatment. Whether a plateau in FFP can be maintained beyond 5 years remains to be seen.

1-(3-biaryloxy-2-oxopropyl)indole-5-carboxylic acids and related compounds as dual inhibitors of human cytosolic phospholipase A2α and fatty acid amide hydrolase.

Cytosolic phospholipase A2α (cPLA2α) and fatty acid amide hydrolase (FAAH) are enzymes that have emerged as attractive targets for the development of analgesic and anti-inflammatory drugs. We recently reported that 1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid (5) is a dual inhibitor of cPLA2α and FAAH. Structure-activity relationship studies revealed that substituents at the indole 3- and 5-positions and replacement of the indole scaffold of this compound by other heterocycles strongly influences the inhibitory potency against cPLA2α and FAAH, respectively. Herein we report the effect of variation of the 4-octyl residue of 5 and an exchange of its carboxylic acid moiety by some bioisosteric functional groups. Several of the compounds assayed were favorably active against both enzymes, and could therefore represent agents with improved analgesic and anti-inflammatory qualities in comparison with selective cPLA2 α and FAAH inhibitors.

Characterization of the cellular and antitumor effects of MPI-0479605, a small-molecule inhibitor of the mitotic kinase Mps1.

Mps1 is a dual specificity protein kinase that is essential for the bipolar attachment of chromosomes to the mitotic spindle and for maintaining the spindle assembly checkpoint until all chromosomes are properly attached. Mps1 is expressed at high levels during mitosis and is abundantly expressed in cancer cells. Disruption of Mps1 function induces aneuploidy and cell death. We report the identification of MPI-0479605, a potent and selective ATP competitive inhibitor of Mps1. Cells treated with MPI-0479605 undergo aberrant mitosis, resulting in aneuploidy and formation of micronuclei. In cells with wild-type p53, this promotes the induction of a postmitotic checkpoint characterized by the ATM- and RAD3-related-dependent activation of the p53-p21 pathway. In both wild-type and p53 mutant cells lines, there is a growth arrest and inhibition of DNA synthesis. Subsequently, cells undergo mitotic catastrophe and/or an apoptotic response. In xenograft models, MPI-0479605 inhibits tumor growth, suggesting that drugs targeting Mps1 may have utility as novel cancer therapeutics.

1-(5-Carboxy- and 5-carbamoylindol-1-yl)propan-2-ones as inhibitors of human cytosolic phospholipase A2alpha: bioisosteric replacement of the carboxylic acid and carboxamide moiety.

Indole-5-carboxylic acids and -carboxamides with 3-aryloxy-2-oxopropyl residues in position 1 were previously reported to be potent inhibitors of cytosolic phospholipase A(2)alpha (cPLA(2)alpha) isolated from human platelets. In continuation of our attempts to develop novel cPLA(2)alpha inhibitors, a number of derivatives of these substances characterized by bioisosteric replacement of the carboxylic acid and carboxamide functionality, respectively, were prepared. The results of the biological evaluation of the obtained compounds enabled us to gain further insight into structural features critical for cPLA(2)alpha inhibition.

Assessment of chronic lymphocytic leukemia and small lymphocytic lymphoma by absolute lymphocyte counts in 2,126 patients: 20 years of experience at the University of Texas M.D. Anderson Cancer Center.

PURPOSE: Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are currently considered the same entity, but controversy remains over whether CLL and SLL should be treated similarly. We assessed whether characteristics of patients with CLL and SLL differ in ways other than the absolute lymphocyte count (ALC) and evaluated treatment outcomes and prognostic factors. METHODS: We searched the electronic database for patients with CLL or SLL who presented to The University of Texas M.D. Anderson Cancer Center (Houston, TX) between 1985 and 2005. We reviewed patient records to determine presenting characteristics, treatment, and clinical outcomes. Cox models using training and validation sets of patients and resampling methods were used to develop a model predicting survival. RESULTS: Among 2,126 consecutive CLL/SLL patients, 312 (15%) had ALC less than 5 x 10(9)/L. Patients with ALC less than 5 x 10(9)/L had lower rates of cytogenetic abnormalities (P = .0002) and higher rates of CD38-positive results (P = .0002) and had mutated immunoglobulin heavy-chain variable region gene status (P = .034). Rates of response, survival, and failure-free survival (FFS) were not different among ALC groups. Regimens that included rituximab and a nucleoside analog were associated with superior rates of response and FFS compared with other therapies, irrespective of ALC. Deletion 17p or 6q with or without other cytogenetic abnormalities, age at least 60 years, beta2-microglobulin at least 2 mg/L, albumin less than 3.5 g/dL, and creatinine at least 1.6 mg/dL were each found to independently predict shorter survival and formed the basis of a scoring system. CONCLUSION: Patients with CLL or SLL can be treated similarly. A new prognostic score is proposed.

Improvement of overall and failure-free survival in stage IV follicular lymphoma: 25 years of treatment experience at The University of Texas M.D. Anderson Cancer Center.

PURPOSE: Advanced-stage follicular lymphoma is considered incurable. The pace of improvements in treatment has been slow. This article analyzes five sequential cohorts of patients with stage IV follicular lymphoma treated between 1972 and 2002. METHODS: Five consecutive studies (two were randomized trials) involving 580 patients were analyzed for overall survival (OS), failure-free survival (FFS), and survival after first relapse. A proportional hazards analysis, and subset analyses using the follicular lymphoma international prognostic index (FLIPI) score were performed. Treatment regimens included: cyclophosphamide, doxorubicin, vincristine, prednisone, bleomycin (CHOP-Bleo); CHOP-Bleo followed by interferon alfa (IFN-alpha); a rotation of three regimens (alternating triple therapy), followed by IFN-alpha; fludarabine, mitoxantrone, dexamethasone (FND) followed by IFN-alpha; and FND plus delayed versus concurrent rituximab followed by IFN-alpha. RESULTS: Improvements in 5-year OS (from 64% to 95%) and FFS (from 29% to 60%) indicate steady progress, perhaps partly due to more effective salvage therapies, but the FFS data also indicate improved front-line therapies; these observations held true after controlling for differences in prognostic factors among the cohorts. The FLIPI model adds rigor to and facilitates comparisons among the different cohorts. An unexpected finding in this study was a trend toward an apparent FFS plateau. CONCLUSION: Evolving therapy, including the incorporation of biologic agents, has led to stepwise significant outcome improvements for patients with advanced-stage follicular lymphoma. The apparent plateau in the FFS curve, starting approximately 8 to 10 years from the beginning of treatment, raises the issue of the potential curability of these patients.

Prognostic factors and treatment of patients with T-cell non-Hodgkin lymphoma: the M. D. Anderson Cancer Center experience.

BACKGROUND: T-cell non-Hodgkin lymphomas (T-NHL) are more aggressive and patients have a poorer prognosis compared with patients with the corresponding B-cell lymphomas. Although intensive treatments have been developed, it is unknown whether they are more effective than CHOP chemotherapy (cyclophosphamide, doxorubicin, oncovorin, and prednisone). METHODS: The authors' retrospective study evaluated the clinical outcome of 135 previously untreated patients with T-NHL who were treated at The University of Texas M. D. Anderson Cancer Center (Houston, TX) between 1996 and 2002. Lymphomas with T-cell histologies with the exception of mycosis fungoides were included. RESULTS: The estimated median overall survival was 46 months. Thirty-seven percent of the patients received CHOP therapy, 48% received intensive therapy, and 15% received other therapy. The estimated 3-year overall survival rates were 62% for the patients treated with CHOP therapy and 56% for the patients who received intensive therapy. After the exclusion of patients with anaplastic large cell lymphoma (ALCL), who are known to have a better prognosis than patients with other T-NHLs, the estimated 3-year overall survival rates were 43% for the patients treated with CHOP therapy and 49% for the patients who received intensive therapy. Parameters that may be independent prognostic factors for survival in T-NHL, excluding ALCL, included ECOG performance status > or = 2, beta-2-microglobulin level > 2 mg/L, lactate dehydrogenase level higher than normal, bulky disease > or = 7 cm, and a higher international prognostic index and tumor score. CONCLUSIONS: The current study data suggested that patients treated with intensive therapies did not fare better than those treated with CHOP therapy. New treatment regimens need to be developed for patients with T-NHL.

Radiotherapy alone for lymphocyte-predominant Hodgkin's disease.

PURPOSE: The purpose of the study was to analyze the results with radiotherapy alone in a select group of asymptomatic adults with nonbulky, early-stage lymphocyte-predominant Hodgkin's disease. PATIENTS AND METHODS: Between 1963 and 1995, 36 patients with nonbulky stage IA (N = 27) or IIA (N = 9) supradiaphragmatic (N = 27) or subdiaphragmatic (N = 9) lymphocyte-predominant Hodgkin's disease were treated with radiotherapy alone. Eleven of the patients underwent laparotomy. Limited-field radiotherapy involving only one side of the diaphragm and extended-field radiotherapy encompassing both sides of the diaphragm were used in 28 and 8 cases, respectively. Median dose to involved areas was 40.0 Gy given daily in 20 2.0-Gy fractions. Salvage treatmentconsisted of MOPP (mechlorethamine, vincristine, prednisone, procarbazine), CVPP/ABDIC (cyclophosphamide, vinblastine, procarbazine and prednisone/doxorubicin, bleomycin, dacarbazine, lomustine, and prednisone), or ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy and/or involved-field radiotherapy. RESULTS: Median follow-up was 8.8 years (range, 3.0-34.4 years). None of the 15 patients with supradiaphragmatic disease who received limited-field radiotherapy to regions that did not include the mediastinal or hilar nodes subsequently experienced relapse there. Only one of 20 patients who received supradiaphragmatic limited-field radiotherapy alone experienced relapse in the paraaortic nodes or spleen. The 5-year relapse-free and overall survival rates for the 20 patients with stage IA lymphocyte-predominant Hodgkin's disease treated with involved-field or regional radiotherapy were 95% and 100%, respectively. There were no cases of severe or life-threatening cardiac toxicity. No solid tumors have been observed in-field in patients treated with limited-field radiotherapy, even though they have been followed up longer than those treated with extended-field radiotherapy (median follow-up, 11.6 vs 5.5 years); two solid tumors have developed in-field in patients who received extended-field radiotherapy. DISCUSSION: Involved-field or regional radiotherapy alone may be adequate in stage IA lymphocyte-predominant Hodgkin's disease patients. Longer follow-up will help to more clearly define the risks of cardiac toxicity and solid tumors that result from involved-field or regional radiotherapy, which appear to be low based on follow-up to date.