Citations

Abstract In idiopathic pulmonary fibrosis, the quantitation of disease severity using pulmonary function tests is often confounded by emphysema. We have identified the composite physiologic index (CPI) most closely reflecting the morphologic extent of pulmonary fibrosis. Consecutive patients with a clinical/computed tomography (CT) diagnosis of idiopathic pulmonary fibrosis (n = 212) were divided into group I (n = 106) and group II (n = 106). The CPI was derived in group I (by fitting pulmonary function tests against disease extent on CT) and was tested in Group II. The formula for the CPI was as follows: extent of disease on CT = 91.0 − (0.65 × percent predicted diffusing capacity for carbon monoxide [DLCO]) − (0.53 × percent predicted FVC) + (0.34 × percent predicted FEV1). In group II, the CPI correlated more strongly with disease extent on CT (r2 = 0.51) than the individual pulmonary function test (DLCO the highest value, r2 = 0.38). A subanalysis demonstrated that the better fit of the CPI was ascribable to a correction of the confounding effects of emphysema. Mortality was predicted more accurately by the CPI than by a pulmonary function test in all clinical subgroups, including a separate cohort of 36 patients with histologically proven usual interstitial pneumonia (CPI, p < 0.0005; FVC, p = 0.002; PO2, p = 0.002). In conclusion, a new CPI, derived against CT and validated using split sample testing, is a more accurate prognostic determinant in usual interstitial pneumonia than an individual pulmonary function test.

Purpose: To evaluate the role of adjuvant interferon alfa after complete resection of locally extensive renal cell carcinoma. Patients and Methods: A total of 283 eligible patients with pT3–4a and/or node-positive disease were randomly assigned after radical nephrectomy and lymphadenectomy to observation or to interferon alfa-NL (Wellferon, Burroughs-Wellcome, Research Park, NC) given daily for 5 days every 3 weeks for up to 12 cycles. Patients were stratified on the basis of pathologic stage. Patients remained on treatment until documented recurrence, excessive toxicity, or patient/physician preference deemed removal appropriate. Results: At median follow-up of 10.4 years, median survival was 7.4 years in the observation arm and 5.1 year in the treatment arm (log-rank P = .09). Median recurrence-free survival was 3.0 years in the observation arm and 2.2 years in the interferon arm (P = .33). Performance status (P = .003), nodal status (N2 v N0, P < .0001), and tumor stage (P = .0002) were significant prognostic factors in multivariate analysis. A proportional hazards model examining the effects of treatment arm and time to recurrence on survival after recurrence among patients who recurred found that random assignment to interferon treatment (P = .009) and shorter time to recurrence (P < .0001) were independent predictors of shorter survival after recurrence. Although no lethal toxicities were observed, severe (grade 4) toxicities including neutropenia, myalgia, fatigue, depression, and other neurologic toxicities occurred in 11.4% of those randomly assigned to interferon treatment. Conclusion: Adjuvant treatment with interferon did not contribute to survival or relapse-free survival in this group of patients.

AbstractMultiple myeloma is a disseminated neoplasm of terminally differentiated plasma cells that is incurable with currently available therapies. Although the disease is radiosensitive, external beam radiation leads to significant toxicity due to sensitive end-organ damage. Thus, genetic approaches for therapy are required. We hypothesized that the incorporation of immunoglobulin promoter and enhancer elements in a self-inactivating (SIN) lentiviral vector should lead to specific and high-level transgene expression in myeloma cells. A SIN lentivector with enhanced green fluorescent protein (EGFP) expression under the control of a minimal immunoglobulin promoter as well as the Kappa light chain intronic and 3′ enhancers transduced myeloma cell lines with high efficiency (30%-90%). EGFP was expressed at a high level in myeloma cells but silent in all nonmyeloma cell lines tested compared with the cytomegalovirus (CMV) promoter/enhancer. Transduction of myeloma cells with the targeted vector coding for the human sodiumiodide symporter (hNIS) led to hNIS expression by these cells allowing them to concentrate radioiodine up to 18-fold compared with controls. Tumor xenografts in severe combined immunodeficiency mice expressing hNIS could be imaged using iodine-123 (123I) and shown to retain iodide for up to 48 hours. These tumor xenografts were completely eradicated by a single dose of the therapeutic isotope iodine-131 (131I) without evidence of recurrence up to 5 months after therapy. We conclude that lentivectors can be transcriptionally targeted for myeloma cells and the use of hNIS as a therapeutic gene for myeloma in combination with 131I needs further exploration.

ABSTRACTWe examined the role of the cytokines gamma interferon (IFN-γ) and interleukin-12 (IL-12) in the model of acute babesiosis with the WA1Babesia. Mice genetically deficient in IFN-γ-mediated responses (IFNGR2KO mice) and IL-12-mediated responses (Stat4KO mice) were infected with the WA1Babesia, and observations were made on the course of infection and cytokine responses. Levels of IFN-γ and IL-12 in serum increased 24 h after parasite inoculation. The augmented susceptibility observed in IFNGR2KO and Stat-4KO mice suggests that the early IL-12- and IFN-γ-mediated responses are involved in protection against acute babesiosis. Resistance appears to correlate with an increase in nitric oxide (NO) production. In order to assess the contribution of different cell subsets to resistance against the parasite, we also studied mice lacking B cells, CD4+T cells, NK cells, and macrophages. Mice genetically deficient in B lymphocytes or CD4+T lymphocytes were able to mount protective responses comparable to those of immunosufficient mice. In contrast, in vivo depletion of macrophages or NK cells resulted in elevated susceptibility to the infection. Our observations suggest that a crucial part of the response that protects from the pathogenicBabesiaWA1 is mediated by macrophages and NK cells, probably through early production of IL-12 and IFN-γ, and induction of macrophage-derived effector molecules like NO.

Single-agent thalidomide (THAL) at “conventional” doses (> 100 mg/d) has been evaluated in myelofibrosis with myeloid metaplasia (MMM) based on its antiangiogenic properties and the prominent neoangiogenesis that occurs in MMM. THAL monotherapy at such doses produces approximately a 20% response rate in anemia but is poorly tolerated (an adverse dropout rate of > 50% in 3 months). To improve efficacy and tolerability, we prospectively treated 21 symptomatic patients (hemoglobin level < 10 g/dL or symptomatic splenomegaly) with MMM with low-dose THAL (50 mg/d) along with a 3-month oral prednisone (PRED) taper (beginning at 0.5 mg/kg/d). THAL-PRED was well tolerated in all enrolled patients, with 20 patients (95%) able to complete 3 months of treatment. An objective clinical response was demonstrated in 13 (62%) patients, all improvements in anemia. Among 10 patients who were dependent on erythrocyte transfusions, 7 (70%) improved and 4 (40%) became transfusion independent. Among 8 patients with thrombocytopenia (platelet count < 100 × 109/L), 6 (75%) experienced a 50% or higher increase in their platelet count. In 4 of 21 patients (19%), spleen size decreased by more than 50%. Responses observed were mostly durable after discontinuation of the PRED. The dose of THAL in this study (50 mg/d) was better tolerated than the higher doses used in previous studies. Adverse events associated with corticosteroid therapy were mild and transient. Clinical responses did not correlate with improvements in either intramedullary fibrosis or angiogenesis. THAL-PRED is well tolerated and preliminarily appears to be a promising drug regimen for treating cytopenias in patients with MMM.

SUMMARYANCA directed against PR3 are highly specific for Wegener's granulomatosis and microscopic polyangiitis, and have been implicated in the pathogenesis of small vessel vasculitis. Most PR3-ANCA are directed against conformational epitopes on PR3. This study was designed to determine whether the cleavage of the N-terminal activation dipeptide of PR3 is required for the binding of PR3-ANCA. Recombinant PR3 (rPR3) variants were expressed in the epithelial cell line, 293. As confirmed by radiosequencing, the rPR3 secreted into the 293 cell culture supernatant is N-terminally unprocessed. Two enzymatically inactive rPR3 mutants were expressed in 293 cells: rPR3-S176A and δ-rPR3-S176A. rPR3-S176A contains the N-propetide Ala-2-Glu-1, δ-rPR3-S176A does not. Culture supernatants of rPR3-S176A and δ-rPR3-S176A expressing 293 cells were used as sources of target antigen for PR3-ANCA testing by capture ELISA. Forty unselected consecutive PR3-ANCA+ sera were tested. With δ-rPR3-S176A as antigen all 40 were recognized, compared with only 34 of 40 when rPR3-S176A served as target antigen. The majority of the serum samples contained a mixture of antibodies reacting with epitopes accessible on the mature and on the proform of PR3. In conclusion, the cleavage of the N-terminal activation dipeptide of PR3 is not an absolute requirement for recognition by all PR3-ANCA. However, a substantial proportion of PR3-ANCA recognize (a) target antigen(s) exposed only after the conformational change of PR3 associated with the N-terminal processing. In 15% of sera this PR3-ANCA subset occurred exclusively. PR3-ANCA subtypes can be differentiated using specifically designed rPR3 variants as target antigens, and non-haematopoietic mammalian cells without regulated secretory pathway can be used for their expression.

Abstract Background Papillary thyroid cancer (PTC) has a generally favourable prognosis, but elderly patients with distant metastases or extracapsular invasion fair poorly. In small studies with short follow-up, young patients presenting with such extracapsular invasion and pulmonary metastases have faired well. This retrospective study was undertaken to clarify the long-term prognosis of such patients with advanced PTC. Methods Twenty-one children and young adults (median age 14 (range 6–20) years) presenting with PTC and pulmonary metastases were treated at a single institution between 1947 and 1998. Mean maximal tumour diameter was 4·65 cm. Initial surgical treatment consisted of total thyroidectomy (n = 16), subtotal thyroidectomy (n = 4) and isthmectomy (n = 1), coupled with a variety of lymph node dissections (n = 20). After operation, 19 patients were treated with ablative and incremental doses of iodine-131 until disease free. All patients were placed on suppressive thyroid hormone after operation. Mean length of follow-up was 21 years (range 3 months to 47 years). Follow-up was less than 3 years in four patients. All patients have undergone post-treatment radionucleotide and radiological evaluation. Results Nine of the 21 patients developed recurrent disease. The risk of recurrence at 5 years was 39 (95 per cent confidence interval 14–57) per cent. Eight had cervical lymph node recurrence and no patient developed recurrent pulmonary disease. All patients with identifiable recurrent disease underwent selective lymph node resection, which involved multiple resections in four. At follow-up, 18 patients remain completely free of disease, one patient has recurrent cervical node disease and two patients have died. The disease-free survival at 5 years was 95 (95 per cent confidence interval 86–100) per cent. Cause-specific death occurred in a single patient who died from extensive local disease at age 29 years after 12 years of multiple cervical lymph node recurrences. Conclusion A stepwise treatment approach including total thyroidectomy, high-dose iodine-131 treatment and early surgical reintervention for suspected local recurrent disease allows long-term survival and frequent ‘cure’ for young patients with PTC and concomitant pulmonary metastases.

Abstract Background Calciphylaxis is a rare, painful, life-threatening problem of cutaneous necrosis and refractory healing seen in patients with uraemia and secondary hyperparathyroidism. The pathogenesis involves abnormalities in calcium and phosphorus metabolism, and acute deposition of calcium in tissues. Methods The clinical course of 16 patients diagnosed with calciphylaxis at this institution from 1994 to 1998 was reviewed. Results Fourteen women and two men, with a mean age of 56 (range 39–70) years, presented with chronic renal disease of various causes, hyperparathyroidism and characteristic skin lesions. All patients underwent intensive medical therapy, including haemodialysis (n = 16), parathyroidectomy (PTX) (n = 7) and skin debridement of cutaneous lesions (n = 8). Mean preoperative serum values in surgical (PTX) versus non-surgical patients were: calcium 9·9 and 9·3 mg dl−1 (P = 0·25); phosphorus 5·8 and 4·9 mg dl−1 (P = 0·04); calcium–phosphorus product 61·6 and 45·2 (P = 0·03); and parathyroid hormone (PTH) 56·8 and 5·9 pmol l−1 (P = 0·0001) respectively. Mean postoperative values for calcium (8·7 mg dl−1), phosphorus (4·2 mg dl−1), calcium–phosphorus product (30·5) and PTH (4·0 pmol l−1) in surgical patients changed significantly (P &lt; 0·05). Median overall survival was 9·4 months with 15 patients now deceased. Median survival was 14·8 and 6·3 months for PTX versus no PTX (P = 0·22), 14·1 and 6·1 months for skin debridement versus no debridement (P = 0·08), 12·4 and 6·6 months for proximal versus distal skin lesions (P = 0·60), and 6·5 and 13·9 months for diabetic versus non-diabetic patients was (P = 0·11). Conclusion Calciphylaxis appears to have a female preponderance with a very dismal prognosis. A multidisciplinary approach using frequent haemodialysis to normalize serum calcium and phosphorus levels, and local debridement of skin lesions seems prudent. PTX cannot be recommended routinely in all such patients unless severe secondary hyperparathyroidism with poorly controlled metabolic disturbance mandates surgery. The exact indications for PTX for calciphylaxis remain unclear.

Abstract Background Primary sarcomas of the liver are extremely rare in adults. Optimal therapeutic approaches remain unclear. Methods Twenty consecutive adult patients who had surgical treatment for primary hepatic sarcomas were reviewed. Patient age ranged from 23 to 80 years. Other than one patient with primary hepatic angiosarcoma who had a history of thorium dioxide colloid (Thorotrast) exposure 23 years before diagnosis, no predisposing causes were apparent. Nineteen patients had hepatic resection and one patient had an orthotopic liver transplant. No patient received neoadjuvant chemotherapy or radiotherapy but radiotherapy was delivered intraoperatively in one patient. Results Leiomyosarcoma was the most common histological type of sarcoma diagnosed (five of 20 patients), followed by malignant solitary fibrous tumour (four) and epithelioid haemangioendothelioma (three). Fourteen tumours were high-grade sarcomas and six were low grade malignancies. Thirteen patients developed a recurrence. Distant metastases (ten patients) and intrahepatic recurrence (six) were the predominant sites of initial treatment failure. Six patients received salvage chemotherapy. Histological grade was the only factor significantly associated with overall patient survival (P = 0·03). With complete resection, patients with high-grade tumours had a 5-year survival rate of 18 (95 per cent confidence interval 5–62) per cent compared with 80 (52–100) per cent for patients with low-grade tumours. The 5-year survival rate for all 20 patients was 37 (20–60) per cent. Conclusion Surgical resection is the only effective therapy for primary hepatic sarcomas at present. Better adjuvant therapy is necessary, especially for high-grade malignancies, owing to the high failure rate with operation alone.