Neoadjuvant Chemotherapy in Locally Advanced Cervical Carcinoma - a Role in Patients with Para-aortic Lymph Node Involvement? A 10-year Institutional Experience.

AIMS: Overall survival and progression-free survival with concomitant chemoradiotherapy for locally advanced cervical carcinoma have been described as 66% and 58%, respectively, at 5 years. Para-aortic lymph node involvement significantly increases the risk of relapse and death. The role of additional chemotherapy in these patients is as yet undefined. This aim of the present study was to determine the outcome of a cohort of para-aortic lymph node-positive patients treated with neoadjuvant chemotherapy followed by extended-field chemoradiation compared with patients treated with extended-field chemoradiation without neoadjuvant chemotherapy. MATERIALS AND METHODS: We reviewed patients with International Federation of Gynaecology and Obstetrics (FIGO) 2014 stage IB1-IVA cervical carcinoma who received extended-field radiotherapy in addition to standard pelvic chemoradiotherapy with or without neoadjuvant chemotherapy, at University College London Hospital (January 2007 to January 2018). Patients in open clinical trials were excluded. RESULTS: Overall, 47 patients (15.8% of 298 eligible patients) with pelvic and/or para-aortic lymph node-positive cervical carcinoma received extended-field radiotherapy. Nineteen patients (40.4%) had both neoadjuvant chemotherapy (all received six cycles) and extended-field radiotherapy (median 44 days); 28 (59.6%) patients received extended-field radiotherapy alone (median 43 days). All patients completed radical radiotherapy within 49 days. We observed evidence that patients receiving neoadjuvant chemotherapy and extended-field radiotherapy had a lower risk of death (median follow-up 4.8 years, three deaths) compared with extended-field radiotherapy alone (median follow-up 3.0 years, 11 deaths; hazard ratio = 0.27, 95% confidence interval 0.08-1.00; P = 0.05). Three-year overall survival rates were 83.3% (95% confidence interval 66.1-100) and 64.6% (95% confidence interval 44.6-84.6), respectively. A PFS benefit was seen (hazard ratio 0.25, 95% confidence interval 0.08-0.77; P = 0.02), with 3-year PFS rates of 77.8% (95% confidence interval 58.6-97.0) and 35.0% (95% confidence interval 14.0-56.0), respectively. CONCLUSIONS: Our institutional experience suggests that the use of additional systemic therapy before chemoradiotherapy benefits patients with locoregionally advanced (FIGO 2018 IIIC2) cervical cancer. Neoadjuvant chemotherapy was associated with longer overall survival and PFS, without compromising definitive extended-field chemoradiation.

Transforming growth factor-beta receptor-associated protein 1 is a Smad4 chaperone.

Members of the transforming growth factor-beta (TGF-beta) superfamily signal through unique cell membrane receptor serine-threonine kinases to activate downstream targets. TRAP1 is a previously described 96-kDa cytoplasmic protein shown to bind to TGF-beta receptors and suggested to play a role in TGF-beta signaling. We now fully characterize the binding properties of TRAP1, and show that it associates strongly with inactive heteromeric TGF-beta and activin receptor complexes and is released upon activation of signaling. Moreover, we demonstrate that TRAP1 plays a role in the Smad-mediated signal transduction pathway, interacting with the common mediator, Smad4, in a ligand-dependent fashion. While TRAP1 has only a small stimulatory effect on TGF-beta signaling in functional assays, deletion constructs of TRAP1 inhibit TGF-beta signaling and diminish the interaction of Smad4 with Smad2. These are the first data to identify a specific molecular chaperone for Smad4, suggesting a model in which TRAP1 brings Smad4 into the vicinity of the receptor complex and facilitates its transfer to the receptor-activated Smad proteins.

Activation of the 9E3/cCAF chemokine by phorbol esters occurs via multiple signal transduction pathways that converge to MEK1/ERK2 and activate the Elk1 transcription factor.

Using primary fibroblasts in culture, we have investigated the signal transduction mechanisms by which phorbol esters, a class of tumor promoters, activate the 9E3 gene and its chemokine product the chicken chemotactic and angiogenic factor. This gene is highly stimulated by phorbol 12,13-dibutyrate (PDBu) via three pathways: (i) a small contribution through protein kinase C (the commonly recognized pathway for these tumor promoters), (ii) a contribution involving tyrosine kinases, and (iii) a larger contribution via pathways that can be interrupted by dexamethasone. All three of these pathways converge into the mitogen-activated protein kinases, MEK1/ERK2. Using a luciferase reporter system, we show that although both the AP-1 and PDRIIkB (a NFkappaB-like factor in chickens) response elements are capable of activation in these normal cells, regions of the 9E3 promoter containing them are unresponsive to PDBu stimulation. In contrast, we show for the first time that activation by PDBu occurs through a segment of the promoter containing Elk1 response elements; deletion and mutation of these elements abrogates 9E3/chicken chemotactic and angiogenic factor expression. Electrophoretic mobility shift assays and functional studies using PathDetect systems show that stimulation of the cells by phorbol esters leads to activation of the Elk1 transcription factor, which binds to its element in the 9E3 promoter.

The interrelationship of wind instrument technic, orthodontic treatment, and orofacial myology.

This article identifies, defines and reviews the synergy between orofacial myofunctional and orthodontic health with regard to wind instrument performance, and summarizes the skills involved in playing an instrument. (i.e. embouchure, articulation, breath support.) Criteria and strategies for choosing an instrument are outlined via orthodontic classifications, therapeutic value or contraindication and team approaches. The author concludes that a team-oriented approach on the part of the professions cited in this article are of the ultimate good for the student/patient.

Parental presence plus oral midazolam decreases frequency of 5% halothane inductions in children.

STUDY OBJECTIVE: To determine the frequency of 5% halothane induction and behavioral distress during inhalation induction with both oral midazolam and parental presence compared with parental presence alone. DESIGN: Randomized, controlled, double blind study. SETTING: Same day anesthesia at a university department of anesthesiology. PATIENTS: 72 ASA status I and II children, 3 to 10 years of age, scheduled for first time anesthesia. INTERVENTIONS: Children were assigned to one of two groups to receive midazolam 0.5 mg/kg orally or placebo. A parent was present during induction. Children were videotaped at baseline, after treatment, and during induction. Tapes were scored for behavioral distress using the revised Observational Scale of Behavioral Distress. MEASUREMENTS AND MAIN RESULTS: Children who received midazolam in the setting of parental presence had significantly fewer 5% halothane inductions than those who received placebo (p < 0.02). They also had less behavioral distress (p < 0.01). CONCLUSIONS: The combination of parental presence plus oral midazolam reduces the likelihood of needing a 5% rapid halothane induction when compared with parental presence without premedication.

Translocation of pro-OmpA across inner membrane vesicles of Escherichia coli occurs in two consecutive energetically distinct steps.

The rate of energy-dependent transfer of pro-OmpA across Escherichia coli inner membrane vesicles in vitro was found to be a function of the ATP concentration. At concentrations above 0.1 mM ATP, the addition of a transmembrane electrochemical potential (proton motive force or pmf) increased the rate of pro-OmpA translocation. Additional experiments demonstrated that the overall reaction proceeded by at least two distinct energy-requiring steps. The first step required only ATP, was nearly unaffected by the pmf, and resulted in the insertion of the amino-terminal domain of pro-OmpA across the membrane. The insertion exposed the signal sequence cleavage site to the periplasmic side of the membrane, as measured by the appearance of a mature length translocation intermediate. However, this intermediate was partially exposed to the cytoplasmic side of the membrane. In a second energy-dependent step, either ATP or the pmf was sufficient to complete the translocation of mature length OmpA across the membrane.

Intravenous self-administration of propoxyphene napsylate: case report and in-vitro studies.

A man who was prescribed propoxyphene napsylate (PN) for treatment of heroin addiction stated that he received no effect from the drug by the oral route. He then decided to administer the drug to himself intravenously in a manner identical to that used by most heroin addicts (heating the tablet with water in a spoon and drawing the liquid through a needle); this procedure brought him immediate subjective relief. Several reports have stated than PN is not efficacious via the intravenous route since it is relatively water insoluble and is therefore not likely to be abuse in this manner. However, in vitro experiments demonstrated that at least 1 mg of PN can be extracted by 10 mL of hot water from a tablet containing 100 mg of the drug. Assuming (as a conservative estimate) that the subject received a bolus injection of approximately 40 mg PN (he used four 100 mg tablets at once), his response may not have been entirely subjective. Moreover, severe cardiovascular and pulmonary complications may ensure as a result of the insoluble material injected.