Percutaneous ultrasound-guided microwave ablation for treatment of hepatocellular carcinomas in dogs: four cases (2019-2020).

OBJECTIVES: To describe ultrasound-guided microwave ablation as a minimally invasive treatment option for primary or metastatic hepatocellular carcinomas. METHODS: Four client-owned dogs underwent percutaneous ultrasound-guided microwave ablation of three primary and one metastatic hepatocellular carcinoma, diagnosed on cytology/histopathology. In each case, multiple ultrasound-guided thermal lesions were created in a 10 to 40 minutes ablation at 30 to 35 W. Real-time monitoring was performed using 10 MHz diagnostic ultrasound transducers. The procedures were performed without complication and CT scans or abdominal ultrasounds were repeated immediately after. Patients were discharged on oral analgesia on the same day or 24 hours later. RESULTS: Hepatocellular carcinomas were successfully ablated, which in some cases resulted in an improvement in clinical signs and laboratory values. The patients were followed up for a time ranging between 39 and 649 days and no evidence of disease progression was found. Three out of four patients are still alive at the time of writing. CLINICAL SIGNIFICANCE: In these four patients, minimally invasive ultrasound-guided microwave ablation was feasible and resulted in no immediate complications. Regular imaging follow-up is recommended after the procedure and further studies on microwave ablation are warranted to establish its effectiveness in dogs with hepatocellular carcinomas.

Surgical removal of a sewing needle penetrated through the foramen lacerum into a canine brain.

An intracranial metallic foreign body (sewing needle) was diagnosed in an 11-month-old Cavalier King Charles Spaniel. Clinical evaluation showed drooling and chewing, but an otherwise normal neurological examination. Skull radiographs showed a metallic foreign body extending from the pharynx into the skull. A CT scan confirmed the presence of a foreign body crossing the right foramen lacerum into the brain. The needle was removed surgically with the aid of fluoroscopy. No complications were noted, except for transient right Horner's syndrome, most likely due to partial damage of the sympathetic postganglionic fibres that lie in the region of the tympanic bulla following surgery. The owner reported the dog being healthy 3 months after surgery.

[The use of RCGO triggers in the obstetric - gynecological procedures: the impact on the reduction of adeverse events. The experience of the Lombardia Region]. / L'utilizzo dei RCOG trigger in area ostetrica - ginecologica e la riduzione degli eventi avversi. L'esperienza della regione Lombardia.

The last few weeks of pregnancy are critical to a baby's health because important organs, including the brain and lungs, are not completely developed until the end of pregnancy. The adverse events during labor and childbirth can have very serious physical, psychological and financial consequences for the child, the family, health professionals and the whole community. These events can be reduced through interventions aimed at improving the safety and quality of care, based on evidence-based knowledge, guidelines and practices that must be widely and effectively applied. This work reports the experience of the Lombardy Region on improvement actions in the obstetric and gynecological procedures for the reduction of adverse events and sentinel events through the monitoring and management of the RCGS trigger tool.

Vaginal birth after prior myomectomy.

OBJECTIVE: The aim of this retrospective cohort study was to evaluate the obstetrical and perinatal outcomes of vaginal birth in case of pregnancies achieved after prior myomectomy. We also analyzed how operative characteristics at the time of surgery might influence the choice of obstetricians about mode of delivery. STUDY DESIGN: We analyzed retrospectively all women who underwent laparoscopic (LPS) or laparotomic (LPT) myomectomy between January 2002 and December 2014, in a network of three Institutions belonging to the University of Milano Bicocca, Italy. Women were contacted by phone interview and only cases with available follow-up data and who had a subsequent pregnancy were included. Operative characteristics and subsequent obstetrical outcomes were recorded and analyzed. RESULTS: 469 women who underwent myomectomy were contacted by phone interview, and 152 pregnancies were achieved after surgery, 96 after LPS and 56 after LPT. A total of 110 pregnancies ended in deliveries at ≥24 weeks. Seventy-three (66.4%) women had trial of labor after myomectomy (TOLAM), while 24 (21.8%) had a planned cesarean delivery (CD). Sixty-six (90.4%) of the TOLAM cases successfully accomplished vaginal delivery. No cases of uterine rupture (UR) were reported, and all deliveries ended in live births. The incidence of Neonatal Intensive Care Unit admission was 14.5% (16/110), with no cases of perinatal death. Comparing the surgical details at the time of myomectomy, the incidence of uterine cavity entered was significantly higher in planned CD group compared to TOLAM cases (p < 0.001). No other significant difference between the two groups was reported. CONCLUSIONS: A successful vaginal delivery was accomplished by 90.4% of women who had TOLAM, without any case of UR or severe maternal and perinatal complications. TOLAM may be considered and offered as feasible and relatively safe option. Obstetricians' attitude toward mode of delivery after prior myomectomy seems to be influenced by the reported entry into the uterine cavity at the time of surgery.

p53-dependent and p53-independent anticancer activity of a new indole derivative in human osteosarcoma cells.

Osteosarcoma (OS) is the most common primary malignant tumor of bone, occurring most frequently in children and adolescents. The mechanism of formation and development of OS have been studied for a long time. Tumor suppressor pathway governed by p53 gene are known to be involved in the pathogenesis of osteosarcoma. Moreover, loss of wild-type p53 activity is thought to be a major predictor of failure to respond to chemotherapy in various human cancers. In previous studies, we described the activity of a new indole derivative, NSC743420, belonging to the tubulin inhibitors family, capable to induce apoptosis and arrest of the cell cycle in the G2/M phase of various cancer cell lines. However, this molecule has never been tested on OS cell line. Here we address the activity of NSC743420 by examine whether differences in the p53 status could influence its effects on cell proliferation and death of OS cells. In particular, we compared the effect of the tested molecule on p53-wild type and p53-silenced U2OS cells, and on SaOS2 cell line, which is null for p53. Our results demonstrated that NSC743420 reduces OS cell proliferation by p53-dependent and p53-independent mechanisms. In particular, the molecule induces proliferative arrest that culminate to apoptosis in SaOS2 p53-null cells, while it brings a cytostatic and differentiating effect in U2OS cells, characterized by the cell cycle arrest in G0/G1 phase and increased alkaline phosphatase activity.

Complexos triazenidos de platina (II): Avaliação in vitro da atividade antibacteriana e citotóxica frente a bactérias e células de medula óssea de pacientes leucêmicos de um hospital escola / Triazenidos complexes of platinum (II): In vitro evaluation of antibacterial and cytotoxic activity against bacteria and bone marrow cells from leukemic patients in a university hospital

Atualmente, apesar da ampla gama de substâncias ativas existentes, progressivamente tem se limitado o arsenal terapêutico disponível na prática clínica, isto se deve, especialmente, pelo surgimento da resistência aos agentes terapêuticos utilizados no tratamento de tumores e infecções bacterianas. Em virtude das diversas propriedades farmacológicas demonstradas pelos triazenos (TZCs), avaliaram-se compostos inéditos na busca de novos agentes biologicamente ativos, estes foram denominados C1 e C2. A atividade antibacteriana foi realizada pelo método convencional da microdiluição em caldo, através da técnica da Concentração Inibitória Mínima (CIM), frente a cepas bacterianas de referência American Type Culture Collection (ATCC) e isolados clínicos com resistência múltipla as drogas (RMD). A citotoxicidade foi analisada através do ensaio colorimétrico baseado na redução do brometo de 3-(4,5-dimetiltiazol-2-il)-2,5?difeniltetrazólio frente a células da medula óssea de dois pacientes (P1 e P2) atendidos no Hospital Universitário de Santa Maria. Os dois compostos testados apresentaram atividade antibacteriana em 26,08% (6/23) das cepas testadas, sendo ativos em 38,46% (5/13) das cepas ATCC e 10% (1/10) dos isolados clínicos RMD, apenas em espécies caracterizadas como Gram positivas. Os resultados foram satisfatórios para ambos os compostos frente à amostra P2, células mononucleares de Leucemia Mielóide Crônica, pois demonstraram indução da morte celular. Pode-se concluir que os resultados obtidos desses compostos demonstraram a existência de atividade antibacteriana, bem como, atividade antileucêmica promissora. Pesquisas complementares relacionadas a esses compostos estão em andamento.(AU)

Currently, despite the wide range of existing active substances has been progressively limited therapeutic arsenal available in clinical practice, this is, in particular, the emergence of resistance to therapeutic agents used in treating tumors and bacterial infections. Because of the diverse pharmacological properties demonstrated by triazenes (TZCs) - evaluated whether unpublished compounds in the search for new biologically active agents, they were called C1 and C2. The antibacterial activity was performed by the conventional method of broth microdilution, using the technique of Minimum Inhibitory Concentration (MIC) against the bacterial strains reference American Type Culture Collection (ATCC) and clinical isolates with multiple drug resistance (MDR). Cytotoxicity was analyzed by colorimetric assay based on the reduction of the bromide of 3 - (4,5- dimethylthiazol-2- yl) -2,5- diphenyltetrazolium against bone marrow cells from two patients (P1 and P2) seen at the Hospital university of Santa Maria. The two compounds tested showed antibacterial activity in 26.08% (6/23) of the strains, being active in 38.46 % (5/13) of the ATCC strains and 10 % (1/10) of clinical isolates MDR only characterized in species such as Gram positive. The results were satisfactory for both the sample compounds front P2, mononuclear cells from chronic myeloid leukemia, as demonstrated induction of cell death. It can be concluded that the results demonstrated the existence of these compounds to antibacterial activity, as well as promising antileukemic activity. Additional research related to these compounds are in progress.(AU)

Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours.

BACKGROUND: Olaparib, an oral PARP inhibitor, has shown antitumour activity as monotherapy in patients with germline BRCA1/2 (gBRCA)-mutated breast and ovarian cancer. This study evaluated olaparib capsules in combination with liposomal doxorubicin (PLD) in patients with advanced solid tumours (NCT00819221). METHODS: Patients received 28-day cycles of olaparib, continuously (days 1-28) or intermittently (days 1-7), plus PLD (40 mg m(-2), day 1); seven olaparib dose cohorts (50-400 mg bid) were explored to determine the recommended dose. Assessments included safety, pharmacokinetics, pharmacodynamics and preliminary efficacy (objective response rate (ORR)). RESULTS: Of 44 patients treated (ovarian, n=28; breast, n=13; other/unknown, n=3), two experienced dose-limiting toxicities (grade 3 stomatitis and fatal pneumonia/pneumonitis (200 mg per 28-day cycle); grade 4 thrombocytopenia (400 mg per 7-day cycle)). The maximum tolerated dose was not reached using continuous olaparib 400 mg bid plus PLD. Grade ≥3 and serious AEs were reported for 27 (61%) and 12 (27%) patients, respectively. No major pharmacokinetic interference was observed between olaparib and PLD. The ORR was 33% (n=14 out of 42; complete response, n=3). A total of 13 responders had ovarian cancer: 10 were platinum-sensitive, 11 had a gBRCA mutation. CONCLUSIONS: Continuous/intermittent olaparib (up to 400 mg bid) combined with PLD (40 mg m(-2)) was generally tolerated and showed evidence of antitumour activity in ovarian cancer.

Osteolytic bone metastasis is hampered by impinging on the interplay among autophagy, anoikis and ossification.

Here we show that the fate of osteolytic bone metastasis depends on the balance among autophagy, anoikis resistance and ossification, and that the hepatocyte growth factor (HGF) signaling pathway seems to have an important role in orchestrating bone colonization. These findings are consistent with the pathophysiology of bone metastasis that is influenced by the cross-talk of supportive and neoplastic cells through molecular signaling networks. We adopted the strategy to target metastasis and stroma with the use of adenovirally expressed NK4 (AdNK4) and Dasatinib to block HGF/Met axis and Src activity. In human bone metastatic 1833 cells, HGF conferred anoikis resistance via Akt and Src activities and HIF-1α induction, leading to Bim isoforms degradation. When Src and Met activities were inhibited with Dasatinib, the Bim isoforms accumulated conferring anoikis sensitivity. The proviability effect of HGF, under low-nutrient stress condition, was related to a faster autophagy deactivation with respect to HGF plus Dasatinib. In the 1833 xenograft model, AdNK4 switched metastasis vasculature to blood lacunae, increasing HIF-1α in metastasis. The combination of AdNK4 plus Dasatinib gave the most relevant results for mice survival, and the following molecular and cellular changes were found to be responsible. In bone metastasis, we observed a hypoxic condition - marked by HIF-1α - and an autophagy failure - marked by p62 without Beclin-1. Then, osteolytic bone metastases were largely prevented, because of autophagy failure in metastasis and ossification in bone marrow, with osteocalcin deposition. The abnormal repair process was triggered by the dysfunctional autophagy/anoikis interplay. In conclusion, the concomitant blockade of HGF/Met axis and Src activity seemed to induce HIF-1α in metastasis, whereas the bone marrow hypoxic response was reduced. As a consequence, anoikis resistance might be hampered favoring, instead, autophagy failure and neoformation of woven bone trabeculae. Mice survival was, therefore, prolonged by overcoming an escape strategy adopted by metastatic cells by disruption of tumor-stroma coevolution, showing the importance of autophagy inhibition for the therapy of bone metastasis.

[Ocular manifestations in chronic granulomatous disease]. / Atteintes ophtalmologiques dans la granulomatose septique chronique.

Chronic granulomatous disease (CGD) is a rare genetic immune deficiency due to defective oxygen metabolism in phagocytic cells. It results in recurrent severe bacterial and fungal infections in patients from an early age on. Inflammatory lesions are also observed, with the formation of granulomas. Diagnosis relies on the demonstration of a deficiency in the oxidative properties of phagocytes. Pulmonary infections are the most frequent clinical manifestations of the disease, yet all organs can be involved, such as the eye, with either infections or inflammatory chorioretinal lesions. The treatment of CGD relies on prophylaxis to avoid infections, and on the rapid management of infectious and inflammatory episodes. The only cure to date is allogenetic bone marrow transplant, which requires a compatible donor and can only be considered in certain clinical situations.

Robotic versus laparoscopic total mesorectal excision for rectal cancer: a comparative analysis of oncological safety and short-term outcomes.

BACKGROUND: We assessed feasibility, short-term oncologic safety, and short-term outcomes in robotic total mesorectal excision (R-TME) for rectal cancer compared with laparoscopic TME. METHODS: From March 2008 to June 2009, 50 patients with proven middle/lower rectal adenocarcinoma underwent minimally invasive TME; 25 received R-TME. The groups were balanced (R-TME versus L-TME) in terms of age (median 69 versus 62 years; p = 0.8), disease stage, and body mass index (median 23 versus 26.5 kg/m(2); p = 0.06). There were 37 (74%) anterior resections and 13 (26%) abdominoperineal resections. Twenty-three (46%) patients received preoperative radiochemotherapy. The robot was a four-arm Da Vinci S (Intuitive Surgical, Sunnyvale, CA, USA). RESULTS: Median operating time (R-TME versus L-TME) was 240 versus 237 min (p = 0.2); first bowel movement was 2 versus 3 days (p = 0.5); median hospital stay was 6.5 versus 6 days (p = 0.4). Major complications with reoperation were two in R-TME (one anastomotic leakage, one small bowel perforation) and three in L-TME (one colonic ischemia, two anastomotic leakage). Postoperative complications were 16% versus 24% (p = 0.5). A median of 18 versus 17 (p = 0.7) lymph nodes were retrieved; distal resection margins were disease free in both groups; circumferential margin was involved (<1.0 mm) in one (4%) of L-TME. There were 0 versus 1 (5%) conversions to laparotomy. CONCLUSIONS: R-TME in rectal cancer is feasible, with short-term oncologic and other outcomes similar to those of L-TME. The greater maneuverability and visibility afforded by the robotic approach are attractive. Future studies should more systematically address advantages and costs of R-TME.

Phase Ib study of weekly mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) with weekly paclitaxel.

BACKGROUND: The additive cytotoxicity in vitro prompted a clinical study evaluating the non-prodrug rapamycin analogue ridaforolimus (AP23573; MK-8669; formerly deforolimus) administered i.v. combined with paclitaxel (PTX; Taxol). MATERIALS AND METHODS: Patients with taxane-sensitive solid tumors were eligible. The main dose escalation foresaw 50% ridaforolimus increments from 25 mg with a fixed PTX dose of 80 mg/m(2), both given weekly 3 weeks in a 4-week cycle. Collateral levels with a lower dose of either drug were planned upon achievement of the maximum tolerated dose in the main escalation. Pharmacodynamic studies in plasma, peripheral blood mononuclear cells (PBMCs) and skin biopsies and pharmacokinetic (PK) interaction studies at cycles 1 and 2 were carried out. RESULTS: Two recommended doses were determined: 37.5 mg ridaforolimus/60 mg/m(2) PTX and 12.5 mg/80 mg/m(2). Most frequent toxic effects were mouth sores (79%), anemia (79%), fatigue (59%), neutropenia (55%) and dermatitis (48%). Two partial responses were observed in pharyngeal squamous cell and pancreatic carcinoma. Eight patients achieved stable disease > or =4 months. No drug interaction emerged from PK studies. Decrease of eukaryotic initiation factor 4E-binding protein1 (4E-BP1) phosphorylation was shown in PBMCs. Similar inhibition of phosphorylation of 4E-BP1 and mitogen-activated protein kinase was present in reparative epidermis and vascular tissues, respectively. CONCLUSION: Potential antiangiogenic effects and encouraging antitumor activity justify further development of the combination.

Are ultrasonographic myoma characteristics associated with blood loss at delivery?

OBJECTIVES: The presence of myomas in pregnancy is associated with greater blood loss at delivery. The aim of this study was to evaluate whether the sonographic characteristics of myomas can predict blood loss at delivery in women with large myomas. METHODS: Among women who underwent second-trimester ultrasound screening at our department between January 1996 and December 2004, 251 had at least one myoma with a mean diameter > or = 5 cm. Number of myomas (single vs. multiple), maximum diameter of the largest myoma, sum of the maximum diameter of each myoma, change in size of myomas between first and last scan, and location in relation to the placenta and to the presenting part of the fetus (above or below) were analyzed in relation to blood loss at delivery and severe postpartum hemorrhage (> or = 1000 mL). RESULTS: Multivariate analysis showed that the presence of multiple myomas was the only parameter independently associated with amount of blood loss at delivery (P = 0.003). The association between the presence of multiple myomas and severe postpartum hemorrhage was of borderline significance for the statistical power of this study (P = 0.08). CONCLUSIONS: In women with large myomas, the presence of multiple tumors is independently associated with heavier blood loss at delivery but not with postpartum hemorrhage of > or = 1000 mL.

Phase I clinical and pharmacokinetic study of trabectedin and cisplatin in solid tumours.

AIM OF THE STUDY: To define the maximum tolerated dose (MTD) and toxicity of trabectedin (T) and cisplatin (C) given on days 1 and 8 every 3 weeks to adult patients with advanced solid tumours. Plasma pharmacokinetics at cycle 1 and a preliminary anti-tumour activity assessment in ovarian and non-small cell lung cancer (OC, NSCLC) were secondary objectives. METHODS: In the dose finding part (DFP) of the study the dose of T given at each administration was escalated by 100 microg/m(2) increments from 300 microg/m(2) up to the MTD, with a fixed dose of C of 40 mg/m(2). The recommended dose (RD) was assessed in the previously treated and untreated OC and NSCLC patients in the expansion of the RD (ERD) part of the study. T was administered with corticosteroids pre-medication as 3-h infusion and C as 30-min infusion. RESULTS: Thirty-nine patients were treated in the DFP and 10 in the ERD. The MTD of T was 700 microg/m(2) due to dose-limiting neutropaenia and the RDs in the previously treated/untreated patients were 500 and 600 microg/m(2), respectively. Most common toxicities were nausea/vomiting (67%), asthenia/fatigue (55%) and reversible ASAT/ALAT elevation (51%). Time to recovery from myelosuppression was dose-dependent and treatment could be repeated after > or = 4 weeks in the majority of patients at 600 microg/m(2). Confirmed partial responses were observed in 4 of 13 evaluable OC patients and in 1 with uterine leiomyosarcoma. No pharmacokinetic interaction was observed. CONCLUSION: The administration of T and C on days 1 and 8 resulted in prolonged neutropaenia requiring treatment delay. The evaluation of a single every 3 week schedule is worthwhile because of the hints of anti-tumour activity observed in OC.

Clinical and pharmacological phase I evaluation of Exherin (ADH-1), a selective anti-N-cadherin peptide in patients with N-cadherin-expressing solid tumours.

BACKGROUND: Upregulation of N-cadherin promotes dysregulated cell growth, motility, invasiveness, plus maintenance of vascular stability and is associated with cancer progression in several human tumour types. N-cadherin is expressed also on tumour cells and the anti-N-cadherin cyclic pentapeptide ADH-1, tested in the present study, can exert a direct antitumour effect. PATIENTS AND METHODS: Adult patients with advanced solid malignancies expressing N-cadherin on tumour biopsies carried out in the previous 12 months received escalating i.v. doses of ADH-1 given weekly (initially for 3 of 4 weeks, then every week). Plasma pharmacokinetics (PK) was studied at cycle 1. Blood flow changes were assessed after first dosing in all patients treated in the initial regimen. RESULTS: In all, 129 patients were screened, 65 (50%) were N-cadherin positive, and 30 were enrolled. The doses ranged from 150 to 2400 mg/m(2); no maximum tolerated dose was reached. Treatment was well tolerated with asthenia as the most frequent adverse event. Two patients with ovarian cancer showed prolonged disease stabilisation while one patient with fallopian tube carcinoma achieved a mixed response. PK was linear in the range of doses tested. CONCLUSION: ADH-1 is the first anti-N-cadherin compound tested in humans. In N-cadherin-positive patients, ADH-1 showed an acceptable toxicity profile, linear PK and hints of antitumour activity in gynaecological cancers.

Phase I clinical and pharmacokinetic study of trabectedin and doxorubicin in advanced soft tissue sarcoma and breast cancer.

The combination of trabectedin (T) and doxorubicin (D) was brought into clinical development in soft tissue sarcoma (STS) and advanced breast cancer (ABC) because of its in vitro and in vivo additive anti-tumour effect, the fact that there are no overlapping toxicities and the anti-tumour activity of T in those tumours. Feasibility and anti-tumour activity of T+D administered every 3 weeks were evaluated in 38 patients (STS=29, ABC=9) untreated for advanced disease. D was given at 60 mg/m(2) and T at escalating doses from 600 to 800 microg/m(2), which was the maximum tolerated dose due to dose-limiting febrile neutropenia and asthenia. The recommended dose--given to 18 patients in total--was 700 microg/m(2) T with 60 mg/m(2) D. The pharmacokinetic profile of T and D at cycle 1 was analysed in 20 patients. The most common toxicities included a severe but reversible ASAT/ALAT increase (94%), nausea/vomiting, neutropenia, asthenia/fatigue, stomatitis. Partial response and stable disease were assessed in 18% and 56% of STS patients and in 55% and 33% of ABC patients. No pharmacokinetic interaction between T and D was observed. The lack of cumulative toxicity and related complications and the promising activity in STS support further development of T+D.

Amnioinfusion in preterm PROM: effects on amnion and cord histology.

OBJECTIVE: To investigate the effects of transabdominal amnioinfusion (TA) on the histology of amnion (A) and umbilical cord (UC). STUDY DESIGN: From a cohort of 56 singleton pregnancies with premature rupture of membranes (PROM) at

suPAR, a soluble form of urokinase plasminogen activator receptor, inhibits human prostate cancer cell growth and invasion.

Urokinase-type plasminogen activator (uPA) and its specific membrane receptor (uPAR) control extracellular matrix proteolysis, cell migration, invasion and cell growth in several cancers. The uPAR released from human cancers is detected in blood as soluble uPAR (suPAR). No information is available on the mechanism(s) of action of suPAR on prostate cancer (PCa) cell growth and invasion. In order to clarify this issue, we tested the effect of a treatment with the human recombinant suPAR (comprising amino acids l-303) on the proliferation, migration and invasion of DU145 cells, a PCa cell line expressing a potent autocrine uPA-uPAR signalling system. The results indicate that suPAR significantly inhibits cell growth, promotes apoptosis and decreases both migration and Matrigel invasion of DU145 cells. The mechanism of action of suPAR seems to be linked to a decrease of ERK and FAK activation. Cleavage of suPAR by chymotripsin reverses these effects. When added to the uPA-negative LNCaP cells, suPAR was ineffective; on the contrary, when LNCaP cells were cultured on fibronectin-coated plates in order to stimulate uPA expression, suPAR significantly decreased cell proliferation. In conclusion, our data suggest that suPAR can function as a potent molecule scavenger for uPA in human PCa cells characterized by high levels of uPA/uPAR as in DU145 cells, while it is ineffective in uPA-deficient LNCaP cells. The molecular mechanism(s) through which suPAR participates in the control of PCa progression may bear relevance for the long-term goal to identify new therapeutic targets aimed at silencing tumours in vivo.

5% Imiquimod cream for external anogenital warts in HIV-infected patients under HAART therapy.

The efficacy of imiquimod in the treatment of external genital warts in HIV positive subjects was compared to a group of patients with normal immune function. Imiquimod 5% cream was applied by patients three times a week until resolution for a maximum of 16 weeks. Assessment for response and the occurrence of side effects was performed every four weeks. Thirty-one per cent of 75 HIV positive patients achieved a complete clearance, a partial response was obtained in 24% of subjects while in 45% we observed no clinical response. In the control group a total clearance was obtained in 62% of subjects, a partial response in 24% and no response in 14%. Recurrences occurred in 4/23 HIV patients and 2/31 immunocompetent patients within three months of follow-up. Side effects were minor to moderate. We conclude that imiquimod 5% cream has an acceptable efficacy and safety on HIV patients.

Phase IB and pharmacological study of the novel taxane BMS-184476 in combination with doxorubicin.

The aim of this study was to define the maximum tolerated dose (MTD) and the pharmacological profile of the paclitaxel analogue BMS-184476 given once every 3 weeks, or on days 1 and 8 every 3 weeks (d1&8), in combination with a fixed dose of 50 mg/m(2) of Doxorubicin (Doxo) administered on day 1 of a 21-day cycle. Adult patients with advanced solid malignancies received escalating doses of BMS-184476 infused over 1 h after bolus Doxo. Pharmacokinetics (PK) of BMS-184476, Doxo and metabolites were investigated. The effect of BMS-184476 on doxorubicinol formation was studied in the cytosol from human myocardium. The MTD of 3-weekly BMS-184476 was 30 mg/m(2). The MTD/recommended Phase II dose was 35 mg/m(2)/week (70 mg/m(2) per cycle) in the d1&8 schedule. The dose-limiting toxicity was neutropenia for both schedules. Other toxicities were loss of appetite, asthenia, and mild, cumulative peripheral neuropathy. The objective response rate in 17 previously untreated or minimally pretreated patients with breast cancer treated at 35 mg/m(2)/week of BMS-184476 was 59% (95% Confidence Interval (CI): 33-82%). Two of the 7 patients not responding to the study regimen later responded to Doxo and paclitaxel. Plasma disposition of BMS-184476 at 30, 35 and 40 mg/m(2) was linear without evidence of a PK interaction with Doxo. In studies with cytosol from human myocardium, the formation of cardiotoxic doxorubicinol was not enhanced by BMS-184476. Dosing of BMS-184476 for 2 consecutive weeks allowed the administration of larger doses of the taxane with a promising antitumour activity in patients with untreated or minimally pretreated breast cancer. The higher than expected myelotoxicity of the 3-weekly schedule is unexplained by the investigated interactions. Lack of enhanced doxorubicinol formation in human myocardium is consistent with the cardiac safety of the regimen.