A systematic review of treating recurrent head and neck cancer: a reintroduction of brachytherapy with or without surgery.

Purpose: To review brachytherapy use in recurrent head and neck carcinoma (RHNC) with focus on its efficacy and complication rates. Material and methods: A literature search of PubMed, Ovid, Google Scholar, and Scopus was conducted from 1990 to 2017. Publications describing treatment of RHNC with brachytherapy with or without surgery were included. The focus of this review is on oncologic outcomes and the safety of brachytherapy in the recurrent setting. Results: Thirty studies involving RHNC treatment with brachytherapy were reviewed. Brachytherapy as adjunctive treatment to surgical resection appears to be associated with an improved local regional control and overall survival, when compared with the published rates for re-irradiation utilizing external beam radiotherapy (RT) or brachytherapy alone. Safety data remains variable with different isotopes and dose rates with implantable brachytherapy demonstrating a tolerable side effect profile. Conclusions: Although surgery remains a mainstay treatment for RHNC, intraoperative interstitial brachytherapy delivery as adjunctive therapy may improve the treatment outcome and may be associated with fewer complication rates as compared to reirradiation using external beam radiotherapy. Further investigations are required to elucidate the role of brachytherapy for RHNC

Mutation signature analysis identifies increased mutation caused by tobacco smoke associated DNA adducts in larynx squamous cell carcinoma compared with oral cavity and oropharynx.

Squamous cell carcinomas of the head and neck (HNSCC) arise from mucosal keratinocytes of the upper aero-digestive tract. Despite a common cell of origin and similar driver-gene mutations which divert cell fate from differentiation to proliferation, HNSCC are considered a heterogeneous group of tumors categorized by site of origin within the aero-digestive mucosa, and the presence or absence of HPV infection. Tobacco use is a major driver of carcinogenesis in HNSCC and is a poor prognosticator that has previously been associated with poor immune cell infiltration and higher mutation numbers. Here, we study patterns of mutations in HNSCC that are derived from the specific nucleotide changes and their surrounding nucleotide context (also known as mutation signatures). We identify that mutations linked to DNA adducts associated with tobacco smoke exposure are predominantly found in the larynx. Presence of this class of mutation, termed COSMIC signature 4, is responsible for the increased burden of mutation in this anatomical sub-site. In addition, we show that another mutation pattern, COSMIC signature 5, is positively associated with age in HNSCC from non-smokers and that larynx SCC from non-smokers have a greater number of signature 5 mutations compared with other HNSCC sub-sites. Immunohistochemistry demonstrates a significantly lower Ki-67 proliferation index in size matched larynx SCC compared with oral cavity SCC and oropharynx SCC. Collectively, these observations support a model where larynx SCC are characterized by slower growth and increased susceptibility to mutations from tobacco carcinogen DNA adducts

Reconstructive trends and complications following parotidectomy: incidence and predictors in 11,057 cases.

BACKGROUND: Parotidectomy is a common treatment option for parotid neoplasms and the complications associated with this procedure can cause significant morbidity. Reconstruction following parotidectomy is utilized to address contour deformity and facial nerve paralysis. This study aims to demonstrate national trends in parotidectomy patients and identify factors associated with adverse postoperative outcomes. This study includes the largest patient database to date in determining epidemiologic trends, reconstructive trends, and prevalence of adverse events following parotidectomy. METHODS: A retrospective review was performed for parotidectomies included in the ACS-NSQIP database between January 2012 and December 2017. CPT codes were used to identify the primary and secondary procedures performed. Univariate and multivariate analysis was utilized to determine associations between pre- and perioperative variables with patient outcomes. Preoperative demographics, surgical indications, and common medical comorbidities were collected. CPT codes were used to identify patients who underwent parotidectomy with or without reconstruction. These pre- and perioperative characteristics were compared with 30-day surgical complications, medical complications, reoperation, and readmission using uni- and multivariate analyses to determine predictors of adverse events. RESULTS: There were 11,057 patients who underwent parotidectomy. Postoperative complications within 30 days were uncommon (1.7% medical, 3.8% surgical), with the majority of these being surgical site infection (2.7%). Free flap reconstruction, COPD, bleeding disorders, smoking, and presence of malignant tumor were the strongest independent predictors of surgical site infection. Readmission and reoperation were uncommon at an incidence of 2.1% each. The strongest factors predictive of readmission were malignant tumor and corticosteroid usage. The strongest factors predictive of reoperation were free flap reconstruction, malignant tumor, bleeding disorder, and disseminated cancer. Surgical volume/contour reconstruction was relatively uncommon (18%). Facial nerve sacrifice was uncommon (3.7%) and, of these cases, only 25.5% underwent facial nerve reinnervation and 24.0% underwent facial reanimation. CONCLUSIONS: There are overall low rates of complications, readmissions, and reoperations following parotidectomy. However, certain factors are predictive of adverse postoperative events and this data may serve to guide management and counseling of patients undergoing parotidectomy. Concurrent reconstructive procedures are not commonly reported which may be due to underutilization or underreporting

Exosome-mediated transfer from the tumor microenvironment increases TGFβ signaling in squamous cell carcinoma

Transforming growth factor-beta (TGFβ) signaling in cancer is context dependent and acts either as a tumor suppressor or a tumor promoter. Loss of function mutation in TGFβ type II receptor (TβRII) is a frequent event in oral cavity squamous cell carcinoma (SCC). Recently, heterogeneity of TGFβ response has been described at the leading edge of SCC and this heterogeneity has been shown to influence stem cell renewal and drug resistance. Because exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways we investigated whether exosomes contain components of the TGFβ signaling pathway and whether exosome transfer between stromal fibroblasts and tumor cells can influence TGFβ signaling in SCC. We demonstrate that exosomes purified from stromal fibroblasts isolated from patients with oral SCC contains TβRII. We also demonstrate that transfer of fibroblast exosomes increases TGFβ signaling in SCC keratinocytes devoid of TβRII which remain non-responsive to TGFβ ligand in the absence of exosome transfer. Overall our data show that stromal communication with tumor cells can direct TGFβ signaling in SCC

TP53-inducible Glycolysis and Apoptosis Regulator (TIGAR) Metabolically Reprograms Carcinoma and Stromal Cells in Breast Cancer.

A subgroup of breast cancers has several metabolic compartments. The mechanisms by which metabolic compartmentalization develop in tumors are poorly characterized. TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. Hence we set out to determine the effects of TIGAR expression on breast carcinoma and fibroblast glycolytic phenotype and tumor growth. The overexpression of this bisphosphatase in carcinoma cells induces expression of enzymes and transporters involved in the catabolism of lactate and glutamine. Carcinoma cells overexpressing TIGAR have higher oxygen consumption rates and ATP levels when exposed to glutamine, lactate, or the combination of glutamine and lactate. Coculture of TIGAR overexpressing carcinoma cells and fibroblasts compared with control cocultures induce more pronounced glycolytic differences between carcinoma and fibroblast cells. Carcinoma cells overexpressing TIGAR have reduced glucose uptake and lactate production. Conversely, fibroblasts in coculture with TIGAR overexpressing carcinoma cells induce HIF (hypoxia-inducible factor) activation with increased glucose uptake, increased 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3), and lactate dehydrogenase-A expression. We also studied the effect of this enzyme on tumor growth. TIGAR overexpression in carcinoma cells increases tumor growth in vivo with increased proliferation rates. However, a catalytically inactive variant of TIGAR did not induce tumor growth. Therefore, TIGAR expression in breast carcinoma cells promotes metabolic compartmentalization and tumor growth with a mitochondrial metabolic phenotype with lactate and glutamine catabolism. Targeting TIGAR warrants consideration as a potential therapy for breast cancer

Cervical Spine Osteomyelitis after Esophageal Dilation in Patients with a History of Laryngectomy or Pharyngectomy and Pharyngeal Irradiation

Dysphagia is a common sequela of the treatment of head and neck cancer and is frequently managed with esophageal dilation in patients with dysphagia secondary to hypopharyngeal stenosis. Reported complications of esophageal dilation include bleeding, esophageal perforation, and mediastinitis. We examine four cases of cervical spine osteomyelitis presenting as a delayed complication of esophageal dilation for hypopharyngeal stenosis in patients with a history of laryngectomy or pharyngectomy and radiation with or without chemotherapy. The history of head and neck surgery and radiation in these patients further complicates the management of the cervical spine osteomyelitis

Stromal Monocarboxylate Transporter MCT4 is a Poor Prognostic Factor in Squamous Cell Carcinoma

ABSTRACT Introduction: Monocarboxylate transporter 4 (MCT4) is the main exporter of lactate out of cells. It is also a critical component in the glycolytic metabolism of cancer cells. In this study, stromal MCT4 in oral SCC was correlated with risk of recurrence (ROR), extent of primary tumor (pT) and nodal metastasis (pN), perineural invasion (PNI), lymphovascular invasion (LVI), HPV status, extracapsular extension (ECE) and positive margin. Methods: Clinical data were collected for 86 consecutive patients with oral HNSCC. Tissue microarrays (TMA) were constructed from paraffin blocks of resection specimens and stained for MCT4. Immunohistochemistry (IHC) staining was assessed and quantified by digital image analysis with Aperio software. Using a co-localization algorithm we assessed the intensity of staining and the percentage of positive cells in the tumoral stromal cells. Correlations of MCT4 expression with clinicopathological features and survival were studied. Results: Increased IHC staining for MCT4 was strongly associated with an increased risk of recurrence, OR 1.96 (95%CI: 1.17-3.40), presence of PNI, OR 2.25 (95%CI: 1.33-3.95), higher pT, OR 1.68 (95%CI: 0.99-2.89), higher pN, OR 2.07 (95%CI: 1.25-3.57) and presence of LVI, OR 2.21 (95%CI: 1.11-4.67). We didn’t find any significant association between stromal MCT4 expression and HPV status, presence of ECE or positive margin. Conclusions: This study demonstrates that MCT4, a marker of glycolysis in cancer-associated stroma, is highly expressed in oral SCC. The IHC staining pattern of stromal MCT4 suggests that high MCT4 expression appears to be a useful marker for tumor progression and prognosis. We propose MCT4 serves as a new prognostic factor in oral SCC and can act as a potential therapeutic target marker considering pharmacological development of MCT4 inhibitors

Avoidance of Maxillary Swing for Nasopharyngectomy via Combined Open Lateral and Endoscopic Approach

Objectives: Nasopharyngectomy performed via a solely endoscopic approach has limitations in access and feasibility, particularly regarding management of the carotid artery. To address these limitations, we report three cases with one cadaver dissection where nasopharyngectomy was performed via a combined open lateral an endoscopic approach. We highlight the benefits and technical considerations for this operative technique. Study Design: Case Series Methods: Patients diagnosed with recurrent nasopharyngeal carcinoma (NPC) that underwent combined open lateral and endoscopic nasopharyngectomy from 2016-2020 were analyzed. A cadaver dissection was also performed. Results: We present the details of the approach and follow-up in three patients with recurrent nasopharyngeal carcinoma. Briefly, a preauricular incision is extended down to the neck. The zygoma and mandibular ramus can be removed and replaced if required. V3, the pterygoid plates and the eustachian tube can be resected or mobilized. The carotid artery may be identified proximally in the neck and traced to the skull base, where the carotid canal may be drilled to the level of the foramen lacerum and protected with a pledget. Then, tumor mucosal cuts are made via an endoscopic endonasal approach and connected to the lateral exposure. No carotid artery injuries occurred. Conclusion: The combined open lateral approach and endoscopic nasopharyngectomy technique is a useful technique in salvage patients. It provides excellent control of major vessels, adequate access to the carotid canal, V3, and remainder of the skull base, and cervical protection.https://jdc.jefferson.edu/otoposters/1009/thumbnail.jp

Tumor Metabolism in the Microenvironment of Nodal Metastasis in Head and Neck Squamous Cell Carcinoma

ABSTRACT Introduction: Monocarboxylate transporter 4 (MCT4) is a cell membrane transporter of lactate. MCT4 is a tumor-specific marker of oxidative stress, glycolysis and hypoxia in tumor stromal cells. We investigated HPV positive and negative tumors with regional metastases to cervical lymph nodes (LN) to study how the metastatic tumor cells interact with their microenvironment. By selecting cancers with extracapsular extension (ECE), we intended to evaluate the interaction between metastases and the surrounding extranodal tissue. Methods: Clinical data were collected from 24 advanced stage oropharyngeal squamous cell carcinoma (OPSCC) patients with neck LN metastasis. All patients presented with at least N1 disease and had ECE. Sixteen cases were negative for HPV and eight were positive. Ten patients (42%) had ECE \u3c 1 mm, and 14 (58%) had ECE \u3e than 1 mm. The extent of ECE was quantified on H&E stains by distance from the edge of capsule. The paraffin-embedded metastatic LN sections were stained with MCT4 and quantification was accomplished using the Aperio Co-localization algorithm. Results: High stromal MCT4 expression was strongly associated with the extent of ECE regardless of HPV status (p=0.031). The stromal MCT4 expression in ECE area was significantly higher as opposed to the surrounding extranodal tissue adjacent to intact capsule (p\u3c0.001). We also found a borderline difference in expression of MCT4 in HPV- LN with ECE \u3e1mm vs. \u3c1mm(p=0.06). Conclusions: MCT4 is a marker of oxidative stress and higher expression of stromal MCT4 in ECE area is significantly correlated with the extent of ECE. The stromal cells separating nests of cancer cells in ECE area have apparent expression of the MCT4. Together these findings provide new insight into the critical role of stromal MCT4 in nodal metastasis and ECE in OPSCC and it may be useful to develop a novel prognostic marker and new anti-cancer agents