Citations

Purpose: A phase III, randomized, double-blind study was conducted by the North Central Cancer Treatment Group to determine the efficacy and toxicity of oral glutamine for the prevention of acute diarrhea in patients receiving pelvic radiation therapy (RT). Patients and Methods: All 129 patients enrolled from 14 institutions between February 1998 and October 1999 were eligible. Patients received 4 g of glutamine or placebo orally, twice a day, beginning with the first or second day of RT and continuing for 2 weeks after RT. During treatment, patients were assessed weekly for toxicity, and a bowel function questionnaire was administered. The primary measures of treatment efficacy were diarrhea levels measured by maximum grade of diarrhea, incidence of diarrhea, and average diarrhea score. After completion of RT, the bowel function questionnaire was administered weekly for 4 weeks and at 12 and 24 months. Toxicity was measured by National Cancer Institute common toxicity criteria. Results: The median age of patients was 69 years (range, 34 to 86 years). The two treatment arms were balanced with respect to all baseline factors. There were no significant differences in toxicity by treatment. Quality-of-life scores and the mean number of problems reported on the bowel function questionnaire were virtually identical for both treatment groups. The incidence of grade 3 or higher diarrhea was 20% for the glutamine arm and 19% for the placebo arm (P = .99). The maximum number of stools per day was 5.1 for the glutamine arm and 5.2 for the placebo arm (P = .99). Conclusion: There is no evidence of a beneficial effect of glutamine during pelvic RT.

AbstractWe reported recently the induction of androgen-dependent iodide uptake activity in the human prostatic adenocarcinoma cell line LNCaP using a prostate-specific antigen (PSA) promoter-directed expression of the sodium iodide symporter (NIS) gene. This offers the potential to treat prostate cancer with radioiodine. In the current study, we examined the regulation of PSA promoter-directed NIS expression and therapeutic effectiveness of 131I in LNCaP cells by all-trans-retinoic acid (atRA). For this purpose, NIS mRNA and protein expression levels in the NIS-transfected LNCaP cell line NP-1 were examined by Northern and Western blot analysis following incubation with atRA (10 −9 to 10−6m) in the presence of 10−9m mibolerone (mib). In addition, NIS functional activity was measured by iodide uptake assay, and in vitro cytotoxicity of 131I was examined by in vitro clonogenic assay. Following incubation with atRA, NIS mRNA levels in NP-1 cells were stimulated 3-fold in a concentration-dependent manner, whereas NIS protein levels increased 2.3-fold and iodide accumulation was stimulated 1.45-fold. This stimulatory effect of atRA, which has been shown to be retinoic acid receptor mediated, was completely blocked by the pure androgen receptor antagonist casodex (10−6m), indicating that it is androgen receptor dependent. The selective killing effect of 131I in NP-1 cells was 50% in NP-1 cells incubated with 10−9m mib. This was increased to 90% in NP-1 cells treated with atRA (10−7m) plus 10−9m mib. In conclusion, treatment with atRA increases NIS expression levels and selective killing effect of 131I in prostate cancer cells stably expressing NIS under the control of the PSA promoter. Therefore atRA may be used to enhance the therapeutic response to radioiodine in prostate cancer cells following PSA promoter-directed NIS gene delivery.

Abstract Tissue structural cells are known in some situations to play a role in the presentation of antigen and in immunoregulation. We assessed the expression of B7 homologs, known to be involved in antigen presentation and lymphocyte costimulation, in human airway epithelial cells. Flow cytometry performed on the airway epithelial cell line BEAS-2B, as well as primary bronchial epithelial cells (PBEC), showed that B7-H2 was constitutively expressed on both BEAS-2B and PBEC, whereas B7-1 and B7-2 were undetectable on either epithelial cell type. B7-H2 expression was confirmed by Western blot using a specific antibody. Stimulation with various cytokines, including tumor necrosis factor-α, interferon-γ, and interleukin-4, slightly downregulated B7-H2 expression detected by flow cytometry, but did not significantly alter the apparent level of protein as assessed by Western blotting. Northern blotting detected mRNA for B7-H2 and B7-1, but not B7-2. B7-H2 was cloned from BEAS-2B cells and the sequence verified. Expression of B7-H2 mRNA was detected by real-time reverse transcriptase–polymerase chain reaction in PBEC from three independent donors. Immunohistochemical analysis of airway derived from autopsies revealed expression of B7-H2 in human airway epithelial cells. These results demonstrate that airway epithelial cells express the costimulatory molecule B7-H2, and suggest the possibility that B7-H2 may participate in antigen presentation by epithelial cells.

Purpose: Radioimmunotherapy (RIT) with yttrium-90 (90Y)-labeled anti-CD20 antibody (90Y ibritumomab tiuxetan; Zevalin, IDEC Pharmaceuticals Corporation, San Diego, CA) has a high rate of tumor response in patients with relapsed or refractory, low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma (NHL). This study presents the safety data from 349 patients in five studies of outpatient treatment with 90Y ibritumomab tiuxetan. Patients and Methods: Patients received rituximab 250 mg/m2 on days 1 and 8, and either 0.4 mCi/kg (15 MBq/kg) or 0.3 mCi/kg (11 MBq/kg) of 90Y ibritumomab tiuxetan on day 8 (maximum dose, 32 mCi). Patients were observed for up to 4 years after therapy or until progressive disease. Results: Infusion-related toxicities were typically grade 1 or 2 and were associated with rituximab. No significant organ toxicity was noted. Toxicity was primarily hematologic, with nadir counts occurring at 7 to 9 weeks and lasting approximately 1 to 4 weeks depending on the method of calculation. After the 0.4-mCi/kg dose, grade 4 neutropenia, thrombocytopenia, and anemia occurred in 30%, 10%, and 3% of patients, respectively, and after the 0.3-mCi/kg dose, these grade 4 toxicities occurred in 35%, 14%, and 8% of patients, respectively. The risk of hematologic toxicity increased with degree of baseline bone marrow involvement with NHL. Seven percent of patients were hospitalized with infection (3% with neutropenia) and 2% had grade 3 or 4 bleeding events. Myelodysplasia or acute myelogenous leukemia was reported in five patients (1%) 8 to 34 months after treatment. Conclusion: Single-dose 90Y ibritumomab tiuxetan RIT has an acceptable safety profile in relapsed NHL patients with less than 25% lymphoma marrow involvement, adequate marrow reserve, platelets greater than 100,000 cells/μL, and neutrophils greater than 1,500 cells/μL.

Abstract Lymphangiomyomatosis (LAM) is characterized by the proliferation of abnormal smooth muscle cells and cystic degeneration of the lung. LAM affects almost exclusively young women. Although lung transplantation provides effective therapy for end-stage LAM, there are reports of LAM recurrence after lung transplantation. Whether these recurrent LAM cells arise from the patient or the lung transplant donor is an area of controversy. We used microsatellite marker fingerprinting and TSC2 gene mutational analysis to study a patient with recurrent LAM after single-lung transplantation. The DNA microsatellite marker pattern indicated the presence of patient-derived LAM cells in the allograft. A somatic one base pair deletion in exon 18 of the TSC2 gene was identified in pulmonary and lymph node LAM cells before transplantation. The same mutation was in the recurrent LAM, demonstrating that the recurrent LAM was derived from the patient. Fluorescence in situ hybridization revealed that cells immunoreactive with the monoclonal antibody HMB-45 did not contain a Y chromosome. These data indicate that histologically benign LAM cells can migrate or metastasize in vivo to the transplanted lung. In addition, the patient had no evidence of a renal angiomyolipoma at autopsy and therefore demonstrated for the first time that somatic TSC2 mutations cause LAM in patients without angiomyolipomas.

The mechanisms by which mammalian cells remodel the actin cytoskeleton in response to motogenic stimuli are complex and a topic of intense study. Dynamin 2 (Dyn2) is a large GTPase that interacts directly with several actin binding proteins, including cortactin. In this study, we demonstrate that Dyn2 and cortactin function to mediate dynamic remodeling of the actin cytoskeleton in response to stimulation with the motogenic growth factor platelet-derived growth factor. On stimulation, Dyn2 and cortactin coassemble into large, circular structures on the dorsal cell surface. These “waves” promote an active reorganization of actin filaments in the anterior cytoplasm and function to disassemble actin stress fibers. Importantly, inhibition of Dyn2 and cortactin function potently blocked the formation of waves and subsequent actin reorganization. These findings demonstrate that cortactin and Dyn2 function together in a supramolecular complex that assembles in response to growth factor stimulation and mediates the remodeling of actin to facilitate lamellipodial protrusion at the leading edge of migrating cells.

Abstract Background The authors have reported a newly recognized hypoglyacemic disorder, non-insulinoma pancreatogenous hypoglycaemia syndrome (NIPHS), which is characterized by postprandial hyperinsulinaemic hypoglycaemia, negative 72-h fast, negative transabdominal and intraoperative ultrasonography, spiral computed tomography and coeliac axis angiography, positive selective arterial calcium stimulation test (SACST), absence of insulinoma but presence of islet hypertrophy and nesidioblastosis, and relief of symptoms from gradient-guided partial pancreatectomy. Experience with the next five patients with this disorder (6–10; 1998–1999) compared with the original five (1–5; 1996–1998) is reported. Results Wide age range, male predominance, postprandial occurrence of symptoms, negative radiological localization, nesidioblastosis/islet hypertrophy, but no insulinoma characterized all ten cases. Response to SACST indicated widespread islet hyperfunction in patients 1 and 5; limitation to distribution of the SPA and GDA in patients 3, 4, 6 and 8, to distribution of the SPA in patients 2, 7 and 9, and to distribution of the SMA in patient 10. Except for patient 5, pancreatic resection to the left of the SMV was performed when only the SPA was positive on the SACST. Patients 5 and 8 have had recurrence of symptoms; they resolved within 3 months for patient 5. Conclusion NIPHS can usually be treated successfully with gradient-guided partial pancreatectomy.

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 < 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.

Coupled vibration of arterial tubes is analyzed with the wave propagation approach and first-order shear deformation theory. Both the interior and exterior fluids are considered as compressible so that acoustic waves can be generated and propagated in the fluids. Results obtained using the theory have been evaluated against those available in the literature and the agreement has been found to be good. The theory can be used for future research on the vibration and acoustics of arterial walls. Vibration experiments were carried out on a silicone rubber tube in a water tank with a novel ultrasound stimulated optical vibrometry system. This system uses the radiation force of ultrasound to vibrate the tube at low frequency and records the resulting response by a laser vibrometer. Both the excitation and measurement are remote and noncontact. The silicone rubber tube was chosen because it has mechanical properties close to those of arteries. The fundamental frequency is well excited by the radiation force and measured with the laser. The measured fundamental frequency is in good agreement with the present theory.