The Current State of Neoadjuvant Therapy in Resectable Advanced Stage Melanoma.

The advent of effective immunotherapy and targeted therapy has significantly improved outcomes in advanced-stage resectable melanoma. Currently, the mainstay of treatment of malignant melanoma is surgery followed by adjuvant systemic therapies. However, recent studies have shown a potential role for neoadjuvant therapy in the treatment of advanced-stage resectable melanoma. Mechanistically, neoadjuvant immunotherapy may yield a more robust response than adjuvant immunotherapy, as the primary tumor serves as an antigen in this setting rather than only micrometastatic disease after the index procedure. Additionally, targeted therapy has been shown to yield effective neoadjuvant cytoreduction, and oncolytic viruses may also increase the immunogenicity of primary tumors. Effective neoadjuvant therapy may serve to decrease tumor size and thus reduce the extent of required surgery and thus morbidity. It also allows for assessment of pathologic response, facilitating prognostication as well as tailoring future therapy. The current literature consistently supports that neoadjuvant therapy, even as little as one dose, is associated with improved outcomes and is well-tolerated. Some patients with a complete pathological response may even avoid surgery completely. These results challenge the current paradigm of a surgery-first approach and provide further evidence supporting neoadjuvant therapy in advanced-stage resectable melanoma. Further research into the optimal treatment schedule and dose timing is warranted, as is the continued investigation of novel therapies and combinations of therapies.

A qualitative study of how team characteristics and leadership are associated with information sharing in multidisciplinary intensive care units.

BACKGROUND: Better information sharing in intensive care units has been associated with lower risk-adjusted mortality. This study explored how team characteristics and leadership are associated with information sharing in 4 intensive care units in a single large urban, academic medical center. METHODS: A qualitative study was conducted to understand how team characteristics and leadership are associated with information sharing. Qualitative data were conducted through ethnographic observations. One postdoctoral research fellow and one PhD qualitative researcher conducted nonparticipant observations of a Medical, Surgical, Neurological, and Cardiothoracic intensive care unit morning and afternoon rounds, as well as nurse and resident handoffs from May to September 2021. Field notes of observations were thematically analyzed using deductive reasoning anchored to the Edmondson Team Learning Model. This study included nurses, physicians (ie, intensivists, surgeons, fellows, and residents), medical students, pharmacists, respiratory therapists, dieticians, physical therapists, physician assistants, and nurse practitioners. RESULTS: We conducted 50 person-hours of observations involving 148 providers. Three themes emerged from the qualitative analysis: (1) team leaders used variable leadership techniques to involve team members in discussions for information sharing related to patient care, (2) predefined tasks for team members allowed them to prepare for effective information sharing during intensive care unit rounds, and (3) a psychologically safe environment allowed team members to participate in discussions for information sharing related to patient care. CONCLUSION: Inclusive team leadership is foundational in creating a psychologically safe environment for effective information sharing.

High-Density IgG4+ Plasma Cells Infiltration Is Associated With Fibroplasia in Fibrostenotic Crohn's Disease.

Transmural fibrosis and stricture formation are key pathogenic processes for Crohn's disease that underlies clinical refractoriness, resulting in severe morbidity. The mechanisms for fibroplasia in Crohn's are not fully elucidated. In this study, we identified a cohort of refractory Crohn's disease with surgically resected bowel specimens including cases with bowel stricture and age-/sex-matched refractory disease without bowel stricture. Via immunohistochemistry, density and distribution of IgG4+ plasma cells in resected cases were analyzed. The histologic severity of fibrosis and association with gross evidence of stricture formation and IgG4+ plasma cells were comprehensively analyzed. Our results showed that density of IgG4+ plasma cells/high-power field (IgG4+ PCs/HPF) was significantly associated with increasing histologic fibrosis score (15 IgG4+ PCs/HPF in specimens with fibrosis score 0 vs 31 IgG4+ PC/HPF in fibrosis score 2 and 3, P = .039). Patients with gross evidence of stricture had significantly higher fibrosis scores compared to those without gross evidence of stricture (P = .044). There was a trend that mean IgG4+ plasma cell count was higher in Crohn's disease with gross stricture formation (P = .26), although it did not reach statistical significance (likely due to multiple pathogenesis events involved in bowel stricture formation besides IgG4+ plasma cells; such as transmural fibrosis, muscular hypertrophy, transmural ulcer/scar formation, and muscular-neural dysfunction). Our findings indicate IgG4+ plasma cells are associated with increasing histologic fibrosis in Crohn's. Further research is needed to establish a role for IgG4+ plasma cells in fibroplasia with an eye toward potential medical therapies targeting IgG4+ plasma cells to prevent transmural fibrosis.

Is the Implementation of an Interprofessional Communication Smart Phone Application Associated With Improved Survival Among Critically Ill Surgical Patients?

INTRODUCTION: Patients admitted to intensive care units (ICUs) have high rates of mortality and morbidity. Improved communication between providers within ICUs may reduce morbidity. The goal of this study is to leverage a natural experiment of the temporally staggered implementation of a smart phone application for interprofessional communication to quantify the association with postoperative mortality and morbidity among critically ill surgical patients. METHODS: We conducted an observational case-control study and utilized a difference-in-difference model to determine the impact of temporally staggered implementation of an interprofessional communication smart phone application on mortality, postoperative hyperglycemia, malnutrition, venous thromboembolism (VTE), and surgical site infections. Our study included patients who underwent surgical procedures and were admitted to the ICU at one of three hospitals (one academic medical center, hospital A, and two community hospitals, hospitals B and C) in a single health system between March 2018 and April 2021. RESULTS: Our cohort consisted of 1457 patients, of which 1174 were hospitalized at hospital A and 283 at hospitals B and C. In the full cohort, 80 (5.6%) patients died during ICU admission. Difference-in-difference analysis demonstrated a relative difference in mortality of 4.8% [1.1%-8.5%] (P = 0.04) at hospitals B and C compared to hospital A after the implementation of the application. Our model demonstrated a 2.5% difference in VTEs [1.1%-3.8%], P = 0.03. There were no significant reductions in hyperglycemia, malnutrition, or surgical site infection. CONCLUSIONS: The implementation of an interprofessional communication smart phone application is associated with reduced mortality and VTE incidence among critically ill surgical patients across three diverse hospitals.

Clinical and histopathologic characterization of SETD2-mutated colorectal cancer.

With the advent of next-generation sequencing (NGS), identifying and better understanding genetic mutations in cancer pathways has become more feasible. A mutation now commonly reported in NGS panels is the SETD2 gene (H3K36 trimethyltransferase). However, its contributions to colorectal cancer (CRC) are not well described. In this study, we describe the clinicopathologic characteristics of SETD2-mutated CRC, determine common mutation sites on the SETD2 gene, and correlate these mutations with the loss of H3K36 trimethylation and the aberrant expression of beta-catenin. By searching pathology reports at our institution which included the 161-gene NGS panel from 2019 to 2021, we identify 24 individuals with SETD2-mutated CRC. All samples were evaluated for microsatellite status, H3K36 trimethylation, and beta-catenin via immunohistochemistry. In this cohort of 24 SETD2-mutated CRC individuals (a median age of 62.4 years [interquartile range: 49.1-73.6]), 10 (41.7%) patients presented at American Joint Committee on Cancer (AJCC) tumor stage II, seven (29.2%) at stage III, six (25%) at stage IV, and one (4.2%) at stage I. Most tumors studied were adenocarcinomas with no further specification (22, 92%), and most tumors were microsatellite stable (18, 82.5%). Thirty-three mutation locations were represented by 24 patients, with one patient having six mutations in the SETD2 gene and two patients having three mutations. The dominant mutation type is missense mutations (N = 29, 87.9%), and no mutation hotspots were found. Only two samples lost trimethylation of histone H3K36, both from individuals with multiple SETD2 mutations and aberrant nuclear beta-catenin expression. SETD2-mutated CRC is similar in clinical and histologic presentation to other commonly reported CRC. SETD2 mutations were missense dominantand showed no hotspots, and multiple mutations are likely necessary for loss of H3K36 trimethylation. These results warrant further study on determining a role of SETD2-histone H3K36 pathway in CRC.

High-Frequency Oscillations in Tumor-Related Epilepsy.

INTRODUCTION: To define the patient characteristics, tumor characteristics, and clinical course of patients with primary brain tumors with high-frequency oscillations (HFOs) recorded on electrocorticography. Furthermore, we evaluated whether the presence of HFOs portends a greater risk of postoperative tumor-related epilepsy and whether the resection of HFO-generating tissue reduces likelihood of postoperative tumor-related epilepsy. METHODS: This was a retrospective study of 35 patients undergoing awake craniotomy for tumor resection, all of whom underwent intraoperative electrocorticography. Electrocorticography data were reviewed to assess the presence of HFOs and determine their contact locations. The data were analyzed to determine whether HFO-generating tissue was included in the resection and relationship to postoperative seizure outcome. RESULTS: Seventeen patients (48.5%) were found to have HFOs. Very few patients (4 of 35, 11.4%) had sharp waves. Patients with and without HFOs did not significantly differ in demographics, presentation, tumor characteristics, or tumor molecular genetics. A history of seizures prior to resection was not associated with the presence of HFOs ( P = 0.62), although when patients had seizures during the same hospitalization as the resection, HFOs were more likely to be present ( P = 0.045). Extent of HFO resection was not associated with the likelihood of postoperative seizure freedom. CONCLUSIONS: Approximately half (48.5%) of patients undergoing resection for a primary brain tumor had HFOs. Although HFO resection was not shown to lead to improved seizure freedom, this study was limited by a small sample size, and further investigation into HFO resection and patient outcomes in this population is warranted.

Druggable sites/pockets of the p53-DNAJA1 protein-protein interaction: In silico modeling and in vitro/in vivo validation.

Mutation of p53 is the most common genetic alteration in human cancer. The vast majority of p53 mutations found in cancer are missense mutations, with some single nucleotide point mutations leading to the accumulation of mutant p53 protein with potential gain of oncogenic function. The mechanism for stabilization and accumulation of missense mutant p53 protein in malignant cells is not fully understood. It is thought that DNAJA1 plays a crucial role as a co-chaperone protein by stabilizing mutant p53 and amplifying oncogenic potential. As such, identifying small molecule inhibitors to disrupt the protein-protein interaction between mutant p53 and DNAJA1 may lead to an effective treatment for preventing carcinogenesis. Studying protein-protein interactions and identifying potential druggable hotspots has historically been limited-protein-protein binding sites require more complex characterization than those of single proteins and the crystal structures of many proteins have not been identified. Due to these issues, identifying salient druggable targets in protein-protein interactions through bench research may take years to complete. However, in silico modeling approaches allow for rapid characterization of protein-protein interfaces and the druggable binding sites they contain. In this chapter, we first review the oncogenic potential of mutant p53 and the crucial role of DNAJA1 in stabilizing missense mutant p53. We then detail our methodology for using in silico modeling and molecular biology to identify druggable protein-protein interaction sites/pockets between mutant p53 and DNAJA1. Finally, we discuss screening for and validating the utility of a small molecule inhibitor identified through our in silico framework. Specifically, we describe GY1-22, a unique compound with activity against mutant p53 that demonstrates therapeutic potential to inhibit cancer cell growth both in vivo and in vitro.

The effect of human immunodeficiency virus and human papillomavirus strain diversity on the progression of anal squamous intraepithelial lesions.

Anal squamous cell carcinoma (SCC) is a human papillomavirus (HPV)-mediated malignancy with increasing incidence. Human immunodeficiency virus (HIV) infection is a significant risk factor for anal SCC; however, it is unknown if HIV infection alters anal lesion progression and HPV strain profile. This study aims to determine whether HIV coinfection is associated with progression of HPV-mediated anal lesions and on their HPV strain diversity. This is a retrospective cohort study of adults with anal squamous intraepithelial lesion (SIL) who presented for anorectal sampling between 2010 and 2019. Using the full cohort, we performed clinicopathologic epidemiologic analysis of HIV coinfection on lesion progression. Using a subset of patients, we conducted molecular analysis of HPV strain diversity as related to HIV status and progression. Our cohort included 2203 individuals, of which 940 (43%) were HIV+. HIV+ status was associated with faster progression at all levels of dysplasia. Our molecular cohort included 329 adults, of which 190 (57.8%) were HIV+. HIV+ status was associated with higher HPV strain diversity (median: 7 [5-9] versus median: 4 [4-6], P < .001). Latent class analysis identified specific HPV strain signatures associated with progression. We demonstrate that HIV+ individuals had faster rates of anal SIL progression and that almost all HPV strains were more prevalent in anal samples from HIV+ adults. Our results imply that HIV+ adults with anal SIL should undergo more frequent screening and obtain HPV genotyping at initial presentation, as it shows value as a biomarker of lesion progression.

Single Center Experience with Incidence, Impact and Predictors of Biliary Complications in Donation After Circulatory Death Liver Transplantation.

Introduction: Utilizing allografts from donors after cardiac death (DCD) has improved organ availability, and DCD livers comprise a growing proportion of transplantations. However, it has been suggested that DCD transplantations have worse outcomes. Research Questions: We aimed to characterize outcomes in a large cohort of DCD transplantations, identify trends in outcomes over time, and identify factors associated with the development of biliary complications. Design: We conducted an observational retrospective cohort study of patients receiving DCD liver allografts within a large academic teaching hospital with a high transplantation volume. Consecutive patients who underwent Type III DCD liver transplantation from 2006-2016 were included in our cohort. Re-transplantations and multi-organ transplant recipients were excluded. Results: Ninety-six type III DCD transplantations occurred between 2006-2016. We report a 1one-year patient survival of 90.6% (87) and a 5five-year patient survival of 69.8% (67). Twenty-nine (30.2%) patients experienced any biliary complication in the first year following discharge, with 17 (17.7%) experiencing ischemic cholangiopathy. Five-year patient (P = 0.04) and graft (P = 0.005) survival improved over time. Post-operative biliary complications experienced during index admission and prior to discharge were found to be associated with the development of biliary complications (P = 0.005) and ischemic cholangiopathy (P = 0.01) following discharge. Conclusion: Our data suggested that outcomes using DCD allografts have improved, however biliary complications remain a significant issue in DCD transplantation. Patients who experienced post-operative biliary complications during index admission may require more frequent screening to allow the initiation of earlier treatment for biliary complications.

The Possible Pathogenic Role of IgG4-Producing Plasmablasts in Stricturing Crohn's Disease.

BACKGROUND: Crohn's disease (CD) is a condition on the spectrum of inflammatory bowel disease that affects up to 20 people per 100,000 in the US annually, and with incidence increasing. One of the most significant sources of morbidity in CD is the formation of strictures, with resultant intestinal blockage a common indication for hospitalization and surgical intervention in these patients. The pathophysiology of stricture formation is not fully understood. However, the fibroplasia that leads to fibrostenotic stricture formation may have shared pathophysiology with IgG4-related fibrosis. SUMMARY: Initial intestinal inflammation recruits innate immune cells, such as neutrophils, that secrete IL-1ß and IL-23, which induces a type 17 CD4+ T-helper T-cell (Th17)-mediated adaptive immune response. These CD4+ Th17 T cells also contribute to inflammation by secreting proinflammatory cytokines such as IL-17 and IL-21. IL-21 recruits and stimulates CD4+ T follicular helper (Tfh) cells, which secrete more IL-21. This causes ectopic germinal center formation, recruiting and stimulating naïve B cells. The IL-17 and IL-21 produced by Th17 cells and Tfh cells also induce IgG4 plasmablast differentiation. Finally, these IgG4-producing plasmablasts secrete platelet-derived growth factor (PDGF), which activates local PDGF-receptor expressing fibroblasts and myofibroblasts, resulting in uncontrolled fibroplasia.

Clinicopathologic characteristics of FBXW7-mutated colorectal adenocarcinoma and association with aberrant beta-catenin localization.

Oncogenic mutations in the adenomatous polyposis coli (APC)/Wnt signaling pathway are well documented. The FBXW7 gene (F-box and WD repeat domain-containing 7) encodes a member of the ubiquitin-proteasome complex that is more recently described to antagonize the oncogenic Wnt pathway by promoting the degradation of ß-catenin encoded by the CTNNB1 gene. The pathologic significance of FBXW7 mutation in colorectal carcinoma (CRC) remains under-reported. In this study, we report the clinicopathologic and ß-catenin immunohistochemical features of a single-institution cohort (83 cases) of FBXW7-mutated CRC compared with CTNNB1-mutated CRC. FBXW7-mutated CRC was more common in older patients (p = 0.031) and in the left/distal colon (p = 0.022). Immunohistochemical analysis revealed that aberrant nuclear/cytoplasmic ß-catenin localization was identified in a significantly high proportion of FBXW7-mutated CRCs. When compared with CTNNB1-mutated CRC, FBXW7-mutated CRC showed a significantly higher proportion of microsatellite instability-stable tumors with intact expression of DNA mismatch repair proteins and had significantly more frequent co-occurrence of missense TP53 and KRAS mutations. The most frequently mutated FBXW7 residues/hotspots were located within the WD repeat domains (aa 378-659), which were also associated with aberrant nuclear/cytoplasmic localization of ß-catenin protein. Our results indicate the unique pathologic characteristics of FBXW7-mutated CRC with frequent co-occurrence of missense mutant TP53 and KRAS. The mutated FBXW7 residues/hotspots and its association with aberrant nuclear/cytoplasmic ß-catenin localization further support the oncogenic role of FBXW7 in colon carcinogenesis.

Human Immunodeficiency Virus Infection Promotes Human Papillomavirus-Mediated Anal Squamous Carcinogenesis: An Immunologic and Pathobiologic Review.

BACKGROUND: Anal squamous cell carcinoma (SCC) is a rare gastrointestinal malignancy with rising incidence, both in the United States and internationally. The primary risk factor for anal SCC is human papillomavirus (HPV) infection. However, there is a growing burden of disease in patients with human immunodeficiency virus (HIV) and HPV coinfection, with the incidence of anal SCC significantly increasing in this population. This is particularly true in HIV-infected men. The epidemiologic correlation between HIV-HPV coinfection and anal SCC is established; however, the immunologic mechanisms underlying this relationship are not well understood. SUMMARY: HIV-related immunosuppression due to low circulating CD4+ T cells is one component of increased risk, but other mechanisms, such as the effect of HIV on CD8+ T lymphocyte tumor infiltration and the PD-1/PD-L1 axis in antitumor and antiviral response, is emerging as significant contributors. The goal of this article is to review existing research on HIV-HPV coinfected anal SCC and precancerous lesions, propose explanations for the detrimental synergy of HIV and HPV on the pathogenesis and immunologic response to HPV-associated cancers, and discuss implications for future treatments and immunotherapies in HIV-positive patients with HPV-mediated anal SCC. Key Messages: The incidence of anal squamous cell carcinoma is increased in human immunodeficiency virus (HIV)-infected patients, even in patients on highly active antiretroviral therapy. Locoregional HIV infection may enhance human papillomavirus oncogenicity. Chronic inflammation due to HIV infection may contribute to CD8+ T lymphocyte exhaustion by upregulating PD-1 expression, thereby blunting cytotoxic antitumor response.

Tumor type, epilepsy burden, and seizure documentation: experiences at a single center neuro-oncology clinic.

BACKGROUND: Patients with both primary and metastatic brain tumors have significant seizure burden due to their tumor. The management of tumor-related epilepsy (TRE) and optimizing antiepileptic drug (AED) regimens requires collaboration between neurologists and seizure specialists, which is facilitated by seizure documentation in clinic notes. We aim to describe seizure incidence in patients seen in neuro-oncology clinical practice. Further, in the subset of those patients with TRE, we aim to analyze seizure documentation. METHODS: This is a retrospective review of patients with a primary or metastatic brain tumor seen in a neuro-oncology clinic in October 2019. Patients with TRE were included in the analysis of seizure documentation. These notes were analyzed for inclusion of seizure descriptors, terminology, AED regimens, and changes in management. RESULTS: Of the full cohort of 356 patients, 199 (55.9%) had TRE. Anaplastic astrocytomas had the highest percentage of patients with TRE. The analysis of seizure documentation in patients with TRE revealed that the majority of notes (90.9%) mentioned seizures. Fewer notes (39.6%) provided additional descriptions of the seizures or commented on AED regimens (58.3%). In notes for patients who had seizures within the previous 6 months, seizure descriptors were more likely. CONCLUSIONS: This study defines the TRE burden in a cohort of patients seen in neuro-oncology clinic. Among patients with TRE, our study shows that documentation of many aspects of the characteristics and management of patient seizures can be improved, which would facilitate further analysis of impact on patient care as well as future research.

Efficacy of clobazam as add-on therapy in brain tumor-related epilepsy.

PURPOSE: Brain tumor-related epilepsy (TRE) is often resistant to currently available antiepileptic medications (AEDs). Clobazam was initially approved as adjunctive AED for patients with Lennox Gastaut syndrome but has been used in TRE, despite limited evidence in this context. This observational study aims to examine the effect of clobazam on seizure frequency on patients who have a primary CNS tumor and continued seizures despite their current AEDs. METHODS: A retrospective review of patients with histologically-confirmed primary brain tumors seen in the neuro-oncology interdisciplinary clinic from April 2016-2019 was completed, and patients on clobazam were identified. Response to clobazam was defined as a greater than 50% reduction in seizure frequency. Additional data including patient and tumor characteristics, treatment course, tolerability, AEDs used prior to addition of clobazam, and AEDs concomitantly used with clobazam were collected. RESULTS: A total of 35 patients with TRE on clobazam were identified, with 2 patients unable to tolerate the medication due to side effects. Of the 33 remaining patients, a total of 31 (93.9%) of patients were deemed responders. Ten patients (30.3%) were seizure free within 6 months of clobazam initiation and 21 (63.6%) reported a significant reduction in seizure frequency. This reduction also allowed several patients to modify concurrent AEDs. CONCLUSIONS: Clobazam is an effective agent to use as add-on AED in TRE, with 94% of patients showing a significant response within 6 months. Furthermore, the addition of clobazam may yield a reduction in polypharmacy, as concomitant AEDs can be reduced and potentially withdrawn.

Diagnosis of epidermodysplasia verruciformis: Two cases highlighting the role of direct HPV L1 gene sequencing.

Epidermodysplasia verruciformis (EV) is a rare skin disease characterized by the development of multiple flat warts with the potential for malignant transformation. Patients are susceptible to human papillomavirus (HPV) infection that develops in a background of either a genetic or acquired immunodeficiency predisposing patients to infection with specific HPV types that are ubiquitous but generally non-pathogenic in healthy individuals. There is no standard clinical methodology for determining the causative HPV from patients with suspected EV. Here, we report the diagnostic workup of two EV cases and describe the use of L1 gene Sanger sequencing as a specific method to accurately identify the causative HPV genotype and confirm the diagnosis of EV.