Assessment of quality of care in laparoscopic cholecystectomy. With the advent of laparoscopic cholecystectomy, assessment of data and its relationship to quality of care became important. The Mount Sinai Hospital Medical Center conducted a prospective survey in conjunction with the Society of American Gastrointestinal Endoscopic Surgeons (SAGES) National Survey. In this survey, only two surgeons operated as surgeon and co-surgeon with an extremely small rate of complication. A national survey of chairpersons in surgery was designed at Rush Presbyterian St. Luke's Hospital, and 4300 chairpersons were mailed questionnaires to record complications of laparoscopic cholecystectomy. There were 36,232 patients and 3111 surgeons in the survey. The Southern Surgeons Club experience, as reported in New England Journal of Medicine, was reviewed. Because of the complexity of understanding the implications of the survey results, the authors have arrived at a simplified system of evaluating quality of care in laparoscopic cholecystectomy. In this system only three considerations are taken into account: (a) elective conversions to standard operation, (b) forced conversions (due to iatrogenic injuries), and (c) reoperation rate (delayed complication). It is hoped that data collection will be simplified and more meaningful.


Federal laws govern the conduct of peer review. The U.S. Supreme Court has ruled that an antitrust plaintiff does not need to prove that defendant physicians and hospitals engaged in interstate commerce in order to assert federal jurisdiction over his claim that peer review proceedings against him violated the law.


Cost effectiveness of primary stroke prevention in atrial fibrillation: Swedish national perspective. To assess the potential effects of primary prevention with anticoagulants or aspirin in atrial fibrillation on Swedish population. Analysis of cost effectiveness based on the following assumptions: about 83,000 people have atrial fibrillation in Sweden, of whom 22,000 would be potential candidates for treatment with anticoagulants and 55,000 for aspirin treatment; the annual 5% stroke rate is reduced by 64% (with anticoagulants) and 25% (with aspirin); incidence of intracranial haemorrhage of 0.3%, 1.3%, or 2.0% per year; direct and indirect costs of a stroke of Kr180,000 and Kr90,000; estimated annual cost of treatment is Kr5030 for anticoagulants and Kr100 for aspirin. Total Swedish population. Direct and indirect costs of stroke saved, number of strokes prevented, and cost of preventive treatment. Depending on the rate of haemorrhagic complications 34 to 83 patients would need to be treated annually with anticoagulants to prevent one stroke; 83 patients would need to be treated with aspirin. Giving anticoagulant treatment only would reduce costs by Kr60 million if the incidence of intracranial haemorrhage were 0.3% but would imply a net expense if the complication rate exceeded 1.3%. The total savings from giving anticoagulant (22,000 patients) and aspirin (55,000 patients) treatment would be Kr175 million per year corresponding to 2 million pounds per million inhabitants each year. Treatment with anticoagulants and, if contraindications exist, with aspirin is cost effective provided that the risk of serious haemorrhage complications due to anticoagulants is kept low.


Atrial fibrillation and stroke: prevalence in different types of stroke and influence on early and long term prognosis (Oxfordshire community stroke project). To determine in patients with first ever stroke whether atrial fibrillation influences clinical features, the need to perform computed tomography, and prognosis. Observational cohort study with maximum follow up of 6.5 years. Primary care, based on 10 general practices in urban and rural Oxfordshire. Consecutive series of 675 patients with first ever stroke registered in the Oxfordshire community stroke project. Prevalence of atrial fibrillation by type of stroke; effect of atrial fibrillation on case fatality rate and risk of recurrent stroke, vascular death, and death from all causes. Prevalence of atrial fibrillation was 17% (95% confidence interval 14% to 20%) for all stroke types (115/675), 18% (15% to 21%) for cerebral infarction (97/545), 11% (4% to 11%) for primary intercerebral haemorrhage (7/66), and 0% (0 to 11%) for subarachnoid haemorrhage (0/33). For patients with cerebral infarction the 30 day case fatality rate was significantly higher with atrial fibrillation (23%) than with sinus rhythm (8%); the risk of early recurrent stroke (within 30 days) was 1% with atrial fibrillation and 4% with sinus rhythm. In patients who survived at least 30 days the average annual risk of recurrent stroke was 8.2% (5.9% to 10.9%) with sinus rhythm and 11% (6.0% to 17.3%) with atrial fibrillation. After a first stroke atrial fibrillation was not associated with a definite excess risk of recurrent stroke, either within 30 days or within the first few years. Survivors with and without atrial fibrillation had a clinically important absolute risk of further serious vascular events.


Nurse practitioners in accident and emergency departments: what do they do? To determine the distribution and scope of nurse practitioner schemes in accident and emergency departments in England and Wales; to describe the caseloads of doctors and nurse practitioners on two representative days; and to estimate the number of patients managed by nurse practitioners in the year to 31 March 1991. A postal survey of accident and emergency departments and a content analysis of case notes of new patients attending a representative sample of accident and emergency departments on two days. All accident and emergency departments in England and Wales.  560 nurses in charge of accident and emergency departments. Census: case notes of 5814 patients in 37 accident and emergency departments.  number of accident and emergency departments with nurse practitioner schemes. Census: demographic and clinical characteristics of new patients attending and whether nurse practitioner or doctor made diagnoses and ordered investigations, treatments, referrals, discharges. 513 replies (92%) from 465 surveyed functioning accident and emergency departments and 48 departments recently closed. 27 (6%) departments used designated nurse practitioners and 159 (34%) "unofficial" nurse practitioners. Only 530 (9%) of the 5814 patients in the census were managed entirely or mainly by nurse practitioners, with higher proportions in ophthalmic departments (nearly 30%) and minor casualty departments (over 40%) than in major departments (3%). Most patients managed by nurse practitioners (86%) had minor trauma. In the year ending 31 March 1991 an estimated 390,000 (95% confidence interval 260,000 to 520,000) patients out of a total of 12.5 million (3.1%, 2.1% to 4.1%) were clinically managed by a nurse practitioner. Designated nurse practitioner schemes are rare. The volume and range of nurse practitioner work in major general accident and emergency departments is small compared with those in specialised and minor accident and emergency departments.


Regional transfusion centre preoperative autologous blood donation programme: the first two years. To assess the efficacy of a regional autologous blood donation programme. Clinical and laboratory data were collected and stored prospectively. Transfusion data were collected retrospectively from hospital blood bank records. Northern Region Blood Transfusion Service and 14 hospitals within the Northern Regional Health Authority. 505 patients referred for autologous blood donation before elective surgery. Patient eligibility, adverse events from donation, autologous blood units provided, and autologous and allogeneic blood units transfused within 10 days of operation. Of 505 patients referred, 354 donated at least one unit. 78 of 151 referred patients who did not donate were excluded at the autologous clinic, mostly because of anaemia or ischaemic heart disease. In 73 cases the patient, general practitioner, or hospital consultant decided against donation. 363 autologous procedures were undertaken. In 213 (59%) cases all requested units were provided. The most common reasons for incomplete provision were late referral or anaemia. Adverse events accompanied 24 of 928 donations (2.6%). Transfusion data were obtained for 357 of the 363 procedures. 281 donors were transfused; autologous blood only was given to 225, autologous and allogeneic blood was given to 52, and allogeneic blood only was given to four. 648 of 902 (72%) units of autologous blood were transfused. Complete provision of requested autologous units was followed by allogeneic transfusion in 12 of 208 procedures (5.8%). Incomplete provision was followed by allogeneic transfusion in 44 of 149 procedures (30%). This study shows the feasibility of a regional autologous transfusion programme. Autologous donors only infrequently received allogeneic transfusion. Patients should be appropriately selected and referred early.


Excision biopsy of malignant melanoma by general practitioners in south east Scotland 1982-91. To examine the management of patients who had a malignant melanoma excised initially by general practitioners in south east Scotland over the past 10 years and to assess the impact of the April 1990 contract on this. A retrospective case-control study. South east Scotland. All patients in south east Scotland who had malignant melanomas excised by general practitioners in 1982-91. Demographic details of patients; Breslow thickness, clearance of excision. 42 patients had malignant melanomas excised by general practitioners in 1982-91: 15 in 1982-9 and 27 in 1990-1. These patients were significantly younger than those who had their tumours excised initially in hospital. Although the longest diameter of melanomas excised by general practitioners was significantly less than of those excised in hospital, the Breslow thicknesses were similar. Completeness of initial excision was doubtful or incomplete in nine (23%) general practitioner excisions compared with 4% of hospital excisions, but the time interval between excision biopsy and wide excision was similar. Pathology requests accompanying excision biopsies mentioned melanoma as a possible diagnosis in 15% (6/40) of general practitioner cases compared with 79% of hospital cases. Thirty nine general practitioners responded to a questionnaire and only 12 had considered melanoma in the differential diagnosis. General practitioners need to think more often of malignant melanoma when they excise pigmented lesions and when they consider this tumour a possibility should perform an excision biopsy with a lateral clearance of at least 2 mm.


Community health services.

Community health services. The Tomlinson report, with its emphasis on primary and community care, offers great scope to community health services, for long the poor relation of the NHS, and particularly poorly resourced in London. The aim is to create services that break down the barriers between primary, secondary, and tertiary health care and concentrate on providing high quality care tailored to individual patients' needs. Thus a range of flexible options needs to be developed between acute hospital based care and the standard home care arrangements currently provided by district nurses. Examples, include hospital at home schemes, nursing beds, and rehabilitation beds. Together community and primary care services need to consider weekend coverage, to conduct research, and to become a setting for education. The infrastructure for primary and community care must, however, be put in place before acute facilities are shut.


Cytogenetic abnormalities in childhood acute lymphoblastic leukemia correlates with clinical features and treatment outcome. Virtually all cases of childhood acute lymphoblastic leukemia have chromosomal abnormalities. Non-random chromosomal abnormalities have been correlated with leukemic cell lineage, the degree of cell differentiation and certain clinical and biologic features. Cytogenetic findings have prognostic significance, but the adverse influence of many rearrangements, including most chromosomal translocations, may be offset by the greater cytoreductive effects of intensified therapy. Cytogenetic abnormalities have also provided focus for molecular studies of leukemogenesis. Such studies have recently identified key genes and their protein products which play important roles in malignant transformation and proliferation.


Chromosome analysis in the management of patients with non-Hodgkin's lymphoma. Analysis of chromosome abnormalities in non-Hodgkin's lymphoma has stimulated a basic inquiry into the mechanisms of gene deregulation in human tumors. A growing literature has also correlated cytogenetic and molecular genetic features of lymphoma with patient prognosis and other clinical features of the disease. The goal of this report is to review those genetic abnormalities which are currently useful in the clinical management of patients with lymphoma, and to provide a conceptual framework for this growing literature.


Molecular mechanisms in the evolution of chronic myelocytic leukemia. Chronic myelocytic or Ph1-positive acute lymphoblastic leukemias have been analyzed for alterations in a variety of proto-oncogenes and anti-oncogenes implicated in the progression of chronic myeloid leukemia (CML) from its chronic phase to blast crisis. The most frequent genetic change found in disease evolution is an alteration of the p53 gene involving a point mutation, a rearrangement or a deletion. These gene changes are common in myeloid and undifferentiated variants of blast crisis but are usually undetectable in lymphoid leukemic transformants. Other molecular changes also occur in the clonal evolution of CML. The retinoblastoma-susceptibility (Rb) gene is an anti-oncogene. Structural abnormalities of Rb are frequent in all types of human acute leukemia, but are particularly common in Ph1-positive leukemia of lymphoid phenotype including both Ph1-positive ALL and lymphoid blast crisis of CML. Changes in Rb occur early in the transition to blast crisis with loss of Rb protein being the common factor. Mutations in the N-RAS gene also occur, but are rare in typical blast crisis. They are sometimes seen in Ph1-negative myeloid blast crisis. Since changes in the p53 gene are generally associated with progression of disease of a myeloid phenotype and changes in the Rb gene occur more often with a lymphoid phenotype, a particular molecular alteration may influence the character of disease evolution in CML.


Variable rate of detection of immunoglobulin heavy chain V-D-J rearrangement by PCR: a systematic study of 41 B-cell non-Hodgkin's lymphomas and leukemias. The use of clonospecific probes has recently been employed for the detection of minimal residual disease in B- and T-cell acute lymphoblastic leukemias. However, these methods are predicated upon the successful amplification of the V-D-J rearrangement in the genome of the tumor cells by the polymerase chain reaction (PCR). In order to determine whether the type of B-cell lymphoid malignancy influenced the rate of success of amplifying the region of the immunoglobulin heavy chain gene rearrangement in these lesions, we studied 41 morphologically and immunologically well characterized B-cell neoplasms. DNA was extracted from frozen tissue of the lymphomas and leukemias, and subjected to PCR amplification using a 5' immunoglobulin heavy chain gene variable region consensus Framework 3 region (FR3) primer, and a 3' consensus primer for the immunoglobulin heavy chain joining region. One or two distinct bands, representing the rearranged immunoglobulin heavy chain gene, were detected in six of six small non-cleaved cell lymphomas, five of five small lymphocytic lymphomas, four of six acute lymphoblastic leukemias, four of six follicular lymphomas, three of six diffuse mixed small and large cell lymphomas, one of six diffuse large cell lymphomas, and one of six immunoblastic large cell lymphomas; all control cases of lymphocyte predominant Hodgkin's disease (5/5) and reactive follicular hyperplasia (5/5) were negative. We therefore conclude that the type of B-cell neoplasm influences the ability to detect immunoglobulin gene rearrangements by PCR with currently used consensus primers.


Hodgkin and Reed-Sternberg cells express interleukin 6 and interleukin 6 receptors. Interleukin 6 (IL-6) is a pleiotropic lymphokine which can stimulate a variety of cells including B and T lymphocytes. It has been suggested that IL-6 plays a crucial role in several diseases such as human plasmacytoma, cardiac myxoma or Castleman's Disease by autocrine or paracrine stimulation. To analyse whether IL-6 is involved in the biology of Hodgkin's Disease (HD), we investigated the expression of IL-6 and IL-6 receptor (IL-6R) in cell lines and primary specimens from patients with HD. IL-6 specific transcripts were detected in three out of six HD derived cell lines by Northern blot analysis and in the culture supernatants of four HD derived cell lines by ELISA. Its biological activity was confirmed by proliferation of an IL-6 dependent cell line. By in-situ hybridization experiments IL-6 specific transcripts were detected in Hodgkin (H) and Reed-Sternberg (RS) cells in primary tissues in two out of three patients. mRNAs specific for the IL-6 receptor were detected in five HD derived cell lines. Staining of HD derived cell lines revealed expression of the receptor molecules in five cell lines; Western blot experiments confirmed the 80kDa receptor protein in the cells. Immunohistology in primary specimens revealed expression of the receptor molecules on H and RS cells in 8 out of 16 cases with HD. Expression was mostly detected in the mixed cellularity subtype of HD. Elevated levels of IL-6 were detected in the sera of more than 50% of patients with HD. Taken together our data suggest that IL-6 might be involved in the biology of HD.


Mitoxantrone in the treatment of chronic lymphocytic leukemia. During the last few years it has been shown that intensive or continuing chemotherapy of patients with advanced chronic lymphocytic leukemia prolongs survival. In the search for new effective drugs with tolerable toxicity, mitoxantrone was evaluated in this phase 2 study. Seven of 11 previously untreated patients achieved complete or partial remission after single agent treatment with mitoxantrone, and 5 of .16 previously treated patients had the same degree of response. Only minor toxicity was observed. Therefore, it appears likely that mitoxantrone is as effective as chlorambucil, and it would seem justified to evaluate mitoxantrone in future combination chemotherapy regimens in patients with advanced chronic lymphocytic leukemia.


Results of a double blind placebo controlled study of ondansetron as an antiemetic during total body irradiation in patients undergoing bone marrow transplantation. Total body irradiation (TBI) is a highly emetogenic component of the majority of conditioning regimens in use for bone marrow transplantation. Conventional antiemetic therapy fails to control nausea and vomiting induced by single fraction TBI in as many as 50% of patients. In a double blind study of 20 patients undergoing marrow transplantation, a single 8 mg ondansetron dose was compared with placebo given immediately prior to TBI. Our routine premedication of phenobarbitone and corticosteroid was also administered to all patients. All patients had received high dose melphalan the previous evening. Only 1 of the 10 patients in the ondansetron group experienced an emetic event compared with 5 of the 10 in the comparison group (p = 0.029). No significant adverse events were observed. Ondansetron appears to have extremely useful antiemetic activity during single fraction low dose rate TBI.


Phospholipase C-induced monocytic differentiation in a human monocytic leukemia cell line THP-1. Previous studies showed that the human monocytic leukemia cell line THP-1 can be induced to undergo monocytic differentiation by tumor promoting phorbol esters (TPA), suggesting that protein kinase C (PK-C), the primary binding site of TPA, may play a role in the control of monocytic differentiation: The effect of exogenous phospholipase C (PLC) on THP-1 cells was investigated. Within 24-48 hr, PLC induced over 40% of THP-1 cells to undergo monocytic differentiation as manifested by adherence, growth arrest, functional expression, morphological changes and expression of c-fms gene which encode for M-CSF receptors. Compared to TPA, however, the inducing activity of PLC was weaker, slower and not as effective. PLC treatment also induced a transient expression of c-fos proto-oncogene prior to c-fms expression. On the contrary, the level of c-myc RNA, which is constitutively expressed in THP-1 cells, was down-regulated 48 hr after PLC treatment. The PLC-induced monocytic differentiation in THP-1 cells was inhibited by staurosporine, a potent PK-C inhibitor, further suggesting that direct activation of the PK-C is one of the metabolic events essential for monocytic differentiation. It is postulated that in THP-1 cells the metabolic pathway transducing PK-C activation has been permanently blocked, thereby leading to uncontrolled proliferation without differentiation.


Concomitant primary low grade non-Hodgkin's lymphoma of the spleen and breast carcinoma. A case is described of a 71 year old woman with scirrhous breast cancer and multiple hypoechogenic lesions in the spleen. The patient was treated successfully by mastectomy and splenectomy. Morphologic examination of the spleen showed a primary, centroblastic-centrocytic, low grade non-Hodgkin's lymphoma. Eight months after splenectomy the patient still remains in complete remission.


Haematological differences between chronic granulocytic leukaemia, atypical chronic myeloid leukaemia, and chronic myelomonocytic leukaemia. Chronic myeloid leukaemia (CML) is a generic term that include five apparently distinct entities. The best known form, the classical Ph-positive subtype, accounts for about 90% of all cases of CML. The morphology of its presentation blood film is highly characteristic but is also seen in about half of the remaining 10% of cases, which are Ph-negative. This classical morphological subtype, whether Ph-positive or Ph-negative I describe as 'chronic granulocytic leukaemia' to refer to the exuberant granulocytic proliferation which is its hallmark. This term is often used indiscriminately and interchangeably with 'chronic myeloid leukaemia' and similar terms, just as 'chronic lymphocytic leukaemia' was, until recently, used to cover the chronic lymphoid leukaemias in general, but is now used in a specific sense. Chronic granulocytic leukaemia (CGL), whether Ph-positive or Ph-negative, is almost always BCR-rearranged and associated with the production of a unique 210-kd protein with enhanced tyrosine kinase activity. Most of the remaining cases of Ph-negative CML are examples of either chronic myelomonocytic leukaemia (CMML), a subtype almost as homogeneous as CGL, and characterized in its presentation blood film by the presence of monocytes and neutrophils but few immature granulocytes, or atypical CML (aCML), distinct from and less homogeneous than either CGL or CMML, in which some cases also share features with CGL while others share some with CMML. CMML and aCML do not show BCR rearrangement and are not associated with the production of p210kd. CGL, CMML, and aCML, though characterized on morphological features differ in their clinical features and behaviour, response to treatment and survival.(ABSTRACT TRUNCATED AT 250 WORDS)


T-cell acute lymphoblastic leukemia with t(11;14) in children. We review and update our examination of the clinical and biologic findings in 19 cases of acute lymphoblastic leukemia (ALL) with the t(11;14) and discuss the literature relevant to the clinical, biologic, and molecular aspects of these translocations. In nine consecutively diagnosed cases at St. Jude Children's Research Hospital and 10 cases reported by other institutions, clinical features did not differ among T-cell ALL patients with and without the t(11;14), although leukemic cells with this translocation were more likely to coexpress CD4 and CD8 antigens. The t(11;14)(p13;q11) appears to occur exclusively in T-cell malignancies of intermediate- or late-stage thymocyte differentiation; further studies will be needed to determine whether it has prognostic significance.


Mutations of the retinoblastoma gene in human lymphoid neoplasms. The inactivation or loss of tumor suppressor genes (anti-oncogenes) has been implicated as a mechanism central to the pathogenesis of many solid tumors. More recently, we and others have identified a role of one rumor suppressor gene, the retinoblastoma gene, in the development of human lymphoid lymphoma and leukemia. Here we review the involvement of the retinoblastoma gene in the control of normal lymphocyte cell division and the consequences of inactivation of the retinoblastoma gene for the development of lymphoid neoplasia. Our survey has disclosed a broad involvement of retinoblastoma gene inactivation in a wide variety of non-Hodgkin's lymphomas and lymphocytic leukemia. Based on these early findings, it appears likely that tumor suppressor genes may well be involved in many hematopoietic neoplasma.


T-cell receptor alpha and delta gene assembly in B-cell precursor acute lymphoblastic leukemia. The status of the TCR-alpha/delta genes in B-precursor ALL and the rearrangement patterns of these gene loci are discussed in this review. Although most of these rearrangements have been characterized, some still remain to be clarified. Almost all rearrangements of the TCRs in B-precursor ALL are incomplete and may reflect early recombinational steps during the TCR differentiation processes in normal T-lineage cells. In addition, even in T-cell malignancies, it is rarely possible to obtain clonal cell populations with TCR rearrangements arrested in very early recombinational steps. Therefore, studies of these as yet uncharacterized rearrangements may lead to the discovery of additional gene segments playing important roles in the TCR recombinational processes and may provide useful information for understanding the processes of T-cell differentiation.


The association of c-myc rearrangements with specific types of human non-Hodgkin's lymphomas. The function of c-myc in physiology is only partially known. Its product has DNA binding properties and plays a role in the control of proliferation and differentiation. In general, increased c-myc expression leads to proliferation and abolishment of differentiation. The involvement of c-myc in mouse plasmacytomas and human Burkitt's lymphoma is well known: due to chromosomal translocation c-myc comes under the influence of regulatory elements of immunoglobulin genes, leading to increased expression of the gene and proliferation of the cells. In man, the chromosomal translocations may occur within the increased pool of (pre) B-cells due to Epstein Barr virus (EBV) and malaria infection with subsequent immunosuppression. Apart from these early (primary?) events in lymphomagenesis, c-myc is also often involved in tumour progression, probably by a similar mechanism. Different types of c-myc involvement are associated with specific types of lymphoma: there are differences between endemic, sporadic and ileocecal Burkitt's lymphoma as well as between those and primary extranodal large cell lymphoma and large cell lymphoma which has progressed. These differences are associated with the differentiation of the involved lymphoid cells and may point to the stage of differentiation in which the oncogenic event occurred.


Human NK cells in health and disease: clinical, functional, phenotypic and DNA genotypic characteristics. Natural killer (NK) cells are the subject of great current interest because of their possible (in vivo) role in tumour cell surveillance and killing, and because of the potential application of cytokine-modulated NK cells in cancer immunotherapy. In addition, clonal proliferations of NK-associated (NKa) cell populations represent a high proportion of chronic (non-B) lymphoid malignancies and abnormal (both clonal and non-clonal) NKa components are being increasingly reported in association with diverse clinical pictures such as autoimmune disease. This communication extensively reviews what is presently known regarding normal and leukaemic NKa phenotypic diversity, the mechanisms of NK-mediated cytolysis, the role of NK cells in malignancy, and the diagnostic and cellular aspects of malignant NKa proliferations.


Relationship between chemical-induced fragile sites and chromosomal breakpoints in malignant cells in children. Many fragile sites in the human genome occur at or near chromosomal breakpoints reportedly involved in translocations of DNA material in neoplastic cells. This fact has led some investigators to postulate that fragile sites have a pathogenic role in human neoplasia. To learn whether caffeine-induced fragile sites relate to breakpoints found in the neoplastic cells of an individual patient, we studied lymphocytes from the peripheral blood of 32 patients in remission from malignant disease. Lymphocytes were cultured in medium containing either 5-Fluoro-2'-deoxyuridine (FdU) or FdU plus caffeine, and G-banded metaphases were examined for nonrandom breaks. Analyses of completely G-banded malignant cell chromosomes from 31 of the 32 patients were available for comparison. In only once case, a 5-year-old child with acute lymphoblastic leukemia, did a caffeine-induced fragile site (1q44) coincide with a breakpoint in the neoplastic cells [dup(1)(q21-->q44)]. Our findings suggest that chromosomal abnormalities in childhood malignancies cannot generally be explained by the presence of FdU- or FdU plus caffeine-induced fragile sites.


Tumor necrosis factor-beta and hypercalcemia. Hypercalcemia in hematological malignancy is frequently encountered in lymphoid malignancies such as adult T-cell leukemia (ATL) and multiple myeloma and is difficult to manage. As a causative agent of hypercalcemia in ATL, tumor necrosis factor-beta (TNF-beta), previously known as lymphotoxin, has been carefully studied and reviewed here. Bone resorption studies showed the presence of activity in culture supernatants of HTLV-I infected cells. Enzyme linked immunosorbent assays (ELISA) for TNF-beta detected elevated TNF-beta in the sera of ATL patients with hypercalcemia. Immunostaining by monoclonal anti-TNF-beta antibody demonstrated the presence of TNF-beta in both HTLV-I infected cell lines and freshly isolated ATL cells. Furthermore biological TNF-beta activity assay including inhibition of anti-TNF-beta antibody confirmed the conventional documentation of TNF-beta activity in the sera and culture supernatants of HTLV-I infected cell lines. These studies showed that the TNF-beta secreted from ATL cells might be one of the factors contributing to the hypercalcemia in patients with ATL functioning as an osteoclast activating factor (OAF).


Poor clinical outcome of patients developing malignant solid tumors after bone marrow transplantation for severe aplastic anemia. From January 1974 to September 1991, 245 consecutive patients with severe aplastic anemia underwent bone marrow transplantation at the Hôpital Saint-Louis, Paris, France. Five cases of solid tumor were observed overall, a number that leads to an 8-year cumulative incidence rate of 7.7% (95% CL: 0.9%, 14.5%). Relative to the general population, the risk was equal to 22 (95% CL: 7, 51; p < 0.001). The present report focuses on the unusual clinical course of patients developing malignant tumors after bone marrow transplantation for severe aplastic anemia. It also aims at reporting the difficulty encountered in comparing data from different sources.


Serum soluble interleukin-2 receptor levels are associated with clinical disease status and histopathological grade in non-Hodgkin's lymphoma and chronic lymphocytic leukemia. Serum soluble Interleukin-2 receptor levels (sIL-2R) were measured in 121 patients (pts) with non-Hodgkin's lymphoma (NHL) and in 30 patients with Chronic lymphocytic leukemia (CLL). Sera collected from 32 normal volunteers and 18 patients with infection or a variety of non malignant hematological disorders served as controls. A small number of patients with Hairy cell leukemia (HCL) and Hodgkin's disease (HD) were also studied. NHL patients were classified according to their clinical status as "active" (82 pts) or "non-active" (39 pts) and CLL according to the stage of their disease. NHL patients were also further classified as low (55 pts), intermediate (38 pts) and high grade malignancy (28 pts), according to the Working formulation scheme. A significant difference was found between the high levels of sIL-2R in patients with "active" disease and the lower levels in patients with quiescent or responsive disease. Significantly different high levels were found in patients with aggressive (intermediate and high grade) lymphoma as opposed to low grade lymphoma and CLL. In CLL itself higher levels of sIL-2R were seen in more advanced disease than in early disease. Thirteen patients with active Hodgkin's disease (HD) had moderately elevated sIL-2R levels, similar to those recorded for patients with infections and some non-malignant hematological disorders while another 13 HD patients in remission, had normal levels comparable to those recorded in normal controls. Extremely high levels of sIL-2R were seen in 2 patients with HD with severe viral infections and levels approaching those seen in HCL, were noted (20-30,000 u/ml).(ABSTRACT TRUNCATED AT 250 WORDS)


Clinical and biological analysis of peripheral T-cell lymphomas: a single institution study. Peripheral T-cell lymphoma (PTCL) accounts for 15-20% of non-Hodgkin's lymphoma in the Western World. Clinical, histopathologic, phenotypic and genotypic data were received from 33 cases of PTCL referred to our institution. The median age order was 50 years, 78% were males, and 18% had a history of a preceding disorder of the lymphoid system. 60% had stage 4 at diagnosis and B symptoms were also present in 60%. The most frequent sites of extranodal involvement were bone marrow (54%), liver (45%) and skin (33%). Twenty-eight of 33 cases were histologically classified according to the Working Formulation (most in the diffuse mixed and large-cell subgroups) and the Kiel updated system. Phenotypic and genotypic studies of malignant cells showed a considerable heterogeneity with respect to the expression of either T-cell receptor (TCR) alpha beta and gamma delta and pan-T differentiation molecules. Of the studied cases 63% expressed TCR-alpha beta. All five patients with PTCL of the TCR-gamma delta subtype had a peculiar extra-nodal presentation. The vast majority of cases expressed an abnormal T-cell phenotype with respect to the expression of pan-T antigens, including the lack of expression of the TCR-associated CD3 molecule in 2 cases. Rearrangements of the TCR beta and/or delta-chain genes showed clonality in 21 of the 23 studied cases. Twenty-five patients were treated with a multiagent chemotherapy regimen with curative intent and the remainder received a less intensive palliative regimen. Only 9 patients achieved CR (8 of whom had received an anthracycline-containing regimen) and the 4-year survival rate was 25%.(ABSTRACT TRUNCATED AT 250 WORDS)


Expression of diphtheria toxin A-chain in mature B-cells: a potential approach to therapy of B-lymphoid malignancy. Specifically targeted expression of a toxin gene potentially represents a novel approach to cancer therapy. With a view to the ablation of B-cell malignancies, we have constructed a plasmid, designated pTHA71, which expresses the A-chain of diphtheria toxin (DT-A) with high efficiency and specificity in transfected, mature B-lymphoid cells. The construction incorporated immunoglobulin (Ig) kappa light chain gene regulatory sequences, including a kappa promoter, small intron, partial constant region exon, and 3'-flanking sequence (but lacking a known enhancer). These sequences conferred substantially more efficient expression of DT-A in mature B-cells than was seen from constructs that included only Ig promoters and enhancers. When transfected into the 70Z/3 murine pre-B-cell line, pTHA71 was only expressed efficiently if the cells were induced to express their endogenous, rearranged Ig kappa gene by prior exposure to lipopolysaccharide. The insertion of the enhancer from the Ig kappa large intron into pTHA71, generating pTHA81, did not markedly influence the level of DT-A expression in 70Z/3 cells. The observed absence of expression in pre-B-cells suggests that DT-A constructs similar to pTHA71 might be used for the therapeutic ablation of malignant B-cells of mature stages, while sparing normal progenitor cells.


Analysis of c-myc, bcl-1 and bcl-2 translocations in human lymphoma by pulsed-field gel electrophoresis. Translocations of the c-myc, bcl-2 and the putative bcl-1 oncogene are recurrent events in B-cell lymphoma. Since it is likely that the rearranged genes contribute to the malignant phenotype of the tumor cells, such oncogene translocation is of major interest. The molecular detection of translocations using conventional Southern hybridization analysis is complicated by the fact that translocation breakpoints are dispersed over large chromosomal regions. In order to overcome this problem we used pulsed-field gel electrophoresis (PFGE) to detect c-myc, bcl-2 and bcl-1 translocations in 29 lymph node biopsies. C-myc translocation could not be detected in this group, either with standard Southern analysis of PFGE. Translocations of the bcl-2 gene were detected by PFGE in 5 samples and the breakpoints were mapped in all cases to the third exon of bcl-2 by standard Southern analysis. Furthermore, we also found rearrangements of the bcl-1 locus in 3 samples. Mapping of the breakpoint failed in one of these cases, which strongly indicates the existence of a breakpoint outside the bcl-1 major breakpoint region. Thus, PFGE allows the rapid detection of translocations in human lymphomas within large stretches of DNA.


Continuous-infusion cyclophosphamide in combination with teniposide and dexamethasone in refractory myeloma. Forty-three consecutive patients with refractory myeloma, median age 60, received monthly courses of teniposide 30 mg/m2 i.v. on days 1-2, dexamethasone 40 mg i.v. on days 1-7 and cyclophosphamide 200 mg/m2 by continuous i.v. infusion for seven days. Major response (decrease > 50% of M-protein) was achieved in 18 of 37 evaluable patients and minor response in 9, with an overall response rate of 73%. Response was irrespective of disease status, time from diagnosis and previous treatments, while beta 2 microglobulin > 6 mg/l was a powerful prognostic factor. All patients experienced transient granulocytopenia but extramedullary toxicity was negligible. Median survival of the whole group is 20 months, with 74% of responding patients projected to be alive at 30 months. In refractory myeloma cyclophosphamide appears to be more active when given by continuous infusion.


Multiphenotypic acute leukemias: clinicopathologic correlations and response to therapy. Multiphenotypic acute leukemias (MAL), defined by the coexpression on most blast cells of antigens classically attributed to different lineages, remain a rare event. We isolated a series of 26 such cases from a cohort of 1565 leukemic patients whose cells were immunophenotyped at diagnosis. Markers of B and myeloid lineage (BM) were associated in 16 cases (62%), 3 coexpressed B and T markers (BT), and T-cell and myeloid antigens (TM) were found in 7 (27%). A tumoral syndrome was observed in 69% of the patients, without significant differences between the immunophenotypic subgroups. Median event free survivals in the three immunophenotypic subgroups as defined were respectively 24 months for BM-MAL, 4 months for TM-MAL and 7 months for BT-MAL respectively. The poorer prognosis of TM-MAL was significantly different from that of BM-MAL (p < 0.001). This concurred with the poorer prognosis associated with CD7 expression or absence or CD10, both characteristic features of TM-MAL.


Detection of platelet-specific protein mRNAs in different megakaryoblasts using the reverse transcriptase polymerase chain reaction. The short segments of cDNA encoding glycoprotein (GP)Ib alpha, GPIIb, GPIIIa and platelet factor (PF) 4 were amplified using reverse transcriptase-polymerase chain reaction (RT-PCR) in order to characterize various types of megakaryoblasts. Cell lines with megakaryocytic features (K562, CMK and HEL) were tested. GPIb alpha, GPIIb and GPIIIa mRNAs were found to be present in K562, CMK and HEL cells, while only HEL cells expressed PF4 or mRNA. These results suggested that megakaryoblastic cell lines could be categorized into two groups, one with the PF4 transcript and the other without it. PF4 mRNA was present in the cells obtained from one Down's syndrome patient with transient myeloproliferative disorder and in one patient with primary myelofibrosis and megakaryoblastosis. On the other hand, one patient with acute megakaryoblastic leukemia transformed from refractory anemia had a poor prognosis with megakaryoblastic leukemia cells which expressed no PF4 mRNA. These observations suggested that the expression of PF4 mRNA in peripheral blood megakaryoblasts may indicate the absence of a true leukemic process.


A numerical prognostic index for clinical use in identification of poor-risk patients with Hodgkin's disease at diagnosis. The Scotland and Newcastle Lymphoma Group (SNLG) Therapy Working Party. The aim of this study was to assess the feasibility of using objective data obtained at the time of diagnosis of Hodgkin's disease to predict those patients who were likely to die of progressive disease within four years. Ninety-two consecutive patients from one centre (Newcastle upon Tyne) were used to construct a numerical index based on disease stage (Ann Arbor), age, haemoglobin and absolute lymphocyte count. Weight was assigned according to a predictive value from univariate and multivariate analyses based on survival. The index produced was then validated on a separate patient set (455) from other centres within the Scotland and Newcastle Lymphoma Group (SNLG) on whom the same prospective information was available. The index produced provided a useful separation of those patients destined to die of disease. In 101 patients with index > 0.5, 62 (61.4%) were dead at four years, whereas with index < 0.5, 61 (18%) of 336 patients were dead at four years. The index includes Ann Arbor stage but possesses additional practical prognostic value which allows identification of patients with early stage destined to die of disease. Of 149 patients with Stage IA and IIA disease 15 patients had index > 0.5, and 10 (60%) have died, whereas the remaining patients had survival of 90% and 85% respectively. This numerical index has now been strengthened by an added factor for bulk disease > 10 cms and in the SNLG it has replaced Ann Arbor staging for selection of patients requiring aggressive therapy. A randomized study of chemotherapy versus chemotherapy plus autotransplant in first remission using high dose melphalan and VP16 is currently in progress.


Indications for autologous bone marrow transplantation in Hodgkin's disease. This paper reviews briefly the most relevant indications for ABMT in Hodgkin's disease. The accurate definition of prognostic categories at the time of first treatment failure and the role of ABMT in the early sequential treatment of highly effective drug combination followed by high dose chemotherapy in very high risk Hodgkin's disease patients, are also discussed.


BEAM autografting in lymphoma--experience at one centre. Since December 1987, we have examined the use of high-dose chemotherapy and unpurged bone marrow rescue in 31 patients with advanced or refractory lymphoma. Twenty-one patients had Hodgkin's disease (HD) and 10 had Non-Hodgkin's lymphoma (NHL). At ABMT, 22 patients had relapsed or resistant disease. All patients, excluding 3 early deaths, engrafted. There was no relationship between cell numbers harvested, CFU-GM and bone marrow recovery. The mean times to 0.5 x 10(9)/l neutrophils and 50 x 10(9)/l platelets were 20 d and 43 d respectively. However, 5 patients with HD had a significantly slower platelet recovery time of up to 203 days (p = 0.05). Disease-free survival was 72% for HD and 40% for NHL at 40 months. Relapsed or refractory disease at ABMT, bulky disease, extensive salvage therapy and Karnofsky scores below 80% were all associated with a poorer outcome. The most striking observation has been the dramatic radiological response of some patients with advanced/refractory disease.


High-dose chemotherapy with bone marrow rescue for treatment of Hodgkin's disease. Between December 1st 1984 and July 1st 1991, 20 patients, 11 males and 9 females, median age 36 years (range 14-54) with Hodgkin's disease were treated with high dose chemo-radiotherapy followed by autologous bone marrow rescue. At the time of autologous bone marrow transplantation, 8 patients were in complete remission, 9 in sensitive relapse and 3 were resistant to conventional treatments. There were 3 early procedure-related deaths: 1 cardiac failure due to cyclophosphamide treatment, 1 veno-occlusive disease, and 1 patient died from CMV interstitial pneumonitis, 4 months after ABMT. Of the 17 other patients, 15 are alive, 12 in complete remission, 2 in relapse and 1 patient is not evaluable due to short-follow-up follow-up. Disease free survival is 65% at 20 months with a follow-up of 60 months. There is a trend for a better disease-free survival in patients in complete remission at the time of autologous bone marrow transplantation vs patients in sensitive relapse, although it does not reach statistical significance (80% vs 37%).


High dose chemotherapy with autologous marrow transplantation in follicular lymphomas. Twenty six adult patients with low grade nodular non Hodgkin's lymphoma (NHL) were treated with autologous bone marrow transplantation. Conditioning regimen was BEAM-BEAC in 15 patients and TBI + Cyclophosphamide in 11 patients. Twenty one patients were grafted with haematopoietic stem cells, 12 after bone marrow purging and five with peripheral blood stem cells (PBSC). Two patients were treated in CR1 of leukemic phase, six in PR1 and eighteen in sensitive relapse. With a median follow-up of 30 months, the actuarial survival is 91% and actuarial event free survival 67%. These data confirm some interest of ABMT in the treatment of low grade follicular NHL.


Use of high-dose cytarabine in autologous bone marrow transplantation in acute myeloid leukemia. Autologous bone marrow transplantation is widely used as late intensification therapy for patients with AML in remission without an HLA identical donor or who are older than 40-45 years. We report our experience in 21 AML patients in 1st or 2nd CR transplanted with a regimen including HD-ARA-C in addition to Cyclophosphamide (CY) and TBI. The median age was 32 years (3-50). Fourteen patients were transplanted in 1st CR and 7 in 2nd CR. In all but one patient BM harvesting and ABMT were done in the same remission status and after at least 3 courses of consolidation therapy. Two patients (9.5%) died from treatment related toxicity on Day +15 and Day +31. The median time to reach 1000 WBC and 50,000 platelets per cmm was 23 (13-55) and 55 (22-790) days respectively. Only 4 (21%) of the 19 evaluable patients (median observation time of 32 months) relapsed, at 3, 8, 18 and 26 months from ABMT. The projected event free survival curve shows survival of 67% at 96 months with a relapse rate of 26%.


Successful treatment of fungal infections in neutropenic patients with liposomal amphotericin (AmBisome)--a report on 40 cases from a single centre. The use of high-dose chemotherapy and the subsequent prolonged neutropenia in patients with haematological diseases has resulted in an increased incidence of fungal infections. The only drug with proven efficacy in the treatment of deep seated fungal infections or invasive aspergillosis is amphotericin B. Unfortunately, this drug has adverse side effects, most importantly dose dependent nephrotoxicity. Furthermore, some patients fail to show a response to amphotericin B. We have treated 40 patients undergoing myeloablative chemotherapy and or bone marrow transplantation for haematological diseases with liposomal amphotericin for proven or suspected fungal infections. All patients had failed treatment with conventional Amphotericin B. Fourteen patients received liposomal amphotericin (AmBisome) due to progression of infection on conventional amphotericin B. Twenty six patients received liposomal amphotericin due to nephrotoxicity caused by conventional Amphotericin B. Nine patients had mycologically proven fungal infection and of these, 7 patients (78%) showed a complete response to liposomal amphotericin. Thirty one patients received liposomal amphotericin due to suspected fungal infection. Eleven of these 31 patients (35%) showed a complete clinical response to liposomal amphotericin. However in the patients with suspected fungal infections 14 patients had no response and 6 patients could not be evaluated for response to liposomal amphotericin. Overall, of the 18 patients showing a response to liposomal amphotericin, 15 patients had either recovered their neutrophil count (> 0.5 x 10(9)/l) or achieved remission from their underlying haematological disease. Recovery from fungal infection in this group of patients occurred when there was complete remission of underlying disease and recovery of neutrophil counts, when concurrently treated by liposomal amphotericin.


The modulatory hematopoietic activities of leukemia inhibitory factor. Leukemia inhibitory factor (LIF) is a multi-potential cytokine which has been implicated in the hematopoietic regulatory machinery. For example, we have found that LIF is constitutively expressed in marrow stroma. Other investigators have reported that LIF affects remodeling of bone, and that, in concert with other growth factors, it stimulates hematopoietic stem cell proliferation. Moreover, in vivo animal trials reveal that, at high doses, administration of LIF induces myelosclerosis whereas, at lower doses, megakaryocytosis and thrombocytosis with reduced bone marrow cellularity and marrow lymphopenia are observed. Therefore, the role of LIF in the pathogenesis of myeloproliferative disorders such as myelofibrosis and sclerosis merits investigation. Further, its megakaryocytic stimulatory properties suggest that LIF may be exploitable in the clinic to enhance platelet production.


Growth of human lymphoma cells in SCID mice. Two EBV-negative human lymphoma cell lines raised in this laboratory and peripheral blood cells of a patient with large cell lymphoma in leukemic phase were injected intravenously or intraperitoneally into C.B.17 SCID mice. One line (OCI-LY18) was derived from the pleural fluid of a patient with a large cell, immunoblastic malignant lymphoma. Cells of this line are of B cell origin and characterized by multiple rearrangements of the JH locus. The second line (OCI-LY17) was grown from the peripheral blood of a patient with a large cell lymphoma of T-cell phenotype which has characteristic rearrangement of the T-cell receptor beta chain. The cells directly obtained from a patient with large cell non-cleaved malignant lymphoma were of B-cell origin. Animals carrying OCI-LY18 developed large tumor masses within 6-8 weeks of inoculation. The tumors were detected in the intestine, mesentery, retroperitoneum, lymph nodes, spleen, lung and kidney. The masses resembled the primary tumor with respect to histological appearance and immunological phenotype. It was possible to generate secondary cell lines from the tumors found in the inoculated SCID mice. Injection of one of these secondary cell lines into SCID mice resulted in the rapid development of lymphoma and as few as 10 cells were sufficient to establish the disease in the inoculated animals. In contrast cells of OCI-LY17 produced small tumor aggregates that did not appear to progress over time and did not cause death of the animals.(ABSTRACT TRUNCATED AT 250 WORDS)


Ultrastructural characteristics of the spleen in hairy cell leukemia. Eighteen spleens derived from patients with hairy cell leukemia (HCL) were analyzed by correlative scanning and transmission electron microscopy. In 15 of the cases, the white pulp areas were markedly decreased or absent when compared to normal spleens, although few hairy cells were observed within this region. In only one case did the white pulp appear normal. In all HCL cases, hairy cells were observed within normal, dilated, and abnormal sinuses. The abnormal sinuses contained hairy cells of typical morphology attached to other hairy cells, to endothelial lining, and to erythrocytes. The degree of sinus filling by hairy cells varied from loosely- to tightly-packed. Endothelial cells exhibiting degenerative changes, such as swelling with smooth surfaces and dilated intercellular spaces, were frequently seen. These results indicate that in addition to the previously described overcrowding of the spleen by hairy cells, the splenic tissue itself is considerably altered and sometimes severely damaged in patients with HCL.


Tumour lysis following hydrocortisone prior to a blood product transfusion in T-cell acute lymphoblastic leukaemia. The acute tumour lysis syndrome is a well recognised complication of chemotherapy for lymphoid malignancies. There are few reports, however, of this complication after corticosteroid therapy alone. We report a case of T-cell acute lymphoblastic leukaemia who developed the biochemical picture of tumour lysis after two doses of hydrocortisone given prior to platelet transfusion. Prophylactic corticosteroids prior to blood product infusion should be reserved for patients who have experienced febrile or allergic reactions in the past and it is suggested that they should only be administered to patients with active lymphoid malignancies with due caution.


Bone marrow microenvironment and the progression of multiple myeloma. The BM microenvironment in MM, in terms of adhesive features, is well organized to entrap circulating precursors with BM-seeking properties and is able to produce cytokines that offer them the optimal conditions for local growth and final differentiation. Likewise, the malignant B cell clone is equipped with adhesion molecules which enable the cell to establish close contacts with BM stromal cells. Furthermore a number of cytokines are released including IL-1 beta and M-CSF activating BM stromal cells to produce other cytokines, such as IL-6, that stimulate the proliferation of plasma cells. Finally, most cytokines produced locally, including IL-1 beta, TNF-beta, M-CSF, IL-3 and IL-6, also have OAF properties, explaining why the expansion of the B cell clone parallels the activation and numerical increase of the osteoclast population.


Complement receptor 1 (CR1) expression in chronic myeloid leukemia. The complement receptor 1 (CR1), also called CD35, is a polymorphic glycoprotein which mediates a variety of neutrophil functions, including phagocytosis and, probably, tumor cell cytotoxicity. The role played by this molecule in chronic myeloid leukemia (CML) is not yet well understood. CML frequently shows a marked decrease of CR1 antigens on both the neutrophil population and myeloid precursors. This reduced expression appears to be related to disease activity, since patients at more advanced clinical stages, as well as those who develop blastic crisis, have been found to express the lowest levels of CR1 antigens. At the onset of the disease low CR1 expression on CML neutrophils seems to be associated with a higher risk of blastic transformation. Furthermore, CML neutrophils deficient in CR1 lack the ability to respond to PMA stimulation, suggesting a failure in CR1 granular storage. In patients lacking CR1, the number of receptors increased to normal levels following exposure of CML cells to therapeutic concentrations of recombinant alpha interferon. The role played by the CR1 molecule in sustaining neutrophil-mediated tumor cell cytotoxicity has yet to be definitively proved; studies performed by our group are relevant here, since complete suppression of tumor lysis following receptor neutralization by anti CR1 monoclonal antibodies was demonstrated in a large number of normal and CML individuals. In CML patients, the evidence of a direct relationship between lytic activity and antigen receptor levels seems to further support the involvement of CR1 molecules in tumor cell lysis, function.(ABSTRACT TRUNCATED AT 250 WORDS)


The role of intensive chemotherapy in myelodysplastic syndromes. We review results of intensive chemotherapy (IC) obtained in myelodysplastic syndromes (MDS). Overall, the complete remission (CR) rates and median CR duration obtained with IC are low in MDS, especially when compared to results obtained in de novo AML treated with the same chemotherapy regimens; very few MDS patients achieve prolonged remissions. Failure to achieve CR, in MDS, results both from a high incidence of resistant disease and toxic deaths, the latter being due to longer periods of aplasia than in de novo AML. However some subgroups of MDS seem to obtain higher CR rates and more prolonged remissions. These include patients younger than 45 to 50 years, those with a large excess of marrow blasts or Auer rods at diagnosis, and patients with a normal karyotype or at least without involvement of chromosomes 5 and/or 7. Results of IC clearly have to be improved in MDS. Higher CR rates may possibly be obtained by intensifying induction regimens, but this will probably require the addition of growth factors, in order to reduce the already very long periods of aplasia seen with IC in MDS. For consolidation therapy, new approaches, and especially autologous bone marrow transplantation, will have to be investigated.


Myelodysplastic syndrome associated with bone marrow fibrosis. Bone marrow biopsy (BMB) in myelodysplastic syndrome (MDS) frequently reveals a slight alteration in the reticulin stroma which does not have any clinical significance. However, in a minority of cases, full-blown bone marrow fibrosis (BMF) can be found. Primary MDS patients with BMF show distinct clinico-pathological features and an unfavourable prognosis mainly attributable to complications deriving from pancytopenia and continuous transfusions, while leukemic transformation occurs only rarely. Since BMF may characterize other hematological disorders, primary MDS with BMF should be included in the differential diagnosis particularly with malignant myelofibrosis (MM) and idiopathic myelofibrosis (IMF). Secondary MDS with BMF represent a variety of preleukemic conditions in subjects treated for previous neoplasias. Unlike the primary forms, they do not form a clearcut clinico-pathological entity.


Inhibitory anti-tumor effects of interleukin-4 on Philadelphia chromosome-positive acute lymphocytic leukemia and other hematopoietic malignancies. IL-4 has been shown to possess a broader spectrum of biological activities. Recently, anti-tumor activities of IL-4 on malignant tumors including hematopoietic tumors has been revealed in vitro or in vivo. We investigated the effect of recombinant human (rhIL-4) on the in vitro growth of human leukemia cells and demonstrated the inhibitory anti-tumor activity of rhIL-4 on Ph1-positive ALL cells in association with the decreased activity of cellular tyrosine kinase. This finding suggests that the clinical evaluation of rhIL-4 may offer promising therapeutic possibility for patients with Ph1-positive ALL. In this paper, we presented the IL-4-dependent inhibition of Ph1-positive ALL cells and reviewed implications for mechanism of IL-4-dependent inhibition and anti-tumor activities of IL-4.


Extremely poor prognosis of pediatric acute lymphoblastic leukemia with translocation (9;22): updated experience. Approximately five percent of pediatric acute lymphoblastic leukemias (ALL) contain a translocation (9;22)(q34;q11) which results in rearrangement of the bcr and abl genes. At a median follow-up of 5 years, we assessed the prognostic implications of translocation (9;22) in 434 children receiving intensive treatment for ALL. Four-year event-free and overall survivals were only 0% and 20%, respectively, in 15 children with translocation (9;22), but were 81% and 89%, respectively, in 419 children lacking translocation (9;22) (P < 0.001). Based on these findings, we recommend very intensive treatment approaches for all children with translocation (9;22)-positive ALL.


Massive mediastinal involvement in stage I-II Hodgkin's disease: response to combined modality treatment. Thirty-seven patients with stage I-II Hodgkin's disease and massive mediastinal involvement, observed between June 1981 and November 1989, underwent combined modality treatment. This treatment included: 3 cycles of mechlorethamine, vincristine, procarbazine, and prednisone followed by mantle-field irradiation, and subsequently by 3 additional cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine. Thirty-five (95%) patients achieved complete responses and only 2 (5%) had partial responses. All the complete responders are living and relapse-free at a median follow-up of 62 months; no major toxic reactions were recorded. These data suggest, as did those of other studies, that combined modality therapy is superior to either radiotherapy or chemotherapy alone for patients in stage I-II with bulky disease, especially in the mediastinum. In fact, in these particular patients, if adequately treated with a combination of chemotherapy and radiotherapy, the role of massive mediastinal involvement as a poor prognostic factor appears to be less significant.


A multiparametric study of malignant lymphoma of mucosa associated lymphoid tissue (MALT). A morphological, immunophenotypic and ultrastructural study, cell cycle estimation, DNA and cytogenetic analysis were performed in ten cases of B-MALT lymphomas. Five had low grade lymphoma and five had high grade. Low and high grade cases showed the same cells but in different percentages: These included centrocyte-like cells with occasional monocytoid cytoplasmic changes, and centroblast-like cells. However, in high grade cases more dysplastic and large cells were present. All cellular types showed an important development of rough endoplasmic reticulum. In all cases a large panel of monoclonal antibodies was employed to study the B-cell immunophenotype. Ki-67 positivity ranged from 5% to 30% in low-grade cases and from 50% to 70% in high-grade cases. Gene rearrangement analysis showed rearrangement with Jh probe and half of the cases were also rearranged with the Kde probe (Kappa constant chain gene). A rearrangement banding pattern with TCR genes was not present in any of the cases. Cytogenetic study showed complex alterations in high grade cases and a normal karyotype in low grade lymphomas. Only one case had rearrangement for the bcl-2 probe.


Constitutive production of the interleukins IL-5 and IL-6 by the lymphoma cell line OCI-Ly 17 derived from a patient with malignant lymphoma and hypereosinophilia. Peripheral blood cells of a patient with diffuse large cell non-Hodgkin's lymphoma presenting with hypereosinophilia were used to establish an EBV negative lymphoma cell line termed OCI-Ly17. Cells of the line stained positive for CD2 and CD5 determinants and demonstrated rearrangement of the T-cell receptor beta chain. The immunoglobulin heavy chain gene was found to be in germ line configuration. Northern blot studies using probes for IL-1 alpha, IL-3, IL-4, IL-5, IL-6, and GM-CSF showed message for IL-5 and IL-6. Supernatants of the cell line were evaluated on normal non-adherent, E-rosette depleted bone marrow cells to determine the presence of growth promoting activities for clonogenic eosinophilic progenitors. Eosinophilic colonies were observed. Their frequency depended upon the amount of supernatant added to the cultures. The growth promoting activity in the supernatant was reduced in a dose dependent manner by preincubation with increasing concentrations of anti-IL-5 antibodies. The supernatants of the cell line were also tested on the IL-6 sensitive human myeloma line OCI-My4 and myeloma colonies grew in response. This stimulatory activity within the supernatant was neutralized by addition of increasing concentrations of anti-IL-6 antibodies. Although producing IL-5 and IL-6 constitutively, the lymphoma line did not increase proliferation in response to either interleukin, nor did it show a reduced proliferative rate when antibodies to IL-5 or IL-6 were added to the cultures.


A commentary on strategies for AIDS prevention from the British perspective. The commentary review similarities between the American and the European perspective of the HIV spread, with particular emphasis on the British mode of transmission among women. Social perceptions of the female role are seen as contributing to the difficulties experienced by British women who are HIV positive. Although there are numerous ongoing programs to assist and support HIV-infected women, the projection of an increased incidence in the spread of HIV among the heterosexual population is one that needs to be addressed. This is recognized as an issue that will reveal the needs of this new infected population and will in turn decide the necessary revisions of all existing programs that offer help and assistance to women. The commentary acknowledges the value of the American-designed peer counseling and leadership training and suggests that international (PCLT) program implementation might be considered.


Analysis of strike-through contamination in saturated sterile dressings. The method of saturating gauze sponges directly in their wrapper was tested to determine strike-through contamination. Contamination occurred in 100% of the uncoated-wrapper sponges, regardless of exposure to Staphylococcus epidermidis or Escherichia coli. Among coated-wrapper sponges, 80% exposed to Staphylococcus epidermidis and 20% exposed to Escherichia coli demonstrated strike-through contamination. Coated-wrapper sponges had a significantly lower rate of contamination than uncoated-wrapper sponges when exposed to Escherichia coli. Occurrence of contamination of all sponges was significantly higher from Staphylococcus epidermidis. The findings render the popular practice of saturating gauze sponges in their wrapper unacceptable.


Mismatched caring in high-risk perinatal situations. A longitudinal study with a phenomenological approach revealed mismatched perceptions between caregivers and women in high-risk perinatal care. The participants were 27 women, 20 of which were recruited during a high-risk pregnancy and 7 who were recruited following the birth of a high-risk newborn. Interviews and diaries were analyzed to gain understanding of the subjective experience of being in a high-risk situation. One of the major discoveries was the inappropriate labeling of mothers as denying the seriousness of the situation. Mothers focused on the possibilities in the situation, whereas caregivers focused on the actual or potential problems. The article describes this mismatch and proposes changes in practice to offset dysynchronous caring.


Why promote clinical nursing scholarship? The rationale for clinical nursing scholarship derives both from the nature of any health profession and from the nature of nursing. Clinical scholarship, whether scientific, evaluative, philosophical, or historical, provides the means for advancing knowledge needed to continuously improve the essential services that nurses provide.


Variations in the hemodialysis treatment process. The Medicare end-stage renal disease (ESRD) program costs more than $2 billion a year. Costs per treatment vary significantly across hemodialysis facilities, yet the relationship of these cost differentials to case mix and outcomes is uncertain. This study analyzed treatment variations in 527 chronic hemodialysis patients dialyzing in four freestanding and three hospital-based facilities. Results indicated that patients receiving care in the hospital-based units received a more costly routine dialysis treatment as well as more intensive nursing care during the treatment process than did patients in freestanding units. Policy and clinical implications of the findings are discussed.


The assessment of coping.

The assessment of coping. Major methodological problems attend any attempt to measure coping. Some of these difficulties relate to the time frame, the units of evaluation, and who should judge the effectiveness of coping behaviors. Account must be taken of factors as diverse as the social context of the individual and the balance of costs and benefits to a person as a result of adopting a given strategy. Although many instruments exist to measure aspects of coping, there is a need to lay a sure foundation in subjective assessments by patients and never to lose sight of the individuality of each person and situation. The article reports on research conducted in the Nursing Research Unit at the University of Edinburgh in which an attempt has been made to examine both measurement issues and the components that explain coping.


What psychiatric nurses say about constant care. As part of a qualitative research project on constant care, 8 psychiatric nurses described their perceptions of the constant care experience and its purposes and values. One of the major domains that emerged from the interviews was "nursing"; it consisted of nine themes, some of which indicated that constant care alters the passage, meaning, and use of time, is a dynamic rather than a static relationship, and enhances a nurse's sense of powerfulness. The findings showed that constant care is a dynamic, and to some, distorting, experience. It demands extra work from the nurses, yet constrains them from doing counseling or other higher-order interventions. Having more nursing experience was seen as an advantage in preparing for constant care, controlling angry feelings, and discriminating for potentially dangerous situations. Also, due to the interactive nature of constant care, a nurse could not merely guard a patient because the nurse is also on constant care. These findings have implications for making patient assignments, teaching novice nurses how to do constant care, affirming current practice even though it is against hospital policies, and illustrating how nurses can be aware of and resourceful when constant care is stressful.


Strategies for AIDS prevention: leadership training and peer counseling for high-risk African-American women in the drug user community. A culturally congruent training program to promote HIV risk-reduction behaviors was implemented in a convenient sample of 9 African-American women in an urban methadone treatment program. At each of eight peer counseling and leadership training (PCLT) program sessions, the transmission and prevention of AIDS were discussed while emphasizing enhancement of participants' self-esteem, confidence, and control over high-risk behaviors. The results indicate that support of the women helped develop their sense of purpose and self-worth, reduced sexual and drug use practices associated with risk for HIV and AIDS infection, and promoted assumption of leadership roles and dissemination of accurate AIDS-related information in their communities. It was apparent that knowledge alone does not change behavior if it conflicts with established norms, values, beliefs, and life-styles and that individuals who have a sense of personal control are more willing to explore alternative lower-risk behaviors.


Comfort: the refocusing of nursing care. Caring is an inadequate concept for nursing practice. Rather, if comfort is used as the central paradigm for nursing, the focus of nursing research changes from the nurse to the patient. The components, limitations and relevance of comfort are discussed in this article. Preliminary results of a study exploring the usefulness of comfort in emergency rooms identified eight types of comforting. The characteristics of each type are described.


Intergenerational geriatric remotivation. This piece of a larger study on intergenerational geriatric remotivation discusses influential program variables. Interviews, participant observation, and videotapes were used to study a program in the Southeast and a comparison program in the Midwest. The variables examined were frequency, longevity, and constancy of intergenerational contact, problem discovery and problem resolution procedures, physical environment, and activity structure. As practitioners contemplate establishing intergenerational programs, a number of issues regarding program structure need to be considered to ensure that outcomes match expectations.


Cultural diversity in the nurse-client encounter. This study examined encounters between nurses and clients who originate from diverse cultures to determine the perspectives of both the nurse and the client concerning the experience of their time spent together. Fifteen nurses and 15 clients were interviewed separately after their encounter, and their responses were compared. Three major themes emerged from the data: descriptions of mutual satisfaction with the encounter (mentioned most often), different or incongruent perceptions of the encounter, and mutual dissatisfaction with the encounter. Themes in the category of mutual satisfaction were markedly similar to the themes of caring described by previous research. Although there were expressions of language difficulties and lack of knowledge of cultural differences, these did not appear to inhibit the mutual caring that was described.


A comparison of childbirth expectations in high-risk and low-risk pregnant women. This study described and compared the childbirth expectations of high-risk and low-risk pregnant women and then examined the influence of anxiety, risk status, and childbirth preparation on these expectations. This descriptive correlational study employed a convenience sample of 75 high-risk nulliparas and 77 low-risk nulliparas. Results indicated that high-risk pregnant women had significantly less positive expectations for their childbirth experience than did low-risk pregnant women. In particular, high-risk pregnant women expected more medical intervention and more difficulty coping with pain during their labor and birth. For both groups of women, anxiety was negatively correlated with childbirth expectations, whereas childbirth preparation was positively correlated with childbirth expectations.


Effects of intraoperative progress reports on anxiety of elective surgical patients' family members. The purpose of this experimental study was to examine the effects of intraoperative progress reports on family members' state anxiety level (STAI S-Anxiety), mean arterial pressure (MAP), and heart rate during elective surgical procedures. Family members of randomly selected surgical patients were eligible to participate. Control group family members (n = 50) received usual care. Family members in the experimental group (n = 50) received a 5- to 10-minute progress report protocol about halfway through a surgical procedure. Families' STAI S-Anxiety scores, MAP, and heart rates were compared between the control and experimental groups using multivariate analysis of variance (MANOVA). Family members in the experimental group reported lower STAI S-Anxiety scores (p < .001), and had significantly lower MAP and heart rates than did the control group (p < .001). Progress reports appear to be a beneficial nursing intervention for reducing anxiety in family members during the intraoperative period.


A comparative study of patients with chronic pain in India and the United States. Pain is the most frequently reported symptom in the health care industry today. Chronic pain in the United States costs millions of dollars annually, and its financial impact is mounting. For individuals living in the United States, chronic pain affects nearly all normal activities and often leaves the person feeling helpless and hopeless. Literature supports the idea that chronic pain does not have the same debilitating effect in the Eastern cultures as it does in the Western cultures. Therefore, clients from both a Western and Eastern culture were studied. This qualitative research, based on grounded theory, sampled 20 persons from India and 20 from the United States. Focused, open-ended interviews were used as the major manner of gathering data. Although the condition of chronic pain was the same for each culture, there were significant differences regarding the phenomenon of chronic pain. This research indicates the need for health professionals to assess, implement a plan of care for, and evaluate patients' suffering and need for improved quality of life rather than focusing only on the elimination of pain.


Home health care: delineation of research priorities and formation of a national network group. The purposes of this national study were (a) to determine priority research questions in home health care nursing and (b) to develop a home health research network group. Collaborative brainstorming was used initially by an interdisciplinary research team to generate a list of research questions. The major content areas covered in the questionnaire were questions relating to home health care as a delivery system, patient classification, quality assurance, nursing diagnosis, and nursing professionalism. A survey of 450 practicing home health care nurses was completed. The questions were rated by the respondents on a scale of high, medium, or low research priority. The response rate was 52%, with home health nurses responding from 30 states. The results clearly indicated the top 10 research priorities for home health care nursing research. The formation of the home health care research network groups are also discussed.


[Free alveolar cells in experimental pulmonary emphysema. I. Statistical analysis of cellular composition and lung morphometry]. The study was carried out on an experimental papain induced model of pulmonary emphysema. The authors assessed the cell populations sampled with lavage. Special emphasis was directed on alveolar macrophages and neutrophils. Extent of emphysema was analysed morphometrically. The authors demonstrated an influx of neutrophils 24 hours after papain was introduced intratracheally. This was followed by a swift decrease of the number of sampled neutrophils. Seven days latter the neutrophil count returned to normal. A significant increase of alveolar macrophages was seen on the seventh day. The increased macrophage count correlated with the extent of the pulmonary emphysema destruction.


[Free alveolar cells in experimental pulmonary emphysema. II. Morphological studies of cells and analysis of their adhesive properties]. Morphological analysis of cells sampled by lavage from alveoli was carried out. Analysis of their adherent properties on a nylon filter was also studied. Morphological analysis was carried out by light and scanning electron microscopy (SEM). The authors have demonstrated a correlation between adherence of the cells to the filter and morphological characteristics of the cells. SEM disclosed a very rich configuration of the cytoplasmatic membrane and/or formation of philopodia and pseudopodia. These results correlated with the extent of emphysemic pulmonary changes. Light microscopy showed a thin veil formed by the cell membrane in cells showing highest adherent properties.


[Does the moment of birth influence future atopic respiratory diseases? I. Statistical analysis]. In order to define the possible role of the time of birth on future presentation of atopic respiratory disorders an analysis of birth rates was studied according to time of birth in the following groups: 111 patients with pollinosis 145 patients non-seasonal allergic respiratory disorders, 117 patients with non-atopic respiratory disorders and 291 healthy volunteers Clinical diagnosis of atopic respiratory disease was based on the presence of conjunctivitis and/or mucosal inflammation and/or bronchial asthma. Confirmation of atopic etiology of the disorders was based on results of skin prick tests with common allergens and/or of allergen specific IgE levels. It was demonstrated that patients with respiratory disorders are born most often in the second quarter of the year. Patients with non-seasonal allergic disorders were born usually in the second and third quarter of the year. Patients that were born in the first quarter of the year developed atopic disorders less frequently.


[Spirographic predicted values for young men in Poland]. Basing on results of VC and FEV1 measurements in 293 males of the age group 15-40 years using the regression calculations new predictive values were calculated. These values were compared with values published 27 years earlier by Nikodemowicz and Morris's normograms. The latter published the highest reference values, on which most computer programs are based on. The analysis demonstrated significantly higher predictive values compared to those of Nikodemowicz, and comparable with the Morris's normograms. It seems that the latter can be used for reference values in Poland.


[Coexistence of asthma and certain symptoms of atopic dermatitis]. The frequency of basic and minor features of atopic dermatitis were compared between 86 patients with coexistent asthma, and 269 without asthma. The coexistence of asthma caused a statistically significantly more frequent presence of one of the basic features: personal or family history of atopy and five minor features. The latter included: early age of onset, recurrent conjunctivitis, tendency toward cutaneous infections, elevated serum IgE and keratosis pilaris.


[The role of radiophotography in tuberculosis control programs in Poland]. The role of mass radiophotography in Poland in the years 1985-1898 is presented basing on routine data from Antituberculous Centers and Radiophotographic Units. Mass radiophotography detects approximately 30% of new registered pulmonary tuberculosis cases. In the analysed period the number of radiophotographic examinations systematically fell. Also the percentage of the population that was screened using this method decreased, as well as, although to a lesser state, the percentage of new detected cases of pulmonary tuberculosis. A significant decrease in usage of mass radiophotography equipment was also seen. The economical cost of such examination increased. The role and place of mass radiophotography in tuberculosis control programs in Poland is discussed by the authors. It seems that first contact physicians will have the most pronounced role in early diagnosis of pulmonary tuberculosis. Also more emphasis should be placed on bacteriological diagnosis of tuberculosis.


[Foreign bodies in the bronchial tree].

[Foreign bodies in the bronchial tree]. In the study tree cases of foreign bodies in bronchial tree were discussed to illustrate a proper way for their removal. According to time of their remaining in bronchial tree a foreign body may be removed immediately after aspiration or after special preparation with surgical and anesthetic assistance. Our studies documented the use of flexible fiberoptic bronchoscope in foreign body removal.


[Cellular analysis of bronchoalveolar lavage fluid (BAL) in patients with acute and chronic bronchitis (preliminary study)]. Cell morphology of BAL- fluid and index bronchitis (by Thompson) were evaluated in 52 patients with acute and chronic bronchitis. A significant increase of index bronchitis and percentage of neutrophils in BAL were observed in acute and chronic bronchitis. There was no correlation between index bronchitis and cell in BAL- fluid.