Implementation and outcomes in benign gynecological surgery with HUGO™ RAS system 12 months initial experience.

We share our experience with the Hugo™ Robotic-Assisted Surgery system in benign gynecological surgeries. We retrospectively analyzed patients who underwent elective robotic surgeries for benign gynecological conditions at our surgical center from February 2023 to February 2024. Data collected included patient demographics, surgery indications, and outcomes. Perioperative data on port-placement time, arm configurations, docking, and console time were documented. Procedural outcome data including troubleshooting and overall satisfaction were also recorded. The primary outcome was perioperative data on port placement, docking time, arm configuration, and console time. The secondary outcome was defined as team satisfaction, system troubleshooting, arm repositioning, and complications graded 3-4 on the Clavien-Dindo Scale. A total of 60 patients underwent procedures for benign gynecological conditions using the Hugo™ RAS over the 12-month study period, primarily for pelvic endometriosis (53%), hysterectomies (27%), and adnexal surgery (10%). The mean port-placement time was 13 min and 41 s. In 31% of cases, low-port placement was used, with arm positioning being asymmetrical in 63% and symmetrical in 37%, demonstrating the system's flexibility in customizing port configurations while optimizing cosmetic outcomes. Docking time averaged 5 min and 51 s, and console time was 1 h and 5 min. Operational challenges included arm tremors and limited workspace for the assistant. This study details our knowledge using the Hugo™ RAS. Learning curves of port placement, arm positioning, docking, and procedure time can be rapidly adapted in a well-trained team. Our experience suggests the technology is still in its learning curve period.

What Predicts Complete Response to Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer?

BACKGROUND: Total neoadjuvant therapy in treatment of stage II-III rectal cancer involves administration of either induction or consolidation chemotherapy with chemoradiation before surgery. Total neoadjuvant therapy is associated with increased complete response rate, which is defined as the proportion of patients who either had pathological complete response after surgery or sustained clinical complete response at least for a year under surveillance. OBJECTIVE: To identify the predictors of complete response to total neoadjuvant therapy and compare different diagnostic tools in predicting complete response. DESIGN: Retrospective cohort study. SETTINGS: A single tertiary-care center. PATIENTS: Stage II-III rectal cancer patients who were diagnosed between January 2015 and December 2021. INTERVENTION: Total neoadjuvant therapy. MAIN OUTCOME MEASURES: Complete response rate, predictors of complete response, sensitivity and specificity of sigmoidoscopy and MRI in predicting complete response. RESULTS: One hundred nineteen patients (mean age 56 [±11.3] years, 47 [39.5%] female, 100 [84%] stage III rectal cancer were included. Median tumor size was 5.1 (4-6.5) cm, 63 (52.9%) were low rectal tumors. Twenty-one (17.6%) patients had extramural vascular invasion, 62 (52.1%) had elevated carcinoembryonic antigen at baseline. One hundred eight (90.8%) patients received consolidation chemotherapy. After total neoadjuvant therapy, 88 (73.9%) out of 119 patients underwent surgery, of whom 20 (22.7%) had pathological complete response. Thirty-one (26.1%) patients underwent watch-and-wait, of whom 24 (77.4%) had sustained clinical complete response. Overall complete response rate was 37%. Low rectal tumors (OR 2.6 [95% CI, 1.1-5.9], p = 0.02) and absence of EMVI [OR 5.4 (95% CI, 1.2-25.1), p = 0.01] were predictors of complete response. In predicting complete response, sigmoidoscopy was more sensitive (76.0% vs. 62.5%) and specific (72.5% vs. 69.2%) than MRI. The specificity further increased when 2 techniques were combined (82.5%). LIMITATIONS: Retrospective study. CONCLUSIONS: Complete response rate after total neoadjuvant therapy was 37%. Low rectal tumors and absence of extramural vascular invasion were predictors of complete response. Sigmoidoscopy was better in predicting incomplete response, whereas combination (MRI and sigmoidoscopy) was better in predicting complete response.

Close margin of adverse histologic factors with a negative primary tumor margin is not associated with increased locoregional recurrence in colon cancer.

PURPOSE: Locoregional recurrence after resection of colon cancer is increased when primary tumor margin is positive (<1 â€‹mm). Data is limited regarding the risk of locoregional recurrence with close margin (<1 â€‹mm) of histologic factors, such as intravascular tumor, intranodal tumor, tumor deposits, or extranodal extension. We hypothesized that close margin of these factors doesn't affect locoregional recurrence. METHODS: A retrospective review of all colon cancer surgical resections for adenocarcinoma from 2007 to 2020 was performed. Inclusion criteria were specimens with a negative primary tumor margin but a close margin of adverse histologic factors, defined as intravascular tumor, intranodal tumor, tumor deposits, or extranodal extension within 1 â€‹mm of a mesenteric or circumferential margin. RESULTS: Among 4435 pathology reports reviewed, 45 (1 â€‹%) of cases met inclusion criteria. Average follow-up was 38 months. The adverse histologic factor was identified as intranodal tumor in 24 (53 â€‹%) cases, intravascular tumor in 8 (17.8 â€‹%), tumor deposits in 5 (11.1 â€‹%), and more than one pathologic feature in 6 (13.3 â€‹%). There were 9 (20 â€‹%) recurrences; 6 (13 â€‹%) had distant recurrences only, 2 (4 â€‹%) patients had locoregional recurrences only, and 1 (2 â€‹%) patient had both locoregional and distant recurrence. The adverse histologic factor in these three patients was intravascular in two and both intravascular and intranodal in one. CONCLUSION: Based on our results, we do not have evidence that the presence of intravascular tumor, intranodal tumor, tumor deposits, or extranodal extension within 1 â€‹mm of a mesenteric or circumferential margin is associated with increased risk of locoregional recurrence.

Segmental Colectomy in Ulcerative Colitis.

BACKGROUND: Segmental colectomy in ulcerative colitis is performed in select patients who may be at increased risk for postoperative morbidity. OBJECTIVE: To identify patients with ulcerative colitis who underwent segmental colectomy and assess their postoperative and long-term outcomes. DESIGN: Retrospective case series. SETTING: A tertiary care IBD center. PATIENTS: Patients with ulcerative colitis who underwent surgery between 1995 and 2022. INTERVENTION: Segmental colectomy. MAIN OUTCOME MEASURES: Postoperative complications, early and late colitis, metachronous cancer development, completion proctocolectomy-free survival rates, and stoma at follow-up. RESULTS: Fifty-five patients were included (20 [36.4%] women; age 67.8 (57.4-77.1) years at surgery; BMI 27.7 (24.2-31.1) kg/m 2 ; median follow-up 37.3 months). Thirty-two patients (58.2%) had ASA score of 3, 48 (87.3%) had at least 1 comorbidity, and 48 (87.3%) had Mayo endoscopic subscores of 0 to 1. Patients underwent right hemicolectomy (n = 28; 50.9%), sigmoidectomy (n = 17; 30.9%), left hemicolectomy (6; 10.9%), low anterior resection (n = 2; 3.6%), or a nonanatomic resection (n = 2; 3.6%) for endoscopically unresectable polyps (n = 21; 38.2%), colorectal cancer (n = 15; 27.3%), symptomatic diverticular disease (n = 13; 23.6%), and stricture (n = 6; 10.9%). Postoperative complications occurred in 16 patients (29.1%; n = 7 [12.7%] Clavien-Dindo class III-V). Early and late postoperative colitis rates were 9.1% and 14.5%, respectively. Metachronous cancer developed in 1 patient. Four patients (7.3%) underwent subsequent completion proctocolectomy with ileostomy. Six patients (10.9%) had a stoma at follow-up. Two- and 5-year completion proctocolectomy-free survival rates were 91% and 88%, respectively. LIMITATIONS: Retrospective study and small sample size. CONCLUSIONS: Segmental colectomy in ulcerative colitis is associated with low postoperative complication rates, symptomatic early colitis and late colitis rates, metachronous cancer development, and the need for subsequent completion proctocolectomy. Therefore, it can be safe to consider select patients, such as the elderly with quiescent colitis and other indications, for colectomy. See Video Abstract . COLECTOMA SEGMENTARIA EN LA COLITIS ULCEROSA: ANTECEDENTES:La colectomía segmentaria en la colitis ulcerosa se realiza en pacientes seleccionados que pueden tener un mayor riesgo de morbilidad posoperatoria.OBJETIVO:Identificar pacientes con colitis ulcerosa sometidos a colectomía segmentaria y evaluar sus resultados postoperatorios y a largo plazo.DISEÑO:Serie de casos retrospectivos.AMBIENTE:Un centro de atención terciaria para enfermedades inflamatorias intestinales.PACIENTES:Pacientes con colitis ulcerosa intervenidos quirúrgicamente entre 1995 y 2022.INTERVENCIÓN(S):Colectomía segmentaria.PRINCIPALES MEDIDAS DE RESULTADO:Complicaciones postoperatorias, colitis temprana y tardía, desarrollo de cáncer metacrónico, tasas de supervivencia sin proctocolectomía completa y estoma en el seguimiento.RESULTADOS:Se incluyeron cincuenta y cinco pacientes [20 (36,4%) mujeres; 67,8 (57,4-77,1) años de edad al momento de la cirugía; índice de masa corporal 27,7 (24,2-31,1) kg/m2; mediana de seguimiento 37,3 meses]. La puntuación ASA fue III en 32 (58,2%) pacientes, 48 (87,3%) tenían al menos una comorbilidad y 48 (87,3%) tenían una subpuntuación endoscópica de Mayo de 0-1. Los pacientes fueron sometidos a hemicolectomía derecha (28, 50,9%), sigmoidectomía (17, 30,9%), hemicolectomía izquierda (6, 10,9%), resección anterior baja (2, 3,6%) o resección no anatómica (2, 3,6%) para; pólipos irresecables endoscópicamente (21, 38,2%), cáncer colorrectal (15, 27,3%), enfermedad diverticular sintomática (13, 23,6%) y estenosis (6, 10,9%). Se produjeron complicaciones postoperatorias en 16 (29,1%) pacientes [7 (12,7%) Clavien-Dindo Clase III-V]. Las tasas de colitis posoperatoria temprana y tardía fueron del 9,1% y el 14,5%, respectivamente. Un paciente desarrolló cáncer metacrónico. A 4 (7,3%) pacientes se les realizó posteriormente proctocolectomía completa con ileostomía. Seis (10,9%) pacientes tenían estoma en el seguimiento. Las tasas de supervivencia sin proctocolectomía completa a dos y cinco años fueron del 91% y 88%, respectivamente.LIMITACIONES:Estudio retrospectivo, tamaño de muestra pequeño.CONCLUSIONES:La colectomía segmentaria en la colitis ulcerosa se asocia con bajas tasas de complicaciones postoperatorias, tasas de colitis sintomática temprana y tasas de colitis tardía, desarrollo de cáncer metacrónico y la necesidad de una posterior proctocolectomía completa. Por lo tanto, puede ser seguro considerar pacientes seleccionados, como los ancianos con colitis inactiva y otras indicaciones de colectomía. (Traducción-Dr. Yolanda Colorado ).

Vaccine value profile for Klebsiella pneumoniae.

Klebsiella pneumoniae causes community- and healthcare-associated infections in children and adults. Globally in 2019, an estimated 1.27 million (95% Uncertainty Interval [UI]: 0.91-1.71) and 4.95 million (95% UI: 3.62-6.57) deaths were attributed to and associated with bacterial antimicrobial resistance (AMR), respectively. K. pneumoniae was the second leading pathogen in deaths attributed to AMR resistant bacteria. Furthermore, the rise of antimicrobial resistance in both community- and hospital-acquired infections is a concern for neonates and infants who are at high risk for invasive bacterial disease. There is a limited antibiotic pipeline for new antibiotics to treat multidrug resistant infections, and vaccines targeted against K. pneumoniae are considered to be of priority by the World Health Organization. Vaccination of pregnant women against K. pneumoniae could reduce the risk of invasive K.pneumoniae disease in their young offspring. In addition, vulnerable children, adolescents and adult populations at risk of K. pneumoniae disease with underlying diseases such as immunosuppression from underlying hematologic malignancy, chemotherapy, patients undergoing abdominal and/or urinary surgical procedures, or prolonged intensive care management are also potential target groups for a K. pneumoniae vaccine. A 'Vaccine Value Profile' (VVP) for K.pneumoniae, which contemplates vaccination of pregnant women to protect their babies from birth through to at least three months of age and other high-risk populations, provides a high-level, holistic assessment of the available information to inform the potential public health, economic and societal value of a pipeline of K. pneumoniae vaccines and other preventatives and therapeutics. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public-private partnerships, and multi-lateral organizations, and in collaboration with stakeholders from the WHO. All contributors have extensive expertise on various elements of the K.pneumoniae VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.

Mortality after non-surgically treated acute type A aortic dissection is higher than previously reported.

OBJECTIVES: It has been commonly accepted that untreated acute type A aortic dissection (ATAAD) results in an hourly mortality rate of 1-2% during the 1st 24 h after symptom onset. The data to support this statement rely solely on patients who have been denied surgical treatment after reaching surgical centres. The objective was to perform a total review of non-surgically treated (NST) ATAAD and provide contemporary mortality data. METHODS: This was a regional, retrospective, observational study. All patients receiving one of the following diagnoses: International Classification of Diseases (ICD)-9 4410, 4411, 4415, 4416 or ICD-10 I710, I711, I715, I718 in an area of 1.9 million inhabitants in Southern Sweden during a period of 23 years (January 1998 to November 2021) were retrospectively screened. The search was conducted using all available medical registries so that every patient diagnosed with ATAAD in our region was identified. The charts and imaging of each screened patient were subsequently reviewed to confirm or discard the diagnosis of ATAAD. RESULTS: Screening identified 2325 patients, of whom 184 NST ATAAD patients were included. The mortality of NST ATAAD was 47.3 ± 4.4%, 55.0 ± 4.4%, 76.7 ± 3.7% and 83.9 ± 4.3% at 24 h, 48 h, 14 days and 1 year, respectively. The hourly mortality rate during the 1st 24 h after symptom onset was 2.6%. CONCLUSIONS: This study observed higher mortality than has previously been reported. It emphasizes the need for timely diagnosis, swift management and emergent surgical treatment for patients suffering an acute type A aortic dissection.

Impact of neoadjuvant therapy on nodal harvest in clinical stage III rectal cancer: Establishing optimum cut-offs by disease response.

INTRODUCTION: A minimum lymph node harvest (LNH) of 12 is the current standard for appropriate nodal staging in resectable rectal cancer. However, the rise of neoadjuvant chemoradiation (NCRT) and total neoadjuvant therapy (TNT) has been associated with decreasing number of LNH. We hypothesize that as tumor response to neoadjuvant therapy increases, the optimum for LNH to achieve appropriate nodal staging should decrease. METHODS: Patients with clinical stage III rectal adenocarcinoma who underwent NCRT/TNT followed by resection were identified from the National Cancer Database. A JoinPoint regression analysis was used to determine the LNH for each tumor regression grade (TRG) category beyond which the rate of positive nodes does not significantly change. RESULTS: Thirteen thousand four hundred and twenty-six patients met inclusion criteria. Of these, 2406 (17.9%) achieved TRG 0 or ypT0 and 8210 (61.2%) achieved ypN0. Collectively, 2043 patients (15.2%) were reported to have a pathologic complete response (ypT0 ypN0). Positive pathologic nodes were found in 15%, 23%, 31%, 54%, and 53% as ypT stage increased from ypT0 to ypT4, respectively. Similarly, ypN+ rates were 15%, 36%, 41%, and 55% in TRG 0-3. No JoinPoint was identified for TRG 0, whereas inflection points were found at 6-10 nodes for TRG1 (p = 0.002) and TRG 2 (p = 0.016), and at 11-15 nodes for TRG 3. CONCLUSION: The benchmark of retrieving 12 nodes in resectable stage III rectal cancer is not consistently achieved after NCRT/TNT. We demonstrate that the LNH requirement to establish accurate pathologic nodal staging can vary depending on the tumor response to neoadjuvant therapies.

Safety & feasibility of targeted mesenteric approaches with Kono-S anastomosis and extended mesenteric excision in ileocolic resection and anastomosis in Crohn's disease.

BACKGROUND: The mesentery has recently been implicated in the pathophysiology of Crohn's disease (CD), and several techniques have been developed to target the mesentery to reduce its influence on recurrence. We aimed to describe short-term safety and feasibility after these approaches. METHODS: This is a comparative, retrospective, single-center cohort study of consecutive CD patients undergoing primary or redo ileocolic resection from 2015 to 2022 with Kono-S anastomosis (KSA), extended mesenteric excision (EME) only, or both: mesenteric excision and exclusion (MEE). RESULTS: 186 patients underwent KSA (n â€‹= â€‹74), EME (n â€‹= â€‹66), or MEE (n â€‹= â€‹46). The groups had comparable baseline characteristics. The MEE group operative time was longer (median: 187 vs. KSA 170, EME 152 â€‹min, p â€‹< â€‹0.01). Postoperatively, the groups had similar lengths of stay (median 4 days), readmissions (9.1 â€‹%), major postoperative complications (6.5 â€‹%), and anastomotic leaks (1.1 â€‹%). CONCLUSION: Targeting the mesentery with novel surgical approaches for ileocolic Crohn's disease was safe and feasible for short-term follow-up.

Predicting pediatric cardiac surgery-associated acute kidney injury using machine learning.

BACKGROUND: Prediction of cardiac surgery-associated acute kidney injury (CS-AKI) in pediatric patients is crucial to improve outcomes and guide clinical decision-making. This study aimed to develop a supervised machine learning (ML) model for predicting moderate to severe CS-AKI at postoperative day 2 (POD2). METHODS: This retrospective cohort study analyzed data from 402 pediatric patients who underwent cardiac surgery at a university-affiliated children's hospital, who were separated into an 80%-20% train-test split. The ML model utilized demographic, preoperative, intraoperative, and POD0 clinical and laboratory data to predict moderate to severe AKI categorized by Kidney Disease: Improving Global Outcomes (KDIGO) stage 2 or 3 at POD2. Input feature importance was assessed by SHapley Additive exPlanations (SHAP) values. Model performance was evaluated using accuracy, area under the receiver operating curve (AUROC), precision, recall, area under the precision-recall curve (AUPRC), F1-score, and Brier score. RESULTS: Overall, 13.7% of children in the test set experienced moderate to severe AKI. The ML model achieved promising performance, with accuracy of 0.91 (95% CI: 0.82-1.00), AUROC of 0.88 (95% CI: 0.72-1.00), precision of 0.92 (95% CI: 0.70-1.00), recall of 0.63 (95% CI: 0.32-0.96), AUPRC of 0.81 (95% CI: 0.61-1.00), F1-score of 0.73 (95% CI: 0.46-0.99), and Brier score loss of 0.09 (95% CI: 0.00-0.17). The top ten most important features assessed by SHAP analyses in this model were preoperative serum creatinine, surgery duration, POD0 serum pH, POD0 lactate, cardiopulmonary bypass duration, POD0 vasoactive inotropic score, sex, POD0 hematocrit, preoperative weight, and POD0 serum creatinine. CONCLUSIONS: A supervised ML model utilizing demographic, preoperative, intraoperative, and immediate postoperative clinical and laboratory data showed promising performance in predicting moderate to severe CS-AKI at POD2 in pediatric patients.

Treatment of rectosigmoid endometriosis by laparoscopic reverse submucosal dissection (LRSD): The Sydney partial thickness discoid excision technique.

BACKGROUND: Laparoscopic reverse submucosal dissection (LRSD) is a standardised surgical technique for removal of rectosigmoid endometriosis which optimises the anatomical dissection plane for excision of endometriotic nodules. AIM: This cohort study assesses the outcomes of the first cohort of women treated by LRSD, for deeply infiltrating rectosigmoid endometriosis. MATERIALS AND METHODS: Primary outcomes assessed were complication rate as defined by the Clavien-Dindo system, and completion of the planned LRSD. Secondary outcomes include mucosal breach, specimen margin involvement, length of hospital admission, and a comparison of pre-operative and post-operative pain, bowel function and quality of life surveys. These included the Endometriosis Health Profile Questionnaire (EHP-30), the Knowles-Eccersley-Scott Symptom Questionnaire (KESS) and the Wexner scale. RESULTS: Of 19 patients treated, one required a segmental resection. The median length of hospital admission was two days (range 1-5) and no post-operative complications occurred. Median pain visual analogue scales (scale 0-10) were higher prior to surgery (dysmenorrhoea 9.0, dyspareunia 7.5, dyschezia 9.0, pelvic pain 6.0) compared to post-surgical median scores (dysmenorrhoea 5.0, dyspareunia 4.0, dyschezia 2.0, pelvic pain 4.0) at a median of six months (range 4-32). Quality of life studies suggested improvement following surgery with pre-operative median EHP-30 and KESS scores (EHP-30: 85 (5-106), KESS score 9 (0-20)) higher than post-operative scores (EHP-30: 48.5 (0-80), KESS score: 3 (0-19)). CONCLUSION: This series highlights the feasibility of LRSD with low associated morbidity as a progression of partial thickness discoid excision (rectal shaving) for the treatment of rectosigmoid deep infiltrating endometriosis.

Fact or fiction? Does the position of the end-to-end (EEA) stapler spike matter for colorectal anastomoses using a double-stapled technique?

AIM: Surgeons often have strong opinions about how to perform colorectal anastomoses with little data to support variations in technique. The aim of this study was to determine if location of the end-to-end (EEA) stapler spike relative to the rectal transection line is associated with anastomotic integrity. METHOD: This study was a retrospective analysis of a quality collaborative database at a quaternary centre and regional hospitals. Patients with any left-sided colon resection with double-stapled anastomosis were included (December 2019 to August 2022). Our primary endpoint was a composite outcome including positive air insufflation test, incomplete anastomotic donut, or thin/eccentric donut. Our secondary endpoint was clinical leak. RESULTS: Overall, 633 patients were included and stratified by location of the stapler spike relative to the rectal transection line. Of note, 86 patients had an end-colon to anterior rectum ("reverse Baker") anastomosis with no crossing staple lines. The rates of the composite endpoint based on position of the stapler spike were 12.4% (anterior), 8.1% (through), 12.8% (posterior), 5.1% (corner), and 2.3% for the "reverse Baker" (p = 0.03). The overall rate of clinical leak was 3.8% and there were no differences between methods. In a multivariate analysis, the "reverse Baker" anastomosis was associated with decreased odds of poor anastomotic integrity when compared to anastomoses with crossing staple lines (OR 0.20, 95% CI: 0.05-0.87, p = 0.03). CONCLUSIONS: For anastomoses with crossing staple lines, the position of the stapler spike relative to the rectal staple line is not associated with differences in anastomotic integrity. In contrast, anastomoses with no crossing staple lines resulted in significantly lower rates of poor anastomotic integrity, but no difference in clinical leaks.

A Force-Matched Approach to Large-Strain Nonlinearity in Elasticity Imaging for Breast Lesion Characterization.

OBJECTIVE: Ultrasound elasticity imaging is a class of ultrasound techniques with applications that include the detection of malignancy in breast lesions. Although elasticity imaging traditionally assumes linear elasticity, the large strain elastic response of soft tissue is known to be nonlinear. This study evaluates the nonlinear response of breast lesions for the characterization of malignancy using force measurement and force-controlled compression during ultrasound imaging. METHODS: 54 patients were recruited for this study. A custom force-instrumented compression device was used to apply a controlled force during ultrasound imaging. Motion tracking derived strain was averaged over lesion or background ROIs and matched with compression force. The resulting force-matched strain was used for subsequent analysis and curve fitting. RESULTS: Greater median differences between malignant and benign lesions were observed at higher compressional forces (p-value < 0.05 for compressional forces of 2-6N). Of three candidate functions, a power law function produced the best fit to the force-matched strain. A statistically significant difference in the scaling parameter of the power function between malignant and benign lesions was observed (p-value = 0.025). CONCLUSIONS: We observed a greater separation in average lesion strain between malignant and benign lesions at large compression forces and demonstrated the characterization of this nonlinear effect using a power law model. Using this model, we were able to differentiate between malignant and benign breast lesions. SIGNIFICANCE: With further development, the proposed method to utilize the nonlinear elastic response of breast tissue has the potential for improving non-invasive lesion characterization for potential malignancy.

Prednisone Decreases Opioid Use in Adults Undergoing Benign Oropharyngeal Surgery.

OBJECTIVE: This study sought to analyze the efficacy and safety of postoperative prednisone to reduce reliance on opioids in adult benign oropharyngeal surgery. STUDY DESIGN: Prospective cohort study. SETTING: Single tertiary-care facility. METHODS: Patients undergoing tonsillectomy (T), tonsillectomy and adenoidectomy (T&A), and/or modified uvulopalatopharyngoplasty (UPPP) from December 2020 to January 2023 received the standard of care postoperative management. A prednisone taper was dependent on surgeon preference. Cohorts were based on the prescription of postoperative steroids. Patients completed a survey to assess opioid usage, pain scores, and steroid compliance. RESULTS: Seventy-two patients were included. The nonsteroid cohort (N = 29) received an average of 467 ± 94.1 morphine milligram equivalents (MME), and the steroid cohort (N = 43) received an average of 285 ± 128 MME (P < 0.001). The nonsteroid cohort consumed 1.62 times more opioids than the steroid cohort (P < 0.002). There were no significant differences in complication or refill rates between treatment groups. There were no significant differences in pain scores on the day of surgery or postoperative days 1, 5, or 10 (P = 0.34, P = 0.66, P = 0.62, and P = 0.22, respectively). Patients undergoing T&A (p = 0.019) or who had current psychiatric medication use (P < 0.006) consumed significantly more opioids. Patients who received a total opioid prescription of >300 MME (40 5-mL doses of 5 mg/5 mL liquid oxycodone) consumed 2.27 times more postoperative opioids than patients with opioid prescriptions ≤300 MME (P < 0.001). CONCLUSION: Patients who did not receive steroids consumed 1.62 times more postoperative opioids compared to those who completed a steroid taper. Corticosteroid use was not associated with changes in pain scores, refill rates, or complication rates and may be considered in a multimodal approach to pain management in adults undergoing benign oropharyngeal surgery, although further study is warranted.

Third generation quinoline-3-carboxamide transcriptional disrupter of HDAC4, HIF-1α, and MEF-2 signaling for metastatic castration-resistant prostate cancer.

BACKGROUND: The quinoline-3-carboxamide, Tasquinimod (TasQ), is orally active as a maintenance therapy with an on-target mechanism-of-action via allosteric binding to HDAC4. This prevents formation of the HDAC4/NCoR1/HDAC3 complex, disrupting HIF-1α transcriptional activation and repressing MEF-2 target genes needed for adaptive survival signaling in the compromised tumor micro environment. In phase 3 clinical testing against metastatic castration-resistant prostate cancer(mCRPC), TasQ (1 mg/day) increased time-to-progression, but not overall survival. METHODS: TasQ analogs were chemically synthesized and tested for activity compared to the parental compound. These included HDAC4 enzymatic assays, qRT-PCR and western blot analyses of gene and protein expression following treatment, in vitro and in vivo efficacy against multiple prostate cancer models including PDXs, pharmacokinetic analyses,AHR binding and agonist assays, SPR analyses of binding to HDAC4 and NCoR1, RNAseq analysis of in vivo tumors, 3D endothelial sprouting assays, and a targeted kinase screen. Genetic knockout or knockdown controls were used when appropriate. RESULTS: Here, we document that, on this regimen (1 mg/day), TasQ blood levels are 10-fold lower than the optimal concentration (≥2 µM) needed for anticancer activity, suggesting higher daily doses are needed. Unfortunately, we also demonstrate that TasQ is an arylhydrocarbon receptor (AHR) agonist, which binds with an EC50 of 1 µM to produce unwanted off-target side effects. Therefore, we screened a library of TasQ analogsto maximize on-target versus off-target activity. Using this approach, we identified ESATA-20, which has ~10-fold lower AHR agonism and 5-fold greater potency against prostate cancer patient-derived xenografts. CONCLUSION: This increased therapeuticindex nominates ESATA-20 as a lead candidate forclinical development as an orally active third generation quinoline-3-carboxamide analog thatretains its on-target ability to disrupt HDAC4/HIF-1α/MEF-2-dependent adaptive survival signaling in the compromisedtumor microenvironment found in mCRPC.

Impact of Total Neoadjuvant Therapy on Postoperative Outcomes After Proctectomy for Rectal Cancer.

BACKGROUND: Total neoadjuvant therapy is an alternative to neoadjuvant chemoradiation alone for rectal cancer and has the benefits of more completion of planned therapy, increased downstaging, earlier treatment of micrometastases, and assessment of chemosensitivity; however, it may increase surgical complications, especially with increased radiation-to-surgery interval. OBJECTIVE: The study aimed to determine the impact of total neoadjuvant therapy on postoperative complications compared with neoadjuvant chemoradiation alone. DESIGN: Retrospective cohort study. SETTINGS: Single tertiary referral center. PATIENTS: The patient included was a stage II/III rectal cancer patient who underwent total neoadjuvant therapy or long-course neoadjuvant chemoradiation followed by surgical resection from 2018-2020. MAIN OUTCOME MEASURES: The main outcome measures included severe postoperative complications (Clavien-Dindo grade ≥3). RESULTS: Of 181 patients, 86 (47.5%) underwent total neoadjuvant therapy and 95 (52.5%) underwent neoadjuvant chemoradiation. There was no difference in severe postoperative complications or any complications. There was also no difference in the rate of complete total mesorectal excision or negative circumferential margin. Total neoadjuvant therapy had a mean operative time of 355.5 minutes and estimated blood loss of 263.6 mL compared with 326.7 minutes and 297.5 mL in the neoadjuvant chemoradiation group. Total neoadjuvant therapy patients had a lower mean lymph node yield than neoadjuvant chemoradiation patients. On multivariable analysis, total neoadjuvant therapy was associated with increased operative time (OR, 1.19; p < 0.001) and estimated blood loss (OR, 1.22; p < 0.001) and decreased lymph node yield (OR, 0.67; p < 0.001). There was no difference in severe complications or any complications. LIMITATIONS: Selection bias uncontrolled by modeling. CONCLUSIONS: We found no difference in risk of postoperative complications between patients who received total neoadjuvant therapy vs neoadjuvant chemoradiation. Total neoadjuvant therapy patients had longer operations and greater estimated blood loss. This may be a reflection of increased operative difficulty because of increased radiation-to-surgery interval and/or the effects of chemotherapy; however, the absolute differences were small and, therefore, should be interpreted cautiously. See Video Abstract at http://links.lww.com/DCR/C44 . IMPACTO DE LA TERAPIA NEOADYUVANTE TOTAL EN LOS RESULTADOS POSOPERATORIOS DESPUS DE UNA PROCTECTOMA POR CNCER DE RECTO: ANTECEDENTES:La terapia neoadyuvante total es una alternativa a la quimiorradiación neoadyuvante sola para el cáncer de recto y tiene los beneficios de una mayor finalización de la terapia planificada, mayor reducción del estadiage, tratamiento más temprano de las micrometástasis y evaluación de la quimiosensibilidad; sin embargo, puede aumentar las complicaciones quirúrgicas, especialmente con un mayor intervalo entre la radiación y la cirugía.OBJETIVO:Determinar el impacto de la terapia neoadyuvante total sobre las complicaciones posoperatorias en comparación con la quimiorradiación neoadyuvante sola.DISEÑO:Estudio de cohorte retrospectivo.ENTORNO CLINICO:Centro único de referencia terciario.PACIENTES:Paciente con cáncer de recto en estadio II/III que se sometieron a terapia neoadyuvante total o quimiorradiación neoadyuvante de larga duración seguida de resección quirúrgica entre 2018 y 2020.PRINCIPALES MEDIDAS DE RESULTADO:Complicaciones postoperatorias graves (grado de Clavien-Dindo ≥3).RESULTADOS:De 181 pacientes, 86 (47,5%) se sometieron a terapia neoadyuvante total y 95 (52,5%) se sometieron a quimiorradioterapia neoadyuvante. No hubo diferencia en las complicaciones postoperatorias graves o cualquier otra complicación. Tampoco hubo diferencia en la tasa de escisión mesorrectal total completa o margen circunferencial negativo. La terapia neoadyuvante total tuvo un tiempo operatorio promedio de 355,5 minutos y una pérdida de sangre estimada de 263,6 ml en comparación con 326,7 minutos y 297,5 ml en el grupo de quimiorradiación neoadyuvante. Los pacientes con terapia neoadyuvante total tuvieron una media de ganglios linfáticos más bajo en comparación con los pacientes con quimiorradioterapia neoadyuvante. En el análisis multivariable, la terapia neoadyuvante total se asoció con un mayor tiempo operatorio (OR = 1,19, p < 0,001) y pérdida de sangre estimada (OR = 1,22, p < 0,001) y menor cantidad los ganglios linfáticos (OR = 0,67, p < 0,001). No hubo diferencia en las complicaciones graves o cualquier complicación.LIMITACIONES:Sesgo de selección no controlado por modelado.CONCLUSIONES:No encontramos diferencias en el riesgo de complicaciones postoperatorias entre los pacientes que recibieron terapia neoadyuvante total versus quimiorradiación neoadyuvante. Los pacientes con terapia neoadyuvante total tuvieron operaciones más prolongadas y una mayor pérdida de sangre estimada. Esto puede ser un reflejo de una mayor dificultad quirúrgica como resultado de un mayor intervalo entre la radiación y la cirugía y/o los efectos de la quimioterapia; sin embargo, las diferencias absolutas fueron pequeñas y, por lo tanto, deben interpretarse con cautela. Consulte Video Resumen en http://links.lww.com/DCR/C44 . (Traducción- Dr. Francisco M. Abarca-Rendon ).

The Impact of Discharge Against Medical Advice on Readmission After Opioid Use Disorder-Associated Infective Endocarditis: a National Cohort Study.

BACKGROUND: Hospitalizations for infective endocarditis (IE) associated with opioid use disorder (O-IE) have increased in the USA and have been linked to high rates of discharge against medical advice (DAMA). DAMA represents a truncation of care for a severe infection, yet patient outcomes after DAMA are unknown. OBJECTIVE: This study aimed to assess readmissions following O-IE and quantify the impact of DAMA on outcomes. DESIGN: A retrospective study of a nationally representative dataset of persons' inpatient discharges in the USA in 2016 PARTICIPANTS: A total of 6018 weighted persons were discharged for O-IE, stratified by DAMA vs. other discharge statuses. Of these, 1331 (22%) were DAMA. MAIN MEASURES: The primary outcome of interest was 30-day readmission rates, stratified by discharge type. We also examined the total number of hospitalizations during the year and estimated the effect of DAMA on readmission. KEY RESULTS: Compared with non-DAMA, those experiencing DAMA were more commonly female, resided in metropolitan areas, lower income, and uninsured. Crude 30-day readmission following DAMA was 50%, compared with 21% for other discharge types. DAMA was strongly associated with readmission in an adjusted logistic regression model (OR 3.72, CI 3.02-4.60). Persons experiencing DAMA more commonly had ≥2 more hospitalizations during the period (31% vs. 18%, p<0.01), and were less frequently readmitted at the same hospital (49% vs 64%, p<0.01). CONCLUSIONS: DAMA occurs in nearly a quarter of patients hospitalized for O-IE and is strongly associated with short-term readmission. Interventions to address the root causes of premature discharges will enhance O-IE care, reduce hospitalizations and improve outcomes.

Intratumoral delivery of TransCon™ TLR7/8 Agonist promotes sustained anti-tumor activity and local immune cell activation while minimizing systemic cytokine induction.

BACKGROUND: Intratumoral (IT) delivery of toll-like receptor (TLR) agonists has shown encouraging anti-tumor benefit in preclinical and early clinical studies. However, IT delivery of TLR agonists may lead to rapid effusion from the tumor microenvironment (TME), potentially limiting the duration of local inflammation and increasing the risk of systemic adverse events. METHODS: To address these limitations, TransCon™ TLR7/8 Agonist-an investigational sustained-release prodrug of resiquimod that uses a TransCon linker and hydrogel technology to achieve sustained and predictable IT release of resiquimod-was developed. TransCon TLR7/8 Agonist was characterized for resiquimod release in vitro and in vivo, in mice and rats, and was assessed for anti-tumor efficacy and pharmacodynamic activity in mice. RESULTS: Following a single IT dose, TransCon TLR7/8 Agonist mediated potent tumor growth inhibition which was associated with sustained resiquimod release over several weeks with minimal induction of systemic cytokines. TransCon TLR7/8 Agonist monotherapy promoted activation of antigen-presenting cells in the TME and tumor-draining lymph nodes, with evidence of activation and expansion of CD8+ T cells in the tumor-draining lymph node and TME. Combination of TransCon TLR7/8 Agonist with systemic immunotherapy further promoted anti-tumor activity in TransCon TLR7/8 Agonist-treated tumors. In a bilateral tumor setting, combination of TransCon TLR7/8 Agonist with systemic IL-2 potentiated tumor growth inhibition in both injected and non-injected tumors and conferred protection against tumor rechallenge following complete regressions. CONCLUSIONS: Our findings show that a single dose of TransCon TLR7/8 Agonist can mediate sustained local release of resiquimod in the TME and promote potent anti-tumor effects as monotherapy and in combination with systemic immunotherapy, supporting TransCon TLR7/8 Agonist as a novel intratumoral TLR agonist for cancer therapy. A clinical trial to evaluate the safety and efficacy of TransCon TLR7/8 Agonist, as monotherapy and in combination with pembrolizumab, in cancer patients is currently ongoing (transcendIT-101; NCT04799054).

Preclinical characterization and clinical translation of pharmacodynamic markers for MK-5890: a human CD27 activating antibody for cancer immunotherapy.

BACKGROUND: Immune checkpoint inhibitors (ICI) have radically changed cancer therapy, but most patients with cancer are unresponsive or relapse after treatment. MK-5890 is a CD27 agonist antibody intended to complement ICI therapy. CD27 is a member of the tumor necrosis factor receptor superfamily that plays a critical role in promoting responses of T cells, B cells and NK cells. METHODS: Anti-CD27 antibodies were generated and selected for agonist activity using NF-кB luciferase reporter assays. Antibodies were humanized and characterized for agonism using in vitro T-cell proliferation assays. The epitope recognized on CD27 by MK-5890 was established by X-ray crystallography. Anti-tumor activity was evaluated in a human CD27 knock-in mouse. Preclinical safety was tested in rhesus monkeys. Pharmacodynamic properties were examined in mouse, rhesus monkeys and a phase 1 dose escalation clinical study in patients with cancer. RESULTS: Humanized anti-CD27 antibody MK-5890 (hIgG1) was shown to bind human CD27 on the cell surface with sub-nanomolar potency and to partially block binding to its ligand, CD70. Crystallization studies revealed that MK-5890 binds to a unique epitope in the cysteine-rich domain 1 (CRD1). MK-5890 activated CD27 expressed on 293T NF-κB luciferase reporter cells and, conditional on CD3 stimulation, in purified CD8+ T cells without the requirement of crosslinking. Functional Fc-receptor interaction was required to activate CD8+ T cells in an ex vivo tumor explant system and to induce antitumor efficacy in syngeneic murine subcutaneous tumor models. MK-5890 had monotherapy efficacy in these models and enhanced efficacy of PD-1 blockade. MK-5890 reduced in an isotype-dependent and dose-dependent manner circulating, but not tumor-infiltrating T-cell numbers in these mouse models. In rhesus monkey and human patients, reduction in circulating T cells was transient and less pronounced than in mouse. MK-5890 induced transient elevation of chemokines MCP-1, MIP-1α, and MIP-1ß in the serum of mice, rhesus monkeys and patients with cancer. MK-5890 was well tolerated in rhesus monkeys and systemic exposure to MK-5890 was associated with CD27 occupancy at all doses. CONCLUSIONS: MK-5890 is a novel CD27 agonistic antibody with the potential to complement the activity of PD-1 checkpoint inhibition in cancer immunotherapy and is currently undergoing clinical evaluation.

TransCon IL-2 ß/γ: a novel long-acting prodrug with sustained release of an IL-2Rß/γ-selective IL-2 variant with improved pharmacokinetics and potent activation of cytotoxic immune cells for the treatment of cancer.

BACKGROUND: Recombinant interleukin-2 (IL-2, aldesleukin) is an approved cancer immunotherapy but causes severe toxicities including cytokine storm and vascular leak syndrome (VLS). IL-2 promotes antitumor function of IL-2Rß/γ+ natural killer (NK) cells and CD8+, CD4+ and gamma delta (γδ) T cells. However, IL-2 also potently activates immunosuppressive IL-2Rα+ regulatory T cells (Tregs) and IL-2Rα+ eosinophils and endothelial cells, which may promote VLS. Aldesleukin is rapidly cleared requiring frequent dosing, resulting in high Cmax likely potentiating toxicity. Thus, IL-2 cancer immunotherapy has two critical drawbacks: potent activation of undesired IL-2Rα+ cells and suboptimal pharmacokinetics with high Cmax and short half-life. METHODS: TransCon IL-2 ß/γ was designed to optimally address these drawbacks. To abolish IL-2Rα binding yet retain strong IL-2Rß/γ activity, IL-2 ß/γ was created by permanently attaching a small methoxy polyethylene glycol (mPEG) moiety in the IL-2Rα binding site. To improve pharmacokinetics, IL-2 ß/γ was transiently attached to a 40 kDa mPEG carrier via a TransCon (transient conjugation) linker creating a prodrug, TransCon IL-2 ß/γ, with sustained release of IL-2 ß/γ. IL-2 ß/γ was characterized in binding and primary cell assays while TransCon IL-2 ß/γ was studied in tumor-bearing mice and cynomolgus monkeys. RESULTS: IL-2 ß/γ demonstrated selective and potent human IL-2Rß/γ binding and activation without IL-2Rα interactions. TransCon IL-2 ß/γ showed slow-release pharmacokinetics with a low Cmax and a long (>30 hours) effective half-life for IL-2 ß/γ in monkeys. In mouse tumor models, TransCon IL-2 ß/γ promoted CD8+ T cell and NK cell activation and antitumor activity. In monkeys, TransCon IL-2 ß/γ induced robust activation and expansion of CD8+ T cells, NK cells and γδ T cells, relative to CD4+ T cells, Tregs and eosinophils, with no evidence of cytokine storm or VLS. Similarly, IL-2 ß/γ enhanced proliferation and cytotoxicity of primary human CD8+ T cells, NK cells and γδ T cells. SUMMARY: TransCon IL-2 ß/γ is a novel long-acting prodrug with sustained release of an IL-2Rß/γ-selective IL-2. It has remarkable and durable pharmacodynamic effects in monkeys and potential for improved clinical efficacy and tolerability compared with aldesleukin. TransCon IL-2 ß/γ is currently being evaluated in a Phase 1/2 clinical trial (NCT05081609).

Superior Hypogastric Plexus Nerve Block in Minimally Invasive Gynecology: A Randomized Controlled Trial.

STUDY OBJECTIVE: To assess the efficacy of a superior hypogastric plexus nerve block in reducing opioid requirements in the first 24 hours after minimally invasive gynecologic surgery. DESIGN: Patient-blinded randomized controlled trial. SETTING: Single-center academic institution (Sydney Women's Endosurgery Centre). Two surgeons administering the blocks in their own surgeries. PATIENTS: Patients undergoing either laparoscopic or robot-assisted laparoscopic hysterectomy or myomectomy for benign indications. INTERVENTIONS: Ropivacaine 10 mL (0.75%) infiltrated into the retroperitoneal space overlying the superior hypogastric plexus vs control of no block given at the completion of surgery. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the total opioid use in the first 24 hours after surgery, measured in morphine milligram equivalents (MME). Standardized fentanyl patient-controlled analgesia was given to all patients in the trial. The secondary outcome was pain measured on a visual analog scale (1 to 10) at 1, 2, 6, 12, and 24 hours after surgery. Fifty patients out of 56 approached for the study participated in, and completed, the study (89.2%). The patients were randomized over a 5-month period, March 2020 to July 2020. A total of 27 patients were randomized to receive a nerve block, and 23 were randomized to the control. There was a difference of -21.8 MME in the block group compared with the no-block group (95% confidence interval [CI], -38.2 to -5.5; p = .008). This correlated to a 38% reduction in opioid use in the block group. The mean opioid use in the patients in the block group was 33.1 MME (95% CI, 24.2-41.9) and in those in the no-block group 54.9 MME (95% CI, 40.7-69.1). For the block group, opioid use ranged from 1.0 to 76.5 MME, with an interquartile range of 37 (14-51). For the control group, the range was 7.5 to 113.5 MME, with a higher interquartile range of 60 (28-88). Pairwise comparisons of the mean pain scores over the 24 hours showed a lower pain score with a nerve block of 1.8 (95% CI, 1.5-2.1) compared with a no-block score of 2.6 (95% CI, 2.3-2.9) No adverse effects of local anesthetic toxicity, nerve injury, or bowel/vascular injury were noted in any patient. CONCLUSION: A superior hypogastric plexus nerve block is a simple technique for reducing postoperative opioid requirements and pain in the first 24 hours after minimally invasive gynecologic surgery.