Human papillomavirus DNA detection and histological findings in women referred for atypical glandular cells or adenocarcinoma in situ in their Pap smears

OBJECTIVE: To evaluate the association between high-risk human papillomavirus (HPV) DNA detection and histological diagnosis in women referred for atypical glandular cells (AGC) or adenocarcinoma in situ (AIS) at Pap smear. METHODS: In this cross-sectional study, 146 women referred for AGC (124), AGC with high-grade squamous intraepithelial lesion (HSIL) (15), or AIS (7) were tested for HPV DNA using Hybrid Capture II (HC II). All women underwent colposcopic examination, and cervical biopsy was performed for 95 patients. Fifty-one women referred due to AGC with normal colposcopy and normal second Pap smear were scheduled for control visits every 4 months. RESULTS: The overall prevalence of HPV DNA was 38%. HPV DNA was detected in 93% of the women with HSIL associated with AGC and in 71% of women with AIS Pap smear, being significantly higher when compared with the prevalence (29%) in women with AGC alone. Forty-five women (30.8%) had clinically significant histological lesions (CIN 2 or worse). High-risk HPV DNA was detected in only 16% of the women without significant abnormalities in biopsy, in contrast to 96% of those who had CIN 2 or CIN 3 and 75% of women with AIS. Eighty-five percent of women with invasive cervical carcinoma (squamous or adenocarcinoma) tested positive for HPV DNA. HPV DNA detection was significantly associated with histological diagnosis of CIN 2 or worse, with an odds ratio (OR) = 51.8 (95% CI 14.3-199.9). CONCLUSION: HPV DNA detection was strongly associated with the severity of cervical lesion (CIN 2 or worse) in women referred for AGC or AIS in their Pap smear. These data implicate the use of HPV testing in triage of women with AGC Pap smears.     

S32504, a novel naphtoxazine agonist at dopamine D3/D2 receptors: II. Actions in rodent, primate, and cellular models of antiparkinsonian activity in comparison to ropinirole

These studies evaluated the potential antiparkinsonian properties of the novel dopamine D(3)/D(2) receptor agonist S32504 [(+)-trans-3,4,4a,5,6, 10b-hexahydro-9-carbamoyl-4-propyl-2H-naphth[1,2-b]-1,4-oxazine] in comparison with those of the clinically employed agonist ropinirole. In rats with a unilateral, 6-hydroxydopamine lesion of the substantia nigra, S32504 (0.0025-0.04 mg/kg, s.c.) more potently elicited contralateral rotation than S32601 [(-)-trans-3,4,4a,5,6, 10b-hexahydro-9-carbamoyl-4-propyl-2H-naphth-[1,2-b]-1,4-oxazine (its less active enantiomer)], ropinirole, and l-3,4-dihydroxyphenylalanine (l-DOPA). Rotation elicited by S32504 was blocked by the D(2)/D(3) receptor antagonists haloperidol and raclopride and by the D(2) antagonist L741,626 [4-(4-chlorophenyl)-1-(1H-indol-3-ylmethyl)piperidin-4-ol], but not by the D(3) antagonist S33084 [(3aR,9bS)-N-[4-(8-cyano-1,3a,4,9b-tetrahydro-3H-benzopyrano[3,4-c]pyrrole-2-yl)-butyl]-(4-phenyl)benzamide]. As assessed by dialysis in both lesioned and nonlesioned animals, S32504 (0.04-2.5 mg/kg, s.c.) reduced striatal levels of acetylcholine. This effect was blocked by raclopride, haloperidol, and L741,626 but not S33084. In rats treated with reserpine, hypolocomotion was reversed by S32504 and, less potently, by ropinirole. In "unprimed" marmosets treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, both s.c. (0.01-0.04 mg/kg) and p.o. (0.04-1.25 mg/kg) administration of S32504 dose-dependently and rapidly (within 10 min) increased locomotor activity and reduced disability. Furthermore, S32504 dose-dependently reversed bradykinesia and improved posture in "L-DOPA-primed" animals, whereas eliciting less pronounced dyskinesia than l-DOPA. Finally, in terminally differentiated SH-SY5Y cells presenting a dopaminergic phenotype, S32504, but not S32601, abrogated the neurotoxic effects of 1-methyl-4-phenylpyridinium, an action inhibited by raclopride and S33084 but not L741,626. Ropinirole was weakly neuroprotective in this model. In conclusion, S32504 displays potent and stereospecific activity in rodent, primate, and cellular models of antiparkinsonian properties. Although activation of D(2) receptors is crucial to the motor actions of S32504, engagement of D(3) receptors contributes to its neuroprotective properties.     

Ferritin heavy/light chain (FTH1/FTL) expression,serum ferritin levels,and their functional as well as prognostic roles in acute myeloid leukemia

Spontaneous remission (SR) of acute myeloid leukemia (AML) represents a rare phenomenon and is usually of short duration although long‐term remissions are reported. Indeed, mechanisms underlying SR remain unclear, but it is suggested that immunactivation, e.g. caused by infections, plays an important role. Here we report on a patient who suffered from pneumonia and simultaneously experienced very late hematologic AML relapse seventeen years after allogeneic blood stem cell transplantation (allo‐BSCT). Surprisingly in parallel to recovery from pneumonia peripheral blood count which previously showed pancytopenia, had normalized and bone marrow (BM) aspiration revealed spontaneous remission of AML. To the best of our knowledge we here report on the latest AML relapse after allo‐BSCT experiencing SR.     

S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1] benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenyl-acetamide), a preferential dopamine D3 versus D2 receptor antagonist and potential antipsychotic agent: III. Actions in models of therapeutic activity and induction of side effects

In contrast to clinically available antipsychotics, the novel benzopyranopyrrolidine derivative, S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenyl-acetamide), behaves as a preferential antagonist of D(3) versus D(2) receptors and does not interact with histamine H(1) and muscarinic receptors. In contrast to haloperidol, clozapine, olanzapine, and risperidone, S33138 (0.16-2.5 mg/kg s.c.) did not disrupt performance in passive-avoidance and five-choice serial reaction time procedures. Furthermore, upon either systemic administration (0.04-2.5 mg/kg s.c.) or introduction into the frontal cortex (0.04-0.63 mug/side), S33138 potently attenuated the perturbation of social recognition by scopolamine or a prolonged intersession delay. Over a comparable and low-dose range, S33138 (0.04-0.63 mg/kg s.c.) elevated dialysis levels of acetylcholine in the frontal cortex of freely moving rats. At higher doses (2.5-10.0 mg/kg s.c.), S33138 also increased frontocortical levels of histamine, whereas monoamines, glutamate, glycine, and GABA were unaffected. By analogy to the other antipsychotics, S33138 (0.63-10.0 mg/kg s.c.) inhibited conditioned avoidance responses in rats, apomorphine-induced climbing in mice, and hyperlocomotion elicited by amphetamine, cocaine, dizocilpine, ketamine, and phencyclidine in rats. S33138 (0.16-2.5 mg/kg s.c.) also blocked the reduction of prepulse inhibition elicited by apomorphine. In comparison with the above actions, only "high" doses of S33138 (10.0-40.0 mg/kg s.c.) elicited catalepsy. To summarize, reflecting preferential blockade of D(3) versus D(2) receptors, S33138 preserves and/or enhances cognitive function, increases frontocortical cholinergic transmission, and is active in models of antipsychotic properties at doses well below those inducing catalepsy. In comparison with clinically available agents, S33138 displays, thus, a distinctive and promising profile of potential antipsychotic properties.     

Cognitive impairment in schizophrenia: a review of developmental and genetic models, and pro-cognitive profile of the optimised D(3) > D(2) antagonist, S33138

In vivo animal models are indispensable both for clarifying the pathological bases of schizophrenia, and for evaluating the potential benefits and disadvantages of novel therapy. Procedures that model mnemonic impairment are of particular interest since currently-available drugs do little to improve cognitive symptoms: this is hardly surprising, in fact, since most of them potently antagonise histamine H(1), muscarinic, and/or alpha(1)-adrenergic receptors. Further, their blockade of D(2) receptors likewise compromises cognitive performance. By contrast, D(3) receptor antagonism improves certain cognitive domains, suggesting that preferential antagonism of D(3) vs. D(2) receptors may permit enhanced effectiveness against cognitive dysfunction. The novel agent, S33138, possesses such an "optimised" profile and shows a unique and broad-based pattern of pro-cognitive properties in rodents and primates, in the absence of extrapyramidal and metabolic side-effects. The present article surveys the preclinical pharmacology of S33138. It also reviews developmental and genetic risk factors for schizophrenia and their experimental modeling in rodents, with a particular emphasis on sensorimotor gating and cognitive deficits.     

Trisomy 8 as sole anomaly or with other clonal aberrations in acute myeloid leukemia: impact on clinical presentation and outcome

One hundred and fifty-four acute myeloid leukemia patients with trisomy 8 were studied for their clinical and biological characteristics, and treatment outcome. Forty-seven patients presented with trisomy 8 as the sole aberration, 107 with trisomy 8 associated with other cytogenetic abnormalities (13 with favorable, 54 with intermediate, and 40 with unfavorable risk cytogenetics). Overall complete remission (CR) proportion was 48%. Median disease-free survival (DFS) and overall survival (OS) were 7.8 and 8.3 months, respectively. In multivariate analysis, age >or=60 years (P<0.0001) and association with unfavorable karyotype (P=0.03) were of poor prognostic value for CR achievement. Age >or=60 years (P<0.0001) and antecedents of dysmyelopoiesis (P=0.02) were of poor prognostic value for OS. Patients with trisomy 8 alone did not show any difference in terms of outcome as compared with those in whom trisomy 8 was associated to intermediate risk cytogenetics (P=0.0002). Trisomy 8 in addition to favorable karyotype maintained a good clinical outcome, while trisomy 8 in addition to unfavorable cytogenetics showed the worst prognosis.     

Intensive chemotherapy with mitoxantrone administered as a single injection in patients with high-risk acute myeloid leukemia: results of the EMA 2000 trial

Following a dose-escalation study performed to assess the maximally tolerated dose of high-dose mitoxantrone in a single injection combined with chemotherapy, a phase II trial (EMA 2000 regimen) was performed in patients with refractory or relapsed acute myelogenous leukemia (AML) between October 2000 and December 2003. Sixty-two patients entered the study and received mitoxantrone 45 mg/m² on day 1 in combination with cytarabine and etoposide. Overall, 39 patients (63%) achieved complete remission (CR). Four patients died during remission induction, and 19 patients had resistant disease. Median time to granulocyte and platelet recovery was 34 and 39 days, respectively. The predominant non-hematologic toxicity was infection, with 53% severe infections. Thirty-three of the 39 remitters received subsequent treatment consisting of maintenance chemotherapy courses in 17 patients, allogeneic stem cell transplantation (SCT) in 7 patients, and autologous SCT in 9 patients. The median overall survival of the entire cohort was 8.1 months, with 18% at 2.5 years. EMA chemotherapy using a single injection of mitoxantrone is effective in the treatment of high-risk AML. CR proportion was significantly higher in patients with a first CR duration 6 months when compared with those from a control trial using standard-dose mitoxantrone (90 vs 70%, p=0.03).     

Evaluating the role of prophylaxis in the management of invasive fungal infections in patients with hematologic malignancy

Invasive fungal infection (IFI) is a persistent problem among critically ill and immunocompromised patients, especially hematopoietic stem cell transplant or solid organ transplant recipients, or patients on intensive chemotherapy for acute leukemia. Although numerous antifungal agents are available, IFI remains a serious problem because of obstacles to timely diagnosis and high morbidity and mortality rates associated with such infection. Improvements in treatment of underlying diseases have rapidly expanded the patient populations at risk for IFI with increased use of immunosuppressants, aggressive chemotherapy, broad-spectrum antibiotics, and narrow-spectrum antifungal prophylaxis. There are various treatment strategies that can be used to manage IFI: prophylaxis, empiric, preemptive, and directed. As the infection progresses, the prospect of successfully treating an infection diminishes; conversely, the earlier the intervention, the greater the possibility of unnecessary treatment. This article discusses the epidemiology of the most important fungal pathogens, identifies high-risk patient groups and risk factors associated with IFI, and critically evaluates the advantages and disadvantages of available diagnostic tests and treatment strategies and the rationale for antifungal prophylaxis. For patients at high risk for IFI, antifungal prophylaxis is an attractive strategy, and numerous randomized, controlled clinical studies have documented the benefit of such prophylaxis as well as the most efficacious of currently available agents.