Citations

Abstract We have retrospectively studied 53 patients with idiopathic pulmonary fibrosis and a histologic diagnosis of usual interstitial pneumonia and evaluated the prognostic significance of four individual histologic features (fibroblastic foci [FF], interstitial mononuclear cell infiltrate, established fibrosis, and intra-alveolar macrophages) using a semiquantitative scale of 0–6. An objective count of FF was also undertaken. Using weighted kappa coefficients, interobserver agreement between pathologists was moderate to good (0.56–0.76). Subjective and objective FF scores were strongly associated (RS = 0.88, < 0.00005). Mortality was independently linked to a high FF score, p = 0.006, and a low percent predicted carbon monoxide diffusing capacity (DlCO), p = 0.01. For pulmonary function, on univariate analysis, the strongest correlations were observed between increasing interstitial mononuclear cell infiltrate or FF scores and greater declines in forced vital capacity (FVC) or DlCO at 6 months. Multivariate models revealed that increasing FF scores were independently associated with greater declines in FVC and DlCO at both 6 and 12 months. Increasing interstitial mononuclear cell infiltrate scores were also independently linked to functional decline, but only at 6 months. These data suggest a reproducible method on biopsy for predicting rate of disease progression in patients with idiopathic pulmonary fibrosis.

Abstract Fibrosing alveolitis associated with systemic sclerosis (FASSc) has a better prognosis than idiopathic pulmonary fibrosis. In view of recent reports that idiopathic nonspecific interstitial pneumonia (NSIP) has a better prognosis than idiopathic usual interstitial pneumonia (UIP), we classified histologic appearances of surgical lung biopsies performed in 80 patients with FASSc. NSIP (n = 62, 77.5%), subcategorized as cellular NSIP (n = 15) and fibrotic NSIP (n = 47) was much more prevalent than UIP (n = 6), end-stage lung disease (ESL, n = 6), or other patterns (n = 6). There were 25 deaths (NSIP 16/62, 26%; UIP/ESL 6/12, 50%). Five-year survival differed little between NSIP (91%) and UIP/ESL (82%); mortality was associated with lower initial carbon monoxide diffusing capacity (DlCO) and FVC levels (p = 0.004 and p = 0.007, respectively). Survival and serial FVC and DlCO trends did not differ between cellular and fibrotic NSIP. Increased mortality in NSIP was associated with lower initial DlCO levels (p = 0.04), higher BAL eosinophil levels (p = 0.03), and deterioration in DlCO levels during the next 3 years (p < 0.005). We conclude that NSIP is the histopathologic pattern in most patients with FASSc. However, outcome is linked more strongly to disease severity at presentation and serial DlCO trends than to histopathologic findings.

Background and aims: This was a prospective blinded study to compare computed tomography (CT) colonography, performed with multidetector arrays CT scan (MDCT), with conventional colonoscopy for the detection of colorectal neoplasia. Methods: Fifty patients were examined by MDCT after standard bowel preparation and rectal air insufflation in the supine and prone positions. Data sets were examined by one radiologist and one gastroenterologist blinded to the patient's history and colonoscopy results. Patients subsequently underwent colonoscopy on the same day, which served as the gold standard. Results: Nine of 11 lesions >10 mm (82%), 5/15 lesions of 6–9 mm (33%), and 1/42 polyps <5 mm (3%) were detected by MDCT colonography. One false positive result for a structure larger than 10 mm was described. Nineteen of 21 patients who had no lesions during conventional colonoscopy were considered free of lesions by MDCT colonography, yielding a per patient specificity of 90%. Conclusion: MDCT colonography provides good data quality and has good sensitivity and specificity for the detection of colonic lesions of 10 mm or more.

PURPOSE: Radioimmunotherapy combines biologic and radiolytic mechanisms to target and destroy tumor cells, thus offering a needed therapeutic alternative for refractory non-Hodgkin’s lymphoma (NHL) patients. This phase III randomized study compares the novel radioimmunotherapy yttrium-90 (90Y) ibritumomab tiuxetan with a control immunotherapy, rituximab, in 143 patients with relapsed or refractory low-grade, follicular, or transformed CD20+transformed NHL.PATIENTS AND METHODS: Patients received either a single intravenous (IV) dose of90Y ibritumomab tiuxetan 0.4 mCi/kg (n = 73) or rituximab 375 mg/m2IV weekly for four doses (n = 70). The radioimmunotherapy group was pretreated with two rituximab doses (250 mg/m2) to improve biodistribution and one dose of indium-111 ibritumomab tiuxetan for imaging and dosimetry. The primary end point, overall response rate (ORR), was assessed by an independent, blinded, lymphoma expert panel.RESULTS: ORR was 80% for the90Y ibritumomab tiuxetan group versus 56% for the rituximab group (P = .002). Complete response (CR) rates were 30% and 16% in the90Y ibritumomab tiuxetan and rituximab groups, respectively (P = .04). An additional 4% achieved an unconfirmed CR in each group. Kaplan-Meier estimated median duration of response was 14.2 months in the90Y ibritumomab tiuxetan group versus 12.1 months in the control group (P = .6), and time to progression was 11.2 versus 10.1 months (P = .173) in all patients. Durable responses of ≥ 6 months were 64% versus 47% (P = .030). Reversible myelosuppression was the primary toxicity noted with90Y ibritumomab tiuxetan.CONCLUSION: Radioimmunotherapy with90Y ibritumomab tiuxetan is well tolerated and produces statistically and clinically significant higher ORR and CR compared with rituximab alone.

Background — Despite the common occurrence of aortic stenosis, the cellular causes of the disorder are unknown, in part because of the absence of experimental models. We hypothesized that atherosclerosis and early bone matrix expression in the aortic valve occurs secondary to experimental hypercholesterolemia and that treatment with atorvastatin modifies this transformation. Methods and Results — To test this hypothesis, we developed an experimental hypercholesterolemic rabbit model. New Zealand White rabbits (n=48) were studied: group 1 (n=16), normal diet; group 2 (n=16), 1% (wt/wt) cholesterol diet; and group 3 (n=16), 1% (wt/wt) cholesterol diet plus atorvastatin (3 mg/kg per day). The aortic valves were examined with hematoxylin and eosin stain, Masson trichrome, macrophage (RAM 11), proliferation cell nuclear antigen (PCNA), and osteopontin immunostains. Cholesterol and highly sensitive C-reactive protein (hsCRP) serum levels were obtained by standard assays. Computerized morphometry and digital image analysis were performed for quantifying PCNA (% area). Electron microscopy and immunogold labeling were performed for osteopontin. Semiquantitative RT-PCR was performed for the osteoblast bone markers [alkaline phosphatase, osteopontin, and osteoblast lineage-specific transcription factor ( Cbfa-1 )]. There was an increase in cholesterol, hsCRP, PCNA, RAM 11, and osteopontin and osteoblast gene markers (alkaline phosphatase, osteopontin, and Cbfa-1 ) in the cholesterol-fed rabbits compared with control rabbits. All markers except hsCRP were reduced by atorvastatin. Conclusions — These findings of increased macrophages, PCNA levels, and bone matrix proteins in the aortic valve during experimental hypercholesterolemia provide evidence of a proliferative atherosclerosis–like process in the aortic valve associated with the transformation to an osteoblast-like phenotype that is inhibited by atorvastatin.

Rituximab is a chimeric murine/human monoclonal antibody that binds to CD20 on B lymphocytes. Although binding of the Fab domain may induce apoptosis, the Fc domain recruits immune effector functions to mediate cell lysis. Interleukin-12 (IL-12) facilitates cytolytic T-cell responses, enhances the lytic activity of natural killer (NK) cells, and induces the secretion of interferon γ (IFN-γ) by both T and NK cells. Therefore, the hypothesis was considered that combining IL-12 with rituximab would augment the immune-mediated cell lysis induced by rituximab. A phase 1 study of IL-12 in combination with rituximab was conducted in 43 adults with B-cell lymphoma to determine the optimal immunologic dose of this combination. Rituximab was administered at a dose of 375 mg/m2 by intravenous infusion weekly for 4 weeks, and IL-12 was given subcutaneously twice weekly. The starting dose of IL-12 was 30 ng/kg and this was escalated to 500 ng/kg. Constitutional symptoms and liver enzyme elevations at 500 ng/kg of IL-12 were dose limiting. A greater than 20-fold increase in the serum levels of IFN-γ and a 2.5- to 5-fold increase in inducible protein 10 (IP-10) levels was seen at IL-12 doses of 100 ng/kg or greater. Objective responses occurred in 29 of the 43 patients (69%), with 8 of 11 complete responses seen at IL-12 doses of 300 ng/kg or greater. The optimal immunologic dose of IL-12 in combination with rituximab was determined to be 300 ng/kg subcutaneously twice weekly starting on day 2. These data suggest that IL-12 and rituximab is an active combination and further studies of this combination in B-cell non-Hodgkin lymphoma are warranted.

Primary systemic amyloidosis (AL) is a plasma cell (PC) dyscrasia with clinical similarities to multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS), but its molecular basis is poorly understood. Translocations at the immunoglobulin heavy-chain (IgH) locus, 14q32, are likely early genetic events in both MM and MGUS and involve several nonrandom, recurrent, partner chromosomes such as 11q13, 16q23, and 4p16.3. Given the similarities between MM, MGUS, and AL, bone marrow clonal PCs were evaluated in 29 patients with AL using interphase fluorescence in situ hybridization (FISH) combined with immunofluorescence detection of the cytoplasmic light-chain (cIg-FISH) for the presence of 14q32 translocations and the t(11;14)(q13;q32). Of 29 patients studied, 21 (72.4%) showed results compatible with the presence of a 14q32 translocation, and 16 (76.2%) of those had translocation (11;14)(q13;q32) for an overall prevalence of the abnormality of 55%. IgH translocations are common in AL, especially the t(11;14)(q13;q32).

AbstractCurrent therapeutic options for myeloid metaplasia with myelofibrosis (MMM) are limited. A pilot study was conducted of autologous peripheral blood stem cell (PBSC) collection in 27, followed by transplantation in 21 patients with MMM. The median age was 59 (range 45-75) years. PBSCs were mobilized at steady state (n = 2), after granulocyte colony-stimulating factor (G-CSF) alone (n = 17), or after anthracycline-cytarabine induction plus G-CSF (n = 8). A median of 11.6 × 106 (range 0 to 410 × 106) CD34+ cells per kilogram were collected. Twenty-one patients then underwent myeloablation with oral busulfan (16 mg/kg) and PBSC transplantation. The median times to neutrophil and platelet recovery after transplantation were 21 (range 10-96) and 21 (range, 13 to ≥ 246) days, respectively. Five patients received back-up PBSC infusion because of delayed neutrophil or platelet recovery. The median follow-up is 390 (range 70-1623) days after transplantation, and the 2-year actuarial survival is 61%. After transplantion, 6 patients died: 3 of nonrelapse causes (1 within 100 days of PBSC infusion) and 3 of disease progression. Erythroid response (hemoglobin ≥ 100 g/L [10 gm/dL] without transfusion for ≥ 8 weeks) occurred in 10 of 17 anemic patients. Four of 8 patients with a platelet count less than 100 × 109/L (100 000/μL) responded with a durable platelet count more than 100 × 109/L (100 000/μL). Symptomatic splenomegaly improved in 7 of 10 patients. It is concluded that (1) PBSC collection was feasible and stable engraftment occurred after transplantation in most patients with MMM, (2) myeloablation with busulfan was associated with acceptable toxicity, (3) a significant proportion of patients derived clinical benefit after treatment, and (4) further investigation of this novel approach is warranted.

Abstract The plasma cell labeling index (PCLI) is a measure of plasma cell proliferative activity and is an important prognostic factor in newly diagnosed multiple myeloma (MM). Occasionally patients have been observed with stable, plateau phase MM with minimal numbers of residual light-chain–restricted monoclonal plasma cells, but a high PCLI. No data are available on the outcomes for such patients. Data from 57 patients with plateau phase MM and a marrow PCLI of more than 1.0% were compared with 105 matched control patients with MM with a marrow PCLI of less than 1.0%. All patients had less than 10% total plasma cells on marrow aspirate and biopsy. The median time to progression and overall survival were 8 months and 20 months, respectively, in the high PCLI group versus 39 months and 56 months, respectively, in the low PCLI group (P &lt; .0001). These findings suggest that a high PCLI in patients with apparently stable, plateau phase MM is an adverse parameter that may predict a short time to disease progression and death.