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BACKGROUND AND STUDY AIMS: Liver abscesses are rare in the Western pediatric population and data on predisposing factors and etiology are scarce. We aimed to describe predisposing factors, microbiological characteristics, and treatment. PATIENTS AND METHODS: Retrospective analysis of children admitted to two tertiary care hospitals in Belgium from 1 January 1996 to 31 December 2019. We analyzed clinical features, predisposing factors, imaging characteristics, microbiological data, treatment, and outcome in children with a liver abscess and compared these data with the literature. RESULTS: We collected 24 cases with a male to female ratio of 1.4 and a median age of 3.2 years at time of diagnosis. Survival was 95.8%. Invasive culture specimens were obtained in 83.3% and showed growth of bacteria in 55%. Parenteral antibiotics were administered before invasive culture sampling in 80%. Liver abscesses were cryptogenic in four (16.7%) patients. Hepatobiliary disease was the most prevalent predisposing factor (n = 6; 25%), followed by recent antineoplastic therapy for malignancies (n = 5; 20.8%), intra-abdominal surgical pathology (n = 4; 16.7%) and umbilical venous catheters (n = 2; 8.3%). In two patients there was a parasitic origin (n = 2; 8.3%) and in one it was caused by Bartonellosis. There was no diagnosis of chronic granulomatous disease (CGD) in our cohort. CONCLUSIONS: Pediatric liver abscesses have a favorable outcome in the developed world. Whenever feasible, invasive abscess culture specimens should be obtained. In patients presenting with a cryptogenic liver abscess or atypical disease course, immunological workup should be ensured. ispartof: ACTA GASTRO-ENTEROLOGICA BELGICA vol:85 issue:3 pages:439-445 ispartof: location:Belgium status: accepted

Chest physiotherapy is regularly prescribed for children, particularly in cystic fibrosis. Gastro-oesophageal reflux is common in this disease and is associated with certain chest physiotherapy manoeuvres.To evaluate the influence of two chest physiotherapy techniques on gastro-oesophageal reflux in children.Twenty-nine children were investigated by routine pHmetry. During the examination, they performed two chest physiotherapy manoeuvres in a seated position for 10 minutes each with a 5 minutes rest between them. The two manoeuvres used were a slow expiration technique (ELPr) and positive expiratory pressure (PEP). It was a prospective study and the order of manoeuvres was randomised. The pH traces were analysed blindly when all the studies had been completed.In the sample, 21% of children had gastro-oesophageal reflux during the physiotherapy session. No relationship was found between reflux during physiotherapy and pathological reflux (P=0.411) nor the physiotherapy technique used (P=0.219).The use of these two chest physiotherapy techniques in children in a seated position can produce gastro-oesophageal reflux.

The efficacy of infliximab (IFX) in inducing and maintaining remission in pediatric Crohn disease is currently well documented. However, the optimal treatment strategy beyond 1 year has not been established. In particular, systematic continuation of maintenance therapy and its association with immunomodulators have not yet been analyzed.The aim of this study was to describe the long-term outcome of pediatric Crohn disease patients on IFX therapy and to evaluate the clinical response to the therapy and the effect on growth.A single-center and retrospective chart review was conducted. The clinical maintenance response to treatment, effect on the linear growth, and long-term outcome were examined. These parameters were analyzed according to the age of the patients, duration and localization of the disease, as well as associated therapies.We identified 52 children with Crohn disease younger than 16 years of age at the time of diagnosis. Of these patients, 20 (38%) received a biologic therapy at a mean age of 13.9±2 years. Fifteen patients received IFX therapy and 13 (86%) were in clinical remission 10 weeks after the first infusion. Among the responders, 82% were still in remission after 1 year of therapy and 66% after 2 years. Among patients treated for more than 1 year, we observed IFX dependency in 89%. Thirty-eight percent of patients with initial IFX response showed a loss of response after a median of 30 months (range, 3-42 months). At 2 years, the median Z score for height among patients with presumed growth potential had improved slightly, from -0.7 to -0.55 DS. No serious adverse events were observed.Our results confirm the continuous efficacy of IFX in pediatric Crohn disease patients after 1 year of treatment. However, a high level of dependency was observed (89 %). A slight beneficial effect on growth was observed after 2 years of treatment.

We report long-term (seven yr) immunological tolerance in a 16-yr-old boy, to a liver allograft donated by his father following a bone marrow transplant at age 2.5 yr from the same donor. The bone marrow transplant was complicated by severe GVHD leading to liver failure and the ensuing need for a liver transplant, performed under planned avoidance of immunosuppression. At one wk post-transplant, although a liver biopsy was histologically compatible with acute rejection, favorable clinical and biochemical evolution precluded initiating immunosuppressive therapy, thus highlighting the need for caution when interpreting early histological changes so that administration of unnecessary immunosuppression can be avoided. Induction of tolerance in transplant recipients remains an elusive goal. In those patients who had received conventional bone marrow transplants and had endured the consequences of GVHD, development of macrochimerism may allow immunosuppression-free solid organ transplantation from the same donor.

The development of pediatric liver transplantation is considerably hampered by the dire shortage of small donor organs. This is a very sad situation because in most experienced centers, liver replacement can offer a long-term hope of survival of more than 70% in a growing variety of pediatric liver disorders. The reported experience with 54 reduced-size grafts on a total of 141 transplants performed in 117 children between 1984 and 1988 demonstrates that the technique of reduced-size liver transplantation not only allows long-term survival but, in fact, offers the same survival hope with the same quality of liver function, regardless of the child's age and clinical condition. The prominent feature of our experience with the reduced liver concerns its deliberate use for elective cases. Seventy-seven per cent of the 30 children who electively received a reduced liver were alive 1 year after transplantation, as were 85% of the 62 children who received a full-size graft. There is no difference in the long-term survival rate of patients who received elective grafts, which is in the range of 75% with both techniques.

Liver cell transplantation is an emerging procedure, consisting of infusing mature adult hepatocytes in the portal system of the recipient. It aims to correct inborn errors of liver metabolism, bridge unstable patients to transplantation, or even allow bridge to recovery in fulminant liver failure. The technique addresses ideally patients with inborn errors of metabolism, unstable but not sick enough for orthotopic transplantation. Best results have so far been obtained in metabolic diseases, such as urea cycle disorders, glycogenosis type I, Crigler Najjar, Refsum disease and factor VII deficiency. Cryopreserved hepatocytes can be used, allowing delay between cell isolation and patient's transplantation. The percentage of engraftment obtained can reach up 10%, with de novo expression of deficient enzyme activity. Better results of engraftment have been obtained in animal studies by different chemical or physical techniques, but not yet applied in humans. Because supply of human cells can be limited, research also aims to obtain transplantable cells from other sources, such as embryonic or adult stem cells, or liver progenitor cells that could be expanded in vitro. Careful progression in this field, and collaboration between centers are mandatory to validate further the technique for wider clinical use.

Transplant patients with primary Epstein-Barr virus (EBV) infection may develop post-transplant lymphoproliferative disorder (PTLD). Since many infants are seronegative at the time of transplantation, PTLD is a major concern for paediatric transplant centres. First manifestations of PTLD are frequently observed in the ENT area with adenoidal and/or tonsillar involvement.Retrospective study of two cases of PTLD with confirmed supraglottic involvement, their management and outcome. Only patients with pathologically and immunologically demonstrated B-cell proliferation were diagnosed as PTLD.Two infants developed an acute stridor during PTLD respectively 8 and 10 months after orthotopic liver transplantation (OLT). These infants were seronegative for EBV at the time of transplantation. IgM anti-EBV and/or detection of EBV genome by polymerase chain reaction were positive. Laryngeal examination revealed hypopharyngeal and/or supraglottic mucosal hyperplasia. Immunostaining of laryngeal biopsy was positive for latent membrane protein-1 (LMP1). Patients were treated by a reduction in immunosuppression as far as tolerated with the intent to recover natural immune response by the patient over the proliferation of EBV-infected cells. Complete remission of PTLD was observed in these two cases.Tonsillar hypertrophy and adenoid enlargement are the most encountered features of PTLD in OLT occurring in the ENT area. Acute stridor with supraglottic involvement may also be observed in PTLD and must be promptly diagnosed as the prognosis of this disorder is related to rapid reduction in immunosuppression and consequently to the recovering of a natural immune response against the EBV infection.

Wilson's disease is an autosomal recessive disease of copper metabolism, with an estimated prevalence of 1:30000. The most common presentations of WD are liver disease and neurological disturbance. For many years the diagnosis was based on the results of several clinical and biochemical tests, for which several limitations had been reported. In recent years the developments of new techniques in genetic and molecular biology have provided useful tools in the diagnosis of Wilson's disease. However, the presence of several mutations and the fact that most patients are compound heterozygote means that the problem is not completely resolved. Chelators and zinc salts have been largely used in the treatment of WD patients with a favorable outcome, but the debate continues as to the agents of first choice. Liver transplantation is a cure for patients with decompensated liver disease but its effect on the neurological outcome is still not clear.

The Paediatric Liver Transplant Program at Saint-Luc University Clinics constitutes a substantial single centre experience, including 667 transplantations performed between March 1984 and April 2003, and the history of this program reflects the tremendous progress in this field since twenty years. Liver transplantation in children constitutes a considerable undertaking and its results depend on multiple, intermingled risk factors. An analysis of the respective impact of several surgical and immunological parameters on patient/graft outcome and allograft rejection after paediatric liver transplantation showed a significant learning curve effect as well as the respective impact of pre-transplant diagnosis on survival and of primary immunosuppression on the rejection incidence. The introduction of living related liver transplantation in 1993 not only permitted to provide access to liver replacement in as many as 74% more candidate recipients, but also resulted in better graft survival and reduced retransplantation rate. The results of a recent pilot study suggest that steroid avoidance is not harmful, and could even be beneficial for paediatric liver recipients, particularly regarding growth, and that combining tacrolimus with basiliximab (anti-CD25 chimeric monoclonal antibody) for steroid substitution appears to constitute a safe alternative in this context. The long-term issues represent the main future challenges in the field, including the possibility of a full rehabilitation through immunosuppression withdrawal and tolerance induction, the development of adolescence transplant medicine, and the risk of early atherogenesis in the adulthood.

Children with chronic hepatitis B, face life long disease and complications of cirrhosis and hepatocarcinoma. Naturally, it is estimated that half to two third of the children will clear the hepatitis Be antigen during childhood. Treatments aim to increase the HBe Ag to Ab seroconversion rate, which may also favour the loss of HBs antigen, ultimate goal. Interferon alpha was the first approved treatment for pediatric chronic hepatitis B, and was shown to increase the HBe ag loss from 11% in control group to 26% in treated patients (5 MU/square meter body surface area for six months) at one year, and 33% at 18 months. Side effects include mainly fever, flu like symptoms, and growth impairment during the treatment phase. Nucleotide analogues have now emerged as a promising alternative to treat chronic hepatitis B. The optimal dose for children is established to 3 mg/kg once daily up to 12 years old. Efficacy trials show complete virologic response in 23% of all treated patients after one year, as compared to 13% in the placebo group, and in 34% of patients with basal transaminases above two times upper limit of normal; versus 16% in controls. Lamivudine inhibits viral DNA which favours cellular immune response. Lamivudine resistance due to variant viruses is observed in 19% of children after one year. Other nucleotide analogues, such as entecavir and adefovir will soon be tested in children, and combination with Lamivudine may improve results. Finally, vaccine technology is being tested in adults, to induce a cellular immune response towards hepatitis B antigens, but no clinical benefit has so far been established.

Portocaval fistulas are rare and only exceptionally discovered in newborns. We report the case of a large portocaval fistula associated with portal hypoperfusion detected at Doppler US imaging in an otherwise asymptomatic 5 week old infant. The patient remained asymptomatic over the following two years. At that time, preoperative angiogram showed a normal portal venous system and the fistula was surgically closed. Postoperative US showed a normal and patent portal system, without evidence of portal hypertension.

Life-expectancy in glycogen storage disease type I (GSD I) has improved considerably. Its relative rarity implies that no metabolic centre has experience of large series of patients and experience with long-term management and follow-up at each centre is limited. There is wide variation in methods of dietary and pharmacological treatment. Based on the data of the European Study on Glycogen Storage Disease Type I, discussions within this study group, discussions with the participants of the international SHS-symposium 'Glycogen Storage Disease Type I and II: Recent Developments, Management and Outcome' (Fulda, Germany; 22-25th November 2000) and on data from the literature, guidelines are presented concerning: (1) diagnosis, prenatal diagnosis and carrier detection; (2) (biomedical) targets; (3) recommendations for dietary treatment; (4) recommendations for pharmacological treatment; (5) metabolic derangement/intercurrent infections/emergency treatment/preparation elective surgery; and (6) management of complications (directly) related to metabolic disturbances and complications which may develop with ageing and their follow-up. Conclusion: In this paper guidelines for the management of GSD I are presented.

The number of adult patients on the liver transplantation waiting lists is growing steadily. Adult living related liver transplantation (LRLT) represents the ultimate means to expand the donor pool. The success of this model of "small for size" grafting relies on strict donor and recipient selection. The choice of the graft (2 left and 4 right hepatectomies) was made on the minimal ratio between estimated graft and recipient body weights (0.8-1%), necessary to meet the recipient's metabolic demands. Our experience with six adults is reported. Donor morbidity was minimal (one wound infection); there was no mortality. Four (66%) recipients are doing well, two died of infectious complications. All recipients had a complicated post-transplant course. Due to its complexity, both in donor and recipient, LRLT should only be developed very carefully in experienced liver transplant centers.

The Brussels series of living related liver transplantation (LRLT) in 77 children (15 years) is reviewed. Median (range) recipient age at liver transplantation was 1.1 year (0.4-13.1). The main indication for LT was biliary atresia in 55/77 cases (71%). The living-related donor was one of the parents in 74 instances. Hepatic segments 2-3 (n = 67) or 2-3-4 (n = 10) were implanted orthotopically, with a median (range) graft weight to recipient body weight ratio of 3.17% (0.91-8.08). No severe complications or significant long-term sequelae were encountered in the living donors. One and five year survival rates were 92% and 89% for the patients, and 90% and 86% for the grafts, respectively. The retransplantation rate was 2/77 (2.6%), the indication being chronic rejection in both instances. In conclusion, LRLT is now a validated procedure in the living donors as well as in pediatric recipients with chronic or acute liver diseases. In the current context of organ shortage, it provides a valuable alternative to cadaveric LT.

Among 39 posttransplant lymphoproliferative diseases (PTLD) in a cohort of 450 pediatric liver transplant recipients, 3 had a malignant lymphoma, unresponsive to arrest of immunosuppression and to gancyclovir, interferon, and anti-interleukin 6 antibodies. Lymphoma appeared 20, 46, and 96 months posttransplantation and 16, 43, and 90 months after primary Epstein-Barr virus infection. In one case, the patient had histological progression from plasmacytic hyperplasia PTLD, concomitant with symptomatic primary infection, to Burkitt-like lymphoma 43 months later. These three patients received five courses of chemotherapy, after a cyclophosphamide, doxorubicin, vincristine, and prednisone regimen for Burkitt-like or LH 89 scheme for Hodgkin-like PTLDs. Chemotherapy was well tolerated, and all three were free of disease and without immunosuppression 19, 14, and 4 months after chemotherapy. In Burkitt-like or Hodgkin-like PTLDs, immunomodulatory or antiviral drugs were inefficient. Chemotherapy is indicated and can be safely and successfully used. Long-term arrest of immunosuppression seems feasible without graft rejection.

Autosomal recessive polycystic kidney disease (RPKD) (also called infantile polycystic kidney disease) and autosomal dominant polycystic kidney disease (DPKD) (or adult form) are the two main types of genetic polycystic kidney diseases (PKD) encountered in children and infants. We report here a case of DPKD with no family history and discuss the main features leading to the differential diagnosis between these two types of PKD, their prognosis and the importance of making the right diagnosis for the genetic counselling.

In adults several trials of successful therapy for chronic hepatitis B using alpha-interferon with rates of seroconversion from HBeAg to anti-HBe of 30-40% have been reported. Despite the experiences in children are limited, alpha-interferon seems to be a promising drug in this age group as well. We report on our results in the treatment of chronic hepatitis B virus carrier using the recombination interferon alpha-2b.24 children aged 0.6-16 years with chronic active or chronic persistent hepatitis B were included in the study. 12 children received 9 million units of alpha-interferon/m2 body surface area three times a week during four months. 12 control patients were not treated. The follow-up period was 9-12 months after the beginning of therapy. HBsAg, anti-HBs, anti-HBe and Hepatitis-B-Virus-DNA were assessed during this time on a regular basis.Only seroconversion of HBe-Ag to anti-HBe was considered as response to interferon treatment. During the follow-up period anti-HBe could be detected in 5 (41.6%) of the treated and in one (8.3%) of the untreated children. In one case additional seroconversion of HBsAg to anti-HBs due to virus elimination was observed. In all children a marked reduction of viral replication could be shown. 9 patients cleared Hepatitis-B-Virus-DNA at least for one time during therapy. Alpha-interferon was well tolerated and no severe side effects were observed.Our results demonstrate that alpha-interferon can be successfully applied to a considerable number of children with chronic hepatitis B. In patients responding to alpha-interferon usually serum transaminases become normal and infectivity of the disease is markedly reduced. alpha-Interferon treatment should be primarily recommended for children with chronic active inflammation.

From a study of the collision-activated fragmentation of bile acids, a qualitative analytical method based on negative ion fast atom bombardment tandem mass spectrometry has been developed. The times for sample preparation and analyses are short. Both free and conjugated bile acids are detected as they occur in biological fluids, without derivatization. For identifying bile acids and conjugates, the method offers better specificity and sensitivity than does the fast atom bombardment mass spectrometric technique alone. Specific scan modes have been developed for the selective detection of taurine conjugates, delta 4-unsaturated taurine conjugates, delta 4-3-keto free acids and their glycine conjugates, free acids and glycine conjugates bearing a hydroxyl group at the C-12 position, sulfates of glycine and taurine conjugates, and a C29 dicarboxylic bile acid, specific for generalized peroxisomal disorders. Applications of this technique demonstrate its potential usefulness, principally in the diagnosis of several peroxisomal disorders.

The clinical course of 196 patients with chronic myelocytic leukemia (CML) was studied. Prognostic factors were analyzed using a standard prognostic model. From a univariate analysis of patients with nonblastic Philadelphia chromosome-positive CML, splenomegaly, bone marrow fibrosis, percentage of blasts and promyelocytes in the peripheral blood and LDH activity were shown to be factors with a significant negative influence on survival. However, age and the platelet count did not influence survival. The standard prognostic model, generated with the 4 variables (1) percentage of blasts and promyelocytes, (2) spleen size, (3) platelet count and (4) age did not provide a useful representation of risk status in this heterogenous patient population. However, the addition of further variables (LDH, additional chromosomal aberrations, percentage of basophiles/eosinophiles and percentage of bone marrow blasts) to the standard model allowed a separation into 2 patient groups: one with low and the other with intermediate to high risk. Our data support the general validity of the prognostic model; however, the applicability of the model may be compromised in hematologic centers with a heterogenous CML population due to the selection of high-risk patients. In this situation additional risk factors may have to be added to the prognostic formula.

In a double-blind study, 114 patients with clinically benign nontoxic goiter were treated either with liothyronine (T3), 50 μg/day, or thyroxine (T4), 200 μg/day. After 12 weeks of therapy, patients whose goiters decreased in size were continued on the same therapy for an additional 16 weeks. Those who did not respond were randomly divided into two groups: in one group the same dose of the same medication was continued, and in the other twice the dose of their original medication was given. By the end of 28 weeks, 40 of 54 patients treated with T3 and 29 of 59 patients treated with T4 showed a significant decrease in goiter size. The difference in effectiveness of the two agents was statistically significant (p T3 produced a uniform and consistent depression of radioiodine uptake and circulating hormonal iodine levels, and was effective shrinking both small and large thyroid nodules, whether or not radioiodine uptake was reduced to hypothyroid levels. T4 uniformly increased circulating hormonal iodine levels. However, in T4-treated patients who responded with regression of thyroid nodules, suppression of radioiodine uptake was substantially greater than in those who did not respond.

Low dose ara-C has been widely used in the treatment of preleukemia and leukemia. These studies have generally utilized either a twice daily, subcutaneous bolus schedule or a continuous intravenous infusion schedule. In order to surmount the logistical problems of long term intravenous infusion while providing prolonged ara-C exposure, we have studied the pharmacology of administering ara-C (20 mg/M2/d) by continuous subcutaneous infusion. The results obtained in eight patients demonstrate that steady state plasma ara-C levels achieved during continuous subcutaneous infusion (24.6-65.6 nM) are not significantly different than those obtained during intravenous infusions (26.2-61.5 nM). Subcutaneous infusions result in prolonged myelosuppression similar to that seen with continuous intravenous infusions. The continuous infusion of low dose ara-C by the subcutaneous route provides a treatment option for some outpatients and offers advantages over intravenous infusions which often require placement of venous catheters or hospitalization.

On the basis of in-vitro studies indicating that low concentrations of cytosine arabinoside exert preferential inhibition of granulocyte-macrophage colony-forming cells from patients with chronic granulocytic leukemia vs normal subjects, we treated two outpatients with low doses of this agent, administered by subcutaneous infusion for 12-31 days. Both patients continued their usual activities, including employment, during these infusions. They exhibited only Ph-positive metaphases at entry into the protocol but in both cases, Ph-positive cells were reduced to approx. 10% of marrow metaphases, after 2-3 successive infusions. Both patients exhibited significant increases in Ph-positive cells, to 46 and 72% of marrow metaphases, during subsequent chemotherapy with hydroxyurea, in dosage sufficient to maintain granulocytopenia and a normal serum B12 level. After additional cytosine arabinoside, both patients again showed decreases in Ph-positive cells, to 7% (p less than 0.01) and 19% (p less than 0.0001), respectively. This clinical experience is consistent with the conclusion that cytosine arabinoside (but not, hydroxyurea) exerts a selective antileukemic effect in some patients with CGL.

Among 60 patients with chronic lymphocytic leukemia, higher in vitro uptake of tritiated (3H) thymidine by leukocytes of a standard volume of peripheral blood was associated with a higher lymphocyte count, a more advanced stage, greater frequency of functional impairment and shorter survival. Appropriate analyses demonstrated that leukocyte thymidine uptake correlated with survival independently of these other disease features. Relative thymidine uptake (radioactivity per 10(3) lymphocytes) did not prove to be a useful prognostic parameter. Among 33 patients not receiving antileukemic therapy at the time of study, 15 of 17 (88 per cent) of those with higher thymidine uptake values, but only 3 of 16 (19 per cent) of those with lower values, were treated during a median follow-up period of four and a half years (p less than 0.001). Seven of the former group, but none of the latter group, died during the first three years of follow-up (p less than 0.01). We conclude that thymidine uptake by circulating leukocytes constitutes a relatively accurate index of the proliferating leukemic cell mass in this disease and provides useful prognostic information.

Forty-six patients in the terminal phase of chronic myelocytic leukemia were treated with combinations of desacetylmethylcolchicine or trimethylcolchicinic acid and 6-mercaptopurine or 6-thioguanine. The drugs were taken by mouth, in dosages intended to avoid severe granulocytopenia. The combinations were generally well tolerated and platelet and granulocyte counts were usually above life-threatening levels, permitting 57% of the patients to be treated principally as out-patients. Complete hematologic and clinical response was achieved in six patients (13%) and partial response was obtained in 18 (39%). There were no karyotypic remissions. Median survival for the 24 responders was 8 months, while that for the 22 patients who had no response or only minor improvement was 4 months. Survival was as good among patients with partial remission as among those with complete response.

Clinical and laboratory findings at the time of diagnosis were correlated with the survival of 242 patients with chronic myelocytic leukemia. Twelve patients with the blastic stage of the disease (blasts greater than or equal to 29%) had a median survival of eight months. Of the nonblastic patients, 28 without the Philadelphia chromosome had a relatively constant mortality averaging 43% per year and a median survival of 13 months, markedly worse than the Ph1-positive group (mortality, 6% in the first year, 17% in the second year, and the 25% per year, with a median survival of 43 months; P less than 0.001). In the latter group of 202 patients, features reflecting the "quantity" of leukemia (leukocyte count, marrow cellularity, and M:E serum B12, different degrees of splenomegaly, presence or absence of symptoms) had weaker or short-term correlations with mortality, while "qualitative" abnormalities (e.g., increased percentage of circulating blast, extramedullary leukemic tumors, major abnormalities of erythropoiesis or platelet production, marked basophilia or eosinophilia) had strong and persistent correlations with mortality. Chromosome abnormalities in addition to the Ph appeared to have a delayed though significant effect on survival. Serum alkaline phosphatase and SGOT levels did not correlate significantly with survival, but major elevations of serum LDH were associated with increased mortality throughout the course of the disease.

CML is best regarded as a benign neoplasm, which regularly transforms into a rapidly fatal malignant one. Survival is determined by the timing of disease transformation. The rate of transformation and death is low initially and increases gradually to a stable annual rate, reached during the third year after diagnosis. This averages 25% per year in large populations of Ph positive patients. Transformation appears to occur randomly; a patient's risk of transformation can be defined, but the time when it will occur cannot be predicted. There is no evidence that conventional antileukaemic therapy changes the risk of transformation; thus, survival is determined principally by the intrinsic biology of the disease. A number of features recorded at the time of diagnosis correlate significantly with survival and can serve as prognostic parameters. Multivariate regression and Cox model analyses can generate hazard ratio formulae which provide quantitative estimates of patients' risk. Several Cox models have been described by different groups, and it is possible that two or more models may describe survival equally well. A four-variable model described by the International CGL Prognosis Study Group in 1984 has recently been tested in a prospective study by the Italian Cooperative Study Group on Chronic Myeloid Leukaemia, and successfully classified patients into three groups with significantly different outcomes. This model produces excellent results in analyses of large patient populations, but is less satisfactory when applied to smaller series. It is likely that current prognostic models can be improved substantially to provide more accurate definition of patient risk over a broader range of hazard ratio values. Such models should prove useful in evaluating therapeutic schedules, selecting patients for investigational or hazardous treatment and making decisions regarding bone marrow transplantation.

A group of 227 cases of non-Hodgkin's lymphoma included seven favorable and four unfavorable histologic classes with collective median survival times of 83 and 16 months, respectively. The favorable group included three follicular subgroups (cleaved, mixed, and large noncleaved) and four diffuse classes (small lymphocytic, cleaved, Burkitt's noncleaved, and convoluted lymphocytic). The unfavorable group consisted of four diffuse subgroups (plasmacytoid lymphocytic, mixed, and small and large noncleaved). There were significant differences in collective median survivals between patients in Stage I--II and those in Stage III--IV in both the favorable group (not reached, NR versus 62 months, P less than 0.001) and the unfavorable group (57 months versus 12 months, P less than 0.01). The incidence of complete response to primary treatment was higher in the favorable than in the unfavorable group (75% versus 56%, P = 0.002) and in those with limited as compared with advanced disease. Complete responders in both prognostic groups had longer survival times than did partial or minimal responders. A significant difference in median complete remission duration was found between responders in Stage I--II versus Stages III-IV in the favorable group (not reached versus 40 months, P = 0.001) but not in the unfavorable one (56 months versus 22 months, P greater than 0.05). The absence of relapses after 41 months among complete responders in the favorable but not in the unfavorable group suggests a potential for cure in a proportion of cases from the former group. The incidence of complete response was lower and median remission duration was shorter after secondary as compared with primary treatment. The results of this study confirm the prognostic value of the Lukes and Collins classification system and the importance of initial staging and of achieving a complete response to primary treatment in both the favorable and unfavorable lymphomas.

Delayed skin test responses to several or all of a battery of six antigens were evaluated in 64 patients with disseminated Hodgkin's disease before, during, and after multiple-agent chemotherapy. Before therapy, 53% of patients had one or more positive skin tests, as compared to 55% during intensive chemotherapy, 79% during maintenance therapy, and 100% after discontinuation of all treatment. Pretreatment skin tests were of no value in predicting clinical response to chemotherapy. Response rates, duration of response, and survival were similar among anergic patients and patients with positive skin tests before treatment. There were too few patients who remained anergic after intensive induction chemotherapy to permit a correlation of immunologic reactivity with course. We conclude that skin test responses to recall antigens, before or during aggressive treatment, are more indicative of Hodgkin's disease activity (and also, of the immunosuppressive effects of treatment routines) than of prognosis.

Granulocyte-macrophage colony-forming (CFU-GM) cells from peripheral blood of normal subjects and patients with chronic granulocytic leukemia (CGL) were cultured in soft agar. Drugs under study were added in a liquid overlay 2 days after initiation of cultures, providing prolonged exposure to these agents thereafter. Dose-dependent inhibition of colony growth was recorded with each of eleven agents examined, and at the higher concentrations tested, colony formation was often completely suppressed. Cytarabine showed selectivity against CFU-GM from patients in the chronic stage of CGL (P = 0.006); the median 50% inhibitory concentration for 12 such patients was 3.4 ng/ml versus 11.8 ng/ml for 15 healthy subjects. Such selectivity was not found with busulfan, hydroxyurea, mercaptopurine, thioguanine, daunorubicin, vincristine, vinblastine, methotrexate, desacetylmethylcolchicine, and trimethylcolchicinic acid. One other group has also reported a preferential effect of cytarabine against colony-forming cells from patients with CGL, and this appears to be the only drug for which such selective activity has been recorded to date.

Two hundred and fifty-two patients with advanced stages of favorable non-Hodgkin's lymphoma (NHL) subtypes (nodular histiocytic (NH), and diffuse well-differentiated lymphocytic (DLWD)) were analyzed for response and survival to moderate (cyclophosphamide-prednisone (CP)) vs. intensive (BCVP or COPP) chemotherapy regimens. The overall complete response (CR) rate was 57%. The median duration of remission for the entire group was 88 weeks and 65% of complete responders were in remission at one year. Survival rates at one year were 87% for BCVP, 86% for COPP, and 91% for CP. The response rate, response duration, and survival rate differences between the groups were not significant. Severe and life threatening hematologic toxicity rates were significantly higher with BCVP and COPP as compared to CP (P less than 0.001). The highest CR rate was obtained in NM (74%) and CP gave the highest CR rate in DLWD (60%). Survival rates at one year for NM (97%) and NLPD (90%) were comparable whereas the one-year survival rate for DLWD was significantly lower (75%) than that for NLPD (P less than 0.005) or NM (P less than 0.001). We conclude that in favorable NHL subtypes, cyclophosphamide-prednisone combination is an effective regimen with minimal toxicity.

Primate and rabbit antisera to different morphologic classes of human leukemia cells, after appropriate absorptions, detected leukemia-associated antigens present on cultured lymphoblastoid cell lines derived from leukemia patients. The primate antisera distinguished antigens on cells derived from myeloid leukemia patients from those on cells derived from lymphocytic leukemia patients. Of particular interest was the fact that antigens of myeloid leukemia, but not of lymphatic leukemia, were detected on lymphoid cell lines established from blood of patients with myeloid leukemia. One of four lymphoblastoid cell lines derived from normal donors expressed antigens of lymphatic leukemia. Leukemia-associated antigens were not found on the HRIK lymphoblastoid line derived from a Burkitt's lymphoma patient on skin fibroblasts or HeLa cells. Expression of these antigens on cultured cells derived from leukemia patients could not be related to the presence of the EB virus or the EB virus genome. Rabbit antisera detected antigens common to cells from patients with myeloid and lymphocytic leukemia. Absorption experiments demonstrated that the antigens detected on cell lines derived from leukemia patients are similar to those detected by the primate and rabbit antisera on fresh peripheral blood leukemic cells. The serologic detection of leukemia-associated antigens on lymphoblastoid cell lines indicates that some of these cultures contain cells with antigenic properties similar to those of human peripheral blood leukemic cells.

A series of antisera to leukemia-associated antigens (LAA) were prepared by immunization of monkeys and rabbits with leukemia cells or leukemia cell extracts and absorption of the resultant antisera with red blood cells and leukocytes from healthy donors. These antisera were used with a complement-dependent microcytotoxicity test procedure at two leukemia treatment centers in a controlled Phase I clinical study designed to evaluate the specificity and sensitivity of the antisera for the detection of LAA and the suitability of the test procedure for routine clinical use. Tests of mononuclear cells prepared from coded blood samples of patients with different types of leukemia in various stages, patients with other malignancies and benign disorders unrelated to leukemia, and healthy controls indicated that several antisera had sufficient specificity and sensitivity for the detection of LAA to be of potential clinical value. These studies also suggested that such antisera might be useful in monitoring patients with leukemia and evaluating the quality of disease control, although the test procedure had some disadvantages for routine use in a general hematology laboratory.

Thymus-derived lymphocytes have been shown to play a role in the regulation of IgE synthesis in the rat. Both anergy and elevated serum IgE levels may be present in patients with Hodgkin’s disease. Cell-mediated immunity (CMI) was investigated by measurement of delayed skin test reactions with five common antigens. Serum IgE levels were determined at the same time. Impaired CMI was more prevalent in patients in stage III (13 of 15) and IV (15 of 19), as compared to patients in stage I and II (9 of 17). All 12 patients with elevated serum IgE levels (> 300 U/ml) had impaired CMI. These findings strongly suggest a relationship between impaired CMI and serum IgE in Hodgkin’s disease patients.

(CGL) is a disease of clonal origin, typically characterized by the presence of the Philadelphia chromosome (Ph) in hematopoietic cells. The Ph was the first consistent chromosomal abnormality to be described in a malignant disease.' It is found in approximately 90% of patients with CGL and appears to be one of the earliest abnormalities detectable in this disease. Many cases of CGL without the Ph are atypical in one respect or another, and there is often uncertainty in defining the disease in the absence of this marker. 2

Of 661 patients with Philadelphia chromosome (Ph)-positive, nonblastic chronic granulocytic leukemia, 58 had cytogenetic abnormalities in addition to the Ph at the time of diagnosis. Twenty patients had reduplication of the Ph in one or more metaphases. Twenty-one patients with a single Ph exhibited hyperdiploidy in one or more metaphases. Eleven patients had two or more hypodiploid metaphases as their only numerical abnormality. The remaining six patients had a variety of abnormalities. Many patients had more than one type of abnormality. Survival of patients in the different subgroups was similar, but these 58 patients had a shorter course than the 603 patients without additional cytogenetic abnormalities (P less than .02). Survival curves for the two populations did not diverge until the 2-year point, after which the annual death rate among patients with additional cytogenetic abnormalities was approximately 40% higher than that of patients without such abnormalities. The two populations had similar relative risk values according to a hazard ratio formula previously described by the International CGL Prognosis Study Group. Thus, they would have been expected to have essentially identical survival curves. We conclude that the presence of additional cytogenetic abnormalities at the time of diagnosis constitutes an independently significant prognostic feature with an unusually delayed influence on survival.