Periconceptional 1,3-butanediol supplementation suppresses the superimposed preeclampsia-like phenotype in the Dahl salt-sensitive rat.

Preeclampsia is a hypertensive pregnancy disorder with no treatment beyond management of symptoms and delivery of the fetus and placenta. Chronic hypertension increases the risk of developing superimposed preeclampsia. Previous reports showed that 1,3-butanediol attenuates hypertension in rodents; however, the therapeutic potential of 1,3-butanediol for the prevention of preeclampsia has not been investigated. This study tested the hypothesis that attenuating hypertension before pregnancy and through the placentation period via 1,3-butanediol prevents the onset of preeclampsia in female Dahl salt-sensitive (SS/Jr) rats. Female Dahl SS/Jr rats were divided into two groups: 1,3-butanediol treated (20% via drinking water) and control (ad libitum water). Both groups were maintained on low-salt rodent chow (Teklad 7034, 0.3% NaCl; n = 8/group). Animals were treated with 1,3-butanediol for 7 wk (baseline), mated, and treated through day 12 of pregnancy. 1,3-Butanediol treatment increased plasma ß-hydroxybutyrate (metabolite of 1,3-butanediol) that negatively correlated with maternal body weight in late pregnancy. Mean arterial pressure was lower in the treated group at baseline, early, and mid pregnancy, but no difference was observed in late pregnancy after treatment ended. Uterine artery resistance index (UARI) was reduced in the treated dams. No adverse fetal effects were observed, and there were no differences in pup weight or length. Placentas from treated dams had decreased vascular endothelial growth factor levels as well as decreased placental basal zone thickness and increased labyrinth zone thickness. These findings support the therapeutic role of physiological ketosis via 1,3-butanediol as a potential therapeutic approach for managing chronic hypertension, thereby preventing and mitigating adverse pregnancy outcomes associated with preeclampsia.NEW & NOTEWORTHY A ketogenic diet or increased ß-hydroxybutyrate levels can reduce hypertension, but the potential of 1,3-butanediol, a ß-hydroxybutyrate precursor, for treatment of preeclampsia is unknown. We hypothesized that attenuating hypertension before and during pregnancy via 1,3-butanediol prevents preeclampsia in Dahl Salt-sensitive rats. 1,3-Butanediol significantly lowered blood pressure and improved uterine artery resistance with no observable adverse fetal effects. Physiological ketosis via 1,3-butanediol may be a potential therapeutic approach for managing hypertension and mitigating adverse pregnancy outcomes.

Opportunities for Cancer Health Care Disparities and Care Delivery Research: An Analysis of the NCI Health Care Delivery Research Program Portfolio.

Cancer health care disparities are complex, involve patient, clinician and health care system factors, and are defined as adverse differences in cancer outcomes. This analysis describes NCI's Healthcare Delivery Research Program's (HDRP) portfolio of disparities-focused research and identifies future research opportunities. Grants through HDRP (fiscal years 2012 to 2016) focused on detecting, understanding, and/or intervening on disparities in or among health disparity populations were reviewed by co-authors. Forty-eight funded grants were identified, coded, and characterized. Descriptive analyses are reported. Most studies focused on racial/ethnic minorities and socioeconomically disadvantaged groups. Colorectal, breast, and cervical cancers were most frequently examined. Almost 40% of studies addressed the intervening phase of the disparities research continuum. Few studies focused on clinician-level factors or involved the community in the research design. A sustained disparities research emphasis is essential to addressing the determinants of and cancer burden among health disparity populations across the cancer care continuum.

DUSP9-mediated reduction of pERK1/2 supports cancer stem cell-like traits and promotes triple negative breast cancer.

Breast cancer remains a complex disease resulting in high mortality in women. A subset of cancer stem cell (CSC)-like cells expressing aldehyde dehydrogenase 1 (ALDH1) and SOX2/OCT4 are implicated in aggressive biology of specific subtypes of breast cancer. Targeting these populations in breast tumors remain challenging. We examined xenografts from three poorly studied triple negative (TN) breast cancer cells (MDA-MB-468, HCC70 and HCC1806) as well as HMLEHRASV12 for stem cell (SC)-specific proteins, proliferation pathways and dual-specific phosphatases (DUSPs) by quantitative real-time PCR (qRT-PCR), immunoblot analysis and immunohistochemistry. We found that pERK1/2 remained suppressed in TN xenografts examined at various stages of growth, while the levels of pp38 MAPK and pAKT was upregulated. We found that DUSP was involved in the suppression of pERK1/2, which was MEK1/2 independent. Our in vitro assays, using HMLEHRASV12 xenografts as a positive control, confirmed increased phosphatase activity that specifically influenced pERK1/2 but not pp38MAPK or pJNK levels. Family members of DUSPs examined, showed increase in DUSP9 expression in TN xenografts. Increased DUSP9 expression in xenografts was consistently associated with upregulation of SC-specific proteins, ALDH1 and SOX2/OCT4. HRAS driven HMLEHRASV12 xenografts as well as mammospheres from TN breast cancer cells showed inverse relationship between pERK1/2 and increased expression of DUSP9 and CSC traits. In addition, treatment in vitro, with MEK1/2 inhibitor, PD 98059, reduced pERK1/2 levels and increased DUSP9 and SC-specific proteins. Depletion of subsets of SOX2/OCT4 by fluorescence-activated cell sorting (FACS), as well as pharmacological and genetic reduction of DUSP9 levels influenced ALDH1 and SOX2/OCT4 expression and reduced mammosphere growth in vitro as well as tumor growth in vivo. Collectively our data support the possibility that DUSP9 contributed to stem cell-like cells that could influence TN breast tumor growth. Conclusion: Our study shows that subsets of TN breast cancers with MEK1/2 independent reduced pERK1/2 levels will respond less to MEK1/2 inhibitors, thereby questioning their therapeutic efficacy. Our study also demonstrates context-dependent DUSP9-mediated reduced pERK1/2 levels could influence stem cell-like traits in TN breast tumors. Therefore, targeting DUSP9 could be an attractive target for improved clinical outcome in a subset of basal-like breast cancers.

Outcomes of multidisciplinary treatment planning in US cancer care settings.

Multidisciplinary treatment planning (MTP) is a process of engaging multiple disciplines to develop or refine the disease management plan. It is widely implemented in US cancer treatment settings and is considered to have favorable effects on both care quality and other outcomes. However, evidence reviews to date regarding MTP effectiveness have based their conclusions on studies conducted predominantly outside the United States. The authors conducted a systematic review of US-based studies to synthesize and critically appraise evidence of the effects of MTP on cancer care quality, health services outcomes, and survival. Database searches identified studies of MTP outcomes conducted in US cancer care settings from 2000 to 2017. Forty-five studies met criteria for inclusion. MTP was associated with favorable effects on several indicators of cancer care quality, including delivery of guideline-concordant treatment and improvements in diagnostic accuracy, staging completeness, surgical technique, and timeliness. Effects on survival and clinical trials enrollment were mixed. Delivery formats for MTP were generally not well described, and study designs were nonrandomized, limiting the ability to identify mediators of intervention effects. Continued study is warranted to clarify effective components of MTP interventions, and to understand the mechanism(s) through which MTP produces favorable effects on outcomes.

Treatment and Survival Disparities in the National Cancer Institute's Patterns of Care Study (1987-2017).

BACKGROUND: Cancer health services research is a primary tool for analyzing the association between various factors, cancer health care delivery, and the resultant outcomes. To address disparities strategies must be developed to target factors that are related to differences in care; however, to date, most disparities studies have been descriptive. The primary objective was to describe cancer treatment and survival disparities in community oncology practice patterns found in the National Cancer Institute's population-based Patterns of Care (POC) Study (1987-2017). Secondarily, we compared POC findings to peer-reviewed literature. In POC data, older age was consistently associated with decreased odds of treatment and increased mortality. Interestingly, in contrast to current literature, few POC studies found race/ethnicity significantly predicted disparities. Cancer health disparities are complex; they are multifactorial, differ by cancer site and may wax and wane. The complexity supports the need for deeper understanding and targeted interventions to ensure equitable cancer care and outcomes.

Elimination of Cancer Health Disparities through the Acceleration of HPV Vaccines and Vaccinations: A Simplified Version of the President's Cancer Panel Report on HPV Vaccinations.

The human papillomavirus (HPV) is a major public health concern affecting both females and males. HPV is associated with cervical, anal, head and neck cancers. About 99% of all cervical cancers are related to HPV. HPV vaccines, Gardasil, Cervarix, and Gardasil 9 are used in the primary prevention of HPV related cancers. Gardasil and Gardasil 9 are available for use in both females and males ages 9 to 26, while Cervarix is available for females ages 9 to 25. Gardasil 9 was approved by the FDA for prevention against additional HPV types. Despite the availability of this preventative measure against cervical cancer, the rate of HPV vaccination in the United States remains lower than that of other industrialized nations. The purpose of this study is to elucidate mechanisms to help increase the HPV vaccination rate by using education as a tool; by simplifying the president report so that lay person can understand the information presented in the report. Through the quantitative examination of the data from the states with the lowest and highest vaccination rates, using SPSS statistical analysis; we analyzed several factors involved with the low uptake of the vaccines. The results collected show that socioeconomic status, misconceptions about HPV, and misconceptions about the safety of the vaccines were identified as possible obstacles to the effective uptake of HPV vaccinations. The proposals made by the President's Cancer Panel to accelerate the uptake of vaccines include, increasing coverage of the vaccines through government-sponsored programs, and the Affordable Care Act; increasing accessibility to vaccines through pharmacies, schools, and clinics; and disseminating more information on HPV to healthcare providers, parents, caregivers, and patients. Allowing greater accessibility to the vaccines for all populations regardless of income, education, and eliminating misconceptions of the vaccines would play a significant role in eliminating cancer.

Feeding Jejunostomy-Associated Small Bowel Necrosis After Elective Esophago-Gastric Resection.

BACKGROUND: Feeding jejunostomy has increasingly become a standard adjunctive procedure during major esophago-gastric resections. They provide nutritional support during the post-operative period as required. However, significant early complications have been reported, most notably small bowel necrosis. Literature reports have been restricted to case reports or series. This study aims to determine the frequency of this complication in a cohort of patients undergoing esophago-gastric resection, and identify any difference in the risk of this complication between patients undergoing esophagectomy and gastrectomy. METHODS: Consecutive patients who had esophago-gastric resections for malignancy and who had a feeding jejunostomy placed were identified from a prospectively maintained database at Leicester Royal Infirmary during the years 2009-2015. Case notes were reviewed to extract information relating to demographics, presenting features and clinical outcome. RESULTS: The study included 360 patients, 285 of which had esophagectomy and 75 had gastrectomy. There were no small bowel complications among esophagectomy patients (0%), while six patients who had total gastrectomy developed small bowel ischemia or necrosis (8%), p = 0.05, in spite of an identical feeding regimen. Every patient that developed the complication underwent surgery with five out six having resection of the infarcted segment and double-barrel stoma formation. A 6-8-week period of parenteral nutrition was required before stoma reversal. One patient had leucocytosis on the day of diagnosis. The other five patients showed no derangements in biochemical or clinical parameters in the preceding 48 h. Five of the six patients survived. CONCLUSIONS: Small bowel necrosis and perforation is a life-threatening complication of feeding jejunostomy. In our cohort, it happened exclusively in total gastrectomy patients. Antecedent signs were lacking. The condition requires prompt attention with earlier use of CT scanning and a return to the operating room. The presence of pneumatosis intestinalis on CT scan should prompt surgical intervention that improves survival.

Patient and Family Caregivers' Experiences of Living With a Jejunostomy Feeding Tube After Surgery for Esophagogastric Cancer.

BACKGROUND: Jejunostomy feeding tubes (JFTs) can be used to provide nutrition support to patients who have had surgery for esophagogastric cancer. Although previous research reports how patients cope with a gastrostomy tube, little is known about the impact of having a JFT. The aim of this qualitative study was to explore how patients and their informal caregivers experience living with a JFT in the first months following surgery. METHODS: Participants were purposively sampled from a cohort of patients recruited to a trial investigating home enteral nutrition vs standard care after esophagogastric surgery for cancer. The sampling framework considered age, sex, and marital status. Informal caregivers were also invited to participate. Interviews were audio recorded, transcribed verbatim, and anonymized. Inductive thematic analysis was used to identify key themes related to living with a JFT. RESULTS: Fifteen patient interviews were conducted; 8 also included a family caregiver. Analysis of the data resulted in 2 main themes: "challenges" and "facilitators" when living with a JFT. While "physical effects," "worries" and "impact on routine" were the main challenges, "support," "adaptation" and "perceived benefit" were what motivated continuation of the intervention. CONCLUSION: Findings suggest that participants coped well with a JFT, describing high levels of compliance with stoma care and the feeding regimen. Nonetheless, disturbed sleep patterns and stoma-related problems proved troublesome. A better understanding of these practical challenges, from the patient and family caregiver perspective, should guide healthcare teams in providing proactive support to avoid preventable problems.

A systematic review of the nutritional consequences of esophagectomy.

BACKGROUND & AIMS: As improved outcomes after esophagectomy have been observed over the last two decades, the focus on care has shifted to survivorship and quality of life. The aim of this review was to determine changes in nutrition after esophagectomy and to assess the evidence for extended nutrition support. METHODS: A search strategy was developed to identify primary research reporting change in nutritional status a minimum of one month after esophagectomy. RESULTS: Changes in nutritional parameters reported by 18 studies indicated a weight loss of 5-12% at six months postoperatively. More than half of patients lost >10% of body weight at 12 months. One study reported a persistent weight loss of 14% from baseline three years after surgery. Three studies reporting on longer term follow up noted that 27%-95% of patients failed to regain their baseline weight. Changes in dietary intake (three studies) indicated inadequate energy and protein intake up to three years after surgery. Global quality of life scores reported in one study correlated with better weight preservation. There were a high frequency of gastrointestinal symptoms reported in six studies, most notably in the first year after surgery, but persisting up to 19 years. Extended enteral nutrition on a selective basis has been reported in several studies. CONCLUSIONS: Nutritional status is compromised in the months/years following oesophagectomy and may never return to baseline levels. The causes/consequences of weight loss/impaired nutritional intake require further investigation. The role of extended nutritional support in this population remains unclear.

A randomised controlled trial of six weeks of home enteral nutrition versus standard care after oesophagectomy or total gastrectomy for cancer: report on a pilot and feasibility study.

BACKGROUND: Poor nutrition in the first months after oesophago-gastric resection is a contributing factor to the reduced quality of life seen in these patients. The aim of this pilot and feasibility study was to ascertain the feasibility of conducting a multi-centre randomised controlled trial to evaluate routine home enteral nutrition in these patients. METHODS: Patients undergoing oesophagectomy or total gastrectomy were randomised to either six weeks of home feeding through a jejunostomy (intervention), or treatment as usual (control). Intervention comprised overnight feeding, providing 50 % of energy and protein requirements, in addition to usual oral intake. Primary outcome measures were recruitment and retention rates at six weeks and six months. Nutritional intake, nutritional parameters, quality of life and healthcare costs were also collected. Interviews were conducted with a sample of participants, to ascertain patient and carer experiences. RESULTS: Fifty-four of 112 (48 %) eligible patients participated in the study over the 20 months. Study retention at six weeks was 41/54 patients (76 %) and at six months was 36/54 (67 %). At six weeks, participants in the control group had lost on average 3.9 kg more than participants in the intervention group (95 % confidence interval [CI] 1.6 to 6.2). These differences remained evident at three months (mean difference 2.5 kg, 95 % CI -0.5 to 5.6) and at six months (mean difference 2.5 kg, 95 % CI -1.2 to 6.1). The mean values observed in the intervention group for mid arm circumference, mid arm muscle circumference, triceps skin fold thickness and right hand grip strength were greater than for the control group at all post hospital discharge time points. The economic evaluation suggested that it was feasible to collect resource use and EQ-5D data for a full cost-effectiveness analysis. Thematic analysis of 15 interviews identified three main themes related to the intervention and the trial: 1) a positive experience, 2) the reasons for taking part, and 3) uncertainty of the study process. CONCLUSIONS: This study demonstrated that home enteral feeding by jejunostomy was feasible, safe and acceptable to patients and their carers. Whether home enteral feeding as 'usual practice' is a cost-effective therapy would require confirmation in an appropriately powered, multi-centre study. TRIAL REGISTRATION: UK Clinical Research Network ID 12447 (main trial, first registered 30 May 2012); UK Clinical Research Network ID 13361 (qualitative substudy, first registered 30 May 2012); ClinicalTrials.gov NCT01870817 (first registered 28 May 2013).

Six weeks of home enteral nutrition versus standard care after esophagectomy or total gastrectomy for cancer: study protocol for a randomized controlled trial.

BACKGROUND: Each year approximately 3000 patients in the United Kingdom undergo surgery for esophagogastric cancer. Jejunostomy feeding tubes, placed at the time of surgery for early postoperative nutrition, have been shown to have a positive impact on clinical outcomes in the short term. Whether feeding out of hospital is of benefit is unknown. Local experience has identified that between 15 and 20% of patients required 'rescue' jejunostomy feeding for nutritional problems and weight loss while at home. This weight loss and poor nutrition may contribute to the detrimental effect on the overall quality of life (QoL) reported in these patients. METHODS/DESIGN: This randomized pilot and feasibility study will provide preliminary information on the routine use of jejunostomy feeding after hospital discharge in terms of clinical benefits and QoL. Sixty participants undergoing esophagectomy or total gastrectomy will be randomized to receive either a planned program of six weeks of home jejunostomy feeding after discharge from hospital (intervention) or treatment-as-usual (control). The intention of this study is to inform a multi-centre randomized controlled trial. The primary outcome measures will be recruitment and retention rates at six weeks and six months. Secondary outcome measures will include disease specific and general QoL measures, nutritional parameters, total and oral nutritional intake, hospital readmission rates, and estimates of healthcare costs. Up to 20 participants will also be enrolled in a qualitative sub-study that will explore participants' and carers' experiences of home tube feeding.The results will be disseminated by presentation at surgical, gastroenterological and dietetic meetings and publication in appropriate peer review journals. A patient-friendly lay summary will be made available on the University of Leicester and the University Hospitals of Leicester NHS Trust websites. The study has full ethical and institutional approval and started recruitment in July 2012. TRIAL REGISTRATION: UKClinical Research Network ID #12447 (Main study); UKCRN ID#13361 (Qualitative sub study); ClinicalTrials.gov #NCT01870817 (First registered 28 May 2013).

High-output stoma after small-bowel resections for Crohn's disease.

BACKGROUND: A 56-year-old Caucasian woman with a history of Crohn's disease and multiple bowel resections resulting in a loop jejunostomy was referred to our Nutritional Unit from a neighboring district general hospital for further management. She was first seen in October 2001, and initial assessment indicated that she was malnourished with fluid depletion, evidenced by the high volume of stomal fluid produced. There had been no sudden change in her medication, her Crohn's disease was quiescent and there was no evidence of any intra-abdominal sepsis. Despite a high calorific intake through her diet, she continued to lose weight. INVESTIGATIONS: Serum urea and electrolytes; magnesium; C-reactive protein; full blood count; urinary spot sodium; anthropometric measurements. DIAGNOSIS: High-output stoma with malabsorption as a consequence of repeated small-bowel surgery. MANAGEMENT: The patient was treated with oral hypotonic fluid restriction (0.5 l/day), 2 l of oral glucose-saline solution per day, high-dose oral antimotility agents (loperamide and codeine phosphate), a proton-pump inhibitor (omeprazole) and oral magnesium replacement. A year later, the patient's loop jejunostomy was closed and an end ileostomy fashioned, bringing an additional 35 cm of small bowel into continuity; macronutrient absorption improved but her problem of dehydration was only slightly reduced. She was stabilized on a twice-weekly subcutaneous magnesium and saline infusion and daily oral 1alpha-hydroxycholecalciferol.