The effect of frailty and age on outcomes in elective paraesophageal hernia repair.

INTRODUCTION: Paraesophageal hernia repair (PEHR) is a safe and effective operation. Previous studies have described risk factors for poor peri-operative outcomes such as emergent operations or advanced patient age, and pre-operative frailty is a known risk factor in other major surgery. The goal of this retrospective cohort study was to determine if markers of frailty were predictive of poor peri-operative outcomes in elective paraesophageal hernia repair. METHODS: Patients who underwent elective PEHR between 1/2011 and 6/2022 at a single university-based institution were identified. Patient demographics, modified frailty index (mFI), and post-operative outcomes were recorded. A composite peri-operative morbidity outcome indicating the incidence of any of the following: prolonged length of stay (≥ 3 days), increased discharge level of care, and 30-day complications or readmissions was utilized for statistical analysis. Descriptive statistics and logistic regression were used to analyze the data. RESULTS: Of 547 patients who underwent elective PEHR, the mean age was 66.0 ± 12.3, and 77.1% (n = 422) were female. Median length of stay was 1 [IQR 1, 2]. ASA was 3-4 in 65.8% (n = 360) of patients. The composite outcome occurred in 32.4% (n = 177) of patients. On multivariate analysis, increasing age (OR 1.021, p = 0.02), high frailty (OR 2.02, p < 0.01), ASA 3-4 (OR 1.544, p = 0.05), and redo-PEHR (OR 1.72, p = 0.02) were each independently associated with the incidence of the composite outcome. On a regression of age for the composite outcome, a cutoff point of increased risk is identified at age 72 years old (OR 2.25, p < 0.01). CONCLUSION: High frailty and age over 72 years old each independently confer double the odds of a composite morbidity outcome that includes prolonged post-operative stay, peri-operative complications, the need for a higher level of care after elective paraesophageal hernia repair, and 30-day readmission. This provides additional information to counsel patients pre-operatively, as well as a potential opportunity for targeted pre-habilitation.

Interventions to Improve Surveillance for Hepatocellular Carcinoma in High-Risk Patients: A Scoping Review.

PURPOSE: Hepatocellular carcinoma (HCC) is most often a sequela of chronic liver disease or chronic hepatitis B infection. Among high-risk patients, surveillance for HCC every 6 months is recommended by international guidelines. However, rates of HCC surveillance are suboptimal (11-64%). Barriers at the patient, provider, and healthcare delivery system levels have been identified. METHODS: We performed a systemic scoping review to identify and characterize interventions to improve HCC surveillance that has previously been evaluated. Searches using key terms in PubMed and Embase were performed to identify studies examining interventions designed to improve the surveillance rate for HCC in patients with cirrhosis or chronic liver disease that were published in English between January 1990 and September 2021. RESULTS: Included studies (14) had the following study designs: (1) randomized clinical trials (3, 21.4%), (2) quasi-experimental (2, 14.3%), (3) prospective cohort (6, 42.8%), and (4) retrospective cohort (3, 21.4%). Interventions included mailed outreach invitations, nursing outreach, patient education with or without printed materials, provider education, patient navigation, chronic disease management programs, nursing-led protocols for image ordering, automated reminders to physicians and nurses, web-based clinical management tools, HCC surveillance databases, provider compliance reports, radiology-led surveillance programs, subsidized HCC surveillance, and the use of oral medications. It was found that HCC surveillance rates increased after intervention implementation in all studies. CONCLUSION: Despite improvements in HCC surveillance rates with intervention, compliance remained suboptimal. Further analysis of which interventions yield the greatest increases in HCC surveillance, design of multi-pronged strategies, and improved implementation are needed.

Improving Access and Quality of Care for Kidney Stone Patients in an Underserved Community.

There is a call to improve Medicaid patient access to health care, enhance quality and outcomes of care, and reduce overall financial burden. We sought to build a comprehensive kidney stone program to help patients navigate through the acute and preventive aspects of stone disease by increasing multidisciplinary referrals and compliance with recommendations and decreasing no-show rates at first follow-up and repeat stone encounters after initial evaluation. A collaborative multidisciplinary program was established at our single institution consisting of urology, nephrology, and dietary specialists to be piloted over a 3-year period. Medicaid-designated patients were evaluated during new patient encounters by urology specialists and then followed for outpatient follow-up, including specialty referrals to nephrology specialists and dietitians, for targeted preventive measures. Subjective compliance reports by patients following interventions and no-show rates at subsequent follow-ups were documented. We also followed patients 6 months beyond the initial encounter to assess repeat Emergency Department (ED) visits for acute stone episodes. One hundred eighty-three Medicaid-designated stone patients were evaluated from 2018 to 2021. Sixty-eight percent of patients identified as White, 18% identified as Black/African American, and 14% identified as "Other." Patients underwent specialty referrals to nephrology or a dietician in 47% and 42% of cases, respectively. Since the program's implementation, reported patient compliance and referrals to multidisciplinary specialists increased from 72.9% to 81.30% and 21.2% to 56.20%, respectively. Repeat ED visits for stone-related encounters within 6 months of initial presentation remained relatively stable (from 17.60% to 18.9%), while no-show rates at first follow-up decreased from 20.0% to 6.30% by study conclusion. There is continued supporting evidence for the importance of a comprehensive kidney stone program specifically for patients of lower socioeconomic status following a 3-year implementation at our institution. Encouraging results indicate increased access to multidisciplinary specialty referrals, with improvement in follow-up and reported compliance related to stone prevention strategies.

Patient-, Provider-, and System-Level Barriers to Surveillance for Hepatocellular Carcinoma in High-Risk Patients in the USA: a Scoping Review.

PURPOSE: Hepatocellular carcinoma has a dismal prognosis, except in patients diagnosed early who are candidates for potentially curative therapies. Most HCC cases develop in patients with chronic liver disease. Therefore, expert society guidelines recommend surveillance every 6 months with ultrasound with or without serum alpha-fetoprotein for high-risk patients. However, fewer than 20% of patients in the USA undergo appropriate surveillance. METHODS: A systematic scoping review was performed with the objective of identifying barriers to screening among high-risk patients in the USA including mapping key concepts in the relevant literature, identifying the main sources and types of evidence available, and identifying gaps in the literature. A total of 43 studies published from 2007 to 2021 were included. Data were extracted and a conceptual framework was created. RESULTS: Assessment of quantitative studies revealed poor surveillance rates, often below 50%. Three categories of barriers to surveillance were identified: patient-level, provider-level, and system-level barriers. Prevalent patient-level barriers included financial constraints, lack of awareness of surveillance recommendations, and scheduling difficulties. Common provider-level barriers were lack of provider awareness of guidelines for surveillance, difficulty accessing specialty resources, and time constraints in the clinic. System-level barriers included fewer clinic visits and rural/safety-net settings. Proposed interventions include improved patient/provider education, patient navigators, increased community/academic collaboration, and EMR-based reminders. CONCLUSION: Based on these findings, there is a crucial need to implement and evaluate proposed interventions to improve HCC surveillance.

mTORC1 regulates a lysosome-dependent adaptive shift in intracellular lipid species.

The mechanistic target of rapamycin complex 1 (mTORC1) senses and relays environmental signals from growth factors and nutrients to metabolic networks and adaptive cellular systems to control the synthesis and breakdown of macromolecules; however, beyond inducing de novo lipid synthesis, the role of mTORC1 in controlling cellular lipid content remains poorly understood. Here we show that inhibition of mTORC1 via small molecule inhibitors or nutrient deprivation leads to the accumulation of intracellular triglycerides in both cultured cells and a mouse tumor model. The elevated triglyceride pool following mTORC1 inhibition stems from the lysosome-dependent, but autophagy-independent, hydrolysis of phospholipid fatty acids. The liberated fatty acids are available for either triglyceride synthesis or ß-oxidation. Distinct from the established role of mTORC1 activation in promoting de novo lipid synthesis, our data indicate that mTORC1 inhibition triggers membrane phospholipid trafficking to the lysosome for catabolism and an adaptive shift in the use of constituent fatty acids for storage or energy production.

Reciprocal effects of mTOR inhibitors on pro-survival proteins dictate therapeutic responses in tuberous sclerosis complex.

mTORC1 is aberrantly activated in cancer and in the genetic tumor syndrome tuberous sclerosis complex (TSC), which is caused by loss-of-function mutations in the TSC complex, a negative regulator of mTORC1. Clinically approved mTORC1 inhibitors, such as rapamycin, elicit a cytostatic effect that fails to eliminate tumors and is rapidly reversible. We sought to determine the effects of mTORC1 on the core regulators of intrinsic apoptosis. In TSC2-deficient cells and tumors, we find that mTORC1 inhibitors shift cellular dependence from MCL-1 to BCL-2 and BCL-XL for survival, thereby altering susceptibility to BH3 mimetics that target specific pro-survival BCL-2 proteins. The BCL-2/BCL-XL inhibitor ABT-263 synergizes with rapamycin to induce apoptosis in TSC-deficient cells and in a mouse tumor model of TSC, resulting in a more complete and durable response. These data expose a therapeutic vulnerability in regulation of the apoptotic machinery downstream of mTORC1 that promotes a cytotoxic response to rapamycin.

Incidental splenosis discovered during robotic assisted radical prostatectomy: A case report.

Splenosis refers to the benign heterotopic auto transplantation of splenic tissue that most commonly arises following traumatic rupture of the spleen. It is most often associated with traumatic rupture of the spleen. While often asymptomatic, splenosis can mimic malignancy and may lead to unnecessary biopsy, chemotherapy, and surgery. This case report highlights an instance of splenosis discovered incidentally during robotic assisted radical prostatectomy. Splenules were sent for frozen section due to concern for malignancy. Retrospective analysis of imaging obtained prior to the procedure was consistent with splenosis.

Colonic intussusception masquerading as diverticulitis: a case report of a 31 year old diagnosed with colorectal carcinoma after multiple presentations to the ED for episodes of acute diverticulitis.

Colonic intussusception is a rare occurrence in adults, with few reported cases in the literature. Patients often present with nonspecific and vague symptoms leading to diagnostic challenges and delayed treatment. Given the high incidence of underlying malignancy associated with cases of adult intussusception, it is important for clinicians to be able to recognize and coordinate appropriate follow-up. A 31-year-old female presented to the emergency department four times over a month with left lower quadrant abdominal pain. Multiple computed tomography scans showed inflammation and diverticulitis of the mid-descending colon along with a short segment of colonic intussusception. A colonoscopy was performed due to concern for malignancy. A partially obstructing mass was found in the descending colon that could not be traversed. Biopsies revealed necrosis and no evidence of malignancy. However, given high suspicion for malignancy, the patient underwent a laparoscopic left colectomy, which revealed a pT3N1b colon adenocarcinoma.

IMPDH inhibitors for antitumor therapy in tuberous sclerosis complex.

Recent studies in distinct preclinical tumor models have established the nucleotide synthesis enzyme inosine-5'-monophosphate dehydrogenase (IMPDH) as a viable target for antitumor therapy. IMPDH inhibitors have been used clinically for decades as safe and effective immunosuppressants. However, the potential to repurpose these pharmacological agents for antitumor therapy requires further investigation, including direct comparisons of available compounds. Therefore, we tested structurally distinct IMPDH inhibitors in multiple cell and mouse tumor models of the genetic tumor syndrome tuberous sclerosis complex (TSC). TSC-associated tumors are driven by uncontrolled activation of the growth-promoting protein kinase complex mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), which is also aberrantly activated in the majority of sporadic cancers. Despite eliciting similar immunosuppressive effects, the IMPDH inhibitor mizoribine, used clinically throughout Asia, demonstrated far superior antitumor activity compared with the FDA-approved IMPDH inhibitor mycophenolate mofetil (or CellCept, a prodrug of mycophenolic acid). When compared directly to the mTOR inhibitor rapamycin, mizoribine treatment provided a more durable antitumor response associated with tumor cell death. These results provide preclinical support for repurposing mizoribine, over other IMPDH inhibitors, as an alternative to mTOR inhibitors for the treatment of TSC-associated tumors and possibly other tumors featuring uncontrolled mTORC1 activity.

mTORC1 Couples Nucleotide Synthesis to Nucleotide Demand Resulting in a Targetable Metabolic Vulnerability.

The mechanistic target of rapamycin complex 1 (mTORC1) supports proliferation through parallel induction of key anabolic processes, including protein, lipid, and nucleotide synthesis. We hypothesized that these processes are coupled to maintain anabolic balance in cells with mTORC1 activation, a common event in human cancers. Loss of the tuberous sclerosis complex (TSC) tumor suppressors results in activation of mTORC1 and development of the tumor syndrome TSC. We find that pharmacological inhibitors of guanylate nucleotide synthesis have selective deleterious effects on TSC-deficient cells, including in mouse tumor models. This effect stems from replication stress and DNA damage caused by mTORC1-driven rRNA synthesis, which renders nucleotide pools limiting. These findings reveal a metabolic vulnerability downstream of mTORC1 triggered by anabolic imbalance.

Endothelial cell senescence with aging in healthy humans: prevention by habitual exercise and relation to vascular endothelial function.

Cellular senescence is emerging as a key mechanism of age-related vascular endothelial dysfunction, but evidence in healthy humans is lacking. Moreover, the influence of lifestyle factors such as habitual exercise on endothelial cell (EC) senescence is unknown. We tested the hypothesis that EC senescence increases with sedentary, but not physically active, aging and is associated with vascular endothelial dysfunction. Protein expression (quantitative immunofluorescence) of p53, a transcription factor related to increased cellular senescence, and the cyclin-dependent kinase inhibitors p21 and p16 were 116%, 119%, and 128% greater (all P < 0.05), respectively, in ECs obtained from antecubital veins of older sedentary (60 ± 1 yr, n = 12) versus young sedentary (22 ± 1 yr, n = 9) adults. These age-related differences were not present (all P > 0.05) in venous ECs from older exercising adults (57 ± 1 yr, n = 13). Furthermore, venous EC protein levels of p53 (r = -0.49, P = 0.003), p21 (r = -0.38, P = 0.03), and p16 (r = -0.58, P = 0.002) were inversely associated with vascular endothelial function (brachial artery flow-mediated dilation). Similarly, protein expression of p53 and p21 was 26% and 23% higher (both P < 0.05), respectively, in ECs sampled from brachial arteries of healthy older sedentary (63 ± 1 yr, n = 18) versus young sedentary (25 ± 1 yr, n = 9) adults; age-related changes in arterial EC p53 and p21 expression were not observed (P > 0.05) in older habitually exercising adults (59 ± 1 yr, n = 14). These data indicate that EC senescence is associated with sedentary aging and is linked to endothelial dysfunction. Moreover, these data suggest that prevention of EC senescence may be one mechanism by which aerobic exercise protects against endothelial dysfunction with age.NEW & NOTEWORTHY Our study provides novel evidence in humans of increased endothelial cell senescence with sedentary aging, which is associated with impaired vascular endothelial function. Furthermore, our data suggest an absence of age-related increases in endothelial cell senescence in older exercising adults, which is linked with preserved vascular endothelial function.

BMI1 induces an invasive signature in melanoma that promotes metastasis and chemoresistance.

Melanoma can switch between proliferative and invasive states, which have identifying gene expression signatures that correlate with good and poor prognosis, respectively. However, the mechanisms controlling these signatures are poorly understood. In this study, we identify BMI1 as a key determinant of melanoma metastasis by which its overexpression enhanced and its deletion impaired dissemination. Remarkably, in this tumor type, BMI1 had no effect on proliferation or primary tumor growth but enhanced every step of the metastatic cascade. Consistent with the broad spectrum of effects, BMI1 activated widespread gene expression changes, which are characteristic of melanoma progression and also chemoresistance. Accordingly, we showed that up-regulation or down-regulation of BMI1 induced resistance or sensitivity to BRAF inhibitor treatment and that induction of noncanonical Wnt by BMI1 is required for this resistance. Finally, we showed that our BMI1-induced gene signature encompasses all of the hallmarks of the previously described melanoma invasive signature. Moreover, our signature is predictive of poor prognosis in human melanoma and is able to identify primary tumors that are likely to become metastatic. These data yield key insights into melanoma biology and establish BMI1 as a compelling drug target whose inhibition would suppress both metastasis and chemoresistance of melanoma.