Context/Objectives:
Pazopanib, an inhibitor of kinases including vascular endothelial growth factor receptor, demonstrated impressive activity in progressive metastatic differentiated thyroid cancer, ...prompting its evaluation in anaplastic thyroid cancer (ATC).
Design/Setting/Patients/Interventions/Outcome Measures:
Preclinical studies, followed by a multicenter single arm phase 2 trial of continuously administered 800 mg pazopanib daily by mouth (designed to provide 90% chance of detecting a response rate of >20% at the 0.10 significance level when the true response rate is >5%), were undertaken. The primary trial end point was Response Evaluation Criteria in Solid Tumors (RECIST) response.
Results:
Pazopanib displayed activity in the KTC2 ATC xenograft model, prompting clinical evaluation. Sixteen trial patients were enrolled; 15 were treated: 66.7% were female, median age was 66 yr (range 45–77 yr), and 11 of 15 had progressed through prior systemic therapy. Enrollment was halted, triggered by a stopping rule requiring more than one confirmed RECIST response among the first 14 of 33 potential patients. Four patients required one to two dose reductions; severe toxicities (National Cancer Institute Common Toxicity Criteria-Adverse Events version 3.0 grades >3) were hypertension (13%) and pharyngolaryngeal pain (13%). Treatment was discontinued because of the following: disease progression (12 patients), death due to a possibly treatment-related tumor hemorrhage (one patient), and intolerability (radiation recall tracheitis and uncontrolled hypertension, one patient each). Although transient disease regression was observed in several patients, there were no confirmed RECIST responses. Median time to progression was 62 d; median survival time was 111 d. Two patients are alive with disease 9.9 and 35 months after the registration; 13 died of disease.
Conclusions:
Despite preclinical in vivo activity in ATC, pazopanib has minimal single-agent clinical activity in advanced ATC.
Anaplastic thyroid cancer (ATC) has perhaps the worst prognosis of any cancer, with a median survival of only about 5 months regardless of stage. Pazopanib monotherapy has promising clinical activity ...in differentiated thyroid cancers (generally attributed to vascular endothelial growth factor receptor inhibition), yet has less effective single-agent activity in ATC. We now report that combining pazopanib with microtubule inhibitors such as paclitaxel produced heightened and synergistic antitumor effects in ATC cells and xenografts that were associated with potentiated mitotic catastrophe. We hypothesized that combined effects may reflect enhanced paclitaxel-induced cytotoxicity mediated by cell cycle regulatory kinase inhibition by pazopanib. Indeed, pazopanib potently inhibited aurora A, with pazopanib/paclitaxel synergy recapitulated by aurora A short hairpin RNA knockdown or by specific aurora A pharmacological inhibition. Pazopanib/paclitaxel synergy was reversed by aurora A knockdown. Moreover, aurora A (but not B or C) message and protein levels were significantly increased in patient ATCs, and durable benefit resulted from pilot clinical translation of pazopanib/paclitaxel therapy in a patient with metastatic ATC. Collectively, these results suggest that the pazopanib/paclitaxel combination is a promising candidate therapeutic approach in ATC and that aurora A may represent a potentially viable therapeutic molecular target in ATC.
We previously reported that chaetocin has potent and selective anti-myeloma activity attributable to reactive oxygen species (ROS) induction imposed by inhibition of the redox enzyme thioredoxin ...reductase; we now detail its effects in solid tumours.
Cellular assays, transcriptional profiling and the NCI60 screen were used to assess the effects of chaetocin in solid tumour and endothelial cells.
NCI-60 screening demonstrated chaetocin to even more potently inhibit proliferation in solid tumour than in haematological cell lines; transcriptional profiling revealed a signature consistent with induction of inflammatory response and cell death pathways. Chaetocin induced ROS, oxidative damage to cellular proteins and apoptosis, with 2-10 nM IC(50)s (24 h exposures) in all tested solid tumour cell lines. The pan-caspase inhibitor zVAD-fmk did not block chaetocin-induced cell death despite inhibiting mitochondrial membrane depolarisation and apoptosis. Further, Molt-4 rho(0) cells lacking metabolically functional mitochondria were readily killed by chaetocin; in addition chaetocin-induced cytotoxicity was unaffected by autophagy inhibitors or hypoxia and consequent HIF-1α upregulation. Moreover, chaetocin inhibited SKOV3 ovarian cancer xenografts producing less vascular tumours, and inhibited human umbilical vein endothelial cell proliferation.
Chaetocin has intriguing and wide-ranging in vitro and in vivo anticancer effects, and is an attractive candidate for further preclinical and clinical development.
Background:
Vascular endothelial growth factor-targeted kinase inhibitors have emerged as highly promising therapies for radioiodine-refractory metastatic differentiated thyroid cancer. ...Unfortunately, drug resistance uniformly develops, limiting their therapeutic efficacies and thereby constituting a major clinical problem.
Approach and Methods:
To study acquired drug resistance and elucidate underlying mechanisms in this setting, BHP2–7 human differentiated thyroid cancer cells were subjected to prolonged continuous in vitro selection with 18 μM pazopanib, a clinically relevant concentration; acquisition of pazopanib resistance was serially assessed, with the resulting resistant cells thereafter subcloned and characterized to assess potential mechanisms of acquired pazopanib resistance.
Results:
Stable 2- to 4-fold in vitro pazopanib resistance emerged in response to pazopanib selection associated with similar in vitro growth characteristics but with markedly more aggressive in vivo xenograft growth. Selected cells were cross-resistant to sunitinib and to a lesser extent sorafenib but not to MAPK kinase (MEK1/2) inhibition by GSK1120212. Genotyping demonstrated acquisition of a novel activating KRAS codon 13 GGC to GTT (glycine to valine) mutation, consistent with the observed resistance to upstream vascular endothelial growth factor receptor inhibition yet sensitivity to downstream MAPK kinase (MEK1/2) inhibition.
Conclusions:
Selection of thyroid cancer cells with clinically utilized therapeutics can lead to acquired drug resistance and altered in vivo xenograft behavior that can recapitulate analogous drug resistance observed in patients. This approach has the potential to lead to insights into acquired treatment-related drug resistance in thyroid cancers that can be subjected to subsequent validation in serially collected patient samples and that has the potential to yield preemptive and responsive approaches to dealing with this important clinical problem.
The purpose of this study is to analyze the effectiveness of surgery and follow-up of children operated on for burn sequelae. For many years, we have organized two missions per year to Benin and ...Togo, one for surgery and one for follow-up. We analyzed the files of children born in Africa and victims of burns from the years 2002 to 2011. Children were referred through a non-governmental organization (NGO) and assessed in Africa by local paediatricians before and after surgery. Treatment consisted in operating on burn sequelae such as contractures, hypertrophic scars and hard cords. Impaired mobility was our only indication for the operation. We kept a database on all patients. Sixty files were reviewed, of which fifty were deemed suitable for analysis. The most common methods of surgery were skin grafting and Z-plasty. There were no complications, such as infection or graft/flap necrosis after immediate surgery. Long-term follow-up revealed a recurrence of hypertrophic scarring (47%), retractions (24%) and hard cords (2%) due to a lack of occupational therapy and physiotherapy treatment. Partnership with an NGO and a local team allows us to treat children with burn injury sequelae in Western Africa. A continued and often long-lasting follow-up by occupational therapists and physiotherapists is highly mandatory in order to guarantee good long-term results. In 2010, we initiated local rehabilitation therapy.
Meticillin resistant Staphylococcus aureus (MRSA) is among the most important causes of nosocomial infections. It possesses a particular ability to spread in hospitals worldwide.
To analyze the ...proportion of MRSA among S. aureus isolated from specimen taken for diagnosis purposes. To make the medical staff aware of the problem of MRSA infections and to take a better care of patients.
During 3 months, a prospective study was carried out in the neonatal unit of centre hospitalier départemental du Zou et Collines in Benin. We identified newborn carriers of SA, particularly MRSA and factors associated with the carriage. Two hundred and ninety patients were admitted in the 3 divisions of the neonatal unit. From 195 specimens examined for diagnosis purposes 48 h after hospitalization, 112 patients were detected by nose swabbing. Concurrently, swabbing of environment was achieved.
Among patients'specimens, 141 isolations of S. aureus were observed. The proportion of MRSA was 36% amongst diagnostic specimens. MRSA represented 39% of the environment specimens. None of the isolated MRSA produces Panton Valentine leukocidin.
Our survey revealed a high level of MRSA among S. aureus isolated from diagnostic specimens. Consecutive to such findings and for decreasing nosocomial infection, an appropriate prevention program was installed, including intensive promotion of hands hygiene, correct sterilization and disinfection of materials and patients.
Staphylococcus aureus résistant à la méticilline (SARM) est 1 des principaux agents pathogènes humains impliqués dans les infections nosocomiales et il démontre une grande propension de dissémination ...intrahospitalière. Les 2 objectifs de cette étude étaient d'établir la proportion de SARM parmi les souches de
S. aureus isolées des prélèvements à visée diagnostique et celles de prélèvements réalisés sur l'environnement des patients.
Au cours d'une étude prospective réalisée sur 3 mois dans le secteur de néonatologie du centre hospitalier départemental du Zou et Collines au Bénin, nous avons identifié les nouveau-nés hospitalisés porteurs de SARM et les facteurs associés à ce portage. Simultanément, des écouvillonnages de l'environnement ont été effectués. Deux cent quatre-vingt-dix patients ont été admis dans les 3 divisions de néonatologie (réanimation, prématurité, et division calme). Cent quatre-vingt-quinze ont eu un prélèvement à visée diagnostique après 48 heures d'hospitalisation, et 112 ont été dépistés à l'admission par écouvillonnage des narines. La leucocidine de Panton et Valentine a été recherchée sur toutes les souches de SARM.
Cent quarante et une souches de
S. aureus ont été isolées chez les patients. Trente-trois étaient issues des prélèvements à visée diagnostique dont 12 SARM (36 %). Cinquante et une souches de
S. aureus dont 20 SARM ont été isolées de 90 prélèvements de l'environnement. Les facteurs pouvant faciliter l'acquisition des souches de
S. aureus étaient le faible poids à la naissance, l'infection maternelle, la prématurité, la présence de cathéter veineux et une hospitalisation prolongée. Aucune des souches de SARM isolées ne produisait la leucocidine de Panton et Valentine. La proportion de SARM parmi les isolats de
S. aureus issus des prélèvements à visée diagnostique était élevée et traduisait l'insuffisance des mesures de prévention.
L'environnement constitue un réservoir important de contaminations dans notre contexte. Une meilleure observance de l'hygiène des mains, de la stérilisation et de la désinfection correcte du matériel sont les pistes principales pour une réduction significative des infections nosocomiales.
Meticillin resistant
Staphylococcus aureus (MRSA) is among the most important causes of nosocomial infections. It possesses a particular ability to spread in hospitals worldwide.
To analyze the proportion of MRSA among
S. aureus isolated from specimen taken for diagnosis purposes. To make the medical staff aware of the problem of MRSA infections and to take a better care of patients.
During 3 months, a prospective study was carried out in the neonatal unit of
centre hospitalier départemental du Zou et Collines in Benin. We identified newborn carriers of SA, particularly MRSA and factors associated with the carriage. Two hundred and ninety patients were admitted in the 3 divisions of the neonatal unit. From 195 specimens examined for diagnosis purposes 48 h after hospitalization, 112 patients were detected by nose swabbing. Concurrently, swabbing of environment was achieved.
Among patients'specimens, 141 isolations of
S. aureus were observed. The proportion of MRSA was 36% amongst diagnostic specimens. MRSA represented 39% of the environment specimens. None of the isolated MRSA produces Panton Valentine leukocidin.
Our survey revealed a high level of MRSA among
S. aureus isolated from diagnostic specimens. Consecutive to such findings and for decreasing nosocomial infection, an appropriate prevention program was installed, including intensive promotion of hands hygiene, correct sterilization and disinfection of materials and patients.
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