Early hydrocephalus in Listeria meningitis: Case report and review of the literature.

Listeria monocytogenes is a gram-positive bacterium with a predilection to infect the central nervous system, often affecting immunocompromised or elderly patients. The most common manifestations are meningitis and rhomboencephalitis. We report two cases of Listeria meningitis complicated by acute hydrocephalus several days after presentation and we further review the literature of similar cases. We conclude that acute hydrocephalus is a significant, not often recognized, complication of Listeria meningitis, usually occurring several days from onset when coverage did not include anti-Listeria antimicrobials. In high risk patients, meningitis combined with acute hydrocephalus is suggestive of LM infection.

International Myeloma Working Group recommendations for global myeloma care.

Recent developments have led to remarkable improvements in the assessment and treatment of patients with multiple myeloma (MM). New technologies have become available to precisely evaluate the biology and extent of the disease, including information about cytogenetics and genetic abnormalities, extramedullary manifestations and minimal residual disease. New, more effective drugs have been introduced into clinical practice, which enable clinicians to significantly improve the outcome of patients but also pose new challenges for the prevention and management of their specific side effects. Given these various new options and challenges, it is important to identify the minimal requirements for diagnosis and treatment of patients, as access to the most sophisticated advances may vary depending on local circumstances. Here, we propose the minimal requirements and possible options for diagnosis, monitoring and treatment of patients with multiple myeloma.

Differential regulation of the apoptotic machinery during megakaryocyte differentiation and platelet production by inhibitor of apoptosis protein Livin.

Livin is a member of the inhibitor of apoptosis proteins (IAP) family of intracellular antiapoptotic proteins that act by binding and inhibiting caspases. Upon strong apoptotic stimuli, it is then specifically cleaved by caspases to produce a truncated protein (tLivin) with a paradoxical proapoptotic activity. Intriguingly, we have detected robust protein levels of Livin in normal mature bone marrow megakaryocyte (MK) and platelets. To evaluate the potential role of Livin in thrombopoiesis, we used the human BCR-ABL+ cell line, LAMA-84, and cord blood CD34+ cells to induce differentiation toward MKs. Upon differentiation, induced by phorbol myristate acetate and concurrent with increase in Livin protein expression, LAMA-84 cells formed functional platelet-like particles. Livin overexpression in CD34+ progenitor cells induced higher endoreplication in the MKs generated. Furthermore, overexpression of Livin increased the ability of both primary MKs and differentiated LAMA-84 cells to produce functional platelets. In the differentiated LAMA-84 cells, we observed accumulation of proapoptotic tLivin concomitant with increased caspase-3 activity. Downregulation of Livin with small interfering RNA in both leukemic and primary MK cells decreased their ability to produce functional platelets. We suggest that Livin has a role in thrombopoiesis by regulating the apoptotic and antiapoptotic balance in MK endoreplication and platelet production.

Stem cell mobilization in patients with newly diagnosed multiple myeloma after lenalidomide induction therapy.

Lenalidomide has raised concerns regarding its potential impact on the ability to collect stem cells for autologous stem cell transplantation, especially after prolonged exposure. The use of cyclophosphamide plus granulocyte colony-stimulating factor (G-CSF) to mobilize peripheral blood stem cells may overcome this concern. In newly diagnosed multiple myeloma (MM) patients, we investigated the influence of lenalidomide on stem cell collection. In a prospective study, 346 patients received four cycles of lenalidomide-dexamethasone (Rd). Stem cells were mobilized with cyclophosphamide and G-CSF. Patients failing to collect a minimum of 4 × 10(6) CD34(+)/kg cells received a second mobilization course. After mobilization, a median yield of 8.7 × 10(6) CD34(+)/kg was obtained from patients receiving Rd induction. After first mobilization, inadequate yield was observed in 21% of patients, whereas only 9% of patients failed to collect the target yield after the second mobilization attempt. In conclusion, we confirm that a short induction with lenalidomide allowed sufficient stem cells collection to perform autologous transplantation in 91% of newly diagnosed patients.

Promoter hypermethylation of mismatch repair genes, hMLH1 and hMSH2 in oral squamous cell carcinoma.

OBJECTIVES: Major risk factors of oral squamous cell carcinoma (OSCC) are environmental and can lead to DNA mutagenesis. Mismatch repair (MMR) system functions to repair small DNA lesions, which can be targeted for promoter hypermethylation. We therefore wanted to test whether hypermethylation of MMR genes (hMLH1, hMSH2) could contribute to oral carcinogenesis by correlating the information to patient clinical data. METHODS: Genomic DNA was extracted from 28 OSCC and six normal oral epithelium samples. The methylation status of the two MMR genes was assessed using Methylation Specific PCR after DNA modification with sodium bisulfite. Serial sections of the same tissues were immunostained with antibodies against hMLH1 and hMSH2 protein. RESULTS: Promoter hypermethylation was observed in 14/28 OSCC cases. Remarkably, 100% of patients with multiple oral malignancies showed hypermethylation in hMLH1 or hMSH2 compared with 31.5% of single tumor patients. In 10 cancer cases, expression of the hMLH1 and hMSH2 genes by immunostaining showed reduced or absence of expression of one of the genes, although some did not reflect the methylation status. CONCLUSIONS: Hypermethylation of hMLH1 and hMSH2 might play a role in oral carcinogenesis and may be correlated with a tendency to develop multiple oral malignancies.

Efficacy and safety of bortezomib in patients with renal impairment: results from the APEX phase 3 study.

Renal impairment is associated with poor prognosis in multiple myeloma (MM). This subgroup analysis of the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study of bortezomib vs high-dose dexamethasone assessed efficacy and safety in patients with relapsed MM with varying degrees of renal impairment (creatinine clearance (CrCl) <30, 30-50, 51-80 and >80 ml min(-1)). Time to progression (TTP), overall survival (OS) and safety were compared between subgroups with CrCl < or =50 ml min(-1) (severe-to-moderate) and >50 ml min(-1) (no/mild impairment). Response rates with bortezomib were similar (36-47%) and time to response rapid (0.7-1.6 months) across subgroups. Although the trend was toward shorter TTP/OS in bortezomib patients with severe-to-moderate vs no/mild impairment, differences were not significant. OS was significantly shorter in dexamethasone patients with CrCl < or =50 vs >50 ml min(-1) (P=0.003), indicating that bortezomib is more effective than dexamethasone in overcoming the detrimental effect of renal impairment. Safety profile of bortezomib was comparable between subgroups. With dexamethasone, grade 3/4 adverse events (AEs), serious AEs and discontinuations for AEs were significantly elevated in patients with CrCl < or =50 vs >50 ml min(-1). These results indicate that bortezomib is active and well tolerated in patients with relapsed MM with varying degrees of renal insufficiency. Efficacy/safety were not substantially affected by severe-to-moderate vs no/mild impairment.

Therapy-related leukemia: clinical characteristics and analysis of new molecular risk factors in 96 adult patients.

Therapy-related leukemia or myelodysplasia (t-leuk/MDS) is a serious problem that is increasing in frequency. We studied the clinical characteristics of 96 patients (pts) with a mean age of 48 years, and analyzed the molecular parameters that could predispose to t-leuk/MDS. Hematological malignancies were the most common primary (53%), followed by breast and ovarian cancer (30% combined). The mean latency until the development of t-AML was 45.5 months. Median survival was 10 months. Cytogenetics was abnormal in 89% of pts. FLT3 internal tandem duplications were found in six of 41 (14.6%) pts, of whom four had an abnormal karyotype. Analysis of drug metabolism and disposition genes showed a protective effect of the CYP3A4 1*B genotype against the development of t-leuk/MDS, whereas the CC genotype of MDR1 C3435T and the NAD(P)H:quinone oxidoreductase1 codon 187 polymorphism were both noncontributory. Microsatellite instability (MSI) analysis using fluoresceinated PCR with ABI sequence analyzer demonstrated that 41% of pts had high levels of MSI in four or more of 10 microsatellite loci. Immunohistochemistry demonstrated reduced expression of MSH2 and MLH1 in 6/10 pts with MSI as compared to 0/5 of pts without MSI. In conclusion, genetic predisposition as well as epigenetic events contribute to the etiology of t-AML/MDS.

CT-guided biopsy with cutting-edge needle for the diagnosis of malignant lymphoma: experience of 267 biopsies.

AIM: We performed a retrospective study of 267 core needle aspiration biopsies in order to estimate the accuracy of CT-guided aspiration core needle biopsies for the diagnosis and subsequent treatment of malignant lymphoma. MATERIALS AND METHODS: Between 1989 and 1999, 267 CT-guided core needle biopsies were performed in 241 patients with either primary or recurrent malignant lymphoma. Patients age ranged from 4--88 years. One hundred and sixty-six (62.2%) nodal and 101 (37.8%) extranodal aspiration biopsies were performed using either 18G or 20G Turner needles. Statistical method used was Chi-square analysis. RESULTS: An accurate histological diagnosis was made in 199 (82.5%) patients, the remaining 42 (17.4%) patients had non-diagnostic CT biopsies. Thirty-seven of them were diagnosed by a surgical biopsy, four by bone marrow biopsy and in one patient by paracentesis. One hundred and seventy-nine patients had non-Hodgkin's lymphoma (NHL) and 62 had Hodgkin's disease (HD); 23 (9.54%) patients underwent repeated CT biopsy which was diagnostic in 17 (73.9%) and non-diagnostic in six (26%). CONCLUSION: CT-guided aspiration core biopsies were sufficient to establish a diagnosis in lymphoproliferative disorders in 82.5% of cases. In the light of this experience we suggest that imaging-guided core needle biopsy be used as the first step in the work up of many patients with lymphoma.

Is chest CT sufficient for follow-up of primary mediastinal B-cell lymphoma in remission?

OBJECTIVE: We aimed to evaluate whether chest CT alone is sufficient for follow-up assessment of patients with primary mediastinal B-cell lymphoma that is in remission. MATERIALS AND METHODS: A retrospective review of medical records and CT examinations of patients who received a diagnosis of primary mediastinal B-cell lymphoma between January 1989 and January 2000 was performed. The first-year follow-up comprised examinations at 3-month intervals of the neck, chest, abdomen, and pelvis, with the examination modality alternating between CT and gallium scintigraphy. Patients who achieved complete remission underwent the same CT protocol twice the following year and then once a year during sequential follow-up. RESULTS: Fifty-three patients with primary mediastinal B-cell lymphoma at presentation--31 females and 22 males, ranging in age from 17 to 61 years (average age at diagnosis, 34 years)--were studied. The follow-up time ranged from 6 to 143 months (average follow-up time, 42.4 months). Although 11 of the patients had only a partial remission, 42 patients (79%) achieved complete remission, with one patient lost to follow-up and thus excluded from study. Recurrence was diagnosed in six of these 42 patients. All six had mediastinal recurrence with additional involvement of the lungs, chest wall, pericardium, and pleura. One patient also had bone marrow involvement at recurrence. CONCLUSION: Recurrence of primary mediastinal B-cell lymphoma in patients who achieve complete remission appears to be confined to the chest. Consequently, chest CT alone is sufficient for routine follow-up of these patients.

Kidney involvement and renal manifestations in non-Hodgkin's lymphoma and lymphocytic leukemia: a retrospective study in 700 patients.

Renal involvement as part of systemic lymphoma (LY) is quite frequent, however, primary extranodal renal non-Hodgkin's lymphoma (NHL) is extremely rare, and only about 65 cases have been reported in the world literature. In a retrospective study of renal manifestations in 700 patients with documented LY and chronic lymphocytic leukemia (CLL) seen at our hospital during 1986-95, 83 patients had signs of acute renal failure. Only five of these had proven renal infiltration, but none of them satisfied the criteria for primary renal LY. Glomerulonephritis (GN) has also rarely been reported in association with LY and CLL, and only 37 glomerular lesions in NHL and 42 in CLL have been documented, respectively. GN may precede, coexist, or follow the diagnosis of LY by several years. Of the 42 cases of CLL reported worldwide, 36 had nephrotic syndrome. Renal failure was seen in about one third. The most common glomerular lesion reported is membranoproliferative GN, followed by membranous GN. In our study, we found only five biopsy-proven cases with GN amongst the 700 patients seen. In this report we also briefly describe some rare interesting associated renal syndromes in CLL and NHL.

Molecular evolution of chronic myeloid leukaemia.

Chronic myeloid leukaemia (CML) is a clonal disorder of the pluripotent haematopoietic stem cell. The typical triphasic course of CML starts with the premalignant chronic phase initiated by BCR-ABL hybrid oncogene formation. Secondary genetic and epigenetic aberrations accompany the progression to the accelerated phase and fatal blastic crisis. Properly timed bone marrow transplantation in eligible patients can result in durable remissions or cure. Both of these states are often accompanied by a long-term persistence of quiescent leukaemic cells. Accordingly, a "functional cure" (i.e. tumour dormancy induction), rather than complete eradication of the malignant cells, is an adequate therapeutical goal. The level of the residual BCR-ABL-positive clones should be monitored and salvage treatment initiated whenever these quiescent leukaemic cells exit their dormant state.

Expression of EBV encoded nuclear small non-polyadenylated RNA (EBER) molecules in 32 cases of childhood Burkitt's lymphoma from Israel.

We have analyzed paraffin sections from 32 children with histologically confirmed Burkitt's Lymphoma (BL) for the presence of EBV using in situ hybridization to detect expression of the EBV-encoded early RNAs (EBERs). EBV was present in the tumors of 11 patients (34%). Sixty nine percent of the children presented with abdominal disease, 19% had bone marrow infiltration and only one child had jaw involvement. There was no statistically significant difference between EBV positive and EBV negative children with regard to age, gender, origin, primary site at presentation, or clinical stage of disease. However, there was a trend for younger age in the children with EBV positive BL with a median age of 4, compared to 7 years in children with EBV negative BL. None of the 7 children of Ashkenazi Jewish origin had EBER positive disease. There was no difference in the treatment outcome between the EBV positive patients (estimated survival at 24 months of 82%) and EBV negative children (estimated survival rate of 71% (p=0.58)). In conclusion, although this is only a small series it seems that childhood BL in Israel has the clinical characteristics of sporadic, non-African type with 34% EBV association and a low incidence of jaw tumors. Our data suggest that Ashkenazi Jewish children with BL are less likely to have EBV positive tumors than other ethnic groups. However, more patients will need to be studied in order to assess the validity of this observation.

ABL1 methylation in Ph-positive ALL is exclusively associated with the P210 form of BCR-ABL.

In human Ph-positive leukemia there is a clear association of different forms of the BCR-ABL oncogene with distinct types of leukemia. The P190 form of BCR-ABL is rarely observed in chronic myeloid leukemia (CML) but is present in 50% of Ph-positive acute lymphoblastic leukemia (ALL). In contrast, the P210 form is observed both in CML and 50% of Ph-positive ALL. Methylation of the proximal promoter of the ABL1 gene has been shown to be a nearly universal event associated with clinical progression of CML. This raises the question of whether methylation of the ABL1 promoter is an epigenetic modification also associated with Ph-positive ALL. To study this issue, we used methylation-specific PCR and bisulfite sequencing to determine the methylation status of the ABL1 promoter in 18 Ph-positive ALL samples. We report here that gene-specific ABL1 promoter methylation is associated mainly with the P210 form of BCR-ABL and not the P190 form. While six out of the seven P210-positive ALL samples had ABL1 promoter methylation, none of the 11 P190-positive ALL samples demonstrated ABL1 promoter methylation. In addition, we estimated the extent and relative abundance of ABL1 promoter methylation in several Ph-positive ALL samples and compared it to the methylation pattern in chronic, accelerated and blastic crisis phases of CML. We put forth a model that correlates the different types of leukemias with the different levels of ABL1 promoter methylation.

Two splicing variants of a new inhibitor of apoptosis gene with different biological properties and tissue distribution pattern.

Using homology searches, we identified a novel human inhibitor of apoptosis (IAP) gene. This gene has two splicing variants that contain open reading frames of 298 and 280 amino acids and both contained a single copy of baculovirus IAP repeat (BIR) and RING domain. We refer here to the longer and shorter variants as Livin alpha and beta, respectively. Semiquantitative reverse transcriptase-polymerase chain reaction demonstrated a tissue-specific and non-correlated expression pattern in both adult and fetal tissues. Both mRNA variants were detected in various transformed cell lines. Despite their very close similarity, the two isoforms have different antiapoptotic properties. Both isoforms have a significant antiapoptotic activity in the Jurkat T cell line after triggering apoptosis via tumor necrosis factor and CD95 receptors. The Livin alpha but not beta protects cells from apoptosis induced by staurosporine, but in contrast, apoptosis initiated by etoposide was blocked only by the beta isoform. This difference in biological activities may indicate the presence of critical amino acids outside the BIR and RING domains. These functional and tissue distribution differences of Livin alpha and beta suggest that Livin may play a complex role in the regulation of apoptosis.

The incidence of lymphoma in first-degree relatives of patients with Hodgkin disease and non-Hodgkin lymphoma: results and limitations of a registry-linked study.

BACKGROUND: The precise incidence of familial Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL) in first-degree relatives is unknown. Through record linkage using two population-based sources, the authors estimated the risk of HD and NHL in family members of lymphoma probands. METHODS: The authors identified 8,037 first-degree relatives of 2,606 lymphoma cases (28.5% HD, 71.5% NHL) treated between 1970 and 1993 in 3 hospitals in Israel via the family file of the Population Registry. The authors linked this file with the Israel Cancer Registry, then calculated the standardized incidence ratio (SIR) by dividing the observed number of cases with the expected, adjusting for age, gender, calendar year, and continent of origin. RESULTS: The family file yielded incomplete ascertainment of relatives (for 771 probands, no relatives were identified). Twenty cases of lymphoma--6 HD and 14 NHL--were identified among relatives of lymphoma patients. The SIR for HD was 1.15 (95% confidence interval [CI]: 0.42-2.51) and for NHL 1.71 (95% CI: 0.93-2.87), considering the entire population of first-degree relatives. SIRs among siblings of lymphoma probands were 3.12 (95% CI: 1.01-7.29) for HD, 2.16 (95% CI: 0.45-6.31) for NHL, and 2.68 (95% CI: 1.15-5.27) for all lymphomas. There were 4 HD/HD, 1 NHL/NHL, and 3 NHL/HD sibling pairs. For HD/HD and NHL/NHL sibling pairs, the interval between lymphoma occurrence in proband and sibling was 1-4 years, whereas for HD/NHL pairs this ranged from 16 to 21 years. CONCLUSIONS: The risk of lymphoma among siblings of lymphoma probands was over 2.5-fold that of the general population and lower among other family members. The temporal proximity of HD/HD and NHL/NHL sibling pairs argues for environmental as well as genetic etiology. This method was hampered by incomplete data.

CT-guided core-needle biopsy in the diagnosis of mediastinal lymphoma.

The advent of radiologic guidance techniques for percutaneous biopsy has changed the approach to the routine diagnosis of mediastinal lymphoma. The aim of the present study was to evaluate the diagnostic accuracy of CT-guided percutaneous core-needle biopsy (PCNB) in the clinical management of patients with mediastinal lymphoma. The results of 49 CT-guided PCNB of mediastinal lymphoma performed under local anesthesia in 42 ambulatory patients were analyzed. A positive diagnosis of lymphoma was obtained in 30 of 42 patients, with an overall success rate of 71.5%. The technique was equally successful in the diagnosis of Hodgkin's and non-Hodgkin's lymphoma. There were no major complications. Percutaneous CT-guided CNB of mediastinal lymphoma is a quick, safe, accurate, and efficient alternative to open biopsy in the evaluation of mediastinal lymphoma, mainly at presentation. It should become the preferred initial diagnostic procedure for obtaining histologic samples in patients with suspected mediastinal lymphoma.

Flow cytometric analysis of autonomous growth of erythroid precursors in liquid culture detects occult polycythemia vera in the Budd-Chiari syndrome.

BACKGROUND/AIMS: Hepatic vein thrombosis (Budd-Chiari syndrome) is associated with various hypercoagulable states, such as polycythemia vera (PV), presence of the lupus anticoagulant, paroxysmal nocturnal hemoglobinuria (PNH) and deficiencies of antithrombin III, protein C and protein S. In recent years, it has become evident that patients with the Budd-Chiari syndrome may have more than one risk factor that may cause a state of hypercoagulability. The aim of the current study was to assess the prevalence of occult PV in patients with Budd-Chiari syndrome using a novel method for the detection of spontaneous erythroid growth. METHODS: Twenty-two patients with Budd-Chiari syndrome were evaluated. As controls, we studied normal donors and four patients with liver cirrhosis and five patients with right-side heart failure, two conditions that in part mimic Budd-Chiari syndrome. The presence of PV was determined by flow cytometric analysis of autonomous growth of erythroid precursors. Patients were considered as having occult PV if they had spontaneous erythroid cell growth in the absence of erythropoietin and with no features of overt PV. RESULTS: Cells from ten patients with Budd-Chiari syndrome demonstrated spontaneous erythroid cell growth; eight patients (32%) were found to have occult PV and two patients had overt PV. None of the controls had spontaneous erythroid growth. Of the eight Budd-Chiari patients with occult PV, six had one or more additional recognized hypercoagulable states. Seven patients (32%) had protein C deficiency, six patients (27%) had activated protein C resistance, five (23%) had anti-cardiolipin antibodies, five (23%) had antithrombin III deficiency, and four patients (18%) had protein S deficiency. Three patients (14%) were homozygous to methyltetra hydrofolate reductase and ten (45.5%) were heterozygous. One patient had PNH. Overall, in 12 patients there were two or more combined risk factors. CONCLUSIONS: Using a flow cytometric analysis of autonomous growth of erythroid precursors we found a clear correlation between Budd-Chiari syndrome and occult PV.

Translocation t(14;18) in healthy individuals: preliminary study of its association with family history and agricultural exposure.

BACKGROUND: The t(14;18) translocation, present in 90% of follicular non-Hodgkin's lymphomas (NHL), has been found to exist in low levels in healthy persons. Its clinical/prognostic significance in healthy populations is unknown, and risk factors for its development have not been determined. Our objectives were to assess the prevalence of t(14;18) in individuals without NHL, comparing residents of agricultural settlements (kibbutzim) with city dwellers, as well as first degree relatives of NHL cases. PATIENTS AND METHODS: Residents of kibbutzim and members of two control groups: 1) Jerusalem residents--randomly selected hospital administrative workers and 2) first degree family members of lymphoma patients were interviewed extensively regarding exposures and had blood drawn for t(14;18) determination. The translocation was detected after B-cell purification of blood samples with CD-19 microbeads (Mini-Macs) using nested PCR. The method detects the translocation in a BCL2 positive cell line after dilutions of up to 1:10(5) with normal peripheral blood lymphocytes. RESULTS: Nineteen of two hundred thirty healthy individuals (8.3%) tested were found to be positive for t(14;18). No statistically significant differences in the prevalence of t(14;18) were detected among the rural and urban populations. Five of thirty-four (11.9%) family members tested positive for t(14;18). No age or sex differences between t(14;18) positive and negative individuals were found. No significant association with exposure to specific agricultural or other chemicals was found. CONCLUSIONS: The presence of the t(14;18) translocation in healthy individuals was not associated with agricultural residence in this preliminary study. Whether relatives of patients with NHL are at increased risk will require further study in larger populations. Specific exposures affecting the onset of this translocation have not been ruled out. The significance of this translocation in healthy individuals remains unknown.

Ageing and the mismatch repair system.

Age-related accumulation of mutations has been extensively documented, and it has been proposed as one of the prominent causes of malignancies in old age. The present review is focused on the particular case of DNA mismatch repair system (MMR), that has drawn increased attention for its possible relevance to malignancy. We also report on our own observations on an age-associated genomic instability that develops with age in the MMR system. Our study was performed on DNA samples that were prepared from peripheral blood cells, obtained at a 10-year interval from young and old human subjects. The two DNA samples from each individual were examined comparatively. The older individuals showed a significantly higher rate of microsatellite instability (MSI) in several loci examined, whereas no difference was found between the paired samples of any of the young subjects. We suggest that this increase in MSI with age may indicate an overall genomic instability in the elderly.