Rectal Cancer Survival for Residual Carcinoma In Situ Versus Pathologic Complete Response After Neoadjuvant Therapy.

BACKGROUND: Pathologic complete response after neoadjuvant chemoradiotherapy for rectal cancer is associated with improved survival. It is unclear whether residual carcinoma in situ portends a similar outcome. OBJECTIVE: To compare the survival of patients with locally advanced rectal cancer who received neoadjuvant therapy and achieved pathologic carcinoma in situ versus pathologic complete response. DESIGN: Retrospective cohort study. SETTING: National public database. PATIENTS: A total of 4594 patients in the National Cancer Database from 2006 to 2016 with locally advanced rectal cancer who received neoadjuvant therapy, underwent surgery, and had node-negative ypTis or ypT0 on final pathology were included. Of these, 4321 patients (94.1%) had ypT0 and 273 (5.9%) had ypTis on final pathology. MAIN OUTCOME MEASURE: Overall survival. RESULTS: The median age was 60 years, and 1822 patients (39.7%) were women. On initial staging, 54.5% (n = 2503) had stage II disease and 45.5% (n = 2091) had stage III disease. The ypTis group had decreased overall survival compared to the ypT0 group (HR 1.42; 95% CI, 1.04-1.95; p = 0.028). Other factors associated with decreased overall survival were older age at diagnosis, increasing Charlson-Deyo score, and poorly differentiated tumor grade. Variables associated with improved survival were female sex, private insurance, and receipt of both neoadjuvant and adjuvant chemotherapy. For the total cohort, there was no difference in survival between clinical stage II and stage III. LIMITATIONS: Standard therapy versus total neoadjuvant therapy could not be abstracted. Overall survival was defined as the time from surgery to death from any cause or last contact, allowing for some erroneously misclassified deaths. CONCLUSIONS: ypTis is associated with worse overall survival than ypT0 for patients with locally advanced rectal cancer who receive neoadjuvant chemoradiotherapy followed by surgery. For this cohort, clinical stage was not a significant predictor of survival. Prospective trials comparing survival for these pathologic outcomes are needed. See Video Abstract . SUPERVIVENCIA DEL CNCER DE RECTO PARA EL CARCINOMA RESIDUAL IN SITU VS RESPUESTA PATOLGICA COMPLETA DESPUS DE LA TERAPIA NEOADYUVANTE: ANTECEDENTESLa respuesta patológica completa después de la quimiorradioterapia neoadyuvante para el cáncer de recto se asocia con una mayor supervivencia. No está claro si el carcinoma residual in situ presagia un resultado similar.OBJETIVOComparar la supervivencia de pacientes con cáncer de recto localmente avanzado que recibieron terapia neoadyuvante y lograron un carcinoma patológico in situ versus una respuesta patológica completa.DISEÑOEstudio de cohorte retrospectivo.ESCENARIOBase de datos pública nacional.PACIENTESSe incluyeron 4,594 pacientes de la Base de Datos Nacional de Cáncer de 2006 a 2016 con cáncer de recto localmente avanzado que recibieron terapia neoadyuvante, fueron sometidos a cirugía y tuvieron ganglios negativos, ypTis o ypT0 en el reporte patológico final. 4.321 (94,1%) tuvieron ypT0 y 273 (5,9%) tuvieron ypTis en el reporte final.PRINCIPALES MEDIDAS DE RESULTADOSupervivencia general.RESULTADOSLa mediana de edad fue de 60 años. 1.822 pacientes (39,7%) fueron mujeres. El 54,5% (n = 2.503) tuvo la enfermedad en estadio II y el 45,5% (n = 2.091) tuvo la enfermedad en estadio III según la estadificación inicial. El grupo ypTis tuvo una supervivencia general reducida en comparación con el grupo ypT0 (HR 1,42, IC 95 % 1,04-1,95, p = 0,028). Otros factores asociados con una menor supervivencia general fueron una edad más avanzada al momento del diagnóstico, un aumento de la puntuación de Charlson-Deyo y un grado tumoral poco diferenciado. Las variables asociadas con una mejor supervivencia fueron el sexo femenino, el seguro privado y la recepción de quimioterapia neoadyuvante y adyuvante. Para la cohorte total, no hubo diferencias en la supervivencia entre el estadio clínico 2 y el estadio 3.LIMITACIONESNo se pudo resumir el tratamiento estándar versus el tratamiento neoadyuvante total. La supervivencia general se definió como el tiempo transcurrido desde la cirugía hasta la muerte por cualquier causa o último contacto, lo que permite algunas muertes erróneamente clasificadas.CONCLUSIONESypTis se asocia con una peor supervivencia general que ypT0 en pacientes con cáncer de recto localmente avanzado que reciben quimiorradioterapia neoadyuvante seguida de cirugía. Para esta cohorte, el estadio clínico no fue un predictor significativo de supervivencia. Se necesitan ensayos prospectivos que comparen la supervivencia de estos resultados patológicos. ( Traducción-Dr Osvaldo Gauto ).

The global burden of lymphoma: estimates from the Global Burden of Disease 2019 study.

OBJECTIVES: The aim of this study was to describe the global trends in the burden of lymphoma from 1990 to 2019. STUDY DESIGN: The data used in this study were from the Global Burden of Disease 2019 study. METHODS: This study described the age-standardised rates of incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life years (DALYs) of lymphoma (non-Hodgkin and Hodgkin's lymphoma, NHL and HL, respectively) annually from 1990 to 2019, stratified by sociodemographic index (SDI) and 21 world regions. The estimated annual percentage changes in these indexes were calculated. RESULTS: In 2019, the age-standardised rates of HL per 100,000 population were lower than those of NHL in terms of incidence (1.1 vs 6.7 per 100,000 person-years, respectively) and prevalence (0.3 vs 5.7 per 100,000 person-years, respectively) but not mortality (21.6 vs 3.2 per 100,000 person-years, respectively). From 1999 to 2019, the global incidence of HL decreased and the incidence of NHL increased, and the prevalence of both HL and NHL increased, but the mortality rates decreased. When stratified by SDI, the incidence of HL decreased in all but middle-SDI regions, the mortality rate of HL decreased in all regions, and both the incidence and mortality rate of NHL increased in all but high-SDI regions. The prevalence of HL and NHL increased in all SDI regions, especially in middle-SDI regions. YLLs and DALYs of HL in all SDI regions and those of NHL in high-SDI regions decreased. YLDs slightly increased in middle- to high-SDI regions. CONCLUSIONS: Lymphoma remains a major public health issue, and better prevention, precise identification, and promising treatments are vitally important.

Assessing the Association Between Endoscopic Tattooing and Lymph Node Yield in Rectal Cancer.

INTRODUCTION: Preoperative endoscopic tattooing is an effective tool for intraoperative tumor localization in colon cancer. Endoscopic tattooing in rectal cancer may have unidentified benefits on lymph node yield, making it easier for pathologists to identify nodes during histopathologic assessment. There remains concern that tattoo ink may alter anatomical planes, increasing surgical difficulty. METHODS: Retrospective chart reviews from 2016 to 2021 of n = 170 patients presenting with rectal cancer were divided into two groups: with (n = 79) and without (n = 91) endoscopic tattoos. Demographics, operative details, tumor characteristics, prior chemoradiation, and pathologic details were collected. Primary outcome was total lymph node yield. Secondary outcomes were rates of adequate (> 12) nodes, margin status, and operative variables including operative time. RESULTS: No differences between pathologic stage, tumor height, high inferior mesenteric artery ligation, operative times, conversion rate, or surgical approach (open versus minimally invasive) were noted between groups. Receipt of neoadjuvant chemoradiation was less frequent in the endoscopic tattooing group (53.2% versus 76.9%, P ≤ 0.001). Total node number and rate of adequate lymph node yield were higher with endoscopic tattooing (20.5 ± 7.6 versus 16.8 ± 6.6 lymph nodes and 100.0% versus 83.5% adequate lymph node harvest, both P ≤ 0.001). Rates of positive circumferential and distal margins and complete total mesorectal excision were also similar. Regression analysis identified endoscopic tattooing (Incidence Risk Ratio 1.17, 95% confidence interval 1.04-1.31) and operative time more than 300 min (Incidence Risk Ratio 0.88, 95% confidence interval 0.77-0.99) had significant effects on lymph node harvest. Removal of patients with inadequate lymph node yield resulted in similar rates of total and positive lymph nodes. CONCLUSIONS: Endoscopic rectal tattooing is associated with increased lymph node yield (including after neoadjuvant chemoradiotherapy) without sacrificing oncologic or perioperative outcomes, although this effect is inconsistent when only considering patients with an adequate lymph node yield.

Increased cost burden associated with robot-assisted rectopexy: do patient outcomes justify increased expenditure?

BACKGROUND: Robot-assisted surgical techniques have flourished over the years, with refinement in instrumentation and optics allowing for adaptation and increasing utilization across surgical fields. Transabdominal rectopexy with mesh for rectal prolapse may stand to benefit significantly from the use of a robotic platform. However, increased operative times and immediate associated costs of robotic surgery may provide a counterargument to widespread adoption. METHODS: To determine which approach to the treatment of rectal prolapse, laparoscopic or robotic, is more cost effective and provides better outcomes with fewer complications, a retrospective review was performed at a single tertiary care academic institution from May 2013 to December 2020. Twenty-two patients underwent transabdominal mesh rectopexy through a robot-assisted DaVinci platform (Intuitive Sunnyvale, CA), and thirty through a laparoscopic platform. Main outcome measures included operative, hospital, and total cost as defined by total charges billed. Secondary outcomes included rate of recurrence, intra-operative complications, median operative time, post-operative complications, average hospital length of stay, inpatient pain medication usage, and post-operative functional outcomes. RESULTS: Cost analysis for robot-assisted versus laparoscopic rectopexy demonstrated operating room costs of $46,118 ± $9329 for the robotic group, versus $33,090 ± $15,395 (p = 0.002) for the laparoscopic group. Inpatient hospital costs were $60,723 ± $20,170 vs. $40,798 ± $14,325 (p = 0.001), and total costs were $106,841 ± $25,513 vs. $73,888 ± $28,129 (p ≤ 0.001). When secondary outcomes were compared for the robotic versus laparoscopic groups, there were no differences in any of the aforementioned outcome variables except for operative time, which was 79 min longer in the robotic group (p ≤ 0.001). CONCLUSIONS: Robot-assisted mesh rectopexy demonstrated no clinical benefit over traditional laparoscopic mesh rectopexy, with significantly higher operative and hospital costs. A reduction in the acquisition and maintenance costs for robotic surgery is needed before large-scale adoption and implementation of the robotic platform for this procedure.

Glucose Deprivation Induces Cancer Cell Death through Failure of ROS Regulation.

In previous work, we showed that cancer cells do not depend on glycolysis for ATP production, but they do on fatty acid oxidation. However, we found some cancer cells induced cell death after glucose deprivation along with a decrease of ATP production. We investigated the different response of glucose deprivation with two types of cancer cells including glucose insensitive cancer cells (GIC) which do not change ATP levels, and glucose sensitive cancer cells (GSC) which decrease ATP production in 24 h. Glucose deprivation-induced cell death in GSC by more than twofold after 12 h and by up to tenfold after 24 h accompanied by decreased ATP production to compare to the control (cultured in glucose). Glucose deprivation decreased the levels of metabolic intermediates of the pentose phosphate pathway (PPP) and the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) in both GSC and GIC. However, glucose deprivation increased reactive oxygen species (ROS) only in GSC, suggesting that GIC have a higher tolerance for decreased NADPH than GSC. The twofold higher ratio of reduced/oxidized glutathione (GSH/GSSG) in GIS than in GSC correlates closely with the twofold lower ROS levels under glucose starvation conditions. Treatment with N-acetylcysteine (NAC) as a precursor to the biologic antioxidant glutathione restored ATP production by 70% and reversed cell death caused by glucose deprivation in GSC. The present findings suggest that glucose deprivation-induced cancer cell death is not caused by decreased ATP levels, but rather triggered by a failure of ROS regulation by the antioxidant system. Conclusion is clear that glucose deprivation-induced cell death is independent from ATP depletion-induced cell death.

The sialidase NEU1 directly interacts with the juxtamembranous segment of the cytoplasmic domain of mucin-1 to inhibit downstream PI3K-Akt signaling.

The extracellular domain (ED) of the membrane-spanning sialoglycoprotein, mucin-1 (MUC1), is an in vivo substrate for the lysosomal sialidase, neuraminidase-1 (NEU1). Engagement of the MUC1-ED by its cognate ligand, Pseudomonas aeruginosa-expressed flagellin, increases NEU1-MUC1 association and NEU1-mediated MUC1-ED desialylation to unmask cryptic binding sites for its ligand. However, the mechanism(s) through which intracellular NEU1 might physically interact with its surface-expressed MUC1-ED substrate are unclear. Using reciprocal coimmunoprecipitation and in vitro binding assays in a human airway epithelial cell system, we show here that NEU1 associates with the MUC1-cytoplasmic domain (CD) but not with the MUC1-ED. Prior pharmacologic inhibition of the NEU1 catalytic activity using the NEU1-selective sialidase inhibitor, C9-butyl amide-2-deoxy-2,3-dehydro-N-acetylneuraminic acid, did not diminish NEU1-MUC1-CD association. In addition, glutathione-S-transferase (GST) pull-down assays using the deletion mutants of the MUC1-CD mapped the NEU1-binding site to the membrane-proximal 36 aa of the MUC1-CD. In a cell-free system, we found that the purified NEU1 interacted with the immobilized GST-MUC1-CD and the purified MUC1-CD associated with the immobilized 6XHis-NEU1, indicating that the NEU1-MUC1-CD interaction was direct and independent of its chaperone protein, protective protein/cathepsin A. However, the NEU1-MUC1-CD interaction was not required for the NEU1-mediated MUC1-ED desialylation. Finally, we demonstrated that overexpression of either WT NEU1 or a catalytically dead NEU1 G68V mutant diminished the association of the established MUC1-CD binding partner, PI3K, to MUC1-CD and reduced downstream Akt kinase phosphorylation. These results indicate that NEU1 associates with the juxtamembranous region of the MUC1-CD to inhibit PI3K-Akt signaling independent of NEU1 catalytic activity.

Multiple functions of pyruvate kinase M2 in various cell types.

Glucose metabolism is a mechanism by which energy is produced in form of adenosine triphosphate (ATP) by mitochondria and precursor metabolites are supplied to enable the ultimate enrichment of mature metabolites in the cell. Recently, glycolytic enzymes have been shown to have unconventional but important functions. Among these enzymes, pyruvate kinase M2 (PKM2) plays several roles including having conventional metabolic enzyme activity, and also being a transcriptional regulator and a protein kinase. Compared with the closely related PKM1, PKM2 is highly expressed in cancer cells and embryos, whereas PKM1 is dominant in mature, differentiated cells. Posttranslational modifications such as phosphorylation and acetylation of PKM2 change its cellular functions. In particular, PKM2 can translocate to the nucleus, where it regulates the transcription of many target genes. It is notable that PKM2 also acts as a protein kinase to phosphorylate several substrate proteins. Besides cancer cells and embryonic cells, astrocytes also highly express PKM2, which is crucial for lactate production via expression of lactate dehydrogenase A (LDHA), while mature neurons predominantly express PKM1. The lactate produced in cancer cells promotes tumor progress and that in astrocytes can be supplied to neurons and may act as a major source for neuronal ATP energy production. Thereby, we propose that PKM2 along with its different posttranslational modifications has specific purposes for a variety of cell types, performing unique functions.

Layer-by-Layer Biomimetic Microgels for 3D Cell Culture and Nonviral Gene Delivery.

Localized release of nucleic acid therapeutics is essential for many biomedical applications, including gene therapy, tissue engineering, and medical implant coatings. We applied the substrate-mediated transfection and layer-by-layer (LbL) technique to achieve an efficient local gene delivery. In the experiments presented herein, we embeded lipoplexes containing plasmid DNA encoding for enhanced green fluorescent protein (pEGFP) within polyelectrolyte alginate-based microgels composed of poly(allylamine hydrochloride) (PAH), chondroitin sulfate (CS), and poly-l-lysine (PLL) with diameters between 70 and 90 µm. Droplet-based microfluidics was used as the main process to produce the alginate (ALG)-based microgels with discrete size, shape, and low coefficient of variation. The physicochemical and morphological properties of the polyelectrolyte microgels were characterized via optical microscopy, scanning electron microscopy (SEM), and zeta potential analysis. We found that polyelectrolyte microgels provide low cytotoxicity and cell-material interactions (adhesion, spreading, and proliferation). In addition, the microsystem showed the ability to load lipoplexes and a loading efficiency equal to 83%, and it enabled in vitro surface-based transfection of MCF-7 cells. This approach provides a new suitable route for cell adhesion and local gene delivery.

Endoscopy Reports for Rectosigmoid Tumors: Frequently Missing Key Information Needed for Surgical Planning.

INTRODUCTION: Endoscopy reports by gastroenterologists describing rectosigmoid tumors often are missing crucial data for surgical planning, leading to high rates of repeat exams before surgical decision-making. We hypothesize that there will be significant deficiencies in the endoscopic reporting of rectosigmoid lesions leading to high rates of repeat endoscopic examination at our institution. METHODS: Retrospective review from January 2016 to November 2019 included 188 patients with rectosigmoid lesions referred for surgery with an outside endoscopy report. Three criteria were abstracted from these reports or included pictures: (1) distance from the tumor to an anatomical landmark (anal verge, dentate line, sphincter), (2) Tattoo placement (if performed) and location, and (3) tumor relationship to the valves of Houston. Reports were classified exemplary, nearly adequate, or inadequate if 3, 2, and ≤ 1 of these criteria were met, respectively. RESULTS: Distance was reported in 38.8% (n = 73) of reports, with the anal verge being the most commonly reported anatomical landmark (32.4%, n = 61 reports). Tattoo was placed in 34.6% (n = 65), though only 21.8% (n = 41) described the location of the tattoo relative to the tumor. Relationship to the valves of Houston was seen in 29.2% (n = 55) of reports. Only 5.3% (n = 10) of outside endoscopy reports were graded as exemplary, 20.2% (n = 38) nearly adequate, and the remaining 74.5% (n = 140) inadequate. A total of 87.5% (n = 165) of patients required repeat endoscopy with a significantly higher proportion from the inadequate group. CONCLUSIONS: Many referring endoscopy reports contain inadequate information for the surgical planning of rectosigmoid tumor resection. Efforts to improve documentation (particularly about distance and location within the rectum) must be undertaken.

Prevalence of and Risk Factors for Incidental Colonic Diverticulosis.

INTRODUCTION: The true prevalence and pathogenesis of diverticulosis is poorly understood. Risk factors for diverticulosis are presently unclear, with most clinicians attributing its development to years of chronic constipation. Previous studies have been limited by their failure to include young, ethnically diverse patient populations. METHODS: Patients who presented to the emergency department of our hospital from January-September 2019 and underwent abdominal computerized tomography (CT) scan for the evaluation of appendicitis were included. CT's were reviewed for the presence of diverticulosis. Risk factors for diverticulosis were determined for two age groups: >40 and ≤ 40. RESULTS: A total of 359 patients were included in the study. The median age was 38.57.1% were male. 81.6% were Hispanic. 43.5% had colonic diverticulosis on CT. 198 patients (55.1%) were ≤ age 40. The rate of diverticulosis in this group was 35.3% (n = 70). Those with diverticulosis were not significantly older (median age 29 versus 27, P = 0.061) but had a higher median body mass index (BMI) (28.4 versus 25.3, P = 0.003) compared to those without diverticulosis. On multivariate analysis, no characteristics were associated with the presence of diverticulosis for this group. Over age 40, 53.4% of patients (n = 86) had diverticulosis. Patients with diverticulosis were more likely to be Hispanic (95.3% versus 73.3%, P ≤ 0.001), less likely to be Asian (2.4% versus 16.0%, P = 0.004), had a higher median BMI (28.7 versus 25.5, P ≤ 0.001), and were more likely to use alcohol (30.2% versus 14.7%, P = 0.024) than those without diverticulosis. On multivariate analysis, characteristics associated with the presence of diverticulosis were BMI >30 (odds ratio OR 2.22, 95% confidence interval CI 1.03-4.80), Hispanic ethnicity (OR 10.05, 95% CI 1.74-58.26), and alcohol use (OR 3.44, 95% CI 1.26-9.39). CONCLUSIONS: There was a higher rate of asymptomatic diverticulosis in the <40 cohort than previously reported in the literature. Obesity, alcohol use, and Hispanic ethnicity were associated with the presence of diverticulosis in patients > age 40, but no risk factors for diverticulosis were identified for patients ≤ age 40, suggesting that diverticular pathogenesis may differ by age. Constipation was not a risk factor for diverticulosis in either age group. The data regarding the prevalence of diverticulosis in Hispanic patients is lacking and should be the focus of future inquiry.

"Unresectable" polyp management utilizing advanced endoscopic techniques results in high rate of colon preservation.

PURPOSE: "Endoscopically unresectable" benign polyps identified during screening colonoscopy are often referred for segmental colectomy. Application of advanced endoscopic techniques can increase endoscopic polyp resection, sparing patients the morbidity of colectomy. This retrospective case-control study aimed to evaluate the success of colon preserving resection of "endoscopically unresectable" benign polyps using advanced endoscopic techniques including endoscopic mucosal resection, endoscopic submucosal dissection, endoluminal surgical intervention, full-thickness laparo-endoscopic excision, and combined endo-laparoscopic resection. METHODS: A prospectively maintained institutional database identified 95 patients referred for "endoscopically unresectable" benign polyps from 2015 to 2018. Cases were compared to 190 propensity score matched controls from the same database undergoing elective laparoscopic colectomy for other reasons. Primary outcome was rate of complete endoscopic polyp removal. Secondary outcomes included length of stay, unplanned 30-day readmission and reoperation, 30-day mortality, and post-procedural complications. RESULTS: Advanced endoscopic techniques achieved complete polyp removal without colectomy in 66 patients (70%). Failure was most commonly associated with previously attempted endoscopic resection and occult malignancy. Compared with matched colectomy controls, endoscopic polyp resection resulted in significantly shorter hospital length of stay (1.13 ± 2.41 vs 3.89 ± 4.57 days; p < 0.001), lower unplanned 30-day readmission (1.1% vs 7.7%; p < 0.05), and fewer postoperative complications (4.2% vs 33.9%; p < 0.001). Unplanned 30-day reoperation (2.1% vs 4.4%; p = 0.34) and 30-day mortality (0% vs 0.6%; p = 0.75) trended lower. CONCLUSIONS: Endoscopic resection of complex polyps can be highly successful, and it is associated with favorable outcomes and decreased morbidity when compared with segmental colon resection. Attempting colon preservation using these techniques is warranted.

Therapeutic Effect of Neuraminidase-1-Selective Inhibition in Mouse Models of Bleomycin-Induced Pulmonary Inflammation and Fibrosis.

Pulmonary fibrosis remains a serious biomedical problem with no cure and an urgent need for better therapies. Neuraminidases (NEUs), including NEU1, have been recently implicated in the mechanism of pulmonary fibrosis by us and others. We now have tested the ability of a broad-spectrum neuraminidase inhibitor, 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (DANA), to modulate the in vivo response to acute intratracheal bleomycin challenge as an experimental model of pulmonary fibrosis. A marked alleviation of bleomycin-induced body weight loss and notable declines in accumulation of pulmonary lymphocytes and collagen deposition were observed. Real-time polymerase chain reaction analyses of human and mouse lung tissues and primary human lung fibroblast cultures were also performed. A predominant expression and pronounced elevation in the levels of NEU1 mRNA were observed in patients with idiopathic pulmonary fibrosis and bleomycin-challenged mice compared with their corresponding controls, whereas NEU2, NEU3, and NEU4 were expressed at far lower levels. The levels of mRNA for the NEU1 chaperone, protective protein/cathepsin A (PPCA), were also elevated by bleomycin. Western blotting analyses demonstrated bleomycin-induced elevations in protein expression of both NEU1 and PPCA in mouse lungs. Two known selective NEU1 inhibitors, C9-pentyl-amide-DANA (C9-BA-DANA) and C5-hexanamido-C9-acetamido-DANA, dramatically reduced bleomycin-induced loss of body weight, accumulation of pulmonary lymphocytes, and deposition of collagen. Importantly, C9-BA-DANA was therapeutic in the chronic bleomycin exposure model with no toxic effects observed within the experimental timeframe. Moreover, in the acute bleomycin model, C9-BA-DANA attenuated NEU1-mediated desialylation and shedding of the mucin-1 ectodomain. These data indicate that NEU1-selective inhibition offers a potential therapeutic intervention for pulmonary fibrotic diseases. SIGNIFICANCE STATEMENT: Neuraminidase-1-selective therapeutic targeting in the acute and chronic bleomycin models of pulmonary fibrosis reverses pulmonary collagen deposition, accumulation of lymphocytes in the lungs, and the disease-associated loss of body weight-all without observable toxic effects. Such therapy is as efficacious as nonspecific inhibition of all neuraminidases in these models, thus indicating the central role of neuraminidase-1 as well as offering a potential innovative, specifically targeted, and safe approach to treating human patients with a severe malady: pulmonary fibrosis.

Transcriptome analysis reveals TOR signalling-mediated plant flush shoots governing Diaphorina citri Kuwayama oviposition.

Asian Citrus Psyllid (ACP), Diaphorina citri, is a key vector transmitting the causative agent of Huanglongbing (HLB) disease. Population growth of ACP is evident after feeding on plant flush shoots, as they only oviposit here. However, the underlying mechanism as to why flush shoots govern oviposition is unclear. This study compares the fecundity and ovarian morphology of ACP between young flush and mature leaves. Furthermore, the transcriptome of mated females infesting Murraya paniculata was analysed. Finally, the gene of the key Target of Rapamycin (TOR) signalling pathway was silenced by RNAi. Results indicated that flush shoot feeding activated the development of the psyllids ovary and therefore induced oviposition. A total of 126 and 2794 differentially expressed genes were detected at 1 and 5 days, respectively, after pest infestation of flush shoots compared to mature leaves. Many genes are involved in protein metabolism, Mitogen-Activated Protein Kinase (MAPK) signalling pathway, hormone synthesis, and TOR signalling pathway: all thought to activate reproduction. Silencing of the positive regulator gene DcRheb in the TOR pathway resulted in lower levels of ecdysone and juvenile hormone and decreased vitellogenin synthesis, further disrupting reproductive ability. This study enhances understanding of the molecular mechanism underlying ACP's reproductive strategy.

Full-Thickness Laparoendoscopic Excision for Management of Complex Colon Polyps.

BACKGROUND: Benign colon polyps are increasingly being detected because of improved colonoscopic screening and early detection of masses on the adenoma-to-carcinoma pathway. Full-thickness laparoendoscopic excision is a colon-preserving technique for endoscopically unresectable polyps consisting of endoscopically guided nonanatomic wedge colectomy. OBJECTIVE: This study aimed to evaluate the safety and success of full-thickness laparoendoscopic excision compared to segmental colectomy for complex polyps not amenable to endoscopic resection. DESIGN: This is a retrospective case-control study. SETTINGS: This study was conducted at a tertiary academic center. PATIENTS: A prospectively maintained institutional database identified 22 patients with benign complex polyps managed with full-thickness laparoendoscopic excision from 2015 to 2020. These patients were compared with 22 propensity score-matched controls from the same database that underwent laparoscopic segmental colectomy. MAIN OUTCOME MEASURES: Primary outcome was inpatient length of stay. Secondary outcomes included operative details and postoperative morbidities. RESULTS: Full-thickness laparoendoscopic excision was successful in all patients. Patients had a median age of 64 years (41-85), and 82% were men. Final pathology revealed complete excision of benign lesions in 20 of 22 patients and adenocarcinoma in 2 of 22. For the adenocarcinomas, 1 patient underwent subsequent elective colectomy without complications, and 1 patient declined surgery. Propensity score matching was successful for age, sex, BMI, ASA score, colon location, and prior abdominal surgery. Compared with controls, cases had significantly shorter operative time (89.5 minutes (46-290) vs 122 minutes (85-200), p = 0.009), length of stay (1 day (0-17) vs 3 days (1-8), p < 0.001), and reduced blood loss (5 mL (2-15) vs 25 mL (10-150), p < 0.001). Thirty-day morbidity (9.1% vs 27.3%, p = 0.240) was not significantly different. An unplanned 30-day reoperation was performed in 1 patient for suspected small-bowel obstruction. There was 1 mortality due to decompensated cirrhosis in the treatment group. LIMITATIONS: This study was limited by its single-institution retrospective design. CONCLUSIONS: Full-thickness laparoendoscopic excision is safe and successful compared with corresponding segmental colectomy for complex polyps. Favorable postoperative outcomes, including decreased operative time, length of stay, and blood loss, make it a useful approach for managing complex polyps throughout the colon.

Reduction of Opioid Overprescribing and Use Following Standardized Educational Intervention: A Survey of Patient Experiences Following Anorectal Procedures.

BACKGROUND: A pilot study conducted at our institution showed that a significant amount of prescribed postoperative opioids is left unused with the potential for diversion and misuse. OBJECTIVE: This study aimed to evaluate the impact of provider- and patient-targeted educational interventions on postoperative opioid prescription and use following anorectal procedures. DESIGN: Patients were enrolled on July 2019 through March 2020 after implementing educational interventions (study) and were compared with the pilot study group (control) enrolled on August 2018 through May 2019. A telephone survey was conducted 1 week postoperatively. SETTINGS: This study was conducted at a 600-bed, safety-net hospital in southern California. PATIENTS: Adult patients undergoing ambulatory anorectal procedures were included. Patients who had undergone an examination under anesthesia, had been incarcerated, and had used opioids preoperatively were excluded. INTERVENTIONS: Educational interventions were developed based on the pilot study results. Providers received education on recommended opioid prescription quantities and a multimodal pain regimen. Standardized patient education infographics were distributed to patients pre- and postoperatively. MAIN OUTCOME MEASURES: The primary outcomes measured were total opioid prescribed, total opioid consumed, pain control satisfaction levels, and the need for additional opioid prescription. RESULTS: A total of 104 of 122 (85%) patients enrolled responded to the survey and were compared with the 112 patients included in the control group. Despite similar demographics, the study cohort was prescribed fewer milligram morphine equivalents (78.8 ± 11.3 vs 294.0 ± 33.1, p < 0.001), consumed fewer milligram morphine equivalents (23.0 ± 28.0 vs 57.1 ± 45.8, p < 0.001), and had a higher rate of nonopioid medication use (72% vs 10%, p < 0.001). The 2 groups had similar pain control satisfaction levels (4.1 ± 1.3 vs 3.9 ± 1.1 out of 5, p = 0.12) and an additional opioid prescription requirement (5% vs 4%, p = 1.0). LIMITATIONS: This study was limited by its single-center experience with specific patient population characteristics. CONCLUSION: Educational interventions emphasizing evidence-based recommended opioid prescription quantities and regimented multimodal pain regimens are effective in decreasing excessive opioid prescribing and use without compromising satisfactory pain control in patients undergoing ambulatory anorectal procedures. See Video Abstract at http://links.lww.com/DCR/B529. REDUCCIN DE LA SOBREPRESCRIPCIN Y EL USO DE OPIOIDES DESPUS DE UNA INTERVENCIN EDUCATIVA ESTANDARIZADA UNA ENCUESTA DE LAS EXPERIENCIAS EN PACIENTES POSTOPERADOS DE PROCEDIMIENTOS ANORRECTALES: ANTECEDENTES:Un estudio piloto realizado en nuestra institución mostró que una cantidad significativa de opioides posoperatorios recetados no se usa, con potencial de desvío y uso indebido.OBJETIVO:Evaluar el impacto de las intervenciones educativas dirigidas al paciente y al proveedor sobre la prescripción y el uso de opioides posoperatorios después de procedimientos anorrectales.DISEÑO:Los pacientes se incluyeron entre julio de 2019 y marzo de 2020 después de implementar intervenciones educativas (estudio) y se compararon con el grupo de estudio piloto (control) inscrito entre agosto de 2018 y mayo de 2019. Se realizó una encuesta telefónica una semana después de la cirugía.ENTORNO CLÍNICO:Hospital de 600 camas en el sur de California.PACIENTES:Pacientes adultos sometidos a procedimientos anorrectales ambulatorios. Los criterios de exclusión fueron pacientes que recibieron un examen bajo anestesia, pacientes encarcelados y uso preoperatorio de opioides.INTERVENCIONES:Se desarrollaron intervenciones educativas basadas en los resultados del estudio piloto. Los proveedores recibieron educación sobre las cantidades recomendadas de opioides recetados y un régimen multimodal para el dolor. Se distribuyeron infografías estandarizadas de educación para el paciente antes y después de la operación.PRINCIPALES MEDIDAS DE RESULTADO:Opioide total prescrito, opioide total consumido, niveles de satisfacción del control del dolor y necesidad de prescripción adicional de opioides.RESULTADOS:Un total de 104 de 122 (85%) pacientes inscritos respondieron a la encuesta y se compararon con los 112 pacientes incluidos en el grupo de control. A pesar de una demografía similar, a la cohorte del estudio se le prescribió menos miligramos de equivalente de morfina (MME) (78,8 ± 11,3 frente a 294,0 ± 33,1, p <0,001), consumió menos MME (23,0 ± 28,0 frente a 57,1 ± 45,8, p <0,001) y presentaron una mayor tasa de uso de medicamentos no opioides (72% vs 10%, p <0,001). Los dos grupos tenían niveles similares de satisfacción del control del dolor (4,1 ± 1,3 frente a 3,9 ± 1,1 de 5, p = 0,12) y la necesidad de prescripción de opioides adicionales (5% frente a 4%, p = 1,0).LIMITACIONES:Experiencia en un solo centro con características específicas de la población de pacientes.CONCLUSIÓN:Las intervenciones educativas que enfatizan las cantidades recomendadas de prescripción de opioides basadas en la evidencia y los regímenes de dolor multimodales reglamentados son efectivas para disminuir la prescripción y el uso excesivos de opioides sin comprometer el control satisfactorio del dolor en pacientes sometidos a procedimientos anorrectales ambulatorios. Video Resumen en http://links.lww.com/DCR/B529.

Prevalence of mesothelin expression in peritoneal disease from colorectal and appendiceal cancers.

BACKGROUND: Mesothelin is a cell surface glycoprotein overexpressed in 28%-58% of colorectal cancer (CRC). We hypothesized that CRC mesothelin expression contributes to peritoneal spread and that it is selectively overexpressed in those with peritoneal metastasis versus distant metastasis. METHODS: This case-controlled study involved mesothelin immunohistochemistry staining of tumor specimens from patients with metastatic CRC/appendiceal cancers between 2017 and 2019. Staining reactivity was graded from trace to 4+ (low ≤1+; high >1+). Staining patterns were characterized on global (focal/patchy/diffuse) and cellular (apical/cytoplasmic) levels. Immunostaining of normal mesothelial cells served as internal control. RESULTS: Thirty-one patients were identified: 11 peritoneal (study) and 20 distant metastasis (control). The control group did not include appendiceal cancers. The study group had greater proportion of high staining reactivity (55% vs. 5%; odds ratio [OR] = 20.4, 95% confidence interval [CI] 1.96-211.8). The study group had more diffuse (36% vs. 0%; OR = 22.2, 95% CI 1.1-465.3) and cytoplasmic staining patterns (73% vs. 28%; OR = 6.9, 95% CI 1.3-37.2). CONCLUSION: Mesothelin expression is higher in CRC/appendiceal cancers with peritoneal metastasis than those with distant metastasis. Immunohistochemistry staining patterns suggestive of propensity towards peritoneal metastasis include diffuse and cytoplasmic staining. Mesothelin may be a potential target for novel treatments of CRC/appendiceal carcinoma with peritoneal involvement.

LigaSure™ haemorrhoidectomy and the risk of postoperative bleeding.

AIM: LigaSure™ is an electro-surgical device that has increasingly been utilized in haemorrhoid surgery. However, recent literature has highlighted a possible increased risk of delayed postoperative bleeding following LigaSure haemorrhoidectomy (LH). We aim to evaluate the rates of postoperative bleeding following LigaSure compared to Ferguson (closed) haemorrhoidectomy (FH). METHODS: A retrospective cohort study was undertaken at our single academic safety-net county hospital from August 2016 through July 2019 evaluating patients who received FH or LH. Patient demographics, surgical data, postoperative emergency department visit for pain or bleeding within 30 days and resulting transfusion requirement, and rates of readmission and interventions within 30 days were collected. RESULTS: Sixty-one FH and 66 LH patients were identified. The groups had no difference in demographics. The LH group and FH group had similar rates of postoperative emergency department visits (29% vs. 23%, P = 0.454), as well as visits for bleeding (20% vs. 11%, P = 0.204). The average operating time was also significantly shorter with LH (14.5 min vs. 24.9 min, P ≤ 0.001). On multivariate analysis, male sex (OR 7.28, 95% CI 1.88-28.25) and haemorrhoid grade ≤2 (OR 4.64, 95% CI 1.31-16.49) were significantly associated with postoperative bleeding on multivariate analysis. Use of LH was not independently associated with postoperative bleeding risk (OR 1.89, 95% CI 0.70-5.11). CONCLUSIONS: LH and FH have similar risks for postoperative bleeding and other complications. Male sex and haemorrhoid Grades 1 or 2 may be associated with increased postoperative bleeding risk. Excisional haemorrhoidectomy should be undertaken with caution for male patients with lower internal haemorrhoid grades.

Neuraminidase 1-mediated desialylation of the mucin 1 ectodomain releases a decoy receptor that protects against Pseudomonas aeruginosa lung infection.

Pseudomonas aeruginosa (Pa) expresses an adhesin, flagellin, that engages the mucin 1 (MUC1) ectodomain (ED) expressed on airway epithelia, increasing association of MUC1-ED with neuraminidase 1 (NEU1) and MUC1-ED desialylation. The MUC1-ED desialylation unmasks both cryptic binding sites for Pa and a protease recognition site, permitting its proteolytic release as a hyperadhesive decoy receptor for Pa. We found here that intranasal administration of Pa strain K (PAK) to BALB/c mice increases MUC1-ED shedding into the bronchoalveolar compartment. MUC1-ED levels increased as early as 12 h, peaked at 24-48 h with a 7.8-fold increase, and decreased by 72 h. The a-type flagellin-expressing PAK strain and the b-type flagellin-expressing PAO1 strain stimulated comparable levels of MUC1-ED shedding. A flagellin-deficient PAK mutant provoked dramatically reduced MUC1-ED shedding compared with the WT strain, and purified flagellin recapitulated the WT effect. In lung tissues, Pa increased association of NEU1 and protective protein/cathepsin A with MUC1-ED in reciprocal co-immunoprecipitation assays and stimulated MUC1-ED desialylation. NEU1-selective sialidase inhibition protected against Pa-induced MUC1-ED desialylation and shedding. In Pa-challenged mice, MUC1-ED-enriched bronchoalveolar lavage fluid (BALF) inhibited flagellin binding and Pa adhesion to human airway epithelia by up to 44% and flagellin-driven motility by >30%. Finally, Pa co-administration with recombinant human MUC1-ED dramatically diminished lung and BALF bacterial burden, proinflammatory cytokine levels, and pulmonary leukostasis and increased 5-day survival from 0% to 75%. We conclude that Pa flagellin provokes NEU1-mediated airway shedding of MUC1-ED, which functions as a decoy receptor protecting against lethal Pa lung infection.