Management of infection in PNH patients treated with eculizumab or other complement inhibitors: Unmet clinical needs.

This article presents the results of group discussion among an ad hoc constituted panel of experts aimed at identifying and addressing unmet clinical needs (UCNs) in the management of infectious risk associated with eculizumab or new terminal complement inhibitors (CIs) in paroxysmal nocturnal hemoglobinuria (PNH). With the Delphi technique, the most clinically relevant UCNs in PNH patients candidate to or on terminal CI were selected. They resulted to be: optimizing the infection prevention measures; developing non pharmacological infectious risk-mitigation strategies; improving the management of disease exacerbation during infectious complications. For each of these issues consensus opinions were provided and, when appropriate, proposals for advancement in clinical practice were addressed. The hope is that this comprehensive overview will serve to improve the practice of CIs therapy and inform the design and implementation of new studies in the field.

Molecular response and quality of life in chronic myeloid leukemia patients treated with intermittent TKIs: First interim analysis of OPTkIMA study.

BACKGROUND: Intermittent treatment with TKIs is an option for the great majority (70%-80%) of CML patients who do not achieve a stable deep molecular response and are not eligible for treatment discontinuation. For these patients, the only alternative is to assume TKI continuously, lifelong. METHODS: The Italian phase III multicentric randomized OPTkIMA study started in 2015, with the aim to evaluate if a progressive de-escalation of TKIs (imatinib, nilotinib, and dasatinib) is able to maintain the molecular response (MR3.0 ) and to improve Health Related Quality of Life (HRQoL). RESULTS: Up to December 2018, 166/185 (90%) elderly CML patients in stable MR3.0 /MR4.0 completed the first year of any TKI intermittent schedule 1 month ON and 1 month OFF. The first year probability of maintaining the MR3.0 was 81% and 23.5% of the patients who lost the molecular response regained the MR3.0 after resuming TKI continuously. Patients' HRQoL at baseline was better than that of matched peers from healthy population. Women was the only factor independently associated with worse baseline HRQoL (p > 0.0001). Overall, global HRQoL worsened at 6 (p < 0.001) but returned to the baseline value at 12 months and it was statistically significantly worse in women (p = 0.001). CONCLUSIONS: De-escalation of any TKI by 1 month ON/OFF schedule maintains the MR3.0 /MR4.0 in 81% of the patients during the first 12-24 months. No patients progressed to accelerated/blastic phase, all the patients (23.5%) losing MR3.0 regained the MR3.0 and none suffered from TKI withdrawn syndrome. The study firstly report on HRQoL in elderly CML patients moving from a continuous daily therapy to a de-escalated intermittent treatment.

A population-based study of chronic myeloid leukemia patients treated with imatinib in first line.

Chronic myeloid leukemia (CML) treatment is based on company-sponsored and academic trials testing different tyrosine kinase inhibitors (TKIs) as first-line therapy. These studies included patients selected according to many inclusion-exclusion criteria, particularly age and comorbidities, with specific treatment obligations. In daily clinical practice (real-life), inclusion-exclusion criteria do not exist, and the treatment outcome does not only depend on the choice of first-line TKI but also on second- and third-line TKIs. To investigate in a real-life setting the response and the outcome on first-line imatinib, with switch to second generation TKIs in case of unsatisfying response or intolerance, we analyzed all newly diagnosed patients (N = 236), living in two Italian regions, registered in a prospective study according to population-based criteria and treated front-line with imatinib. A switch from imatinib to second-generation TKIs was reported in 14% of patients for side effects and in 24% for failure or suboptimal response, with an improvement of molecular response in 57% of them. The 5-year overall survival (OS) and leukemia-related survival (LRS) were 85% and 93%, respectively; the 4-year rates of MR3.0 and MR4.0 were 75% and 48%, respectively. Cardiovascular complications were reported in 4% of patients treated with imatinib alone and in 6% of patients receiving nilotinib as second-line. Older age (≥70 years) affected OS, but not LRS. These data provide an unbiased reference on the CML management and on the results of TKI treatment in real-life, according to ELN recommendations, using imatinib as first-line treatment and second-generation TKIs as second-line therapy. Am. J. Hematol. 92:82-87, 2017. © 2016 Wiley Periodicals, Inc.

Long term outcome of Ph+ CML patients achieving complete cytogenetic remission with interferon based therapy moving from interferon to imatinib era.

Interferon α (IFNα) prolongs survival of CML patients achieving CCyR and potentially synergizes with TKIs. We report on the molecular status and long term outcome of 121 patients who were treated in Italy between 1986 and 2000 with IFNα based therapy and who obtained CCyR. After a median follow up of 16.5 years, 74 (61%) patients were switched to standard imatinib: 48 (65%) lost the CCyR on IFNα, and 36 (75%) are alive and in CCyR; 26 (35%) were switched to imatinib when they were still in CCyR on IFNα, and all 26 are alive and in CCyR. Forty-seven patients (39%) were never switched to imatinib: 24 (51%) continued and 23 (49%) discontinued IFNα, respectively, and 39/47 (83%) are alive and in CCyR. At last follow-up, the BCR-ABL transcripts level was available in 96/101 living patients (95%) The BCR-ABL:ABL ratio was between 0.1 and 0.01% (MR(3.0) ) in 17%, and less than 0.01% (MR(4.0) ) in 81% of patients. No patient was completely molecular negative (MR(4.5) or MR(5.0) ). The OS at 10 and 20 years is 92 and 84%, respectively. This study confirms that CCyR achieved with IFNα and maintained with or without imatinib or any other therapy significantly correlates with long term survival in CML patients who mostly have MR(4.0) . Complete molecular response (MR(4.5) or MR(5.0) ) seems to be unnecessary for such a long survival. This study further supports development of studies testing the clinical effect of the combinations of TKIs with IFNα.

Effects and outcome of a policy of intermittent imatinib treatment in elderly patients with chronic myeloid leukemia.

We report a study of an alternative treatment schedule of imatinib (IM) in chronic myeloid leukemia (CML). Seventy-six Philadelphia-positive (Ph+), BCR-ABL-positive patients aged 65 years or older who had been treated with IM for more than 2 years and who were in stable complete cytogenetic response (CCgR) and major molecular response (MMR) were enrolled in a single-arm study to test the effects of a policy of intermittent IM (INTERIM) therapy for 1 month on and 1 month off. With a minimum follow-up of 4 years, 13 patients (17%) lost CCgR and MMR and 14 (18%) lost MMR only. All these patients resumed continuous IM and all but one (lost to follow-up) regained CCgR and MMR. No patients progressed to accelerated or blastic phase or developed clonal chromosomal abnormalities in Ph+ cells or BCR-ABL mutations. In elderly Ph+ CML patients carefully selected for a stable CCgR (lasting >2 years), the policy of INTERIM treatment affected the markers of residual disease, but not the clinical outcomes (overall and progression-free survival). This trial was registered at www.clinicaltrials.gov as NCT 00858806.

The influence of planned kinds of delivery on pregnant women's emotional state.

OBJECTIVE: To evaluate if labour induction and elective caesarean section could influence anxiety and depression in pregnant women. METHODS: One hundred and sixteen consecutive pregnant women with uncomplicated singleton pregnancy at term, scheduled for these two obstetric procedures were enrolled. An anonymous questionnaire with two self-rating instruments STAI and HAM-A for anxiety and HAM-D for depression was administered. RESULTS: Anxiety levels did not show significant differences while a light depressive mood was evidenced among pregnant women waiting for labour induction (p = 0.01). CONCLUSIONS: An adequate psychological support could be considered a helpful tool for pregnant women scheduled for labour induction.

Maternal thyroid function in different conditions of iodine nutrition in pregnant women exposed to mild-moderate iodine deficiency: an observational study.

OBJECTIVE: We examined the effect of different conditions of nutritional iodine intake on maternal thyroid function throughout gestation in a cohort of healthy, anti-thyroid antibody-negative women from a mild-moderately iodine-deficient (ID) area. DESIGN: Observational cohort study. PATIENTS: The study included 168 women receiving prenatal preparations containing 150 µg of iodine from early pregnancy (150-I group); 105 women who had regularly used (>2 years) iodized salt prior to becoming pregnant (I-salt group); 160 women neither taking iodine supplements nor using iodized salt (no-I group). MEASUREMENTS: Maternal TSH, FT3 and FT4 were determined throughout gestation. RESULTS: Mean TSH concentrations were higher among the 150-I women than in the remaining two groups, and in a high proportion of them, TSH values were found to exceed the upper limit for gestational age. Conversely, the prevalence of low free-thyroxine levels in the 150-I women was similar to that observed in the I-salt women and markedly lower than that recorded for the no-I group. CONCLUSIONS: The regular use of iodine-containing supplements proved effective in reducing the risk of inappropriately low FT4 levels during pregnancy. The observed TSH increase in 150-I women may be because of a transient stunning effect on the thyroid gland, occurring as a result of the abrupt increase in daily iodine intake. Whilst the importance of gestational iodine supplementation is undisputed, we believe that in mild-moderately ID areas, women considering conception should be advised to take iodine supplementation for several months prior to pregnancy.

Thyroid function in women found to have early pregnancy loss.

BACKGROUND: Pregnancy influences thyroid function and may bring to light mild and latent disorders. Thyroid dysfunction has been related to obstetrical complications such as premature delivery, gestational hypertension, preeclampsia, and placental abruption. The aim of our study was to evaluate whether the occurrence and timing of pregnancy loss could be related to thyroid autoimmunity or subclinical hypothyroidism (SH) per se. METHODS: Two hundred sixteen apparently healthy pregnant women with no previous history of thyroid disease and with diagnosis of early miscarriage (before the 12th week of gestation) were enrolled. Miscarriages were classified as very early pregnancy loss (EPL) or embryo loss (crown rump length < or =10 mm) and EPL or fetal loss (crown rump length > 10 mm). Women were subdivided into four groups: euthyroid (ET), SH, overt hypothyroidism, and thyroid autoimmunity group. RESULTS: One hundred seventy-six women had a normal thyroid function (84.6%), 24 patients were found to have positive thyroid antibodies (11.5%), 8 women (3.8%) an SH, and 8 cases were excluded. Thyroid-stimulating hormone levels were found to be higher in the very early (1.4 +/- 1.0 mU/L) than in the EPL group (1.1 +/- 0.7 mU/L) (p = 0.04), and in patients affected by SH (3.9 +/- 0.1 mU/L) compared to ET (1.0 +/- 0.5 mU/L) (p < 0.001) and autoimmune women (1.0 +/- 0.4 mU/L) (p < 0.001). Although the multivariate logistic regression analysis revealed that both autoimmunity and SH were independently correlated with the onset of very EPL, abortion was more precocious in the SH group (6.5 +/- 0.9 weeks), followed by the autoimmune (8.2 +/- 2.1 weeks) and ET groups (8.2 +/- 1.6 weeks) (p = 0.02). CONCLUSIONS: Both thyroid diseases SH and autoimmune disorder are independently associated with very early embryo loss, but women suffering from SH have a lower gestational age at abortion.

Wound length and corticosteroid administration as risk factors for surgical-site complications following cesarean section.

OBJECTIVE: To evaluate the effect of some specific gestational factors and other known variables associated with poor wound healing in women who delivered by cesarean section. DESIGN: Observational, prospective study. SETTING: University Hospital of Messina. POPULATION: A total of 212 consecutive pregnant women at term delivering by elective cesarean section. METHODS: All data regarding demographic and gestational characteristics were collected at admission. The subcutaneous tissue depth was intra-operatively measured from the fascia to the skin surface, while the incision length was measured after skin closure. MAIN OUTCOME MEASURES: Onset of wound complications such as infection, seroma, hematoma, abscess or dehiscence > 1 cm. RESULTS: Body mass index (BMI) at term [odd ratio (OR) 1.2, 95%CI 1.03-1.38; p = 0.01], wound length (OR 1.03, 95%CI 1.01-1.05; p < 0.001) and corticosteroid administration (OR 3.4, 95%CI 1.5-7.9; p = 0.004) were found to be correlated with wound complications. The receiver operating characteristics curve analysis suggested a cut-off of 31.1 for the BMI at term and 166 mm for the wound length with an OR of 2.28 (95%CI 1.18-4.39; p = 0.013) and 4.3 (95%CI 2.2-8.6; p < 0.001), respectively. The multivariate logistic regression model, applied to these variables and to corticosteroid administration, showed an independent correlation (at term BMI > 31.1: OR 2.04, 1.01-4.13, p = 0.047; wound length > 166 mm: OR 4.89, 2.36-10.14, p < 0.001; corticosteroid administration: OR 3.11, 1.38-6.95, p = 0.006). CONCLUSIONS: To avoid wound complications obstetricians should be careful in the administration of steroids before surgery, in the skin incision length that should be kept as short as possible and in carefully observing gestational BMI.

General versus spinal anaesthesia for elective caesarean sections: effects on neonatal short-term outcome. A prospective randomised study.

OBJECTIVE: To compare neonatal short-term outcome in patients who underwent spinal, general anaesthesia and conversion from spinal to general anaesthesia. METHODS: One hundred seventy-nine pregnant women undergoing elective caesarean section were allocated randomly to general (n=89) or spinal anaesthesia (n=90) and compared with 63 patients who required conversion to general anaesthesia. Umbilical cord artery pH, Apgar score as well as its individual parameter and need for assisted ventilation were evaluated. RESULTS: No differences were found in pH values (p=0.35), while the need for assisted ventilation differed significantly (p=0.001). The rate of depressed newborns was 1.1% in the spinal group, 25.9% in the general group and 12.7% in the conversion group with a significant difference for all comparisons. At 5-min, all newborns were vigorous. At 1 min, a higher score for each parameter was found in spinal group with respect to general group, while 'activity', 'grimace' and 'respiration' showed a higher score in conversion group than in general group. At 5 min, a difference was found only for 'activity'. CONCLUSIONS: All kinds of anaesthesia seem to be safe, but loco-regional blockade shows more advantages on the neonatal outcome also when a conversion is necessary.

Short-term thalidomide incorporated into double autologous stem-cell transplantation improves outcomes in comparison with double autotransplantation for multiple myeloma.

PURPOSE: To assess potential benefits with thalidomide incorporated into double autologous stem-cell transplantation (ASCT) for younger patients with newly diagnosed multiple myeloma (MM). PATIENTS AND METHODS: One hundred thirty-five patients who received thalidomide from induction until the second ASCT were retrospectively analyzed in comparison with an equal number of pair mates treated with double ASCT not including thalidomide. RESULTS: On an intention-to-treat basis, the addition of thalidomide to double ASCT effected a significant improvement in the rate (68% v 49%; P = .001) and duration (62% v 33% at 4 years; P < .001) of at least very good partial response (VGPR), time to progression (TTP; 61% v 41% at 4 years; P < .001) and progression-free survival (PFS; 51% v 31% at 4 years; P = .001). A trend was also noted for extended overall survival (OS) among thalidomide-treated patients (69% at 5 years v 53% for the control group), although the difference between the two groups was not statistically significant (P = .07). Benefits with thalidomide in increasing the rate of VGPR or better response, TTP, and PFS were confirmed in a multivariate analysis. Median OS after relapse was 24 months for patients receiving thalidomide added to double ASCT and 25 months for the control group. Overall, 17% of patients discontinued thalidomide, including 8% because of drug-related adverse events. CONCLUSION: In comparison with double ASCT, the addition of first-line thalidomide to double ASCT improved clinical outcomes. Short-term thalidomide was generally well tolerated and had no adverse impact on postrelapse survival.

Long-term follow-up of 386 consecutive patients with essential thrombocythemia: safety of cytoreductive therapy.

Cytotoxic agents like Hydroxyurea, Busulfan and Interferon-alpha are to date the most commonly used therapeutic approaches in Essential Thrombocythemia (ET). However, few data on the efficacy and safety of these agents in the long-term are currently available. We report a retrospective analysis of the long-term outcome of 386 consecutive ET patients, followed at single Institution for a median follow-up of 9.5 years (range, 3-28.5). Cytoreductive therapy was administered to 338 patients (88%), obtaining a response in 86% of cases. Forty-five patients (12%) experienced a thrombosis. Among baseline characteristics, only history of vascular events prior to ET diagnosis predicted a higher incidence of thrombosis. Evolution in acute leukemia/myelofibrosis occurred in 6 (1,5%) and 20 (5%) patients, and was significantly higher in patients receiving sequential cytotoxic agents. Overall survival was 38% at 19 years and was poorer for patients older than 60 years, with higher leukocytes count (>15 x 10(9)/L), hypertension and mellitus diabetes at ET diagnosis and for patients experiencing a thrombotic event during follow-up. Cytoreductive therapy was effective in decreasing platelet number with negligible toxicity; however, thrombocytosis control did not reduce the incidence of thrombosis and, for patients who received sequential therapies, the probability of disease evolution was higher and survival was poorer.

Gestational thyroid function abnormalities in conditions of mild iodine deficiency: early screening versus continuous monitoring of maternal thyroid status.

OBJECTIVE: To longitudinally evaluate the timing of maternal thyroid underfunction occurrence in mildly iodine-deficient (ID) pregnant women, and ultimately assess the benefit of thyroid function testing at early gestation only in identifying maternal thyroid underfunction. PARTICIPANTS/METHODS: Serum free-thyroxine and TSH were measured in 220 consecutive women once in early pregnancy (by week 12) and twice per trimester subsequently. Anti-thyroperoxidase and anti-thyroglobulin were also determined at initial and final observation. RESULTS: Thyroid autoantibodies were detectable in 8.2% women. Overall, the prevalence of hypothyroidism over the course of gestation was 11.8% (26/220), with a relative risk of hypothyroidism in antibody-positive women of 5.0 (chi(2) 20.02, P<0.0005). Nonetheless, almost 70% hypothyroid women tested negative for thyroid autoantibodies. Fifteen/26 (57.7%) hypothyroid women were identified at presentation, and the remaining 11 at either early (6/11) or late (5/11) phases of the 2nd trimester. Isolated hypothyroxinemia was observed in 56/220 (25.4%) women, mostly from the 2nd trimester onwards. CONCLUSIONS: In mildly ID areas thyroid function testing early in gestation seems to be only partly effective in identifying thyroid underfunction in pregnant women. Indeed, in our series more than 40% hypothyroid women would not have been diagnosed had we limited our observation to early thyroid function tests alone. Although thyroid autoimmunity carried a 5-fold increased risk of hypothyroidism, iodine deficiency seems to be a major determinant in the occurrence of thyroid underfunction. Adequate iodine supplementation should be strongly recommended to meet the increased hormone demand over gestation.

Prenatal identification of isolated bilateral radial dysplasia.

Radial aplasia or hypoplasia is characterized by complete or partial absence of the radius and/or radial ray structure occurring in 1:30,000 live births. It may be unilateral or bilateral of varying severity, and may be isolated or associated with other anomalies. We report an unusual case of isolated radial aplasia at 20 weeks' gestation with complete absence of the right radius and thumb associated with marked hypoplasia of the left radius. The intrauterine 2- and 3-dimensional findings, postnatal radiographic evaluation, and autopsy results are reported.

Emotional state and dreams in pregnant women.

The aim of this study was to investigate the frequency of recall and the content of dreams during pregnancy, as well as their correlation with socio-demographic, obstetric and physician-patients relationship variables, emotional state and duration of labour. A questionnaire, designed to analyse background characteristics, was given to 290 women in the third trimester of gestation. The psychiatric analysis of anxiety and depression was performed using the Hamilton Rating Scale for Anxiety and the Montgomery-Asberg Depression Rating Scale, while dreams were divided into masochistic and pleasant according to Beck's criteria. Oneiric activity was found to be associated with age >or= 35 years, higher family income, higher educational level, and a "satisfactory" physician-patient relationship. Masochistic content was associated with age<35 years, quality of information and frequent thoughts of delivery. Concerning the emotional state, depression levels were higher in women reporting masochistic dreams, while no difference in anxiety levels was found. Labour duration was shorter in the dreamer group and in patients with masochistic dream content. These findings may indicate that, also in pregnancy, the number and the content of dreams are influenced by women's mood and that the evaluation of the oneiric activity might represent a useful tool for clinicians either to investigate the women's emotional state or to predict its repercussions on the course of labour.

Endoglin, PlGF and sFlt-1 as markers for predicting pre-eclampsia.

OBJECTIVE: To evaluate the ability of endoglin, placental growth factor (PlGF) and the soluble form of vascular endothelial growth factor receptor (sFlt-1) measurements in gestational weeks 24-28 were used to predict pre-eclampsia. DESIGN: Observational, prospective study. Setting. Department of Gynecological, Obstetrical Sciences and Reproductive Medicine, University of Messina. Sample. Fifty-two pre-eclamptic and 52 healthy pregnant women. METHODS: A maternal serum sample was frozen and stored at 1-h 50-g glucose challenge test between 24 and 28 weeks' gestation. A second maternal serum sample was collected at admission for the onset of the disease in the pre-eclamptic group and at admission for delivery in the control group. Levels of endoglin, sFlt-1 and the PlGF were measured in the stored serum. Pre-eclamptic subjects were also divided into women with early-onset (<37 weeks) and women with late-onset pre-eclampsia (> or =37 weeks). RESULTS: Levels of endoglin, sFlt-1, and sFlt-1:PlGF ratio were found to be higher in the pre-eclamptic group in both trimesters. No differences were found between early- and late-onset pre-eclamptic. The Receiver Operating Characteristics curve, applied to the second trimester marker values, showed the best diagnostic profile for sFlt-1:PlGF (area under the curve, AUC=0.92) followed by endoglin (AUC=0.88), sFlt-1 (AUC=0.87) and PlGF (AUC=0.83). This finding was confirmed by Bayesian analysis which highlighted a specificity, a sensitivity, a diagnostic accuracy, a positive predictive value and a negative predictive value of 88.5% for sFlt-1:PlGF using a cut-off of 38.47. CONCLUSIONS: Endoglin, PlGF and sFlt-1 might be used as markers for predicting pre-eclampsia, but sFlt-1:PlGF seems to be more accurate.

Long-term outcome of complete cytogenetic responders after imatinib 400 mg in late chronic phase, philadelphia-positive chronic myeloid leukemia: the GIMEMA Working Party on CML.

PURPOSE: Imatinib mesylate (IM) has rapidly become the front-line treatment of Philadelphia-positive (Ph-pos) chronic myeloid leukemia, but the number of patients who were treated and are being treated with IM second-line is still substantial. PATIENTS AND METHODS: We have monitored and analyzed the cytogenetic and molecular response to IM 400 mg/d in a cohort of 277 late chronic phase (LCP) patients who were resistant or intolerant to interferon-alpha and were observed for 48 to 79 months (median, 72 months). RESULTS: One hundred fifty-three patients (55%) achieved a complete cytogenetic response (CCgR). Seventy-seven percent of them were still in CCgR after 5 years. The rate of response loss did not increase over time. The 6-year progression-free survival and overall survival of these 153 complete cytogenetic responders were 90% and 91%, respectively. Molecular response was less than major in 21%, major in 78%, and complete in one patient only. CONCLUSION: These data confirm that, in LCP the CCgR rate to IM is 50% to 60%, and show that CCgR is stable and is associated with a prolonged survival, even if leukemia continues to be molecularly detectable.

Effects of antepartum electronic fetal monitoring on maternal emotional state.

BACKGROUND: To evaluate the emotional state of pregnant women undergoing computerised cardiotocography (cCTG). METHODS: A questionnaire including questions about socio-demographic background, personal obstetric history and physician-patient relationship was given to 204 pregnant women about to undergo cCTG. The Edinburgh Post-natal Depression Scale (EPDS) was used to assess patients' mood state before CTG, while the Spielberger State-Trait Anxiety Inventory (STAI) was used to evaluate anxiety levels before and after this examination. RESULTS: Mean STAI T-anxiety score did not differ before and after CTG (p=0.38), but higher levels of basal anxiety were found in women who had undergone only occasional prenatal controls (p=0.04), as well as smokers (p=0.01), and women preferring a vaginal delivery (p=0.01). The mean STAI S-anxiety score of 43.6+/-4.03 before the cardiotographic examination, increased to 45.2+/-5.4 after this test with a statistically significant difference (p=0.0001). This increase was found to be correlated with the presence of obstetric complications during the current pregnancy (p=0.036) and a lower number of fetal active movements (p=0.029). Based on the EPDS, 22 patients (14.1%) were found to be depressed, but this condition was not correlated with significant increases in anxiety levels. CONCLUSIONS: Anxiety levels in pregnant women who undergo routine CTG are increased, and this emotional reaction seems to be influenced by the perception of fetal movement during the examination, and is more evident in pregnancies affected by obstetric complications.