ERAS for Head and Neck Tissue Transfer Reduces Opioid Usage, Peak Pain Scores, and Blood Utilization.

OBJECTIVES: We implement a novel enhanced recovery after surgery (ERAS) protocol with pre-operative non-opioid loading, total intravenous anesthesia, multimodal peri-operative analgesia, and restricted red blood cell (pRBC) transfusions. 1) Compare differences in mean postoperative peak pain scores, opioid usage, and pRBC transfusions. 2) Examine changes in overall length of stay (LOS), intensive care unit LOS, complications, and 30-day readmissions. METHODS: Retrospective cohort study comparing 132 ERAS vs. 66 non-ERAS patients after HNC tissue transfer reconstruction. Data was collected in a double-blind fashion by two teams. RESULTS: Mean postoperative peak pain scores were lower in the ERAS group up to postoperative day (POD) 2. POD0: 4.6 ± 3.6 vs. 6.5 ± 3.5; P = .004) (POD1: 5.2 ± 3.5 vs. 7.3 ± 2.3; P = .002) (POD2: 4.1 ± 3.5 vs. 6.6 ± 2.8; P = .000). Opioid utilization, converted into morphine milligram equivalents, was decreased in the ERAS group (POD0: 6.0 ± 9.8 vs. 10.3 ± 10.8; P = .010) (POD1: 14.1 ± 22.1 vs. 34.2 ± 23.2; P = .000) (POD2: 11.4 ± 19.7 vs. 37.6 ± 31.7; P = .000) (POD3: 13.7 ± 20.5 vs. 37.9 ± 42.3; P = .000) (POD4: 11.7 ± 17.9 vs. 36.2 ± 39.2; P = .000) (POD5: 10.3 ± 17.9 vs. 35.4 ± 45.6; P = .000). Mean pRBC transfusion rate was lower in ERAS patients (2.1 vs. 3.1 units, P = .017). There were no differences between ERAS and non-ERAS patients in hospital LOS, ICU LOS, complication rates, and 30-day readmissions. CONCLUSION: Our ERAS pathway reduced postoperative pain, opioid usage, and pRBC transfusions after HNC reconstruction. These benefits were obtained without an increase in hospital or ICU LOS, complications, or readmission rates. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:E792-E799, 2021.

Management of esophageal gastrointestinal stromal tumor: review of one hundred seven patients.

Gastrointestinal stromal tumors (GIST) are the most common type of gastrointestinal mesenchymal tumor, but are rarely found in the thoracic esophagus. There is no clear consensus about the optimal treatment of this rare disease. A systematic search of the literature was performed for localized esophageal GIST that was resected between 2000 and 2015, and individual patients were included from two major academic institutions. We obtained information on demographics, tumor size and location, mitotic rate, treatment method, and time to recurrence or death. We performed univariate and multivariate Cox regression analyses to evaluate the factors associated with recurrence or death. A total of 28 studies met our inclusion and exclusion criteria, and with two patients from two academic institutions, we had a total of 107 patients in the study. Due to lack of uniformity among studies, there were several missing data for different variables. The average patient age was 56 (n = 98) with mostly males (60%, n = 91). The average tumor size on the CT scan was 7.9 ± 5.4 cm (n = 91), located mostly in the distal esophagus (81%, n = 74). A similar number of patients underwent enucleation (n = 47) compared to esophagectomy (n = 42). Approximately half of the patients had a mitotic rate of 0-4 mitosis per 50 high-powered field (48%, n = 80). The median survival time was 73 months with a 5-year disease free survival of 57% (n = 97). Univariate Cox regression analyses showed that a large tumor, undergoing esophagectomy, and a high mitotic rate were associated with poor survival or recurrence control. We found that patients with a lesion smaller than or equal to 5 cm on the CT scan had a better disease-free survival rate than those with a size greater than 5 cm (HR = 12.41, p = 0.014) and had a 5-year survival rate of 92% with 90% of those patients undergoing enucleation (n = 29). Esophageal GIST is a very rare malignancy. The tumor size and mitotic rate of the tumor are associated with poor survival. However, patients with esophageal GIST measuring 5 cm or smaller may be safely treated with esophageal enucleation.

Targeting KRas-dependent tumour growth, circulating tumour cells and metastasis in vivo by clinically significant miR-193a-3p.

KRas is mutated in a significant number of human cancers and so there is an urgent therapeutic need to target KRas signalling. To target KRas in lung cancers we used a systems approach of integrating a genome-wide miRNA screen with patient-derived phospho-proteomic signatures of the KRas downstream pathway, and identified miR-193a-3p, which directly targets KRas. Unique aspects of miR-193a-3p biology include two functionally independent target sites in the KRas 3'UTR and clinically significant correlation between miR-193a-3p and KRas expression in patients. Rescue experiments with mutated KRas 3'UTR showed very significantly that the anti-tumour effect of miR-193a-3p is via specific direct targeting of KRas and not due to other targets. Ex vivo and in vivo studies utilizing nanoliposome packaged miR-193a-3p demonstrated significant inhibition of tumour growth, circulating tumour cell viability and decreased metastasis. These studies show the broader applicability of using miR-193a-3p as a therapeutic agent to target KRas-mutant cancer.

Is a severe clinical profile an effect modifier in a Web-based depression treatment for adults with type 1 or type 2 diabetes? Secondary analyses from a randomized controlled trial.

BACKGROUND: Depression and diabetes are two highly prevalent and co-occurring health problems. Web-based, diabetes-specific cognitive behavioral therapy (CBT) depression treatment is effective in diabetes patients, and has the potential to be cost effective and to have large reach. A remaining question is whether the effectiveness differs between patients with seriously impaired mental health and patients with less severe mental health problems. OBJECTIVE: To test whether the effectiveness of an eight-lesson Web-based, diabetes-specific CBT for depression, with minimal therapist support, differs in patients with or without diagnosed major depressive disorder (MDD), diagnosed anxiety disorder, or elevated diabetes-specific emotional distress (DM-distress). METHODS: We used data of 255 patients with diabetes with elevated depression scores, who were recruited via an open access website for participation in a randomized controlled trial, conducted in 2008-2009, comparing a diabetes-specific, Web-based, therapist-supported CBT with a 12-week waiting-list control group. We performed secondary analyses on these data to study whether MDD or anxiety disorder (measured using a telephone-administered diagnostic interview) and elevated DM-distress (online self-reported) are effect modifiers in the treatment of depressive symptoms (online self-reported) with Web-based diabetes-specific CBT. RESULTS: MDD, anxiety disorder, and elevated DM-distress were not significant effect modifiers in the treatment of self-assessed depressive symptoms with Web-based diabetes-specific CBT. CONCLUSIONS: This Web-based diabetes-specific CBT depression treatment is suitable for use in patients with severe mental health problems and those with a less severe clinical profile. CLINICALTRIAL: International Standard Randomized Controlled Trial Number (ISRCTN): 24874457; http://www.controlled-trials.com/ISRCTN24874457 (Archived by WebCite at http://www.webcitation.org/63hwdviYr).

Web-based depression treatment for type 1 and type 2 diabetic patients: a randomized, controlled trial.

OBJECTIVE: Comorbid depression is common in patients with type 1 and type 2 diabetes, adversely affecting quality of life, diabetes outcomes, and mortality. Depression can be effectively treated with cognitive behavior therapy (CBT). The Internet is a new and attractive method for delivering CBT intervention on a large scale at relatively low costs. This study evaluated the effectiveness of Web-based CBT for depression treatment in adults with type 1 or type 2 diabetes, with minimal guidance. RESEARCH DESIGN AND METHODS: A randomized controlled trial was conducted in the Netherlands in 255 adult diabetic patients with elevated depressive symptoms. Primary outcomes were depressive symptoms. Secondary outcomes were diabetes-specific emotional distress and glycemic control. Assessments were at baseline, after treatment, and at the 1-month follow-up. RESULTS: The Web-based CBT was effective in reducing depressive symptoms by intention-to-treat analyses (P = 0.04, d = 0.29; clinical improvement 41% vs. 24% P < 0.001) and by per-protocol analyses (P < 0.001, d = 0.70; clinical improvement, 56% vs. 24% P < 0.001). The intervention reduced diabetes-specific emotional distress (P = 0.03) but had no beneficial effect on glycemic control (P > 0.05). CONCLUSIONS: Web-based CBT depression treatment is effective in reducing depressive symptoms in adults with type 1 and type 2 diabetes. In addition, the intervention reduces diabetes-specific emotional distress in depressed patients.

Src family kinases as mediators of endothelial permeability: effects on inflammation and metastasis.

Src family kinases (SFKs) are signaling enzymes that have long been recognized to regulate critical cellular processes such as proliferation, survival, migration, and metastasis. Recently, considerable work has elucidated mechanisms by which SFKs regulate normal and pathologic processes in vascular biology, including endothelial cell proliferation and permeability. Further, when inappropriately activated, SFKs promote pathologic inflammatory processes and tumor metastasis, in part through their effects on the regulation of endothelial monolayer permeability. In this review, we discuss the roles of aberrantly activated SFKs in mediating endothelial permeability in the context of inflammatory states and tumor cell metastasis. We further summarize recent efforts to translate Src-specific inhibitors into therapy for systemic inflammatory conditions and numerous solid organ cancers.

Web-based cognitive behavioural therapy (W-CBT) for diabetes patients with co-morbid depression: design of a randomised controlled trial.

BACKGROUND: Depression is common among people with diabetes, negatively affecting quality of life, treatment adherence and diabetes outcomes. In routine clinical care, diabetes patients have limited access to mental health services and depression therefore often remains untreated. Web-based therapy could potentially be an effective way to improve the reach of psychological care for diabetes patients, at relatively low costs. This study seeks to test the effectiveness of a web-based self-help depression programme for people with diabetes and co-morbid depression. METHODS/DESIGN: The effectiveness of a web-based self-help course for adults with diabetes with co-morbid depression will be tested in a randomised trial, using a wait-list controlled design. The intervention consists of an 8-week, moderated self-help course that is tailored to the needs of persons living with diabetes and is offered on an individual basis. Participants receive feedback on their homework assignments by e-mail from their coach. We aim to include 286 patients (143/143), as power analyses showed that this number is needed to detect an effect size of 0.35, with measurements at baseline, directly after completing the web-based intervention and at 1, 3, 4 and 6 months follow-up. Patients in the control condition are placed on a waiting list, and follow the course 12 weeks after randomisation. Primary outcomes are depressive symptoms and diabetes-specific emotional distress. Secondary outcomes are satisfaction with the course, perceived health status, self-care behaviours, glycaemic control, and days in bed/absence from work. Questionnaires are administered via the Internet. DISCUSSION: The intervention being trialled is expected to help improve mood and reduce diabetes-specific emotional distress in diabetes patients with depression, with subsequent beneficial effects on diabetes self-care and glycaemic outcomes. When proven efficacious, the intervention could be disseminated to reach large groups of patients with diabetes and concurrent depressive symptoms. TRIAL REGISTRATION: Current Controlled Trials ISRCTN24874457.

Protein kinase C-alpha coordinately regulates cytosolic phospholipase A(2) activity and the expression of cyclooxygenase-2 through different mechanisms in mouse keratinocytes.

Transgenic mice (K5-PKC alpha) in which the keratin 5 promoter directs the expression of protein kinase C-alpha (PKC alpha) to epidermal keratinocytes display a 10-fold increase in PKC alpha protein in their epidermis and alterations in phorbol ester-induced cutaneous inflammation [J Cell Science 1999;112:3497-3506]. In the current study, we have used these K5-PKC alpha mice to examine the role of PKC alpha in keratinocyte phospholipid metabolism/eicosanoid production and cutaneous inflammation. Primary keratinocytes from wild-type and transgenic mice were prelabeled in culture with [(3)H]arachidonic acid (AA) and subsequently treated with TPA. Compared with wild-type keratinocytes, K5-PKC alpha keratinocytes displayed a 2-fold increase in AA release. TPA treatment resulted in the phosphorylation of cPLA(2). PKC inhibitors GF-109203X or H7, but not mitogen-activated protein/extracellular signal-regulated protein kinase (MEK) inhibitor PD 98059, could inhibit phosphorylation and AA release. Topical 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment of K5-PKC alpha mice resulted in a 5-fold increase in epidermal COX-2 induction and a 2- to 3-fold increase in prostaglandin (PG) E(2) levels above that observed in TPA-treated wild-type mice. PD 98059, GF-109203X, or H7 could block cyclooxygenase-2 (COX-2) induction by TPA. Because C/EBP beta, a basic leucine zipper transcription factor, can be activated via a PKC alpha/mitogen-activated protein kinase pathway and can influence COX-2 expression, we examined whether C/EBP beta is involved in TPA-induced epidermal COX-2 expression. TPA-induced COX-2 expression was similar in C/EBP beta nullizygous and wild-type mice. In summary, our results indicate that epidermal PKC alpha coordinately regulates cPLA(2) activity and COX-2 expression resulting in increased levels of AA and PGE(2). Furthermore, PKC alpha-induced AA release and cPLA(2) phosphorylation are independent of MEK, whereas PKC alpha-induced COX-2 expression and PGE(2) production are MEK-dependent and C/EBP beta-independent events.