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1.
Ann Oncol ; 34(10): 920-933, 2023 10.
Article in English | MEDLINE | ID: mdl-37704166

ABSTRACT

BACKGROUND: Patients with advanced non-small-cell lung cancer (NSCLC) treated with immune checkpoint blockers (ICBs) ultimately progress either rapidly (primary resistance) or after durable benefit (secondary resistance). The cancer vaccine OSE2101 may invigorate antitumor-specific immune responses after ICB failure. The objective of ATALANTE-1 was to evaluate its efficacy and safety in these patients. PATIENTS AND METHODS: ATALANTE-1 was a two-step open-label study to evaluate the efficacy and safety of OSE2101 compared to standard-of-care (SoC) chemotherapy (CT). Patients with human leukocyte antigen (HLA)-A2-positive advanced NSCLC without actionable alterations, failing sequential or concurrent CT and ICB were randomized (2 : 1) to OSE2101 or SoC (docetaxel or pemetrexed). Primary endpoint was overall survival (OS). Interim OS futility analysis was planned as per Fleming design. In April 2020 at the time of interim analysis, a decision was taken to prematurely stop the accrual due to coronavirus disease 2019 (COVID-19). Final analysis was carried out in all patients and in the subgroup of patients with ICB secondary resistance defined as failure after ICB monotherapy second line ≥12 weeks. RESULTS: Two hundred and nineteen patients were randomized (139 OSE2101, 80 SoC); 118 had secondary resistance to sequential ICB. Overall, median OS non-significantly favored OSE2101 over SoC {hazard ratio (HR) [95% confidence interval (CI)] 0.86 [0.62-1.19], P = 0.36}. In the secondary resistance subgroup, OSE2101 significantly improved median OS versus SoC [11.1 versus 7.5 months; HR (95% CI) 0.59 (0.38-0.91), P = 0.017], and significantly improved post-progression survival (HR 0.46, P = 0.004), time to Eastern Cooperative Oncology Group (ECOG) performance status deterioration (HR 0.43, P = 0.006) and Quality of Life Questionnaire Core 30 (QLQ-C30) global health status compared to SoC (P = 0.045). Six-month disease control rates and progression-free survival were similar between groups. Grade ≥3 adverse effects occurred in 11.4% of patients with OSE2101 and 35.1% in SoC (P = 0.002). CONCLUSIONS: In HLA-A2-positive patients with advanced NSCLC and secondary resistance to immunotherapy, OSE2101 increased survival with better safety compared to CT. Further evaluation in this population is warranted.


Subject(s)
COVID-19 , Cancer Vaccines , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Cancer Vaccines/adverse effects , HLA-A2 Antigen/therapeutic use , Lung Neoplasms/drug therapy , Lung Neoplasms/etiology , Quality of Life , Treatment Outcome , Antineoplastic Combined Chemotherapy Protocols/adverse effects , COVID-19/etiology , Immunotherapy
2.
Ann Oncol ; 31(11): 1536-1544, 2020 11.
Article in English | MEDLINE | ID: mdl-32861806

ABSTRACT

BACKGROUND: In AURA3 (NCT02151981), osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly prolonged progression-free survival and improved response in patients with EGFR T790M advanced non-small-cell lung cancer (NSCLC) and progression on prior EGFR-TKI treatment. We report the final AURA3 overall survival (OS) analysis. PATIENTS AND METHODS: Adult patients were randomized 2 : 1 to osimertinib (80 mg orally, once daily) or pemetrexed plus carboplatin/cisplatin (platinum-pemetrexed) intravenously, every 3 weeks (≤6 cycles). Patients could crossover to osimertinib on progression confirmed by blinded independent central review. OS and safety were secondary end points. RESULTS: A total of 279 patients were randomly assigned to receive osimertinib and 140 to platinum-pemetrexed (136 received treatment). At data cut-off (DCO; 15 March 2019), 188 patients (67%) receiving osimertinib versus 93 (66%) receiving platinum-pemetrexed had died. The hazard ratio (HR) for OS was 0.87 [95% confidence interval (CI) 0.67-1.12; P = 0.277]; the median OS was 26.8 months (95% CI 23.5-31.5) versus 22.5 months (95% CI 20.2-28.8) for osimertinib and platinum-pemetrexed, respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively. After crossover adjustment, there was an HR of 0.54 (95% CI 0.18-1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage toward osimertinib (HR 0.21, 95% CI 0.16-0.28; P < 0.001). At DCO, 99/136 (73%) patients in the platinum-pemetrexed arm had crossed over to osimertinib, 66/99 (67%) of whom had died. The most common adverse events possibly related to study treatment were diarrhea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3, <1%) in the osimertinib arm, versus nausea (47%; grade ≥3, 3%) in the platinum-pemetrexed arm. CONCLUSIONS: In patients with T790M advanced NSCLC, no statistically significant benefit in OS was observed for osimertinib versus platinum-pemetrexed, which possibly reflects the high crossover rate of patients from platinum-pemetrexed to osimertinib. CLINICAL TRIALS NUMBER: ClinicalTrials.gov NCT02151981; https://clinicaltrials.gov/ct2/show/NCT02151981.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Acrylamides , Adult , Aniline Compounds/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/genetics , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mutation , Pemetrexed/therapeutic use , Platinum/therapeutic use , Protein Kinase Inhibitors/adverse effects , Survival Analysis
3.
Ann Oncol ; 31(6): 789-797, 2020 06.
Article in English | MEDLINE | ID: mdl-32240796

ABSTRACT

BACKGROUND: Dysregulation of receptor tyrosine kinase MET by various mechanisms occurs in 3%-4% of non-small-cell lung cancer (NSCLC) and is associated with unfavorable prognosis. While MET is a validated drug target in lung cancer, the best biomarker strategy for the enrichment of a susceptible patient population still remains to be defined. Towards this end we analyze here primary data from a phase I dose expansion study of the MET inhibitor capmatinib in patients with advanced MET-dysregulated NSCLC. PATIENTS AND METHODS: Eligible patients [≥18 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤2] with MET-dysregulated advanced NSCLC, defined as either (i) MET status by immunohistochemistry (MET IHC) 2+ or 3+ or H-score ≥150, or MET/centromere ratio ≥2.0 or gene copy number (GCN) ≥5, or (ii) epidermal growth factor receptor wild-type (EGFRwt) and centrally assessed MET IHC 3+, received capmatinib at the recommended dose of 400 mg (tablets) or 600 mg (capsules) b.i.d. The primary objective was to determine safety and tolerability; the key secondary objective was to explore antitumor activity. The exploratory end point was the correlation of clinical activity with different biomarker formats. RESULTS: Of 55 patients with advanced MET-dysregulated NSCLC, 40/55 (73%) had received two or more prior systemic therapies. All patients discontinued treatment, primarily due to disease progression (69.1%). The median treatment duration was 10.4 weeks. The overall response rate per RECIST was 20% (95% confidence interval, 10.4-33.0). In patients with MET GCN ≥6 (n = 15), the overall response rate by both the investigator and central assessments was 47%. The median progression-free survival per investigator for patients with MET GCN ≥6 was 9.3 months (95% confidence interval, 3.8-11.9). Tumor responses were observed in all four patients with METex14. The most common toxicities were nausea (42%), peripheral edema (33%), and vomiting (31%). CONCLUSIONS: MET GCN ≥6 and/or METex14 are suited to predict clinical activity of capmatinib in patients with NSCLC (NCT01324479).


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Benzamides , Biomarkers , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Humans , Imidazoles , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mutation , Proto-Oncogene Proteins c-met/genetics , Triazines
4.
Ultrasound Obstet Gynecol ; 56(1): 86-95, 2020 07.
Article in English | MEDLINE | ID: mdl-31006924

ABSTRACT

OBJECTIVES: Incompatibility between currently available fetoscopes and the anatomical constraints of the distended fetal bladder, with the resulting curvature around the bladder neck, account for most technical difficulties during fetal cystoscopy in lower urinary tract obstruction (LUTO). The aim of this anatomical study was to assess by magnetic resonance imaging (MRI) the variation in three bladder angles (bladder-neck angle (BNA), vesicourethral angle (VUA) and angle between bladder dome and posterior urethra (DUA)), according to gestational age (GA), bladder volume and the presence of LUTO. METHODS: From our fetal medicine database, we retrieved for review 46 MRI examinations of male fetuses between 2015 and 2019, including 17 with LUTO, examined at a mean GA of 28.1 (range, 17.3-35.0) weeks and 29 age-matched controls, examined at 29.9 (range, 21.9-35.0) weeks. We measured bladder volume, bladder-wall thickness and the three bladder angles, and used the Mann-Whitney U-test to compare values between groups. Variations according to GA and bladder volume were determined using analysis of variance (ANOVA). A reliability study was performed using the Bland-Altman method and Lin's correlation coefficient was calculated. RESULTS: Both bladder volume and bladder-wall thickness were significantly greater in the LUTO group (P < 0.01). BNA was significantly larger in LUTO compared with control fetuses: the mean (range) was 127.1° (101.6-161.6°) vs 111.2° (88.5-157.3°) (P < 0.01). DUA averaged 117° and showed no difference between the groups (P = 0.92). No statistical comparison was performed on VUA since this was not measurable in most control fetuses. ANOVA showed no variation of any angle with bladder volume in both LUTO fetuses and control fetuses. BNA in LUTO fetuses was the only angle to vary with GA, being larger after, compared with at or before, 25 weeks (P = 0.04). The reliability study showed an acceptable bias for both intra- and interobserver reproducibility for all three angles. CONCLUSION: The findings that BNA is increased by approximately 15° in fetuses with LUTO and DUA averages 117° could aid in development of a customized fetal cystoscope and help to overcome the current technical challenges of fetal cystoscopy. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.


Subject(s)
Prenatal Diagnosis , Urinary Bladder Neck Obstruction/diagnostic imaging , Adult , Biometry , Case-Control Studies , Cystoscopy/methods , Female , Gestational Age , Humans , Magnetic Resonance Imaging , Male , Pregnancy , Retrospective Studies , Ultrasonography, Prenatal , Urinary Bladder Neck Obstruction/congenital
5.
Clin Transl Oncol ; 22(3): 294-301, 2020 Mar.
Article in English | MEDLINE | ID: mdl-31630357

ABSTRACT

PURPOSE: Anaplastic lymphoma kinase (ALK) rearrangement confers sensitivity to ALK inhibitors (ALKis) in non-small-cell lung cancer (NSCLC). Although several drugs provided an impressive outcome benefit, the most effective sequential strategy is still unknown. We describe outcomes of real-life patients according to the treatment strategy received. PATIENTS: We retrospectively collected 290 ALK rearranged advanced NSCLC diagnosed between 2011 and 2017 in 23 Italian institutions. RESULTS: After a median follow-up of 26 months, PFS for crizotinib and a new generation ALKis were 9.4 [CI 95% 7.9-11.2] and 11.1 months [CI 95% 9.2-13.8], respectively, while TTF were 10.2 [CI 95% 8.5-12.6] and 11.9 months [CI 95% 9.7-17.4], respectively, being consistent across the different settings. The composed outcomes (the sum of PFS or TTF) in patients treated with crizotinib followed by a new generation ALKis were 27.8 months [CI 95% 24.3-33.7] in PFS and 30.4 months [CI 95% 24.7-34.9] in TTF. The median OS from the diagnosis of advanced disease was 39 months [CI 95% 31.8-54.5]. Patients receiving crizotinib followed by a new generation ALKis showed a higher median OS [57 months (CI 95% 42.0-73.8)] compared to those that did not receive crizotinib [38 months (CI 95% 18.6-NR)] and those who performed only crizotinib as target agent [15 months (CI 95% 11.3-34.0)] (P < 0.0001). CONCLUSION: The sequential administration of crizotinib and a new generation ALKis provided a remarkable clinical benefit in this real-life population, being an interesting option to consider in selected patients.


Subject(s)
Anaplastic Lymphoma Kinase/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Adult , Aged , Aged, 80 and over , Anaplastic Lymphoma Kinase/antagonists & inhibitors , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Crizotinib/therapeutic use , Female , Gene Rearrangement , Humans , Italy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Middle Aged , Retrospective Studies , Treatment Outcome , Young Adult
6.
Invest New Drugs ; 33(2): 472-9, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25693886

ABSTRACT

PURPOSE: This is a first-in-human, phase I, dose-escalation study to determine the maximum tolerated dose (MTD) of intravenous, flat-dosed ST-1968 (namitecan), a new hydrophilic camptothecan derivative. METHODS: Namitecan was administered intravenously over 2 h on day 1 and day 8 every 21 days (D1-D8-Q21D), starting at a flat dose of 2.5 mg, and increased according to a 3 + 3 cohort design. Due to frequent skipping of day 8 dosing for cytopenias, the study was expanded to test namitecan dosing on day 1 every 21 days (D1-Q21) at a starting dose of 17.5 mg. Major dose-limiting toxicity (DLT) was defined as grade (G) 4 neutropenia persisting >5 days, febrile neutropenia, G3 thrombocytopenia or G2 non-hematological toxicity. RESULTS: Thirty-four patients were included into the D1-D8-Q21D group (2.5, 5, 10, 15, 17.5, 20 mg dosing cohorts), 29 patients into the D1-21D group (17.5, 20, 23, 27, 30 mg dosing cohorts). Neutropenia was the DLT in both groups, with 15 mg being defined as the recommended dose (RD) for the D1-D8-Q21D group, and 23 mg for the D1-Q21D group. Non-hematological toxicity was negligible. One patient with endometrial cancer in the D1-D8-Q21D group and one patient with cholangiocellular carcinoma in the D1-Q21D group experienced a partial remission. Namitecan exhibited fully dose-proportional pharmacokinetics. CONCLUSIONS: This study demonstrates clinical safety, favourable pharmacokinetics and preliminary antitumor activity of the novel hydrophilic camptothecin analogue namitecan in patients with heavily pretreated solid malignancies, when given either on a 2 out of 3 weeks or 3-weekly regimen.


Subject(s)
Camptothecin/analogs & derivatives , Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols , Area Under Curve , Camptothecin/administration & dosage , Camptothecin/adverse effects , Camptothecin/pharmacokinetics , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Half-Life , Humans , Male , Maximum Tolerated Dose , Metabolic Clearance Rate , Middle Aged
7.
Br J Clin Pharmacol ; 80(1): 128-38, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25580946

ABSTRACT

AIMS: Namitecan is a new camptothecan compound undergoing early clinical development. This study was initiated to build an integrated pharmacokinetic (PK) and pharmacodynamic (PD) population model of namitecan to guide future clinical development. METHODS: Plasma concentration-time data, neutrophils and thrombocytes were pooled from two phase 1 studies in 90 patients with advanced solid tumours, receiving namitecan as a 2 h infusion on days 1 and 8 every 3 weeks (D1,8) (n = 34), once every 3 weeks (D1) (n = 29) and on 3 consecutive days (D1-3) (n = 27). A linear three compartment PK model was coupled to a semiphysiological PD-model for neutrophils and thrombocytes. Data simulations were used to interrogate various dosing regimens and give dosing recommendations. RESULTS: Clearance was estimated to be 0.15 l h(-1), with a long terminal half-life of 48 h. Body surface area was not associated with clearance, supporting flat-dosing of namitecan. A significant and clinically relevant association was found between namitecan area under the concentration-time curve (AUC) and the percentage drop of neutrophils (r(2) = 0.51, P < 10(-4)) or thrombocytes (r(2) = 0.49, P < 10(-4)). With a target for haematological dose-limiting toxicity of <20%, the recommended dose was defined as 12.5 mg for the D1,8 regimen, 23 mg for the once every 3 week regimen and 7 mg for the D1-3 regimen. CONCLUSION: This is the first integrated population PK-PD analysis of the new hydrophilic topoisomerase I inhibitor namitecan, that is currently undergoing early clinical development. A distinct relationship was found between drug exposure and haematological toxicity, supporting flat-dosing once every 3 weeks as the most adequate dosing regimen.


Subject(s)
Camptothecin/analogs & derivatives , Topoisomerase I Inhibitors/pharmacokinetics , Adult , Aged , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/adverse effects , Antineoplastic Agents, Phytogenic/blood , Antineoplastic Agents, Phytogenic/pharmacokinetics , Area Under Curve , Blood Platelets/cytology , Blood Platelets/drug effects , Camptothecin/administration & dosage , Camptothecin/adverse effects , Camptothecin/blood , Camptothecin/pharmacokinetics , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Half-Life , Humans , Male , Middle Aged , Neutrophils/cytology , Neutrophils/drug effects , Topoisomerase I Inhibitors/administration & dosage , Topoisomerase I Inhibitors/adverse effects , Topoisomerase I Inhibitors/blood
9.
Ann Oncol ; 25(11): 2244-2251, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25193991

ABSTRACT

BACKGROUND: Lucitanib is a potent, oral inhibitor fibroblast growth factor receptor types 1 and 2 (FGFR), vascular endothelial growth factor receptor types 1, 2, and 3 (VEGFR), platelet-derived growth factor receptor types α and ß (PGFRα/ß), which are essential kinases for tumor growth, survival, migration, and angiogenesis. Several tumor types, including breast carcinoma, demonstrate amplification of fibroblast growth factor (FGF)-related genes. There are no approved drugs for molecularly defined FGF-aberrant (FGFR1- or FGF3/4/19-amplified) tumors. METHODS: This open-label phase I/IIa study involved a dose-escalation phase to determine maximum tolerated dose (MTD), recommended dose (RD), and pharmacokinetics of lucitanib in patients with advanced solid tumors, followed by a dose-expansion phase to obtain preliminary evidence of efficacy in patients who could potentially benefit from treatment (i.e. with tumors harboring FGF-aberrant pathway or considered angiogenesis-sensitive). RESULTS: Doses from 5 to 30 mg were evaluated with dose-limiting toxic effects dominated by vascular endothelial growth factor (VEGF) inhibition-related toxic effects at the 30 mg dose level (one case of grade 4 depressed level of consciousness and two cases of grade 3 thrombotic microangiopathy). The most common adverse events (all grades, all cohorts) were hypertension (91%), asthenia (42%), and proteinuria (57%). Exposure increased with dose and t½ was 31-40 h, suitable for once daily administration. Seventy-six patients were included. All but one had stage IV; 42% had >3 lines of previous chemotherapy. Sixty-four patients were assessable for response; 58 had measurable disease. Clinical activity was observed at all doses tested with durable Response Evaluation Criteria In Solid Tumors (RECIST) partial responses in a variety of tumor types. In the angiogenesis-sensitive group, objective RECIST response rate (complete response + partial response) was 26% (7 of 27) and progression-free survival (PFS) was 25 weeks. In assessable FGF-aberrant breast cancer patients, 50% (6 of 12) achieved RECIST partial response with a median PFS of 40.4 weeks for all treated patients. CONCLUSION: Lucitanib has promising efficacy and a manageable side-effect profile. The spectrum of activity observed demonstrates clinical benefit in both FGF-aberrant and angiogenesis-sensitive populations. A comprehensive phase II program is planned.


Subject(s)
Dose-Response Relationship, Drug , Naphthalenes/analysis , Neoplasms/drug therapy , Neovascularization, Pathologic/drug therapy , Protein Kinase Inhibitors/administration & dosage , Quinolines/analysis , Adult , Aged , Disease-Free Survival , Drug-Related Side Effects and Adverse Reactions/pathology , Female , Humans , Middle Aged , Neoplasms/classification , Neoplasms/pathology , Neovascularization, Pathologic/pathology , Protein Kinase Inhibitors/adverse effects , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Receptor, Fibroblast Growth Factor, Type 2/antagonists & inhibitors , Receptors, Platelet-Derived Growth Factor , Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors
10.
Psychooncology ; 23(3): 322-9, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24123459

ABSTRACT

OBJECTIVE: In a previous study, we found that patients who were offered the possibility of participation in a clinical trial had unexpressed concerns and fears that prevented them from making free or fully knowledgeable choices about their trial participation. In a selected population of patients who were offered participation in a phase I trial, we prospectively investigated whether a face-to-face discussion about their unexpressed fears might lead to a more conscious decision about whether to accept/refuse participation in the trial. METHODS: After the presentation of the trial, a questionnaire was administered to assess the presence of specific fears. Before the patients decided whether to participate in the trial, they discussed any fears that they had; finally, the impact of the discussion on the patients' choice to participate was evaluated. RESULTS: The majority (86%) of the patients thought that physicians conduct clinical trials for scientific interest, 13% felt exploited as 'guinea pigs' and 20% believed they were offered participation because they had no further hope for improvement. These existing fears were not elicited during the trial interview because the patients were themselves unaware of having them (28%) and because of fear of the doctors (3%). The possibility of discussing these fears was felt as an opportunity and made patients feel more conscious (92%) and freer (97%) when making their choice. CONCLUSIONS: Recognising and discussing misconceptions and fears, often unexpressed, make patients freer and more aware when facing the choice of whether or not \to participate in a phase I clinical trial.


Subject(s)
Clinical Trials, Phase I as Topic/psychology , Decision Making , Health Knowledge, Attitudes, Practice , Neoplasms/psychology , Patient Participation , Adult , Aged , Choice Behavior , Communication , Fear , Female , Humans , Male , Middle Aged , Neoplasms/drug therapy , Surveys and Questionnaires
11.
Chemotherapy ; 57(3): 217-24, 2011.
Article in English | MEDLINE | ID: mdl-21597285

ABSTRACT

BACKGROUND: Ifosfamide and doxorubicin combination is an active regimen for patients with advanced soft tissue sarcomas (STS) but is burdened by high toxicity. A phase II trial was designed to assess the activity of continuous infusion ifosfamide and doxorubicin combination. PATIENTS AND METHODS: Thirty-four chemotherapy-naive patients with advanced STS were treated with ifosfamide (13 g/m(2)/12 days as continuous infusion) and doxorubicin (75 mg/m(2) on day 8) every 28 days with granulocyte colony-stimulating factor. RESULTS: The major toxicity was hematological: grade 3/4 neutropenia, anemia and thrombocytopenia occurred in 63, 30 and 12% of patients, respectively. The disease control rate was 68% and the median time to progression was 7.1 months. Among leiomyosarcomas, 2 partial responses and 4 stable diseases were observed. CONCLUSIONS: Our study confirms that the ifosfamide and doxorubicin combination has a very low non-hematological toxicity profile. This regimen attained a high disease control rate with moderate activity. Further investigation into leiomyosarcoma is warranted.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Doxorubicin/administration & dosage , Ifosfamide/administration & dosage , Sarcoma/drug therapy , Soft Tissue Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Doxorubicin/adverse effects , Drug Administration Schedule , Female , Granulocyte Colony-Stimulating Factor/administration & dosage , Humans , Ifosfamide/adverse effects , Male , Middle Aged , Sarcoma/pathology , Sarcoma/secondary , Soft Tissue Neoplasms/pathology , Soft Tissue Neoplasms/secondary
12.
Abdom Imaging ; 31(4): 503-5, 2006.
Article in English | MEDLINE | ID: mdl-16447078

ABSTRACT

Multiple symmetrical lipomatosis, also known as Madelung disease, Launois-Bensaude syndrome, and benign symmetrical lipomatosis, is an uncommon disease that is characterized by the presence of multiple and symmetrical deposits of nonencapsulated adipose tissue in the neck, upper trunk, arms, and legs. It affects mainly men, with a higher incidence in the Mediterranean area, and is typically associated with high alcohol consumption and a high prevalence of peripheral neuropathy that usually appears long after the development of lipomatous masses. We report the case of a patient with involvement of the scrotum. We present clinical, ultrasound, and magnetic resonance appearances of these scrotal lipomatous masses for the first time.


Subject(s)
Genital Diseases, Male/diagnosis , Lipomatosis, Multiple Symmetrical/diagnosis , Scrotum/pathology , Adult , Humans , Magnetic Resonance Imaging , Male , Scrotum/diagnostic imaging , Ultrasonography
13.
Int J Clin Pract ; 60(1): 99-103, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16409436

ABSTRACT

Intrahepatic cysts are generally classified as congenital, traumatic, infectious or neoplastic. Non-parasitic hepatic cysts (NPHCs) include simple cysts and adult polycystic liver disease in which the liver is diffusely occupied by cysts. NPHCs usually reach a large size before causing symptoms, unless a complication such as rupture, bleeding, infection, obstructive jaundice or neoplastic transformation occurs. We report the case of a 67-year-old man with spontaneous rupture of simple liver cyst. The clinical pictures and the unusual ultrasound features of this rare condition are discussed.


Subject(s)
Cysts/diagnostic imaging , Liver Diseases/diagnostic imaging , Aged , Humans , Male , Remission, Spontaneous , Rupture, Spontaneous/diagnostic imaging , Ultrasonography
14.
Hum Mol Genet ; 9(2): 217-26, 2000 Jan 22.
Article in English | MEDLINE | ID: mdl-10607832

ABSTRACT

Dysferlin, the gene product of the limb girdle muscular dystrophy (LGMD) 2B locus, encodes a membrane-associated protein with homology to Caenorhabditis elegans fer-1. Humans with mutations in dysferlin ( DYSF ) develop muscle weakness that affects both proximal and distal muscles. Strikingly, the phenotype in LGMD 2B patients is highly variable, but the type of mutation in DYSF cannot explain this phenotypic variability. Through electronic database searching, we identified a protein highly homologous to dysferlin that we have named myoferlin. Myoferlin mRNA was highly expressed in cardiac muscle and to a lesser degree in skeletal muscle. However, antibodies raised to myoferlin showed abundant expression of myoferlin in both cardiac and skeletal muscle. Within the cell, myoferlin was associated with the plasma membrane but, unlike dysferlin, myoferlin was also associated with the nuclear membrane. Ferlin family members contain C2 domains, and these domains play a role in calcium-mediated membrane fusion events. To investigate this, we studied the expression of myoferlin in the mdx mouse, which lacks dystrophin and whose muscles undergo repeated rounds of degeneration and regeneration. We found upregulation of myoferlin at the membrane in mdx skeletal muscle. Thus, myoferlin ( MYOF ) is a candidate gene for muscular dystrophy and cardiomyopathy, or possibly a modifier of the muscular dystrophy phenotype.


Subject(s)
Membrane Proteins/genetics , Muscle Proteins/genetics , Muscular Dystrophies/genetics , Amino Acid Sequence , Animals , Blotting, Northern , Calcium-Binding Proteins , Cell Membrane/metabolism , Dysferlin , Humans , Membrane Proteins/biosynthesis , Membrane Proteins/isolation & purification , Mice , Mice, Inbred mdx , Molecular Sequence Data , Muscle Proteins/biosynthesis , Muscle Proteins/isolation & purification , Muscle, Skeletal/metabolism , Muscular Dystrophies/metabolism , Myocardium/metabolism , Nuclear Envelope/metabolism , RNA, Messenger/analysis
15.
Biochemistry ; 37(8): 2596-606, 1998 Feb 24.
Article in English | MEDLINE | ID: mdl-9485410

ABSTRACT

A combined experimental and theoretical investigation of the deuterium isotope effects on the bacterial luciferase reaction is described. The experimental studies focus on determining if the unusual aldehydic deuterium isotope effect of approximately 1.5 observed in these reactions is an intrinsic isotope effect resulting from a single rate-limiting step or is a composite of multiple rate-limiting steps. The isotope effect observed is not significantly affected by variation in the aldehyde chain length, changes in the pH over a range of 6-9, use of alphaC106A and alphaC106S site-directed mutants, or chloride substitution at the 8-position of the reduced flavin, though the isotope effect is decreased when the 8-methoxy-substituted flavin is used as a substrate. From these observations it is concluded that the aldehydic isotope effect arises from the change in rate of a single kinetic step. A stopped-flow kinetic analysis of the microscopic rate constants for the reactions of 1-[1H]decanal and 1-[2H]decanal in the bacterial luciferase reaction was carried out, and aldehyde hydration isotope effects were determined. From the results it is estimated that the aldehydic deuterium isotope effect is approximately 1.9 after formation of an intermediate flavin C4a-hydroperoxy hemiacetal. Ab initio calculations were used to examine the transformation of the aldehyde into a carboxylic acid and to predict isotope effects for possible mechanisms. These calculations indicate that the mechanism involving rate-limiting electron transfer from the flavin C4a-hydroxide to an intermediate dioxirane is consistent with the enigmatic aldehydic isotope effect and that the intermediacy of a dioxirane is energetically plausible.


Subject(s)
Deuterium/chemistry , Luciferases/chemistry , Luciferases/metabolism , Aldehydes/chemistry , Binding Sites/genetics , Escherichia coli/genetics , Flavin Mononucleotide/chemistry , Hydrogen-Ion Concentration , Kinetics , Luciferases/genetics , Luminescent Measurements , Mutagenesis, Site-Directed , Recombination, Genetic , Solvents , Spectrophotometry , Thermodynamics , Vibrio/enzymology , Vibrio/genetics
16.
In. Asociación Interamericana de Ingeniería Sanitaria y Ambiental; Asociación Argentina de Ingeniería Sanitaria y Ciencias del Ambiente. Ingeniería ambiental para el desarrollo sostenible. Buenos Aires, AIDIS, 1994. p.9, ilus.
Monography in Spanish | BINACIS | ID: bin-138013

ABSTRACT

Ante la carencia de información sobre la residualidad biócida de atrazina en las diversas regiones del Sudoeste de la Pcia. de Buenos Sires, los autores presentan este trabajo proporcionando resultados de tres suelos de los partidos de Balcarce, González Chaves y San Cayetano, sobre los que se efectuaron aplicaciones de 1, 2 y 4 kg. i.a.ha-1. El estudio se realizó mediante biotest con avena sativa, en condiciones controladas, determinando el efecto del herbicida sobre la evolución del peso seco. Se determinó que la atrazina tuvo una persistencia biócida de más de 223 días en el suelo de menor contenido orgánico(San Cayetano)


Subject(s)
Argentina , Sanitary Engineering , Herbicides , Congress
17.
In. Asociación Interamericana de Ingeniería Sanitaria y Ambiental; Asociación Argentina de Ingeniería Sanitaria y Ciencias del Ambiente. Ingeniería ambiental para el desarrollo sostenible. Buenos Aires, AIDIS, 1994. p.9, ilus. (64162).
Monography in Spanish | BINACIS | ID: bin-64162

ABSTRACT

Ante la carencia de información sobre la residualidad biócida de atrazina en las diversas regiones del Sudoeste de la Pcia. de Buenos Sires, los autores presentan este trabajo proporcionando resultados de tres suelos de los partidos de Balcarce, González Chaves y San Cayetano, sobre los que se efectuaron aplicaciones de 1, 2 y 4 kg. i.a.ha-1. El estudio se realizó mediante biotest con avena sativa, en condiciones controladas, determinando el efecto del herbicida sobre la evolución del peso seco. Se determinó que la atrazina tuvo una persistencia biócida de más de 223 días en el suelo de menor contenido orgánico(San Cayetano)


Subject(s)
Sanitary Engineering , Herbicides , Congress
18.
In. Asociación Argentina de Ingeniería Sanitaria y Ciencias del Ambiente. Anales. Mar del Plata, AIDIS-AR, 1993. p.441-9, ilus.
Monography in Spanish | BINACIS | ID: bin-137775

ABSTRACT

Se carece de información sobre la residualidad biocida de atrazina en las diversas regiones del sudeste, de la Pcia. de Bs.As. El presente trabajo proporciona resultados de tres suelos de los partidos de Balcarce, Gonzáles Chaves y San Cayetano, sobre los que se efectuaron aplicaciones de 1,2 y 4 kg.i.a.ha-1. El estudio se realizó mediante biotests con Avena sativa, en condiciones controladas, determinando el efecto del herbicida sobre la evolución del peso seco. Se determinó que la atrazina tuvo una persistencia biocida de más de 223 días en el suelo de menor contenido orgánico (San Cayetano)


Subject(s)
Argentina , Sanitary Engineering , Pesticides , Water Pollution , Congress
19.
In. Asociación Argentina de Ingeniería Sanitaria y Ciencias del Ambiente. Anales. Mar del Plata, AIDIS-AR, 19931017. p.441-449, ilus. (64308).
Monography in Spanish | BINACIS | ID: bin-64308

ABSTRACT

Se carece de información sobre la residualidad biocida de atrazina en las diversas regiones del sudeste, de la Pcia. de Bs.As. El presente trabajo proporciona resultados de tres suelos de los partidos de Balcarce, Gonzáles Chaves y San Cayetano, sobre los que se efectuaron aplicaciones de 1,2 y 4 kg.i.a.ha-1. El estudio se realizó mediante biotests con Avena sativa, en condiciones controladas, determinando el efecto del herbicida sobre la evolución del peso seco. Se determinó que la atrazina tuvo una persistencia biocida de más de 223 días en el suelo de menor contenido orgánico (San Cayetano)


Subject(s)
Sanitary Engineering , Pesticides , Water Pollution , Congress
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