A benign form of chronic lympholeukemia]

According to the classification of chronic lymphocytic leukemia (CLL) proposed by A. I. Vorob'ev and M. D. Brilliant in 1983, benign CLL is a distinct form of CLL which is characterized by low level of absolute lymphocytosis, absent or mild peripheral lymphadenopathy, slow progression. No specific therapy is needed. The paper presents clinical, morphological and immunological analysis of 34 cases of benign CLL (17 males and 17 females, mean age 58 years). Patients were included in the study if they had lymphocyte count less than 30,000 and no significant growth of lymphoid tissue for at least 3 years. They were followed up from 3 to 24 years (11 years, on the average). The main features of benign CLL are the following: no "B" symptoms, no essential enlargement of the lymphoid organs, a stable low level of absolute lymphocytosis, low prolymphocyte count in the blood smear (0.95% +/- 0.2), nodular or nodular-interstitial proliferation in the bone marrow. We failed to find any cases with paraprotein secretion. There was immunophenotype typical for CLL in 91% of cases (CD19+, CD20+, CD23+, CD5+, EM+, CR1-/CR2+, sIg+(-)). None was positive for CD38 activation marker. One trisomy 12 cases was detected by FISH method. 8 patients died so far, but not because of the tumor progression or transformation, median survival was 22 years.     

A recombinant adenovirus expressing wild type p53 induces apoptosis in drug-resistant human breast cancer cells: a gene therapy approach for drug-resistant cancers

The different therapeutic options available for the treatment of chronic leukemias and myelofibrosis are discussed. In reference to chronic myeloid leukemia (CML), the choice of the most appropriate treatment must take into account not only the clinical condition but also the age of the patient. While subjects under 50 might benefit from the options offered by alpha-interferon, bone marrow and peripheral stem cell transplant, in older age groups treatment of the chronic phase must still rely on standard treatment. Chronic lymphocytic leukemia (CLL) and its variants is a disease of mostly middle and late life, with a variable clinical course. Patients show wide differences in morbidity and mortality. Many features have been shown to influence the prognosis, and the most important ones are incorporated into the staging systems currently in use. The results obtained from the study of large trials support the concept that treatment of patients with stable stage A CLL should be postponed until progression of disease. Treatment relies principally on alkylating agents, corticosteroids and radiation therapy; the new nucleoside analogues, such as fludarabine and 2-chlorodeoxyadenosine, have recently acquired established value in improving overall survival. With regard to myelofibrosis, the histological and biological features that influence the natural course of the disease are described, as well as the choice of the most appropriate treatment, which ranges from the use of alkylating agents and androgens, to splenectomy and splenic irradiation.     

Total body irradiation of chronic lymphocytic leukemia. Relationship between therapeutic response and prognosis

There is lack of evidence to date that treatment of chronic lymphocytic leukemia (CLL) alters the natural history of disease or influences survival. In the present series, total body irradiation (TBI) produced a range of therapeutic responses among patients with active, progressive CLL. One-third of patients experienced virtually complete clinical and hematologic remissions with the initial course of TBI. These patients did not differ from the less complete responders with respect to age or sex, degree of lymphocytosis in the peripheral blood, incidence of anemia and/or thrombocytopenia, or the frequency of constitutional symptoms. However, the patients with complete remissions noted a return to normal performance status, had fewer serious infections, demonstrated recovery from depressed immunoglobulin levels, and had significantly longer survival. These data indicate that TBI is capable of inducing remissions which modify the course of disease in patients with CLL and that prognosis has a direct correlation with the response to therapy.     

Effects of prednisolone in 6 cases of glucocorticoid receptor-positive CLL

The effect of treatment with prednisolone on clinical and laboratory variables was studied in 6 patients with chronic lymphocytic leukaemia (CLL). The laboratory variables analyzed on the leukaemic cells were surface immunoglobulin (S-Ig), sheep red blood cell receptors (SRBC), proliferative activity (PI) and glucocorticoid receptor (GR). In all cases the CLL was of B-cell type and the leukaemic cells contained a significant amount of GR. 4 out of 6 patients had a progressive disease with increased PI. On treatment they went into clinical remission, which was paralleled by a reduction in the leukaemic B-cell number and in PI. The amount of GR was unaffected. In 2 patients with nonprogressive disease, prednisolone produced no clearcut effect on clinical or laboratory variables.     

Calcific tendinitis in the posterior proximal thigh as a self-limited condition: pathogenic role of inflammatory responses

OBJECTIVE: Calcific tendinitis occurs rarely in the posterior proximal thigh. We investigated whether it is self-limited and how the natural course of the disease progresses. METHODS: We treated 6 patients with no surgical intervention, and analyzed laboratory and radiological findings in the followup period of more than one year (average followup, 2.5 yrs). RESULTS: Although tendinitis was severe, rapid relief was observed within 2 weeks (average 5 days). Radiological features including extraskeletal calcifications did not change within 2 weeks, and then improved by 6 weeks. Four of 6 cases showed abnormal laboratory variables. All elevated white blood cell counts and C-reactive protein levels improved within one week with clinical resolution. In comparison with time course of the symptoms, changes in the radiological findings over time appeared not to be parallel with the clinical course, but laboratory progression appeared to correspond well with clinical resolution. CONCLUSION: Inflammatory responses to hydroxyapatite crystals may play a role in the pathogenesis of symptoms of calcific tendinitis in the posterior proximal thigh, most of which are self-limited.     

The spectrum of chronic lymphoproliferative disorders in Hong Kong. A prospective study

We report the incidence of the chronic lymphoproliferative disorders evolving with leukaemia in Hong Kong. Our findings demonstrate that B cell malignancies are significantly more frequent than mature T cell neoplasms, a picture similar to that seen in Western countries but different from other Eastern countries, eg Japan, where T cell malignancies are more frequent. In contrast to the West, where chronic lymphocytic leukaemia (CLL) is the most common disorder, in Hong Kong there is a clear predominance of B cell lymphomas in leukaemic phase accounting for two-thirds of the cases and particularly those displaying lymphoplasmacytic features or with villous lymphocytes. CLL in Hong Kong has similar clinical and laboratory features to the disease in patients from the West. Distinct disease categories, rare in the West such as the variant form of hairy cell leukaemia and T cell prolymphocytic leukaemia, are also documented. It is unclear whether the differences in prevalence of disease subtypes between Hong Kong and the West relate to different genetic background or environmental factors determinant of the development or progression of the leukaemia. Further studies investigating the genetic/molecular lesions may help to clarify whether the aetiopathogenesis of the lymphoid disorders in Hong Kong is similar to that of Western countries.     

Clinical characteristics, treatment, and outcome of adult onset Still's disease in southern Chinese

OBJECTIVE: To study the clinical characteristics, treatment outcome, and complications of patients with adult onset Still's disease (AOSD) in our local Chinese population. METHODS: Patients with AOSD were identified among others who attended our rheumatology clinics from 1967 to 1997 and were followed. Their clinical and laboratory features at presentation, treatment, and outcome were recorded and compared with other reported series. RESULTS: Sixteen patients with AOSD were identified. Eleven (69%) were female. Nine (56%) had onset of the disease between 16 and 35 years of age. The commonest presenting features were fever (100%), arthritis (94%), rash (85%), weight loss (69%), and sore throat (63%). Fifteen patients presented with pyrexia of unknown origin and the median duration of fever before the establishment of the diagnosis was 6 weeks (range 4-75). The acute phase response was marked in all patients with gross elevation of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and complement levels. Hyperferritinemia (> 5 times normal) was present in 90% of cases. Most patients (81%) required corticosteroid therapy and 85% of those steroid treated patients received additional disease modifying agents. The mean duration of followup of our patients was 93.3 months (range 8-362). Five (33%) had monocyclic systemic disease, 6 (40%) had polycyclic systemic disease, and 4 (27%) had frequent relapses that progressed to a chronic arthropathy. CONCLUSION: AOSD in southern Chinese tends to run a benign course, with few patients evolving into chronic inflammatory arthropathy. A significantly lower incidence of serositis, lung involvement, and enlargement of the reticuloendothelial organs was observed at presentation compared with patients of different ethnic origins.     

Evaluation of the accuracy of calcaneus bone tissue findings by a contact ultrasound system. Comparison with the most used absorptiometry methods

Peripheral blood samples from 61 patients (36 male, 25 female) with all stages of B-type chronic lymphocytic leukemia (CLL) were studied for MDR1 phenotype using monoclonal antibodies and rhodamine-123 dye exclusion, a functional assay of MDR1 expression. The duration of the disease varied from 1 month to 22 years at the time of initial study. Overall, 74% of the patients were positive for rhodamine-123 exclusion. When analyzed by gender, significantly more men than women were positive (89% versus 48%, p<0.001). There were more positive men than women for every stage of the disease. Female patients were found to be either MDR1 phenotype positive or negative at any stage of the disease. In contrast, all male patients with early (stages 0-II) disease were MDR1 phenotype positive. One early-stage (stage II) male patient converted from rhodamine-efflux positive to rhodamine-efflux negative as he progressed from stage-II to stage-IV disease. We suggest that some of the differences in disease biology of male versus female CLL patients (women having a more benign course) may be due to gender-dependent differences in drug-resistance gene activity, including MDR1. Our results also emphasize the need to take into account gender in evaluating the clinical course of patients with CLL.     

Serum hepatitis G virus RNA in patients with chronic viral hepatitis

OBJECTIVES: The hepatitis G virus (HGV) is a newly described flavivirus that affects a high proportion of patients with chronic viral hepatitis: our objective was to determine what role HGV might play in the course of disease. METHODS: We evaluated stored serum samples from 108 patients with chronic hepatitis B and 99 patients with chronic hepatitis C who participated in trials of alpha-interferon or ribavirin for the presence of hepatitis B virus (HBV) DNA and hepatitis C virus (HCV) RNA by branched DNA and for the presence of HGV RNA by polymerase chain reaction (PCR), using primers from the NS5 region of the genome. RESULTS: Initially, 20 (19%) patients with hepatitis B and 11 (11%) with hepatitis C had HGV RNA in their serum. Patients with and without HGV infection were similar with regard to clinical features, laboratory tests, and hepatic histology. HGV RNA levels fell during interferon therapy and became undetectable in those receiving the highest doses; however, HGV RNA levels returned to pretreatment values when therapy was stopped. With ribavirin therapy, HGV RNA levels did not change. Two- to 12-yr follow-up serum samples were available from 17 initially HGV RNA-positive patients, of whom only 10 (59%) were still positive. CONCLUSIONS: HGV infection is common among patients with chronic hepatitis B and C but has little effect on the short-term course of disease or response to therapy. HGV RNA levels are suppressed but not eradicated by alpha-interferon and are unaffected by ribavirin treatment. Spontaneous loss of HGV RNA occurs over time in a proportion of patients.     

The clinical and radiological features of cholecystocolic fistulae

The clinical and radiological features of seven patients presenting with cholecystocolic fistulae are reviewed. The majority of the patients were elderly (age range 43-85 years, mean 70.7 years) and there was a female preponderance (6:1). The condition usually has a benign clinical course. Diarrhoea was the most common presenting symptom and the typical clinical features of gallbladder disease were absent. Cholangitis occurred in only one patient. The time between onset of symptoms and diagnosis varied from 1 week to 2 years (mean 22 weeks). In only one patient was the diagnosis of biliary-intestinal fistula suspected on the basis of the plain abdominal radiograph (Case 5). A diagnosis of cholecystocolic fistula was established by barium enema (5 cases), endoscopic retrograde cholangiopancreatography (ERCP) (1 case) and diagnostic laparotomy (1 case). The only cause identified in this series was acute or chronic cholecystitis.     

Autosomal dominant overfolding of the helices

We report the case of a patient with chronic lymphocytic leukemia (CLL) who developed fatal intravascular autoimmune hemolytic anemia (AIHA) after fludarabine treatment. He had previously received several treatments including two courses of fludarabine. The direct antiglobulin test (DAT) was negative at diagnosis but was found to be positive with anti-IgG after the first fludarabine treatment. When the patient was treated again with fludarabine nine months later, the DAT became positive with anti-IgG and anti-C3d antiglobulins after the second course of treatment. Abrupt, fatal intravascular hemolysis occurred after the third course. The occurrence of severe AIHA in CLL patients treated with fludarabine has been reported by several authors. Physicians should be aware of the risk of severe AIHA in CLL patients with a history of AIHA or positivation of the DAT during previous fludarabine administration, or in case of secondary fixation of complement to the red cell membrane occurring during fludarabine treatment.     

The Vogt-Koyanagi-Harada uveomeningoencephalitic syndrome

VKHS is an inflammatory system disease with a subacute chronic course. It has a very variable, selective involvement of certain pigment cells of the eye, skin, inner ear, and meninges. Due in part to the fact that its symptoms are responsive to immunosuppressive therapy, pathogenesis as an autoimmune disease is considered. The clinical course of one of our patients is discussed. Early diagnosis of VKHS, although often very difficult, is mandatory for appropriate and timely treatment.     

Serum beta(2)-microglobulin and serum thymidine kinase are independent predictors of progression-free survival in chronic lymphocytic leukemia and immunocytoma

Chronic lymphocytic leukemia (CLL) and immunocytoma (IC) are remarkably heterogeneous with regard to their clinical course. The current staging systems can distinguish prognostic subgroups, but do not seem to predict the risk of disease progression of an individual patient with sufficient accuracy. Given the increase of treatment options for CLL and IC, additional parameters are needed to decide which patients may benefit from early or intensified treatment. It has been shown that two biochemical markers, serum beta 2-microglobulin (s-beta 2M) and serum thymidine kinase (s-TK), might identify CLL and IC patients at high risk of disease progression. Therefore, the prognostic value of these two serum parameters was compared with a panel of several established prognostic factors in a prospective clinical trial. 113 patients with CLL and 41 patients with IC (mean age +/- SD 63.9 +/- 10.7 years) were included. The following parameters were determined: histopathological diagnosis (IC vs. CLL), age, sex, performance status (Karnofsky index), B symptoms, peripheral blood lymphocyte count, platelet count, blood hemoglobin, serum lactate dehydrogenase (s-LDH), s-beta 2M, s-TK, serum creatinine, number of lymph node areas involved, prior therapy, and the time from diagnosis to inclusion in the study. Univariate analyses showed that nine parameters (Karnofsky index, peripheral blood lymphocytosis, platelet count, blood hemoglobin, lymph node areas involved, pretreatment, s-LDH, s-beta 2M, and s-TK) significantly predicted progression-free survival. In a Cox regression model, only four of these parameters provided independent prognostic information on progression-free survival: 1. s-beta 2M, 2. Karnofsky index, 3. platelet count, and 4. s-TK. The results show that s-beta 2M and s-TK independently predict progression-free survival in patients with CLL and IC, and suggest that these prognostic factors may allow an improved prediction of progression-free survival, particularly in early disease stages.     

Gastric inflammatory myofibroblastic proliferation in children

Gastric inflammatory myofibroblastic proliferation (IMP) is an extremely rare entity in children, which to our knowledge has only been mentioned in case reports. We describe the ninth pediatric case and review the literature concerning the etiology, clinical and laboratory features, pathology, treatment, and outcome. There has been a predominance in preschool females. Abdominal pain, upper gastrointestinal hemorrhage, and an abdominal mass, either isolated or associated, have been the main clinical features. Iron-deficiency anemia has been a constant finding. Lesions are elevated and involve the full thickness of the gastric wall, usually with ulceration of the luminal surface; extragastric extension suggesting malignancy is frequent. Diagnosis is made by histology after surgical excision. There was no mortality directly related to gastric IMP, and only one case recurred after surgical excision. The pathogenesis is controversial, but the finding of Helicobacter pylori in our case may indicate an inflammatory origin. Awareness of this benign lesion and its mimicry of malignancy is important so that inappropriately aggressive therapy can be avoided.     

2-Chlorodeoxyadenosine therapy in advanced chronic lymphocytic leukaemia

The therapeutic potential of 2-chlorodeoxyadenosine (CdA) in patients with advanced chronic lymphocytic leukaemia (CLL) remains controversial with response rates in clinical trials ranging from 44 to 67%. This report describes our experience with CdA in 22 CLL patients having already undergone previous treatment. CdA was given by continuous intravenous infusion at a dose of 4 mg/m2/day for 7 days (4 patients) or as 2-h intravenous infusions at a dose of 5.6 mg/m2/day for 5 days (18 patients). Partial (n = 5) or complete (n = 2) response was obtained in 7 cases. As compared to unresponsive patients, responding subjects received CdA earlier in the course of their disease (mean interval between diagnosis and CdA therapy 58 vs 102 months), were less thrombocytopenic at initiation of CdA (mean platelet count 165 x 10(9)/L vs 81 x 10(9)/L) and experienced less severe neutropenia during the first course of therapy (mean minimal neutrophil count 1.55 x 10(9)/L vs 0.43 x 10(9)/L). None of 6 patients with CLL refractory to fludarabine responded to CdA. An evaluation of haematological toxicity during the first course of treatment showed grade 4 neutropenia (< 0.5 x 10(9)/L) in 7 cases and grade 4 thrombocytopenia (< 25 x 10(9)/L) in one of 19 cases where the platelet count was greater than 25 x 10(9)/L at initiation of CdA. In comparison with earlier reports, the present series of patients had received relatively heavy prior therapy, experienced more severe haematological toxicity and demonstrated a lower total response rate.     

BDNF, and full length and truncated TrkB expression in the hippocampus of the rat following kainic acid excitotoxic damage. Evidence of complex time-dependent and cell-specific responses

We report on the long-term clinical course of 4 boys with Menkes disease, treated from early infancy with parenteral copper-histidine, with follow-up over 10-20 years. Three of the 4 had male relatives with a severe clinical course compatible with classical Menkes disease. As a consequence of early treatment, our patients have normal or near-normal intellectual development, but have developed many of the more severe somatic abnormalities of the related disorder, occipital horn syndrome, including severe orthostatic hypotension in 2. In addition, 1 boy developed a previously unreported anomaly, namely, massive splenomegaly and hypersplenism as a consequence of a splenic artery aneurysm. Previously reported molecular studies in 2 of these patients had shown gene defects which would have predicted a truncated and probably nonfunctional gene product. Despite the favorable effects on the neurological symptoms, parenteral copper treatment for Menkes disease should still be regarded as experimental. The development of more effective treatments must await a more precise delineation of the role which the Menkes protein plays in intracellular copper trafficking.     

Origin of the Hodgkin/Reed-Sternberg cells in chronic lymphocytic leukemia with "Hodgkin's transformation"

A lymphoma with the characteristic features of Hodgkin's disease (HD) occasionally develops in patients with B-cell chronic lymphocytic leukemia (CLL), and has been called Richter's syndrome with HD features. In such cases, large tumor cells have the morphological and immunophenotypic features of classical Hodgkin and Reed-Sternberg (H-RS) cells. However, it is not known whether the H-RS cells arise from transformation of the underlying CLL cells or from a different pathological process. We report herein a study of the clonal relationship between the CLL cells and the H-RS cells in three cases of Richter's syndrome with HD features by using a single cell assay. We isolated single CLL cells and H-RS cells from immunostained tissue sections by micromanipulation. The immunoglobulin heavy chain gene (IgH) complementarity determining region (CDR) III of each cell was amplified by the polymerase chain reaction (PCR). The products were then compared by gel electrophoresis and nucleotide sequencing. The IgH CDRIII sequences from the H-RS cells were identical to those from the CLL cells in two cases. In one case, the clonal relationship between the two types of cells could not be determined because PCR products could not be obtained from any of the H-RS cells. This study shows that the H-RS cells and the CLL cells belong to the same clonal population in some cases of Richter's syndrome with HD features. Furthermore, our findings indicate that mature B cells can undergo transformation to cells with the features of H-RS cells, in association with a cellular background typical of HD. This study also supports recent findings suggesting that the H-RS cells in classical HD are derived from transformed B cells.     

Isolated U-fiber involvement in MS: preliminary observations

Mantle cell lymphoma is a distinct clinicopathological entity associated with t(11;14) and cyclin D1 overexpression. The majority of cases show uniform morphological and phenotypic features characterized by a monotonous proliferation of small-to-medium-sized irregular B cells that express CD5 and bright surface immunoglobulin IgM and IgD. By sequence analysis of the rearranged immunoglobulin heavy chain variable genes (VH), it has been shown that these lymphoma cells carry little if no somatic mutations, as described for the fetal CD5+ cells or B1 cells. Besides mantle cell lymphoma with classic histological features, a morphological variant of mantle cell lymphoma with blastic features and a more aggressive clinical course has been described. To investigate whether this variant is closely related, by the cell of origin, to typical cases, we analysed the presence and the pattern of somatic mutations of the VH genes in a series of nine cases diagnosed as such. Our cases of blastic mantle cell lymphomas rearrange most frequently VH4 and VH3 family genes. In three cases there was a complete homology to published germline genes, and a near complete homology was documented in another three. In contrast, the remaining three cases showed somatic mutations in their rearranged VH genes. Mutation analysis revealed evidence for antigen selection in one of these three cases. Taken together, these data are similar to those of normal adult-type B1 cells and those described for chronic lymphocytic leukaemia (CLL) but slightly different to those reported for classic mantle cell lymphoma. It is likely that blastic mantle cell lymphoma as well as CLL originates from adult-type B1 cells. More cases will need to be studied to determine whether classic mantle cell lymphoma is different from the blastic subtype and if it arises from fetal-type B1 cells.     

Autoimmune disease and chronic lymphocytic leukemia: autoimmune hemolytic anemia, pure red cell aplasia, and autoimmune thrombocytopenia

Immune dysregulation, a hallmark of chronic lymphocytic leukemia (CLL), manifests itself in three autoimmune diseases: warm autoimmune hemolytic anemia (AIHA); idiopathic thrombocytopenia (ITP); and, pure red cell aplasia (PRCA). AIHA occurs in 11% of advanced stage CLL patients. Prednisone is the first treatment of choice, with 90% responses and 65% complete responses. More than 60% of patients relapse when treatment is stopped. Intravenous immunoglobulin, the next line of treatment, causes responses in 40% of patients. While the data are very limited, cyclosporine A is a reasonable choice for third-line therapy. Alkylating agents, danazol, plasma exchange, immunoabsorption, vincristine-loaded platelets, splenectomy, and splenic irradiation are also reported to cause responses. The data on mechanisms of AIHA are most consistent with immune dysregulation leading to loss of tolerance to a self antigen which in turn leads to the immune-based hemolytic anemia. PRCA is underrecognized in CLL with 6% of CLL patients having PRCA when tested for it. Unlike AIHA, PRCA often occurs in early stage disease. Anemia, reticulocytopenia, and a marrow virtually devoid of red blood cell precursors are hallmarks of PRCA. Corticosteroid therapy is the first line of treatment. If a response is not obtained in 4 weeks, cyclosporine A should be added. Although the data on pathophysiology are very limited, PRCA appears to be the result of an abnormal T cell that both fails in its normal function to support growth and inhibits the growth of erythroid progenitor cells. ITP occurs in 2-3% of CLL patients, occurs in early stage disease and may be a presenting manifestation. Initial therapy for ITP mirrors the guidelines for primary ITP. Initial therapy should consist of prednisone. Seventy percent of patients respond. Splenectomy is a reasonable second-line treatment. Autoimmune phenomena, largely related to blood cells, are based in the immune dysregulation of CLL. Longer survivals in CLL patients, more treatment regimens per patient, and more immunosuppression with modern treatments, allow us to predict an increasing incidence of autoimmune blood cell diseases in CLL.     

Mathematics preparation and professional development of deaf education teachers

Tumors of the nasal fossa and paranasal region are uncommon and have non-specific initial clinical features. This complicates the diagnosis and delays treatment. We reviewed all our cases of nasal sinus tumors (84 benign, 50 malignant and 15 moderately malignant) and the relevant literature. This data was use to develop a protocol for classifying the symptoms, clinical and radiological features, coded diagnosis, and the most suitable treatment and follow-up.