Metabolic tumor volume predicts outcome in patients with advanced stage follicular lymphoma from the RELEVANCE trial.

BACKGROUND: We investigated the prognostic value of baseline positron emission tomography (PET) parameters for patients with treatment-naïve follicular lymphoma (FL) in the phase III RELEVANCE trial, comparing the immunomodulatory combination of lenalidomide and rituximab (R2) versus R-chemotherapy (R-chemo), with both regimens followed by R maintenance therapy. PATIENTS AND METHODS: Baseline characteristics of the entire PET-evaluable population (n = 406/1032) were well balanced between treatment arms. The maximal standard uptake value (SUVmax) and the standardized maximal distance between tow lesions (SDmax) were extracted, the standardized distance between two lesions the furthest apart, were extracted. The total metabolic tumor volume (TMTV) was computed using the 41% SUVmax method. RESULTS: With a median follow-up of 6.5 years, the 6-year progression-free survival (PFS) was 57.8%, the median TMTV was 284 cm3, SUVmax was 11.3 and SDmax was 0.32 m-1, with no significant difference between arms. High TMTV (>510 cm3) and FLIPI were associated with an inferior PFS (P = 0.013 and P = 0.006, respectively), whereas SUVmax and SDmax were not (P = 0.08 and P = 0.12, respectively). In multivariable analysis, follicular lymphoma international prognostic index (FLIPI) and TMTV remained significantly associated with PFS (P = 0.0119 and P = 0.0379, respectively). These two adverse factors combined stratified the overall population into three risk groups: patients with no risk factors (40%), with one factor (44%), or with both (16%), with a 6-year PFS of 67.7%, 54.5%, and 41.0%, respectively. No significant interaction between treatment arms and TMTV or FLIPI (P = 0.31 or P = 0.59, respectively) was observed. The high-risk group (high TMTV and FLIPI 3-5) had a similar PFS in both arms (P = 0.45) with a median PFS of 68.4% in the R-chemo arm versus 71.4% in the R2 arm. CONCLUSIONS: Baseline TMTV is predictive of PFS, independently of FLIPI, in patients with advanced FL even in the context of antibody maintenance.

The ECHELON-2 Trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma.

BACKGROUND: For patients with peripheral T-cell lymphoma (PTCL), outcomes using frontline treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like therapy are typically poor. The ECHELON-2 study demonstrated that brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) exhibited statistically superior progression-free survival (PFS) per independent central review and improvements in overall survival versus CHOP for the frontline treatment of patients with systemic anaplastic large cell lymphoma or other CD30-positive PTCL. PATIENTS AND METHODS: ECHELON-2 is a double-blind, double-dummy, randomized, placebo-controlled, active-comparator phase III study. We present an exploratory update of the ECHELON-2 study, including an analysis of 5-year PFS per investigator in the intent-to-treat analysis group. RESULTS: A total of 452 patients were randomized (1 : 1) to six or eight cycles of A+CHP (N = 226) or CHOP (N = 226). At median follow-up of 47.6 months, 5-year PFS rates were 51.4% [95% confidence interval (CI): 42.8% to 59.4%] with A+CHP versus 43.0% (95% CI: 35.8% to 50.0%) with CHOP (hazard ratio = 0.70; 95% CI: 0.53-0.91), and 5-year overall survival (OS) rates were 70.1% (95% CI: 63.3% to 75.9%) with A+CHP versus 61.0% (95% CI: 54.0% to 67.3%) with CHOP (hazard ratio = 0.72; 95% CI: 0.53-0.99). Both PFS and OS were generally consistent across key subgroups. Peripheral neuropathy was resolved or improved in 72% (84/117) of patients in the A+CHP arm and 78% (97/124) in the CHOP arm. Among patients who relapsed and subsequently received brentuximab vedotin, the objective response rate was 59% with brentuximab vedotin retreatment after A+CHP and 50% with subsequent brentuximab vedotin after CHOP. CONCLUSIONS: In this 5-year update of ECHELON-2, frontline treatment of patients with PTCL with A+CHP continues to provide clinically meaningful improvement in PFS and OS versus CHOP, with a manageable safety profile, including continued resolution or improvement of peripheral neuropathy.

Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma.

We report follow-up results from the randomized, placebo-controlled, phase 3 HELIOS trial of ibrutinib+bendamustine and rituximab (BR) for previously treated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) without deletion 17p. Overall, 578 patients were randomized 1:1 to either ibrutinib (420 mg daily) or placebo, in combination with 6 cycles of BR, followed by ibrutinib or placebo alone. Median follow-up was 34.8 months (range: 0.1-45.8). Investigator-assessed median progression-free survival (PFS) was not reached for ibrutinib+BR, versus 14.3 months for placebo+BR (hazard ratio [HR] [95% CI], 0.206 [0.159-0.265]; P < 0.0001); 36-month PFS rates were 68.0% versus 13.9%, respectively. The results are consistent with the primary analysis findings (HR = 0.203, as assessed by independent review committee, with 17-month median follow-up). Median overall survival was not reached in either arm; HR (95% CI) for ibrutinib+BR versus placebo: 0.652 (0.454-0.935; P = 0.019). Minimal residual disease (MRD)-negative response rates were 26.3% for ibrutinib+BR and 6.2% for placebo+BR (P < 0.0001). Incidence of treatment-emergent adverse events (including grades 3-4) were generally consistent with the initial HELIOS report. These long-term data support improved survival outcomes and deepening responses with ibrutinib+BR compared with BR in relapsed CLL/SLL.

A phase II trial of lenalidomide plus rituximab in previously untreated follicular non-Hodgkin's lymphoma (NHL): CALGB 50803 (Alliance).

BACKGROUND: This multicenter, phase II trial tested the tolerability and efficacy of lenalidomide plus rituximab in patients with previously untreated follicular lymphoma (FL). PATIENTS AND METHODS: Patients with grade 1-3a FL, stage 3-4 or bulky stage 2, FL international prognostic index (FLIPI) 0-2, and no prior therapy were eligible to receive rituximab 375 mg/m2 weekly during cycle 1 and day 1 of cycles 4, 6, 8, and 10, plus lenalidomide 20-25 mg on days 1-21 for twelve 28-day cycles. The primary objectives were to evaluate response rates [complete (CR) and overall] and time to progression. Secondary objectives included toxicity, response according to polymorphisms in FcgR2A and FcgR3A, and changes in circulating pro-angiogenic cells. RESULTS: From October 2010 to September 2011, 66 patients were enrolled. Median age was 53 years, 34 were female, 15 had bulky disease, 21 were FLIPI 0-1, 43 FLIPI 2, and 2 FLIPI 3. One patient withdrew before receiving treatment. Fifty-one patients completed 12 cycles of lenalidomide. Reasons for discontinuation included withdrawal (n = 6), adverse events (n = 6), progression (n = 2). Grade 3-4 hematologic toxicity included neutropenia (21%), lymphopenia (9%), and thrombocytopenia (2%), infection (11%), and rash (8%). Grade 1-2 toxicity included fatigue (78%), diarrhea (37%), rash (32%), and febrile neutropenia in one patient. The overall response rate was 95%; the CR rate was 72% (95% confidence interval, 60% to 83%). With a median follow-up of 5 years, the 2- and 5-year progression-free survival were 86% and 70%, respectively, and the 5-year overall survival was 100%. There was no association between CR rate or PFS and FLIPI, histological grade, bulky disease, FcgR2A/FcgR3A polymorphism, or change in circulating endothelial cell/hematopoietic progenitor cell. CONCLUSION: Lenalidomide plus rituximab was associated with low rates of grade 3-4 toxicity, yielded a CR rate and PFS similar to chemotherapy-based treatment and may represent a reasonable alternative to immunochemotherapy in previously untreated FL. CLINICALTRIALS.GOV IDENTIFIER: NCT01145495.

Ultraviolet photochemical reaction of [Fe(III)(C2O4)3](3-) in aqueous solutions studied by femtosecond time-resolved X-ray absorption spectroscopy using an X-ray free electron laser.

Time-resolved X-ray absorption spectroscopy was performed for aqueous ammonium iron(III) oxalate trihydrate solutions using an X-ray free electron laser and a synchronized ultraviolet laser. The spectral and time resolutions of the experiment were 1.3 eV and 200 fs, respectively. A femtosecond 268 nm pulse was employed to excite [Fe(III)(C2O4)3](3-) in solution from the high-spin ground electronic state to ligand-to-metal charge transfer state(s), and the subsequent dynamics were studied by observing the time-evolution of the X-ray absorption spectrum near the Fe K-edge. Upon 268 nm photoexcitation, the Fe K-edge underwent a red-shift by more than 4 eV within 140 fs; however, the magnitude of the redshift subsequently diminished within 3 ps. The Fe K-edge of the photoproduct remained lower in energy than that of [Fe(III)(C2O4)3](3-). The observed red-shift of the Fe K-edge and the spectral feature of the product indicate that Fe(III) is upon excitation immediately photoreduced to Fe(II), followed by ligand dissociation from Fe(II). Based on a comparison of the X-ray absorption spectra with density functional theory calculations, we propose that the dissociation proceeds in two steps, forming first [(CO2 (•))Fe(II)(C2O4)2](3-) and subsequently [Fe(II)(C2O4)2](2-).

The role of body mass index in survival outcome for lymphoma patients: US intergroup experience.

BACKGROUND: The role of body mass index (BMI) in survival outcomes is controversial among lymphoma patients. We evaluated the association between BMI at study entry and failure-free survival (FFS) and overall survival (OS) in three phase III clinical trials, among patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Hodgkin's lymphoma (HL). PATIENTS AND METHODS: A total of 537, 730 and 282 patients with DLBCL, HL and FL were included in the analysis. Baseline patient and clinical characteristics, treatment received and clinical outcomes were compared across BMI categories. RESULTS: Among patients with DLBCL, HL and FL, the median age was 70, 33 and 56; 29%, 29% and 37% were obese and 38%, 27% and 37% were overweight, respectively. Age was significantly different among BMI groups in all three studies. Higher BMI groups tended to have more favorable prognosis factors at study entry among DLBCL and HL patients. BMI was not associated with clinical outcome with P-values of 0.89, 0.30 and 0.40 for FFS, and 0.64, 0.67 and 0.09 for OS, for patients with DLBCL, HL and FL, respectively. The association remains non-significant after adjusting for other clinical factors in the Cox model. A subset analysis of males with DLBCL treated on R-CHOP revealed no differences in FFS (P = 0.48) or OS (P = 0.58). CONCLUSION: BMI was not significantly associated with clinical outcomes among patients with DLBCL, HD or FL, in three prospective phase III clinical trials. The findings contradict some previous reports of similar investigations. Further work is required to understand the observed discrepancies.

IL-15 complexes induce NK- and T-cell responses independent of type I IFN signaling during rhinovirus infection.

Rhinoviruses are among the most common viruses to infect man, causing a range of serious respiratory diseases including exacerbations of asthma and COPD. Type I IFN and IL-15 are thought to be required for antiviral immunity; however, their function during rhinovirus infection in vivo is undefined. In RV-infected human volunteers, IL-15 protein expression in fluid from the nasal mucosa and in bronchial biopsies was increased. In mice, RV induced type I IFN-dependent expressions of IL-15 and IL-15Rα, which in turn were required for NK- and CD8(+) T-cell responses. Treatment with IL-15-IL-15Rα complexes (IL-15c) boosted RV-induced expression of IL-15, IL-15Rα, IFN-γ, CXCL9, and CXCL10 followed by recruitment of activated, IFN-γ-expressing NK, CD8(+), and CD4(+) T cells. Treating infected IFNAR1(-/-) mice with IL-15c similarly increased IL-15, IL-15Rα, IFN-γ, and CXCL9 (but not CXCL10) expression also followed by NK-, CD8(+)-, and CD4(+)-T-cell recruitment and activation. We have demonstrated that type I IFN-induced IFN-γ and cellular immunity to RV was mediated by IL-15 and IL-15Rα. Importantly, we also show that IL-15 could be induced via a type I IFN-independent mechanism by IL-15 complex treatment, which in turn was sufficient to drive IFN-γ expression and lymphocyte responses.

Inhaled dsRNA and rhinovirus evoke neutrophilic exacerbation and lung expression of thymic stromal lymphopoietin in allergic mice with established experimental asthma.

BACKGROUND: Rhinovirus infection or dsRNA stimulation increased thymic stromal lymphopoietin (TSLP), an upstream pro-allergic cytokine, in asthmatic bronchial epithelial cells. We hypothesized that dsRNA challenges superimposed on established experimental allergic asthma constitute a useful exacerbation model. We further hypothesized that TSLP is induced at dsRNA- and rhinoviral infection-induced exacerbations. METHODS: Allergic mice were challenged with OVA followed by three daily intranasal challenges with dsRNA or saline. Bronchoalveolar lavage fluid (BALF) was analysed for total protein, lactate dehydrogenase (LDH), CXCL1/KC, CCL2/MCP-1 and differential cell counts. Lung tissue histology, neutrophils and TSLP, TNF-α, IFN-ß and IFN-λ mRNA were examined. Alternatively, allergen-challenged mice received intranasal rhinovirus-(RV)-1B followed by lung TSLP immunostaining. RESULTS: In mice with allergic airway inflammation, dsRNA challenges caused a significant exacerbation increasing lung tissue inflammation score and tissue neutrophilia. Bronchoalveolar lavage fluid neutrophils, total protein, LDH, CXCL1/KC and CCL2/MCP-1 were also increased (P < 0.01), and so were lung tissue expressions of TNF-α, IFN-λ and TSLP (P < 0.01), but IFN-ß was not increased. TSLP, IFN-λ and LDH were not increased by allergen or dsRNA challenges alone, but increased exclusively at exacerbations. RV1B infection-induced exacerbation also increased lung tissue TSLP (P < 0.05). CONCLUSIONS: dsRNA-induced exacerbation in mice with experimental asthma involved general inflammation, cytokines and interferons, in agreement with previous observations in exacerbating human asthma. Additionally, both dsRNA and RV1B infection increased lung TSLP exclusively at exacerbations. Our data suggest that dsRNA challenges superimposed on allergic inflammation are suited for pharmacological studies of asthma exacerbations including the regulation of lung tissue TSLP, TNF-α, IFN-ß and IFN-λ.

γδT cells suppress inflammation and disease during rhinovirus-induced asthma exacerbations.

Most asthma exacerbations are triggered by virus infections, the majority being caused by human rhinoviruses (RV). In mouse models, γδT cells have been previously demonstrated to influence allergen-driven airways hyper-reactivity (AHR) and can have antiviral activity, implicating them as prime candidates in the pathogenesis of asthma exacerbations. To explore this, we have used human and mouse models of experimental RV-induced asthma exacerbations to examine γδT-cell responses and determine their role in the immune response and associated airways disease. In humans, airway γδT-cell numbers were increased in asthmatic vs. healthy control subjects during experimental infection. Airway and blood γδT-cell numbers were associated with increased airways obstruction and AHR. Airway γδT-cell number was also positively correlated with bronchoalveolar lavage (BAL) virus load and BAL eosinophils and lymphocytes during RV infection. Consistent with our observations of RV-induced asthma exacerbations in humans, infection of mice with allergic airways inflammation increased lung γδT-cell number and activation. Inhibiting γδT-cell responses using anti-γδTCR (anti-γδT-cell receptor) antibody treatment in the mouse asthma exacerbation model increased AHR and airway T helper type 2 cell recruitment and eosinophilia, providing evidence that γδT cells are negative regulators of airways inflammation and disease in RV-induced asthma exacerbations.

False estimates of stimulated Raman pumping efficiency caused by the optical Stark effect.

One technique for measuring the fraction of molecules pumped to the excited state in stimulated Raman pumping (SRP) is to record the depletion of molecules in the lower state by resonance enhanced multiphoton ionization (REMPI). The presence of electric fields on the order of 10(7) V/cm arising from the pulsed SRP laser beams is sufficient to shift the line position of the REMPI transition to such an extent that the estimate of the pumping efficiency is overestimated unless this shift is accounted for.

Rhinovirus induces MUC5AC in a human infection model and in vitro via NF-κB and EGFR pathways.

Rhinovirus (RV) infections are the major cause of asthma exacerbations, the major cause of morbidity and mortality in asthma. MUC5AC is the major mucin produced by bronchial epithelial cells. Whether RV infection upregulates MUC5AC in vivo is unknown and the molecular mechanisms involved are incompletely understood. We investigated RV induction of MUC5AC in vivo and in vitro to identify targets for development of new therapies for asthma exacerbations. RV infection increased MUC5AC release in normal and asthmatic volunteers experimentally infected with RV-16, and in asthmatic, but not normal, subjects, this was related to virus load. Bronchial epithelial cells were confirmed a source of MUC5AC in vivo. RV induction of MUC5AC in bronchial epithelial cells in vitro occurred via nuclear factor-κB-dependent induction of matrix metalloproteinase-mediated transforming growth factor-α release, thereby activating an epidermal growth factor receptor-dependent cascade culminating, via mitogen-activated protein kinase activation, in specificity protein-1 transactivation of the MUC5AC promoter. RV induction of MUC5AC may be an important mechanism in RV-induced asthma exacerbations in vivo. Revealing the complex serial signalling cascade involved identifies targets for development of pharmacologic intervention to treat mucus hypersecretion in RV-induced illness.

Serious pulmonary toxicity in patients with Hodgkin's lymphoma with SGN-30, gemcitabine, vinorelbine, and liposomal doxorubicin is associated with an FcγRIIIa-158 V/F polymorphism.

BACKGROUND: Based on in vitro synergistic cytotoxicity when anti-CD30 antibodies are combined with gemcitabine, the Cancer and Leukemia Group B conducted a double-blind, randomized, phase II trial of SGN-30 with gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD) in patients with relapsed Hodgkin's lymphoma. PATIENTS AND METHODS: In part 1 of the trial, 16 patients received SGN-30 with GVD to assess the safety of the combination. In part 2, patients were randomly allocated to SGN-30 (n = 7) or placebo (n = 7) with GVD to determine overall response rate (ORR). RESULTS: ORR in all 30 patients was 63% (65% with SGN-30 plus GVD, n = 23, and 57% with placebo plus GVD, n = 7). Median event-free survival was 9.0 months, with no difference between the two arms. Grades 3-5 pneumonitis occurred in five patients receiving SGN-30 and GVD, leading to premature closure of the trial. All five patients with pulmonary toxicity had a V/F polymorphism in the FcγRIIIa gene (P = 0.008). CONCLUSIONS: Together with historical data demonstrating a 2% incidence of pulmonary events with GVD, these results indicate that SGN-30 cannot safely be administered concurrently. The risk of pneumonitis with SGN-30 and GVD is greatest in patients with an FcγRIIIa V/F polymorphism.

Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin's lymphoma: CALGB 59804.

BACKGROUND: Because of high single-agent activity and modest toxicity, we hypothesized the combination of gemcitabine (G), vinorelbine (V), and pegylated liposomal doxorubicin (D) would be an effective salvage therapy for Hodgkin's lymphoma (HL). PATIENTS AND METHODS: A total of 91 patients participated. GVD was administered on days 1 and 8 every 21 days at doses of G 1000 mg/m(2), V 20 mg/m(2), and D 15 mg/m(2) for transplant-naive patients, and G 800 mg/m(2), V 15 mg/m(2), and D 10 mg/m(2) for post-transplant patients. RESULTS: The dose-limiting toxicity was mucositis for the transplant-naive patients and febrile neutropenia for post-transplant patients. The overall response rate (RR) for all patients was 70% [95% confidence interval (CI) 59.8, 79.7], with 19% complete remissions. The 4-year event-free and overall survival rates in transplant-naive patients treated with GVD followed by autologous transplant were 52% (95% CI 0.34, 0.68) and 70% (95% CI 0.49, 0.84), and in the patients in whom prior transplant failed, these were 10% (95% CI 0.03, 0.22) and 34% (95% CI 0.17, 0.52), respectively. CONCLUSIONS: GVD is a well-tolerated, active regimen for relapsed HL with results similar to those reported for more toxic regimens. High RRs in patients in whom prior transplant failed confirms this regimen's activity even in heavily pretreated patients.

Control of nausea and vomiting after chemotherapy: what is the evidence?

The control of nausea and vomiting is an important problem for patients undergoing chemotherapy. With the introduction of newer agents, including 5-HT3 antagonists, nausea and vomiting control after chemotherapy has much improved but is not always optimal. While there is an intrinsic limitation to the efficacy of anti-emetic drugs, their efficacy can be further reduced if the drugs are not used appropriately. In some circumstances newer anti-emetics may be unnecessary and better nausea and vomiting control may be established by use of older agents. This paper summarizes current evidence regarding the optimal approach to management of nausea and vomiting in patients undergoing chemotherapy.

Dose-escalated cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE) chemotherapy for patients with diffuse lymphoma: Cancer and Leukemia Group B studies 8852 and 8854.

BACKGROUND: To address the feasibility and outcome of moderate dose intensification with granulocyte-colony stimulating factor (G-CSF) for patients with aggressive non-Hodgkin lymphoma (NHL), the Cancer and Leukemia Group B (CALGB) conducted two studies evaluating dose-escalated cyclophosphamide and etoposide in the cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide (CHOPE) regimen. METHODS: Eligibility criteria included histologically documented, diffuse small cleaved, diffuse mixed, diffuse large cell, or immunoblastic lymphoma, Stage III--IV or bulky Stage II disease, and an ECOG performance status of 0--1. CALGB 8852, a group-wide study, accrued 227 patients: 120 patients in the pilot study to determine the maximum tolerated dose (MTD) without G-CSF and 107 in the pilot study of dose-escalated CHOPE with G-CSF. CALGB 8854, a limited-institution, Phase I study, enrolled 38 patients and determined the MTD of CHOPE with G-CSF to be used in CALGB 8852. The MTD in both studies was defined as the dose at which 50% of patients had 1) Grade 4 neutropenia or thrombocytopenia lasting 7 days or more, or 2) Grade 3--4 hemorrhage or nonhematologic toxicity (excluding alopecia, nausea, and emesis), or 3) were prevented from receiving 100% of drug on Day 22. RESULTS: The MTD of CHOPE without G-CSF was cyclophosphamide 1000 mg/m(2) on Day 1 and etoposide 100 mg/m(2) on Days 1--3 with doxorubicin 50 mg/m(2) on Day 1, vincristine 1.4 mg/m(2) (maximum, 2 mg) on Day 1, and prednisone 100 mg on Days 1--5. With the addition of G-CSF at 200 microg/m(2) on Days 5--19, the MTD was cyclophosphamide 1500 mg/m(2) and etoposide 160 mg/m(2) on Days 1-3 with standard doses of doxorubicin, vincristine, and prednisone. Increasing the dose of G-CSF from 200 microg/m(2) to 400 microg/m(2) did not allow for further dose escalation. The primary toxicity in all cohorts was neutropenia. Four toxic deaths occurred on CALGB 8852. The 5-year failure free survival (FFS) and overall survival (OS) rates for eligible patients on CALGB 8852 were 31% (95% confidence interval [95%CI], 23--39) and 48% (95%CI, 40--57), respectively. The 5-year FFS and OS rates for eligible patients on CALGB 8854 were 34% (95%CI, 17--52) and 51% (95%CI, 33--70), respectively. CONCLUSIONS: Moderate dose escalation with G-CSF is feasible. However, response and survival rates of patients who receive dose-escalated CHOPE, even with the addition of G-CSF, appear similar to the rates reported with standard-dose CHOP.

Biodistribution and dosimetry results from a phase III prospectively randomized controlled trial of Zevalin radioimmunotherapy for low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma.

UNLABELLED: Radiation dosimetry studies were performed in patients with non-Hodgkin's lymphoma (NHL) treated with 90Y Zevalin (90yttrium ibritumomab tiuxetan, IDEC-Y2B8) on a Phase III open-label prospectively randomized multicenter trial. The trial was designed to evaluate the efficacy and safety of 90Y Zevalin radioimmunotherapy compared to rituximab (Rituxan, MabThera) immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed NHL. An important secondary objective was to determine if radiation dosimetry prior to 90Y Zevalin administration is required for safe treatment in this patient population. METHODS: Patients randomized into the Zevalin arm were given a tracer dose of 5 mCi (185 MBq) (111)In Zevalin (111indium ibritumomab tiuxetan) on Day 0, evaluated with dosimetry, and then administered a therapeutic dose of 0.4 mCi/kg (15 MBq/kg) 90Y Zevalin on Day 7. Both Zevalin doses were preceded by an infusion of 250 mg/m(2) rituximab to clear peripheral B-cells and improve Zevalin biodistribution. Following administration of (111)In Zevalin, serial anterior and posterior whole-body scans were acquired and blood samples were obtained. Residence times for 90Y were estimated for major organs, and the MIRDOSE3 computer software program was used to calculate organ-specific and total body radiation absorbed dose. Patients randomized into the rituximab arm received a standard course of rituximab immunotherapy (375 mg/m(2) weekly x 4). RESULTS: In a prospectively defined 90 patient interim analysis, the overall response rate was 80% for Zevalin vs. 44% for rituximab. For all patients with Zevalin dosimetry data (N=72), radiation absorbed doses were estimated to be below the protocol-defined upper limits of 300 cGy to red marrow and 2000 cGy to normal organs. The median estimated radiation absorbed doses were 71 cGy to red marrow (range: 18-221 cGy), 216 cGy to lungs (94-457 cGy), 532 cGy to liver (range: 234-1856 cGy), 848 cGy to spleen (range: 76-1902 cGy), 15 cGy to kidneys (0.27-76 cGy) and 1484 cGy to tumor (range: 61-24274 cGy). Toxicity was primarily hematologic, transient, and reversible. The severity of hematologic nadir did not correlate with estimates of effective half-life (half-life) or residence time of 90Y in blood, or radiation absorbed dose to the red marrow or total body. CONCLUSION: 90Y Zevalin administered to NHL patients at non-myeloablative maximum tolerated doses delivers acceptable radiation absorbed doses to uninvolved organs. Lack of correlation between dosimetric or pharmacokinetic parameters and the severity of hematologic nadir suggest that hematologic toxicity is more dependent on bone marrow reserve in this heavily pre-treated population. Based on these findings, it is safe to administer 90Y Zevalin in this defined patient population without pre-treatment (111)In-based radiation dosimetry.

Cyclin D1 as an aid in the diagnosis of mantle cell lymphoma in skin biopsies: a case report.

Mantle cell lymphoma (MCL), an uncommon and aggressive form of non-Hodgkin lymphoma, typically involves lymph nodes. It usually only secondarily involves extranodal sites. We describe an unusual case of a MCL that presented and relapsed in the earlobes. Light microscopic findings were initially regarded as suggestive of small lymphocytic lymphoma, although subsequent analysis of fresh tissue by flow cytometry led to the diagnosis of MCL. Retrospective application of a broad panel of recently developed markers suitable for analysis of routinely processed tissue yielded results that also permitted a diagnosis of MCL. If these results had been available at the time of initial presentation, they would have obviated the need for rebiopsy. Greater awareness not only of the phenotypic criteria by which lymphomas are classified but of the lymphoma markers available for evaluation of routinely processed tissue should facilitate the accurate diagnosis of diseases like MCL and minimize the risk of misdiagnosis as an indolent disorder.

Hodgkin's disease: prognostic factors and short-course regimens.

Both topics discussed in this review, prognostic factors and short-course regimens for Hodgkin's disease, have been the focus of recent research with the goal of developing tools and treatments that will result in the highest cure rates with the least long-term sequelae. A new "prognostic score" for advanced-stage Hodgkin's disease and several potential prognostic factors, including soluble CD30, soluble interleukin-2 receptor, activated cytotoxic T-lymphocytes, and Epstein-Barr virus, are discussed. Preliminary reports of short-course chemotherapy regimens with and without radiotherapy for all stages of Hodgkin's disease are summarized.

Assessment of the stanford V regimen and consolidative radiotherapy for bulky and advanced Hodgkin's disease: Eastern Cooperative Oncology Group pilot study E1492.

PURPOSE: This study was performed, in a multi-institutional setting, to evaluate the efficacy and feasibility of the Stanford V chemotherapy regimen plus radiotherapy to bulky Hodgkin's disease sites. PATIENTS AND METHODS: A two-stage design was implemented in a phase II study involving 47 patients with bulky mediastinal stage I/II or stage III/IV Hodgkin's disease. Twelve weeks of the Stanford V chemotherapy regimen were given with consolidative radiotherapy (36 Gy) to lymph nodes >/= 5 cm and/or macroscopic splenic disease. Treatment was administered in one of five institutions participating in the Eastern Cooperative Oncology Group. RESULTS: With a median follow-up of 4.8 years, 45 patients are alive and 40 have been continuously disease-free. The estimated freedom from progression was 87% at 2 years and 85% at 5 years. Overall survival was 96% at 2 and 5 years. There was one death from Hodgkin's disease and one death from an M5 acute leukemia. Six of seven relapsed patients received high-dose therapy and autologous stem-cell transplantation. The freedom from second progression for the seven relapsed patients was estimated at 98% at 3 years. CONCLUSION: Stanford V chemotherapy and consolidative radiotherapy to bulky disease is effective in bulky and advanced Hodgkin's disease in a multi-institutional setting. On this basis, an Intergroup study comparing doxorubicin, bleomycin, vinblastine, and dacarbazine with the Stanford V regimen has been initiated.

M-F interatomic distances and effective volumes of second and third transition series MF6- and MF6(2-) anions.

Synchrotron X-ray powder diffraction data (SPDD) for representative LiMF6 and Li2MF6 salts of the second and third transition series have provided unit-cell parameters and, from Rietveld analysis, M-F interatomic distances. M-F distances have also been obtained from X-ray single-crystal structural analyses of LiOsF6, Li2PtF6, and KRhF6. The LiMF6 all have the LiSbF6 structure type (space group R3). For M = Ta to Au the primitive unit cell volume decreases with increasing nuclear charge (Z), the volumes (sigma = 0.01 A3) being as follows: Ta, 111.26; Os, 102.42; Ir, 100.77; Pt, 99.62; and Au, 99.12 A3. A similar contraction, with increase in Z, occurs from Nb to Rh, the primitive cell volume (sigma = 0.01 A3) being: Nb, 110.92; Ru, 100.51; and Rh, 98.64 A3. For the TaF6- to AuF6- the M-F distances are not significantly different across the series, at approximately 1.87(1) A; also, Nb-F, Ru-F, and Rh-F = 1.86(1) A. In each series, the a and c values of the hexagonal-cell representation for the LiMF6 structure (separate layers of MF6- and Li+ stacked along c) change smoothly. As Z increases, a decreases and c increases. The variation in a, like the volume change, indicates that the size of MF6- is decreasing with Z. The variation in c suggests that the charge on the F-ligand is decreasing with Z. In the trirutile Li2MF6 series, M = Mo to Pd, the formula-unit volume decreases with Z(Mo, 100.92(6); Ru, 98.21(1); Rh, 97.43(1); Pd, 96.83(1) A3) and a shortening in M-F occurs (Mo-F = 1.936(4); Ru-F = 1.921(7); Rh-F = 1.910(7); Pd-F = 1.899(4) A). The less abundant data for MF6(2-) salts of the third transition series indicate similar trends. For both series, M-F distances of MF6(2-) are longer by 0.03-0.09 A than in MF6-.