DOG1 expression in neuroendocrine neoplasms: Potential applications and diagnostic pitfalls.

Neuroendocrine neoplasms represent a heterogeneous group of rare tumors, more frequently arising from gastroenteropancreatic tract and lungs. At the time of diagnosis, 20% of cases are metastatic, and 10% of cases are considered as cancer of unknown primary origin. Several immunohistochemical markers are routinely used to confirm the neuroendocrine differentiation, first among all Synaptophysin and Chromogranin-A; on the other hand, different immunohistochemical markers are used to establish primary anatomical site, as TTF1, CDX2, Islet-1 and Calcitonin, but no marker is available in order to distinguish among different sites of the digestive tract. DOG1 (discovered on GIST-1) is a gene normally expressed in interstitial cells of Cajal and, in routine practice, DOG1 immunostaining is used in diagnosis of GIST (gastrointestinal stromal tumor). DOG1 expression has been described in several neoplasms other than GIST, both in mesenchymal and epithelial neoplasms. In the present study, DOG1 immunostaining has been performed in a large cohort of neuroendocrine neoplasms, including neuroendocrine tumors and neuroendocrine carcinomas, in order to evaluate frequency, intensity and pattern of expression in different anatomical site and in different tumor grade. DOG1 expression was detected in a large percentage of neuroendocrine tumors, with statistically significant association between DOG1 expression and gastrointestinal tract neuroendocrine tumors. As a consequence, DOG1 could be included in marker panel for the identification of primary site in neuroendocrine metastases of unknown primary origin; moreover, these results recommend careful evaluation of DOG1 expression in gastrointestinal neoplasms, in particular in differential diagnosis between epithelioid GIST and neuroendocrine tumors.

CDK12 promotes tumorigenesis but induces vulnerability to therapies inhibiting folate one-carbon metabolism in breast cancer.

Cyclin-dependent kinase 12 (CDK12) overexpression is implicated in breast cancer, but whether it has a primary or only a cooperative tumorigenic role is unclear. Here, we show that transgenic CDK12 overexpression in the mouse mammary gland per se is sufficient to drive the emergence of multiple and multifocal tumors, while, in cooperation with known oncogenes, it promotes earlier tumor onset and metastasis. Integrative transcriptomic, metabolomic and functional data reveal that hyperactivation of the serine-glycine-one-carbon network is a metabolic hallmark inherent to CDK12-induced tumorigenesis. Consistently, in retrospective patient cohort studies and in patient-derived xenografts, CDK12-overexpressing breast tumors show positive response to methotrexate-based chemotherapy targeting CDK12-induced metabolic alterations, while being intrinsically refractory to other types of chemotherapy. In a retrospective analysis of hormone receptor-negative and lymph node-positive breast cancer patients randomized in an adjuvant phase III trial to 1-year low-dose metronomic methotrexate-based chemotherapy or no maintenance chemotherapy, a high CDK12 status predicts a dramatic reduction in distant metastasis rate in the chemotherapy-treated vs. not-treated arm. Thus, by coupling tumor progression with metabolic reprogramming, CDK12 creates an actionable vulnerability for breast cancer therapy and might represent a suitable companion biomarker for targeted antimetabolite therapies in human breast cancers.

Emerging and re-emerging infectious disease in otorhinolaryngology.

SUMMARY: Emerging and re-emerging infectious disease in otorhinolaryngology (ENT) are an area of growing epidemiological and clinical interest. The aim of this section is to comprehensively report on the epidemiology of key infectious disease in otorhinolaryngology, reporting on their burden at the national and international level, expanding of the need of promoting and implementing preventive interventions, and the rationale of applying evidence-based, effective and cost- effective diagnostic, curative and preventive approaches. In particular, we focus on i) ENT viral infections (HIV, Epstein-Barr virus, Human Papilloma virus), retrieving the available evidence on their oncogenic potential; ii) typical and atypical mycobacteria infections; iii) non-specific granulomatous lymphadenopathy; iv) emerging paediatric ENT infectious diseases and the prevention of their complications; v) the growing burden of antimicrobial resistance in ENT and the strategies for its control in different clinical settings. We conclude by outlining knowledge gaps and action needed in ENT infectious diseases research and clinical practice and we make references to economic analysis in the field of ENT infectious diseases prevention and care.

Laryngotracheal reconstruction in glottic-subglottic stenosis associated with DiGeorge syndrome in a four and a half-month-old infant.

Neonatal subglottic stenosis still remains a substantial challenge for paediatric ENT surgeons. Herein, we present a case of a single stage laryngotracheal reconstruction for a glottic-subglottic stenosis in an 18-week-old, 7.2 kg infant with DiGeorge syndrome. Our surgical approach was compared with those reported in the literature. Paediatric airway surgery should be tailored to individual patients according to age, weight, comorbidities and family collaboration, with the ultimate objective to minimise the invasiveness of the procedure.

Value of real-time gastric juice analysis in upper gastrointestinal endoscopy.

AIM: Esophagogastroduodenoscopy (EGDS) cannot identify microscopic lesions. We determined the contribution of real-time gastric juice analysis in detecting lesions non-detectable with the simple endoscopic inspection. METHODS: Endoscopy, histology and gastric juice analysis were performed in 216 patients. We assessed six diagnostic strategies: EGDS (strategy-1), EGDS with antral biopsies (hematoxylin-eosin staining) in hypochlorhydrics (strategy-2) or all patients (strategy-3), EGDS with antral and fundic biopsies (hematoxylin-eosin staining) in hypochlorhydrics (strategy-4) or all patients (strategy-5), EGDS with antral and fundic biopsies (hematoxylin-eosin + immunohistochemical staining) in hypochlorhydrics (strategy-6). Then, we determined how many of the pathological conditions identified by the complete histological evaluation would have been detected by each strategy. RESULTS: In total, 220 pathological conditions were identified. Hypochlorhydria was correlated (r=0.67; P<0.01) with histological lesions (85% lesions were detected in hypochlorhydrics) and high ammonium levels, with H.pylori infection (r=0.69; P<0.01). Strategy-1 identified only 5% conditions, while strategies 3 and 5 detected 68.6% and 83.2% conditions, respectively. Strategies 2, 4 and 6 (based on gastric juice analysis) yielded detection rates (61.4%, 75.5%, 90.9%) similar to or better than those of strategies 3 and 5. CONCLUSION: Real-time gastric juice analysis provided information about the presence of gastric lesions in an otherwise "normal" stomach at EGDS. It improved the diagnostic yield and optimized resource utilization without any additional effort by the endoscopist.

Perendoscopic real-time assessment of pH improves detection of gastric preneoplastic conditions.

AIM: Gastric juice may constitute a precious source of clinicopathological information. We assessed the usefulness of real-time, perendoscopic, gastric juice pH determination in identifying preneoplastic conditions of the stomach, that often escape the mere endoscopic evaluation. METHODS: The study included 245 patients (115M; 130F; age 47±17). In each of them perendoscopic gastric juice pH was assessed by means of an innovative device, the Endofaster, and the results were correlated with histological evaluation (H&E, immunohistochemistry, argyrophil stains), and gastric acid secretion (BAO-PAO), and serum gastrin levels. The conditions evaluated were: atrophy, intestinal metaplasia, endocrine cell hyperplasia, hypergastrinemia. RESULTS: A total of 136 pathological conditions were detected and these resulted to be correlated with pH (r=0.67; P<0.01). The rate of pathological conditions was low in normochlorhydric patients (14.1%); most of these conditions were concentrated in patients with hypochlorhydria (85.9%) (P<0.001). Specifically, the number of patients with one or more pathological conditions increased proportionately with the rise in pH levels. An inverse correlation was detected between gastric juice pH and basal acid output (BAO) (r=-0.72; P<0.01). Endoscopic feature was normal/mild in most of patients with pathological conditions. CONCLUSION: Hypochlorhydria is a sensitive indicator of gastric risk conditions. Perendoscopic real-time assessment of pH can improve and extend optical analysis by allowing the detection of pathological conditions (either preneoplastic or not) that often escape diagnosis because not correlated with specific endoscopic pattern.

Efeito da adição de agentes tróficos na dieta de leitões desmamados sobre a estrutura e ultraestrutura do intestino delgado e sobre o desempenho / The effect of the addition of trofic agents in weaned piglet diets over the structure and ultra-structure of small intestine and over performance

Foram estudados os efeitos da glutamina, dos ácidos graxos poli-insaturados e da parede celular de levedura (PCL) sobre a estrutura e ultraestrutura do intestino delgado e o desempenho de leitões. Foram utilizados 45 leitões, desmamados aos 21 dias de idade, para testar os seguintes tratamentos: T1 - dieta basal; T2 - dieta basal + 1 por cento de glutamina; T3 - dieta basal + 0,2 por cento de PCL; T4 - dieta basal + 5 por cento de óleo de peixe. Nos dias sete e 14 pós-desmame, foram abatidos cinco leitões de cada tratamento. Os aditivos testados não alteraram a altura e a densidade dos vilos nem a profundidade das criptas do intestino delgado. Foi observado efeito de idade, mostrando redução na altura e na densidade dos vilos e na profundidade das criptas após o desmame. No duodeno e jejuno, foram observados maiores valores de relação vilo:cripta, que aumentaram com a idade pós-desmame. Ocorreram redução da altura dos microvilos do duodeno aos sete dias e aumento da largura dos microvilos do jejuno aos 14 dias pós-desmame. A área de superfície apical dos enterócitos não foi alterada pelos fatores estudados. Os aditivos estudados não foram eficientes em prevenir a atrofia da mucosa intestinal do jejuno, ao não interferir na sua ultraestrutura. Os aditivos incluídos na dieta não influenciaram o desempenho dos leitões no pós-desmame.

The effects of glutamine, poliunsatured fatty acids and cellular wall of yeast (CWY) under the structure and ultra structure of the small gut and the performance of the piglets were studied. Forty five piglets weaned at 21 days were used to test the following treatments: T1 - basal diet; T2 - basal diet + 1 percent of glutamine; T3 - basal diet + 0,2 percent of CWY; T4 - basal diet + 5 percent of fish oil. At seven and 14 post weaning days, five piglets of each treatment were slaughtered. The height, density of villus and depth of small gut crypts were not altered by the inclusion of additives. The effect of age was observed, showing a reduction in the height and density of villus and depth of crypts after weaning. In duodenum and jejunum higher values were observed in the relation villus:crypt, which increased with the post wean age. There was a decrease in the height of microvillus of the duodenum at 7 days and an increase of the width of the microvillus of jejunum at 14 days after wean. The area of the apical surface of the enterocytes was not altered by the studied factors. The studied additives were not efficient to prevent the atrophy of the intestinal mucosa of the jejunum, since they did not interfere on its ultra structure. Piglet performance was not affected by the additives included in the diet.

Current and emerging therapeutic approaches in HCV-related mixed cryoglobulinemia.

Recognition of hepatitis C virus (HCV) as an etiological factor in mixed cryoglobulinemia (MC) has dramatically changed our point of view in its treatment. Emphasis is placed on abatement and clearance of viral load and deletion of clonal expansions of IgM molecules with rheumatoid factor activity-synthesising B cells. The purpose of this review is to discuss the underlying scientific rationale and results of clinical studies of new treatment approaches to MC, with a focus on cell-depleting therapies and chemokine blockade. Additional antiviral agents directed to several phases of HCV life cycle acting with different or alternate mechanisms are proposed with the goal to enhance response rates more broadly suitable for MC patients with vasculitis and peripheral neuropathies. The majority of the available data on these new treatment approaches stems from open-label studies, but controlled trials are under way. Therapy directed against chemokines and/or cytokines represents an interesting and promising future target.

Hepatitis C virus productive infection in mononuclear cells from patients with cryoglobulinaemia.

The relationship between the occurrence of cryoglobulins and hepatitis C virus (HCV) productive infection in peripheral blood and bone marrow-derived lymphocytes was explored. HCV minus strand RNA, the viral replicative intermediate, was searched for by a polyA(+) tract strand-specific Tth-based reverse transcriptase-polymerase chain reaction (RT-PCR) in lymphoid cells of 46 patients with acute and chronic infection. The HCV minus strand was demonstrated in RNA extracted from six (13%) and five (11%) peripheral blood and bone marrow-derived lymphocytes, respectively. The HCV replicating form in lymphoid cells was associated strictly with mixed cryoglobulinaemia (MCG), in that it was found in six of 13 (46%) MCG patients, including two with B cell non-Hodgkin's lymphoma (NHL). No traces of HCV-negative strand RNA were found in four patients with acute hepatitis C, in 15 with chronic active hepatitis without extrahepatic disorders, in seven with monoclonal gammopathy of undetermined significance, and in seven with B-NHL without MCG. These results emphasize the direct role of the virus in the pathogenesis of MCG and support the contention that HCV is not specifically lymphotropic, its entry and replication in lymphoid cells being determined largely by selective interactions.

HCV-NS3 and IgG-Fc crossreactive IgM in patients with type II mixed cryoglobulinemia and B-cell clonal proliferations.

We demonstrate that in three cases of MC (two with immunocytoma), the IgM-RF+ component of their cryoprecipitated represents the circulating counterpart of the B-cell receptor (BCR) of the monoclonal overexpanded B-cell population. These IgMs were isolated and used to demonstrate a crossreactivity against both hepatitis C virus (HCV) NS3 antigen and the Fc portion of IgG. Epitopes were identified in a fraction of exemplary samples by using epitope excision approach (NS(31250-1334) and IgG Fc(345-355)). The same phenomenon of crossreactivity has been shown to occur in vivo after immunization of a mouse with the NS3(1251-1270) peptide. To verify if the same reaction was also present in MC samples characterized by an oligo/polyclonal B-cell proliferation, IgM crossreactivity was tested in 14 additional samples. Five out of the 14 were reactive against HCV NS3 and 11 out of 14 were reactive against IgG-Fc peptide. The data support the role of HCV NS3 antigen in a subset of patients with MC, whereas the high frequency of the IgG-Fc epitope suggests that these B cells originate from precursors strongly selected for auto-IgG specificity. We suggest that engagement of specific BCRs by NS3 (or NS3-immunocomplex) antigen could explain the prevalence of IgM cryoglobulins in these patients.

Type II mixed cryoglobulinaemia as an oligo rather than a mono B-cell disorder: evidence from GeneScan and MALDI-TOF analyses.

OBJECTIVE: To identify and characterize rheumatoid factor (RF)-producing B-cells and cryoprecipitate immunoglobulin (Ig) M in hepatitis C virus (HCV)-positive patients. METHODS: We purified and characterized, by peptide mass fingerprinting integrated with an NCBI IgBlast data bank search, the IgM component of cryoprecipitate and analysed the VDJ pattern of bone marrow B-cells by gene scan analysis of 17 HCV-positive patients with type II mixed-cryoglobulinaemia. RESULTS: IgM purified from all of the patients presented an RF specificity. In three of these patients a high and predominant B-cell clone (>or=30%) was found in the bone marrow. B-cell-receptor sequences were determined and immunophenotyping of these clones was performed. Peptide masses originating after tryptic digestion of the B-cell-receptor combinatory regions and those originating by tryptic digestion of the cryoprecipitated IgM from the same patient were comparable. In the remaining patients an oligoclonal/polyclonality was found. However, in some of these patients we were able to find peptides that matched with the B-cell-receptor sequences of overexpanded B cells, indicating that, even in the absence of a clear monoclonal expansion, a fraction of total cryoprecipated IgM may derive from overexpanded B-cell clones found in patients' bone marrow. CONCLUSIONS: In the majority of mixed cryoglobulinaemia-HCV-positive patients, both in the serum and in B cells from the bone marrow, an oligoclonal pattern is the main molecular picture. When a monoclonal B-cell clone is found, its B-cell-receptor shows an antigen-binding fragment identical to that of cryoprecipitable RF-IgM. Phenotypically, B cells are CD20-positive but CD5-negative, suggesting that the B-1 B-cell subset is not likely to produce high-affinity IgM-RF molecules.

Virological analysis and phenotypic characterization of peripheral blood lymphocytes of hepatitis C virus-infected patients with and without mixed cryoglobulinaemia.

In clinical and pathological terms hepatitis C virus (HCV)-infected patients can be subdivided into two main groups with and without mixed cryoglobulinaemia (MC). Involvement of blood mononuclear cells by HCV has potentially important implications. To this end, HCV-RNA levels in peripheral blood lymphocytes (PBL) preparations of 20 chronically HCV-infected patients with MC were measured and compared with those found in a group of 20 patients without MC matched for age, serum HCV-RNA, infectious genotype, source and presumable duration of infection. Phenotypic abnormalities of PBL subsets in each group of patients were determined by cell surface marker expression and compared. Results showed a significant enrichment of HCV-RNA in PBL of MC patients compared with a non-MC group (P = 0.01). Different distribution of HCV-RNA was accompanied by evidence of an increased frequency of circulating B cells. These data indicate that MC patients are characterized distinctly by a higher quota of cell-associated viral load.

The cryoglobulins: an overview.

Cryoglobulins are cold-precipitable immunoglobulins associated with a number of infectious, autoimmune and neoplastic disorders. Their appearance along with rheumatoid factor (RF) can be considered a normal event in the clearance of immune complexes and rarely produces any symptoms. The association between hepatitis C virus (HCV) and mixed cryoglobulinemia (MC) has been rendered evident since the recognition of serological markers of HCV infection. There is thus every reason to suppose that direct or indirect involvement of B cells on the part of the HCV results in their persistent stimulation, clonal expansion and release of molecules with RF activity. The formation of RF/IgG immune complexes is the key pathogenetic mechanism. The close correlation between HCV infection and MC also throws new light on the interpretation of autoimmune phenomena in the course of viral infection and on the close link between autoimmune diseases and lymphoproliferative disorders. The higher risk of non-Hodgkin's lymphoma (NHL) displayed by HCV positive subjects, especially in the Mediterranean basin, suggests that the HCV's chronic lymphoproliferative drive may progress towards frank lymphoid neoplasia. The presence of MC does not represent an in situ or 'occult' NHL, because recent evidences indicate that none of the clones interpreted as predominant displays the molecular features of a true neoplastic process. The cryoglobulinemic syndrome is probably the consequence of pathogenic noxae that act upon the immune system of a host in which regulation of the peripheral T cell response appears to be in some way altered.

Molecular characterization of B cell clonal expansions in the liver of chronically hepatitis C virus-infected patients.

PCR DNA amplification of IgH genes was performed on liver biopsy samples of 42 unselected hepatitis C virus (HCV)-positive patients. Genotypic analysis and signal amplification by branched DNA were used to characterize and quantitate HCV RNA genomic sequences. Intraportal lymphoid follicle-like structures were isolated from surrounding hepatocytes by microdissection technique. IgH VDJ PCR products were cloned and sequenced. IgH VDJ gene rearrangements were detected in the liver of 26 (62%) patients. Unequivocal monoclonal or oligoclonal patterns of B cell expansions were found in 14 (33.3%) and 12 (28.6%) patients, respectively. Patients with intrahepatic B cell monoclonal expansions showed liver HCV RNA levels higher than those with oligoclonal or polyclonal features (1106.4 +/- 593.5 vs 677.3 +/- 424.3 vs 406.2 +/- 354.3 pg HCV RNA/g tissue; p = 0.048 and p = 0.001, respectively). Although a single dominant band was obtained with total DNA, characterization of DNA recovered from intraportal inflammatory aggregates resulted in the detection of multiple IgH VDJ gene rearrangements, pointing to an oligoclonal pattern of lymphoproliferation. Cloning and sequence analyses showed that B cell clonalities were differently distributed in adjacent portal tracts of the same liver area. In addition, HCV RNA genomic sequences could be consistently amplified from each of the portal inflammatory aggregates examined. These data support the concept that in chronic HCV infection the intrahepatic B cell repertoire is frequently clonally restricted and that HCV may have a direct role in sustaining in situ B cell proliferation.

Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine.

PURPOSE: To assess thiopurine S-methyltransferase (TPMT) phenotype and genotype in patients who were intolerant to treatment with mercaptopurine (MP) or azathioprine (AZA), and to evaluate their clinical management. PATIENTS AND METHODS: TPMT phenotype and thiopurine metabolism were assessed in all patients referred between 1994 and 1999 for evaluation of excessive toxicity while receiving MP or AZA. TPMT activity was measured by radiochemical analysis, TPMT genotype was determined by mutation-specific polymerase chain reaction restriction fragment length polymorphism analyses for the TPMT*2, *3A, *3B, and *3C alleles, and thiopurine metabolites were measured by high-performance liquid chromatography. RESULTS: Of 23 patients evaluated, six had TPMT deficiency (activity < 5 U/mL of packed RBCs [pRBCs]; homozygous mutant), nine had intermediate TPMT activity (5 to 13 U/mL of pRBCs; heterozygotes), and eight had high TPMT activity (> 13.5 U/mL of pRBCs; homozygous wildtype). The 65.2% frequency of TPMT-deficient and heterozygous individuals among these toxic patients is significantly greater than the expected 10% frequency in the general population (P <.001, chi(2)). TPMT phenotype and genotype were concordant in all TPMT-deficient and all homozygous-wildtype patients, whereas five patients with heterozygous phenotypes did not have a TPMT mutation detected. Before thiopurine dosage adjustments, TPMT-deficient patients experienced more frequent hospitalization, more platelet transfusions, and more missed doses of chemotherapy. Hematologic toxicity occurred in more than 90% of patients, whereas hepatotoxicity occurred in six patients (26%). Both patients who presented with only hepatic toxicity had a homozygous-wildtype TPMT phenotype. After adjustment of thiopurine dosages, the TPMT-deficient and heterozygous patients tolerated therapy without acute toxicity. CONCLUSION: There is a significant (> six-fold) overrepresentation of TPMT deficiency or heterozygosity among patients developing dose-limiting hematopoietic toxicity from therapy containing thiopurines. However, with appropriate dosage adjustments, TPMT-deficient and heterozygous patients can be treated with thiopurines, without acute dose-limiting toxicity.

Oxazolium-derived azomethine ylides. External oxazole activation and internal dipole trapping in the synthesis of an aziridinomitosene.

Intermolecular alkylation of the aziridinyl oxazole 20 using PhSO(2)CH(2)CH(2)OTf is possible despite the presence of potentially nucleophilic aziridine nitrogen. The resulting oxazolium salt 22 reacts with BnNMe(3)(+)CN(-) to produce the azomethine ylide 24b via electrocyclic ring opening of an oxazoline 23b. Internal cycloaddition affords 26 in 66% yield. After saponification and base-induced cleavage of the N-phenylsulfonylethyl group, conventional cyclization provides access to 33. Deprotection and DDQ oxidation completes the synthesis of the aziridinomitosene derivative 9b. The starting cis-disubstituted aziridine ester 16 can be prepared by the aza-Darzens reaction of 15 with tert-butyl chloroacetate.

A self-assembled cylindrical capsule: new supramolecular phenomena through encapsulation.

The synthesis and spectroscopic characterization of self-assembled cylindrical capsule 1a x 1a of nanometer dimensions is described. Encapsulation studies of large organic guest molecules were performed by using 1H NMR sprectroscopy in [D12]mesitylene solution. In addition to the computational (MacroModel 5.5, Amber* force field) analysis of the capsule's shape and geometry, an experimental approach towards estimation of the internal cavity dimensions is described. This involves using series of homologous molecular "rulers" (e.g. aromatic amides 5a-i). The available space inside the capsule 1a x 1a can be estimated as 5.7 x 14.7 A (error +/- 0.2 A) with this technique. Dibenzoyl peroxide is readily encapsulated in [D12]mesitylene and was shown to be stable to decomposition for at least three days at 70 degrees C inside the capsule. Moreover, 1a x 1a prevents the encapsulated peroxide from oxidizing Ph3P or diphenyl carbazide present in solution. The normal chemical reactivity of the peroxide is restored by release from the capsule by DMF, a solvent that competes for the hydrogen bonds that hold the capsule together. The protection and release of encapsulated species augurs well for the application of capsules in catalysis and delivery.

Bloodstream infections in children with cancer: a multicentre surveillance study of the Italian Association of Paediatric Haematology and Oncology. Supportive Therapy Group-Infectious Diseases Section.

A one-year prospective, multicentre surveillance study on aetiology, main clinical features and outcome of bloodstream infections in children with cancer was conducted in 18 paediatric haematology centres belonging to the Italian Association for Paediatric Haematology and Oncology. A total of 191 bloodstream infections were reported during the study period. Of them, 123 (64%) occurred in neutropenic and 68 (36%) in non-neutropenic patients. Gram-positive cocci caused 45% (85/191) of the episodes, gram-negative rods 41% (78/191), and fungi 9% (18/191). The remaining 5% (10/191) of the episodes were poly-microbial infections. A total of 204 pathogens were isolated (46% gram-positive cocci; 44% gram-negative rods; and 10% fungi). The aetiologic distribution was similar among neutropenic and non-neutropenic patients. A correlation between the infection and the presence of an indwelling central venous catheter was found in 20% (23/114) of the episodes among neutropenic patients and in 55% (23/62) among non-neutropenic patients. Gram-negative micro-organisms were isolated in an unusually high proportion of catheter-related infections (48%). The overall mortality rate from any cause within 30 days from the first positive blood culture was 11%, and was higher among patients who were neutropenic at the onset of the infection than among those who were not neutropenic (15 versus 4%, P = 0.03). In addition, the mortality was significantly higher in recipients of bone marrow transplantation than in patients with acute leukaemia or solid tumour (21, 11 and 6%, respectively) and was also higher in fungaemias and poly-microbial infections (22 and 30%) than in single gram-positive and gram-negative bacteraemias (11 and 6%).