Citations

Abstract Inhibition of the epidermal growth factor receptor (EGFR) is an established treatment that extends patient survival across a variety of tumor types. EGFR inhibitors fall into two main categories: anti-EGFR monoclonal antibodies, such as cetuximab and panitumumab, and first-generation tyrosine kinase inhibitors, such as afatinib, gefitinib, and erlotinib. Skin reactions are the most common EGFR inhibitor-attributable adverse event, resulting in papulopustular (acneiform) eruptions that can be painful and debilitating, and which may potentially have a negative impact on patients’ quality of life and social functioning, as well as a negative impact on treatment duration. Shortened treatment duration can, in turn, compromise antineoplastic efficacy. Similarly, appropriate management of skin reactions is dependent on their accurate grading; however, conventional means for grading skin reactions are inadequate, particularly within the context of clinical trials. Treating a skin reaction only once it occurs (reactive treatment strategies) may not be the most effective management approach; instead, prophylactic approaches may be preferable. Indeed, we support the viewpoint that prophylactic management of skin reactions should be recommended for all patients treated with EGFR inhibitors. Appropriate prophylactic management could effectively reduce the severity of skin reactions in patients treated with EGFR inhibitors and therefore has the potential to directly benefit patients and improve drug adherence. Accordingly, here we review published and still-emerging data, and provide practical and evidence-based recommendations and algorithms regarding the optimal prophylactic management of EGFR inhibitor-attributable skin reactions.

Ciliated muconodular papillary tumors (CMPTs) are rare peripheral lung lesions, characterized by papillary architecture and ciliated columnar cells admixed with mucinous cells and basal cells. They often have prominent surrounding intra-alveolar mucin, which can lead to diagnostic confusion with mucinous adenocarcinoma. Recognition of the ciliated component is the key to diagnosis of CMPT. The literature contains few reported cases to date, all occurring in East-Asian patients. Although follow-up data are limited, CMPT seems to be an indolent tumor with very good prognosis, leading some to question whether it is a reactive or hamartomatous lesion. However, a very recent molecular study has identified BRAF (40%) and EGFR (30%) alterations in CMPT, supporting a truly neoplastic process. Here for the first time, we report 4 cases of morphologically typical CMPT in western patients, occurring in 1 man (60 y) and 3 women (71 to 83 y). Interestingly, 1 case occurred in background of pronounced small airway disease with necrotizing bronchiolitis and multiple carcinoid tumorlets. We further analyzed 1 tumor using a 50 gene next-generation sequencing oncology panel that identified 2 pathogenic mutations (BRAF V600E and AKT1 E17K). Our study is the first to describe that CMPT can occur in western (non-Asian) patients. Our data confirm BRAF V600E mutation as a probable driver in a subset of these tumors, along with AKT1 mutation, which further supports that CMPT are indolent pulmonary neoplasms.

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ObjectiveBeneficial effects of adrenalectomy on cardiovascular risk factors in patients with subclinical Cushing’s syndrome (SCS) are uncertain. We sought to conduct a systematic review and meta-analysis with the following objectives: (i) determine the effect of adrenalectomy compared with conservative management on cardiovascular risk factors in patients with SCS and (ii) compare the effect of adrenalectomy on cardiovascular risk factors in patients with SCS vs those with a nonfunctioning (NF) adrenal tumor.MethodsMEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE and Cochrane Central Register of Controlled Trial were searched on 17 November 2015. Reviewers extracted data and assessed methodological quality in duplicate.ResultsWe included 26 studies reporting on 584 patients with SCS and 457 patients with NF adrenal tumors. Studies used different definitions of SCS. Patients with SCS undergoing adrenalectomy demonstrated an overall improvement in cardiovascular risk factors (61% for hypertension, 52% for diabetes mellitus, 45% for obesity and 24% for dyslipidemia). When compared with conservative management, patients with SCS undergoing adrenalectomy experienced improvement in hypertension (RR 11, 95% CI: 4.3–27.8) and diabetes mellitus (RR 3.9, 95% CI: 1.5–9.9), but not dyslipidemia (RR 2.6, 95% CI: 0.97–7.2) or obesity (RR 3.4, 95% CI: 0.95–12). Patients with NF adrenal tumors experienced improvement in hypertension (21/54 patients); however, insufficient data exist for comparison to patients with SCS.ConclusionsAvailable low-to-moderate-quality evidence from heterogeneous studies suggests a beneficial effect of adrenalectomy on cardiovascular risk factors in patients with SCS overall and compared with conservative management.

Galectin-9, a β-galactoside-binding protein, is defined as a negative regulator of T helper 1 (Th1) immune responses, favoring Th2 bias. Systemic immunity in patients with metastatic melanoma is predominantly Th2 biased. We hypothesized that galectin-9 can modulate systemic immunity toward Th2 polarization in patients with advanced melanoma. The presence or concentration of galectin-9 was assessed in tumors and plasma, in patients with metastatic melanoma. The immunomodulatory function of galectin-9 was determined by exposing human peripheral blood mononuclear cells to galectin-9 in vitro. Galectin-9 was expressed in 57% of tumors and was significantly (3.6-fold) increased in the plasma of patients with advanced melanoma compared with healthy controls (P<0.001). High plasma galectin-9 concentration was associated with systemic Th2 polarization and reduced 2-year survival compared with low/no galectin-9 expression. In-vitro, galectin-9 reduced proliferation of healthy peripheral blood mononuclear cells, and promoted Th1 cell apoptosis, Th2-biased cell phenotypes, and cytokine secretion. Galectin-9 also stimulated monocyte differentiation toward an M2 macrophage phenotype, as assessed by chemokine/cytokine secretion and CD206 expression, observed both in vitro as well as in patients with metastatic melanoma. Elevated galectin-9 in patient plasma correlated with Th2 systemic bias and less favorable clinical outcomes for patients with metastatic melanoma. This Th2 bias appears to be not only a feature of the known mechanisms of Th1 apoptosis by T-cell immunoglobulin and mucin-domain containing-3 binding, but also mediated by myeloid cell differentiation toward an M2 phenotype, that favors tumor progression. These data support galectin-9 as a novel therapeutic target for patients with metastatic melanoma.

Objectives Socioeconomic status (SES) is a well-established risk factor for many health outcomes. Recently, we developed an SES measure based on 4 housing-related characteristics (termed HOUSES) and demonstrated its ability to assess health disparities. In this study, we aimed to evaluate whether fewer housing-related characteristics could be used to provide a similar representation of SES. Study setting and participants We performed a cross-sectional study using parents/guardians of children aged 1–17 years from 2 US Midwestern counties (n=728 in Olmsted County, Minnesota, and n=701 in Jackson County, Missouri). Primary and secondary outcome measures For each participant, housing-related characteristics used in the formulation of HOUSES (assessed housing value, square footage, number of bedrooms and number of bathrooms) were obtained from the local government assessor's offices, and additional SES measures and health outcomes with known associations to SES (obesity, low birth weight and smoking exposure) were collected from a telephone survey. Housing characteristics with the greatest contribution for predicting the health outcomes were added to formulate a modified HOUSES index. Results Among the 4 housing characteristics used in the original HOUSES, the strongest contributions for predicting health outcomes were observed from assessed housing value and square footage (combined contribution ranged between 89% and 96%). Based on this observation, these 2 were used to calculate a modified HOUSES index. Correlation between modified HOUSES and other SES measures was comparable to the original HOUSES for both locations. Consistent with the original HOUSES formula, the strongest association with modified HOUSES was observed with smoking exposure (OR=0.24 with 95% CI 0.11 to 0.49 for comparing participants in highest HOUSES vs lowest group; overall p<0.001). Conclusions The modified HOUSES requires only 2 readily available housing characteristics thereby improving the feasibility of using this index as a proxy for SES in multiple communities, especially in the US Midwestern region.

Background Since 1972, patients with large nasal perforations, who were symptomatic, and who were not candidates for surgery, had the option of custom prosthetic closure at Mayo Clinic. Although septal prostheses have helped many patients, 27% of pre-1982 patients chose not to keep the prosthesis in place. Two-dimensional computed tomography (CT) sizing resulted in more of the patients choosing to retain the prosthesis. The introduction of three-dimensional (3-D) printing to the sizing process offered the potential of further improved retention by refinement in prosthesis fit. Objective To describe the fabrication of nasal septal prostheses by using 3-D printing for sizing and to compare the retention rate of 3-D-sized prostheses with those that used previous sizing methods. Methods Twenty-one consecutive patients who had placement of septal prostheses sized by using 3-D printed templates were studied. CT image data were used to print 3-D templates of the exact shape of the patient's septal perforation, and medical-grade silastic prostheses were fabricated to fit. In four cases, the 3-D printed template allowed preoperative surgical simulation. Metrics collected included prosthesis retention; symptoms, including intranasal crusting and epistaxis; and previous prosthetic closure failures. Results Twenty of the twenty-one patients had improvement in symptoms. The mean diameter of the perforations was 2.4 cm; the mean closure time by the end of the study period was 2.2 years. All but two patients chose to keep their prosthesis in place, for a retention rate of 90%. Seven patients with successful closure had failed previously with prior prosthesis sized without the current 3-D printing methodology. This 90% retention rate exceeded the previous rates before the introduction of 3-D sizing. Conclusion Sizing done by 3-D printing for prosthetic closure of nasal septal perforations resulted in a higher retention rate in helping patients with these most-challenging nasal septal perforations.

Background Giant frontal mucoceles, characterized by significant intracranial and/or intraorbital extension, can present with significant neurologic symptoms. Although typical mucoceles are managed endoscopically, giant mucoceles are often treated with an open or combined approach due to various concerns, including frontal lobe displacement, size, and rapid decompression of the intracranial component. The impact of significant intracranial extension on outcomes is not well described. Objective This review studied key neurologic considerations in the management of giant frontal sinus mucoceles and analyzed outcomes of different management strategies. Methods Systematic literature review by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Results Thirty-two articles, which represented 85 cases, met inclusion criteria. Neurologic symptoms on presentation ranged from headache (24.7%) and vision loss (12.9%) to extremity weakness (1.2%), frontal lobe syndrome (2.4%), and seizures (4.7%). Twenty-eight patients were treated endoscopically (34.1%), and 54 (65.9%) were treated with an external approach. Twenty-five of the open procedures included a craniotomy. Indications for the open approach included subdural empyema, enucleation, or large anterior table defects. Perioperative antibiotics were not consistently used. No perioperative seizures were reported with any approach. There were six cerebrospinal fluid leaks, all in the patients who underwent open procedures. The overall recurrence rate was 3.5%, with no recurrences reported in patients treated with an open approach. Follow-up ranged from 1 week to 8 years. Conclusions Giant frontal mucoceles often present with various neurologic symptoms. Both open and endoscopic techniques offer excellent results. Endoscopic management is effective and preferred, except in special circumstances. An interdisciplinary team approach should be used to optimize surgical planning.

Objective: To determine the optimal environmental conditions for chondrogenic differentiation of human adipose tissue–derived mesenchymal stromal/stem cells (AMSCs). In this investigation we specifically investigate the role of oxygen tension and 3-dimensional (3D) culture systems. Design: Both AMSCs and primary human chondrocytes were cultured for 21 days in chondrogenic media under normoxic (21% oxygen) or hypoxic (2% oxygen) conditions using 2 distinct 3D culture methods (high-density pellets and poly-ε-caprolactone [PCL] scaffolds). Histologic analysis of chondro-pellets and the expression of chondrocyte-related genes as measured by reverse transcriptase quantitative polymerase chain reaction were used to evaluate the efficiency of differentiation. Results: AMSCs are capable of expressing established cartilage markers including COL2A1, ACAN, and DCN when grown in chondrogenic differentiation media as determined by gene expression and histologic analysis of cartilage markers. Expression of several cartilage-related genes was enhanced by low oxygen tension, including ACAN and HAPLN1. The pellet culture environment also promoted the expression of hypoxia-inducible cartilage markers compared with cells grown on 3D scaffolds. Conclusions: Cell type–specific effects of low oxygen and 3D environments indicate that mesenchymal cell fate and differentiation potential is remarkably sensitive to oxygen. Genetic programming of AMSCs to a chondrocytic phenotype is effective under hypoxic conditions as evidenced by increased expression of cartilage-related biomarkers and biosynthesis of a glycosaminoglycan-positive matrix. Lower local oxygen levels within cartilage pellets may be a significant driver of chondrogenic differentiation.