Premalignant Progression in the Lung: Knowledge Gaps and Novel Opportunities for Interception of Non-Small Cell Lung Cancer. An Official American Thoracic Society Research Statement.

RATIONALE: Despite significant advances in precision treatments and immunotherapy, lung cancer is the most common cause of cancer death worldwide. To reduce incidence and improve survival rates, a deeper understanding of lung premalignancy and the multistep process of tumorigenesis is essential, allowing for timely and effective intervention before cancer development. OBJECTIVES: To summarize existing information, identify knowledge gaps, formulate research questions, prioritize potential research topics, and propose strategies for future investigations into the premalignant progression in the lung. METHODS: An international multidisciplinary team of basic, translational, and clinical scientists reviewed available data to develop and refine research questions pertaining to the transformation of premalignant lung lesions to advanced lung cancer. RESULTS: This research statement identifies significant gaps in knowledge and proposes potential research questions aimed at expanding our understanding of the mechanisms underlying the progression of premalignant lung lesions to lung cancer in an effort to explore potential innovative modalities to intercept lung cancer at its nascent stages. CONCLUSIONS: The identified gaps in knowledge about the biological mechanisms of premalignant progression in the lung, along with ongoing challenges in screening, detection, and early intervention, highlight the critical need to prioritize research in this domain. Such focused investigations are essential to devise effective preventive strategies that may ultimately decrease lung cancer incidence and improve patient outcomes.

Drug and biomarker tissue levels in a randomized presurgical trial on exemestane alternative schedules.

The drug's activity at the target tissue could help to define the minimal effective dose to promote cancer preventive therapy. Here we present exemestane and sex hormone concentrations within breast tissue from a pre-surgical study of alternative exemestane schedules. Postmenopausal women candidate for breast surgery for estrogen receptor-positive breast cancer were randomized to exemestane 25 mg once daily (QD), 25 mg three times/week (TIW), or 25 mg per/week (QW) for 4-6 weeks before surgery. Drug and sex hormones were analyzed from homogenized frozen tissue using a QTRAP 6500+ LC-MS/MS System. Tissue drug concentrations were detectable only in the QD arm with higher concentrations in non-malignant tissue. Estradiol was nearly suppressed in all groups in the non-malignant tissue (QD vs TIW p = .364 and QD vs QW p = .693). In contrast, a dose-response trend was observed in cancer tissue. Based on estradiol suppression in non-malignant tissue, lower exemestane schedules should be explored for breast cancer preventive therapy.

Changes in Time to Initial Physician Contact and Cancer Stage Distribution during the COVID-19 Pandemic in Patients with Head and Neck Squamous Cell Carcinoma at a Large Hungarian Cancer Center.

The aim of our study was to compare the characteristics and time to initial physician contact in patients with head and neck squamous cell carcinoma (HNSCC) before and during the COVID-19 pandemic at a large Hungarian cancer center. This was a retrospective study of patients 18 years or older presenting at the regional cancer center of Pécs Clinical Center with HNSCC between 1 January 2017, and 15 March 2020 (the pre-COVID-19 period) and between 16 March 2020, and 13 May 2021 (the COVID-19 period). Demographic and clinical data were collected, and the time between initial symptom onset and initial physician contact (TTP) was determined. Descriptive and exploratory statistical analyses were performed. On average, the number of patients diagnosed with HNSCC per month during the pandemic decreased by 12.4% compared with the pre-COVID-19 period. There was a significant increase in stage I and stage II cancers (from 15.9% to 20.3% and from 12.2% to 13.8%, respectively; p < 0.001); a decrease in stage III and IVa,c cancers; and a significant increase in stage IVb cancers (from 6% to 19.9%; p < 0.001) during the pandemic. The median TTP increased during the pandemic from 43 to 61 days (p = 0.032). To our knowledge, this is the first study investigating the effect of COVID-19 on patients with HNSCC in the Central-Eastern European region. We found a bidirectional shift in cancer stages and increased TTP during the pandemic. Our findings highlight the necessity for more nuanced analyses of the effects of COVID-19.

Investigation of Phosphatidylcholine by MALDI Imaging Mass Spectrometry in Normal and IVF Early-Stage Embryos.

The receptive phase of the uterus is marked by structural and functional maturation of the endometrium. During this limited time span, the blastocyst competency is superimposed on the receptive endometrium. It is a well-known fact that lipid signalling in early-stage pregnancy has a crucial role in successful embryogenesis. In our study, CD-1 mouse uteri after normal and in vitro fertilization (IVF) were investigated at 6.5, 8.5, and 10.5 days of pregnancy. Matrix-assisted laser desorption/ionization time-of-flight imaging mass spectrometry and liquid chromatography coupled tandem mass spectrometry were used for identification of phosphatidylcholine (PC) lipid structures. In the embryonal tissues, PC 32:0 and PC 34:0 were increased, while in the antemesometrial (AM) decidua the two 20:4-containing PCs, PC 36:4 and PC 38:4 were increased. In transferred uterus samples, higher expressions of PC 34:0, PC 34:1, PC 34:2, PC 36:1, and PC 36:2 in mesometrial decidua were seen, whereas the two 20:4-containing PCs, PC 36:4 and PC 38:4 showed increased expression in the AM and lateral decidua. This paper shows a significant spatio-temporal change in lipid metabolism during IVF procedures for the first time.

NCI Resources for Cancer Immunoprevention Research.

Cancer prevention and early detection, the first two of the eight primary goals of the National Cancer Plan released in April 2023, are at the forefront of the nation's strategic efforts to reduce cancer incidence and mortality. The Division of Cancer Prevention (DCP) of the NCI is the federal government's principal component devoted to promoting and supporting innovative cancer prevention research. Recent advances in tumor immunology, cancer immunotherapy, and vaccinology strongly suggest that the host immune system can be effectively harnessed to elicit protective immunity against the development of cancer, that is, cancer immunoprevention. Cancer immunoprevention may be most effective if the intervention is given before or early in the carcinogenic process while the immune system remains relatively uncompromised. DCP has increased the emphasis on immunoprevention research in recent years and continues to expand program resources and interagency collaborations designed to facilitate research in the immunoprevention field. These resources support a wide array of basic, translational, and clinical research activities, including discovery, development, and validation of biomarkers for cancer risk assessment and early detection (Early Detection Research Network), elucidation of biological and pathophysiological mechanistic determinants of precancer growth and its control (Translational and Basic Science Research in Early Lesions), spatiotemporal multiomics characterization of precancerous lesions (Human Tumor Atlas Network/Pre-Cancer Atlas), discovery of immunoprevention pathways and immune targets (Cancer Immunoprevention Network), and preclinical and clinical development of novel agents for immunoprevention and interception (Cancer Prevention-Interception Targeted Agent Discovery Program, PREVENT Cancer Preclinical Drug Development Program, and Cancer Prevention Clinical Trials Network).

Accrual Quality Improvement Program for clinical trials.

BACKGROUND: The Early Phase Cancer Prevention Clinical Trials Program (Consortia), led by the Division of Cancer Prevention, National Cancer Institute, supports and conducts trials assessing safety, tolerability, and cancer preventive potential of a variety of interventions. Accrual to cancer prevention trials includes the recruitment of unaffected populations, posing unique challenges related to minimizing participant burden and risk, given the less evident or measurable benefits to individual participants. The Accrual Quality Improvement Program was developed to address these challenges and better understand the multiple determinants of accrual activity throughout the life of the trial. Through continuous monitoring of accrual data, Accrual Quality Improvement Program identifies positive and negative factors in real-time to optimize enrollment rates for ongoing and future trials. METHODS: The Accrual Quality Improvement Program provides a web-based centralized infrastructure for collecting, analyzing, visualizing, and storing qualitative and quantitative participant-, site-, and study-level data. The Accrual Quality Improvement Program approaches cancer prevention clinical trial accrual as multi-factorial, recognizing protocol design, potential participants' characteristics, and individual site as well as study-wide implementation issues. RESULTS: The Accrual Quality Improvement Program was used across 39 Consortia trials from 2014 to 2022 to collect comprehensive trial information. The Accrual Quality Improvement Program captures data at the participant level, including number of charts reviewed, potential participants contacted and reasons why participants were not eligible for contact or did not consent to the trial or start intervention. The Accrual Quality Improvement Program also captures site-level (e.g. staffing issues) and study-level (e.g. when protocol amendments are made) data at each step of the recruitment/enrollment process, from potential participant identification to contact, consent, intervention, and study completion using a Recruitment Journal. Accrual Quality Improvement Program's functionality also includes tracking and visualization of a trial's cumulative accrual rate compared to the projected accrual rate, including a zone-based performance rating with corresponding quality improvement intervention recommendations. CONCLUSION: The challenges associated with recruitment and timely completion of early phase cancer prevention clinical trials necessitate a data collection program capable of continuous collection and quality improvement. The Accrual Quality Improvement Program collects cumulative data across National Cancer Institute, Division of Cancer Prevention early phase clinical trials, providing the opportunity for real-time review of participant-, site-, and study-level data and thereby enables responsive recruitment strategy and protocol modifications for improved recruitment rates to ongoing trials. Of note, Accrual Quality Improvement Program data collected from ongoing trials will inform future trials to optimize protocol design and maximize accrual efficiency.

Predictive factors of basic palliative and hospice care among patients with cancer visiting the emergency department in a Hungarian tertiary care center.

Introduction: Patients with advanced cancer tend to utilize the services of the health care system, particularly emergency departments (EDs), more often, however EDs aren't necessarily the most ideal environments for providing care to these patients. The objective of our study was to analyze the clinical and demographic characteristics of advanced patients with cancer receiving basic palliative care (BPC) or hospice care (HC), and to identify predictive factors of BPC and HC prior to their visit to the ED, in a large tertiary care center in Hungary. Methods: A retrospective, detailed analysis of patients receiving only BPC or HC, out of 1512 patients with cancer visiting the ED in 2018, was carried out. Sociodemographic and clinical data were collected via automated and manual chart review. Patients were followed up to determine length of survival. Descriptive and exploratory statistical analyses were performed. Results: Hospital admission, multiple (≥4x) ED visits, and respiratory cancer were independent risk factors for receiving only BPC (OR: 3.10, CI: 1.90-5.04; OR: 2.97, CI: 1.50-5.84; OR: 1.82, CI: 1.03-3.22, respectively), or HC (OR: 2.15, CI: 1.26-3.67; OR: 4.94, CI: 2.51-9.71; OR: 2.07, CI: 1.10-3.91). Visiting the ED only once was found to be a negative predictive factor for BPC (OR: 0.28, CI: 0.18-0.45) and HC (OR: 0.18, 0.10-0.31) among patients with cancer visiting the ED. Conclusions: Our study is the first from this European region to provide information regarding the characteristics of patients with cancer receiving BPC and HC who visited the ED, as well as to identify possible predictive factors of receiving BPC and HC. Our study may have relevant implications for health care planning strategies in practice.

Trans isomeric fatty acids in human milk and their role in infant health and development.

It is well known that long chain polyunsaturated fatty acids (LCPUFAs) play an important role in neurodevelopment in the perinatal life. The most important source of these fatty acids is the diet, however, they can also be formed in the human body from their shorter chain precursors, the essential fatty acids. Since the WHO recommends exclusive breastfeeding for the first six months after birth, the exclusive source of these fatty acids for breastfed infants is human milk, which can be influenced by the mother's diet. Unsaturated fatty acids can have either cis or trans configuration double bond in their chain with distinct physiological effects. Cis isomeric unsaturated fatty acids have several beneficial effects, while trans isomers are mostly detrimental, because of their similar structure to saturated fatty acids. Trans fatty acids (TFAs) can be further subdivided into industrial (iTFA) and ruminant-derived trans fatty acids (rTFA). However, the physiological effects of these two TFA subgroups may differ. In adults, dietary intake of iTFA has been linked to atherosclerosis, insulin resistance, obesity, chronic inflammation, and increased development of certain cancers, among other diseases. However, iTFAs can have a negative impact on health not only in adulthood but in childhood too. Results from previous studies have shown that iTFAs have a significant negative effect on LCPUFA levels in the blood of newborns and infants. In addition, iTFAs can affect the growth and development of infants, and animal studies suggest that they might even have lasting negative effects later in life. Since the only source of TFAs in the human body is the diet, the TFA content of breast milk may determine the TFA supply of breastfed infants and thus affect the levels of LCPUFAs important for neurodevelopment and the health of infants. In this review, we aim to provide an overview of the TFA content in human milk available in the literature and their potential effects on infant health and development.

Antibiotics and probiotics-induced effects on the total fatty acid composition of feces in a rat model.

Fatty acids (FAs) play important roles as membrane components and signal transduction molecules. Changes in short chain FA (SCFA) composition are associated with gut microbiota modifications. However, the effect of bacteria-driven changes on the detailed FA spectrum has not been explored yet. We investigated the effect of antibiotics (ABx) and/or probiotics, in four treatment groups on rat stool FA composition. Principal component analysis indicated that the chromatogram profiles of the treatment groups differ, which was also observed at different time points. Linear mixed effects models showed that in the parameters compared (sampling times, treatments. and their interactions), both the weight percentage and the concentration of FAs were affected by ABx and probiotic administration. This study found that the gut microbiome defines trans and branched saturated FAs, most saturated FAs, and unsaturated FAs with less carbon atoms. These results are among the first ones to demonstrate the restoring effects of a probiotic mixture on a substantial part of the altered total FA spectrum, and also revealed a previously unknown relationship between gut bacteria and a larger group of FAs. These findings suggest that intestinal bacteria produce not only SCFAs but also other FAs that may affect the host's physiological processes.

Randomized controlled trial of nasogastric tube use after esophagectomy: study protocol for the kinetic trial.

Esophagectomy is a complex and complication laden procedure. Despite centralization, variations in perioparative strategies reflect a paucity of evidence regarding optimal routines. The use of nasogastric (NG) tubes post esophagectomy is typically associated with significant discomfort for the patients. We hypothesize that immediate postoperative removal of the NG tube is non-inferior to current routines. All Nordic Upper Gastrointestinal Cancer centers were invited to participate in this open-label pragmatic randomized controlled trial (RCT). Inclusion criteria include resection for locally advanced esophageal cancer with gastric tube reconstruction. A pretrial survey was undertaken and was the foundation for a consensus process resulting in the Kinetic trial, an RCT allocating patients to either no use of a NG tube (intervention) or 5 days of postoperative NG tube use (control) with anastomotic leakage as primary endpoint. Secondary endpoints include pulmonary complications, overall complications, length of stay, health related quality of life. A sample size of 450 patients is planned (Kinetic trial: https://www.isrctn.com/ISRCTN39935085). Thirteen Nordic centers with a combined catchment area of 17 million inhabitants have entered the trial and ethical approval was granted in Sweden, Norway, Finland, and Denmark. All centers routinely use NG tube and all but one center use total or hybrid minimally invasive-surgical approach. Inclusion began in January 2022 and the first annual safety board assessment has deemed the trial safe and recommended continuation. We have launched the first adequately powered multi-center pragmatic controlled randomized clinical trial regarding NG tube use after esophagectomy with gastric conduit reconstruction.

Alternative dosing regimen of exemestane in a randomized presurgical trial: the role of obesity in biomarker modulation.

In a 3-arm presurgical trial, four-six weeks exemestane 25 mg three times/week (TIW) was non-inferior to 25 mg/day (QD) in suppressing circulating estradiol in postmenopausal women with ER-positive breast cancer. Since obesity may decrease exemestane efficacy, we analyzed changes in sex steroids, adipokines, Ki-67, and drug levels in relation to obesity. Postmenopausal women with early-stage ER-positive breast cancer were randomized to either exemestane 25 mg QD (n = 57), 25 mg TIW (n = 57), or 25 mg/week (QW, n = 62) for 4-6 weeks before breast surgery. Serum and tissue pre- and post-treatment biomarkers were stratified by body mass index (BMI)< or ≥30 kg/m2. Post-treatment median exemestane and 17-OH exemestane levels were 5-6 times higher in the QD arm compared to the TIW arm. For obese women, TIW maintained comparable reductions to QD in systemic estradiol levels, although the reduction in estrone was less with the TIW regimen. There was less suppression of SHBG with the TIW versus the QD dose schedule in obese women which should result in less systemic bioavailable estrogens. Metabolically, the effect of the TIW regimen was similar to the QD regimen for obese women in terms of leptin suppression and increase in the adiponectin-leptin ratio. Reduction in tissue Ki-67 was less for obese women on the TIW regimen than QD, although changes were similar for non-obese women. Our findings suggest that TIW exemestane should be explored further for primary cancer prevention in both normal weight and obese cohorts.

The impact of the bougie size and the extent of antral resection on weight-loss and postoperative complications following sleeve gastrectomy: results from the Scandinavian Obesity Surgery Registry.

BACKGROUND: The optimal sleeve diameter and distance from the pylorus to the edge of the resection line in laparoscopic sleeve gastrectomy (LSG) remain controversial. OBJECTIVES: To evaluate the influence of bougie size and antral resection distance from the pylorus on postoperative complications and weight-loss results in LSG. SETTING: Nationwide registry-based study. METHODS: This study included all LSGs performed in Sweden between 2012 and 2019. Data were obtained from the Scandinavian Obesity Surgery Registry. Reference bougie size of 35-36 Fr and an antral resection distance of 5 cm from the pylorus were compared to narrower bougie size (30-32 Fr), shorter distances (1-4 cm), and extended distances (6-8 cm) from the pylorus in assessing postoperative complications and weight loss as the outcomes of LSG. RESULTS: The study included 9,360 patients with postoperative follow-up rates of 96%, 79%, and 50% at 30 days, 1 year, and 2 years, respectively. Narrow bougie and short antral resection distance from the pylorus were significantly associated with increased postoperative weight loss. Bougie size was not associated with increased early or late complications. However, short antral resection distance was associated with high risk of overall early complications [odds ratio: 1.46 (1.17-1.82, P = .001)], although no impact on late complications at 1 and 2 years was observed. CONCLUSIONS: Using a narrow bougie and initiating resection closer to the pylorus were associated with greater maximum weight loss. Although a closer resection to the pylorus was associated with an increased risk of early postoperative complications, no association was observed with the use of narrow bougie for LSG.

The Swedish Standardized Course of Care-Diagnostic Efficacy in Esophageal and Gastric Cancer.

Fast-track pathways for diagnosing esophageal or gastric cancer (EGC) have been implemented in several European countries. In Sweden, symptoms such as dysphagia, early satiety, and other alarm symptoms call for a referral for gastroscopy, according to the Swedish Standardized Course of Care (SCC). The aim of this study was to evaluate the diagnostic yield of the SCC criteria for EGC, to review all known EGC cases in Region Örebro County between March 2017 and February 2021, and to compare referral indication(s), waiting times, and tumor stage. In our material, EGC was found in 6.2% of the SCC referrals. Esophageal dysphagia had a positive predictive value (PPV) of 5.6%. The criterion with the highest PPV for EGC was suspicious radiological findings, with a PPV of 24.5%. A total of 139 EGCs were diagnosed, 99 (71%) through other pathways than via the SCC. Waiting times were approximately 14 days longer for patients evaluated via non-SCC pathways. There was no statistically significant association between referral pathway and primary tumor characteristics. The results show that a majority of the current SCC criteria are poor predictors of EGC, and some alarm symptoms lack a sufficiently specific definition, e.g., dysphagia. Referral through this fast track does not seem to have a positive impact on disease outcomes.

Benefits and Harms of Edible Vegetable Oils and Fats Fortified with Vitamins A and D as a Public Health Intervention in the General Population: A Systematic Review of Interventions.

This systematic review aims to assess whether edible vegetable oils and fats fortified with vitamin A and/or D are effective and safe in improving vitamin intake and ameliorating deficiency states in the general population. In November 2022, we systematically searched MEDLINE, Cochrane CENTRAL, Scopus, Global Index Medicus, ClinicalTrials.gov, and WHO ICTRP (International Clinical Trials Registry Platform) for randomized controlled trials (RCT) and non-randomized studies of interventions (NRSI) investigating the fortification of edible vegetable oils and fats with either vitamin A or vitamin D or both as compared to the same vegetable oils and/or fats without vitamin A and D fortification or no interventions, in the general population, without age restriction. We assessed the methodological quality of included RCTs using Cochrane's risk of bias tool 2.0 and of NRSIs using ROBINS-I tool. We performed random-effects meta-analysis and assessed certainty of evidence using GRADE. We included eight studies. Available evidence showed no significant effect of fortification with vitamin A on serum retinol levels (RCTs: MD 0.35 µmol/L, 95% CI -0.43 to 1.12; two trials; 514 participants; low-certainty evidence; CCTs: MD 0.31 µmol/L, 95% CI -0.18 to 0.80; two trials; 205 participants; very low-certainty evidence) and on subclinical vitamin A deficiency. Low-certainty evidence showed no effect of vitamin D fortification on serum 25-hydroxy vitamin D concentration (MD 6.59 nmol/L, 95% CI -6.89 to 20.07; one trial; 62 participants). In conclusion, vitamin A-fortified vegetable oils and fats may result in little to no difference in serum retinol levels in general populations. The dose of vitamin A used in the trials may be safe but may not be sufficient to reduce subclinical vitamin A deficiency. Further, the evidence suggests that vitamin D fortification results in little to no difference in serum 25-hydroxy vitamin D concentration. Several aspects of providing fortified oils and fats to the general population as a public health intervention should be further investigated, including optimal fortification dose, effects on vitamin D deficiency and its clinical symptoms and potential adverse effects.

The Effect of Additional Whole-Body Vibration on Musculoskeletal System in Children with Cerebral Palsy: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

Nowadays, whole-body vibration (WBV) has become increasingly popular as an additional therapy in the intervention of patients with cerebral palsy (CP). However, the impact of WBV remains a subject of debate. Consequently, a systematic review and meta-analysis were undertaken to evaluate the effects of WBV on the musculoskeletal system in children with CP. Randomized controlled trials (RCTs) were sought in the most frequent databases. The intervention studied was WBV combined with conventional physiotherapy (PT) compared with conventional PT as the control; the main outcomes were changes in the musculoskeletal system. Weighted mean differences with 95%CIs were calculated. A random-effects model was applied, and the publication bias was checked using funnel plots. On the basis of the inclusion and exclusion criteria, 16 articles, including 414 patients, were considered in the final analysis. The improvement in walking performance (speed and step length) was statistically significant (p < 0.05), and although there were no significant differences in the further outcomes, a clear positive tendency was visible in the case of improved muscle strength, decreased spasticity, enhanced gross motor functions, and overall stability. Based on the findings, a clear assessment of the usefulness of this intervention cannot be made; nonetheless, due to the promising results, it would be worthwhile to conduct additional RCTs to enhance the available evidence in this field. Due to the wide range of vibration configurations, including varying durations and intensities, it is suggested to establish guidelines and a strategy for the incorporation of this additional treatment.

Reliability of the DSS-Swe Questionnaire.

BACKGROUND: Symptomatic postbariatric hypoglycemia (PBH) is a known complication that can occur a few years after Roux-en-Y gastric bypass (RYGB). There is currently no established rating scale for PBH-associated symptoms developed for use in Swedish populations. The aim of the study was to translate an already existing questionnaire into Swedish and to test its reliability. METHODS: The study included forward and backward translations of the original Dumping Severity Scale (DSS) questionnaire with 8 items regarding symptoms of early dumping and 6 items regarding hypoglycemia, with each item graded on a 4-point Likert scale. The reliability of the Swedish translated questionnaire (DSS-Swe) was estimated using internal consistency and test-retest methods. RESULTS: A total of 200 patients were included in the study. Good internal consistency was demonstrated regarding the items related to early dumping symptoms, with a Cronbach's alpha coefficient of 0.82, and very good agreement in terms of test-retest reliability, with an overall intraclass correlation coefficient (ICC) of 0.91 (95% CI 0.88-0.93). The items related to hypoglycemia yielded a good Cronbach's alpha coefficient of 0.76 and an ICC of 0.89 (95% CI 0.85-0.91). CONCLUSION: The DSS-Swe questionnaire shows good reliability regarding both internal consistency and test-retest performance for use in Swedish populations.

Phase Ib trial of inhaled iloprost for the prevention of lung cancer with predictive and response biomarker assessment.

Introduction: Iloprost, a prostacyclin analog, has lung cancerpreventive activity in preclinical models and improved dysplasia in former smokers in a phase IIb trial. Oral iloprost is currently unavailable. We performed a phase Ib trial of inhaled iloprost in former smokers to assess tolerance and compliance. Methods: Participants self-administered nebulized iloprost (5ug) or placebo four (QID) or two (BID) times daily. As QID dose was well tolerated and due to expiration of the placebo, the BID dosing and placebo were eliminated early on in the trial. Bronchoscopy with biopsyat six standard sites was performed at treatment initiation and two months post-iloprost, with exploratory histological analysis. Bulk RNA sequencing, single cell RNA sequencing and an in vitro assay of epithelial progenitor cell iloprost response were performed on a subset of biopsies in an exploratory investigation of response mechanisms and predictive biomarkers. Results and discussion: Thirty-four of a planned 48 participants were recruited to the trial.Inhaled iloprost was well tolerated with no adverse events > grade 2. Compliance was 67% in the QID group. The trial was not powered to detect histologic response and none was found. Bulk RNA sequencing of biopsies pre/post iloprost suggest that iloprost is immunomodulatory and downregulates cell proliferation pathways. Single cell RNA sequencing showed an increase in CD8-positive T cells with upregulation of genes in interferon γ signaling. In vitro iloprost response by epithelial progenitor cells correlated with histologic response with kappa coefficient of 0.81 (95% CI 0.47, 1.0). Inhaled iloprost was well tolerated with suboptimal compliance. Molecular analysis suggested that iloprosthas immunomodulatory and antiproliferative effects.The progenitor cell iloprost response assay may be a promising avenue to develop predictive biomarkers. Clinical trial registration: https://clinicaltrials.gov/study/NCT02237183, identifier NCT02237183.

Non-response After Gastric Bypass and Sleeve Gastrectomy-the Theoretical Need for Revisional Bariatric Surgery: Results from the Scandinavian Obesity Surgery Registry.

BACKGROUND: Revisional surgery is a second-line treatment option after sleeve gastrectomy (SG) and gastric bypass (GBP) in patients with primary or secondary non-response. The aim was to analyze the theoretical need for revisional surgery after SG and GBP when applying four indication benchmarks. METHOD: Based on data from the Scandinavian Obesity Surgery Registry, SG and GBP were compared regarding four endpoints: 1. excess weight loss (%EWL) < 50%, 2. weight regain of more than 10 kg after nadir, 3. fulfillment of previous IFSO-guidelines, or 4. ADA criteria for bariatric metabolic surgery 2 years after primary surgery. RESULTS: A total of 60,426 individuals were included in the study (SG: n = 7856 and GBP: n = 52,570). Compared to patients in the GBP group, more SG patients failed to achieve a %EWL > 50% (23.0% versus 8.5%, p < .001), regained more than 10 kg after nadir (4.3% versus 2.5%, p < .001), and more often fulfilled the IFSO criteria (8.0% versus 4.5%, p < .001) or the ADA criteria (3.3% versus 1.8%, p < 001) at the 2-year follow-up. CONCLUSION: SG is associated with a higher risk for weight non-response compared to GBP. To offer revisional bariatric surgery to all non-responders exceeds the bounds of feasibility and operability. Hence, individual prioritization and intensified evaluation of alternative second-line treatments are necessary.

Plasma Somatostatin Levels Increase during Scoliosis Surgery, but Not Herniated Disc Operations: Results of a Pilot Study.

Somatostatin (SST) released from capsaicin-sensitive sensory nerves in response to stimulation exerts systemic anti-inflammatory, analgesic actions. Its elevation correlates with the extent of tissue injury. We measured plasma SST alterations during spine operations (scoliosis and herniated disc) to determine whether its release might be a general protective mechanism during painful conditions. Sampling timepoints were baseline (1), after: soft tissue retraction (2), osteotomy (3), skin closure (4), the following morning (5). Plasma SST-like immunoreactivity (SST-LI) determined by radioimmunoassay was correlated with pain intensity and the correction angle (Cobb angle). In scoliosis surgery, postoperative pain intensity (VAS 2.) 1 day after surgery significantly increased (from 1.44 SEM ± 0.68 to 6.77 SEM ± 0.82, p = 0.0028) and positively correlated with the Cobb angle (p = 0.0235). The baseline Cobb degree negatively correlated (p = 0.0459) with the preoperative SST-LI. The plasma SST-LI significantly increased in fraction 3 compared to the baseline (p < 0.05), and significantly decreased thereafter (p < 0.001). In contrast, in herniated disc operations no SST-LI changes were observed in either group. The VAS decreased after surgery both in the traditional (mean 6.83 to 2.29, p = 0.0005) and microdiscectomy groups (mean 7.22 to 2.11, p = 0.0009). More extensive and destructive scoliosis surgery might cause greater tissue damage with greater pain (inflammation), which results in a significant SST release into the plasma from the sensory nerves. SST is suggested to be involved in an endogenous postoperative analgesic (anti-inflammatory) mechanism.

Impact of socioeconomic status on new chronic opioid use after gastric bypass surgery.

BACKGROUND: Socioeconomic status may influence weight loss, postoperative complications, and health-related quality of life after bariatric surgery. Chronic use of opioid analgesics is a known risk after bariatric surgery, but whether socioeconomic factors are associated with new chronic use of opioid analgesics has not been investigated in depth. OBJECTIVES: The aim of this study was to identify socioeconomic factors associated with the development of new chronic use of opioid analgesics after gastric bypass surgery. SETTING: All hospitals performing bariatric surgery in Sweden. METHODS: This was a retrospective cohort study with prospectively collected data including all primary gastric bypass procedures in Sweden between 2007 and 2015. Data were collected from the Scandinavian Obesity Surgery Registry, the Swedish Prescribed Drug Register, and Statistics Sweden. The primary outcome was new chronic opioid use. RESULTS: Of the 44,671 participants, 1438 patients became new chronic opioid users. Longer education (secondary education; odds ratio [OR] = .71; 95% CI, .62-.81) or higher education (OR = .45; 95% CI, .38-.53), higher disposable income (20th-50th percentile: OR = .75; 95% CI, .66-.85; 50th-80th percentile: OR = .50; 95% CI, .43-.58; and the highest 80th percentile: OR = .40; 95% CI, .32-.51) were significantly associated with lower risk for new chronic opioid use. Being a second-generation immigrant (OR = 1.54; 95% CI, 1.24-1.90), being on a disability pension or early retirement (OR = 3.04; 95% CI, 2.67-3.45), receiving social benefits (OR = 1.88; 95% CI, 1.59-2.22), being unemployed for <100 days (OR = 1.25; 95% CI, 1.08-1.45), being unemployed for >100 days (OR = 1.41; 95% CI, 1.16-1.71), and being divorced or a widow or widower (OR = 1.35; 95% CI, 1.17-1.55) were significantly associated with a higher risk for chronic opioid use. CONCLUSION: Given that long-term opioid use has detrimental effects after bariatric surgery, it is important that information and follow-up are optimized for patients with shorter education, lower income, and disability pension or early retirement because they are at an increased risk of new chronic opioid analgesics use.