Development of Clinical Algorithm Utilizing Vibration-Controlled Transient Elastography to Detect Advanced Hepatic Fibrosis in Liver Transplant Recipients.

INTRODUCTION: Vibration-controlled transient elastography (VCTE) based liver stiffness measurement (LSM) is an excellent 'rule-out' test for advanced hepatic fibrosis in liver transplant (LT) recipients, however, its ability to 'rule-in' the disease is suboptimal. The study aimed to improve diagnostic performance of LSM in LT recipients. METHODS: Adult LT recipients with a liver biopsy and VCTE were included (N = 150). Sequential covering analysis was performed to create rules to identify patients at low or high risk for advanced fibrosis (stage 3-4). RESULTS: Advanced hepatic fibrosis was excluded in patients with either LSM < 7.45 kPa (n = 72) or 7.45 ≤ LSM < 12.1 kPa and time from LT < 5.6 years (n = 25). Conversely, likelihood of advanced fibrosis was 95% if patients had LSM > 14.1 and controlled attenuation parameter > 279 dB/m (n = 21). Thus, 118 (79%) were correctly identified and 32 (21%) would have required a biopsy to establish the diagnosis. Compared to previously established LSM based cutoff values of 10.5 kPa (Youden index) and 13.3 kPa (maximized specificity), the false positive rates of sequential covering analysis was 1% compared to 16.5% with LSM ≥ 10.5 kPa and 8.3% with LSM ≥ 13.3 kPa. The true positive rates were comparable at 87% for sequential covering analysis, 93% for LSM ≥ 10.5 kPa and 83% for LSM ≥ 13.3 kPa. CONCLUSION: The proposed clinical sequential covering analysis allows for better risk stratification when evaluating for advanced fibrosis in LT recipients compared to LSM alone. Additional efforts are necessary to further reduce the number of patients with indeterminate results in whom a liver biopsy may be required.

Discovery of novel anticancer flavonoids as potential HDAC2 inhibitors: virtual screening approach based on molecular docking, DFT and molecular dynamics simulations studies.

Virtual screening of a library of 329 flavonoids obtained from the NPACT database was performed to find out potential novel HDAC2 inhibitors. Eleven out of 329 selected flavonoids were screened based on molecular docking studies, as they have higher binding affinities than the standard drugs vorinostat and panobinostat. All screened compounds occupying the catalytic site of HDAC2 showed important molecular interaction with Zn2+ and other important amino acids in the binding pocket. The screened compounds were validated using ADMET filtration and bioactivity prediction from which we obtained six compounds, NPACT00270, NPACT00676, NPACT00700, NPACT001008, NPACT001054, and NPACT001407, which were analyzed using DFT studies. DFT studies were performed for all six screened flavonoids. In DFT studies, three flavonoids, NPACT00700, NPACT001008, and NPACT001407, were found to be better based on HOMO-LUMO and molecular electrostatic potential (MEP) analyses. Furthermore, MD simulations were performed for 100 ns for the three compounds. In the MD analysis, NPACT001407 was found to be more stable in the active site of HDAC2 as zinc formed a coordination bond with ASP181, HIS183, ASP269, and GLY305, along with two hydroxyl groups of the ligand. Our findings reveal that these flavonoids can interact as ligands with the active site of HDAC2. Because of the absence of a hydroxamate group in flavonoids, there are no possibilities for the formation of isocyanate. This suggests that the major drawback of current HDACs inhibitors may be solved. Further experimental validation is needed to understand the selectivity of flavonoids as HDAC2 inhibitors. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03912-5.

Isolated Colonic Varices in Pancreatic Adenocarcinoma.

Colonic varices are a rare subtype of ectopic varices and form due to portal hypertension, splenic or portal vein thrombosis, and mesenteric vein obstruction. When present, they are most common in the rectum. We discuss a patient with hematochezia who had isolated right-sided colonic varices related to pancreatic cancer, which is rare. The mass involved the superior mesenteric vein, leading to left-sided portal hypertension and resultant varices. These are difficult to diagnosis because they flatten with insufflation on colonoscopy, so computed tomography or angiography is the gold standard. Treatment options are limited and may require a multidisciplinary approach.

Clinical and Healthcare Resource Use Outcomes between Dual-plane and Prepectoral Techniques in Implant-based Breast Reconstruction: A Multicenter Retrospective Study.

This multicenter, retrospective study compared clinical outcomes and healthcare resource use in patients who underwent dual-plane (DP) or prepectoral (PP) implant-based breast reconstruction (IBR) after mastectomy in the United States. Methods: Medical records were selected for patients at five sites undergoing immediate one-stage direct-to-implant (first hospitalization) or two-stage IBR (first and second hospitalization) using either DP or PP. Inverse probability of treatment weighting was used to adjust for potential confounders. Complications and healthcare resource use were assessed with logistic regression; pain severity was assessed with ordinary least-squares regression. Results: After inverse probability of treatment weighting, data from 255 patients (DP = 130, PP = 125) and 441 breasts (DP = 226, PP = 215) were analyzed. Mean pain severity scores were lower with PP versus DP immediately after IBR for first (P = 0.0002) and second hospitalizations (P = 0.0145), and before discharge for first (P < 0.0001) and second hospitalizations (P = 0.0002). A greater proportion of PP versus DP patients had a shorter hospital length of stay (≤ 23 hours) for first hospitalization (P = 0.0052); proportions were similar for second hospitalization (P = 0.5499). Intravenous narcotics were prescribed less frequently to PP versus DP patients during first (61.1% versus 69.8%, respectively; P = 0.1486) and second (37.5% versus 55.3%, respectively; P = 0.0172) hospitalizations. Complication rates were low in both groups after first hospitalization discharge (DP: 13.6%, PP: 12.5%, P = 0.7225). Conclusion: This retrospective study suggests that the PP technique in IBR may offer benefits related to clinical outcomes and health resource utilization; however, larger studies, including randomized controlled trials, are needed to confirm.

Derivation and Validation of a Model to Predict Clinically Significant Portal Hypertension Using Transient Elastography and FIB-4.

BACKGROUND: Liver biopsy and hepatic venous pressure gradient (HVPG), the gold standard for assessing advanced fibrosis (AF) and clinically significant portal hypertension (CSPH), are invasive, costly, and time-consuming. GOAL: We investigated if the combination of fibrosis index based on 4 factors (FIB-4) and liver stiffness measure (LSM) can identify AF and more importantly, CSPH. PATIENTS AND METHODS: Patients with chronic liver disease referred for transjugular liver biopsy were analyzed retrospectively. FIB-4 and LSM were compared with liver histology for diagnosing AF. FIB-4, LSM, and platelet count were compared with HVPG for diagnosing CSPH. Optimal cutoffs for predicting CSPH were determined by grid search. A composite log-odds to predict CSPH was derived from logistic regression using LSM, FIB-4, and gender. Internal bootstrap validation and external validation were performed. RESULTS: A total of 142 patients were included in the derivation; 42.3% had AF, and 11.3% had CSPH using the current gold standards. The area under the receiver operating characteristic curve (AUROC) for LSM, FIB-4, and their combination to predict AF were 0.7550, 0.7049, and 0.7768, respectively. LSM, FIB-4, and platelet count predicted CSPH with AUROC 0.6818, 0.7532, and 0.7240, respectively. LSM plus FIB-4 showed the best performance in predicting CSPH with AUROC 0.8155. Based on LSM, FIB-4, and gender, a novel model-the Portal Hypertension Assessment Tool (PHAT)-was developed to predict CSPH. PHAT score ≥-2.76 predicted CSPH with sensitivity 94%, specificity 67%, positive predictive value 27%, negative predictive value 99%, and accuracy 70%. In internal and external validation, AUROCs for the model were 0.8293 and 0.7899, respectively. CONCLUSION: A model consisting of FIB-4, LSM, and gender can identify CSPH among patients with chronic liver disease.

Evaluation of liver stiffness measurement-based scores in liver transplantation recipients.

Combining bioclinical parameters with liver stiffness measurement (LSM) has improved the diagnostic performance of vibration-controlled transient elastography (VCTE) for detection of advanced fibrosis in patients with chronic liver disease. However, this approach has not yet been tested in liver transplantation (LT) recipients. Thus, the aim of this study was to evaluate the diagnostic performance of combining LSM-based scores with LSM alone for the detection of advanced fibrosis in LT recipients. Adult LT recipients with a liver biopsy, VCTE, and clinical data necessary to construct LSM-based fibrosis models (FibroScan-AST [FAST], AGILE-3+, and AGILE-4) were included ( n = 132). The diagnostic statistics for advanced fibrosis (fibrosis stage 0-2 vs. 3-4) were determined by optimal cut-off using the Youden index. The area under the receiver operating characteristic curve (AUROC) for LSM was 0.94 (95% confidence interval [95% CI], 0.89-0.99), FAST was 0.65 (95% CI, 0.50-0.79), AGILE-3+ was 0.90 (95% CI, 0.83-0.97), and AGILE-4 was 0.90 (95% CI, 0.83-0.97). No statistically significant differences were noted between the AUROC of LSM versus LSM-based scores. The false-positive rates for AGILE-3+ and AGILE-4 were 14.5% and 11.8% compared with 8.3% for LSM alone. The false-positive rates in LSM-based scores were higher among patients with diabetes mellitus, higher AST levels, and lower platelet counts. The LSM-based scores did not improve the diagnostic performance of LSM alone in LT recipients for the detection of advanced fibrosis. This lack of improvement in diagnostic performance results from the impact of immunosuppression on bioclinical profile and underscores the importance of developing LSM-based scores that are specific to LT patients.

Epidemiology of early esophageal adenocarcinoma.

BACKGROUND/AIMS: Endoscopic resection has become the preferred treatment approach for select early esophageal adenocarcinoma (EAC); however, the epidemiology of early stage disease has not been well defined. METHODS: Surveillance Epidemiology and End Results (SEER) data were analyzed to determine age-adjusted incidence rates among major epithelial carcinomas, including EAC, from 1973 to 2017. The percent change in incidence over time was compared according to tumor subtype. Early T-stage, node-negative EAC without metastasis was examined from 2004 to 2017 when precise T-stage data were available. RESULTS: The percent change in annual incidence from 1973 to 2017 was 767% for EAC. Joinpoint analysis showed that the average annual percent change in EAC from 1973 to 2017 was 5.11% (95% confidence interval, 4.66%-5.56%). The annual percent change appeared to plateau between 2004 and 2017; however, early EAC decreased from 2010 to 2017, with an annual percent change of -5.78%. CONCLUSION: There has been a 7-fold increase in the incidence of EAC, which was significantly greater than that of the other major epithelial malignancies examined. More recently, the incidence of early EAC has been decreasing. Approximately one in five patients has node negative, potentially resectable early stage disease.

Lymph node involvement in gastric adenocarcinoma.

BACKGROUND: Endoscopic management of early gastric cancer is limited by the risk of lymph node metastasis. We aimed to examine the incidence and predictors of nodal metastasis in early gastric adenocarcinoma in a large national US cohort. METHODS: Cases were abstracted from the National Cancer Database from 2004 to 2016. The incidence and predictors of lymph node involvement for patients with Tis, T1a, and T1b tumors were examined. RESULTS: A total of 202,216 cases of gastric adenocarcinoma were identified in the NCDB. Cases with unknown patient or tumor characteristics, presence of other cancers, and prior neoadjuvant chemotherapy or radiotherapy were excluded. 1839 cases of Tis, T1a, and T1b tumors were identified. Lymph node metastases were present in 18.1% of patients. Lymphovascular invasion (LVI), high-grade histology, stage T1b, and larger size (> 3 cm) were independently associated with an increased risk of nodal metastasis on multivariate analysis (P < 0.05). The presence of LVI was the strongest predictor of nodal metastasis with an OR (95% CI) of 5.7 (4.3-7.6), P < 0.001. No lymph node metastasis was found in any Tis tumors. Small T1a low-grade tumors with no LVI had a low risk of nodal metastasis (0.6% < 2 cm and 0.9% < 3 cm). CONCLUSION: In this large national cohort, size, lymphovascular invasion, higher grade histology, and T stage were independently associated with lymph node metastasis. For patients with low-grade tumors, < 3 cm, without lymphovascular invasion, the risk of nodal involvement was very low, suggesting that this Western cohort could be considered for endoscopic resection.

High Participant Satisfaction Achieved Using Cryolipolysis for Fat Reduction of the Abdomen and Flanks.

BACKGROUND: Patient-reported outcome (PRO) data evaluating the physical and psychosocial impact of cryolipolysis (CoolSculpting) treatment are limited. OBJECTIVES: The aim of this study was to assess, by means of PRO instruments, multidimensional aspects of satisfaction following cryolipolysis treatment of the flanks and abdomen. METHODS: This was a multinational, prospective, single-cohort, interventional study. The primary endpoint was the proportion of participants stating they were "satisfied" or "very satisfied" with treatment at 12 weeks post final treatment. Secondary endpoints included satisfaction categorized by treatment area, total number of treatment cycles, baseline BMI, and fat volume reduction measured by 3-dimensional photography at 12 weeks post final treatment. Exploratory endpoints assessed the physical and psychosocial impacts of treatment. Safety was monitored throughout the study. RESULTS: Of 112 participants who were treated, 74.1% were female. The mean age and BMI were 42.5 years and 24.9 kg/mg2, respectively. Of the 106 evaluable participants, 89.6% were "satisfied" or "very satisfied" with treatment results. Satisfaction was high regardless of body area(s), total number of treatment cycles, or baseline BMI. Mean [standard deviation] fat volume reduction was 264.8 [411.4] mL. Overall, 90.6% reported "noticeable" or "very noticeable" fat reduction, 89.6% were "likely" or "very likely" to treat additional areas, and 93.4% would recommend cryolipolysis to a friend. Twenty-four (21.4%) participants reported treatment-emergent adverse events; 23 (20.5%) reported these as adverse device effects. No serious device-related or unanticipated adverse effects occurred. CONCLUSIONS: Cryolipolysis (CoolSculpting) for fat reduction of the flanks and/or abdomen was well-tolerated and associated with high levels of satisfaction across multidimensional PROs.

Long-term Outcome of Per-oral Endoscopic Myotomy Performed in the Endoscopy Unit With Trainees.

INTRODUCTION: Per-oral endoscopic myotomy (POEM) has been widely adopted for the treatment of achalasia as it provides a precise, tailored myotomy in a minimally invasive endoscopic procedure. Several short-term studies and a few long-term studies have confirmed that POEM is a safe and effective treatment for achalasia. However, the long-term outcome of POEM performed by trainees is unknown. MATERIALS AND METHODS: We conducted a retrospective study of all patients who underwent POEM for achalasia at our tertiary care center during December 2012 and January 2019. All procedures performed with trainees were included. The primary outcome was the clinical response to POEM, defined as an Eckardt score of <3 after POEM. Trainees were trained in performing mucosotomy and submucosal dissection, creating a submucosal tunnel, identifying gastroesophageal junction, and performing myotomy and closure of mucosal incision in a step-by-step fashion. Trainees' performance was evaluated by the mentor based on several key points in each step. RESULTS: A total of 153 consecutive patients with a median age of 57±18 years were analyzed in this study. Of the total patients, 69 (45%) were male. The median length of follow-up after POEM was 32 months (range: 7 to 77 mo). A clinically significant response to POEM was achieved in 95% of patients at year 1, 84% at year 2, 80% at year 3, 79% at year 4, 78% at year 5, and 78% at year 6 and above. All trainees obtained competence within 6 cases for each step and could perform the procedure alone after 20 supervised cases. CONCLUSIONS: Overall, 78% of patients maintained positive clinical response at 6 years following POEM procedure. The recurrence rate of symptoms following POEM was 22% at a 6-year follow-up. This long-term outcome of POEM performed with trainees was comparable to those without trainees in other studies. To our knowledge, this is the longest follow-up and the largest number of patients after the POEM procedure performed with trainees.

Association Between Obesity and Cancer Mortality: An Internal Medicine Outpatient Clinic Perspective.

BACKGROUND: Obesity is one of the leading preventable causes of cancer that has a causal relationship with cancers of esophagus, breast and colon. Paradoxically, there are studies demonstrating that obesity is associated with improved survival in cancer patients. The aim of our study was to investigate the association of obesity and cancer mortality in adult patients. METHODS: Retrospective medical record review of 784 adult patients was performed who had a diagnosis of cancer and who were seen in our outpatient Internal Medicine Clinic between January 1, 2019 and December 31, 2019. RESULTS: Forty-three (5.2%) patients were cancer non-survivors and 741 (94.8%) were cancer survivors. The mean age of the cancer non-survivors group was significantly higher than that of the cancer survivors (78.7 vs. 68.0 years, respectively; P < 0.001). For every unit increase in age, there was 7.6% increased odds of cancer death (95% confidence interval (CI): 3-12%) (P = 0.001). Average body mass index (BMI) of the patients in the cancer non-survivors group was significantly lower than that of the cancer survivors group (25.0 vs. 28.1 kg/m2; P = 0.008). Non-obese patients had 4.9 times greater odds of cancer death (95% CI: 1.51 - 15.81) (P = 0.008). The mean glycosylated hemoglobin (HbA1c) was significantly higher in the cancer non-survivors group compared to the cancer survivors group (7.1% vs. 6.0%; P < 0.001), and for every unit increase in HbA1c there was 1.6 times greater odds of cancer death (95% CI: 1.14 - 2.23) (P = 0.006). Patients with peripheral artery disease (PAD) had 3.5 times greater odds of cancer death compared to those without PAD (95% CI: 1.18 - 10.19) (P = 0.023). CONCLUSIONS: Non-obese patients with cancer had higher odds of cancer death. Rising HbA1c, increasing age, and presence of PAD were associated with increased cancer mortality.

Gas Leak and Mucosal Injury During Endoscopic Esophageal Myotomy After Previous Myotomy: A Single-Center Experience.

PURPOSE: Peroral endoscopic myotomy (POEM) after prior myotomy (PM-POEM) can be technically challenging with possible increased adverse events. We aimed to assess gas leak and mucosal injury incidence during PM-POEM, compared to an index POEM (iPOEM), and post-procedure extubation time. PATIENTS AND METHODS: A retrospective study comparing PM-POEM to iPOEM from March 2016 to August 2018. RESULTS: There were 21 subjects in the PM-POEM and 56 subjects in the iPOEM. The PM-POEM group was younger (average age 44.33 vs 57.57 years, p=0.0082). Gas leak incidence did not differ between groups (28.6% in PM-POEM vs 14.3% in iPOEM, p=0.148). For cases with imaging available postoperatively, there was a trend towards higher incidence of gas leak in the PM-POEM, but it was not statistically significant (60% vs 42.1%, p=0.359). The post-procedure extubation time was not different between PM-POEM and iPOEM (11.38 vs 9.46 minutes, p=0.93), but it was longer when gas leak occurred (15.92 vs 8.67 minutes, p=0.027). The odds of mucosal injury were four-fold higher (OR, 4.31; 95% CI, 1.32-14.08), and more clips were used to close mucosal injuries (0.62 vs 0.14 clips, p=0.0053) in the PM-POEM group. More procedures were deemed difficult or challenging in the PM-POEM (33.3% vs 7.1%, p=0.007). The number of clips used to close the mucosotomy was not different between groups (4.05 vs 3.84 clips, p=0.498). Although the myotomy was shorter in PM-POEM, it was not statistically significant (6.38 vs 7.14 cm, p=0.074). However, the procedure was longer in PM-POEM (61.28 vs 45.39 minutes, p=0.0017). There was no intervention or ICU admission required pertinent to the procedure. CONCLUSION: Performing PM-POEM can be more difficult with more mucosal injuries. Gas leak was associated with a slightly longer post-procedure extubation time, but clinical relevance is unclear given incidence of gas leak was unknown at time of extubation.

Prevalence and Risk Factors for Intraductal Papillary Mucinous Neoplasm in Patients With Chronic Kidney Disease: A Single-Center Case-Control Study.

OBJECTIVES: The exact prevalence for intraductal papillary mucinous neoplasm (IPMN) in patients with chronic kidney disease (CKD) remains unknown. In this single-center case-control study, we aimed to study the prevalence and risk factors for IPMN in patients with CKD. METHODS: We performed a retrospective case-control study comparing patients with and without CKD who had magnetic resonance imaging of the abdomen performed between January 2018 and December 2018. Patient demographic, clinical, and imaging metrics were extracted from chart review. The prevalence of IPMN was compared between the 2 groups. RESULTS: A total of 800 patient charts were reviewed. There were 400 patients with CKD compared with an age-matched control group of 400 patients without CKD. The total prevalence of IPMN in patients with CKD was 13.7% (55/400) compared with 7.8% (29/400; P = 0.002) in non-CKD patients. The prevalence of diabetes mellitus was significantly higher in the CKD group (41% vs 14%, P = 0.0001). The percentage of patients consuming alcohol was significantly higher in the non-CKD group (23% vs 35%, P = 0.002). CONCLUSIONS: Patients with CKD have a significantly higher prevalence of IPMN compared with non-CKD patients. Larger population-based studies are needed to confirm these findings.

Development and Validation of the Patient-Reported Submental Fat Rating Scale and the Patient-Reported Submental Fat Impact Scale.

BACKGROUND: No validated assessment tools are available to evaluate patient-reported outcomes specifically related to submental fat (SMF). OBJECTIVE: To develop and validate scales measuring the severity (Patient-Reported SMF Rating Scale [PR-SMFRS]) and psychological impact (Patient-Reported SMF Impact Scale [PR-SMFIS]) of SMF. MATERIALS AND METHODS: A literature review, content validation interviews (concept elicitation [n = 29] and cognitive debriefing [n = 15]) in adults with SMF, and expert interviews (n = 3) were conducted to develop the PR-SMFRS and PR-SMFIS. Psychometric validity (acceptability, reliability, and validity) for the PR-SMFRS and PR-SMFIS was assessed using data from 1 phase 2 and 5 phase 3 ATX-101 studies in patients with excess SMF. RESULTS: The PR-SMFRS was constructed as a single-item, 5-point rating of the SMF amount/size. The PR-SMFIS was constructed as a 6-item scale, with an 11-point numeric rating for each item. Both scales demonstrated acceptable psychometric properties (test-retest reliability and internal consistency). The anchor-based minimally important difference analysis suggests a 1-point improvement on the PR-SMFRS (scale of 0‒4) and a 3-point improvement on the PR-SMFIS (scale of 0‒10) represent clinically meaningful change. CONCLUSION: The PR-SMFRS and PR-SMFIS are reliable, valid instruments for assessing the severity and psychosocial impact, respectively, of SMF and detecting clinically meaningful change with intervention.

CERE-120 Prevents Irradiation-Induced Hypofunction and Restores Immune Homeostasis in Porcine Salivary Glands.

Salivary gland hypofunction causes significant morbidity and loss of quality of life for head and neck cancer patients treated with radiotherapy. Preventing hypofunction is an unmet therapeutic need. We used an adeno-associated virus serotype 2 (AAV2) vector expressing the human neurotrophic factor neurturin (CERE-120) to treat murine submandibular glands either pre- or post-irradiation (IR). Treatment with CERE-120 pre-IR, not post-IR, prevented hypofunction. RNA sequencing (RNA-seq) analysis showed reduced gene expression associated with fibrosis and the innate and humoral immune responses. We then used a minipig model with CERE-120 treatment pre-IR and also compared outcomes of the contralateral non-IR gland. Analysis of gene expression, morphology, and immunostaining showed reduced IR-related immune responses and improved secretory mechanisms. CERE-120 prevented IR-induced hypofunction and restored immune homeostasis, and there was a coordinated contralateral gland response to either damage or treatment. CERE-120 gene therapy is a potential treatment for head and neck cancer patients to influence communication among neuronal, immune, and epithelial cells to prevent IR-induced salivary hypofunction and restore immune homeostasis.