Correction to: Occult HBV infection in the oncohematological setting.

The original version of this article unfortunately contained a mistake.

Eighteen-month lamivudine prophylaxis on preventing occult hepatitis B virus infection reactivation in patients with haematological malignancies receiving immunosuppression therapy.

This study evaluated the long-term efficacy and safety of an 18-month lamivudine prophylaxis in 68 HBsAg-negative/anti-HBc-positive patients with oncohaematological disease. All 68 consecutive HBsAg-negative/anti-HBc-positive patients with an oncohaematological disease and naïve for chemotherapy observed from April 2008 to December 2012 at 2 Hematology Units in Naples were treated with lamivudine for 18 months after stopping chemotherapy and monitored for HBsAg at months 1 and 3 during chemotherapy and then every 3 months after its discontinuation. During follow-up, 13 (19.1%) of the 68 patients died of complications related to their oncohaematological disease, and 3 (4%) showed a virological HBV reactivation (retroconversion to HBsAg positivity) 1-7 months after the discontinuation of lamivudine prophylaxis (2 treated for chronic lymphocytic leukaemia and one for Waldenstrom's disease); of these, 2 showed a biochemical reactivation. Comparing the demographic and clinical characteristics of the 3 patients with a virological HBV reactivation to the 65 without, the former were older (median age and range: 67 years [75-78] vs. 61 [24-88]; P = .05) and were less frequently treated for B-cell non-Hodgkin lymphoma (B-NHL) (0 vs. 70.7%, P = .03). In conclusion, a 18 months of lamivudine prophylaxis was effective in preventing HBV reactivation in HBsAg-negative/anti-HBc-positive patients treated for B-NHL. However, in patients with chronic and severe immunodepression, such as those with chronic lymphocytic leukaemia and Waldenstrom's disease, prophylaxis should be continued for an indefinite period.

Occult HBV infection in the oncohematological setting.

INTRODUCTION: Occult hepatitis B infection (OBI), a virological condition characterized by a low release of Hepatitis B Virus (HBV) from liver cells and low HBV-DNA levels in serum and/or liver tissue of HBsAg-negative subjects, may reactivate in oncohematological patients undergoing immunosuppression by aggressive chemotherapy or hematopoietic stem cell transplantation. The entity of OBI reactivation varies from an increase in HBV replication without liver damage to an active HBV replication followed by liver cell necrosis, frequently severe and in some cases life threatening. Because of a possible severe outcome associated with OBI reactivation (hepatic failure or death due to the discontinuation of chemotherapy), prophylaxis with anti-HBV nucleot(s)ide analogues is recommended in relation to the foreseeable degree of immunosuppression. MATERIALS AND METHODS: This review article focuses on the clinical impact of OBI in the oncohematological setting and is addressed to all health care workers having in care oncohematological patients or involved in the treatment of HBV infection and OBI prophylaxis. CONCLUSION: International guidelines have indicated lamivudine prophylaxis in hematopoietic stem cell transplantation and when high-dose corticosteroids or anti-CD20 or anti-CD52 monoclonal antibodies are used. Entecavir or tenofovir should replace lamivudine for patients with advanced liver diseases for whom reactivation of OBI may be life threatening. When anti-CD20 or anti-CD52 sparing schedules or other non-aggressive chemotherapies are used, monitoring may be indicated, but very early treatment with highly effective antiviral drugs (entecavir or tenofovir) should be administered once a reactivation of OBI has occurred.

Effects of lenvatinib on glucose, cholesterol, triglycerides and estimated cardiovascular risk in patients with advanced thyroid cancer.

PURPOSE: Multitarget kinase inhibitors (MKIs) are effective options in the treatment of cancer, significantly increasing the progression-free survival (PFS) of many tumors. Data about severity and prevalence of metabolic adverse events is scarce and may be significant in patients with a better survival. The aim of this study was to investigate glucose and lipids values of patients treated with lenvatinib. Secondary aims included evaluating changes in the estimated risk of cardiovascular disease and the relationship between metabolic alterations and tumor response to therapy. METHODS: A retrospective pilot study on 29 patients with advanced differentiated thyroid cancer was conducted. Clinical and biochemical characteristics were collected at the day of therapy initiation and follow up. The 10-year risk of cardiovascular disease was estimated with the SCORE2 and SCORE2-OP algorithms. Tumor burden change was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: No differences in glucose values were observed. A significant increase in total cholesterol (208 ± 41 versus 245 ± 67 mg/dl), triglycerides (112 [interquartile range, 58-326] versus 157 [78-296] mg/dl), calculated LDL cholesterol (128 [66-204] versus 140 [81-308] mg/dl) and cardiovascular risk was observed from baseline to follow up. Furthermore, these parameters increase progressively with increasing tumor response to therapy. CONCLUSIONS: Despite limitations, this study shows an association between the use of lenvatinib and the development of lipid alterations in patients with advanced thyroid cancer. However, further investigation is necessary for a more comprehensive understanding of the adverse metabolic profile of MKIs.

Abdominal fat interacts with PNPLA3 I148M, but not with the APOC3 variant in the pathogenesis of liver steatosis in chronic hepatitis C.

The patatin-like phospholipase domain-containing 3 gene (PNPLA3) and the apolipoprotein C3 gene (APOC3) have been studied in relation to liver steatosis and liver disease outcome. The aim of this study was to evaluate the influence of PNPLA3 p.I148M and APOC3 rs2854116 and rs2854117 polymorphisms on the clinical and histological presentation of chronic hepatitis C in an Italian population and their relationship with viral and anthropometric parameters. Patients with hepatitis C (n = 166) entered the study receiving a clinical, histological, virological and biochemical evaluation. APOC3 (rs2854116 and rs2854117) and PNPLA3 (p.I148M) variants were genotyped. PNPLA3 polymorphisms were associated with liver steatosis, which was significantly higher in patients with p.148I/M (P = 0.034) and p.148M/M (P = 0.004) variants than those homozygous for the PNPLA3 wild type. Excluding patients with HCV genotype 3, the association with liver steatosis and PNPLA3 variants was more marked (p.148I/I genotype vs p.148I/M, P = 0.02, and vs p.148M/M, P = 0.005). The APOC3 polymorphism was not associated with any of the evaluated parameters. Among the interacting factors, BMI and waist circumference correlated with liver steatosis (P = 0.008 and 0.004, respectively). Relationship between waist circumference and liver steatosis was analysed for the different PNPLA3 genotypes. Homozygous 148M patients showed a stronger correlation between waist circumference and steatosis than those carrying the other genotypes (P = 0.0047). In our hepatitis C-infected population, the PNPLA3 polymorphism influenced the development of liver steatosis, but not fibrosis progression. APOC3 polymorphisms had no effect on the development of steatosis and no influence on the PNPLA3 polymorphism. The amount of abdominal fat can increase the association of PNPLA3 p.I148M with liver steatosis.

Tolerability and efficacy of anti-HBV nucleos(t)ide analogues in HBV-DNA-positive cirrhotic patients with HBV/HCV dual infection.

We evaluated tolerability and virological and clinical impact of anti-Hepatitis B Virus (HBV) nucleos(t)ide analogues in cirrhotic patients with HBV/Hepatitis C Virus (HCV) coinfection. The virological and clinical course of 24 consecutive HBsAg/HBV-DNA/anti-HCV-positive patients with cirrhosis was compared with that of 24 HBsAg/HBV-DNA-positive, anti-HCV-negative cirrhotic patients, pair-matched for age (±5 years), sex, HBeAg/anti-HBe status and Child-Pugh class. Patients in both groups were previously untreated with oral antiviral agents at enrollment and were treated for at least 24 months (range 24-54). At the 12th and 18th month of treatment, HBV-DNA was negative in 21 (87.5%) and 23 (95.8%) patients with hepatitis B and C and in 20 (83.3%) and 22 (91.6%) in patients with isolated HBV; all patients in both groups were HBV-DNA-negative at month 24 and at subsequent observations. Treatment was well tolerated by all patients in both groups. At the last observation (for co-infected patients, median 44 months and range 24-54; for mono-infected patients, median 40 months and range 24-54), a deterioration in Child class was observed in eight (47%) of 17 patients in patients with both HBV and HCV who were HCV-RNA-positive at baseline, but in none of seven HCV-RNA-negative patients in the same group, and in one patient (4.2%) in the mono-infected patients. Reactivation of HCV infection was relatively infrequent (12.5% of cases) and never associated with a clinical deterioration. Treatment with nucleotides in HBsAg/HBV-DNA/anti-HCV-positive patients with cirrhosis showed a favourable virological effect in all cases, but a favourable clinical result only in the HCV-RNA-negative at baseline.

The role of ejaculatory dysfunction on male infertility.

BACKGROUND: The aim of this study was to evaluate: 1) the prevalence of male infertility due to ejaculatory dysfunction (premature ejaculation-PE, intravaginal ejaculatory dysfunction-IVEjD, anejaculation-AE, and retrograde ejaculation-RE); and 2) the hormonal profile and semen characteristics of such subjects. METHODS: N.3280 subjects who were referred to our andrology unit for infertility were studied. Exclusion criteria: the presence of known causes of male infertility and erectile dysfunction. In all subjects were performed: medical history and andrological physical examination; hormonal profile; semen analysis or centrifugation/resuspension of post-orgasmic urine; IIEF-5 questionnaire for the diagnosis of ED; PEDT questionnaire for the diagnosis of EP. RESULTS: the prevalence of ejaculatory dysfunctions in infertile males was 1.8% (59/3280). The causes were: a) absence of ejaculation in 37/3280 subjects (1.1%); among them, 23/3280 (0.7%) subjects showed a condition of RE and 14/3280 (0.4%) of AE; b) PE in 16/3280 subjects (0.5%); and c) IVEjD in 6/3280 subjects (0.2%). Hormonal values and seminal parameters (when semen analysis was possible) were within the normal ranges in all the cases. In subjects with RE, sperm recovery was possible in 69.9% (16/23) subjects after centrifugation and resuspension of post-orgasmic urine. CONCLUSIONS: The prevalence of male infertility due to ejaculatory dysfunctions is overall just under 2%. The main cause is retrograde ejaculation; psychogenic origins could also have an important role. It is important to identify the cause of ejaculatory dysfunction in order to decide upon correct management (PE treatment, centrifugation and resuspension of post-orgasmic urine, penile vibratory stimulation, and psychological counselling).

The effect of an antimicrobial stewardship programme in two intensive care units of a teaching hospital: an interrupted time series analysis.

OBJECTIVES: To evaluate the effect of an antimicrobial stewardship programme in two intensive care units (ICUs) of a teaching hospital. METHODS: Between January 2017 and June 2018 we conducted a prospective, interventional, interrupted time-series study, based on Prospective Audit and Feedback in two ICUs of an acute-care teaching hospital. The primary outcomes were the difference in the antibiotic consumption, and the incidence of bloodstream infections (BSI) caused by multidrug-resistant (MDR) organisms. The secondary outcomes included the hospital mortality rate, the mean length of stay and the antibiotic expense. RESULTS: During the study, 231 audits were performed, evaluating 693 antibiotic prescriptions. The programme led to a global reduction in antibiotic consumption, with a change in level (CL) of -324.8 defined daily doses (DDD)/100 patient-days (PD), p 0.04, and particularly in the use of fluoroquinolone: (CL: -63.48 DDD/100 PD, p < 0.001). A non-significant reduction was obtained for the consumption of carbapenems (CL: -34.7 DDD/100 PD, p 0.25) and third- and fourth-generation cephalosporins (CL: -27.3 DDD/100 PD, p 0.102). Furthermore, we registered a significant decrease in all BSI (CL: -5.8 events/100 PD, p 0.026) and in BSI due to MDR Gram-negative organisms (CL: -2.96 events/100 PD, p 0.043). No difference was observed in the hospital mortality and length of stay. CONCLUSIONS: Our study demonstrated that implementation of an antimicrobial stewardship programme in two ICUs of a teaching hospital induced a significant reduction in antibiotic consumption and in the incidence of BSI due to MDR Gram-negative organisms, without any impact on the mortality rate.

Polyclonal lymphocytosis of T-cells associated with human T-cell leukemia virus I.

A patient with antibodies to human T-cell leukemia virus type I and the presence of integrated sequences of this virus in T-lymphocytes was investigated. In contrast to previous reports, the T-cell lymphocytosis was found to be polyclonal by analysis of human T-cell leukemia virus type I integration sites and T-cell antigen receptor rearrangements. Polyclonal T-cell infection by human T-cell leukemia virus type I may represent an infrequently observed stage of leukemogenesis.

Molecular characterization of variant translocations in chronic myelogenous leukemia.

Five to ten percent of the Ph-positive cases of chronic myelogenous leukemia (CML), termed variant translocations, involve at least one chromosome in addition to 9 and 22 in the abnormality. The involvement of chromosome 9 band q34, where the c-abl oncogene has been localized, is not always cytogenetically detectable in so called variant translocations due to complex rearrangements. We present two cases having the most frequently involved chromosomes (#3 and #17) in such translocations. In one case, both chromosome 9's were cytogenetically normal while in the other, band 9q34 was so called 'masked' or 'hidden'. After molecular evaluation using in situ hybridization and Southern blotting techniques, the involvement of the altered bcr/abl gene was demonstrated and the cytogenetic analysis was revised. Utilization of molecular probes in the evaluation of such cases should become a routine diagnostic procedure in detecting the exchange of bcr and c-abl sequences.

Polycystic kidneys and del (4)(q21.1q21.3): further delineation of a distinct phenotype.

A three year-old boy was evaluated because of growth and developmental delay, hypotonia and dysmorphic features. G-banding analysis revealed a small interstitial deletion of the long arm of chromosome four described as 46,XY,del (4)(q21.1q21.3). This patient's findings on physical exam included relative macrocephaly, frontal bossing, short fingers with clinodactyly and were consistent with the phenotypes of previously reported deletions involving the 4q21--> 4q22 band region (Am. J. Med. Genet. 68 (1997) 400-405). To date there are 10 reported live-born cases with such deletions and similar features. The case reported here delimits a minimal critical region for this phenotype to chromosomal region 4q21. Our patient was also found to have cysts in both his kidneys. The gene for type II polycystic kidney disease (PKD2) has been mapped to chromosomal region 4q21--> 4q23. FISH analysis, with a probe including the PKD2 gene, demonstrated hemizygosity at this locus. Thus the absence of one of the PKD2 alleles in the case reported here is associated with early bilateral cyst development. Kidney ultrasound/autopsy studies were reported in seven of the patients with the characteristic phenotype, and were positive for cysts in four cases including the one presented here (Clin. Genet. 31 (1987) 199-205; Am. J. Med. Genet. 68 (1997) 400-405; Am. J. Med. Genet. 40 (1991) 77-790. Our report supports the presence of a distinct phenotype associated with a deleted chromosomal region within 4q21. Hemizygosity for the PKD2 gene is likely in such deletions and may lead to renal cyst formation.

T-cell receptor J beta I/J beta II locus rearrangements concurring with a complex chromosomal aberration in an HTLV-1 positive T-cell lymphoma.

Human T-lymphotropic virus type I (HTLV-1) integration has been associated with the development of adult T-cell leukemia/lymphoma (ATL). Recently, a correlation between T-cell receptor (TCR) gene rearrangements and chromosomal aberrations has been implicated in this leukemia. We present a case of HTLV-1 infected adult T-cell lymphoma that initially presented with a normal karyotype and germline J beta I/J beta II loci. As the disease evolved to the aggressive stage, a complex chromosomal rearrangement with a duplication of chromosome 6p23-->pter translocated to a derivative chromosome 16, was identified by molecular cytogenetic techniques. The nature of this complex abnormality would have been difficult to determine if only conventional banding techniques were performed. Rearrangement involving one J beta allele was also detected at that time. After initiation of chemotherapy, no germline J beta loci were detected, suggesting a possible second rearrangement involving this locus that was homologous. Although no known immune response genes are located at the breakpoints involved in this abnormality, the chromosomal aberration concurred with the initial J beta rearrangement.

The impact of the CB2-63 polymorphism on the histological presentation of chronic hepatitis B.

The impact of the cannabinoid receptor 2 (CB2) rs35761398 polymorphism on chronic hepatitis B (CHB) was evaluated in 106 consecutive biopsy-proven CHB patients naive for antiviral therapy. A histological activity index (HAI) > 8 (Ishak scoring) was more frequent in patients with CB2-63 RR than in those with CB2-63 QR or QQ (37% vs. 16.7%, p < 0.05). The logistic regression analysis identified CB2-63 RR (p < 0.05) and a fibrosis score >3 (p < 0.005) as independently associated with an HAI >8. The observation that the CB2-63 RR variant is an independent predictor of extensive necroinflammation opens up new prospects in the study of CHB.

Genomic diversity of Philadelphia-positive chronic myelogenous leukemia.

The incidence of breakpoints in CML patients with variant translocations was investigated. There was no relationship between the length of various chromosomes with breakpoint frequency. However, a significantly higher (p less than 0.05) incidence of breaks were seen on the long arms as compared to the short arms due mainly to the involvement of 9q and 22q in these translocations. Chromosome 17 showed a significantly (p less than 0.005) higher involvement in these translocations, however only when 9q34-qter was not cytogenetically involved. A total of 683 breaks were found in 225 cases. 362 of these were located at c-abl and c-sis, while 110 were at other oncogenetic sites. The prognostic and hematologic features of patients with variant translocations are not significantly different from those of CML cases with the typical 9q;22q translocation. Some of these complex translocation, where the breakpoints are correlated with oncogenetic sites, are further discussed in molecular terms.

A simple method for short-term culturing bone marrow and unstimulated blood from acute leukemias.

It has become routine practice to culture bone marrow and/or unstimulated peripheral blood for cytogenetic analysis due to associations of consistent chromosomal abnormalities within specific subgroups of leukemias. Unfortunately, two leukemias for which numerous chromosomal aberrations have been recorded, acute myelogenous leukemia (AML) and acute lymphocytic leukemia (ALL), frequently present with very low cell counts often resulting in unsuccessful cultures. Furthermore, when cultures are successful, chromosomes are often contracted and metaphase spreads can be of poor quality. In the present investigation, by first treating blood or bone marrow from AML and ALL patients with ammonium chloride (1.5 mM) we were able to obtain chromosomal preparations often similar in quality to those obtained from normal stimulated blood cultures. With this improved culturing method it is also possible to generate high-quality chromosomes and DNA from the same sample.

Origin of near-haploidy in malignant hematopoietic cells.

Hyperdiploidy is common in neoplastic diseases but severe hypodiploidy or near-haploidy is extremely rare. Acute lymphocytic leukemia (ALL) and blast phase of chronic myelocytic leukemia (BC/CML) are the two most common leukemias where metaphases with as low as 23 chromosomes have been reported. Recent studies have indicated that during the course of malignant development, cells undergo numerous changes, however, it is still not known whether malignant transformation proceeds or results from the near-haploid state. Retrospectively, we have examined 100 metaphases with chromosome counts of 23 to 35 in patients with CML who have not yet progressed to the blastic phase, to see whether such metaphases share any common characteristics with published cases. The unusual behavior of chromosomes 8, 17 and the presence of Ph-chromosomes in 85% of the cells are highly unique features in our study. These observations are compatible with those found in BC/CML patients reported earlier. Therefore, it is hypothesized that selective chromosome loss is a gradual phenomenon and one of these near-haploid clones may replace a diploid clone as the dominant component of the population during blast transformation. Several hypotheses are proposed as to the origin of such clones in malignant hematopoietic stem cells.

Inversion-duplication of bands q13----q21 of human chromosome 9.

Structural abnormalities involving heterochromatic regions of the human genome are difficult to characterize because these segments are G-band negative by GTG technique, a routinely used procedure in clinical cytogenetic laboratories. Chromosome abnormalities of such cases have gone undetected or were incorrectly characterized because these regions are so-called heteromorphisms or variants. Consequently, much anxiety has been aroused by the confusion between a chromosome abnormality and a normal heteromorphic variant. We report the first documented case with a so-called highly unusual h region of chromosome 9 which is not a variation but a structural rearrangement involving a paracentric inversion and a duplication. The major clinical features were psychomotor retardation, microcephaly, narrow palpebral fissures, renal and genital anomalies, vertebral anomalies, protruding tongue, and learning and behavioral problems. A concise review of variable duplicated segments of 9q is also provided.

Two Prader-Willi/Angelman syndrome loci present in an isodicentric marker chromosome.

We found an abnormal 47,XX,+mar karyotype in a patient with developmental delay, hypotonia, microcephaly, failure to thrive, and cognitive delay. When metaphases were hybridized with Prader-Willi and Angelman loci-specific probes by the FISH technique, two sites were noted at opposite positions on the marker chromosome. The alphoid satellite DNA probe documented the isodicentric nature while retention of the p arms on both sides of the marker chromosome was demonstrated by beta satellite probe. The patient does not exhibit manifestations of either syndrome despite the presence of these loci in tetrasomic dose. The present investigation suggests that other marker chromosomes be reevaluated, as their clinical manifestations are quite variable.

Molecular characterization of a complex translocation in a newborn infant.

A newborn infant was referred because of low-set ears, mild downward slant of the palpebral fissures, micrognathia with high-arched palate, a flat midface, small mouth, and thin upper lip with cupid bow configuration. To some extent her cry resembled that associated with cri du chat syndrome. Cytogenetic findings with G- and Q-banding alone failed to characterize precisely the complex translocations. By the chromosome in situ suppression (CISS) hybridization technique using whole chromosome specific probes, a complex 4 breakpoint rearrangement involving both arms of a single chromosome 1 with the long arms of chromosomes 5 and 11 was disclosed, i.e., 46,XX, der(1),t(1;5) t(1;11) (5qter-->5q31::1p31.3-->1q44::11q23-->11 qter;5pter-->5q31::1p31.3-->1pter;11pter-- >11q 23::1q44-->1qter). Gene deregulation and position effect may explain the multiple anomalies in individuals with apparently balanced translocations. The molecular characterization of such cytogenetically balanced translocations may shed some light towards unveiling the clinical consequences associated with aberrations which are presumably balanced.