PurposeSonic hedgehog (SHH), an activating ligand of smoothened (SMO), is overexpressed in > 70% of pancreatic cancers (PCs). We investigated the impact of vismodegib, an SHH antagonist, plus gemcitabine (GV) or gemcitabine plus placebo (GP) in a multicenter phase Ib/randomized phase II trial and preclinical PC models.Patients and MethodsPatients with PC not amenable to curative therapy who had received no prior therapy for metastatic disease and had Karnofsky performance score ≥ 80 were enrolled. Patients were randomly assigned in a one-to-one ratio to GV or GP. The primary end point was progression-free-survival (PFS). Exploratory correlative studies included serial SHH serum levels and contrast perfusion computed tomography imaging. To further investigate putative biologic mechanisms of SMO inhibition, two autochthonous pancreatic cancer models (KrasG12D; p16/p19fl/fl; Pdx1-Cre and KrasG12D; p53R270H/wt; Pdx1-Cre) were studied.ResultsNo safety issues were identified in the phase Ib portion (n = 7), and the phase II study enrolled 106 evaluable patients (n = 53 in each arm). Median PFS was 4.0 and 2.5 months for GV and GP arms, respectively (95% CI, 2.5 to 5.3 and 1.9 to 3.8, respectively; adjusted hazard ratio, 0.81; 95% CI, 0.54 to 1.21; P = .30). Median overall survival (OS) was 6.9 and 6.1 months for GV and GP arms, respectively (95% CI, 5.8 to 8.0 and 5.0 to 8.0, respectively; adjusted hazard ratio, 1.04; 95% CI, 0.69 to 1.58; P = .84). Response rates were not significantly different. There were no significant associations between correlative markers and overall response rate, PFS, or OS. Preclinical trials revealed no significant differences with vismodegib in drug delivery, tumor growth rate, or OS in either model.ConclusionThe addition of vismodegib to gemcitabine in an unselected cohort did not improve overall response rate, PFS, or OS in patients with metastatic PC. Our preclinical and clinical results revealed no statistically significant differences with respect to drug delivery or treatment efficacy using vismodegib.

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BackgroundThe use of telemedicine is growing, but its efficacy for achieving comparable or improved clinical outcomes has not been established in many medical specialties. The objective of this systematic review was to evaluate the efficacy of telemedicine interventions for health outcomes in two classes of application: home-based and office/hospital-based.MethodsData sources for the study included deports of studies from the MEDLINE, EMBASE, CINAHL, and HealthSTAR databases; searching of bibliographies of review and other articles; and consultation of printed resources as well as investigators in the field. We included studies that were relevant to at least one of the two classes of telemedicine and addressed the assessment of efficacy for clinical outcomes with data of reported results. We excluded studies where the service did not historically require face-to-face encounters (e.g., radiology or pathology diagnosis). All included articles were abstracted and graded for quality and direction of the evidence.ResultsA total of 25 articles met inclusion criteria and were assessed. The strongest evidence for the efficacy of telemedicine in clinical outcomes comes from home-based telemedicine in the areas of chronic disease management, hypertension, and AIDS. The value of home glucose monitoring in diabetes mellitus is conflicting. There is also reasonable evidence that telemedicine is comparable to face-to-face care in emergency medicine and is beneficial in surgical and neonatal intensive care units as well as patient transfer in neurosurgery.ConclusionsDespite the widespread use of telemedicine in virtually all major areas of health care, evidence concerning the benefits of its use exists in only a small number of them. Further randomized controlled trials must be done to determine where its use is most effective.

The activation of signal transducer and activator of transcription 3 (Stat3) has been implicated in the oncogenesis of cancer and is regarded as a novel target for cancer therapy. Stat3 is classified as a proto-oncogene, because an activated form of Stat3 can mediate oncogenic transformation in cultured cells and tumour formation in nude mice. The constitutive activation of Stat3 has been frequently detected in various types of human cancers. However, the constitutive activation of Stat3 in endometrial and cervical cancers has not been studied. We examined tyrosine phosphorylation of Stat3 (activated form of Stat3) in multiple endometrial and cervical cancer tissues using tissue microarray slides as well as cancer cell lines to explore the possible activation of Stat3. Our results indicated that elevated phosphorylation of Stat3 was detected in cervical and endometrial cancer cell lines. Our results also showed that elevated levels of phosphorylation of Stat3 protein were detected in the endometrial and cervical cancer specimens. This is the first study to demonstrate that Stat3 is activated in human endometrial and cervical cancer tissues. Immunohistochemical staining showed that activated Stat3 is associated with increased expression of downstream antiapoptotic genes, Bcl-xL, survivin, and Mcl-1 in these tissues. Expression of a dominant-negative Stat3 mutant using adenovirus-mediated gene transfer inhibited cell growth and induced apoptosis in HeLa and SiHa cervical cancer cell lines expressing elevated levels of Stat3 phosphorylation. Further, a JAK/Stat3 small molecular inhibitor, JSI-124, induced apoptosis more selectively in HeLa and SiHa cancer cell lines than Ishikawa cell line without elevated levels of Stat3 phosphorylation. These results indicate that Stat3 is activated in human endometrial and cervical cancers and the inhibition of constitutive Stat3 signaling may be an effective target for cancer intervention in these two cancers.

The issue of final apical preparation size remains controversial despite considerable clinical and in vitro research. The astute clinician must be aware of this research before choosing any instrumentation system because the informed clinician's decision must be guided by the best available evidenced-based information. This review article generated a Medline-based search strategy to disclose these studies and provides a critique and summary of the results.From the University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania.Address request for reprints to Dean Baugh, DDS. E-mail address: baughdf@yahoo.com.Copyright © 2005 by the American Association of Endodontists T he most important objective of root canal therapy is to minimize the number of microorganisms and pathologic debris in root canal systems to prevent or treat apical periodontitis. This process of chemomechanical debridement, or cleaning of the root canal systems, has been described as the removal of all of the contents of the root canal systems before and during shaping. Grossman (1) described mechanical cleaning as the most important part of root canal therapy. Schilder (2) also considered cleaning and shaping as the foundation for successful endodontic therapy.Thorough instrumentation of the apical region has long been considered to be an essential component in the cleaning and shaping process. It was discussed as a critical step as early as 1931 by Groove (3). Simon (4) later recognized the apical area as the critical zone for instrumentation. Other authors (5, 6) concluded that the last few millimeters that approach the apical foramen are critical in the instrumentation process. Mechanical instrumentation and irrigation are sound endodontic principles and essential components of successful endodontics (7,8). Research has shown that mechanical instrumentation greatly reduces the number of microorganisms remaining in the root canal system. Mechanical instrumentation (9) has been shown to reduce bacterial count even without irrigants or dressings. A combination of mechanical instrumentation and irrigation (9, 10) further reduced the number of microorganisms by 100 to 1000 times. However, mechanical instrumentation with irrigation does not reliably disinfect an infected root canal system (11-14).Manufacturers developed nickel-titanium rotary instrumentation systems to facilitate the cleaning and shaping process. They are popular because of their apparent ease of use and reduced number of instruments. However, Spangberg (6) noted that the strong emphasis on reducing the number of instruments and limiting apical preparations to small sizes does not produce clean apical preparations in diseased teeth. Given this controversial and important topic, we conducted a broad-based Medline search of the literature to characterize the major factors involved in apical canal instrumentation. Table 1 provides the Medline search strategy used to identify relevant articles for this review. A secondary search was then conducted using the refere...

Cancer communication near the end of life has a growing evidence base, and requires clinicians to draw on a distinct set of communication skills. Patients with advanced and incurable cancers are dealing with the emotional impact of a life-limiting illness, treatment decisions that are complex and frequently involve consideration of clinical trials, and the challenges of sustaining hope while also having realistic goals. In this review, we sought to provide a guide to important evidence about communication for patients with advanced cancer regarding: Communication at diagnosis; Discussing prognosis; Decision-making about palliative anticancer therapy and Phase 1 trials; Advance care planning, Transitions in focus from anticancer to palliative care; and Preparing patients and families for dying and death.