Reconstructive Techniques in Pediatric Congenital Microtia: A Systematic Review and Meta-analysis.

Autografts and allografts are commonly used in microtia reconstruction. We aimed to systematically review and compare these reconstructive materials in pediatric congenital microtia reconstruction. A systematic review of the literature was performed. MEDLINE, Embase, PubMed, Web of Science, and CINAHL databases were searched for original studies on congenital microtia reconstruction in pediatric patients since database inception to 2021. Microtia grade was stratified as high or low. Meta-analysis of pooled proportions and continuous variables was performed using inverse variance weighting with a random effects model to compare between the autograft and allograft groups. Sixty-eight studies with a total of 5,546 patients used autografts (n = 5,382) or alloplastic implants (n = 164). Four other studies used prosthesis, cadaveric homografts, or tissue engineering. The allograft group was on average younger than the autograft group (8.4 vs. 11.1 years). There were no syndromic patients in the allograft group, compared to 43% in the autograft group. Patients treated with allografts had higher microtia grade than those treated with autograft (98 vs. 72%). Autografts were more commonly utilized by plastic surgeons and allografts by otolaryngologists (95 vs. 38%). No autografts and 41% of allografts were done concurrently with atresiaplasty or bone conduction implant. Satisfaction rates were similarly high (>90%) with similar complication rates (<10%). Microtia reconstruction using autografts and allografts had similar satisfaction and complication rates. Allografts were preferred for younger patients and concurrent hearing restoration. Further large-scale studies are required to evaluate the long-term efficacy of these reconstructive techniques.

HPV-negative head and neck cancers with adverse pathological features carry specific molecular changes that are associated with survival.

BACKGROUND: Adverse pathological features following surgery in head and neck squamous cell carcinoma (HNSCC) are strongly associated with survival and guide adjuvant therapy. We investigated molecular changes associated with these features. METHODS: We downloaded data from the Cancer Genome Atlas and Cancer Proteome Atlas HNSCC cohorts. We compared tumors positive versus negative for perineural invasion (PNI), lymphovascular invasion (LVI), extracapsular spread (ECS), and positive margins (PSM), with multivariable analysis. RESULTS: All pathological features were associated with poor survival, as were the following molecular changes: low cyclin E1 (HR = 1.7) and high PKC-alpha (HR = 1.8) in tumors with PNI; six of 13 protein abundance changes with LVI; greater tumor hypoxia and high Raptor (HR = 2.0) and Rictor (HR = 1.6) with ECS; and low p38 (HR = 2.3), high fibronectin (HR = 1.6), low annexin A1 (HR = 3.1), and high caspase-9 (HR = 1.6) abundances with PSM. CONCLUSIONS: Pathological features in HNSCC carry specific molecular changes that may explain their poor prognostic associations.

Lenvatinib in multimodal therapy for unresectable radioactive iodine-naïve differentiated thyroid cancer: A case report with literature review.

BACKGROUND: Patients with unresectable or metastatic differentiated thyroid carcinoma (DTC) are rare and require individualized therapy. This may require approaches not typically used in resectable disease. We report a patient treated with lenvatinib and external beam radiation therapy. CASE: An 87-year-old woman presented with cT4N1aM1 papillary thyroid carcinoma with tracheal invasion. She was not a candidate for surgery, radioactive-iodine, or radiation, so a trial of lenvatinib was offered. Her tumor showed clinical, biochemical, and radiological response after 5 months of lenvatinib, and she subsequently received external beam radiation. She enjoys good quality of life without evidence of cancer progression off therapy 21 months post-initiation of treatment. CONCLUSION: Lenvatinib may be effective in RAI-naïve advanced DTC patients as a component of individualized multimodal therapy when conventional options are not feasible.

3p Arm Loss and Survival in Head and Neck Cancer: An Analysis of TCGA Dataset.

Loss of the 3p chromosome arm has previously been reported to be a biomarker of poorer outcome in both human papillomavirus (HPV)-positive and HPV-negative head and neck cancer. However, the precise operational measurement of 3p arm loss is unclear and the mutational profile associated with the event has not been thoroughly characterized. We downloaded the clinical, single nucleotide variation (SNV), copy number aberration (CNA), RNA sequencing, and reverse phase protein assay (RPPA) data from The Cancer Genome Atlas (TCGA) and The Cancer Proteome Atlas HNSCC cohorts. Survival data and hypoxia scores were downloaded from published studies. In addition, we report the inclusion of an independent Memorial Sloan Kettering cohort. We assessed the frequency of loci deletions across the 3p arm separately in HPV-positive and -negative disease. We found that deletions on chromosome 3p were almost exclusively an all or none event in the HPV-negative cohort; patients either had <1% or >97% of the arm deleted. 3p arm loss, defined as >97% deletion in HPV-positive patients and >50% in HPV-negative patients, had no impact on survival (p > 0.05). However, HPV-negative tumors with 3p arm loss presented at a higher N-category and overall stage and developed more distant metastases (p < 0.05). They were enriched for SNVs in TP53, and depleted for point mutations in CASP8, HRAS, HLA-A, HUWE1, HLA-B, and COL22A1 (false discovery rate, FDR < 0.05). 3p arm loss was associated with CNAs across the whole genome (FDR < 0.1), and pathway analysis revealed low lymphoid-non-lymphoid cell interactions and cytokine signaling (FDR < 0.1). In the tumor microenvironment, 3p arm lost tumors had low immune cell infiltration (FDR < 0.1) and elevated hypoxia (FDR < 0.1). 3p arm lost tumors had lower abundance of proteins phospho-HER3 and ANXA1, and higher abundance of miRNAs hsa-miR-548k and hsa-miR-421, which were all associated with survival. There were no molecular differences by 3p arm status in HPV-positive patients, at least at our statistical power level. 3p arm loss is largely an all or none phenomenon in HPV-negative disease and does not predict poorer survival from the time of diagnosis in TCGA cohort. However, it produces tumors with distinct molecular characteristics and may represent a clinically useful biomarker to guide treatment decisions for HPV-negative patients.

All HPV-negative head and neck cancers are not the same: Analysis of the TCGA dataset reveals that anatomical sites have distinct mutation, transcriptome, hypoxia, and tumor microenvironment profiles.

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) affects various anatomical sites, which often dictates whether the cancer is managed with primary surgery or radiation. This study aimed to assess differences in single nucleotide variation (SNV), copy number, mRNA abundance, methylation, and tumor microenvironment (TME) between HPV-negative oral cavity (OC), oropharyngeal (OPC), hypopharyngeal (HPC), and laryngeal (LC) cancers within The Cancer Genome Atlas (TCGA). METHODS: We downloaded the clinical information and molecular data for the TCGA HNSCC cohort from the data portal and published literature. The TME was estimated using mRNA abundance data. We conducted our analyses within the Bioconductor statistical framework in the R environment. CNA and mRNA abundance results were correlated and grouped with SNV results for downstream pathway analysis. RESULTS: LC had a higher mutational burden than OC and OPC (p <10-4). LC tumors were enriched in CSMD3, NSD1, DCHS2 and ANK2 SNVs, while OC tumors were enriched in CASP8 SNVs (FDR < 0.1). LCs were enriched for neuronal and glycosylation pathways, while OCs were enriched for extracellular matrix pathways. B cells and endothelial cells were more abundant in LC while monocytes were more abundant in OC (FDR < 0.1). OPC was the most hypoxic, followed by OC then LC (FDR < 0.05). OC had greater methylation of Hox genes than LC. Subsite analysis revealed that oral tongue cancers had fewer CASP8 and FBN2 mutations and higher dendritic cell abundance than other oral cavity cancers. CONCLUSIONS: We identified significant genomic, transcriptional, and microenvironmental differences between HPV-negative HNSCC. Further study is warranted to determine if these findings portend differential response to specific treatment modalities.

Analysis of the TCGA Dataset Reveals that Subsites of Laryngeal Squamous Cell Carcinoma are Molecularly Distinct.

Laryngeal squamous cell carcinoma (LSCC) from different subsites have distinct presentations and prognosis. In this study, we carried out a multiomic comparison of LSCC subsites. The Cancer Genome Atlas (TCGA) LSCC cohort was analyzed in the R statistical environment for differences between supraglottic and glottic cancers in single nucleotide variations (SNVs), copy number alterations (CNAs), mRNA abundance, protein abundance, pathway overrepresentation, tumor microenvironment (TME), hypoxia status, and patient outcome. Supraglottic cancers had significantly higher overall and smoking-associated SNV mutational load. Pathway analysis revealed upregulation of muscle related pathways in glottic cancer and neural pathways in supraglottic cancer. Proteins involved in cancer relevant signaling pathways including PI3K/Akt/mTOR, the cell cycle, and PDL1 were differentially abundant between subsites. Glottic and supraglottic tumors have different molecular profiles, which may partially account for differences in presentation and response to therapy.

Modern treatment outcomes for early T-stage oropharyngeal cancer treated with intensity-modulated radiation therapy at a tertiary care institution.

BACKGROUND: Transoral surgery (TOS), particularly transoral robotic surgery (TORS) has become the preferred modality in the United States for the treatment of early stage oropharyngeal cancer, largely due to assumptions of fewer toxicities and improved quality of life compared to primary radiotherapy (RT). However, these assumptions are based on retrospective analysis, a subset of which utilize primary RT groups not limited to T1-2 stage tumors for which transoral robotic surgery is FDA approved. Thus, there is potential for underestimating survival and overestimating toxicity, including treatment related mortality, in primary RT. METHODS: Consecutive cases of early T-stage (T1-T2) oropharyngeal cancer presenting to the London Health Sciences Centre between 2014 and 2018 treated with RT or chemoradiation (CRT) were reviewed. Patient demographics, treatment details, survival outcomes and toxicity were collected. Toxicities were retrospectively graded using the Common Terminology Criteria for Adverse Events criteria. RESULTS: A total of 198 patients were identified, of which 82% were male and 73% were HPV-positive. Sixty-eight percent of patients experienced a grade 2 toxicity, 48% a grade 3 and 4% a grade 4. The most frequent toxicities were dysphagia, neutropenia and ototoxicity. The rates of gastrostomy tube dependence at 1 and 2 years were 2.5% and 1% respectively. There were no grade 5 (fatal) toxicities. HPV-positive patients experienced improved 5-year overall survival (86% vs 64%, p = 0.0026). CONCLUSIONS: Primary RT or CRT provides outstanding survival for early T-stage disease, with low rates of severe toxicity and feeding tube dependence. This study provides a reference for comparison for patients treated with primary transoral surgery.

Sex disparities in head & neck cancer driver genes: An analysis of the TCGA dataset.

OBJECTIVES: Survival in head and neck squamous cell carcinoma (HNSCC) has been associated with patient sex, typically with males experiencing poorer outcomes. It is unclear if this disparity is based in divergent tumor biology. We analyzed the TCGA HNSCC cohort to uncover disparities in the somatic single nucleotide variation (SNV), copy number alteration (CNA) and mRNA abundance profiles between males and females. Critically, we stratified our results by tumor HPV status to control for this significant confounder. METHODS: SNV, CNA and mRNA abundance differences between males and females were compared separately for the HPV-positive (n = 67) and negative (n = 431) TCGA HNSCC cohorts. Overall survival outcomes were compared in males and females in both HPV-positive and HPV-negative subsets of patients. RESULTS: Females were found to have poorer overall survival than males (p = 0.048), largely due to higher rates of HPV-positive disease among men. SNV analysis revealed that in HPV-positive disease, there were no differences by sex after accounting for the false discovery rate (FDR). In HPV-negative tumors, BRWD3 mutations occurred more frequently in the tumors of female patients compared to males after adjusting for the FDR (p = 0.02). Further, HPV-negative BRWD3 mutant tumors were found to have significantly worse 5-year overall survival compared to wildtype on multivariate analysis (p = 0.02). There were 88 heterozygous deletions and 14 amplifications that were differentially altered between male and female HPV-negative tumors and associated with expression changes. Pathway analysis of these genes revealed that tumors from males were enriched in five pathways including chemokine and phosphophatidylinositol signaling. CONCLUSIONS: Reanalysis of the TCGA HNSCC dataset stratified by sex revealed that males in this cohort had a significant survival advantage, due to a higher proportion of HPV-positive disease. Mutations in BRWD3 were more frequent in HPV-negative tumors of females and were associated with poorer overall survival. BRWD3 may represent a novel biomarker of patient outcomes, but will require additional validation.