Automated spatial omics landscape analysis approach reveals novel tissue architectures in ulcerative colitis.

The utility of spatial omics in leveraging cellular interactions in normal and diseased states for precision medicine is hampered by a lack of strategies for matching disease states with spatial heterogeneity-guided cellular annotations. Here we use a spatial context-dependent approach that matches spatial pattern detection to cell annotation. Using this approach in existing datasets from ulcerative colitis patient colonic biopsies, we identified architectural complexities and associated difficult-to-detect rare cell types in ulcerative colitis germinal-center B cell follicles. Our approach deepens our understanding of health and disease pathogenesis, illustrates a strategy for automating nested architecture detection for highly multiplexed spatial biology data, and informs precision diagnosis and therapeutic strategies.

Exploring the effects of taurolidine on tumor weight and microvessel density in a murine model of osteosarcoma.

Background: Osteosarcoma is the most common malignant primary bone tumor. The prognosis for patients with disseminated disease remains very poor despite recent advancements in chemotherapy. Moreover, current treatment regimens bear a significant risk of serious side effects. Thus, there is an unmet clinical need for effective therapies with improved safety profiles. Taurolidine is an antibacterial agent that has been shown to induce cell death in different types of cancer cell lines. Methods: In this study, we examined both the antineoplastic and antiangiogenic effects of taurolidine in animal models of osteosarcoma. K7M2 murine osteosarcoma cells were injected, both intramuscular and intraperitoneal, into 60 BALB/c mice on day zero. Animals were then randomized to receive treatment with taurolidine 2% (800 mg/kg), taurolidine 1% (400 mg/kg), or NaCl 0.9% control for seven days by intravenous or intraperitoneal administration. Results: After 35 days, mice were euthanized, and the tumors were harvested for analysis. Eighteen mice were excluded from the analysis due to complications. Body weight was significantly lower in the 2% taurolidine intraperitoneal treatment group from day 9 to 21, consistent with elevated mortality in this group. Intraperitoneal tumor weight was significantly lower in the 1% (p = 0.003) and 2% (p = 0.006) intraperitoneal taurolidine treatment groups compared to the control. No antineoplastic effects were observed on intramuscular tumors or for intravenous administration of taurolidine. There were no significant differences in microvessel density or mitotic rate between treatment groups. Reduced body weight and elevated mortality in the 2% taurolidine intraperitoneal group suggest that the lower 1% dose is preferable. Conclusions: In conclusion, there is no evidence of antiangiogenic activity, and the antitumor effects of taurolidine on osteosarcoma observed in this study are limited. Moreover, its toxic profile grants further evaluation. Given these observations, further research is necessary to refine the use of taurolidine in osteosarcoma treatment.

The impact of distance to facility on treatment modality, short-term outcomes, and survival of patients with HPV-positive oropharyngeal squamous cell carcinoma.

PURPOSE: This study compared treatment and outcomes for patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) based on their travel distance to treatment facility. MATERIALS AND METHODS: Patients with cT1-4, N0-3, M0 HPV-positive OPSCC in the National Cancer Database from 2010 to 2019 were identified and split into four quartiles based on distance to facility, with quartile 4 representing patients with furthest travel distances. Multivariable-adjusted logistic regression and Cox proportional hazards modeling were used to analyze the primary outcome of treatment received, and secondary outcomes of clinical stage, overall survival, surgical approach (i.e., TORS versus other), and 30-day surgical readmissions. RESULTS: 17,207 patients with HPV-positive OPSCC were evenly distributed into four quartiles. Compared to patients in quartile 1, patients in quartile 4 were 40 % less likely to receive radiation versus surgery (OR = 0.60; 95 % CI = 0.54-0.66). Among the patients who received surgery, quartile 4 had a higher odds of receiving TORS treatment compared to quartile 1 (4v1: OR = 2.38; 95 % CI = 2.05-2.77), quartile 2 (4v2: OR = 2.31, 95 % CI = 2.00-2.66), and quartile 3 (4v3: OR = 1.75; 95 % CI = 1.54-1.99). Quartile 4 had a decreased odds of mortality compared to Quartile 1 (4v1: OR = 0.87; 95 % CI = 0.79-0.97). There were no differences among the quartiles in presenting stage and 30-day readmissions. CONCLUSIONS: This study found that patients with furthest travel distance to facility were more often treated surgically over non-surgical management, with TORS over open surgery, and had better overall survival. These findings highlight potential disparities in access to care for patients with HPV-positive OPSCC.

Metastatic merkel cell carcinoma to the thyroid gland: Case report and review of the literature.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive and rare neuroendocrine tumor, accounting for less than 1% of skin cancers. Metastasis primarily manifests in the cervical lymph nodes but rarely affect the thyroid. METHODS: We report a case of primary head and neck cutaneous MCC with metastasis to the thyroid gland. A review of the literature of MCC with thyroid metastasis was conducted. RESULTS: We identified five cases of MCC with thyroid metastasis. Primary sites included the distal upper and lower extremities, axilla, buttock, and groin. Treatment courses varied including thyroidectomy, immunotherapy, and expectant palliative measures. Time from initial diagnosis to thyroid metastasis ranged from four months to four years. Tissue diagnosis was achieved in 5 of 6 cases. CONCLUSIONS: MCC with thyroid metastasis is rare and likely represents aggressive disease. Despite advances in treatment and surveillance, outcomes for MCC remain poor. Ongoing research may establish predictors for treatment response.

Frozen Section Timeout: Pilot Study to Reconcile Margins Using 3D Resected Specimen and Defect Scans.

OBJECTIVE: Opportunities exist to improve intraoperative communication and documentation of resection margin details. We instituted a "frozen section timeout" that centers around visualization of the paired resection specimen and surgical defect-facilitating effective, bidirectional exchange of information. METHODS: We designed an interactive form for use during the "frozen section timeout" including annotated 3D virtual models of the resected specimen and surgical defect, plus a "line-item" table for primary and supplemental margin results. The "timeout" was conducted over a Zoom call between the operating room and frozen section laboratory. The form was simultaneously projected and discussed while all members of the surgical care team stopped activities. Nurses, co-surgeons, and all other members of the surgical team were encouraged to take part in this process. RESULTS: Twenty-six frozen section timeouts were conducted during head and neck surgeries in the Department of Otolaryngology at Mount Sinai West Hospital. These timeouts were facilitated by the lead surgeon, and all other activities were halted to ensure that critical information was shared, documented, and agreed upon. During the timeout, the annotated specimen and defect scans were displayed, clearly demonstrating the at-risk margins and the corresponding location and breadth of supplemental margins harvested. CONCLUSION: Incorporating a frozen section timeout can improve intraoperative communication, increase transparency, and potentially eliminate uncertainty regarding margin status and tumor clearance. Visualization of at-risk margins and the corresponding location and breadth of supplemental margins promises an unprecedented level of documentation and understanding. This novel technique can establish a new and improved standard of care. LEVEL OF EVIDENCE: NA Laryngoscope, 134:725-731, 2024.

The Impact of Hospital Safety-Net Burden Status on Patients with HPV-Positive Oropharyngeal Cancer.

OBJECTIVES: The objective of this study was to compare treatment characteristics and outcomes between patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) treated at hospitals of varying safety-net burden status. METHODS: Patients with cT1-4, N0-3, M0 HPV-positive OPSCC who underwent definitive surgery or radiation were included. Patients were grouped based on their treating hospital safety-net burden status, defined as the percentage of uninsured and Medicaid-insured patients with OPSCC treated at the facility and stratified as low burden (LBH: 0-25th percentile), medium burden (MBH: 25th-75th percentile), or high burden (HBH: 75th-100th percentile). The primary outcome was primary treatment with surgery versus radiation, evaluated with multivariable-adjusted logistic regression. Secondary outcomes included TORS versus open surgical approach, and overall survival evaluated with Cox proportional hazards analysis. RESULTS: Of the 19,810 patients with cT1-4, N0-3, M0 HPV-positive OPSCC included in this study, 4921 (24.8%) were treated at LBH, 12,201 (61.6%) were treated at MBH, and 2688 (13.6%) were treated at HBH. In multivariable-adjusted analysis, compared with treatment at LBH, treatment at HBH was associated with more frequent radiation over surgical treatment (OR: 1.26, 95% CI: 1.12-1.40, p < 0.001). For patients undergoing surgery, patients at HBH had less frequent transoral robotic surgery (OR: 0.30, 95% CI 0.24-0.38, p < 0.001) compared with patients treated at LBH. Overall survival of patients treated at HBH was worse than that of patients treated at LBH (HR: 1.27, 95% CI 1.13-1.43, p < 0.001). CONCLUSION: These findings highlight underlying disparities at higher safety-net burden facilities that impact patterns of care and outcomes for patients with OPSCC. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:1733-1740, 2024.

An Update on Protein Kinases as Therapeutic Targets-Part II: Peptides as Allosteric Protein Kinase C Modulators Targeting Protein-Protein Interactions.

Human protein kinases are highly-sought-after drug targets, historically harnessed for treating cancer, cardiovascular disease, and an increasing number of autoimmune and inflammatory conditions. Most current treatments involve small molecule protein kinase inhibitors that interact orthosterically with the protein kinase ATP-binding pocket. As a result, these compounds are often poorly selective and highly toxic. Part I of this series reviews the role of PKC isoforms in various human diseases, featuring cancer and cardiovascular disease, as well as translational examples of PKC modulation applied to human health and disease. In the present Part II, we discuss alternative allosteric binding mechanisms for targeting PKC, as well as novel drug platforms, such as modified peptides. A major goal is to design protein kinase modulators with enhanced selectivity and improved pharmacological properties. To this end, we use molecular docking analysis to predict the mechanisms of action for inhibitor-kinase interactions that can facilitate the development of next-generation PKC modulators.

An Update on Protein Kinases as Therapeutic Targets-Part I: Protein Kinase C Activation and Its Role in Cancer and Cardiovascular Diseases.

Protein kinases are one of the most significant drug targets in the human proteome, historically harnessed for the treatment of cancer, cardiovascular disease, and a growing number of other conditions, including autoimmune and inflammatory processes. Since the approval of the first kinase inhibitors in the late 1990s and early 2000s, the field has grown exponentially, comprising 98 approved therapeutics to date, 37 of which were approved between 2016 and 2021. While many of these small-molecule protein kinase inhibitors that interact orthosterically with the protein kinase ATP binding pocket have been massively successful for oncological indications, their poor selectively for protein kinase isozymes have limited them due to toxicities in their application to other disease spaces. Thus, recent attention has turned to the use of alternative allosteric binding mechanisms and improved drug platforms such as modified peptides to design protein kinase modulators with enhanced selectivity and other pharmacological properties. Herein we review the role of different protein kinase C (PKC) isoforms in cancer and cardiovascular disease, with particular attention to PKC-family inhibitors. We discuss translational examples and carefully consider the advantages and limitations of each compound (Part I). We also discuss the recent advances in the field of protein kinase modulators, leverage molecular docking to model inhibitor-kinase interactions, and propose mechanisms of action that will aid in the design of next-generation protein kinase modulators (Part II).

iPad Annotation of 3D Surgical Models Using Procreate®: Novel Documentation of Supplemental Margins.

We present a novel, efficient approach to demonstrating supplemental margins during oncologic resection. Surgeons and pathologists annotated 10 virtual models of surgical defects and resection specimens in 3D using an iPad-based application, Procreate®. Incorporating this method into the surgical workflow can improve interdepartmental communication and provide visual documentation of surgical steps taken to address at-risk margins. Laryngoscope, 2023.

Intraoperative three-dimensional scanning of head and neck surgical defects: Enhanced communication and documentation of harvested supplemental margins.

BACKGROUND: We have demonstrated the effectiveness of 3D resection specimen scanning for communicating margin results. We now address the corresponding surgical defect by debuting 3D defect models, which allow for accurate annotations of harvested supplemental margins. METHODS: Surgical defects were rendered into 3D models, which were annotated to document the precise location of harvested supplemental margins. 3D defect scans were also compared with routine 2D photography and were analyzed for quality, clarity, and the time required to complete the scan. RESULTS: Forty defects were scanned from procedures including segmental mandibulectomy, maxillectomy, and laryngopharyngectomy. Average duration of defect scan was 6 min, 45 s. In six of ten 2D photographs, the surgeon was unable to precisely annotate the extent of at least one supplemental margin. CONCLUSION: 3D defect scanning offers advantages in that this technique enables documentation of the precise location and breadth of supplemental margins harvested to address margins at-risk.

Report of a vagal paraganglioma at the cervicothoracic junction.

BACKGROUND: Vagus nerve paragangliomas are rare tumors, comprising 0.03% of head and neck neoplasms. These tumors are usually located cephalad to the hyoid bone, and there is only one previously reported case that arose from the lower third of the neck. METHODS: We describe the second reported case of a lower neck vagus nerve paraganglioma that was managed with a limited sternotomy for access and surgical removal. RESULTS: A 66-year-old male presented with a long-standing lesion of the cervicothoracic junction. CT, MRI, and Ga-68 DOTATATE PET/CT showed an avidly enhancing 5.2 × 4.2 × 11.5 cm mass extending from C6 to approximately T4 level. FNA confirmed the diagnosis. The patient underwent catheter angiography and embolization via direct puncture technique followed by excision of the mass via a combined transcervical and limited sternotomy approach. CONCLUSION: We describe an unusual case of vagal paraganglioma at the cervicothoracic junction with retrosternal extension requiring a sternotomy for surgical excision.

Mass-Cytometry-Based Quantification of Global Histone Post-Translational Modifications at Single-Cell Resolution Across Peripheral Immune Cells in IBD.

BACKGROUND AND AIMS: Current understanding of histone post-translational modifications [histone modifications] across immune cell types in patients with inflammatory bowel disease [IBD] during remission and flare is limited. The present study aimed to quantify histone modifications at a single-cell resolution in IBD patients during remission and flare and how they differ compared to healthy controls. METHODS: We performed a case-control study of 94 subjects [83 IBD patients and 11 healthy controls]. IBD patients had either ulcerative colitis [n = 38] or Crohn's disease [n = 45] in clinical remission or flare. We used epigenetic profiling by time-of-flight [EpiTOF] to investigate changes in histone modifications within peripheral blood mononuclear cells from IBD patients. RESULTS: We discovered substantial heterogeneity in histone modifications across multiple immune cell types in IBD patients. They had a higher proportion of less differentiated CD34+ haematopoietic progenitors, and a subset of CD56bright natural killer [NK] cells and γδ T cells characterized by distinct histone modifications associated with gene transcription. The subset of CD56bright NK cells had increases in several histone acetylations. An epigenetically defined subset of NK cells was associated with higher levels of C-reactive protein in peripheral blood. CD34+ monocytes from IBD patients had significantly decreased cleaved H3T22, suggesting they were epigenetically primed for macrophage differentiation. CONCLUSION: We describe the first systems-level quantification of histone modifications across immune cells from IBD patients at a single-cell resolution, revealing the increased epigenetic heterogeneity that is not possible with traditional ChIP-seq profiling. Our data open new directions in investigating the association between histone modifications and IBD pathology using other epigenomic tools.

The Tumor Immune Microenvironment in Pancreatic Ductal Adenocarcinoma: Neither Hot nor Cold.

Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic tumor and is associated with poor prognosis and treatment response. The tumor microenvironment (TME) is recognized as an important factor in metastatic progression across cancers. Despite extensive study of the TME in PDAC, the cellular and molecular signaling networks remain poorly understood, largely due to the tremendous heterogeneity across tumors. While earlier work characterized PDAC as an immunologically privileged tumor poorly recognized by the immune system, recent studies revealed the important and nuanced roles of immune cells in the pathogenesis of PDAC. Distinct lymphoid, myeloid, and stromal cell types in the TME exert opposing influences on PDAC tumor trajectory, suggesting a more complex organization than the classical "hot" versus "cold" tumor distinction. We review the pro- and antitumor immune processes found in PDAC and briefly discuss their leverage for the development of novel therapeutic approaches in the field.

Metalloendopeptidase ADAM-like Decysin 1 (ADAMDEC1) in Colonic Subepithelial PDGFRα+ Cells Is a New Marker for Inflammatory Bowel Disease.

Metalloendopeptidase ADAM-Like Decysin 1 (ADAMDEC1) is an anti-inflammatory peptidase that is almost exclusively expressed in the gastrointestinal (GI) tract. We have recently found abundant and selective expression of Adamdec1 in colonic mucosal PDGFRα+ cells. However, the cellular origin for this gene expression is controversial as it is also known to be expressed in intestinal macrophages. We found that Adamdec1 mRNAs were selectively expressed in colonic mucosal subepithelial PDGFRα+ cells. ADAMDEC1 protein was mainly released from PDGFRα+ cells and accumulated in the mucosal layer lamina propria space near the epithelial basement membrane. PDGFRα+ cells significantly overexpressed Adamdec1 mRNAs and protein in DSS-induced colitis mice. Adamdec1 was predominantly expressed in CD45- PDGFRα+ cells in DSS-induced colitis mice, with only minimal expression in CD45+ CD64+ macrophages. Additionally, overexpression of both ADAMDEC1 mRNA and protein was consistently observed in PDGFRα+ cells, but not in CD64+ macrophages found in human colonic mucosal tissue affected by Crohn's disease. In summary, PDGFRα+ cells selectively express ADAMDEC1, which is localized to the colon mucosa layer. ADAMDEC1 expression significantly increases in DSS-induced colitis affected mice and Crohn's disease affected human tissue, suggesting that this gene can serve as a diagnostic and/or therapeutic target for intestinal inflammation and Crohn's disease.

Oral cancer patients achieve comparable survival at high safety-net burden hospitals.

PURPOSE: To evaluate the impact of hospital safety-net burden and social demographics on the overall survival of patients with oral cavity squamous cell carcinoma. MATERIALS AND METHODS: We identified 48,176 oral cancer patients diagnosed between the years 2004 to 2015 from the National Cancer Database and categorized treatment facilities as no, low, or high safety-net burden hospitals based on the percentage of uninsured or Medicaid patients treated. Using the Kaplan Meier method and multivariate analysis, we examined the effect of hospital safety-net burden, sociodemographic variables, and clinical factors on overall survival. RESULTS: Of the 1269 treatment facilities assessed, the median percentage of uninsured/Medicaid patients treated was 0% at no, 11.6% at low, and 23.5% at high safety-net burden hospitals and median survival was 68.6, 74.8, and 55.0 months, respectively (p < 0.0001). High safety-net burden hospitals treated more non-white populations (15.4%), lower median household income (<$30,000) (23.2%), and advanced stage cancers (AJCC III/IV) (54.6%). Patients treated at low (aHR = 0.97; 95% CI = 0.91-1.04, p = 0.405) and high (aHR = 1.05; 95% CI = 0.98-1.13, p = 0.175) safety-net burden hospitals did not experience worse survival outcomes compared to patients treated at no safety-net burden hospitals. CONCLUSION: High safety-net burden hospitals treated more oral cancer patients of lower socioeconomic status and advanced disease. Multivariate analysis showed high safety-net burden hospitals achieved comparable patient survival to lower burden hospitals.

Limited English proficiency and head and neck cancer outcomes.

PURPOSE: Limited English proficiency (LEP) is common among hospitalized patients and may impact clinical care and outcomes. This study aimed to examine the relationship between LEP and clinical oncological outcomes for patients with head and neck cancer (HNC). MATERIALS AND METHODS: A single center retrospective review was conducted including adult patients with squamous cell carcinoma of the head and neck who received treatment with curative intent between January 1, 2014 and July 1, 2019. Clinical data collected included patient demographics and clinical variables. Univariate and multivariate analysis was performed to determine whether there was an association between LEP and demographic and clinical factors. RESULTS: There were 477 patients included in the study; 426 (81%) were English proficient (EP) while 51 (10.7%) were LEP. The LEP patients were diagnosed with cancer at a later overall stage (p = 0.03) and less frequently treated with surgery alone compared to English speaking patients (p < 0.001). After adjusting for overall stage and primary site, LEP patients were significantly more likely to receive primary surgical management compared to primary non-surgical management [OR = 2.29 95% CI (0.93, 5.58), p = 0.008]. There was also a significant association between LEP and primary site of tumor (p < 0.01). Kaplan-Meyer curves for overall survival and disease specific survival showed no significant differences between the two cohorts (p = 0.8063 and p = 0.4986, respectively). CONCLUSIONS: LEP may impact access to care resulting in more advanced overall tumor stage at presentation and treatment with primary surgery compared to non-surgical management after adjusting for tumor stage and primary site. Interventions to provide better access to care, awareness of HNC in the LEP populations, and earlier detection may improve outcomes for LEP patients.

Disease exacerbation is common in inflammatory bowel disease patients treated with immune checkpoint inhibitors for malignancy.

BACKGROUND: Colitis is a known potential toxicity of immune checkpoint inhibitors (ICIs). Studies evaluating the risk of disease exacerbation following ICI treatment in patients with pre-existing inflammatory bowel disease (IBD) are limited. AIM: To assess the clinical characteristics of IBD patients treated with ICIs and determine prevalence of subsequent IBD exacerbations. METHODS: We conducted a retrospective cohort study of all patients in the Stanford Research Repository database with pre-existing IBD who were exposed to ICIs. RESULTS: The prevalence of IBD exacerbation following ICI was 36.8% amongst 19 patients meeting inclusion criteria. Patients with exacerbations had more gastrointestinal-related hospitalizations (4 of 7) than patients without exacerbations (0 of 12; P = 0.0090). CONCLUSION: The prevalence of IBD exacerbations following ICI was higher than reported rates of ICI-induced colitis and diarrhea in the general population and was associated with hospitalization.

The effect of a statewide prescription drug monitoring program on opioid prescribing patterns.

PURPOSE: Determine whether opioid prescribing patterns have changed as a result of implementation of a prescription drug monitoring program (PDMP) in the state of Massachusetts. MATERIALS AND METHODS: A multicentered retrospective study was performed including patients who received tonsillectomy, parotidectomy, thyroidectomy or direct laryngoscopy and biopsy with or without rigid esophagoscopy and/or rigid bronchoscopy at Lahey Hospital and Medical Center (Burlington, MA) or Boston Medical Center (Boston, MA). Opioid prescribing patterns were compared for the 12 months prior to implementation of the Massachusetts Prescription Awareness Tool (MassPAT) to 36 months of prescribing patterns post implementation. Quantity of opioids prescribed was based on morphine milligram equivalents (MME). Continuous variables were compared using analysis of variance (ANOVA) while categorical variables were compared using chi-squared test or Fisher's exact test. Multivariate analysis was performed using linear regression. RESULTS: A total of 2281 patients were included in the study. There was a significant association in mean overall MME prescribed comparing pre-MassPAT and post-MassPAT data [tonsillectomy: 635.9 ± 175.6 vs 463.3 ± 177.7 (p < 0.0001), parotidectomy: 250.4 ± 71.33 vs 169.8 ± 79.26 (p < 0.0001), thyroidectomy: 186.2 ± 81.14 vs 118.3 ± 88.79 (p < 0.0001), direct laryngoscopy with biopsy: 308.3 ± 246.9 vs 308.3 ± 246.9 (p = 0.0201)]. There was also a significant association between length of opioid prescription (days) and implementation of MassPAT, but there was no significant difference in the percent of patients requiring refills pre- MassPAT and post-MassPAT. CONCLUSION: This study demonstrates that prescribers have been able to significantly decrease the amount of opioids prescribed for tonsillectomy, parotidectomy, thyroidectomy, and direct laryngoscopy and biopsy and patients have not required additional opioid refills.