The Do Over Mk Schiller Epub Bud
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the do over mk schiller epub bud
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First-line chemotherapy for lung cancer often includes a platinum-based drug (cisplatin or carboplatin) in combination with another FDA-approved chemotherapy drug (paclitaxel, docetaxel, etoposide, gemcitabine, pemetrexed)[3]. However, in a subset of patients with non-small-cell-lung cancer (NSCLC), there is overexpression of epidermal growth factor receptor (EGFR). Stimulation of the EGFR pathway leads to a series of intracellular events culminating in increased mitotic and growth potential, increased ability to metastasize, and increased angiogenesis (new blood vessel formation) in the cancer cells.
65 year old female with NSCLC. Initial CT scan shows large soft tissue mass in the RML (Figure 4A). After 3 cycles of Bevacizumab (Avastin) the mass demonstrates typical antiangiogenesis effect with peripheral and cavitation associated with mild overall decrease in the size of the mass (Figure 4B).
The overall increase in size and decrease in tracer uptake in a mass is a phenomenon that has been extensively described in gastrointestinal stromal tumor treated with imatinib mesylate (Gleevec), reflecting therapy response[13]. In our series we also observed similar findings in patients with lung cancer. Once the patient is treated, the tumor usually decreases in size upon response. In some responding tumors, the tumor size increases as a result of intratumoral and perilesional hemorrhage, necrosis, or myxoid degeneration. The attenuation of the tumor decreases significantly, as the tumor becomes homogeneous.
The discovery of the correlation of EGFR mutations and response to EGFR TKI therapy has demonstrated that molecular typing of tumors to guide therapy selection for lung cancer is possible. Prospective trials will need to validate the feasibility and efficacy of selecting therapy based on tumor molecular profiles. Also, numerous molecularly targeted agents are in clinical development, and future studies will need to identify molecular and clinical tools to guide the use of these agents, particularly in combination with current therapies such as surgery, radiation, cytotoxic chemotherapy, and other targeted therapies.
58 year old female on trastuzumab (Herceptin). A. MUGA scan obtained after 3 months of therapy with Herceptin shows that the EF has dropped significantly to 49% (Figure16A). B. The ejection fraction recovers to 72% (Figure16B) 1 week after discontinuation of therapy. Trastuzumab is known to cause this effect, which is worsened with concomitant anthracycline administration.
With the discovery and introduction of new MTT agents, the treatment for a wide variety of cancers has been revolutionized. As these treatments become increasingly recognized as therapeutic options, physicians who interpret imaging studies should be aware of different patterns of response and possible side effects of these new MTT agents.
Vimentin is 57 kDa intermediate filament generally restricted to mesenchymal cells [85]. Vimentin regulation is a complex interplay of epigenetic and post-translational modifications in addition to transcriptional regulation. Of note, the human vimentin promoter contains an NF-κB binding site as well as a TGF-β1 response element [86],[87]. Akt1 protects vimentin from caspase proteolysis via phosphorylation of Ser39 [88]. During EMT, epithelial cells, which normally express keratin intermediate filaments, begin to express vimentin. Overexpression of vimentin is evident in breast and prostate cancers, among many other types, and overexpression generally correlates with invasiveness, migration, and poor prognosis [89] [91]. Snail1 upregulates vimentin during EMT [54].
Snail1 is expressed in many types of cancer. Snail1 overexpression usually correlates with increased migration, invasion, and metastasis. An inverse relationship with E-cadherin is expected, and Snail1 consequently corresponds with poor differentiation as well. Frequently, more advanced malignancies and poor prognosis also accompany elevated Snail1 expression (Table 3).
Snail1 is not present in normal breast epithelium, nor is it present in ILCs (n = 21). Of 17 patients, Snail1 was expressed in 47% of IDCs, and its expression correlated with lymph node metastases and high histologic grades [128]. E-cadherin and Snail1 expression levels are inversely related, and high expression levels of Snail1 correlate with shorter effusion-free, disease-free, and overall survival rates (n = 16) [129]. As such, Snail1 has prognostic significance as a marker of IDC malignancy [128].
Snail1 mRNA and protein levels are inversely correlated with E-cadherin in hepatocellular carcinoma (HCC) [130]. Snail1 overexpression, which in one study included 23% of cases (n = 47), is associated with portal vein invasion, metastasis, and poor differentiation. Furthermore, Snail1 expression correlates with a poor prognosis in recurrence-free survival and, thus, is considered a potential risk factor for early recurrence [131],[132].
E-cadherin expression is drastically reduced in gastric carcinoma, and Snail1 expression levels once again share an inverse relationship with E-cadherin expression levels [129]. Snail1 expression levels are more comparable to breast than ovarian carcinomas, and Snail1 expression is still higher in diffuse rather than intestinal varieties of gastric carcinomas [129],[134]. Elevated Snail1 expression increases cells' capacities for migration and invasion. Overexpression correlates with tumor size, depth of invasion, and lymph node metastasis. Shortened survival rates are also directly related to Snail1 overexpression, and Snail1 is considered a predictor of poor prognosis [135].
Prostate cancer is the second most commonly diagnosed cancer in men worldwide, with estimates of over 900,000 new cases per year [146]. A Gleason grade, which describes the two most important histopathological patterns of that patient's cancer, accompanies a diagnosis. The grade ranges from 2-10 with a higher score meaning less differentiated [147]. Significant losses of E-cadherin and syndecan 1, two proteins involved in cellular adhesion, have been observed in malignant prostate cancer [148],[149]. Both promoters contain E-boxes, so Snail1 can directly bind and repress them [150],[151]. The presence of E-boxes may explain the inverse correlation between E-cadherin/syndecan 1 and Snail1 expression levels. Poblete et al. found that high Snail1 expression correlated with a high Gleason grade and increased malignancy. Furthermore, in more malignant cell lines, like PC3, Snail1 had exclusively nuclear localization. By contrast, Snail1 had both cytoplasmic and nuclear localization in less malignant cell lines [152].
Poor differentiation, sphere-forming capacity, self-renewal, and typical markers such as ALDH and CD44, among other properties, characterize the stem-like phenotype [15]. Clearly, Snail1 overexpression is associated with all of these properties. After Snail1 induces EMT, cells adopt a mesenchymal morphology, become more invasive, increase migratory capacity, and express a stem-like phenotype. Knockdown of Snail1 causes the reverse process, mesenchymal-epithelial transition (MET), which prompts cells to become less invasive, migratory, and stem-like, as well as more sensitized to drugs. Thus, Snail1-induced EMT is a critical link between resistance, metastasis, and stem-like characteristics.
Zhu et al. have examined the relationship between the expression of the Response Gene to Complement-32 (RGC-32) and TGF-β-mediated EMT [160]. RGC-32 is over-expressed in many cancers and correlates with the lower level of expression of E-cadherin in pancreatic cancer. Stimulation of cells with TGF-β was associated with the upregulation of RGC-32 and EMT. Noteworthy, the findings that RGC-32 mediated TGF-beta-induced EMT and cell migration was corroborated with the use of RGC-32 siRNA. The authors extrapolated that RGC-32 regulates Snail1 expression and EMT.
Huang et al. investigated the expression level of Notch1 in lung adenocarcinoma and its relationship to metastasis [161]. They found that lung tumors express low levels of Notch1 and were associated with advanced clinical stage and lymph node metastasis. In contrast, patients with positive Notch1 expression had the prolonged progression of overall survival. Thus, Notch1 expression regulates negatively the EMT phenotype. Dysregulation of the Notch signaling pathway plays an important role in the pathogenesis of many cancers. Notch1 is one receptor of the Notch signaling pathway. Notch1 is involved in the regulation of tumor cell growth, proliferation, apoptosis, metastasis, and chemoradioresistance. Notch1 protects Snail1 from degradation by preventing GSK-3β-mediated phosphorylation via LOXL2 oxidation, as detailed above [18].