Immune markers of severe acute pancreatitis.

PURPOSE OF THE REVIEW: Acute pancreatitis is a common acute inflammatory disorder of the pancreas, and its incidence has been increasing worldwide. Approximately 10% of acute pancreatitis progresses to severe acute pancreatitis (SAP), which carries significant morbidity and mortality. Disordered immune response to pancreatic injury is regarded as a key event that mediates systemic injury in SAP. In this article, we review recent developments in immune biomarkers of SAP and future directions for research. RECENT FINDINGS: Given the importance of the NLRP3-inflammasome pathway in mediating systemic inflammatory response syndrome and systemic injury, recent studies have investigated associations of SAP with systemic levels of activators of NLRP3, such as the damage associated molecular patterns (DAMPs) for the first time in human SAP. For example, circulating levels of histones, mitochondrial DNAs, and cell free DNAs have been associated with SAP. A panel of mechanistically relevant immune markers (e.g., panel of Angiopoeitin-2, hepatocyte growth factor, interleukin-8 (IL-8), resistin and sTNF-α R1) carried higher predictive accuracies than existing clinical scores and individual immune markers. Of the cytokines with established relevance to SAP pathogenesis, phase 2 trials of immunotherapies, including tumor necrosis factor (TNF)-alpha inhibition and stimulation of IL-10 production, are underway to determine if altering the immunologic response can reduce the severity of acute pancreatitis (AP). SUMMARY: Circulating systemic levels of various DAMPs and a panel of immune markers that possibly reflect activities of different pathways that drive SAP appear promising as predictive biomarkers for SAP. But larger multicenter studies are needed for external validation. Studies investigating immune cellular pathways driving SAP using immunophenotyping techniques are scarce. Interdisciplinary efforts are also needed to bring some of the promising biomarkers to the bedside for validation and testing for clinical utility. Studies investigating the role of and characterization of altered gut-lymph and gut-microbiota in severe AP are needed.

Alterations in exocrine pancreatic function after acute pancreatitis.

Exocrine pancreatic dysfunction (EPD) is a malabsorptive complication of pancreatic disorders that can lead to a host of symptoms ranging from flatulence to diarrhea and contribute to weight loss and metabolic bone disease. It is increasingly recognized to occur after acute pancreatitis (AP), including episodes with mild severity. The risk of developing EPD after AP is influenced by a range of factors, including the degree of acinar cell destruction and inflammation during AP, and persistent structural derangements following AP. In this article, we discuss the epidemiology, pathophysiology, and clinical management of EPD after AP while highlighting key knowledge gaps.

Development of a novel CT-based index for predicting the number of extracorporeal shockwave lithotripsy (ESWL) sessions required for successful fragmentation of obstructing pancreatic duct stones.

BACKGROUND & AIM: Extracorporeal shock wave lithotripsy (ESWL) is used for the treatment of pancreatic duct stones (PDS) in patients with chronic pancreatitis (CP). We aimed to develop a CT based index to predict the required number of ESWL sessions for technical success. METHODS: We retrospectively evaluated patients with PDS secondary to CP who underwent ESWL. Technical success was defined as the complete fragmentation of stones to <3 mm. CT features including PDS size, number, location, and density in Hounsfield units (HU) were noted. We analyzed the relationship between PDS characteristics and the number of ESWL sessions required for technical success. A multiple linear regression model was used to combine size and density into the pancreatic duct stone (PDS) index that was translated into a web-based calculator. RESULTS: There were 206 subjects (mean age 38.6 ± 13.7 years, 59.2% male) who underwent ESWL. PDS size showed a moderate correlation with the number of ESWL sessions (r = 0.42, p < 0.01). PDS in the head required a fewer number of sessions in comparison to those in the body (1.4 ± 0.6 vs. 1.6 ± 0.7, p = 0.01). There was a strong correlation between PDS density and the number of ESWL sessions (r = 0.617, p-value <0.01). The PDS index {0.3793 + [0.0009755 x PDS density (HU)] + [0.02549 x PDS size (mm)]} could accurately predict the required number of ESWL sessions with an AUC of 0.872 (p < 0.01). CONCLUSION: The PDS index is a useful predictor of the number of ESWL sessions needed for technical success that can help in planning and patient counseling.

Intracystic injection of large surface area microparticle paclitaxel for chemoablation of intraductal papillary mucinous neoplasms: Insights from an expanded access protocol.

AIMS: A novel large surface area microparticle paclitaxel (LSAM-PTX) has unique properties of long retention in cystic spaces while maintaining high drug concentration. We prospectively evaluated the safety and response of EUS-guided fine needle injection (EUS-FNI) of LSAM-PTX to chemoablate branch duct (BD)-IPMNs. METHODS: Subjects diagnosed with BD-IPMNs exhibiting at least one worrisome criteria and considered non-surgical were enrolled in a multicenter clinical trial (NCT03188991) and subsequently included in an Expanded Access Protocol (EAP) where they received EUS-FNI of LSAM-PTX (15 mg/mL). RESULTS: Six BD-IPMNs measuring (mean ± SD) 3.18 ± 0.76 cm in diameter among 5 subjects (mean age: 66 years) were treated by EUS-FNI of LSAM-PTX. A mean of 4 doses of LSAM-PTX (mean dose/cyst: 73 ± 31 mg) were administered, and subjects were followed for up to 32 months. The mean volume reduction/cyst ranged from 42 to 89% (9.58 ± 5.1 ml to 2.2 ± 1.1 ml (p = 0.016)). The mean surface area reduction ranged from 31 to 83% (21.9 ± 8.7 cm2 to 5.7 ± 2.5 cm2 (p = 0.009)). Higher dosing-frequency of EUS-FNI of LSAM-PTX significantly correlated with a reduction in cyst volume (R2 = 0.87, p = 0.03) and surface area (R2 = 0.83, p = 0.04). Comparing pre- and post-ablation samples, molecular analysis of the cyst fluid revealed a loss of IPMN-associated mutations in 5 cases (83.3%), while reemergence was observed in 1 case and persistence in 1 case. Intracystic changes (fibrosis/calcification) were observed in 83.3% (n = 5). One subject developed mild acute pancreatitis (1 of 22 EUS-FNIs of LSAM-PTX). CONCLUSION: In this EAP, EUS-FNI of LSAM-PTX into BD-IPMNs was safe and resulted in volume and surface area reduction, morphological changes, and loss of pathogenic mutations.

Comparison of urological outcomes and quality of life after pelvic exenteration: partial vs radical cystectomy.

OBJECTIVE: To compare perioperative morbidity, functional and quality-of-life (QoL) outcomes in patients with partial cystectomy vs radical cystectomy as part of pelvic exenteration. PATIENTS AND METHODS: Retrospective analysis of a prospectively maintained database of pelvic exenteration patients (1998-2021) was conducted in a single centre. Study outcomes included postoperative complications, quality-of-life, functional and stoma-related outcomes. The 36-item Short-Form Health Survey Physical and Mental Health Components, Functional Assessment of Cancer Therapy-Colorectal questionnaires and Distress Thermometer were available pre- and postoperatively. QoL outcomes were compared at the various time points. Stoma embarrassment and care scores were compared between patients with a colostomy, urostomy, and both. RESULTS: Urological complications were similar between both groups, but patients with partial cystectomy experienced less wound-related complications. Overall, 34/81 (42%) partial cystectomy patients reported one or more long-term voiding complication (i.e., incontinence [17 patients], frequency [six], retention [three], high post-voiding residuals [10], permanent suprapubic catheter/indwelling catheter [14], recurrent urinary tract infection [nine], percutaneous nephrostomy [three], progression to urostomy [three]). The QoL improved following surgery in both the partial and radical cystectomy groups, differences between cohorts were not significant. Patients with two stomas reported higher embarrassment scores than patients with one stoma, although this did not result in more difficulties in stoma care. CONCLUSIONS: Partial cystectomy patients have fewer postoperative wound-related complications than radical cystectomy patients, but often experience long-term voiding issues. The QoL outcomes are similar for both cohorts, with significant improvement following surgery.

Impact of Intraoperative Decision-Making on Pathological Margin Status in Patients Undergoing Pelvic Exenteration for Locally Recurrent Rectal Cancer.

BACKGROUND: A key component of preoperative preparation for pelvic exenteration surgery is the development of an operative plan in a multidisciplinary setting based on the extent of local tumor invasion on preoperative imaging. Changes to the extent of resection or operative plan may occur intraoperatively based on intraoperative findings. OBJECTIVE: To report the frequency and extent of intraoperative deviation from the planned extent of resection during pelvic exenteration for locally recurrent rectal cancer and determine whether this resulted in a more or less radical resection. DESIGN: Retrospective observational study. SETTINGS: A high-volume pelvic exenteration center. PATIENTS: Patients who underwent pelvic exenteration for locally recurrent rectal cancer between January 2015 and December 2020. MAIN OUTCOME MEASURES: Frequency and extent of intraoperative deviation from the planned extent of resection, R0 resection rate. RESULTS: One hundred thirty-six patients underwent pelvic exenteration for locally recurrent rectal cancer, of whom 110 (81%) had R0 resection margins. Twelve patients were excluded because of missing information, and 49 patients (40%) had a change to the operative plan. Operative changes were major in 30 patients (61%), more radical in 40 patients (82%), and margin relevant in 24 patients (49%). In patients in whom there was a change to the operative plan and R0 resection was achieved, the median distance to a relevant margin was 2.5 mm (range, 0.1-10 mm). Of 8 patients with a change in operative plan and R1 resection, 3 were margin relevant, of whom all were considered major, and 2 were more radical and 1 was less radical. LIMITATIONS: Generalizability outside of specialist units may be limited. CONCLUSIONS: Intraoperative changes to the planned extent of resection occur commonly and most often result in an unanticipated major or more radical resection. Such changes may contribute to high rates of R0 resection margins in specialist pelvic exenteration units that use an ultraradical approach in these patients. See Video Abstract . IMPACTO DE LA TOMA DE DECISIONES INTRAOPERATORIA SOBRE EL ESTADO DEL MARGEN PATOLGICO EN PACIENTES SOMETIDOS A EXENTERACIN PLVICA POR RECURRENCIA LOCAL EN CNCER DE RECTO: ANTECEDENTES:Un componente clave de la preparación preoperatoria para exenteración pélvica es el desarrollo de un plan quirúrgico en un entorno multidisciplinario, basado en el grado de invasión tumoral local en las imágenes preoperatorias. Es posible que se produzcan cambios intraoperatorios en la extensión de la resección o en el plan quirúrgico según los hallazgos intraoperatorios.OBJETIVO:Informar la frecuencia y la extensión de la desviación intraoperatoria de la extensión planificada de la resección durante la exenteración pélvica para el cáncer de recto localmente recurrente, y si esto resultó en una resección más o menos radical.DISEÑO:Estudio observacional retrospectivo.ESCENARIO:Un centro de exenteración pélvica de alto volumen.PACIENTES:Pacientes sometidos a exenteración pélvica por cáncer de recto localmente recurrente entre enero de 2015 y diciembre de 2020.PRINCIPALES MEDIDAS DE RESULTADO:Frecuencia y extensión de desviación intraoperatoria de la extensión planeada de resección, tasa de resección R0.RESULTADOS:136 pacientes fueron sometidos a exenteración pélvica por cáncer de recto localmente recurrente, de los cuales 110 (81%) tuvieron márgenes de resección R0. 12 pacientes fueron excluidos por falta de información y 49 pacientes (40%) tuvieron un cambio en el plan quirúrgico. Los cambios operatorios fueron mayores en 30 pacientes (61%), más radicales en 40 pacientes (82%) y con relevancia sobre márgenes en 24 pacientes (49%). En los pacientes en los que hubo un cambio en el plan quirúrgico y se logró la resección R0, la distancia mediana hasta un margen relevante fue de 2.5 mm (rango 0.1-10 mm). De ocho pacientes con un cambio en el plan quirúrgico y resección R1, tres tuvieron relevancia sobre márgenes de los cuales todos se consideraron mayores, dos fueron más radicales y uno fue menos radical.LIMITACIONES:La generalización fuera de las unidades especializadas puede ser limitada.CONCLUSIONES:Los cambios intraoperatorios en la extensión planificada de la resección ocurren comúnmente y con mayor frecuencia resultan en una resección mayor imprevista y más radical. Dichos cambios pueden contribuir a altas tasas de márgenes de resección R0 en unidades especializadas en EP que emplean un enfoque ultrarradical en estos pacientes. (Traducción-Dr. Jorge Silva Velazco ).

Outcomes Following Pelvic Exenteration for Locally Recurrent Rectal Cancer With and Without En Bloc Sacrectomy.

BACKGROUND: Extended radical resection is often the only chance of cure for locally recurrent rectal cancer. Recurrence in the posterior compartment often necessitates en bloc sacrectomy as part of pelvic exenteration to obtain clear resection margins and provide survival benefit. OBJECTIVE: To compare oncological outcomes, morbidity, and quality-of-life outcomes following pelvic exenteration with and without en bloc sacrectomy for recurrent rectal cancer. DESIGN: Comparative cohort study with retrospective analysis of prospectively collected data. SETTING: This study was conducted at a high-volume pelvic exenteration center. PATIENTS: Patients who underwent pelvic exenteration for locally recurrent rectal cancer between 1994 and 2022. MAIN OUTCOME MEASURES: Overall survival, postoperative morbidity, R0 resection margin, and quality-of-life outcomes. RESULTS: Of 965 patients, 305 (31.6%) underwent pelvic exenteration for locally recurrent rectal cancer. Among these patients, 64.3% were men and the median age was 62 years (range, 29-86). One hundred eighty-five patients (60.7%) underwent en bloc sacrectomy, 65 (35.1%) underwent high transection, and 119 (64.3%) had sacrectomy below S2. R0 resection was achieved in 80% of patients with sacrectomy and 72.5% of patients without sacrectomy. Sacrectomy patients experienced more postoperative complications without increased mortality. The median overall survival was 52 months; median survival was 47 months with sacrectomy and 73 months without ( p = 0.059). Quality-of-life scores were not significantly different across physical component ( p = 0.346), mental component ( p = 0.787), or Functional Assessment of Cancer Therapy-Colorectal ( p = 0.679) scores at 24-month follow-up. LIMITATIONS: The generalizability of these findings may be limited outside of subspecialist exenteration units. Selection bias exists in a retrospective analysis. CONCLUSIONS: Patients undergoing pelvic exenteration with and without en bloc sacrectomy for locally recurrent rectal cancer experience similar rates of R0 resection, survival, and quality-of-life outcomes. As R0 remains the most important predictor of survival, the requirement of sacral resection should prompt referral to a subspecialist center that performs sacrectomy routinely. See Video Abstract . RESULTADOS DESPUS DE LA EXENTERACIN PLVICA PARA EL CNCER DE RECTO CON RECURRENCIA LOCAL, CON Y SIN SACRECTOMA EN BLOQUE: ANTECEDENTES:La resección radical ampliada es generalmente la única posibilidad de curación para el cáncer de recto con recurrencia local. La recurrencia en el compartimento posterior generalmente requiere sacrectomía en bloque como parte de la exenteración pélvica para obtener márgenes de resección claros y proporcionar un beneficio de supervivencia.OBJETIVO:Comparar los resultados oncológicos, de morbilidad y de calidad de vida después de la exenteración pélvica con y sin sacrectomía en bloque para el cáncer de recto recurrente.DISEÑO:Estudio de cohorte comparativo con análisis retrospectivo de datos recopilados prospectivamente.AMBIENTE AJUSTE:Estudio realizado en un centro de exenteración pélvica de alto volumen.PACIENTES:Aquellos sometidos a exenteración pélvica por cáncer de recto con recurrencia local entre 1994 y 2022.PRINCIPALES MEDIDAS DE RESULTADO:Supervivencia general, morbilidad posoperatoria, margen de resección R0 y resultados de calidad de vida.RESULTADOS:305 (31,6%) de 965 pacientes se sometieron a exenteración pélvica por cáncer de recto con recurrencia local. El 64,3% de los pacientes eran hombres con una mediana de edad de 62 años (rango 29-86). 185 pacientes (60,7%) fueron sometidos a sacrectomía en bloque, 65 (35,1%) fueron sometidos a transección alta, 119 (64,3%) tuvieron sacrectomía por debajo de S2. La resección R0 se logró en el 80% de los pacientes con sacrectomía y en el 72,5% sin ella. Los pacientes de sacrectomía experimentaron más complicaciones postoperatorias sin aumento de la mortalidad. La mediana de supervivencia global fue de 52 meses, 47 meses con sacrectomía y 73 meses sin sacrectomía ( p = 0,059). Las puntuaciones de calidad de vida no fueron significativamente diferentes entre las puntuaciones del componente físico ( p = 0,346), componente mental ( p = 0,787) o la evaluación funcional de la terapia contra el cáncer - colorrectal ( p = 0,679) a los 24 meses de seguimiento.LIMITACIONES:La generalización de estos hallazgos puede estar limitada fuera de las unidades de exenteración de subespecialistas. Existe un sesgo de selección en un análisis retrospectivo.CONCLUSIONES:Los pacientes sometidos a exenteración pélvica con y sin sacrectomía en bloque por cáncer de recto con recurrencia local experimentan tasas similares de resección R0, supervivencia y resultados de calidad de vida. Como R0 sigue siendo el predictor más importante de supervivencia, la necesidad de resección sacra debe provocar la derivación a un centro subespecialista que realice sacrectomía de forma rutinaria. (Traducción-Dr. Fidel Ruiz Healy ).

A Review on Endoscopic Management of Acute Cholecystitis: Endoscopic Ultrasound-Guided Gallbladder Drainage and Endoscopic Transpapillary Gallbladder Drainage.

A percutaneous cholecystostomy tube (PCT) is the conventionally favored nonoperative intervention for treating acute cholecystitis. However, PCT is beset by high adverse event rates, need for scheduled reintervention, and inadvertent dislodgement, as well as patient dissatisfaction with a percutaneous drain. Recent advances in endoscopic therapy involve the implementation of endoscopic transpapillary drainage (ETP-GBD) and endoscopic ultrasound-guided gallbladder drainage (EUS-GBD), which are increasingly preferred over PCT due to their favorable technical and clinical success combined with lower complication rates. In this article, we provide a comprehensive review of the literature on EUS-GBD and ETP-GBD, delineating instances when clinicians should opt for endoscopic management and highlighting potential risks associated with each approach.

Relationship of circulating levels of long-chain fatty acids to persistent organ failure in acute pancreatitis.

During acute pancreatitis (AP), free fatty acids (FFAs) are liberated from circulating triglycerides (TG) and injured adipocytes by pancreatic lipase. Circulating FFAs have been suspected as a source of systemic lipotoxicity in AP. However, assessment of FFAs is difficult and time-consuming, and little is known about relative levels of FFAs between patients with different severities of AP and controls. This study's aims were to assess early circulating levels of FFAs, (both saturated and unsaturated) in patients with AP vs. controls, and associations between FFA levels and AP severity. Serum samples from patients with AP were collected at enrollment (day 1 of hospital stay); serum samples were also collected from controls. FFAs including palmitic, palmitoleic, stearic, oleic, and linoleic acid were extracted and quantitated using gas chromatography separation. Severity of AP was determined by Revised Atlanta Classification. Differences in FFA levels and percentages of total FFAs were assessed between patients with AP and controls and patients with AP of different severity grades. A total of 93 patients with AP (48 female, 52%) and 29 controls (20 female, 69%) were enrolled. Of the patients with AP, 74 had mild/moderate and 19 had severe AP. Serum levels of all FFAs except stearic acid were significantly higher in patients with AP compared with controls. A strong and independent association between elevated palmitoleic acid levels and severe AP was found. Serum unsaturated FFA levels, specifically palmitoleic acid, appear to correlate with severe AP. These findings have potential clinical implications for targeted AP therapies.NEW & NOTEWORTHY Drivers of the inflammatory response in acute pancreatitis remain incompletely understood. Unsaturated fatty acids, specifically palmitoleic, appear to have an association with more severe acute pancreatitis. This finding presents a new clinical understanding of fatty acid toxicity and highlights a potential future target for treatment in severe acute pancreatitis.

Improving Surgical Outcomes in Pelvic Exenteration Surgery: Comparison of Prone Sacrectomy With Anterior Cortical Sacrectomy Techniques.

OBJECTIVE: To assess the effect of changing our sacrectomy approach from prone to anterior on surgical and oncological outcomes. BACKGROUND: In patients with advanced pelvic malignancy involving the sacrum, pelvic exenteration (PE) with en-bloc sacrectomy is the only potential curative option but morbidity is high. Over time sacrectomy techniques have evolved from prone sacrectomy (PS) to abdominolithotomy sacrectomy (ALS, ≤S3) and high anterior cortical sacrectomy (HACS, >S3) to optimize surgical outcomes. METHODS: A retrospective, single institution analysis of prospectively collected data for patients undergoing PE with en-bloc sacrectomy between 1994 and 2021 was performed. RESULTS: A total of 363 patients were identified and divided into PS (n=77, 21.2%), ALS (n=247, 68.0%), and HACS (n=39, 10.7%). Indications were: locally advanced (n=92) or recurrent (n=177) rectal cancer, primary other (n=31), recurrent other (n=60), and benign disease (n=3). PS resulted in longer operating time ( P <0.01) and more blood loss ( P <0.01). Patients with HACS had more major nerve (87.2%) and vascular (25.6%) resections ( P <0.01). Vertical rectus abdominis myocutaneous flap repair was less common following HACS (7.7%) than ALS (25.5%) and PS (27.3%) ( P =0.040). R0 rate was 80.8%, 65.8%, and 76.9% following ALS, PS, and HACS, respectively ( P =0.024). Wound-related complications and re-operations were significantly reduced following ALS and HACS compared with PS. CONCLUSIONS: Changing our practice from PS to an anterior approach with ALS or HAS has been safe and improved overall surgical and perioperative outcomes, while maintaining good oncological outcomes. Given the improved perioperative and surgical outcomes, it would be important for surgeons to learn and adopt the anterior sacrectomy approaches.

Lactated Ringers Use in the First 24 Hours of Hospitalization Is Associated With Improved Outcomes in 999 Patients With Acute Pancreatitis.

INTRODUCTION: Recent pilot trials in acute pancreatitis (AP) found that lactated ringers (LR) usage may result in decreased risk of moderately severe/severe AP compared with normal saline, but their small sample sizes limit statistical power. We investigated whether LR usage is associated with improved outcomes in AP in an international multicenter prospective study. METHODS: Patients directly admitted with the diagnosis of AP were prospectively enrolled at 22 international sites between 2015 and 2018. Demographics, fluid administration, and AP severity data were collected in a standardized prospective manner to examine the association between LR and AP severity outcomes. Mixed-effects logistic regression analysis was performed to determine the direction and magnitude of the relationship between the type of fluid administered during the first 24 hours and the development of moderately severe/severe AP. RESULTS: Data from 999 patients were analyzed (mean age 51 years, female 52%, moderately severe/severe AP 24%). Usage of LR during the first 24 hours was associated with reduced odds of moderately severe/severe AP (adjusted odds ratio 0.52; P = 0.014) compared with normal saline after adjusting for region of enrollment, etiology, body mass index, and fluid volume and accounting for the variation across centers. Similar results were observed in sensitivity analyses eliminating the effects of admission organ failure, etiology, and excessive total fluid volume. DISCUSSION: LR administration in the first 24 hours of hospitalization was associated with improved AP severity. A large-scale randomized clinical trial is needed to confirm these findings.

Incident diabetes following acute pancreatitis in a multicenter prospective observational cohort.

Diabetes mellitus following an episode of acute pancreatitis (AP) is an increasingly discussed complication, but there are sparse prospective data on the incidence and risk factors. We evaluated data from a prospective, multicenter observational cohort study that enrolled adults hospitalized with AP between 2017 and 2021 and followed them for one year. Ninety-eight participants who completed 12-month follow-up were included in this analysis. Diabetes status was assessed using a combination of measured glycated hemoglobin (HbA1c) at predetermined time intervals or physician diagnosis. In 68 participants without diabetes at enrollment, the cumulative incidence of new-onset diabetes was 4.4 % (n = 3) at 3 months and 10.3 % (n = 7) at 12 months. No differences were observed in demographic or pancreatitis-related characteristics between those who did versus did not develop diabetes, in part due to small sample size. In summary, new-onset diabetes was identified in approximately 10 % within one year after an episode of AP. Larger prospective studies are needed to further define the incidence, risk factors, and mechanisms of diabetes and pre-diabetes following AP. NCT03063398.

Structured training program on confocal laser endomicroscopy for pancreatic cystic lesions: a multicenter prospective study among early-career endosonographers (with video).

BACKGROUND AND AIMS: Data on how to teach endosonographers needle-based confocal laser endomicroscopy (nCLE)-guided histologic diagnosis of pancreatic cystic lesions (PCLs) are limited. Hence, we developed and tested a structured educational program to train early-career endosonographers in nCLE-guided diagnosis of PCLs. METHODS: Twenty-one early-career nCLE-naïve endosonographers watched a teaching module outlining nCLE criteria for diagnosing PCLs. Participants then reviewed 80 high-yield nCLE videos, recorded diagnoses, and received expert feedback (phase 1). Observers were then randomized to a refresher feedback session or self-learning at 4 weeks. Eight weeks after training, participants independently assessed the same 80 nCLE videos without feedback and provided histologic predictions (phase 2). Diagnostic performance of nCLE to differentiate mucinous versus nonmucinous PCLs and to diagnose specific subtypes were analyzed using histopathology as the criterion standard. Learning curves were determined using cumulative sum analysis. RESULTS: Accuracy and diagnostic confidence for differentiating mucinous versus nonmucinous PCLs improved as endosonographers progressed through nCLE videos in phase 1 (P < .001). Similar trends were observed with the diagnosis of PCL subtypes. Most participants achieved competency interpreting nCLE, requiring a median of 38 assessments (range, 9-67). During phase 2, participants independently differentiated PCLs with high accuracy (89%), high confidence (83%), and substantial interobserver agreement (κ = .63). Accuracy for nCLE-guided PCL subtype diagnoses ranged from 82% to 96%. The learned nCLE skills did not deteriorate at 8 weeks and were not impacted by a refresher session. CONCLUSIONS: We developed a practical, effective, and durable educational intervention to train early-career endosonographers in nCLE-guided diagnosis of PCLs.

Pelvic Exenteration for Squamous Cell Carcinoma of the Anus: Oncological, Morbidity, and Quality-of-Life Outcomes.

BACKGROUND: Salvage surgery is the only potentially curative treatment option for recurrent squamous cell carcinoma of the anus. Where adjacent pelvic viscera, soft tissues, and bone are involved, pelvic exenteration with a wide perineal excision may be required to ensure clear surgical margins and increase the likelihood of long-term survival. OBJECTIVE: To report oncological, morbidity, and quality-of-life outcomes of pelvic exenteration for anal squamous cell carcinoma. DESIGN: Cohort study with retrospective analysis of prospectively collected data. SETTINGS: This study was conducted at a high-volume pelvic exenteration center. PATIENTS: Those who underwent pelvic exenteration for anal squamous cell carcinoma between 1994 and 2022. MAIN OUTCOME MEASURES: Local recurrence-free and overall survival, intraoperative and postoperative complication rates, R0 resection rate, and long-term quality-of-life outcomes. RESULTS: Of 958 patients who underwent pelvic exenteration, 66 (6.9%) had anal squamous cell carcinoma. Thirty-two patients (48.5%) were male and the median age was 57 years (range, 31-79). Ten patients (15%) had primary anal squamous cell carcinoma, 49 (74%) had a recurrent tumor, and 7 (11%) had a re-recurrent tumor. Twenty-two patients (33%) and 16 patients (24%) had a major complication and unplanned return to the operating theater, respectively. Of the 62 patients who underwent pelvic exenteration with curative intent, 50 (81%) had R0 resection, and the 5-year overall and local recurrence-free survival rates were 41% and 37%, respectively. R0 resection was associated with a higher 5-year overall survival (50% vs 8%, p < 0.001). The mental health component scores and several individual quality-of-life domains presented improved trajectories postoperatively (all p values <0.05). LIMITATIONS: The generalizability of the findings outside specialist pelvic exenteration centers may be limited. CONCLUSIONS: Morbidity, long-term survival, and quality-of-life outcomes after pelvic exenteration for anal squamous cell carcinoma are comparable to published outcomes of pelvic exenteration for other tumor types. EXENTERACIN PLVICA POR CARCINOMA EPIDERMOIDE DE ANO RESULTADOS ONCOLGICOS, DE MORBILIDAD Y DE CALIDAD DE VIDA: ANTECEDENTES:La cirugía de rescate es la única opción de tratamiento potencialmente curativa para el carcinoma de células escamosas del ano recurrente. Cuando están involucradas vísceras pélvicas, tejidos blandos y huesos adyacentes, puede ser necesaria una exenteración pélvica con una escisión perineal amplia para asegurar márgenes quirúrgicos claros y aumentar la probabilidad de supervivencia a largo plazo.OBJETIVO:Informar sobre los resultados oncológicos, de morbilidad y de calidad de vida de la exenteración pélvica por carcinoma anal de células escamosas.DISEÑO:Estudio de cohortes con análisis retrospectivo de datos recogidos prospectivamente.ENTORNO CLINICO:Este estudio se realizó en un centro de exenteración pélvica de alto volumen.PACIENTES:Aquellos que se sometieron a exenteración pélvica por carcinoma anal de células escamosas entre 1994 y 2022.PRINCIPALES MEDIDAS DE VALORACIÓN:Supervivencia global y libre de recidiva local, tasas de complicaciones intraoperatorias y posoperatorias, tasa de resección R0 y resultados de calidad de vida a largo plazo.RESULTADOS:De 958 pacientes que se sometieron a exenteración pélvica, 66 (6,9%) tenían carcinoma anal de células escamosas. 32 pacientes (48,5%) eran varones y la mediana de edad fue de 57 años (rango 31-79). 10 pacientes (15%) tenían carcinoma anal primario de células escamosas, 49 (74%) tenían un tumor recurrente y 7 (11%) tenían una segunda recurrencia. 22 (33%) y 16 pacientes (24%) tuvieron una complicación mayor y regreso no planificado al quirófano, respectivamente. De los 62 pacientes que se sometieron a una exenteración pélvica con intención curativa, 50 (81%) tuvieron una resección R0, las tasas de supervivencia global y libre de recidiva local a los 5 años fueron del 41% y el 37%, respectivamente. La resección R0 se asoció con una mayor supervivencia general a los 5 años (50% frente a 8%, p < 0,001). Las puntuaciones del componente de salud mental y varios dominios de calidad de vida individuales presentaron trayectorias mejoradas después de la operación (todos los valores de p < 0,05).LIMITACIONES:La generalización de los hallazgos fuera de los centros especializados en exenteración pélvica puede ser limitada.CONCLUSIONES:Los resultados de morbilidad, supervivencia a largo plazo y calidad de vida después de la EP para el carcinoma anal de células escamosas son comparables a los resultados publicados de la exenteración pélvica para otros tipos de tumores. (Traducción-Dr. Ingrid Melo ).

Severe acute pancreatitis exhibits distinct cytokine signatures and trajectories in humans: a prospective observational study.

Severe acute pancreatitis (SAP) is associated with substantial morbidity and mortality. Several cytokines have been identified to have pathophysiological significance in SAP, but studies characterizing their early trajectories are lacking. Here we characterize the early trajectories of seven key cytokines associated with SAP and compare them with non-SAP subjects. Five proinflammatory cytokines (angiopoietin-2, interleukin-6, interleukin-8, monocyte chemoattractant protein-1, resistin) and two anti-inflammatory cytokines (hepatocyte growth factor, and soluble tumor necrosis factor-α receptor-1A) were measured in a prospective cohort of acute pancreatitis subjects (2012-2016) at the time of enrollment and then every 24 h for 5 days or until discharge. The cytokines' levels and trajectories were calibrated based on date of pain onset and were compared between healthy controls and three severity categories (mild, moderate, and severe). The cohort (n = 170) consisted of 27 healthy controls, 65 mild, 38 moderate, and 40 SAP. From day 1 of symptom onset, SAP subjects exhibited significantly higher levels of both pro- and anti-inflammatory cytokines compared with non-SAP and healthy subjects. But in SAP subjects, all proinflammatory cytokines' levels trended downward after day 2 (except for a flat slope for angiopoeitin-2) whereas for non-SAP subjects, the trajectory was upward: this trajectory difference between SAP versus non-SAP subjects resulted in narrowing of the differences initially seen on day 1 for proinflammatory cytokines. For anti-inflammatory cytokines, the trajectories were uniformly upward for both SAP and non-SAP subjects. Proinflammatory cytokine response is an early and time-sensitive event in SAP that should be accounted for when designing future biomarker studies and/or therapeutic trials.NEW & NOTEWORTHY In this study, we showed that the proinflammatory cytokine response in SAP is an early event, with subsequent downregulation of proinflammatory cytokines beginning at day 1 of symptom onset. Our findings underscore the importance of enrolling subjects very early in the disease course when conducting studies to investigate early immune events of SAP; this current study also serves as an important reference for the design of future biomarker studies and therapeutic trials in SAP.

The Modified Pancreatitis Activity Scoring System Shows Distinct Trajectories in Acute Pancreatitis: An International Study.

BACKGROUND & AIMS: The aims of this study were to: (1) assess the performance of the Pancreatitis Activity Scoring System (PASS) in a large intercontinental cohort of patients with acute pancreatitis (AP); and (2) investigate whether a modified PASS (mPASS) yields a similar predictive accuracy and produces distinct early trajectories between severity subgroups. METHODS: Data was prospectively collected through the Acute Pancreatitis Patient Registry to Examine Novel Therapies In Clinical Experience (APPRENTICE) consortium (2015-2018) involving 22 centers from 4 continents. AP severity was categorized per the revised Atlanta classification. PASS trajectories were compared between the three severity groups using the generalized estimating equations model. Four mPASS models were generated by modifying the morphine equivalent dose (MED), and their trajectories were compared. RESULTS: A total of 1393 subjects were enrolled (median age, 49 years; 51% males). The study cohort included 950 mild (68.2%), 315 (22.6%) moderately severe, and 128 (9.2%) severe AP. Mild cases had the lowest PASS at each study time point (all P < .001). A subset of patients with outlier admission PASS values was identified. In the outlier group, 70% of the PASS variation was attributed to the MED, and 66% of these patients were from the United States centers. Among the 4 modified models, the mPASS-1 (excluding MED from PASS) demonstrated high performance in predicting severe AP with an area under the receiver operating characteristic curve of 0.88 (vs area under the receiver operating characteristic of 0.83 in conventional PASS) and produced distinct trajectories with distinct slopes between severity subgroups (all P < .001). CONCLUSION: We propose a modified model by removing the MED component, which is easier to calculate, predicts accurately severe AP, and maintains significantly distinct early trajectories.

The relationship between pre-existing diabetes mellitus and the severity of acute pancreatitis: Report from a large international registry.

BACKGROUND/OBJECTIVES: The relationship between pre-existing diabetes mellitus (DM) and acute pancreatitis (AP) severity has not been established. We assessed the impact of pre-existing DM on AP severity in an international, prospectively ascertained registry. METHODS: APPRENTICE registry prospectively enrolled 1543 AP patients from 22 centers across 4 continents (8 US, 6 Europe, 5 Latin America, 3 India) between 2015 and 2018, and collected detailed clinical information. Pre-existing DM was defined a diagnosis of DM prior to AP admission. The primary outcome was AP severity defined by the Revised Atlanta Classification (RAC). Secondary outcomes were development of systemic inflammatory response syndrome (SIRS) or intensive care unit (ICU) admission. RESULTS: Pre-existing DM was present in 270 (17.5%) AP patients, of whom 252 (93.3%) had type 2 DM. Patients with pre-existing DM were significantly (p < 0.05) older (55.8 ± 16 vs. 48.3 ± 18.7 years), more likely to be overweight (BMI 29.5 ± 7 vs. 27.2 ± 6.2), have hypertriglyceridemia as the etiology (15% vs. 2%) and prior AP (33 vs. 24%). Mild, moderate, and severe AP were noted in 66%, 23%, and 11% of patients, respectively. On multivariable analysis, pre-existing DM did not significantly impact AP severity assessed by the RAC (moderate-severe vs. mild AP, OR = 0.86, 95% CI 0.63-1.18; severe vs. mild-moderate AP, OR = 1.05, 95% CI, 0.67-1.63), development of SIRS, or the need for ICU admission. No interaction was noted between DM status and continent. CONCLUSION: About one in 5 patients with AP have pre-existing DM. Once confounding risk factors are considered, pre-existing DM per se is not a risk factor for severe AP.

Long-term surgical complications following pelvic exenteration: Operative management of the empty pelvis syndrome.

AIM: Pelvic exenteration (PE) has become the standard of care for locally advanced and recurrent rectal cancer. The high short-term morbidity reported from this procedure is well established; however, longer term complications of such radical surgery and their management have not been fully addressed. This study aimed to investigate the incidence, indications and outcomes of long-term (more than 90-day) reoperative surgery in this group of patients, with a focus on the empty pelvis syndrome (EPS). METHODS: Clinical data were extracted from a prospectively maintained database, with additional data pertaining to indications, operative details and outcomes of reoperative surgery obtained from electronic medical records. Patients were excluded if reoperative surgery was endoscopic or radiologically guided, was for the investigation or treatment of recurrent disease, or was clearly unrelated to previous surgery. RESULTS: Of 716 patients who underwent PE, 75 (11%) required 101 reoperative abdominal or perineal procedures, 52 (51%) of which were in 40 (6%) patients for complications of EPS. This group were more likely to have undergone a total PE (65% vs. 43%; P < 0.01) with either major bony (70% vs. 50%; P < 0.01) and/or nerve (40% vs. 25%; P = 0.03) resections at index exenteration. The patho-anatomy, surgical management and outcomes of these patients are described herein, considering separately complications of entero-cutaneous fistula, entero-perineal fistula, small bowel obstruction and local management of perineal wound complications. CONCLUSION: Six per cent of PE patients will require re-intervention for the management of EPS. Reliable strategies for preventing EPS remain elusive; however, surgical management is feasible with acceptable short-term outcomes with the optimum strategy to be selected on an individual patient basis.

The antigenic link between thyroid autoimmunity and breast cancer.

The association between breast cancer and benign thyroid disorders, in particular thyroid autoimmunity, has been debated for decades. Autoantibodies to thyroid peroxidase, the hallmark of thyroid autoimmunity, have a higher prevalence among patients with breast cancer compared with the general population. Furthermore a correlation between their positivity and a better prognosis of breast cancer was found in several independent small-scale studies, even if such observation was not confirmed in a subsequent retrospective study conducted on the largest patient cohort to date. The thyroid and mammary glands present several biological similarities, therefore the hypothesis of an immune response to shared thyroid/breast antigens could in part explain the association between thyroid autoimmunity and breast cancer. The sodium iodide symporter is expressed in both glands, however it seems unlikely to be the key common antigen, considering that autoantibodies targeting it are rare. Instead thyroid peroxidase, one of the major thyroid autoantigens, is also expressed in breast tissue and therefore represents the main antigenic link between thyroid autoimmunity and breast cancer. Furthermore lactoperoxidase, an enzyme of the same family that shares structural similarities with thyroid peroxidase, is expressed in neoplastic breast cells and is responsible for the cross-reactivity with some autoantibodies to thyroid peroxidase. Novel strategies for the diagnosis and treatment of breast cancer might take advantage of the antigenic link between thyroid and breast tissues.

Sciatic and Femoral Nerve Resection During Extended Radical Surgery for Advanced Pelvic Tumours: Long-term Survival, Functional, and Quality-of-life Outcomes.

OBJECTIVE: To report survival, functional, and quality-of-life (QoL) outcomes after extended radical resection for advanced pelvic tumors with en bloc sciatic or femoral nerve resection. BACKGROUND: Advanced pelvic tumors involving the sciatic or femoral nerve have traditionally been considered inoperable. Small studies have suggested acceptable functional outcomes can be achieved after pelvic exenteration with en bloc sciatic nerve resection. METHOD: Consecutive patients who underwent extended radical pelvic surgery with en bloc resection of the sciatic or femoral nerves at a single center were included. RESULTS: Of 713 radical pelvic resections, 68 patients (9.5%) had en bloc sciatic or femoral nerve resection. Complete sciatic, partial sciatic, and complete femoral nerve resection was performed in 26 (38%), 38 (56%), and 4 patients (6%), respectively. Overall and major postoperative complication rates were 63% and 40%, respectively. R0 resection was achieved in 65% of patients, which translated to 55% and 76% overall and local recurrence-free 5-year survival in those with colorectal cancer. Twenty-two (96%) and 25 (92%) patients could mobilize independently after complete and partial sciatic nerve resection, respectively. Physical QoL was significantly lower at 6 months after surgery compared with baseline (P = 0.041), but returned to baseline at 12 months (P = 0.163). There was no difference in mental or overall QoL at 6 or 12 months compared with baseline. CONCLUSION: En bloc sciatic and femoral nerve resection can be performed during extended radical pelvic resections with morbidity and survival outcomes comparable with existing exenteration literature, including in patients with recurrent rectal cancer. Physical QoL may be impaired after surgery, but returns to baseline by 12 months.