Treatment of lymphoid malignancies in patients with ataxia-telangiectasia

The present study tested the idea that if subjects rely more on scene-based pictorial cues when binocular cues are not available, then both their perceptual judgements and their grasp might be influenced by pictorial illusions such as the Ebbinghaus (Titchener) Circles Illusion under monocular viewing conditions. Under binocular viewing conditions, subjects were always able to scale their grip accurately to the true size of the target disc and were unaffected by the illusion. Under monocular viewing, however, subjects appeared to be influenced by the illusion. Thus, when confronted with physically different target discs displayed on backgrounds that made them appear equivalent in size, subjects treated the two discs as equivalent--even when picking them up. These results, combined with earlier work from our laboratory suggests that binocular information plays a critical role in normal human prehension but when this information is not available the visuomotor system is able to "fall back" on the remaining monocular cues, which can cause the visuomotor system to be more susceptible to pictorial illusions.     

Factors associated with successful mobilization of peripheral blood progenitor cells in 200 patients with lymphoid malignancies

To examine the repertoire of Pneumocystis carinii antigens recognized by antibody-secreting B cells from tracheobronchial lymph nodes isolated immediately following recovery from P. carinii pneumonia, monoclonal antibodies (MAbs) were produced from these cells. In contrast to previous studies of systemic immunity, P. carinii gpA was not the immunodominant antigen recognized by these B cells. Forty-nine (91%) of 54 P. carinii-specific hybridoma culture supernatants reacted with P. carinii antigens other than gpA. Many of the resulting MAbs recognized a previously uncharacterized antigen expressed on the surface of both cysts and trophozoites. Western blotting using one of the cloned MAbs revealed reactivity with a broad range of antigenic material, with the most intense reactivity in the 50- to 65-kDa region of the blot. The antigens identified by these MAbs merit further investigation regarding protective immunity to P. carinii because they were recognized by B cells in the context of recovery from P. carinii pneumonia.     

2-Chlorodeoxyadenosine: a newer purine analog active in the treatment of indolent lymphoid malignancies

OBJECTIVE: To review the structure, mechanism of action, pharmacologic features, and clinical trial results of the newer purine analog, 2-chlorodeoxyadenosine (2-CdA). DATA SOURCES AND STUDY SELECTION: English-language medical literature review of more than 70 articles. DATA SYNTHESIS: 2-Chlorodeoxyadenosine is unique compared with traditional antimetabolite drugs in that it is equally active against dividing and resting lymphocytes, which may be especially important in indolent lymphoid malignancies, such as chronic lymphocytic leukemia, because most cells in these disorders are in the resting phase. In patients with alkylator-refractory chronic lymphocytic leukemia who were treated with 2-CdA, 44% achieved a response (4% complete responses, 40% partial responses), and 54%, scored as nonresponders, had a sustained reduction in their peripheral lymphocytosis. Patients with untreated chronic lymphocytic leukemia had an 85% response rate (25% complete responses, 60% partial responses). Patients with previously treated low-grade lymphoma achieved an overall response rate of 43%. The most striking clinical effects of this drug have been seen in hairy cell leukemia, in which a single course of therapy induces complete remissions in 85% of partial remissions in 12%. Activity has also been shown in cutaneous T-cell lymphoma and the myeloid leukemias. CONCLUSIONS: 2-Chlorodeoxyadenosine is a newer purine analog with potent activity in the treatment of indolent lymphoproliferative diseases and illustrates the model for rational drug development.     

Xenotransplantation of human lymphoid malignancies is optimized in mice with multiple immunologic defects

While it is known that mice with genetic immune defects are useful for establishing durable engraftment of human tumor xenografts, the relative role of components of host innate and adoptive immunity in engraftment has not been determined. We directly compared the ability of four strains of genetically immunodeficient mice (NOD/SCID, SCID, Nude and Rag-1-deficient) to successfully engraft and support the human cell lines Daudi, Raji, Namalwa and Molt-4 as subcutaneous tumors. We additionally examined the effect of further immunosuppression of the mice by whole body irradiation at a dose of 600 cGy for Nude and Rag-1 and 300 cGy for SCID mice and by administration of anti-natural killer (asialo-GM1) antibody on tumor growth. Mice with each of the defects supported xenografts to varying degrees. We found differences in growth characteristics in the cell lines tested, with Namalwa consistently producing the largest tumors. With all cell lines studied, optimal growth was achieved using NOD/SCID mice. Overall, tumor growth was somewhat enhanced by pretreatment with radiation with little additional benefit from the addition of anti-asialo-GM1 antibody. The importance of multiple components of the innate and adoptive immune system in xenotransplantation were best demonstrated when results in untreated NOD/SCID mice were compared to SCID, nude and RAG-1-deficient mice. The NOD/SCID mouse with or without additional immunosuppression provides the optimal model for the study of the biology and treatment of human leukemias and lymphomas.     

Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies

PURPOSE: To investigate the use of a nonmyeloablative fludarabine-based preparative regimen to produce sufficient immunosuppression to allow engraftment of allogeneic stem cells and induction of graft-versus-leukemia/lymphoma (GVL) as the primary treatment modality for patients with chronic lymphocytic leukemia (CLL) and lymphoma. PATIENTS AND METHODS: Fifteen patients were studied. Six patients were in advanced refractory relapse, and induction therapy had failed in two patients. Patients with CLL or low-grade lymphoma received fludarabine 90 to 150 mg/m2 and cyclophosphamide 900 to 2,000 mg/m2. Patients with intermediate-grade lymphoma or in Richter's transformation received cisplatin 25 mg/m2 daily for 4 days; fludarabine 30 mg/m2; and cytarabine 500 mg/m2 daily for 2 days. Chemotherapy was followed by allogeneic stem-cell infusion from HLA-identical siblings. Patients with residual malignant cells or mixed chimerism could receive a donor lymphocyte infusion of 0.5 to 2 x 10(8) mononuclear cells/kg 2 to 3 months posttransplantation if graft-versus-host disease (GVHD) was not present. RESULTS: Eleven patients had engraftment of donor cells, and the remaining four patients promptly recovered autologous hematopoiesis. Eight of 11 patients achieved a complete response (CR). Five of six patients (83.3%) with chemosensitive disease continue to be alive compared with two of nine patients (22.2%) who had refractory or untested disease at the time of study entry (P = .04). CONCLUSION: These findings indicate the feasibility of allogeneic hematopoietic transplantation with a nonablative preparative regimen to produce engraftment and GVL against lymphoid malignancies. The ability to induce remissions with donor lymphocyte infusion in patients with CLL, Richter's, and low-grade and intermediate-grade lymphoma is direct evidence of GVL activity against these diseases. This approach appears to be most promising in patients with chemotherapy-responsive disease and low tumor burden.     

Seroprevalence study of HTLV-1 and HIV infection in blood donors and patients with lymphoid malignancies in Lagos, Nigeria

OBJECTIVE: To document the seroprevalence of HTLV-1 and HIV in blood donors and in patients with lymphoma and leukaemia in Lagos metropolis. DESIGN: Cross sectional. SETTING: The Lagos University Teaching Hospital (LUTH) and General Hospital, Lagos (GH). SUBJECTS: 406 apparently healthy voluntary blood donors from the LUTH and GH and 30 patients [20 patients with histological diagnosis of Non-Hodgkin's Lymphoma (NHL) and 10 patients with diagnosis of Chronic Lymphocytic Leukaemia (CLL)] were recruited at LUTH. MAIN OUTCOME MEASURES: HTLV-1 and HIV-1 seroprevalence. RESULTS: Out of 406 donors, three (0.7%) were positive for HTLV-1 and 20 (4.9%) were positive for HIV-1. None of the 30 patients with NHL or CLL were positive for HTLV-1. Five of NHL patients were positive for HIV-1. CONCLUSION: HTLV-1 seroprevalence is low among Lagos donors. Routine screening of donors for this virus will not be cost effective. NHL is one of the AIDS related malignancies which has been documented in this study.     

Clinical evaluation of cefozopran for infections associated with hematological malignancies

Cefozopran (CZOP) was used as an initial antibacterial therapy for infections in patients with hematological malignancies. CZOP was given at a daily dose of 4 g by drip intravenously to patients who were febrile over 38 degrees C and were suspected as having bacterial infections. As underlying diseases, 8 patients had acute lymphoblastic leukemia (ALL), 9 acute myeloblastic leukemia (AML), 2 aplastic anemia (AA), 2 adult T cell leukemia/lymphoma (ATLL), 28 non Hodgkin lymphoma (NHL), and 2 multiple myeloma (MM). Bacterial infections diagnosed were sepsis in 7 patients, suspected sepsis in 32, bronchitis in 6, pneumonia in 5 and acute peritonitis in 1. Clinical responses among 51 evaluable cases were excellent in 14, good in 15, fair in 3, poor in 19 and the overall response rate was 57%. The overall response rates for AML, ALL, AA, ATLL, NHL and MM were 56%, 63%, 100%, 50%, 50%, and 100%, respectively. Those for sepsis, suspected sepsis, bronchitis, pneumonia and acute peritonitis were 14%, 63%, 100%, 40%, and 0%, respectively. This therapy was effective in 53% (9/17) of patients whose granulocyte count remained below 500/microliter throughout the course of CZOP therapy. Six bacterial and one fungal strains were isolated from blood and sputum of six patients including five sepsis cases; two bacteria were eradicated and bacterial change was observed in one case. As side adverse effects, 10 patients had liver dysfunction, 1 anemia, 2 proteinemia, 1 indirect bilirubinemia, 2 thrombocytopenia, and 1 eosinophilia. We tried to establish a scoring system for the severities of patients with their infections, underlying diseases, treatments for the underlying disease, and granulocyte counts in order to evaluate the efficacy of CZOP more precisely. This scoring system was consisted of three grades; severe, moderate, and mild. CZOP was effective on mild and moderate grades. These results indicate that the initial antibacterial therapy by CZOP is useful for the treatment of mild and moderate grade infections complicated with hematological malignancies.     

CD30 ligand is frequently expressed in human hematopoietic malignancies of myeloid and lymphoid origin

CD30 ligand (CD30L) is a type-II membrane glycoprotein capable of transducing signals leading to either cell death or proliferation through its specific counterstructure CD30. Although several lines of evidence indicate that CD30L plays a key role as a paracrine- or autocrine-acting surface molecule in the deregulated cytokine cascade of Hodgkin's disease, little is known regarding its distribution and biologic significance in other human hematopoietic malignancies. By analyzing tumor cells from 181 patients with RNA studies and immunostaining by the anti-CD30L monoclonal antibody M80, we were able to show that human hematopoietic malignancies of different lineage and maturation stage display a frequent and broad expression of the ligand. CD30L mRNA and surface protein were detected in 60% of acute myeloid leukemias (AMLs), 54% of B-lineage acute lymphoblastic leukemias (ALLs), and in a consistent fraction (68%) of B-cell lymphoproliferative disorders. In this latter group, hairy cell leukemia and high-grade B-cell non-Hodgkin's lymphoma (B-NHL) expressed a higher surface density of CD30L as compared with B-cell chronic lymphocytic leukemia and low-grade B-NHL. Purified plasmacells from a fraction of multiple myeloma patients also displayed CD30L mRNA and protein. A more restricted expression of CD30L was found in T-cell tumors that was mainly confined to neoplasms with an activated peripheral T-cell phenotype, such as T-cell prolymphocytic leukemia, peripheral T-NHL, and adult T-cell leukemia/lymphoma. In contrast, none of the T-lineage ALLs analyzed expressed the ligand. In AML, a high cellular density of CD30L was detected in French-American-British M3, M4, and M5 phenotypes, which are directly associated with the presence on tumor cells of certain surface structures, including the p55 interleukin-2 receptor alpha-chain, the alpha(M) (CD11b) chain of beta2 integrins, and the intercellular adhesion molecule-1 (CD54). Analysis of normal hematopoietic cells evidenced that, in addition to circulating and tonsil B cells, a fraction of bone marrow myeloid precursors, erythroblasts, and subsets of megakaryocytes also express CD30L. Finally, we have shown that native CD30L expressed on primary leukemic cells is functionally active by triggering both mitogenic and antiproliferative signals on CD30+ target cells. As opposed to CD30L, only 10 of 181 primary tumors expressed CD30 mRNA or protein, rendering therefore unlikely a CD30-CD30L autocrine loop in human hematopoietic neoplasms. Taken together, our data indicate that CD30L is widely expressed from early to late stages of human hematopoiesis and suggest a regulatory role for this molecule in the interactions of normal and malignant hematopoietic cells with CD30+ immune effectors and/or microenvironmental accessory cells.     

Sepsis associated with hematological malignancies: prophylaxis of Pseudomonas aeruginosa sepsis

Imaging of anorectal region has drastically changed during the last decade. Transrectal ultrasound and transrectal MRI can be used for staging the rectal tumours. Endoanal sonography can be applied for the classification of perianal fistulae and identification of anal sphincter defects in patients with faecal incontinence. Due to the limitations of endoanal sonography, endoanal MRI was introduced to assess the pathology related to the anal sphincter complex. Endoanal MRI seems superior to endoanal sonography. This paper describes the new developments of the imaging techniques and presents new insights in anatomy and pathology of the anorectum.     

Systemic amyloidosis associated with common variable hypogammaglobulinemia and intestinal lymphoid nodular hyperplasia

Common variable hypogammaglobulinemia syndrome with lymphoid nodular hyperplasia of the intestine forms part of the so-called hypogammaglobulinemic enteropathies. It is characterized by decreased serum immunoglobulins, recurrent respiratory tract infections and chronic diarrhea. The development of systemic amyloidosis is infrequent, but it can be explained by the multiple infections in this setting. The case of a 47-years old woman with hypogammaglobulinemic enteropathy, who developed systemic amyloidosis is presented. It was manifested as a nephrotic syndrome. The previously published reports include 12 cases of common variable hypogammaglobulinemia with systemic amyloidosis. Half of them presented nephrotic syndrome as a manifestation of their amyloidosis. It is important to keep in mind this complication in these patients' follow-up in order to increase the doses of gammaglobulin. That is the way to compensate their additional losses because of the nephrotic syndrome that they usually develop.     

Radiotherapy in the treatment of dermatologic malignancies

A large set of monoclonal antibodies (MAbs) directed against the fusion glycoprotein complex F1F2 of bovine respiratory syncytial virus (BRSV) and several polyclonal sera from infected or vaccinated animals were tested in Pepscan to locate linear epitopes on the F-protein. The polyclonal sera mapped to antigenic sites that correspond exactly to known antigenic sites on the F protein of human RSV. Only the neutralizing MAb 3 could be mapped with Pepscan. MAb 3 reacted with three successive overlapping linear peptides that shared the amino acid sequence 173STNKAVVSLS182. The sequence of this novel neutralization site is conserved in all known BRSV- and human RSV-strains and is located on the N-terminus of F1, adjacent to the hydrophobic, putative fusion-related region. This region is probably part of a central coiled-coil stem that is structurally conserved in paramyxovirus fusion and orthomyxovirus hemagglutinin glycoproteins. This linear conserved epitope may be a potential candidate for a peptide-based vaccine which can induce neutralizing antibodies against all groups and subgroups of RSV. Furthermore, the proposed structural features of the neutralization site may aid in the design of a peptide-based vaccine.     

Association of hyperuricemia with hyperlipidemia and obesity

Various epidemiological evidences have shown the increased incidence of hyperuricemia in the subjects with hyperlipidemia and/or obesity. Our clinical study indicated the association was more close in hypertriglyceridemia to hyperuricemia than in hypercholesterolemia. Serum uric acid level increased more in Type IIb with elevated lipoprotein lipase (LPL) than those with low or normal LPL. Elevated LPL may be involved in the retarded uric acid clearance due to increased free fatty acids (FFA) in the serum, resulting in the elevation of uric acid and may be linked to the obesity-insulin resistance syndrome. Increased FFA may play an important role on the association of hyperuricemia with hypertriglyceridemia.     

Comparison of two algorithms and their associated charges when evaluating adrenal masses in patients with malignancies

OBJECTIVE: This study was performed to compare two proposed algorithms used when evaluating an adrenal mass discovered during staging evaluation of a patient with a known malignancy. Such evaluation was meant to lead to determination of the relative charges associated with each algorithm. SUBJECTS AND METHODS: Fifty-four patients with known malignancies who required evaluation of an adrenal mass underwent both chemical shift imaging (CSI) and CT-guided for CSI. The hospital charges incurred for each procedure and any associated complications were normalized using national relative-value scale charges and conversion factors. A decision analysis was performed to compare the relative charges that would have been incurred if adrenal MR imaging had been performed in all patients, followed by CT-guided biopsy only in those patients with MR findings not diagnostic of adrenocortical adenoma, and the relative charges incurred if only CT-guided adrenal biopsy had been performed in every patient. RESULTS: Twenty-three (43%) of 54 adrenal masses were shown to be metastases by CT-guided biopsy. The sensitivity and specificity of CSI for the diagnosis of adrenocortical adenoma were 94% and 100%, respectively. The charges incurred by performing MR imaging as the initial examination with subsequent CT-guided biopsy only in those patients with CSI findings not diagnostic of adenoma would have been similar to those incurred by first performing CT-guided adrenal biopsy in every patient. CONCLUSION: CSI is an accurate, noninvasive technique for evaluating adrenal masses in patients with cancer. If CT-guided biopsy is used only when CSI is not diagnostic of adrenocortical adenoma, the associated charges would be virtually the same as when CT-guided biopsy is performed as the first test in every patient. Moreover, biopsies could have been avoided in 54% of these patients.     

Xanthine oxidase activity associated with arterial blood pressure in spontaneously hypertensive rats

Recent evidence in vivo indicates that spontaneously hypertensive rats (SHR) exhibit an increase in oxyradical production in and around microvascular endothelium. This study is aimed to examine whether xanthine oxidase plays a role in overproduction of oxidants and thereby may contribute to hypertensive states as a consequence of the increasing microvascular tone. The xanthine oxidase activity in SHR was inhibited by dietary supplement of tungsten (0.7 g/kg) that depletes molybdenum as a cofactor for the enzyme activity as well as by administration of (-)BOF4272 [(-)-8-(3-methoxy-4-phenylsulfinylphenyl)pyrazolo(1,5-alpha)-1,3, 5-triazine-4-monohydrate], a synthetic inhibitor of the enzyme. The characteristic elevation of mean arterial pressure in SHR was normalized by the tungsten diet, whereas Wistar Koto (WKY) rats displayed no significant alteration in the pressure. Multifunctional intravital videomicroscopy in mesentery microvessels with hydroethidine, an oxidant-sensitive fluoroprobe, showed that SHR endothelium exhibited overproduction of oxyradicals that coincided with the elevated arteriolar tone as compared with WKY rats. The tungsten diet significantly repressed these changes toward the levels observed in WKY rats. The activity of oxyradical-producing form of xanthine oxidase in the mesenteric tissue of SHR was approximately 3-fold greater than that of WKY rats, and pretreatment with the tungsten diet eliminated detectable levels of the enzyme activity. The inhibitory effects of the tungsten diet on the increasing blood pressure and arteriolar tone in SHR were also reproducible by administration of (-)BOF4272. These results suggest that xanthine oxidase accounts for a putative source of oxyradical generation that is associated with an increasing arteriolar tone in this form of hypertension.     

Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency

Leigh disease associated with cytochrome c oxidase deficiency (LD[COX-]) is one of the most common disorders of the mitochondrial respiratory chain, in infancy and childhood. No mutations in any of the genes encoding the COX-protein subunits have been identified in LD(COX-) patients. Using complementation assays based on the fusion of LD(COX-) cell lines with several rodent/human rho0 hybrids, we demonstrated that the COX phenotype was rescued by the presence of a normal human chromosome 9. Linkage analysis restricted the disease locus to the subtelomeric region of chromosome 9q, within the 7-cM interval between markers D9S1847 and D9S1826. Candidate genes within this region include SURF-1, the yeast homologue (SHY-1) of which encodes a mitochondrial protein necessary for the maintenance of COX activity and respiration. Sequence analysis of SURF-1 revealed mutations in numerous DNA samples from LD(COX-) patients, indicating that this gene is responsible for the major complementation group in this important mitochondrial disorder.     

Ureteral injuries associated with gynecologic surgery: prevention and management

Gynecologic surgery is responsible for most of the ureteral injuries that occur. The "easy" operation--the "simple" abdominal hysterectomy--and not the technically difficult pelvic one, is responsible for most ureteral injuries. Total abdominal hysterectomy accounts for almost 50% of the genitourinary fistulas and perhaps 80-99% of all surgical ureteral injuries. This problem will persist until a most important surgical axiom is applied routinely during the accomplishment of all pelvic operations: With all dissections, the contiguous structures subject to injury must be exposed. This step not only will avoid injuries to the ureter but also will facilitate an equally important aspect, that is, urinary tract injuries must be recognized at the time of operation. With recognition and adequate repair, problems such as fistula formation and serious morbidity (and litigation) can be avoided almost entirely. Because the gnecologic surgeon frequently will find that urologic consultation is not available at the time of urinary tract injury, he or she must be aware of and familiar with the various ureteral reconstructive procedures that may be required. The gynecologic surgeon must devote time and study to the management of urinary tract injuries before their occurrence. All pelvic surgeons eventually will encounter ureteral problems. The methods of bladder mobilization and ureteroneocystostomy should be within the ability of all who operate within the pelvis. When extensive damage has occurred and a urologist is not available, the gynecologist who is unfamiliar with the more demanding techniques (that is, ureteroureterostomy, bladder flaps, ileal conduits) should avoid additonal damage to the urinary tract and accomplish a simple catheter ureterostomy, deffering the definitive repair for a urologist.