Characterizing the Immune Environment in Peritoneal Carcinomatosis: Insights for Novel Immunotherapy Strategies.

BACKGROUND OR PURPOSE: Carcinomatosis, a distinct pattern of metastatic cancer in the peritoneal cavity, poses challenges for treatment and has limited therapeutic options. Understanding the immune environment of peritoneal surface malignancies is crucial for developing effective immunotherapeutic approaches. This study characterizes soluble immune mediators in the peritoneal fluid of patients with and without carcinomatosis to identify targets for novel treatment strategies. PATIENTS AND METHODS: Serum and peritoneal fluid samples were collected from surgical patients, and a multianalyte analysis was performed using the Luminex platform. Patient characteristics, tumor sites, and sample collection details were recorded. Soluble immune mediator levels were measured and compared between peritoneal fluid and serum samples and among clinical subgroups. Statistical analysis was conducted to assess differences in analyte concentrations and correlations between samples. RESULTS: There were 39 patients included in the study, with varying surgical indications. Significant differences were observed in soluble immune mediator levels between peritoneal fluid and serum, with peritoneal fluid exhibiting lower concentrations. Carcinomatosis was associated with elevated levels of proinflammatory mediators, including IL-6 and IL-8, while adaptive immune response markers were low in peritoneal fluid. CONCLUSIONS: The peritoneal immune microenvironment in carcinomatosis favors innate immunity, presenting a challenging environment for effective antitumor response. High levels of proinflammatory mediators suggest potential targets for intervention, such as the IL-6 axis, FGF2, IL-8, and CCL2; these could be explored as potential mitigators of malignant ascites and enhance anti-tumor immune responses. These findings provide valuable insights for developing immunotherapy strategies and improving outcomes in patients with peritoneal carcinomatosis.

Defining the Values and Quality of Life of Cancer Survivors Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: An International Survey Study.

BACKGROUND: Advances in treatment of peritoneal surface malignancies including cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS±HIPEC) have led to long-term survivorship, yet the subsequent quality of life (QOL) and values of these patients are unknown. PATIENTS AND METHODS: Survivors were offered surveys via online support groups. Novel items assessed how patients prioritized experience, costs, longevity, and wellbeing. RESULTS: Of the 453 gastrointestinal/hepatobiliary (GI/HPB) surgical patients that responded, 74 underwent CRS±HIPEC and were 54±12 years old, 87% female, and 93% white. Respondents averaged 29 months from diagnosis, with a maximum survival of 20 years. With a moderate level of agreement (W = 39%), rankings of value metrics among respondents were predictable (p < 0.001). Longevity and functional independence were ranked highest; treatment experience and cost of treatment were ranked lowest (p < 0.001). Those who underwent CRS±HIPEC or other GI/HPB surgeries reported the same rank order. QOL in CRS±HIPEC survivors, both mental (M-QOL) (44±13) and physical (P-QOL) (41±11) were lower than in the general population (50±10); p < 0.001. Impairments persisted throughout survivorship, but M-QOL improved over time (p < 0.05). When comparing CRS±HIPEC with other GI/HPB cancer surgery survivors, M-QOL (43±13 versus 43±14, p = 0.85) and P-QOL (40±11 versus 42±12, p = 0.41) were similar. CONCLUSIONS: Although CRS±HIPEC survivors experience long-term mental and physical health impairments, they were similar to those experienced by survivors of other GI/HPB cancer surgeries, and their QOL improved significantly throughout survivorship. As CRS±HIPEC survivors prioritize longevity above all other metrics, survival benefit may outweigh a temporary reduction in QOL.

Clinical and Socioeconomic Factors that Predict Non-completion of Adjuvant Chemotherapy for Colorectal Cancer in a Rural Cancer Center.

BACKGROUND: Previous literature demonstrates correlations between comorbidities and failure to complete adjuvant chemotherapy. Frailty and socioeconomic disparities have also been implicated in affecting cancer treatment outcomes. This study examines the effect of demographics, comorbidities, frailty, and socioeconomic status on chemotherapy completion rates in colorectal cancer patients. METHODS: This was an observational case-control study using retrospective data from Stage II and III colorectal cancer patients offered chemotherapy between January 01, 2013 and January 01, 2018. Data was obtained using the cancer registry, supplemented with chart review. Patients were divided based on treatment completion and compared with respect to comorbidities, age, Eastern Cooperative Oncology Group (ECOG) score, and insurance status using univariate and multivariate analyses. RESULTS: 228 patients were identified: 53 Stage II and 175 Stage III. Of these, 24.5% of Stage II and 30.3% of Stage III patients did not complete chemotherapy. Neither ECOG status nor any comorbidity predicted failure to complete treatment. Those failing to complete chemotherapy were older (64.4 vs 60.8 years, P = .043). Additionally, those with public assistance or self-pay were less likely to complete chemotherapy than those with private insurance (P = .049). Both factors (older age/insurance status) remained significant on multivariate analysis (increasing age at diagnosis: OR 1.03, P =.034; public insurance: OR 1.84, P = .07; and self-pay status: OR 4.49, P = .03). CONCLUSIONS: No comorbidity was associated with failure to complete therapy, nor was frailty, as assessed by ECOG score. Though frailty was not significant, increasing age was, possibly reflecting negative attitudes toward chemotherapy in older populations. Insurance status also predicted failure to complete treatment, suggesting disparities in access to treatment, affected by socioeconomic factors.

Management of the Crura During Laparoscopic Sleeve Gastrectomy.

METHODS: This is a retrospective cohort study that evaluated patients undergoing LSG performed by a single surgeon in a 7-year period. Data were collected via chart review. The primary endpoint was hiatal hernia presence at 5 years post-operatively. Secondary endpoints included post-procedural complications (nausea, vomiting, dysphagia, or reflux) at 30 days post-operatively. RESULTS: A total of 361 patients were included in the analysis: 154 without crural closure, 164 primary crural closure, and 43 primary crural closure with mesh reinforcement. Rates of hiatal hernia occurrence at 5 years were 9.7% (no closure), 14.0% (primary closure), and 16.3% (closure with mesh reinforcement), respectively, and did not differ significantly among the 3 cohorts (P = .37). Overall rates of 30-day complications were 11.5%, 21.5%, and 28.6%, respectively (P = .015). CONCLUSION: Rates of hiatal hernia after sleeve gastrectomy do not differ, regardless of management of the crura. In addition, and perhaps more significantly, avoidance of crural closure was associated with fewer 30-day complications. In fact, the highest rate of 30-day complications was seen in the group that received closure with mesh reinforcement. These data suggest that crural closure during LSG should be avoided. Further prospective study of these findings is warranted.

The Impact of Under-triage on Trauma Outcomes in Older Populations ≥65 Years.

BACKGROUND: Undertriage of older trauma patients is implicated as a cause for outcome disparities. Undertriage is defined by an Injury Severity Score (ISS) ≥16 without full trauma activation. We hypothesized that in patients ≥65 years, undertriage is associated with unfavorable discharge. METHODS: This is a retrospective study of patients ≥65 years admitted at a Level 1 Trauma Center between July 2016 and June 2018 with blunt trauma. The Matrix method was used to determine the undertriage rate, and outcomes were compared between undertriaged and fully activated patients with ISS ≥16. Favorable outcomes in undertriaged patients instigated further analyses to determine factors that predicted unfavorable discharge condition, defined by discharge from the hospital with severe disability, persistent vegetative state, and in-hospital death. RESULTS: The undertriage rate was 7.9%. When compared to fully activated patients with ISS ≥16, a lower percentage of undertriaged patients were discharged in an unfavorable condition (16.6% vs 64.7%, P < .001). On the multivariate analysis, male sex (OR = 1.52), preexisting coronary artery disease (OR = 1.86), age >90 years (OR = 2.31), ISS 16-25 (OR = 3.50), Glasgow Coma Score (GCS) ≤14 (OR = 6.34), and ISS >25 (OR = 9.64) were significant independent risk factors for unfavorable discharge. DISCUSSION: The undertriage rate in patients ≥65 years was higher than the accepted standard (5%). However, undertriaged patients had better outcomes than those fully activated with ISS ≥16. Factors more predictive of unfavorable discharge condition were GCS ≤14 and ISS >25. These data suggest that ISS alone is a poor marker for assessing undertriage in older patients. Additional parameters established in this study should be considered as potential markers for better predicting outcomes in older trauma patients.

The Provision of Acute Pediatric Surgical Care by Adult Acute Care General Surgeons : Is There a Learning Curve?

BACKGROUND: At our hospital, acute surgical care of children aged 6 and older is managed by adult acute care surgeons. Previously published data from a 10-year experience with this model demonstrated no differences in outcomes when compared with pediatric surgical benchmark data. This study assesses for the effects of a learning curve in the care of pediatric patients by comparing outcomes of patients treated in the first three years with those treated in the last 3 years during a 10-year experience with this model. DESIGN: This was a retrospective study of pediatric patients aged 6 and older who underwent an emergent or urgent, nontrauma surgical procedure by a general surgeon. Data was obtained via chart review and descriptive statistics were compared between patients operated on between January 1, 2009-January 1, 2012 and January 1, 2016-January 1, 2019. RESULTS: In all, 208 cases were performed in the early cohort and 192 cases in the late cohort. Appendectomy was the most common procedure in both intervals (88% early, 94.8% late). Although there was a significant decrease in open procedures in the later cohort (22.6% vs 4.7%, P < .001), there was no significant change in disease-specific complications or negative appendectomies. No consults to a fellowship-trained pediatric surgeon were required during either time period, although one was available if needed. CONCLUSIONS: Our data demonstrated a decrease in the number of open procedures in the later cohort. This may be due to an increased comfort level with pediatric laparoscopy over time. However, no significant changes in outcomes were observed. This study supports that acute care general surgeons can provide comparable care to pediatric patients within this age demographic and that although a learning curve, appears to exist with respect to pediatric laparoscopy, it is insignificant in terms of its effect on overall outcomes.

Supplements, nutrition, and alternative therapies for the treatment of traumatic brain injury.

Studies using traditional treatment strategies for mild traumatic brain injury (TBI) have produced limited clinical success. Interest in treatment for mild TBI is at an all time high due to its association with the development of chronic traumatic encephalopathy and other neurodegenerative diseases, yet therapeutic options remain limited. Traditional pharmaceutical interventions have failed to transition to the clinic for the treatment of mild TBI. As such, many pre-clinical studies are now implementing non-pharmaceutical therapies for TBI. These studies have demonstrated promise, particularly those that modulate secondary injury cascades activated after injury. Because no TBI therapy has been discovered for mild injury, researchers now look to pharmaceutical supplementation in an attempt to foster success in human clinical trials. Non-traditional therapies, such as acupuncture and even music therapy are being considered to combat the neuropsychiatric symptoms of TBI. In this review, we highlight alternative approaches that have been studied in clinical and pre-clinical studies of TBI, and other related forms of neural injury. The purpose of this review is to stimulate further investigation into novel and innovative approaches that can be used to treat the mechanisms and symptoms of mild TBI.

Do Age and Anticoagulants Affect the Natural History of Acute Subdural Hematomas?

Acute subdural hematoma is a serious complication following traumatic brain injury. Large volume hematomas or those with underlying brain injury can cause mass effect, midline shift, and eventually herniation of the brain. Acute subdural hematomas in the young are associated with high-energy trauma and often have underlying contusions, while acute subdural hematomas in the elderly are associated with minor trauma and an absence of underlying contusions, even though the elderly are more likely to be on anticoagulants or anti-platelet therapy. In the young patients with high impact injuries the hematomas tend to be small and the underlying brain injury and swelling is responsible for the increased intracranial pressure and midline shift. In the elderly, the injuries are low impact (e.g fall from standing), the underlying brain is intact, and the volume of the hematoma itself produces symptoms. In addition the use of anticoagulants and antiplatelet agents in the elderly population has been thought to be a poor prognostic indicator and is considered to be responsible for larger hematomas and poor outcome. When managed conservatively, acute subdural hematomas can sometimes progress to chronic subdural hematoma formation, further enlargement, seizures, and progressive midline shift. Another potential difference in the young and the elderly is brain atrophy, which increases the potential space to accommodate a larger hematoma. It is not known if these two groups differ in other ways that might have implications for treatment or prognosis. In this paper, we investigate the clinical course of 80 patients admitted to our institution with acute subdural hematomas, to identify differences in patients above or below the age of 65 years. The natural progression/resolution of acute subdural hematomas was mapped by measuring volume expansion/regression over time. In this retrospective chart review, we investigated clinical baseline metrics and subsequent volumetric expansion outcomes between patients < 65 years old (N=44) and those > 65 years old (N=36). Volume was estimated by the ABC/2 method. We observed a statistically significant difference between groups in use of anticoagulants χ2 =40.305 with p < 0.001, corrective platelet administration χ2 =19.380 with p < 0.001, gender χ2 =14.573 with p < 0.001, and Glasgow Coma Scale with χ2 =23.125 (p=0.026). Overall outcomes were similar in the two groups. Younger patients on average had worse presenting GCS scores, but recovered comparable to older patients. No significant difference in rate of volume expansion, resolution time, or need for surgical treatment was seen between these two groups. We conclude that the initial volume, size, and severity of subdural hematoma determined by the Glasgow Coma Scale score is more likely to predict surgery or future expansion than age of the patient. Patients on oral anti-coagulants that are given appropriate medical reversal agents early do quite well and no impact on the eventual outcome could be demonstrated. Further work is needed to establish better predictors of future volume expansion, and progression to chronic subdural hematoma based on improved severity scales.

Bryostatin-1 Restores Blood Brain Barrier Integrity following Blast-Induced Traumatic Brain Injury.

Recent wars in Iraq and Afghanistan have accounted for an estimated 270,000 blast exposures among military personnel. Blast traumatic brain injury (TBI) is the 'signature injury' of modern warfare. Blood brain barrier (BBB) disruption following blast TBI can lead to long-term and diffuse neuroinflammation. In this study, we investigate for the first time the role of bryostatin-1, a specific protein kinase C (PKC) modulator, in ameliorating BBB breakdown. Thirty seven Sprague-Dawley rats were used for this study. We utilized a clinically relevant and validated blast model to expose animals to moderate blast exposure. Groups included: control, single blast exposure, and single blast exposure + bryostatin-1. Bryostatin-1 was administered i.p. 2.5 mg/kg after blast exposure. Evan's blue, immunohistochemistry, and western blot analysis were performed to assess injury. Evan's blue binds to albumin and is a marker for BBB disruption. The single blast exposure caused an increase in permeability compared to control (t = 4.808, p < 0.05), and a reduction back toward control levels when bryostatin-1 was administered (t = 5.113, p < 0.01). Three important PKC isozymes, PKCα, PKCδ, and PKCε, were co-localized primarily with endothelial cells but not astrocytes. Bryostatin-1 administration reduced toxic PKCα levels back toward control levels (t = 4.559, p < 0.01) and increased the neuroprotective isozyme PKCε (t = 6.102, p < 0.01). Bryostatin-1 caused a significant increase in the tight junction proteins VE-cadherin, ZO-1, and occludin through modulation of PKC activity. Bryostatin-1 ultimately decreased BBB breakdown potentially due to modulation of PKC isozymes. Future work will examine the role of bryostatin-1 in preventing chronic neurodegeneration following repetitive neurotrauma.