Multiomics Analysis Reveals Distinct Immunogenomic Features of Lung Cancer with Ground-Glass Opacity.

Rationale: Ground-glass opacity (GGO)-associated lung cancers are common and radiologically distinct clinical entities known to have an indolent clinical course and superior survival, implying a unique underlying biology. However, the molecular and immune characteristics of GGO-associated lung nodules have not been systemically studied. Objectives: To provide mechanistic insights for the treatment of these radiologically distinct clinical entities. Methods: We initiated a prospective cohort study to collect and characterize pulmonary nodules with GGO components (nonsolid and part-solid nodules) or without GGO components, as precisely quantified by using three-dimensional image reconstruction to delineate the molecular and immune features associated with GGO. Multiomics assessment conducted by using targeted gene panel sequencing, RNA sequencing, TCR (T-cell receptor) sequencing, and circulating tumor DNA detection was performed. Measurements and Main Results: GGO-associated lung cancers exhibited a lower tumor mutation burden than solid nodules. Transcriptomic analysis revealed a less active immune environment in GGO components and immune pathways, decreased expression of immune activation markers, and less infiltration of most immune-cell subsets, which was confirmed by using multiplex immunofluorescence. Furthermore, T-cell repertoire sequencing revealed lower T-cell expansion in GGO-associated lung cancers. HLA loss of heterozygosity was significantly less common in lung adenocarcinomas with GGO components than in those without. Circulating tumor DNA analysis suggested that the release of tumor DNA to the peripheral blood was correlated with the tumor size of non-GGO components. Conclusions: Compared with lung cancers presenting with solid lung nodules, GGO-associated lung cancers are characterized by a less active metabolism and a less active immune microenvironment, which may be the mechanisms underlying their indolent clinical course. Clinical trial registered with www.clinicaltrials.gov (NCT03320044).

Weight loss with exercise improves muscle architecture and progenitor cell populations compared with weight loss alone in mice with preneoplastic colorectal lesions.

Weight loss and exercise reduce colorectal cancer (CRC) risk in persons with obesity. Whether weight loss and exercise effect myofiber characteristics and muscle stem/progenitor cell populations in mice with preneoplastic colorectal lesions, a model of CRC risk, is unknown. To address this gap, male C57Bl/6J mice were fed a high-fat diet (HFD) to induce obesity or a control (CON) diet prior to azoxymethane injection to induce preneoplastic colorectal lesions. The HFD group was then randomized to weight loss conditions that included (1) switching to the CON diet only (HFD-SED) or switching to the CON diet with treadmill exercise training (HFD-EX). Average myofiber cross-sectional area was not different between groups. There were more smaller-sized fibres in HFD-EX (p < 0.05 vs. CON), and more fibrosis in HFD-SED (p < 0.05 vs. HFD-EX and CON). There was a trend for more committed (Pax7+MyoD+) myoblasts (p = 0.059) and more fibro-adipogenic progenitors in HFD-EX (p < 0.05 vs. CON). Additionally, the canonical pro-inflammatory marker p-NF-κB was markedly reduced in the interstitium of HFD-EX (p < 0.05 vs. CON and HFD-SED). Our findings suggest that in mice with preneoplastic colorectal lesions, HFD followed by weight loss with exercise reduces muscle fibrosis and results in a higher content of muscle stem/progenitor cells. Novelty: Exercise improves muscle architecture in mice with preneoplastic colorectal lesion Exercise increases fibro/adipogenic progenitors and reduces inflammatory signaling in mice with preneoplastic colorectal lesions.

Metabolome and microbiome alterations in tongue coating of gastric precancerous lesion patients.

Objective: This paper seeks to provide mechanistic insight into the pathological transition through the analysis of metabolites and microorganisms in the tongue coating of gastric precancerous lesions (GPL) patients.Methods: GC-TOF-MS and UHPLC-QE-MS metabolomics, combined with 16S rRNA microbiome techniques, were performed to explore the changes in metabolites and microorganisms in the tongue coating of GPL patients.Results: When compared with 15 controls, 133 metabolites were found to be differentially expressed in 60 GPL cases, of which could be divided into ten categories. Among them, most of the differentially expressed metabolites identified were lipids or lipid-like molecules. These metabolites were implicated in 6 metabolic pathways including glycine, serine and threonine metabolism, arginine and proline metabolism, sphingolipid metabolism, valine, leucine and isoleucine degradation, arachidonic acid metabolism, and tyrosine metabolism. The relative abundances of Alloprevotella, Solobacterium, Rothia, Eikenella, and Aggregatibacter in the GPL group increased significantly relative to the controls and were associated with lipids and lipid-like molecules, organic nitrogen compounds, organic oxygen compounds, phenylpropanoids and polyketides, and organoheterocyclic compounds, respectively.Conclusions: Compared with healthy people, the changes of tongue coating metabolites in GPL patients were mainly characterized by alterations in lipid metabolism and were associated with localized changes in the microbiome.

Reduced Esophageal Contractility Is Associated with Dysplasia Progression in Barrett's Esophagus: A Multicenter Cohort Study.

BACKGROUND: The incidence of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) continues to rise, and risk stratification of patients with BE is needed. Impaired esophageal motility is associated with gastroesophageal reflux disease; however, whether esophageal dysmotility is a risk factor for dysplasia progression in BE is incompletely understood. This study aimed to characterize esophageal motility patterns in patients with BE and identify physiologic factors associated with dysplasia progression in BE. METHODS: This multicenter retrospective study assessed data from adult patients with histologically confirmed BE who underwent high-resolution esophageal manometry from 1/2014 to 1/2018 at four tertiary care centers. Longitudinal data were collected when available among patients with non-dysplastic BE (NDBE) and separated as: no dysplastic progression or positive dysplastic progression. Multivariable logistic regression assessed for independent predictors of dysplasia progression. RESULTS: Among 193 patients, histology at index endoscopy identified 152 (79%) NDBE, 23 (12%) low-grade dysplasia, 14 (7%) high-grade dysplasia, and 4 (2%) EAC. Ninety-eight (51%) had abnormal esophageal motor function on manometry. Longitudinal data were available for 84 of 152 patients with initial NDBE. Twelve (14%) exhibited dysplastic progression to low-grade (6) or high-grade (6) dysplasia. Mean esophageal distal contractile integral was lower for patients that progressed [455 mmHg s cm (SD 515)] compared with patients who did not progress [987 mmHg s cm (SD 953); aOR 1.21 (95% CI 1.01, 1.44)]. CONCLUSION: In this retrospective study of 193 BE patients, the majority exhibited abnormal esophageal motor function. Reduced esophageal contractility was independently associated with dysplastic progression in BE. Characterizing esophageal physiology in BE may help to risk stratify patients.

ADAR1 function affects HPV replication and is associated to recurrent human papillomavirus-induced dysplasia in HIV coinfected individuals.

Infection by human papillomavirus (HPV) alters the microenvironment of keratinocytes as a mechanism to evade the immune system. A-to-I editing by ADAR1 has been reported to regulate innate immunity in response to viral infections. Here, we evaluated the role of ADAR1 in HPV infection in vitro and in vivo. Innate immune activation was characterized in human keratinocyte cell lines constitutively infected or not with HPV. ADAR1 knockdown induced an innate immune response through enhanced expression of RIG-I-like receptors (RLR) signaling cascade, over-production of type-I IFNs and pro-inflammatory cytokines. ADAR1 knockdown enhanced expression of HPV proteins, a process dependent on innate immune function as no A-to-I editing could be identified in HPV transcripts. A genetic association study was performed in a cohort of HPV/HIV infected individuals followed for a median of 6 years (range 0.1-24). We identified the low frequency haplotype AACCAT significantly associated with recurrent HPV dysplasia, suggesting a role of ADAR1 in the outcome of HPV infection in HIV+ individuals. In summary, our results suggest that ADAR1-mediated innate immune activation may influence HPV disease outcome, therefore indicating that modification of innate immune effectors regulated by ADAR1 could be a therapeutic strategy against HPV infection.

Clonal hematopoiesis in human aging and disease.

As people age, their tissues accumulate an increasing number of somatic mutations. Although most of these mutations are of little or no functional consequence, a mutation may arise that confers a fitness advantage on a cell. When this process happens in the hematopoietic system, a substantial proportion of circulating blood cells may derive from a single mutated stem cell. This outgrowth, called "clonal hematopoiesis," is highly prevalent in the elderly population. Here we discuss recent advances in our knowledge of clonal hematopoiesis, its relationship to malignancies, its link to nonmalignant diseases of aging, and its potential impact on immune function. Clonal hematopoiesis provides a glimpse into the process of mutation and selection that likely occurs in all somatic tissues.

Glans Resurfacing with Skin Graft for Penile Cancer: A Step-by-Step Video Presentation of the Technique and Review of the Literature.

INTRODUCTION: Glans resurfacing has been suggested as a treatment option for the surgical management of superficial penile cancer (Tis, Ta, T1aG1, T1aG2). In this article we describe in detail the glans resurfacing technique with skin graft for penile cancer in a video presentation and we review the current knowledge of the literature. MATERIAL AND METHODS: The procedure is described in a stepwise fashion. Initially the patient is circumcised. The glans is marked in quadrants and completely stripped by dissecting and removing the epithelium and subepithelium layer of the glans. Deep spongiosal biopsies are taken to exclude invasion. Each quadrant is sent separately for biopsy. The surface of the graft size needed is estimated. A partial thickness skin graft is harvested from the thigh with a dermatome. The skin graft is then fenestrated. The graft is rolled over the glans and quilted with multiple sutures. A silicone 16F Foley catheter and a suprapubic catheter are placed. The penis is dressed with multiple gauzes and compressed with an elastic band. RESULTS: The patient is discharged the next day. The dressing and Foley catheter are removed in 7 days. The patient continues to use the suprapubic catheter for 7 more days. The patient refrains from any sexual activity for 6 weeks and is closely followed. CONCLUSIONS: Glans resurfacing is an emerging new appealing surgical technique that is already a recommendation in the EAU guidelines for the treatment of premalignant and superficial penile lesions. The overall satisfaction rate and recovery of the sexual function are acceptable, and it can be considered an ideal procedure to treat superficial penile cancer.

Contributions of Fibroblasts, Extracellular Matrix, Stiffness, and Mechanosensing to Hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. A unique feature of liver cancer is its close association with liver fibrosis. About 90% of HCCs develop in advanced liver fibrosis or cirrhosis, suggesting an important role for the fibrotic microenvironment in driving HCC development. Here, the authors will discuss functional contributions of liver fibrosis to the development of HCC, focusing on mechanisms through which fibrosis may promote HCC development such as hepatic stellate cell-derived extracellular matrix, growth factors, and cytokines, stiffness-induced signaling pathways, and immunosuppression. Better understanding of these factors in HCC development and progression may provide the basis for novel stromal-based therapies for tumor prevention or therapy.

Referring Physicians Assess the Quality of Outpatient Diagnostic Imaging Services: Development and Psychometric Evaluation of a Questionnaire.

GOAL: In order to ensure high-quality cooperation between referring physicians and imaging services, it is important to assess the quality of imaging services as perceived by referring physicians. The present study aimed to develop and validate a questionnaire for referring physicians to assess the quality of outpatient diagnostic imaging services. MATERIALS & METHODS: The questionnaire was developed by discussing and modifying an existing instrument by the German Association of Surgeons. After qualitative pretesting, the instrument was tested with physicians referring to four outpatient diagnostic imaging services in Switzerland. The results were first assessed using descriptive statistics. The final instrument was tested for validity using the concept of known-groups validity. The hypothesis underlying this procedure was that physicians referring frequently to services estimated the quality of these services to be higher than physicians who referred less often to services. The differences in ratings were assessed using a one-sided two-sample Wilcoxon test. The final questionnaire was tested for internal consistency and reliability using Cronbach's Alpha. RESULTS: Results show a high level of satisfaction of referring physicians with the relevant services but also potential for quality improvement initiatives. The psychometric evaluation of the final questionnaire shows that it is a valid instrument, showing significant differences between the ratings of physicians referring with high and low frequency. Furthermore, the instrument proves to be consistent and reliable. CONCLUSION: The final instrument presents a valid, consistent and reliable option for assess the quality of outpatient diagnostic imaging services as perceived by referring physicians. Results can be used as a basis for quality improvement. KEY POINTS: · A newly developed questionnaire assesses the quality of outpatient diagnostic imaging services as perceived by referring physicians. The questionnaire was developed and tested in Switzerland.. · Psychometric evaluation showed the questionnaire to be a valid, consistent and reliable instrument.. · Results are of interest for imaging services as well as for initiatives encompassing several services.. CITATION FORMAT: · Jossen M, Valeri F, Heilmaier C et al. Referring Physicians Assess the Quality of Outpatient Diagnostic Imaging Services: Development and Psychometric Evaluation of a Questionnaire. Fortschr Röntgenstr 2019; 191: 725 - 731.

Short-term gain, long-term pain: the senescence life cycle and cancer.

Originally thought of as a stress response end point, the view of cellular senescence has since evolved into one encompassing a wide range of physiological and pathological functions, including both protumorignic and antitumorigenic features. It has also become evident that senescence is a highly dynamic and heterogenous process. Efforts to reconcile the beneficial and detrimental features of senescence suggest that physiological functions require the transient presence of senescent cells in the tissue microenvironment. Here, we propose the concept of a physiological "senescence life cycle," which has pathological consequences if not executed in its entirety.

Voice Profile Recovery and Quality of Life Changes After Microdirect Laryngoscopy in Three Categories of Glottis Lesions: Benign, Precancerous, and Malignant.

The aim of the study was comparison of voice and life quality after microdirect laryngoscopy in three patient histopathological categories: benign, precancerous, and malignant glottic lesions. A totalnof 137 patients treated with microdirect laryngoscopy were included in the study. Each patient was evaluated with a multidimensional protocol before and 3, 6, and 12 months after treatment. Final 1-year evaluations were achieved in 74.5% (102). The assessment included laryngovideostroboscopy (LVS), perceptual (GRBAS) grading, aerodynamic measures including maximum phonation time and phonation quotient and acoustic measurements (Kay Elemetrics Multi-Speech program), Voice Handicap Index (VHI), Voice-Related Quality of Life questionnaire; and World Health Organization Quality of Life Scale-Brief Version (WHOQoL-BREF). An improvement in mean value of LVS ratings was obtained in all three groups; however, only in benign lesion group was it consistently statistically significant for each time period (P < 0.001). Perceptual evaluation revealed significant improvement of G, R, and B parameters in benign lesions for each time period. In malignant neoplasms R and B parameters improved 3 and 6 months post microsurgery. In patients with benign lesions the maximum phonation time increased, but the improvement was significant only after 3 months. The acoustic parameters improved in all three groups. VHI significantly improved in patients with benign lesions after 3 and 12 months. VHI in the malignant neoplasm group significantly worsened on the first follow-up visit. Considering quality of life (QoL) results, only in patients with benign lesions was there a significant improvement in overall assessment of their QoL and general health.

HISTOPATHOLOGIC FINDINGS IN WOMEN UNDERGOING HYSTEROSCOPIC RESECTION OF ENDOMETRIAL POLYPS AND UTERINE MYOMAS.

The aim of our study was to determine the prevalence of endometrial premalignant and malignant lesions in women undergoing hysteroscopy and to identify anthropologic factors related to the presence of malignancy. Data on 3470 women with submucosal myomas or endometrial polyps suspected on ultrasound were retrospectively analyzed. Hysteroscopy was performed in all these women in order to make a more precise diagnosis. Histologic analysis of endometrial samples obtained during hysteroscopy was used to confirm the diagnosis. Statistical analysis was performed using the SPSS 20.0.0 software. The mean age of study women was 49.1±13.3 years. The number of procedures performed due to the referral diagnosis of endometrial or submucosal myoma significantly increased over the 16-year study period. A significantly higher number of women had a benign histopathologic diagnosis. Histologic analysis revealed malignancy in 67 women. The youngest woman and oldest woman with malignant findings was aged 32 and 75, respectively. A significantly higher number of women with atypical hyperplasia and malignancy were in menopause. A comparable number of women with different histologic findings lived in urban and rural areas. There were a significantly larger proportion of widows among women with the histologic diagnosis of atypical hyperplasia or malignancy. The prevalence rate of malignancy in women having undergone hysteroscopy for polyps and myoma found by ultrasound was 1.93%. Postmenopausal status and older age were associated with an increased risk of malignancies, but premalignant changes and malignancies were also found in young and premenopausal women. Therefore, diagnostic hysteroscopy can be recommended in women of all age groups.

Non-invasive method for the assessment of gastric acid secretion.

Methods for the measure of gastric acid secretion include invasive and non-invasive tests. The gold-standard to measure the acid output is the collection of gastric after in basal condition (Basal Acid Output, B.A.O.) and after an i.m. injection of pentagastrin (Maximal Acid Output, M.A.O.). However, direct measurement of gastric acid production is out of order in clinical practice, but many GI symptoms are claimed to be related with acid disorders and empirically cured. Hypochlorhydria is associated with precancerous conditions such as chronic atrophic gastritis (CAG). Acid measurement with non-invasive methods (pepsinogens) is supported by international guidelines.

Associations among Gastric Juice pH, Atrophic Gastritis, Intestinal Metaplasia and Helicobacter pylori Infection.

BACKGROUND/AIMS: Gastric juice plays a crucial role in the physiology of the stomach. The aim of this study is to evaluate associations among the pH of gastric juice, atrophic gastritis (AG), intestinal metaplasia (IM), pepsinogen, and Helicobacter pylori infection. METHODS: Gastric biopsies and juice were collected from 46 subjects who underwent endoscopies at Seoul National University Bundang Hospital between November 2011 and March 2013. H. pylori, AG and IM were evaluated, and pepsinogen I or II, I/II ratio, and interleukin (IL)-1ß levels were measured. RESULTS: The mean pH of gastric juice was higher in the H. pylori-positive group (n=17) than that in the H. pylori-negative group (n=29) (4.54 vs 2.46, p=0.002). When patients were divided into pH ＜3 (n=28) and pH ≥3 (n=18) groups, H. pylori was lower in the pH ＜3 group (21.4%) than in the pH ≥3 group (61.1%) (p=0.007). The pH ≥3 group demonstrated AG and IM more frequently than the pH ＜3 group in the body (p=0.047 and p=0.051, respectively) but not in the antrum. There were no differences in pepsinogen I or II, I/II ratio, and IL-1ß levels between the two groups. CONCLUSIONS: There is a relationship between chronic H. pylori infection and gastric juice pH ≥3, which may originate from AG and IM in the body.

Lesion oxygenation associates with clinical outcomes in premalignant and early stage head and neck tumors treated on a phase 1 trial of photodynamic therapy.

BACKGROUND: We report on a Phase 1 trial of photodynamic therapy (PDT) for superficial head and neck (H&N) lesions. Due to known oxygen dependencies of PDT, translational measurements of lesion hemoglobin oxygen saturation (StO2) and blood volume (tHb) were studied for associations with patient outcomes. METHODS: PDT with aminolevulinc acid (ALA) and escalating light doses was evaluated for high-grade dysplasia, carcinoma-in-situ, and microinvasive carcinomas of the H&N. Among 29 evaluable patients, most (18) had lesions of the tongue or floor of mouth (FOM). Disease was intact in 18 patients and present at surgical margins in 11 patients. In 26 patients, lesion StO2 and tHb was measured. RESULTS: Local control (LC) at 24 months was 57.5% among all patients. In patients with tongue/FOM lesions LC was 42.7%, and it was 50.1% for those with intact lesions. Lesion tHb was not associated with 3-month complete response (CR), but StO2 was higher in patients with CR. In tongue/FOM lesions, baseline StO2 [mean(SE)] was 54(4)% in patients (n=12) with CR versus 23(8)% in patients (n=6) with local recurrence/persistence (p=0.01). Similarly, for intact disease, baseline StO2 was 54(3)% in patients (n=10) with CR versus 28(8)% in patients (n=5) without CR (p=0.03). In patients with intact disease, higher baseline StO2 associated with 24-month local control (p=0.02). CONCLUSIONS: Measurement of the physiologic properties of target lesions may allow for identification of patients with the highest probability of benefiting from PDT. This provides opportunity for optimizing light delivery based on lesion characteristics and/or informing ongoing clinical decision-making in patients who would most benefit from PDT.

Nutrition Implications for Long-Term Survivors of Pancreatic Cancer Surgery [Formula: see text].

With slowly increasing survival rates in pancreatic cancer and international consensus guidelines recommending surgical resection of premalignant lesions, survival post-pancreatic resection is increasing. With longer survival time, the significant comorbidities of such major surgery have far-reaching effects on the nutrition status of the survivor of pancreatic cancer. This review describes the many nutrition-related side effects of pancreatic surgery, including the development of pancreatic enzyme insufficiency, micronutrient deficiencies, diabetes, fatty liver, and metabolic bone disease. Beyond causing additional medical problems, each of these can have significant effects on quality of life and functional status. The potential mechanisms, diagnosis criteria, and potential treatments of these conditions are described. Overall, little literature exists to fully describe the effects of these comorbidities, and even less is able to guide effective treatments for this population. Clinicians caring for these patients should begin incorporating goals for promotion of long-term health and reduction of these known and reported comorbidities in patients who have undergone pancreatic surgery. Treatment plans in this population remain understudied, and clinicians may need to consider recommendations for similar disease states when developing interventions for these patients.