Lipid absorption and overall intestinal lymphatic transport are impaired following partial small bowel resection in mice.

Short bowel syndrome (SBS) is associated with diminished levels of serum fats caused by unknown mechanisms. We have shown that mesenteric lymphatics remodel to a more primitive state one week after small bowel resection (SBR); therefore, this study focuses on the effect of chronic lymphatic remodeling and magnitude of resection on intestinal lipid uptake and transport. C57BL6 and Prox1 creER-Rosa26LSLTdTomato (lymphatic reporter) mice underwent 50% or 75% proximal SBR or sham operations. Functional transport of lipids and fecal fat content was measured and lymphatic vasculature was compared via imaging. There was a significant reduction in functional transport of cholesterol and triglyceride after SBR with increasing loss of bowel, mirrored by a progressive increase in fecal fat content. We also describe significant morphological changes in the lymphatic vasculature in both the lamina propria and mesentery. Intestinal lymphatic drainage assay in vivo demonstrated a marked reduction of systemic absorption after resection. Intestinal lymphatic vessels significantly remodel in the setting of chronic SBS. This remodeling may account at least in part for impaired intestinal uptake and transport of fat via the compromised lymphatic architecture. We believe that these changes may contribute to the development of intestinal failure associated liver disease (IFALD), a major morbidity in patients with SBS.

Liver injury after small bowel resection is prevented in obesity-resistant 129S1/SvImJ mice.

Intestinal failure-associated liver disease is a major morbidity associated with short bowel syndrome. We sought to determine if the obesity-resistant mouse strain (129S1/SvImJ) conferred protection from liver injury after small bowel resection (SBR). Using a parenteral nutrition-independent model of resection-associated liver injury, C57BL/6J and 129S1/SvImJ mice underwent a 50% proximal SBR or sham operation. At postoperative week 10, hepatic steatosis, fibrosis, and cholestasis were assessed. Hepatic and systemic inflammatory pathways were evaluated using oxidative markers and abundance of tissue macrophages. Potential mechanisms of endotoxin resistance were also explored. Serum lipid levels were elevated in all mouse lines. Hepatic triglyceride levels were no different between mouse strains, but there was an increased accumulation of free fatty acids in the C57BL/6J mice. Histological and serum markers of hepatic fibrosis, steatosis, and cholestasis were significantly elevated in resected C57BL/6J SBR mice as well as oxidative stress markers and macrophage recruitment in both the liver and visceral white fat in C57BL/6J mice compared with sham controls and the 129S1/SvImJ mouse line. Serum endotoxin levels were significantly elevated in C57BL/6J mice with significant elevation of hepatic TLR4 and reduction in PPARα expression levels. Despite high levels of serum lipids, 129S1/SvImJ mice did not develop liver inflammation, fibrosis, or cholestasis after SBR, unlike C57BL/6J mice. These data suggest that the accumulation of hepatic free fatty acids as well as increased endotoxin-driven inflammatory pathways through PPARα and TLR4 contribute to the liver injury seen in C57BL/6J mice with short bowel syndrome.NEW & NOTEWORTHY Unlike C57BL/6 mice, the 129S1/SvImJ strain is resistant to liver inflammation and injury after small bowel resection. These disparate outcomes are likely due to the accumulation of hepatic free fatty acids as well as increased endotoxin-driven inflammatory pathways through PPARα and TLR4 in C57BL/6 mice with short bowel syndrome.

EGFR in enterocytes & endothelium and HIF1α in enterocytes are dispensable for massive small bowel resection induced angiogenesis.

BACKGROUND: Short bowel syndrome (SBS) results from significant loss of small intestinal length. In response to this loss, adaptation occurs, with Epidermal Growth Factor Receptor (EGFR) being a key driver. Besides enhanced enterocyte proliferation, we have revealed that adaptation is associated with angiogenesis. Further, we have found that small bowel resection (SBR) is associated with diminished oxygen delivery and elevated levels of hypoxia-inducible factor 1-alpha (HIF1α). METHODS: We ablated EGFR in the epithelium and endothelium as well as HIF1α in the epithelium, ostensibly the most hypoxic element. Using these mice, we determined the effects of these genetic manipulations on intestinal blood flow after SBR using photoacoustic microscopy (PAM), intestinal adaptation and angiogenic responses. Then, given that endothelial cells require a stromal support cell for efficient vascularization, we ablated EGFR expression in intestinal subepithelial myofibroblasts (ISEMFs) to determine its effects on angiogenesis in a microfluidic model of human small intestine. RESULTS: Despite immediate increased demand in oxygen extraction fraction measured by PAM in all mouse lines, were no differences in enterocyte and endothelial cell EGFR knockouts or enterocyte HIF1α knockouts by POD3. Submucosal capillary density was also unchanged by POD7 in all mouse lines. Additionally, EGFR silencing in ISEMFs did not impact vascular network development in a microfluidic device of human small intestine. CONCLUSIONS: Overall, despite the importance of EGFR in facilitating intestinal adaptation after SBR, it had no impact on angiogenesis in three cell types-enterocytes, endothelial cells, and ISEMFs. Epithelial ablation of HIF1α also had no impact on angiogenesis in the setting of SBS.

Effects of high-fat diet on liver injury after small bowel resection.

BACKGROUND: The optimal regimen for enteral nutritional support in the management of children with short bowel syndrome (SBS) is not well characterized. A high fat, enteral diet is theoretically beneficial due to increased caloric density and enhanced structural adaptation. We therefore sought to determine the long-term effects of a high fat diet (HFD) on liver injury, a common complication of SBS, compared to a standard chow (SC) diet. METHODS: Using a parenteral nutrition-independent model of resection-associated liver injury, C57BL/6 mice underwent a sham operation or a 50% or 75% proximal small bowel resection (SBR). Mice in each group were then fed either a HFD (35% kcal fat) or SC (13% kcal fat). At post-operative week 15, markers of liver injury were quantified. RESULTS: Liver triglyceride levels were increased from 7- to 19-fold in mice on the HFD compared to mice fed SC in the sham, 50%, and 75% resection groups. Serum ALT (2.2-fold increase in 75% resected mice compared to sham controls) and AST (2.0- and 2.7-fold increases in 50% and 75% resected mice, respectively) levels as well as fibrotic liver staining were elevated only in resected mice fed a HFD. CONCLUSION: Long-term enteral feeding of HFD in our murine SBS model is associated with hepatic steatosis and liver injury. Our observation that liver steatosis and injury occur independent of parenteral nutrition suggests that enteral feeding composition and magnitude of intestinal loss may make a significant contribution to intestinal failure-associated liver disease.

A Prospective Analysis of Radiation Oncologist Compliance With Early Peer Review Recommendations.

PURPOSE: We conducted a prospective observational cohort study of physician compliance with daily early pretreatment planning peer review recommendations and quantified factors associated with compliance. METHODS AND MATERIALS: All patient cases in our department are presented at 2 peer review conferences: (1) "early" preplanning, occurring daily for patients who have undergone simulation review, and (2) "late" (chart rounds), occurring weekly for patients who have started treatment. Peer review recommendations were prospectively recorded during early review, and compliance with recommendations was determined at chart rounds. Recommendations were assigned magnitude scores (minor, moderate, or major). We analyzed the association of patient, physician, and recommendation characteristics and compliance (scored as a binary variable) with early peer review recommendations, using logistic regression with a mixed effects model. RESULTS: From February 2017 to May 2018, 1271 patient cases underwent early peer review, and 326 (26%) received peer-based recommendations. Of 356 recommendations, 37% were minor, 36% were moderate, and 27% were major. Overall compliance was 59% (95% confidence interval, 54%-64%). On univariate analysis, compliance decreased as the recommendation magnitude increased (minor, 65%; moderate, 60%; major, 47%; P = .019; odds ratio, 0.71 per increase in magnitude). Compliance also differed among different treating physicians (range, 38%-73%, χ2 test, P = .003) but was not associated with other physician characteristics. Disease group and treatment technique were not associated with compliance. On multivariable analysis, increasing recommendation magnitude remained significantly associated with decreased compliance (multivariate P = .042; odds ratio, 0.74). CONCLUSIONS: Daily early peer review resulted in a substantial proportion of recommended changes. Compliance with early peer review recommendations was fair but varied among physicians. Compliance declined with increasing recommendation magnitude, suggesting that physicians may be reluctant to adopt major changes. These results highlight the potential importance of peer review timing.

Assessment of Risk of Xerostomia After Whole-Brain Radiation Therapy and Association With Parotid Dose.

Importance: Whole-brain radiation therapy (WBRT) delivers a substantial radiation dose to the parotid glands, but the parotid glands are not delineated for avoidance and xerostomia has never been reported as an adverse effect. Minimizing the toxic effects in patients receiving palliative treatments, such as WBRT, is crucial. Objective: To assess whether xerostomia is a toxic effect of WBRT. Design, Setting, and Participants: This observational cohort study enrolled patients from November 2, 2015, to March 20, 2018, at 1 academic center (University of North Carolina Hospitals) and 2 affiliated community hospitals (High Point Regional Hospital and University of North Carolina Rex Hospital). Adult patients (n = 100) receiving WBRT for the treatment or prophylaxis of brain metastases were enrolled. Patients who had substantial baseline xerostomia or did not complete WBRT or at least 1 postbaseline questionnaire were prospectively excluded from analysis and follow-up. Patients received 3-dimensional WBRT using opposed lateral fields covering the skull and the C1 or C2 vertebra. Per standard practice, the parotid glands were not prospectively delineated. Main Outcomes and Measures: Patients completed the University of Michigan Xerostomia Questionnaire and a 4-point bother score at baseline, immediately after WBRT, at 1 month, at 3 months, and at 6 months. The primary end point was the 1-month xerostomia score, with a hypothesized worsening score of 10 points from baseline. Results: Of the 100 patients enrolled, 73 (73%) were eligible for analysis and 55 (55%) were evaluable at 1 month. The 73 patients included 43 women (59%) and 30 men (41%) with a median (range) age of 61 (23-88) years. The median volume of parotid receiving at least 20 Gy (V20Gy) was 47%. The mean xerostomia score was 7 points at baseline and was statistically significantly higher at each assessment period, including 21 points immediately after WBRT (95% CI, 16-26; P < .001), 23 points (95% CI, 16-30; P < .001) at 1 month, 21 points (95% CI, 13-28; P < .001) at 3 months, and 14 points (95% CI, 7-21; P = .03) at 6 months. At 1 month, the xerostomia score increased by 20 points or more in 19 patients (35%). The xerostomia score at 1 month was associated with parotid dose as a continuous variable and was 35 points in patients with parotid V20Gy of 47% or greater, compared with only 9 points in patients with parotid V20Gy less than 47% (P < .001). The proportion of patients who self-reported to be bothered quite a bit or bothered very much by xerostomia at 1 month was 50% in those with parotid V20Gy of 47% or greater, compared with only 4% in those with parotid V20Gy less than 47% (P < .001). At 3 months, this difference was 50% vs 0% (P = .001). Xerostomia was not associated with medication use. Conclusions and Relevance: Clinically significant xerostomia occurred by the end of WBRT, appeared to be persistent, and appeared to be associated with parotid dose. The findings from this study suggest that the parotid glands should be delineated for avoidance to minimize these toxic effects in patients who undergo WBRT and often do not survive long enough for salivary recovery.

Postherpetic Nevocentric Erythema Multiforme.

A previously healthy 35-year-old Caucasian woman presented with abrupt onset of erythematous, mildly pruritic plaques surrounding the majority of the nevi present on her neck, chest, back, and upper and lower extremities. She denied history of any recent systemic illnesses and was not taking any medications. On further questioning, the patient reported a recent episode of recurrent herpes labialis 2 weeks prior. The patient has a Fitzpatrick type I skin type with more than 100 brown and reddish brown pigmented macules and papules over her entire body. Plaques ranged in size from 0.4 cm to 1.5 cm depending on the size of the corresponding nevus. The patient's skin was examined in its entirety, and there were no lesions suspicious for melanoma. Two biopsies were performed from the patient's back: one from the nevus itself and another from the surrounding erythematous plaque. The nevocentric erythematous plaques were visible for approximately 1 week at which time they gradually disappeared without treatment. As these areas improved, the patient noticed targetoid lesions on the dorsal hands without associated nevi. Two weeks later, the targetoid lesions had spontaneously resolved.

Augmentation of Venlafaxine with Aripiprazole in a Case of Treatment-resistant Excoriation Disorder.

We present a case of a 21-year-old woman with excoriation disorder that was resistant to currently reported treatment options. Severe lesions were present on multiple sites of her body. The skin picking appeared to be associated with anxiety surrounding her current medical stay and medical condition. The addition of aripiprazole to the venlafaxine she was already taking resulted in resolution of her unconscious picking. This medication combination may be considered by clinicians in the future for treatment-resistant excoriation disorder as its side effect profile is favorable for patients who have failed first-line treatment options. Large-scale studies investigating the use of second generation antipsychotics combined with selective serotonin reuptake inhibitors/serotonin norepinephrine reuptake inhibitors for the treatment of excoriation disorder is recommended.

Treatment of necrobiotic xanthogranuloma with 2-chlorodeoxyadenosine.

A 71-year-old man presented with ulcerating yellow-red plaques of the back, chest, face, and extremities (Figure 1). He had a 10-year history of these lesions. The initial plaque appeared on the back followed by rapid progression of multiple similar lesions involving the face, chest, abdomen, and extremities. The plaques on his face were predominately in the periorbital and eyelid regions. Skin biopsy revealed an ulcerated epidermis. Dense sheets of foamy histiocytes were present in the dermis and contained foci of necrobiosis. Numerous Touton giant cells were present and cholesterol clefts were prominent. Special stains for organisms were negative. On further laboratory evaluation, serum protein electrophoresis revealed a monoclonal spike of 0.5 g/dL IgG lambda. Results from bone marrow biopsy were negative. Other significant laboratory findings included an elevated sedimentation rate and low serum complement. Clinical findings, histopathology, and laboratory evaluations were consistent with the diagnosis of necrobiotic xanthogranuloma (NXG).

Lymphoplasmacytic plaque in children: a report of two new cases with review of the literature.

Lymphoplasmacytic plaque in children has been proposed as a rare, emerging clinicopathologic entity characterized by solitary, extratruncal, asymptomatic papules and plaques that are typically found in healthy young Caucasian females. Biopsy of these lesions reveals a dermal lymphoplasmacytic infiltrate with or without epithelioid granulomas. Two unique patients with lymphoplasmacytic plaque in children are presented in this report, including a 26-month-old female with a lesion on her finger, who represents both the youngest described patient and the first documented with a finger lesion, as well as a 17-year-old young woman with a left thigh lesion, who represents the patient with the longest clinically and histopathologically observed lesion to date. These two additional patients corroborate the experience of lymphoplasmacytic plaque in children in the six previously reported cases and further expand the clinicopathologic spectrum of the disease. Recognition of lymphoplasmacytic plaque in children is important to facilitate distinction from potential differential considerations, including lymphoproliferative disorders and infectious conditions, particularly as the experience to date appears to suggest that lymphoplasmacytic plaque in children represent a reactive (pseudolymphomatous) condition.