Long-term exposure to house dust mites accelerates lung cancer development in mice.

BACKGROUND: Individuals with certain chronic inflammatory lung diseases have a higher risk of developing lung cancer (LC). However, the underlying mechanisms remain largely unknown. Here, we hypothesized that chronic exposure to house dust mites (HDM), a common indoor aeroallergen associated with the development of asthma, accelerates LC development through the induction of chronic lung inflammation (CLI).  METHODS: The effects of HDM and heat-inactivated HDM (HI-HDM) extracts were evaluated in two preclinical mouse models of LC (a chemically-induced model using the carcinogen urethane and a genetically-driven model with oncogenic KrasG12D activation in lung epithelial cells) and on murine macrophages in vitro. Pharmacological blockade or genetic deletion of the Nod-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, caspase-1, interleukin-1ß (IL-1ß), and C-C motif chemokine ligand 2 (CCL2) or treatment with an inhaled corticosteroid (ICS) was used to uncover the pro-tumorigenic effect of HDM.  RESULTS: Chronic intranasal (i.n) instillation of HDM accelerated LC development in the two mouse models. Mechanistically, HDM caused a particular subtype of CLI, in which the NLRP3/IL-1ß signaling pathway is chronically activated in macrophages, and made the lung microenvironment conducive to tumor development. The tumor-promoting effect of HDM was significantly decreased by heat treatment of the HDM extract and was inhibited by NLRP3, IL-1ß, and CCL2 neutralization, or ICS treatment. CONCLUSIONS: Collectively, these data indicate that long-term exposure to HDM can accelerate lung tumorigenesis in susceptible hosts (e.g., mice and potentially humans exposed to lung carcinogens or genetically predisposed to develop LC).

Treatment of recurrent mucosal melanoma of the oral cavity with topical imiquimod and pembrolizumab achieves complete histopathologic remission.

Mucosal melanomas constitute a subtype of melanoma with less effective treatments than cutaneous melanomas. We present a case of oral mucosal melanoma that recurred despite multiple resections and adjuvant temozolomide. Treatment with topical imiquimod combined with pembrolizumab achieved remission. A 56-year-old woman presented with a pigmented mass on her left anterior hard palate. Biopsy revealed malignant melanoma. The patient had resection with neck dissection with 3 months of adjuvant temozolomide due to positive margins. Malignant melanoma involving the hard palate recurred 1 year later requiring additional resection. Two years later, two additional pigmented lesions were found; further resections were deferred due to expected morbidity. Following 6 weeks of topical imiquimod treatment, the lesions shrunk significantly. Adjuvant pembrolizumab was added and complete histopathologic remission was observed in 6 months. The patient remained in remission for 4 years before new melanoma in situ was diagnosed, requiring five additional months of imiquimod. As of April 2021, there is no clinical evidence of melanoma. There are limited reports of oral melanoma treated with topical imiquimod. Here, imiquimod administered in combination with pembrolizumab achieved complete pathologic response.

UltraPlex Hapten-Based Multiplexed Fluorescent Immunohistochemistry.

The UltraPlex method for multiplexed two-dimensional fluorescent immunohistochemistry is described, in which hapten tags conjugated to primary antibodies facilitate multiplexed imaging of four or more antigens per tissue section at once. Anti-hapten secondary antibodies labeled with fluorophores provide amplified signal for detection, which is accomplished using a standard fluorescent microscope or digital slide scanner. The protocol is rapid and straightforward and utilizes conventionally prepared tissue samples. The resulting staining is highly sensitive and specific, enabling high-resolution imaging of multiple cellular subtypes within tissue samples. Tumor cells and tumor-infiltrating lymphocytes are presented as examples. Multiple 4-plex-stained tissue samples can be digitally overlaid to create 8-plex (or more) high-content images, enabling visualization of distribution of complex cellular subtypes across tissues.

MicroRNA-Based Cancer Mortality Risk Scoring System and hTERT Expression in Early-Stage Oral Squamous Cell Carcinoma.

We have previously constructed a novel microRNA (miRNA)-based prognostic model and cancer-specific mortality risk score formula to predict survival outcome in oral squamous cell carcinoma (OSCC) patients who are already categorized into "early-stage" by the TNM staging system. A total of 836 early-stage OSCC patients were assigned the mortality risk scores. We evaluated the efficacy of various treatment regimens in terms of survival benefit compared to surgery only in patients stratified into high (risk score ≥0) versus low (risk score <0) mortality risk categories. For the high-risk group, surgery with neck dissection significantly improved the 5-year survival to 75% from 46% with surgery only (p < 0.001); a Cox proportional hazard model on time-to-death demonstrated a hazard ratio of 0.37 for surgery with neck dissection (95% CI: 0.2-0.6; p=0.0005). For the low-risk group, surgery only was the treatment of choice associated with 5-year survival benefit. Regardless of treatment selected, those with risk score ≥2 may benefit from additional therapy to prevent cancer relapse. We also identified hTERT (human telomerase reverse transcriptase) as a gene target common to the prognostic miRNAs. There was 22-fold increase in the hTERT expression level in patients with risk score ≥2 compared to healthy controls (p < 0.0005). Overexpression of hTERT was also observed in the patient-derived OSCC organoid compared to that of normal organoid. The DNA cancer vaccine that targets hTERT-expressing cells currently undergoing rigorous clinical evaluation for other tumors can be repurposed to prevent cancer recurrence in these high-risk early-stage oral cancer patients.

A Phase 1 Trial Assessing the Safety and Tolerability of a Therapeutic DNA Vaccination Against HPV16 and HPV18 E6/E7 Oncogenes After Chemoradiation for Cervical Cancer.

PURPOSE: This study assessed the safety and tolerability of therapeutic immunization against the human papillomavirus (HPV) viral oncoproteins E6 and E7 in patients with cervical cancer after chemoradiation. METHODS AND MATERIALS: MEDI0457 (INO-3112) is a DNA-based vaccine targeting E6 and E7 of HPV-16/18 that is coinjected with an IL-12 plasmid followed by electroporation with the CELLECTRA 5P device. At 2 to 4 weeks after chemoradiation, patients with newly diagnosed stage IB1-IVA (cohort 1) or persistent/recurrent (cohort 2) cervical cancers were treated with 4 immunizations of MEDI0457 every 4 weeks. The primary endpoints were incidence of adverse events and injection site reactions. Immune responses against HPV antigens were measured by ELISpot for interferon-γ (IFNγ), enzyme-linked immunosorbent assay for antibody responses and multiplexed immunofluorescence for immune cells in cervical biopsy specimens. RESULTS: Ten patients (cohort 1, n = 7; cohort 2, n = 3) with HPV16 (n = 7) or HPV18 (n = 3) cervical cancers received MEDI0457 after chemoradiation. Treatment-related adverse events were all grade 1, primarily related to the injection site. Eight of 10 patients had detectable cellular or humoral immune responses against HPV antigens after chemoradiation and vaccination: 6 of 10 patients generated anti-HPV antibody responses and 6 of 10 patients generated IFNγ-producing T cell responses. At the completion of chemoradiation and vaccination, cervical biopsy specimens had detectable CD8+ T cells and decreased PD-1+CD8+, PD-L1+CD8+, and PD-L1+CD68+ subpopulations. All patients cleared detectable HPV DNA in cervical biopsies by completion of chemoradiation and vaccination. CONCLUSIONS: Adjuvant MEDI0457 is safe and well tolerated after chemoradiation for locally advanced or recurrent cervical cancers, supporting further investigation into combining tumor-specific vaccines with radiation therapy.

An easy and reproducible parameter for the assessment of the pressure gradient in patients with aortic stenosis disease: A magnetic resonance study.

AIM: Cardiovascular magnetic resonance (CMR) has been increasingly used as an alternative method to evaluate the severity of aortic stenosis. The aim of our study was to evaluate whether the indirect measurement of the aortic gradient (Calc-PG), derived from Gorlin's formula, is a reproducible parameter for gradient assessment. Then, we evaluated if this parameter is correlated with left ventricular hypertrophy, considered as a marker of severity of aortic stenosis, better than phase-contrast sequences-derived pressure gradient (PC-PG) and aortic valve area. METHODS: Forty-one patients with isolated aortic stenosis underwent CMR. Calc-PG was obtained from the formula (cardiac output/aortic valve area)(2), and it was compared to PC-PG. RESULTS: We found that the Calc-PG has higher correlation with left ventricle mass than PC-PG (r(2) 0.44, p<0.001 vs. r(2) 0.26, p<0.01), also after multivariate analysis adjusting for age, gender and hypertension (p<0.001). Furthermore, Calc-PG was more reproducible than PC-PG. The receiver operating characteristic comparison curve analysis showed that Calc-PG has a significantly higher ability to describe the presence of left ventricular hypertrophy than PC-PG (area under the curve 0.85, 95% CI 0.70-0.94, p<0.0001 vs. 0.74, 95% CI 0.58-0.87, p=0.03). CONCLUSIONS: We propose that transaortic gradient indirectly calculated by using the simplified Gorlin's equation could be an alternative method to assess the severity of aortic stenosis.