Summary Objective To gain an understanding of head and neck mucosal premalignant recurrence and progression based on histology, treatment modality, and risk factors. Design Retrospective chart ...review. Setting Academic medical center. Patients Patients who were followed or treated for oral cavity dysplasia/carcinoma in situ. Main outcomes measures Comparisons with clinical features, degree of dysplasia, anatomical location, rate of recurrences as well as malignant transformation and overall outcome were made. Results Of the 136 patients who were included in the study, 20% ( n = 27) initially presented with mild dysplasia, 39% ( n = 53) with moderate dysplasia, 21% ( n = 29) with severe dysplasia, and 20% ( n = 27) with carcinoma in situ. Wide local excision (HR 0.54, p = 0.05) was associated with reduced local recurrence in comparison to observation. In comparison to observation, both wide local excision (HR 0.43, p = 0.04) and CO2 /NO Yag laser treatment (HR 0.14, p = 0.02) of dysplastic lesions significantly reduced progression to cancer. Management of mild dysplasia included observation ( n = 13), excision ( n = 10) and laser therapy ( n = 3). Six of the 13 observed patients suffered a premalignancy recurrence, whereas only 4 of the 13 patients who underwent excision/laser treatment experienced a recurrence. Similarly, 5/13 observed patients eventually progressed to malignancy in comparison to only 2/13 patients who underwent initial excision/laser treatment. Conclusion Wide excision and/or ablation of head and neck mucosal premalignancy is more effective than observation in preventing recurrence of premalignancy and progression to malignancy. Mild dysplasia has a potentially high rate of recurrence and progression to malignancy when observed, and may be treated by wide excision or ablation.
Background
We investigated a novel minimally invasive surgical platform for use in the oropharynx, hypopharynx, and larynx for single-port transoral surgery used in concert with standard transoral ...laryngeal and pharyngeal instrumentation.
Methods
The preclinical investigational device by Fortimedix Surgical B.V. (Netherlands) features two channels for manually controlled flexible articulating surgical instruments. A third central channel accepts both rigid and flexible endoscopes. The system is coupled to a standard laryngoscope for transoral access. In three cadaver models, we evaluated the surgical capabilities using wristed grasping instruments, microlaryngeal scissors, monopolar cautery, and a laser fiber sheath. Procedures were performed within the oropharynx, supraglottis, glottis, subglottis, and hypopharynx.
Results
Within the oropharynx, we found adequate strength, range of motion, and dexterity to perform lateral oropharyngectomy and tongue base resection. Within the larynx, visualization was achieved with a variety of instruments including a flexible, 0° and 30° rigid endoscope. The glottis, supraglottis, pyriform sinuses, post-cricoid space, and esophageal inlet were readily accessible. Visualization and manipulation of grasping, laser, and monopolar cautery instruments were also possible within the subglottis. Instrument reach and accuracy facilitated completion of a delicate micro-flap on the true vocal fold. Other procedures included vocal fold resection, cricopharyngeal myotomy, and resection of subglottic mucosa.
Conclusions
From this initial proof of concept experience with this novel platform, we found a wide range of procedures within the oropharynx, larynx, and hypopharynx to be feasible. Further work is needed to evaluate its applicability to the clinical setting. The ability of this platform to be used with conventional instrumentation may provide an opportunity for complex transoral surgery to be performed in a facile manner at greatly reduced cost.
Head and neck squamous cell carcinoma (HNSCC) is largely divided into two groups based on their etiology, human papillomavirus (HPV)-positive and -negative. Global DNA methylation changes are known ...to drive oncogene and tumor suppressor expression in primary HNSCC of both types. However, significant heterogeneity in DNA methylation within the groups results in different transcriptional profiles and clinical outcomes. We applied a meta-pathway analysis to link gene expression changes to DNA methylation in distinguishing HNSCC subtypes. This approach isolated specific epigenetic changes controlling expression in HPV- HNSCC that distinguish it from HPV+ HNSCC. Analysis of genes identified Hedgehog pathway activation specific to HPV- HNSCC. We confirmed that GLI1, the primary Hedgehog target, showed higher expression in tumors compared to normal samples with HPV- tumors having the highest GLI1 expression, suggesting that increased expression of GLI1 is a potential driver in HPV- HNSCC. Our algorithm for integration of DNA methylation and gene expression can infer biologically significant molecular pathways that may be exploited as therapeutics targets. Our results suggest that therapeutics targeting the Hedgehog pathway may be of benefit in HPV- HNSCC. Similar integrative analysis of high-throughput coupled DNA methylation and expression datasets may yield novel insights into deregulated pathways in other cancers.
B cells play a key role in outcomes of cancer patients and responses to checkpoint blockade immunotherapies. However, the effect of radiation therapy on B cell populations is poorly understood. Here ...we characterize the effects of radiation on the development, survival, and phenotype of physiological B-cell subsets.
Naïve and immunized tumor bearing and nontumor bearing mice were treated with large-field or focal stereotactic radiation and distinct B-cell subsets of varying developmental stages were analyzed by flow cytometry and real-time reverse transcription polymerase chain reaction.
We first report that focal stereotactic radiation is highly superior to large-field radiation at inducing tumor infiltration of B cells, CD8
T cells, and macrophages. We observed that radiation affects B cell development in the bone marrow, increasing frequencies of early pro-B cells and late pro-B cells while inducing upregulation of programmed cell death protein 1. We then demonstrate that class switched B cells and plasma cells are highly resistant to radiation therapy compared with naïve B cells and upregulate activation markers programmed cell death 1 ligand 2 and major histocompatibility complex class II) after radiation. Mechanistically, radiation upregulates Xbp1 and Bcl6 in plasma cells, conferring radioresistance. Furthermore, using an immunization approach, we demonstrate that radiation enhances activation-induced cytidine deaminase mediated class switching and somatic hypermutation in primed B cells.
These data demonstrate that stereotactic radiation is superior to large-field radiation at inducing infiltration of immune cells into tumors and that plasma cells and class switched B cells are highly resistant to radiation therapy. These results represent the most comprehensive analysis of the effects of radiation on B cells to date and identify novel mechanisms by which radiation modulates immune cells within the tumor microenvironment.
Summary
Defects in telomere maintenance genes cause pathological telomere shortening, and manifest in syndromes which have prominent phenotypes in tissues of high turnover: the skin and bone marrow. ...Because the gastrointestinal (GI) epithelium is highly proliferative, we sought to determine whether telomere syndromes cause GI disease, and to define its prevalence, spectrum, and natural history. We queried subjects in the Johns Hopkins Telomere Syndrome Registry for evidence of luminal GI disease. In sixteen percent of Registry subjects (6 of 38), there was a history of significant GI pathology, and 43 additional cases were identified in the literature. Esophageal stenosis, enteropathy, and enterocolitis were the recurrent findings. In the intestinal mucosa, there was striking villous atrophy, extensive apoptosis, and anaphase bridging pointing to regenerative defects in the epithelial compartment. GI disease was often the first and most severe manifestation of telomere disease in young children. These findings indicate that telomere dysfunction disrupts the epithelial integrity in the human GI tract manifesting in recognizable disease processes. A high index of suspicion should facilitate diagnosis and management.
Accurate oncologic staging meeting clinical practice guidelines is essential for guideline adherence, quality assessment, and survival outcomes. However, timely and uniform documentation in the ...electronic health record (EHR) at the time of diagnosis is a challenge for providers. This quality improvement project aimed to increase provider compliance of timely clinical TNM (cTNM) or pathologic TNM (pTNM) staging for newly diagnosed oncologic patients.
Providers in the following site-specific oncologic teams were included: head and neck, skin, breast, genitourinary, gastrointestinal, lung and thoracic, gynecologic, colorectal, and bone marrow transplant. Interventions to facilitate timely cTNM and pTNM staging included standardized EHR-based workflows, learning modules, stakeholder meetings, and individualized provider training sessions. For most teams, staging was considered compliant if it was completed in the EHR within the first 7 days of the calendar month after the date of the patient visit. Factors associated with staging compliance were analyzed using logistic regression models.
From January 1, 2014, to December 31, 2018, 7,787 preintervention and 5,152 postintervention new patient visits occurred. During the preintervention period, staging was compliant in 5.6% of patients compared with 67.4% of patients after intervention (P<.001). In the final month of the postintervention period, the overall staging compliance rate was 78.1%. At most recent tracking, staging compliance was 95%, 97%, and 93% in December 2019, January 2020, and February 2020, respectively. Logistic regression found that increasing years of provider experience was associated with decreased staging compliance.
High rates of staging compliance in complex multidisciplinary academic oncologic practice models can be achieved via comprehensive quality improvement and structured initiatives. This approach serves as a model for improving oncologic documentation systems to facilitate clinical decision-making and multidisciplinary coordination of care.
The pathogenesis of breast cancer involves multiple genetic and epigenetic events. In this study, we report an epigenetic alteration of
DFNA5 in human breast cancer.
DFNA5 gene was silenced in breast ...cancer cell lines that were methylated in the
DFNA5 promoter, and restored by treatment with the demethylating agent, 5-aza-dC, and gene knock-down of
DFNA5 increased cellular invasiveness
in vitro. The mRNA expression of
DFNA5 in breast cancer tissues was down-regulated as compared to normal tissues. Moreover, the
DFNA5 promoter was found to be methylated in primary tumor tissues with high frequency (53%, 18/34). Quantitative methylation-specific PCR of
DFNA5 clearly discriminated primary breast cancer tissues from normal breast tissues (15.3%, 2/13). Moreover, methylation status of
DFNA5 was correlated with lymph node metastasis in breast cancer patients. Our data implicate
DFNA5 promoter methylation as a novel molecular biomarker in human breast cancer.
Cancer/testis antigens (CTAs) were first discovered as immunogenic targets normally expressed in germline cells, but differentially expressed in a variety of human cancers. In this study, we used an ...integrative epigenetic screening approach to identify coordinately expressed genes in human non-small cell lung cancer (NSCLC) whose transcription is driven by promoter demethylation.
Our screening approach found 290 significant genes from the over 47,000 transcripts incorporated in the Affymetrix Human Genome U133 Plus 2.0 expression array. Of the top 55 candidates, 10 showed both differential overexpression and promoter region hypomethylation in NSCLC. Surprisingly, 6 of the 10 genes discovered by this approach were CTAs. Using a separate cohort of primary tumor and normal tissue, we validated NSCLC promoter hypomethylation and increased expression by quantitative RT-PCR for all 10 genes. We noted significant, coordinated coexpression of multiple target genes, as well as coordinated promoter demethylation, in a large set of individual tumors that was associated with the SCC subtype of NSCLC. In addition, we identified 2 novel target genes that exhibited growth-promoting effects in multiple cell lines.
Coordinated promoter demethylation in NSCLC is associated with aberrant expression of CTAs and potential, novel candidate protooncogenes that can be identified using integrative discovery techniques. These findings have significant implications for discovery of novel CTAs and CT antigen directed immunotherapy.
Background
Sinonasal squamous cell carcinoma (SNSCC) is the most common malignancy of the paranasal sinuses. Surgery is the mainstay of treatment, yet positive surgical margins (PSM) are common and ...the prognostic impact on overall survival (OS) is mixed. Given the heterogeneity of impact of PSM on OS within the literature, we hypothesized that extent of tumor extirpation (microscopic PSM vs macroscopic PSM) may play a role in OS.
Methods
Patients with SNSCC were identified in the National Cancer Database (NCDB, n = 7808). Of these, 4543 patients underwent surgery, 3265 patients underwent nonsurgical therapy. Kaplan‐Meier curves were used to compare OS between negative surgical margin (NSM), micro‐PSM, and macro‐PSM cohorts vs patients undergoing primary nonsurgical therapy in a propensity‐score‒matched analysis. Multivariable analysis of factors associated with macro‐PSM was also performed.
Results
One thousand thirty‐three (22.0%) of the surgery patients had PSM, and approximately half (n = 521, 50.6%) of these had macro‐PSM. When compared with nonsurgical treatment, propensity‐score‒matched results demonstrated improved OS in patients with NSM and micro‐PSM (p < 0.001), but macro‐PSM patients did not demonstrate improvement (p = 0.20). Tumor within the paranasal sinuses and advanced nodal classification (N2/N3) (odds ratio OR, 1.18; p = 0.02; and OR, 15.09; p = 005, respectively) was associated with increased odds of macro‐PSM on multivariable analysis.
Conclusion
We demonstrate that the degree of tumor extirpation correlates with OS. Macro‐PSM did not confer a benefit to OS when compared with nonsurgical therapy, and factors including tumor location and advanced nodal status affect whether surgery will result in macro‐PSM. Given these findings, informed, shared decisionmaking between patient and surgeon regarding nonsurgical alternatives should occur before electing to proceed with surgery in SNSCC.
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