Aprepitant versus metoclopramide, both combined with dexamethasone, for the prevention of cisplatin-induced delayed emesis: a randomized, double-blind study.

BACKGROUND: A combination of aprepitant, a 5-HT3 receptor antagonist (r.a.), and dexamethasone is recommended for the prophylaxis of cisplatin-induced nausea and vomiting in the acute phase, and aprepitant + dexamethasone (A + D) in the delayed phase. The aim of this study was to verify if A + D is superior to metoclopramide plus dexamethasone (M + D) in preventing delayed emesis in cancer patients receiving the same prophylaxis for acute emesis. PATIENTS AND METHODS: A randomized double-blind study comparing A + D versus M + D was completed in previously untreated cancer patients. Before chemotherapy, all patients were treated with intravenous palonosetron 0.25 mg and dexamethasone 12 mg, and oral aprepitant 125 mg. On day 2-4, patients randomly received oral dexamethasone 8 mg plus aprepitant 80 mg once daily (days 2-3) or metoclopramide 20 mg four times daily plus dexamethasone 8 mg bid. Primary endpoint was rate of complete response (no vomiting, no rescue treatment) in day 2-5 after chemotherapy. RESULTS: Due to difficulty in the accrual of patients, 303 of the 480 planned patients were enrolled, 284 were fully evaluable, 147 receiving A + D, 137 M + D. Day 1 results were similar in both arms. On day 2-5, complete response rate was not significantly different (80.3% with A + D versus 82.5% with M + D, P < 0.38, respectively), and all secondary endpoints were also similar (complete protection, total control, no vomiting, no nausea, and score of Functional Living Index-Emesis; P < 0.24). Adverse events incidence was not significantly different between the two treatments. CONCLUSIONS: In cancer patients submitted to cisplatin-based chemotherapy, receiving the same antiemetic prophylaxis for acute emesis, A + D is not superior to M + D in preventing delayed emesis, and both treatments present similar toxicity. CLINICALTRIALSGOV NUMBER: NCT00869310.

Ultrasound study of the myoendometrial border.

Abnormal thickening of the Endometrial Subendometrial Myometrium Unit (ESEMy Unit, including basal endometrium and inner myometrium) has been detected on imaging and referred to as "diffuse adenomyosis" in infertile patients with proven endometriosis. However, no robust relationship exists between enlargement of the ESEMy Unit and adenomyosis proven on hysterectomy specimen examination; moreover, if any correlation exists, it lacks histological validation in women wishing to preserve fertility. While adenomyosis effects on fertility, if any, remain elusive, thickening of the ESEMy Unit have been consistently linked to fertility impairment in both experimental and clinical models. The hypothesis tested herein is that a novel condition exists, called "ESEMy Unit disruption disease"; it is epidemiologically different from adenomyosis, diagnosable on imaging and bears a clear impact on human fertility through various mechanisms. A new wave of good quality studies may be elicited by a clear distinction between adenomyosis and the "ESEMy Unit disruption disease".

Tracking the time-varying cortical connectivity patterns by adaptive multivariate estimators.

The directed transfer function (DTF) and the partial directed coherence (PDC) are frequency-domain estimators that are able to describe interactions between cortical areas in terms of the concept of Granger causality. However, the classical estimation of these methods is based on the multivariate autoregressive modelling (MVAR) of time series, which requires the stationarity of the signals. In this way, transient pathways of information transfer remains hidden. The objective of this study is to test a time-varying multivariate method for the estimation of rapidly changing connectivity relationships between cortical areas of the human brain, based on DTF/PDC and on the use of adaptive MVAR modelling (AMVAR) and to apply it to a set of real high resolution EEG data. This approach will allow the observation of rapidly changing influences between the cortical areas during the execution of a task. The simulation results indicated that time-varying DTF and PDC are able to estimate correctly the imposed connectivity patterns under reasonable operative conditions of signal-to-noise ratio (SNR) ad number of trials. An SNR of five and a number of trials of at least 20 provide a good accuracy in the estimation. After testing the method by the simulation study, we provide an application to the cortical estimations obtained from high resolution EEG data recorded from a group of healthy subject during a combined foot-lips movement and present the time-varying connectivity patterns resulting from the application of both DTF and PDC. Two different cortical networks were detected with the proposed methods, one constant across the task and the other evolving during the preparation of the joint movement.

Ectopic TAL-1/SCL expression in phenotypically normal or leukemic myeloid precursors: proliferative and antiapoptotic effects coupled with a differentiation blockade.

The TAL-1 gene specifies a basic helix-loop-helix domain (bHLH) transcription factor, which heterodimerizes with E2A gene family proteins. tal-1 protein is abnormally expressed in the majority of T-cell acute lymphoblastic leukemias (T-ALLs). tal-1 is expressed and plays a significant role in normal erythropoietic differentiation and maturation, while its expression in early myeloid differentiation is abruptly shut off at the level of late progenitors/early differentiated precursors (G. L. Condorelli, L. Vitelli, M. Valtieri, I. Marta, E. Montesoro, V. Lulli, R. Baer, and C. Peschle, Blood 86:164-175, 1995). We show that in late myeloid progenitors (the phenotypically normal murine 32D cell line) and early leukemic precursors (the human HL-60 promyelocytic leukemia cell line) ectopic tal-1 expression induces (i) a proliferative effect under suboptimal culture conditions (i.e., low growth factor and serum concentrations respectively), via an antiapoptotic effect in 32D cells or increased DNA synthesis in HL-60 cells, and (ii) a total or marked inhibitory effect on differentiation, respectively, on granulocyte colony-stimulating factor-induced granulopoiesis in 32D cells or retinoic acid- and vitamin D3-induced granulo- and monocytopoiesis in HL-60 cells. Furthermore, experiments with 32D temperature-sensitive p53 cells indicate that aberrant tal-1 expression at the permissive temperature does not exert a proliferative effect but causes p53-mediated apoptosis, i.e., the tal-1 proliferative effect depends on the integrity of the cell cycle checkpoints of the host cell, as observed for c-myc and other oncogenes. tal-1 mutant experiments indicate that ectopic tal-1 effects are mediated by both the DNA-binding and the heterodimerization domains, while the N-terminally truncated tal-1 variant (M3) expressed in T-ALL malignant cells mimics the effects of the wild-type protein. Altogether, our results (i) indicate proliferative and antidifferentiative effects of ectopic tal-1 expression, (ii) shed light on the underlying mechanisms (i.e., requirement for the integrity of the tal-1 bHLH domain and cell cycle checkpoints in the host cell, particularly p53), and (iii) provide new experimental models to further investigate these mechanisms.

Enforced TAL-1 expression stimulates primitive, erythroid and megakaryocytic progenitors but blocks the granulopoietic differentiation program.

In human adult hematopoiesis, the TAL-1 gene is up- and down-modulated in erythropoiesis and granulopoiesis, respectively [G. L. Condorelli et al., Blood, 86: 164-175, 19951. Here, it is shown that, in a hematopoietic progenitor cell (HPC) unilineage differentiation culture, tal-1 is induced and then expressed, in a sustained manner, in the megakaryopoietic lineage, whereas it is barely or not detected in the monocytopoietic series. We have investigated the role of enforced tal-1 expression by retroviral transfer into HPCs [erythroid burst-forming units and megakaryocytic and granulomonocytic colony-forming units (CFUs)], primitive HPCs (high proliferative potential colony-forming cells), and putative hematopoietic stem cells (HSCs), assayed as long-term culture initiating cells. TAL-1 overexpression induces an increase of erythroid burst-forming unit colony number and size and megakaryocytic CFU colony number and an inhibition of granulomonocytic CFU and granulocytic CFU (CFU-G) but not monocytic CFU colony number; conversely, TAL-1 mutants with defective heterodimerizing or DNA-binding domains do not exert these effects at a significant level. Although it does not affect long-term culture initiating cells, exogenous TAL-1 causes a significant proliferative stimulus on primary and secondary high proliferative potential colony-forming cells. In conclusion, exogenous tal-1 exerts differential and stage- and lineage-specific effects on the HPC/HSC differentiation/proliferation gene programs. Thus, it induces a stimulatory effect at the level of erythroid and megakaryocytic HPCs, while exerting a selective proliferative action on downstream erythropoiesis. Furthermore, it induces differential effects on the myeloid series: the partial blockade of CFU-G differentiation is possibly linked to the sharp down-modulation of endogenous TAL-1 expression at the level of the CFU-G-to-granulopoietic precursor differentiation step; in contrast, no significant effect is observed on monocytic CFU colony formation. Finally, the stimulatory effect on primitive HPCs but not putative stem cells suggests subtle differences in the effects exerted by tal-1 overexpression on primitive HPC/HSC subsets in adult life.

Comparison of fresh, cryopreserved and cultured haematopoietic stem cells from fetal liver.

The cryopreservation and long-term culture of fetal liver (FL) cells may offer a ready source of haematopoietic stem cells (HSC). To compare these two techniques, an H-2-incompatible murine model was used, in conditions close to those of stem cell transplantation in humans. After cryopreservation, the recovery of colony-forming unit-culture (CFU-C) and of 14-day colony-forming unit-spleen (CFU-S) was 55.5% and 23%, respectively, compared with fresh cells. The rate of engraftment of donor cells was very high in mice reconstituted with either cryopreserved or fresh cells and the resulting chimerism was virtually complete in both cases. Functionally, both groups showed a significant humoral response to sheep red blood cells. Chimeric mice obtained by injection of cryopreserved cells were able to reject third-party SJL mouse (H-2s) skin grafts (11.4 +/- 1.6 days); at the same time, they specifically tolerated skin grafts from BDF1 (H-2b x H-2d) donor mice, indicating that cryopreserved FL cells could induce both tolerance to donor antigens and restore normal immunological responses to third-party alloantigens. Following 4-week cultures, consistent losses in the total number of CFU-C and CFU-S (2.5% and 8.6% yield, respectively) were observed. Cultured FL failed to protect the animals from the lethal effects of irradiation, due to insufficient reconstitution. These results favour the possible use of cryopreserved FL in clinical settings. At present, however, techniques to improve FL cultures and their efficiency for in vivo reconstitution are required.

Diagnostic pitfalls of echography in a case of hepatic cavernous hemangioma.

An ecographic study of the liver in a 55-year-old female, with a history of mastectomy for a breast ductal cancer, showed multiple focal lesions. On computer tomography, we interpreted these lesions as metastatic disease. 99m Tc-labeled RBC showed non-homogeneous flow distribution in the right lobe of the liver. Fine needle aspiration biopsy under ecographic guidance showed no metastatic disease, and suggested a vascular lesion. The presence of spindle-shaped cells, reactive for CD 34 and for factor VIII, enabled definitive diagnosis of angiomatous lesion. Cytological confirmation of each hepatic mass is a mandatory prerequisite for any therapy.

Bone marrow biopsy for the staging of non-Hodgkin's lymphoma: bilateral or unilateral trephine biopsy?

AIM: The occurrence of unilateral involvement in bilateral bone marrow trephine biopsies in non-Hodgkin's lymphomas (NHL) at disease onset (10-20% of cases) has been reported since the early 70s. Therefore, although these studies were based on small series, the use of bilateral bone marrow biopsies has become the rule. However, the clinical value of this procedure has never been clearly established. The aim of the present study was to ascertain the true value of bilateral bone marrow biopsy in the staging of NHL. STUDY DESIGN: We examined 368 cases of NHL (A-H according to the Working Formulation) (WF), without leukemic involvement of the peripheral blood, in order to evaluate: 1) the incidence of unilateral bone marrow involvement; 2) the percentage of patients who, as a result of unilateral bone marrow involvement, changed from stages I-II to stage IV; 3) assessment of response to therapy for patients with both bilateral or unilateral bone marrow involvement. RESULTS: In the A-C NHL groups of WF there was a unilateral bone marrow involvement of 8.8%. Overall, bone marrow involvement induced a change from clinical stages I-II to stage IV in 5.6% of cases, a figure which would correspond to a false negative rate of 2.8%, if unilateral bone marrow biopsy was performed. In the D-F and G, H groups of WF, unilateral involvement was 10.1% and 8.5% respectively; the change in stage from I-II to IV by unilateral bone marrow involvement respectively amounted to 1.4% and 2.8%, which correspond to respective false negative rates of 0.7% and 1.4%. CONCLUSIONS: On the basis of these results and of the present therapeutic strategies, we propose: bilateral bone marrow biopsy for clinical stages I-II of all NHL; no bone marrow biopsy at disease onset for clinical stages III and IV of A to H histologic subtypes of the WF; unilateral bone marrow biopsy (A-C subtypes of the WF) or bilateral (D-H of the WF), after the regression of extramedullary localizations.

[Evaluation of indications for cesarean section. Comparison of two decades. Preliminary results]. / Evoluzione delle indicazioni al taglio cesareo. Confronto fra due decenni. Risultati preliminari.

We have retrospectively analysed the incidence of cesarean section during the periods 1970-79 and 1981-90 and the evolution, if any, of the principal indication over time. The average incidence of cesarean section was 9.01% in the seventies and 11.63% in the eighties: the difference was statistically significant. Four classes of indication show significant differences between the periods considered: previous cesarean, feto-pelvic disproportion, anomalous presentation, gestosis. An evolution of cesarean section indications is shown: minus parity, better health, sanitary and environmental conditions, better physiopathological and clinical knowledge of pregnancy complication and labor seem to be causes of that evolution.

[Surgical delivery: comparison of two 5-year periods]. / Il parto operativo. Due quinquenni a confronto.

Operative delivery prevalence is considered in two periods: 1980-1985 and 1986-1990. Reduced prevalence of repeated cesarean section is reported for the second period as opposed to the first one. A larger prevalence of cesarean sections for anomalous presentation (breech presentation included), fetal distress. EPH gestosis, abruptio placentae is reported in the second half of '80's. Vacuum Extractor applications are reduced in the second period compared to the first one for with concern secondary uterine hypokinesia; larger V.E. applications are reported in the second period for fetal distress in the second stage of labor. Relatively rare forceps applications in both periods.

[A case of intestinal obstruction in pregnancy]. / Su di un caso di occlusione intestinale in gravidanza.

Intestinal obstruction during pregnancy is a rare and dangerous complication. The causes of its occurrence are previous operations ad inflammation and one of their results: adhesions. Symptoms of intestinal obstruction (nausea, vomiting, constipation) rarely occur simultaneously and often accompany normal pregnancy, hampering diagnosis. Abdominal X-ray often represents the only complementary investigation diriment for diagnosis. A case of intestinal obstruction at 36 weeks gestation is reported to emphasize diagnostic difficulties of this rare pregnancy complication.

[Use of the TUT (Tension-free Vaginal Tape) in the treatment of female urinary stress incontinence. Preliminary results]. / Utilizzazione del TVT (Tension-free Vaginal Tape) nel trattamento dell'incontinenza urinaria femminile da sforzo. Risultati preliminari.

BACKGROUND: The Tension-free Vaginal Tape (TVT) represents the most recent technique for the treatment of genuine stress urinary incontinence (GSUI). The various number of surgical procedures proposed for the treatment of GSI very often do not lead to a complete remission of this pathology. The data from the literature show how TVT is a effective procedure for the treatment of female urinary incontinence. METHODS: Twenty-nine women with diagnosis of urinary incontinence underwent application of polypropilene band (TVT: tension-free vaginal tape) underneath the uretra, in order to treat this disorder. The procedure has been carried out in peripheral anesthesia. RESULTS: A complete remission of the urinary incontinence was obtained in 24 patients. In the remaining cases there was an improvement of the symptoms in two patients, whereas in two patients remained a secondary detrusor instability. In one case the external iliac vein was perforated thus requiring a surgical repair. CONCLUSION: The short surgical time, the feasibility of the procedure and the following short hospitalization made this technique well accepted either by the surgeons ang the patients. Moreover the possibility to carry out the procedure in peripheral anesthesia allows to have the collaboration of the patient. However this technique is not free of risks, how the serious complication we had can demonstrate.

[An unusual case of twin birth with two live infants delivered in two consecutive years, at a 36-day interval]. / Uno strano caso di parto gemellare con due feti vivi nati in anni diversi a distanza di 36 giorni uno dall'altro.

The paper describes the obstetric management of an unique case of twin, bicorial, biamniotic pregnancy in which the second twin born 36 days after the first. Both twins are living today.

[Prolymphocytic leukemia: the therapeutic strategy]. / La leucemia prolinfocitica: strategia terapeutica.

Prolymphocytic leukemia (PLL) is a malignant lymphoproliferative disorder, characterized by massive splenomegaly, predominance of prolymphocytes in the peripheral blood and bone marrow, minimal lymph nodes enlargement and poor prognosis. It accounts for a 5-10% case of chronic lymphocytic leukemia (CLL). Patients age is usually over the fifth decade, the disease is 4.1 more common in males. More than 80% are B-lymphocytic derived cells showing a post-thymic phenotype. Median survival of B-PLL patients is 3 years, while only 7 months in T-PLL. Standard therapy of CLL with alkylating agents and prednisone have been not much effective in the treatment of PLL with a response rate of about 20%. Up to date no ideal treatment is available for PLL. A realistic goal is probably to achieve a clinical course transformation, from aggressive to mild, thus changing from short to long term prognosis. For this purpose the initial therapeutic approach cannot be limited to a single agent only. Splenic irradiation, intensive anthracyclines-based regimens, leukapheresis combine together represent the best therapeutic choice. Alkylating agents with or without prednisone may play a role in keeping indolent clinical course. Fludarabine has shown antileukemic activity against PPL even in patients resistant.

Esophageal atresia and prenatal exposure to mycophenolate.

Mycophenolate mofetil is a widely prescribed immunosuppressive agent for transplant patients and autoimmune diseases. Potential teratogenic effects after in utero exposure to mycophenolate mofetil has been described in human clinical observations. The complete clinical pattern is still being delineated. We present four newborns with esophageal atresia and other congenital anomalies, prenatally exposed to mycophenolate mofetil during the first trimester. Two of the cases had other defects related to the embryopathy: microtia, eye abnormalities and oral clefts. Two cases did not show major craniofacial anomalies. We propose that esophageal atresia with or without tracheoesophageal fistula is a feature of mycophenolate embryopathy even without the presence of other major craniofacial anomalies. The human teratogenicity of MMF is reinforced by this report, and the current contraceptive recommendations about its use in fertile women are stressed.