Platelet Count Does Not Predict Bleeding in Cirrhotic Patients: Results from the PRO-LIVER Study.

OBJECTIVES: Thrombocytopenia is a hallmark for patients with cirrhosis and it is perceived as a risk factor for bleeding events. However, the relationship between platelet count and bleeding is still unclear. METHODS: We investigated the relationship between platelet count and major or clinical relevant nonmajor bleedings during a follow-up of ∼4 years. RESULTS: A total of 280 cirrhotic patients with different degrees of liver disease (67% males; age 64±37 years; 47% Child-Pugh B and C) were followed up for a median of 1,129 (interquartile range: 800-1,498) days yielding 953.12 patient-year of observation. The annual rate of any significant bleeding was 5.45%/year (3.57%/year and 1.89%/year for major and minor bleeding, respectively). Fifty-two (18.6%) patients experienced a major (n=34) or minor (n=18) bleeding event, predominantly from gastrointestinal origin. Platelet counts progressively decreased with the worsening of liver disease and were similar in patients with or without major or minor bleeding: a platelet count ≤50 × 103/µl was detected in 3 (6%) patients with and in 20 (9%) patients without any bleeding event. Conversely, prothrombin time-international normalized ratio was slightly higher in patients with overall or major bleeding. On Cox proportional hazard analysis, only a previous gastrointestinal bleeding (hazard ratio (HR): 1.96; 95% confidence interval: 1.11-3.47; P=0.020) and encephalopathy (HR: 2.05; 95% confidence interval: 1.16-3.62; P=0.013) independently predicted overall bleeding events. CONCLUSIONS: Platelet count does not predict unprovoked major or minor bleeding in cirrhotic patients.

High incidence of post-transplant cytomegalovirus reactivations in myeloma patients undergoing autologous stem cell transplantation after treatment with bortezomib-based regimens: a survey from the Rome transplant network.

The incidence of cytomegalovirus (CMV) reactivations in patients with multiple myeloma (MM) receiving autologous stem cell transplantation (ASCT) is relatively low. However, the recent increased use of novel agents, such as bortezomib and/or immunomodulators, before transplant, has led to an increasing incidence of Herpesviridae family virus infections. The aim of the study was to establish the incidence of post-engraftment symptomatic CMV reactivations in MM patients receiving ASCT, and to compare this incidence with that of patients treated with novel agents or with conventional chemotherapy before transplant. The study was a survey of 80 consecutive patients who underwent ASCT after treatment with novel agents (Group A). These patients were compared with a cohort of 89 patients treated with VAD regimen (vincristine, doxorubicin, and dexamethasone) before ASCT (Group B). Overall, 7 patients (4.1%) received an antiviral treatment for a symptomatic CMV reactivation and 1 died. The incidence of CMV reactivations was significantly higher in Group A than in Group B (7.5% vs. 1.1%; P = 0.048). When compared with Group B, the CMV reactivations observed in Group A were significantly more frequent in patients who received bortezomib, whether or not associated with immunomodulators (9.4% vs. 1.1%; P = 0.019), but not in those treated with immunomodulators only (3.7% vs. 1.1%; P = 0.396). These results suggest that MM patients treated with bortezomib-based regimens are at higher risk of developing a symptomatic CMV reactivation after ASCT.

Interleukin-28B (IL-28B) single-nucleotide polymorphisms and interferon plus ribavirin treatment outcome in Italian chronically HCV-infected patients.

To determine the single or combined effect of both rs12979860 and rs8099917 SNPs on HCV treatment response, these variants were genotyped in samples from a cohort of 170 patients infected with different HCV genotypes (HCVGT). The favourable rs12979860 CC genotype was found only in patients with sustained or rapid virological responses (SVR/RVR) and at significantly high proportions in HCVGT1/4 SVR patients. A significant association was also found between the rs8099917 TT genotype and SVR in both HCVGT1/4 and HCVGT2/3 groups of patients. In contrast, we found that there was significantly more of the rs8099917 GG genotype in nonresponders (NR) than in SVR patients which suggests a good association of the minor homozygote GG with the lack of treatment response. The combination of rs12979860/rs8099917 CC/TT favourable genotypes was found only in SVR patients and matched the frequency observed for their rs12979860 CC genotypes alone. By contrast, the inverse unfavourable correlate rs12979860/rs8099917 TT/GG genotype was seen more in NR than in SVR patients as observed for the single GG genotype. This study confirms the impact of both rs12979860 and/or rs8099917 IL-28B SNPs on treatment-induced clearance of HCV-RNA and demonstrates that the rs12979860 CC genotype is stronger than rs8099917 TT genotype in predicting a positive treatment response in HCVGT1/4 patients. The unfavourable rs8099917 GG genotype seems to be more important in predicting the failure of treatment response independently from HCV genotype.

A cluster analysis-derived classification of psychological distress and illness behavior in the medically ill.

BACKGROUND: The classification of psychological distress and illness behavior in the setting of medical disease is still controversial. Current psychiatric nosology does not seem to cover the spectrum of disturbances. The aim of this investigation was to assess whether the joint use of DSM-IV categories and the Diagnostic Criteria for Psychosomatic Research (DCPR), that provide identification of syndromes related to somatization, abnormal illness behavior, irritable mood, type A behavior, demoralization and alexithymia, could yield subtyping of psychosocial variables in the medically ill. METHOD: A cross-sectional assessment using both DSM-IV and the DCPR was conducted in eight medical centers in the Italian Health System. Data were submitted to cluster analysis. Participants were consecutive medical out-patients and in-patients for whom a psychiatric consultation was requested. A total of 1700 subjects met eligibility criteria and 1560 agreed to participate. RESULTS: Three clusters were identified: non-specific psychological distress, irritability and affective disturbances with somatization. CONCLUSIONS: Two-step cluster analysis revealed clusters that were found to occur across clinical settings. The findings indicate the need of expanding clinical assessment in the medically ill to include the various manifestations of somatization, illness behavior and subclinical distress encompassed by the DCPR.

Distortion-product otoacoustic emissions: a useful test for monitoring ototoxicity induced by pegylated interferon and ribavirin treatment in patients with chronic hepatitis C.

Pegylated-interferon (peg-IFN) and ribavirin combination therapy for the treatment of hepatitis C virus (HCV) infection is well known to be associated with significant adverse effects. Several studies have investigated a possible auditory pathway involvement during IFN therapy, but a method to monitor the potential auditory involvement during treatment has not yet been described. The aim of this study is to evaluate possible modifications of the outer hair cell (OHC) function in HCV patients receiving peg-IFN and ribavirin combination therapy. Thirteen adult HCV patients (8 F/5 M, mean age 52∓12 years) treated with peg-IFN and ribavirin combination therapy underwent Pure Tone Audiogram and Distortion Product Otoacoustic Emission (DPOAE) tests. We compared mean auditory thresholds (PTA) and mean DPOAE amplitude before, at month 3 during, and at the end of treatment (T0, T3, and Tend, respectively), and 3 months after treatment discontinuation (Tfu). No significant differences were found in hearing levels at the different time points analyzed. During treatment, three patients developed tinnitus, which in 2 cases resolved spontaneously after the end of therapy. Compared to T0 (19.5±0.83), a statistically significant DPOAE increase at T3 (30±1,26) and Tend (28.6±2.16) was found (p<0.05 at both time points), while DPOAEs returned to pre-treatment levels at Tfu (19.3±1.3). In our group, none of the patients reported a permanent auditory impairment, excluding one patient with persistent tinnitus. Peg-IFN could produce an increase of motility of the OHCs by means of intracellular pathways. DPOAE test could be considered a new method for monitoring ototoxicity induced by IFN. On the basis of recent literature and our audiological results, physicians should be aware of the possible ototoxic effects of peg-IFN, requiring appropriate surveillance, and the patient should be informed of the potential side effects of IFN therapy on the auditory pathway.

Type A behaviour: a reappraisal of its characteristics in cardiovascular disease.

AIMS: The role of type A behaviour in cardiovascular disease is controversial and most of the research is based on self-rating scales. The aim of this study was to assess the prevalence of type A behaviour in cardiology and in other medical settings using reliable interview methods that reflect its original description. METHODS: A sample of 1398 consecutive medical patients (198 with heart transplantation, 153 with a myocardial infarction, 190 with functional gastrointestinal disorders, 104 with cancer, 545 with skin disorders and 208 referred for psychiatric consultation) was administered the Structured Clinical Interview for the DSM-IV and the Structured Interview for the Diagnostic Criteria for Psychosomatic Research (DCPR) which identifies 12 clusters, including type A behaviour. RESULTS: A cardiac condition was present in 366 patients. There was a significant difference in the prevalence of type A behaviour in cardiovascular disease (36.1%) compared with other medical disorders (10.8%). Type A behaviour frequently occurred together with psychiatric and psychosomatic disturbances, particularly irritable mood, even though in the majority of cases it was not associated with DSM-IV diagnoses. Among cardiac patients, those with type A behaviour were less depressed, demoralised and worried about their illness. CONCLUSIONS: Type A behaviour was found to occur in about a third of cases of patients with cardiovascular disease. Only in a limited number of cases was it associated with depression. It has a lifestyle connotation that may have important clinical consequences as to stress vulnerability and illness behaviour.

Development and preliminary validation of the PC-SAD5, a screener-derived short depression severity measure.

BACKGROUND: The prevalence of depressive disorders is high among patients with skin disease. The PC-SAD is a 37-item self-administered depression screening questionnaire that has been validated in dermatological patients. OBJECTIVE: The aim of this study was to develop and validate a brief depression severity instrument derived from the PC-SAD that can be used to assess severity and monitor ongoing clinical course. METHODS: Two patient samples participated in the study: 72 adult dermatological inpatients and 73 adults attending six primary care practices. Psychiatric assessment included the Structured Clinical Interview for DSM-IV and an 18-item version of the PC-SAD; moreover, dermatological patients completed the Patient Health Questionnaire depression scale (PHQ-9), while primary care patients were administered the Montgomery-Asberg Depression Rating Scale (MADRS). A subset of five PC-SAD items showing the best psychometric properties were selected, and the reliability and validity of the resulting instrument (PC-SAD5) were examined. RESULTS: The PC-SAD5 showed satisfactory internal consistency in both samples. There was a high correlation between PC-SAD5 and PHQ-9 and MADRS scores. Multiple regression analysis revealed a gradient of PC-SAD5 scores from patients with no mental disorder, those with milder forms of depression, to those with Major Depressive Disorder. Similar results were observed for the 18-item version of the PC-SAD. CONCLUSION: The availability of valid and reliable continuous measures of depression severity derived from the PC-SAD extends its field of application from depression screening to use as a follow-up measure of depression severity in routine clinical practice. A validated very short instrument such as the PC-SAD5 may have substantial clinical value.

Gilteritinib as treatment for extra-medullary relapse of FLT3-ITD acute myeloid leukemia FLT3-ITD, after allogeneic haematopoietic stem cell transplantation.

Case of a patient with acute myeloid leukemia (AML) positive for mutations in both genes NPM1 and FLT3-ITD who underwent two allogeneic haematopoietic stem cell transplants (HSCT); the second allograft one was followed by extramedullary relapse (granulocytic sarcoma of right breast), with blast cells positive for FLT3-ITDmutation.  Treatment with Gilteritinib, a second generation selective oral type I FLT3 inhibitor, was started after the second HSCT with complete regression of breast granulocytic sarcoma in absence of hematological and extra hematologic toxicity. We conclude that Gilteritinib can represent an effective therapy for extra hematologic relapse, with acceptable toxicity and outpatient management.

Rapid virological response as a predictor of sustained response in HCV-infected patients with persistently normal alanine aminotransferase levels: A multicenter study.

Rapid virological response (RVR) is now considered the strongest predictor of sustained virological response (SVR) in patients with HCV undergoing antiviral treatment, and thus, shorter antiviral treatment for these patients has been suggested. However, no data exist on the predictive value of RVR in HCV carriers with normal ALT values. A total of 137 patients with persistently normal ALT treated with peginterferon alfa 2a and ribavirin were studied. Fifteen patients dropped out early because of side effects, and in 10 patients with HCV-1 treatment was discontinued because of lack of early virological response (EVR). RVR was observed in 68% of the patients (42% patients with HCV-1, 90% HCV-2 and 64% HCV-3). An end-of-treatment response was observed in 86% of the patients (68% HCV-1, 100% HCV-2 and 91% HCV-3). SVR was maintained in 91 patients (46% HCV-1, 97% HCV-2 and 82% HCV-3). Overall, 92% patients with rapid response did obtain HCV eradication vs only 38% of those without rapid response. HCV-1 patients with baseline HCV RNA <400×10(3) IU/mL were more likely to achieve RVR and SVR than those with higher HCV RNA levels. We conclude that patients with genotype 1 and normal ALT who achieve HCV RNA negativity at week 4 may have a higher probability of eradicating their infection. Because of the concomitant favourable demographic and virological features often found in this particular subset of patients, the duration of therapy in these people might be shortened in the case of RVR. Persistently normal alanine aminotransferase levels patients with genotype 2 or 3 have a high chance of achieving SVR, so retesting of HCV RNA during treatment may have no additional practical value in these subjects.

Apoptosis and autoimmunity induced by clodronate in systemic lupus erythematosus mononuclear circulating cells.

The aim of this study is to evaluate the effect of clodronate on apoptosis of human systemic lupus erythematosus circulating mononuclear cells and to analyze possible correlations with changes in autoantibody production in vitro. Lympho-monocytes from 20 SLE patients were isolated and incubated with or without addition of 1 microM clodronate for 72 hours. Apoptosis and release of genomic material was assessed by immunofluorescent detection of cleaved caspase-3 and by Cell-Death-Detection ELISAPLUS kit (Roche). Anti-Nucleosome IgG and anti-dsDNA IgM and IgG autoantibody levels were determined in supernatants by commercially available ELISA kits. Clodronate induced apoptosis in monocytes as confirmed by cleaved caspase-3 immunostaining and by quantification of cleaved nucleosome in the supernatants (treated 0.22+/-0.05 O.D. vs untreated 0.09+/-0.04 O.D.; P less than 0.001). This finding was coupled with a significant increasing in supernatants of IgG anti-Nucleosome (treated 6.5+/-1.1 vs untreated 5.5+/-0.6 IU/mL; p=0.001) and IgM (treated 3.0+/-1.3 vs 2.2+/-0.9 IU/mL; p=0.02) and IgG (treated 4.0+/-1.8 vs untreated 2.8+/-1.5 IU/mL; p=0.02) anti-dsDNA autoantibody levels. Our findings stressed the pro-apoptotic activity of clodronate, as well as its potential autoimmunity induction in SLE mononuclear circulating cells. Clinical studies could clarify the role of bisphosphonates on autoantibody production and worsening of disease activity.

Discussion about switch strategy in the adjuvant hormonal therapy of breast cancer: psychological aspects of physician-patient communication.

BACKGROUND: A survey of oncologists was conducted in Italy to evaluate the potential problems of physician-patient discussion about hormonal switch in the adjuvant therapy of breast cancer. MATERIALS AND METHODS: A questionnaire, including both closed and open-ended questions, was administered to 70 oncologists. Fifty-one of them returned completely filled questionnaires. RESULTS: Forty-seven percent of the physicians reported difficulties in proposing the hormonal switch, and 60% stated that they found it difficult to make the therapeutic change acceptable to patients. The oncologist's barriers to propose the switch were related mostly to scientific and economic issues, such as the lack of certain advantages of aromatase inhibitors over tamoxifen (28%), their costs (14%) and their side-effects (34%). On the other hand, according to physicians, the patient's barriers to accept the therapeutic change were mainly due to psychological-relational factors, in particular the anxiety produced by the change (40%) and the bad patient-physician communication experienced in the past (26%). CONCLUSIONS: Patient-physician communication difficulties about switch strategy in the adjuvant hormonal treatment of breast cancer are, at least in part, related to psychological and relational factors. It is likely that training programs, improving doctor's communication skills, can overcome these problems.

Depression and the existential domain in the assessment of quality of life in HIV outpatients with the McGill questionnaire.

AIM: The aim of the present study was to further test criterion validity and factorial validity of the McGIll Quality Of Life (MQOL) questionnaire, and to assess its reliability and sensitivity to clinical change in outpatients with HIV infection. METHODS: The authors present a longitudinal study on a consecutive sample of 216 adults treated with HAART at the outpatient facility of an hospital-based tertiary care center in Italy. Patients completed the MQOL and the Beck Depression Inventory (BDI) both at baseline and follow-up assessments. Patients were classified into subgroups (improved, unchanged, worsened) based on change in BDI scores or CD4 count over time. RESULTS: The pattern of correlation between MQOL subscales and the BDI was as hypothesised. A fairly simple factor structure emerged, with a striking resemblance between the factors and the MQOL subscales. The internal consistency of the MQOL and its subscales was high. The test-retest reliability in clinically unchanged patients was satisfactory. Sensitivity to change, as measured by Guyatt responsiveness statistic, was also satisfactory. CONCLUSIONS: This study contributed to building evidence of reliability and validity for the MQOL questionnaire, which may be particularly useful to assess the so-called "existential" aspects of QOL that are particularly relevant for patients infected with HIV.

Mental health in patients with systemic sclerosis: a controlled investigation.

BACKGROUND: Despite the undeniable impact of systemic sclerosis (SS) on quality of life, only a few studies so far have focused on its psychiatric or psychological aspects. We aimed at assessing psychiatric symptoms and self-image in inpatients with SS and comparing them with patients with either a very mild skin condition or a serious skin condition. METHODS: Three groups were recruited: (i) 38 consecutive female inpatients with SS; (ii) 38 age-matched female outpatients with melanocytic naevi; (iii) 35 age-matched female inpatients with melanoma. All participants completed the Zung Anxiety Scale, the Zung Depression Scale and a self-report questionnaire measuring self-perceived personal qualities. Patients with SS were also clinically interviewed by a psychologist. RESULTS: The clinical interview revealed the presence of a psychiatric disorder in most (81%) patients with SS. The Zung scales corroborated the presence of mild to moderate anxiety and depression among patients with SS, who scored significantly higher than patients with either naevi or melanoma on both scales. Scores on the questionnaire assessing self-perceived personal qualities were very similar in the three groups and indicated a fairly high level of self-esteem. CONCLUSIONS: This study suggested that psychosocial issues are quite relevant in patients with SS and underscored the need for a biopsychosocial approach to the clinical management of these patients. Timely detection of psychosocial difficulties and appropriate psychological or psychiatric intervention may represent important steps toward better adherence to medical treatment and improved psychological well-being and quality of life.

Retinoic acid and arsenic trioxide sensitize acute promyelocytic leukemia cells to ER stress.

Retinoic acid (RA) in association with chemotherapy or with arsenic trioxide (ATO) results in high cure rates of acute promyelocytic leukemia (APL). We show that RA-induced differentiation of human leukemic cell lines and primary blasts dramatically increases their sensitivity to endoplasmic reticulum (ER) stress-inducing drugs at doses that are not toxic in the absence of RA. In addition, we demonstrate that the PERK pathway, triggered in response to ER stress, has a major protective role. Moreover, low amounts of pharmacologically induced ER stress are sufficient to strongly increase ATO toxicity. Indeed, in the presence of ER stress, ATO efficiently induced apoptosis in RA-sensitive and RA-resistant APL cell lines, at doses ineffective in the absence of ER stress. Our findings identify the ER stress-related pathways as potential targets in the search for novel therapeutic strategies in AML.

Efficacy of caspofungin as secondary prophylaxis in patients undergoing allogeneic stem cell transplantation with prior pulmonary and/or systemic fungal infection.

Transplanted patients with a history of invasive fungal infection (IFI) are at high risk of developing relapse and fatal complications. Eighteen patients affected by hematological malignancies and a previous IFI were submitted to allogeneic stem cell transplantation, using Caspofungin as a secondary prophylaxis. Patients had a probable or proven fungal infection and 16 had a pulmonary localization. No side effects were recorded during treatment with Caspofungin. Compared to pre-transplant evaluation, stability or improvement of the previous IFI was observed in 16 of the 18 patients at day 30, in 13 of the 15 evaluable patients at day 180 and in 11 of the 11 evaluable patients at day 360 post transplant. In particular, all the six patients with a proven fungal infection were alive, with a stable or improved IFI after 1 year from transplant. At a maximum follow-up of 31 months, eight patients died for disease progression or transplant-related complications, but only two had evidence of fungal progression. Secondary prophylaxis with Caspofungin may represent a suitable approach to limit IFI relapse or progression, allowing patients with hematological malignancies to adhere to the planned therapeutic program.

Changes in depression, anxiety, anger, and personality after resective surgery for drug-resistant temporal lobe epilepsy: a 2-year follow-up study.

OBJECTIVE: To further elucidate the psychiatric outcome of surgical treatment for temporal lobe epilepsy (TLE). METHODS: Fifty-two consecutive patients with drug-resistant TLE and IQ > or = 70 completed the Minnesota Multiphasic Personality Inventory, Beck Depression Inventory, Spielberger State-Trait Anxiety Inventory, and Spielberger State-Trait Anger Expression Inventory before epilepsy surgery, after 1 year, and after 2 years. Some patients also completed the 31-item Quality of Life in Epilepsy (N=29) and WHOQOL-100 (N=24) questionnaires. During the follow-up period, patients were maintained on a stable medication regimen. Multivariate repeated measures analysis of variance was used to examine changes in psychiatric variables over time. RESULTS: Seizure outcome was excellent (89% in Engel class I after 2 years). There were only a few significant changes over time in the MMPI profile, suggesting a decrease in interpersonal sensitivity, irritability, and social introversion. Anxiety decreased significantly with a gradual decline, anger dropped significantly after remaining basically flat during the first year, while depression showed a gradual but non-significant decline. Younger age and shorter duration of epilepsy were associated with greater improvement in several anger dimensions. In the patient subgroup with quality of life data available, greater improvement in overall quality of life and key life domains (income, work capacity, personal relationships) was found to be associated with greater decrease in depression, anxiety, and anger. CONCLUSION: The relatively slow decrease of emotional distress over time and its correlation with changes in some key life domains suggest that patients may experience difficulties in switching from a 'sick' role to a 'normal' role, and may easily be disappointed if expectations of positive life changes are not rapidly met. Some counselling sessions early after surgery may be useful to address these issues. The findings also suggest that surgery may yield greater emotional benefits if performed early.

[Fast stress evaluation in nurses]. / La valutazione rapida dello stress negli infermieri.

The aim of the study was to assess subjective stress to 92 nurses by administering the Rapid Stress Assessment (RSA) Scale, a self-rated tool. The self-administered test, easily understandable, which is quickly drawn up and which allows a quick scooring, appears to be suitable to select subjects deserving a thorough specialistic investigation. The test itself becomes therefore a useful professional means for the occupational health physician, who has to evaluate the workers' psychic and physical attitude.

Identification of the novel allele, HLA-A*02:653, in an Italian patient.

HLA-A*02:653 differs from A*02:01:01:01 by a C to T substitution in exon 2.