Augmentation of tumor expression of HLA-DR, CXCL9, and CXCL10 may improve olfactory neuroblastoma immunotherapeutic responses.

BACKGROUND: Olfactory neuroblastoma is a rare malignancy of the anterior skull base typically treated with surgery and adjuvant radiation. Although outcomes are fair for low-grade disease, patients with high-grade, recurrent, or metastatic disease oftentimes respond poorly to standard treatment methods. We hypothesized that an in-depth evaluation of the olfactory neuroblastoma tumor immune microenvironment would identify mechanisms of immune evasion in high-grade olfactory neuroblastoma as well as rational targetable mechanisms for future translational immunotherapeutic approaches. METHODS: Multispectral immunofluorescence and RNAScope evaluation of the tumor immune microenvironment was performed on forty-seven clinically annotated olfactory neuroblastoma samples. A retrospective chart review was performed and clinical correlations assessed. RESULTS: A significant T cell infiltration was noted in olfactory neuroblastoma samples with a stromal predilection, presence of myeloid-derived suppressor cells, and sparse natural killer cells. A striking decrease was observed in MHC-I expression in high-grade olfactory neuroblastoma compared to low-grade disease, representing a mechanism of immune evasion in high-grade disease. Mechanistically, the immune effector stromal predilection appears driven by low tumor cell MHC class II (HLA-DR), CXCL9, and CXCL10 expression as those tumors with increased tumor cell expression of each of these mediators correlated with significant increases in T cell infiltration. CONCLUSION: These data suggest that immunotherapeutic strategies that augment tumor cell expression of MHC class II, CXCL9, and CXCL10 may improve parenchymal trafficking of immune effector cells in olfactory neuroblastoma and augment immunotherapeutic responses.

Comprehensive comparative analysis of the periodontal pathogen Porphyromonas gingivalis: exploring the pan-genome, the reconstruction of the gene regulatory network and genome-scale metabolic network.

Porphyromonas gingivalis is a nonmotile, obligate anaerobic, Gram-negative bacterium known for its association with periodontal disease and its involvement in systemic diseases such as atherosclerosis, cardiovascular disease, colon cancer, and Alzheimer's disease. This bacterium produces several virulence factors, including capsules, fimbriae, lipopolysaccharides, proteolytic enzymes, and hemagglutinins. A comparative genomic analysis revealed the open pangenome of P. gingivalis and identified complete type IV secretion systems in strain KCOM2805 and almost complete type VI secretion systems in strains KCOM2798 and ATCC49417, which is a new discovery as previous studies did not find the proteins involved in secretion systems IV and VI. Conservation of some virulence factors between different strains was observed, regardless of their genetic diversity and origin. In addition, we performed for the first time a reconstruction analysis of the gene regulatory network, identifying transcription factors and proteins involved in the regulatory mechanisms of bacterial pathogenesis. In particular, QseB regulates the expression of hemagglutinin and arginine deaminase, while Rex may suppress the release of gingipain through interactions with PorV and the formatum/nitrate transporter. Our study highlights the central role of conserved virulence factors and regulatory pathways, particularly QseB and Rex, in P. gingivalis and provides insights into potential therapeutic targets.

Chordoma cancer stem cell subpopulation characterization may guide targeted immunotherapy approaches to reduce disease recurrence.

Introduction: Cancer stem cells (CSCs), a group of tumor-initiating and tumor-maintaining cells, may be major players in the treatment resistance and recurrence distinctive of chordoma. Characterizing CSCs is crucial to better targeting this subpopulation. Methods: Using flow cytometry, six chordoma cell lines were evaluated for CSC composition. In vitro, cell lines were stained for B7H6, HER2, MICA-B, ULBP1, EGFR, and PD-L1 surface markers. Eighteen resected chordomas were stained using a multispectral immunofluorescence (mIF) antibody panel to identify CSCs in vivo. HALO software was used for quantitative CSC density and spatial analysis. Results: In vitro, chordoma CSCs express more B7H6, MICA-B, and ULBP1, assessed by percent positivity and mean fluorescence intensity (MFI), as compared to non-CSCs in all cell lines. PD- L1 percent positivity is increased by >20% in CSCs compared to non-CSCs in all cell lines except CH22. In vivo, CSCs comprise 1.39% of chordoma cells and most are PD-L1+ (75.18%). A spatial analysis suggests that chordoma CSCs cluster at an average distance of 71.51 mm (SD 73.40 mm) from stroma. Discussion: To our knowledge, this study is the first to identify individual chordoma CSCs and describe their surface phenotypes using in vitro and in vivo methods. PD-L1 is overexpressed on CSCs in chordoma human cell lines and operative tumor samples. Similarly, potential immunotherapeutic targets on CSCs, including B7H6, MICA-B, ULBP1, EGFR, and HER2 are overexpressed across cell lines. Targeting these markers may have a preferential role in combating CSCs, an aggressive subpopulation likely consequential to chordoma's high recurrence rate.

Triphasic response after endoscopic craniopharyngioma resection and its dependency on infundibular preservation or sacrifice.

OBJECTIVE: Surgery is the primary treatment for craniopharyngioma with the preservation of hypothalamic function of paramount importance. Infundibular preservation is debated, as maximal resection decreases recurrence rates but causes hypopituitarism. A triphasic response of diabetes insipidus (DI), syndrome of inappropriate antidiuretic hormone secretion (SIADH), and recurrent DI has been described after pituitary surgery, but the impact of infundibular preservation on the triphasic response following craniopharyngioma resection has not been well established. The authors' objective was to assess postoperative fluid and sodium balance and differences in ADH imbalance management following endonasal craniopharyngioma resection based on infundibular transection status. METHODS: This is a retrospective cohort study of 19 patients with craniopharyngioma treated with endoscopic endonasal resection between 2014 and 2021. Resection was dichotomized into infundibular transection or preservation. Postoperative triphasic response, time to DI, and time to ADH replacement were compared using Fisher's exact test and Kaplan-Meier analysis. RESULTS: Based on surgeon impression, 10 patients had infundibular transection and 9 had infundibular preservation. Overall, 16 patients experienced DI, 12 experienced persistent DI, and 6 experienced SIADH. A postoperative triphasic response occurred in 40% (n = 4) of transection patients without preoperative DI and 11% (n = 1) of preservation patients without preoperative DI. The median time to postoperative DI (0.5 vs 18.0 hours, p = 0.022) and median time to ADH replacement therapy (4.5 vs 24 hours, p = 0.0004) were significantly shorter in the transection group than in the preservation group. CONCLUSIONS: Following endonasal craniopharyngioma resection, the triphasic response occurs in nearly half of infundibular transection cases. DI begins earlier with infundibular transection. On the basis of the study findings in which no patients met the criteria for SIADH or were endocrinologically unstable after postoperative day 6, it is reasonable to suggest that otherwise stable patients can be discharged at or before postoperative day 6 when ADH fluctuations have normalized and endocrinopathy is appropriately managed with oral desmopressin. Infundibular transection status may impact postoperative hormonal replacement strategies, but additional studies should evaluate their efficacies.

Exploiting the immunogenic potential of standard of care radiation or cisplatin therapy in preclinical models of HPV-associated malignancies.

BACKGROUND: While radiation and chemotherapy are primarily purposed for their cytotoxic effects, a growing body of preclinical and clinical evidence demonstrates an immunogenic potential for these standard therapies. Accordingly, we sought to characterize the immunogenic potential of radiation and cisplatin in human tumor models of HPV-associated malignancies. These studies may inform rational combination immuno-oncology (IO) strategies to be employed in the clinic on the backbone of standard of care, and in so doing exploit the immunogenic potential of standard of care to improve durable responses in HPV-associated malignancies. METHODS: Retroviral transduction with HPV16 E7 established a novel HPV-associated sinonasal squamous cell carcinoma (SNSCC) cell line. Three established HPV16-positive cell lines were also studied (cervical carcinoma and head and neck squamous cell carcinoma). Following determination of sensitivities to standard therapies using MTT assays, flow cytometry was used to characterize induction of immunogenic cell stress following sublethal exposure to radiation or cisplatin, and the functional consequence of this induction was determined using impedance-based real time cell analysis cytotoxicity assays employing HPV16 E7-specific cytotoxic lymphocytes (CTLs) with or without N803 (IL-15/IL-15-Rα superagonist) or exogenous death receptor ligands. In vitro observations were translated using an in vivo xenograft NSG mouse model of human cervical carcinoma evaluating cisplatin in combination with CTL adoptive cell transfer. RESULTS: We showed that subpopulations surviving clinically relevant doses of radiation or cisplatin therapy were more susceptible to CTL-mediated lysis in four of four tumor models of HPV-associated malignancies, serving as a model for HPV therapeutic vaccine or T-cell receptor adoptive cell transfer. This increased killing was further amplified by IL-15 agonism employing N803. We further characterized that radiation or cisplatin induced immunogenic cell stress in three of three cell lines, and consequently demonstrated that upregulated surface expression of Fas and TRAIL-R2 death receptors at least in part mediated enhanced CTL-mediated lysis. In vivo, cisplatin-induced immunogenic cell stress synergistically potentiated CTL-mediated tumor control in a human model of HPV-associated malignancy. CONCLUSION: Standard of care radiation or cisplatin therapy induced immunogenic cell stress in preclinical models of HPV-associated malignancies, presenting an opportunity poised for exploitation by employing IO strategies in combination with standard of care.

Multi-spectral immunofluorescence evaluation of the myeloid, T cell, and natural killer cell tumor immune microenvironment in chordoma may guide immunotherapeutic strategies.

Background: Chordoma is a rare, invasive, and devastating bone malignancy of residual notochord tissue that arises at the skull base, sacrum, or spine. In order to maximize immunotherapeutic approaches as a potential treatment strategy in chordoma it is important to fully characterize the tumor immune microenvironment (TIME). Multispectral immunofluorescence (MIF) allows for comprehensive evaluation of tumor compartments, molecular co-expression, and immune cell spatial relationships. Here we implement MIF to define the myeloid, T cell, and natural killer (NK) cell compartments in an effort to guide rational design of immunotherapeutic strategies for chordoma. Methods: Chordoma tumor tissue from 57 patients was evaluated using MIF. Three panels were validated to assess myeloid cell, T cell, and NK cell populations. Slides were stained using an automated system and HALO software objective analysis was utilized for quantitative immune cell density and spatial comparisons between tumor and stroma compartments. Results: Chordoma TIME analysis revealed macrophage infiltration of the tumor parenchyma at a significantly higher density than stroma. In contrast, helper T cells, cytotoxic T cells, and T regulatory cells were significantly more abundant in stroma versus tumor. T cell compartment infiltration more commonly demonstrated a tumor parenchymal exclusion pattern, most markedly among cytotoxic T cells. NK cells were sparsely found within the chordoma TIME and few were in an activated state. No immune composition differences were seen in chordomas originating from diverse anatomic sites or between those resected at primary versus advanced disease stage. Conclusion: This is the first comprehensive evaluation of the chordoma TIME including myeloid, T cell, and NK cell appraisal using MIF. Our findings demonstrate that myeloid cells significantly infiltrate chordoma tumor parenchyma while T cells tend to be tumor parenchymal excluded with high stromal infiltration. On average, myeloid cells are found nearer to target tumor cells than T cells, potentially resulting in restriction of T effector cell function. This study suggests that future immunotherapy combinations for chordoma should be aimed at decreasing myeloid cell suppressive function while enhancing cytotoxic T cell and NK cell killing.

Human Papillomavirus-Related Carcinomas of the Sinonasal Tract.

Purpose of review: The sinonasal tract is home to a uniquely heterogenous collection of malignant tumors. Human papillomavirus (HPV) has been detected in a number of these, but the virus' role as an oncogenic driver or coincidental finding remains unclear. We aim to highlight five sinonasal tumor types and synthesize the prevalence, etiologic role, and known clinicopathologic relevance of HPV in each. Recent findings: The last decade has seen an expansion of investigation into HPV's oncogenic and prognostic significance within sinonasal malignancies. The sinonasal tract poses challenges to HPV detection where p16 lacks value as an accurate surrogate. A growing body of data supports a potentially favorable clinical profile for certain sinonasal HPV-positive lesions. Summary: HPV represents a potential biologically and clinically relevant factor for some sinonasal malignancies. Definitive conclusions regarding HPV's role as a potential oncogenic agent require routine testing using validated methodologies, genomic interrogation, and large-scale prospective studies.

Emerging concepts in sinonasal tumor research.

PURPOSE OF REVIEW: Sinonasal malignancies are rare and understudied, often diagnosed at late stages, and may behave aggressively. This review explores investigative diagnostic, therapeutic, and scientific advances specific to sinonasal undifferentiated carcinoma (SNUC), intestinal-type adenocarcinoma (ITAC), and olfactory neuroblastoma (ONB). RECENT FINDINGS: A number of studies have recently contributed more robust knowledge of the genetic and molecular landscapes of SNUC, ITAC, and ONB. These analyses have identified SMARCB1 and IDH2 mutations in SNUC, potentially allowing for the tumor's subdivision. Recent studies have also defined a role for induction chemotherapy in SNUC. Somatic mutations for ITAC have been identified and may be potentially targetable with FDA approved therapies. Studies defining the tumor microenvironment for ITAC and ONB have introduced the possibility of immune checkpoint inhibition for these tumor types. SUMMARY: Studies reviewed here detail promising results of the most current and novel characterization of SNUC, ITAC, and ONB genetic and molecular landscapes, which have informed ongoing therapeutic discovery. With continued multi-institutional efforts, the field of sinonasal tumor research will achieve higher disease control and improved treatment outcomes for patients afflicted with these rare cancers.

Durability and Performance of 2298 Trifecta Aortic Valve Prostheses: A Propensity-Matched Analysis.

BACKGROUND: Reports of early failure of the Trifecta externally wrapped, bovine pericardial aortic valve prosthesis (Abbott Laboratories, Abbott Park, IL) raise concerns about its durability. This study evaluated the hemodynamic performance and explant of Trifecta valves compared with the PERIMOUNT bovine pericardial prosthesis (Edwards Lifesciences, Irvine, CA). METHODS: From October 2007 to July 2017, 2305 patients received a Trifecta bioprosthesis during aortic valve replacement at Cleveland Clinic. Trends in postoperative valve hemodynamics were assessed from 4971 transthoracic echocardiograms and valve explants by systemic follow-up. To compare outcomes, 2298 patients receiving a Trifecta valve were 1:1 propensity matched from 17,281 patients receiving a PERIMOUNT bioprosthesis. RESULTS: Mean age at implant was 69 years in both matched groups. Compared with PERIMOUNT valves, early transvalvular mean gradient of Trifecta valves was lower (11 vs 15 mm Hg at 1 year, P < .001); however, its longitudinal rate of rise was greater (P < .001), resulting in 5-year mean gradients of 17 vs 16 mm Hg, and more patients experienced severe aortic regurgitation (2.4% vs 0.81%; P < .001). At 5 years, 35 Trifecta valves had been explanted vs 14 PERIMOUNT valves; freedom from explant at 1, 3, and 5 years was 98.9%, 98.0%, and 95.9%, respectively, for the Trifecta group vs 99.3%, 99.0%, and 98.7% for the PERIMOUNT group (P < .001). CONCLUSIONS: Compared with an older-generation internally mounted bovine pericardial valve, the Trifecta externally wrapped bioprosthesis exhibits superior early hemodynamic performance, but has a rapid increase in transvalvular gradient and more aortic regurgitation, with lower freedom from explant at 5 years. These findings raise concern regarding long-term Trifecta durability despite favorable early hemodynamics.

Evaluación del conocimiento sobre efecto del cigarrillo en internas fumadoras. Pereira 2004 / Evaluation of Inpatient Smokers’ Knowledge of the Effect of Cigarettes. Pereira 2004

El objetivo general de este estudio fue evaluar el nivel de conocimiento sobre los daños causados por el cigarrillo, en las internas que fuman en un Establecimiento Penitenciario y Carcelario de Mujeres de Pereira, durante el segundo semestre de 2004. Inicialmente se identificaron y cuantificaron las condenadas fumadoras, obteniendo como población estudio un total de 34 internas entre las 149 presentes en la institución. Luego se aplicó una encuesta semiestructurada, la cual permitió recolectar las variables: continuas (nombre, edad etc.) y discontinuas, divididas en variables dicotómicas (procedencia, ¿tiene hijos?) y discretas (escolaridad, cambios en el organismo desde que comenzó a fumar). La información recolectada se condensó en una base de datos en epiinfo, la cual se analizó en forma univariada; posteriormente se realizó análisis bivariado, entre las variables más representativas. Las principales limitaciones en el desarrollo del trabajo fueron la falta de cooperación de las internas, algunas de las cuales presentaron una actitud apática y desconfiada alterando los datos de la encuesta y ocasionando de esta manera sesgos de información, además del horario para la recolección de información, ya que se cruzaba con otras actividades realizadas por ellas o por los estudiantes. El 91 por cien de las internas conoce que el hábito del cigarrillo trae efectos adversos para la salud; de ese 91 por cien, 52 por cien cree que causa cáncer de pulmón; el 15 por cien que causa ‘enfermedad en los pulmones’. El análisis bivariado mostró que a mayor edad, mayor es el conocimiento acerca de los efectos que el cigarrillo ejerce sobre la salud y la relación con el número de cigarrillos consumidos diariamente. Las internas tienen algún conocimiento de los efectos adversos del cigarrillo, porque la mayoría aceptó la relación de éste con enfermedades; pero la concordancia es básicamente para problemas respiratorios, más no para alteraciones sistémicas; además creen que to...