A Multidisciplinary Minimally Invasive Approach Is Necessary for the Contemporary Management of Esophageal Diverticula.

Background: Esophageal diverticula were traditionally treated with open surgery, which is associated with significant morbidity and mortality rates. Management has shifted to minimally invasive approaches with several advantages. We examine outcomes in patients with esophageal diverticula treated with minimally invasive techniques by a multidisciplinary surgical team at a single center. Materials and Methods: A retrospective review of a prospectively maintained database was performed for patients who underwent minimally invasive surgery for esophageal diverticula at our institution from June 2010 to December 2022. Primary outcomes were 30-day morbidity and mortality rates. Secondary outcomes were symptom resolution, length of stay (LOS), readmission, and need for reintervention. Results: A total of 28 patients were identified. Twelve patients had pharyngeal diverticula, 7 patients had midesophageal diverticula, and 9 patients had epiphrenic diverticula. Thirty-day morbidity and readmission rates were 10.7% (3 patients), 1 pharyngeal (sepsis), 1 midesophageal (refractory nausea), and 1 epiphrenic (poor oral intake). There were no esophageal leaks. Average LOS was 2.3 days, with the pharyngeal group experiencing a significantly shorter LOS (1.3 days versus 3.4 days for midesophageal, P < .01 versus 2.8 days for epiphrenic, P < .05). Symptom resolution after initial operation was 78.6%. Reintervention rate was 17.9%, and symptom resolution after reintervention was 100%. There were no mortalities. Conclusion: This study demonstrates that esophageal diverticula can be repaired safely and efficiently when performed by a multidisciplinary team utilizing advanced minimally invasive endoscopic and robotic surgical techniques. We advocate for the management of this rare condition at a high-volume center with extensive experience in foregut surgery.

Flexible Endoscopic Zenker's Diverticulotomy with an Articulating Bipolar Energy Sealer.

The surgical management of Zenker's diverticula is performed through open or endoscopic approaches. The purpose of this report is to review our early experience with flexible endoscopic diverticulotomy with an articulating bipolar energy sealer for cricopharyngeal and diverticular wall division in a series of 5 patients where transoral rigid access was not possible. In addition to technical details, safety and efficacy data are included. The average diverticulum size was 2.5 cm. All patients reported symptom resolution, and there were no surgical complications. Liquid diet was initiated on postoperative day 1 for all patients and solids on day 11.8 ± 14.4 (mean ± SD) per protocol. Results demonstrate that treatment of Zenker's diverticula can safely and successfully be performed with flexible endoscopic visualization and utilization of an articulating bipolar energy sealer to perform diverticulotomy in a population of patients where transoral diverticulotomy would not otherwise be feasible due to anatomic constraints. Early results support obtaining further experience to study this technology as an alternative to open surgery, especially when visualization and access are suboptimal with rigid endoscopy.

Undifferentiated sarcoma presenting as a slowly enlarging facial mass.

Head and neck sarcomas are rare and consist of a variety of histologic subtypes. We present a case of undifferentiated/unclassified sarcoma (UUS) of the maxillary sinus, a tumor subtype historically known as malignant fibrous histiocytoma (MFH) or undifferentiated pleomorphic sarcoma (UPS). A 50-year-old female patient presented with worsening facial pain and dysphagia. Physical examination demonstrated a large, ulcerated mass protruding from the oral cavity. Computed tomography demonstrated a large, enhancing mass centered in the right maxillary sinus with local invasion. The initial biopsy was read as "central giant cell granuloma." Conservative management yielded no improvement, and the tumor grew steadily. The patient underwent a total maxillectomy with resection of the orbital floor and an anterior ethmoidectomy, followed by radiation and chemotherapy. In addition to treatment of this patient, we discuss a review of the literature and the clinical presentation, radiologic, and histologic findings of this disease.

Esophageal dilation in head and neck cancer patients: A systematic review and meta-analysis.

OBJECTIVE: To characterize the safety profile and effectiveness of esophageal dilation in head and neck cancer patients. METHODS: A systematic review was undertaken for articles reporting outcomes of esophageal dilation in head and neck cancer patients. The Medline, Scopus, Web of Science, and Cochrane databases were searched in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Complications related to esophageal dilation in head and neck cancer patients was the primary outcome of interest. Success rates, demographic data, cancer staging, and treatment data were assessed secondarily. Statistical analyses included both qualitative and quantitative assessments. A limited meta-analysis and pooling of the data was performed using a random effects model. RESULTS: Of the collective 8,243 initial candidate articles, 15 retrospective studies containing data for a collective 449 patients were ultimately included in the analysis. There was significant heterogeneity in the outcomes data. With an overall complication rate of 10.6% (95% confidence interval [CI]: 4.1%,17%) and a pooled success rate of 72.9% (95% CI: 65.7%,80.1%) per patient, the articles generally supported the use of dilation. CONCLUSION: Head and neck cancer patients experience a higher rate of complications following dilation compared to patients with other causes of benign stricture. Esophageal dilation is effective in improving dysphagia, but these benefits are often transient and thus necessitate repeat interventions. Laryngoscope, 128:111-117, 2018.

Phase I Trial of Intravenous Oncolytic Vaccinia Virus (GL-ONC1) with Cisplatin and Radiotherapy in Patients with Locoregionally Advanced Head and Neck Carcinoma.

Purpose: Preclinical models have shown that the effectiveness of GL-ONC1, a modified oncolytic vaccinia virus, is enhanced by radiation and chemotherapy. The purpose of this study was to determine the safety of GL-ONC1 when delivered intravenously with chemoradiotherapy to patients with primary, nonmetastatic head and neck cancer.Experimental Design: Patients with locoregionally advanced unresected, nonmetastatic carcinoma of the head/neck, excluding stage III-IVA p16-positive oropharyngeal cancers, were treated with escalating doses and cycles of intravenous GL-ONC1, along with radiotherapy and chemotherapy. The primary aims were to define the MTD and dose-limiting toxicities, and to recommend a dose for phase II trials.Results: Between May 2012 and December 2014, 19 patients were enrolled. The most frequent adverse reactions included grade 1-2 rigors, fever, fatigue, and rash. Grade 3 adverse reactions included hypotension, mucositis, nausea, and vomiting. In 2 patients, the rash was confirmed as viral in origin by fluorescence imaging and viral plaque assay. In 4 patients, viral presence in tumor was confirmed on midtreatment biopsy by quantitative PCR. In 1 patient, live virus was confirmed in a tongue tumor 7 days after receiving the first dose of virus. The MTD was not reached. With median follow-up of 30 months, 1-year (2-year) progression-free survival and overall survival were 74.4% (64.1%) and 84.6% (69.2%), respectively.Conclusions: Delivery of GL-ONC1 is safe and feasible in patients with locoregionally advanced head/neck cancer undergoing standard chemoradiotherapy. A phase II study is warranted to further investigate this novel treatment strategy. Clin Cancer Res; 23(19); 5696-702. ©2017 AACR.

Total laryngectomy: national and regional case volume trends 1998-2008.

OBJECTIVE: The management of advanced laryngeal cancer is evolving, with increasing use of chemoradiation as initial treatment. Recent reports confirm a decline in total laryngectomies (TLs) in the United States. A study was undertaken to evaluate national and regional trends in TLs performed over the most recent decade for which data were available and to use multivariate analysis to characterize these trends in more detail. STUDY DESIGN: Population-based cohort study. SETTING: Healthcare Cost and Utilization Project-Nationwide Inpatient Sample from 1998 to 2008. SUBJECTS AND METHODS: All patients underwent radical or complete laryngectomy. Descriptive statistics and linear and multivariate regressions were performed on both raw case volumes and nationally extrapolated figures. RESULTS: In this nationally representative sample, 8288 TL cases met inclusion criteria between 1998 and 2008. The TL case volumes decreased by 27.3 per year (P = .005) and showed increasing trends in high-volume centers. The number of hospitals performing TLs decreased by 12.3 per year (P < .0005). The South and Midwest showed higher case volumes even after controlling for multiple covariates. CONCLUSION: Total laryngectomy cases are decreasing and concentrating into high-volume centers. This study demonstrated unexplained regional variation in case volumes. These findings may affect patients, otolaryngology residency training, surgeons, and reimbursement.

EGFR kinase promotes acquisition of stem cell-like properties: a potential therapeutic target in head and neck squamous cell carcinoma stem cells.

Members of the EGFR/ErbB family of tyrosine kinases are found to be highly expressed and deregulated in many cancers, including head and neck squamous cell carcinoma (HNSCC). The ErbB family, including EGFR, has been demonstrated to play key roles in metastasis, tumorigenesis, cell proliferation, and drug resistance. Recently, these characteristics have been linked to a small subpopulation of cells classified as cancer stem cells (CSCs) which are believed to be responsible for tumor initiation and maintenance. In this study, we investigated the possible role of EGFR as a regulator of "stemness" in HNSCC cells. Activation of EGFR by the addition of EGF ligand or ectopic expression of EGFR in two established HNSCC cell lines (UMSCC-22B and HN-1) resulted in the induction of CD44, BMI-1, Oct-4, NANOG, CXCR4, and SDF-1. Activation of EGFR also resulted in increased tumorsphere formation, a characteristic ability of cancer stem cells. Conversely, treatment with the EGFR kinase inhibitor, Gefinitib (Iressa), resulted in decreased expression of the aforementioned genes, and loss of tumorsphere-forming ability. Similar trends were observed in a 99.9% CD44 positive stem cell culture derived from a fresh HNSCC tumor, confirming our findings for the cell lines. Additionally, we found that these putative cancer stem cells, when treated with Gefitinib, possessed a lower capacity to invade and became more sensitive to cisplatin-induced death in vitro. These results suggest that EGFR plays critical roles in the survival, maintenance, and function of cancer stem cells. Drugs that target EGFR, perhaps administered in combination with conventional chemotherapy, might be an effective treatment for HNSCC.

Metastases to the thyroid: a review of the literature from the last decade.

BACKGROUND: Although clinically evident metastases of nonthyroid malignancies (NTMs) to the thyroid gland are uncommon, it is important to suspect them in patients who present with a new thyroid mass and a history, however far back, of prior malignancy. In fact, metastases from NTMs to the thyroid gland have been reported in 1.4%-3% of all patients who have surgery for suspected cancer in the thyroid gland. Here we review the literature over the last decade regarding this topic. SUMMARY: Based on recent literature, the most common NTMs that metastasize to the thyroid gland are renal cell (48.1%), colorectal (10.4%), lung (8.3%), and breast carcinoma (7.8%), and sarcoma (4.0%). Metastases of NTMs to the thyroid are more common in women than men (female to male ratio=1.4 to 1) and in nodular thyroid glands (44.2%). The mean and median intervals between diagnosing NTMs and their metastases to thyroid gland are 69.9 and 53 months, respectively. In 20% of cases the diagnosis of the NTM and its metastases to the thyroid was synchronous. Recent reports indicate that there is a higher frequency of sarcoma metastasizing to the thyroid gland than reported in prior years. Fine-needle aspiration biopsy (FNAB) of thyroid masses is useful in diagnosis of thyroid metastases. However, this requires information about the NTM so that the proper antibodies can be used for immunohistochemical analysis; therefore it is of lesser utility if the NTM is occult. In patients with preexisting thyroid pathology the FNAB diagnosis can be more difficult due to more than one lesion being present. CONCLUSIONS: It is important to keep in mind that the thyroid gland can be a site of metastases for a variety of tumors when evaluating a thyroid nodule, especially in a patient with a prior history of malignancy. In patients with thyroid lesions and a history of malignant disease, regardless of time elapsed since the initial diagnosis of the primary neoplasm, disease recurrence or progression of malignancy must be considered until proven otherwise.

Nicotine promotes acquisition of stem cell and epithelial-to-mesenchymal properties in head and neck squamous cell carcinoma.

The ability of nicotine to enhance the malignancy of cancer cells is known; however, the possibility that nicotine could regulate a cancer stem cell phenotype remains to be well-established. In this study we sought to determine whether long-term exposure to nicotine could promote cancer stem cell-like properties in two head and neck squamous cell carcinoma cell lines, UMSCC-10B and HN-1. Nicotine treatment induced epithelial-to-mesenchymal transition (EMT) in both cell lines by repressing E-cadherin expression, and led to the induction of stem cell markers Oct-4, Nanog, CD44 and BMI-1, which was reversed upon ectopic re-expression of E-cadherin. Nicotine-treated cells formed spheres at a higher efficiency than non-treated cells, formed larger tumors when injected into mice, and formed tumors with 4-fold greater efficiency compared to control cells when injected at limiting doses. Consistent with previous literature, nicotine-treated cells demonstrated a greater capacity for survival and also a higher tendency to invade. Comparison of microRNA profiles between nicotine and control cells revealed the upregulation of miR-9, a repressor of E-cadherin, and the downregulation of miR-101, a repressor of EZH2. Taken together, these results suggest that nicotine may play a critical role in the development of tobacco-induced cancers by regulating cancer stem cell characteristics, and that these effects are likely mediated through EMT-promoting, microRNA-mediated pathways. Further characterization of such pathways remains a promising avenue for the understanding and treatment of tobacco-related cancers.

Recombinant human erythropoietin promotes the acquisition of a malignant phenotype in head and neck squamous cell carcinoma cell lines in vitro.

BACKGROUND: Recent studies indicate an increase in tumor progression and recurrence in head and neck squamous cell carcinomas (HNSCC) of cancer patients taking recombinant human erythropoietin (rhEpo) for anemia. This study was undertaken to investigate the potential role of rhEpo in invasion, proliferation, and cisplatin-induced cell death in HNSCC cell lines. METHODS: The following experiments were performed with two HNSCC cell lines, UMSCC-10B and UMSCC-22B. Presence of EpoR in both cell lines was determined by western blot and quantitative PCR. Colorimetric MTS assays and clonogenic assays were used to study the effect of rhEpo at pharmacologically relevant doses on cell proliferation. Matrigel invasion assays were performed in order to determine effects of exogenous rhEpo on invasive abilities. Clonogenic assays were also used to study potential cytoprotective effects of rhEpo against cisplatin. Immunoblotting was done to analyze the effect of rhEpo on Akt phosphorylation. Finally, MTS and TUNEL assays were performed to test our hypothesis that Akt activation by PI3K was involved in rhEpo-mediated cisplatin resistance. RESULTS: HNSCC cell lines were shown to express Epo receptor (EpoR). RhEpo increased invasion 1.8-fold in UMSCC-10B and 2.6-fold in UMSCC-22B compared to control. RhEpo at 10 U/ml increased cell proliferation by 41% and 53% in UMSCC-10B and UMSCC-22B, respectively, and colony formation by 1.5-fold and 1.8-fold. UMSCC-10B treated with cisplatin and exposed to rhEpo at 1 and 10 U/ml resulted in a 1.7-fold and 3.0-fold increase in colony number compared to control, respectively. UMSCC-22B treated with cisplatin and rhEpo at 1 or 10 U/ml resulted in ~2.5-fold increase in colony number. A TUNEL assay demonstrated a 30.5% and 76.5% increase in survival in UMSCC-10B and UMSCC-22B cells, respectively, in cisplatin and rhEpo-treated cells compared to cisplatin alone. MTS assay showed similar cytoprotective effects. Western blot revealed increased phosphorylation of Akt upon exposure of HNSCC cell lines to rhEpo. MTS assay and TUNEL analyses implicate Akt as a likely contributor to regulation of rhEpo-mediated cytoprotection. CONCLUSIONS: The results demonstrate that, in HNSCC cells expressing functional EpoR, rhEpo promotes invasion, cell proliferation, and induces resistance to cisplatin, which may contribute to tumor progression.

STI-571 (Gleevec) potentiates the effect of cisplatin in inhibiting the proliferation of head and neck squamous cell carcinoma in vitro.

OBJECTIVE: The objective of this study was to determine whether STI-571 (Gleevec; imatinib mesylate) could sensitize established head and neck squamous cell carcinoma (HNSCC) cell lines to the effects of cisplatin. METHODS: Western blot analysis and immunofluorescence were used to examine the expression of the tyrosine kinases that are known targets of Gleevec, including c-kit, c-Abl, and platelet-derived growth factor receptor, on the cell lines, and immunohistochemistry was performed to determine the expression of these kinases in human HNSCC tissue. Once these targets were confirmed, clonogenic cell survival assays were performed to determine the effect STI-571 had on growth and proliferation when used in combination with cisplatin compared with STI-571 alone or cisplatin alone. Cells were incubated with a range of doses of STI-571 24 hours before the addition of cisplatin. Flow cytometry analysis was performed to determine cell-cycle distribution and to measure apoptosis caused by the various treatments. An annexin V assay was also used to further measure apoptosis. RESULTS: Our results indicate that STI-571 potentiates the effect of cisplatin and leads to a significant decrease in cell proliferation and colony formation compared with cisplatin alone in a dose-dependent fashion. Surprisingly, there was a slight decrease in the level of apoptosis when Gleevec was used in combination with cisplatin compared with cisplatin alone. Gleevec alone resulted in a slight increase in G1 phase of the cell cycle, whereas cisplatin alone resulted in a G2 arrest. The addition of Gleevec to cisplatin resulted in an enhanced S/G2 phase accumulation. Although we did not demonstrate an increase in cisplatin-induced cell death, we postulate that the increased S/G2 arrest resulting from the DNA damage in the presence of Gleevec results in decreased proliferation of HNSCC, resulting in a net decrease in colony formation. CONCLUSIONS: The small molecule inhibitor Gleevec, which targets specific tyrosine kinases that are expressed in HNSCC, can significantly potentiate the antiproliferative effects of cisplatin. Because Gleevec alone has minimal side effects, treatment with the combination treatment of cisplatin and Gleevec may result in increased efficacy of cisplatin in treating this cancer. Additional studies are warranted, keeping in mind that drug combinations may result in unexpected toxicities that are not frequently seen with either drug alone.

EGFR regulates the side population in head and neck squamous cell carcinoma.

OBJECTIVE: To identify the presence of side population (SP) cells in established head and neck squamous carcinoma cell (HNSCC) lines and to determine the role of EGFR in the regulation of the side population of these cells. METHODS: SP cells were identified using flow cytometry analysis by the ability of these cells to extrude the Hoechst 33342 dye via the drug transporter BCRP1/ABCG2. Effect of EGFR on the side population was determined also by difference in Hoechst extrusion and by immunofluorescence. Immunohistochemical staining was performed to show the presence of the BCRP1/ABCG2 transporter and the phosphorylated form of EGFR in HNSCC tissue. RESULTS: SP cells are present in HNSCC cell lines. With the Hoechst 33342 extrusion assay, SP cells were found to comprise an average of 0.69% of the UMSCC10B cells and 0.91% of HN12 cells. Addition of the EGF ligand increased the SP population while inactivation of the EGFR kinase by Iressa significantly decreased SP. CONCLUSION: In established head and neck squamous cell carcinoma cell lines, SP cells were found using methods that determine expression and function of the drug transporter BCRP1/ABCG2. Activation of EGFR, a gene implicated in tumorigenesis in HNSCC leads to increased SP, and conversely, inhibition of EGFR leads to decrease in SP. This finding could help explain the role of EGFR in regulating cancer stem cells and thus tumorigenesis in HNSCC.

Prospective study of perioperative factors predicting hypocalcemia after thyroid and parathyroid surgery.

OBJECTIVE: To identify whether perioperative 1,25-dihydroxyvitamin D or parathyroid hormone (PTH) levels will predict the development of hypocalcemia after thyroid and parathyroid surgery. DESIGN: Prospective study. SETTING: University hospital. PATIENTS: The study included 103 patients who underwent thyroid or parathyroid surgery between 2002 and 2004, with a comparison of the patients who underwent thyroid lobectomy (TL; n = 34), total thyroidectomy (TT; n = 27), parathyroid adenoma excision (PAE; n = 34), and subtotal parathyroidectomy for hyperplasia (SP; n = 8). MAIN OUTCOME MEASURES: Preoperative 1,25-dihydroxyvitamin D levels, number of patients requiring calcium replacement, and postoperative PTH and calcium levels. RESULTS: No patients in the TL or PAE group developed postoperative hypocalcemia that required calcium replacement. Six patients (22%) in the TT group and 3 patients (38%) in the SP group required calcium replacement for clinically significant hypocalcemia (P<.001). All patients who required calcium replacement had PTH levels of less than 15 pg/mL (1.6 pmol/L) 8 hours after surgery. Among the patients with postoperative PTH levels of less than 15 pg/mL (1.6 pmol/L) 8 hours after surgery, no patients in the PAE group required calcium replacement, compared with 75% of patients in the TT and SP groups (P<.001). The patients in the TT group had significantly lower postoperative calcium levels than those in the TL (P<.001) or the PAE (P<.005) group. The patients in the TL group reached stable calcium levels significantly earlier than those in the other groups (15.8 hours after surgery; P<.05). There was no relationship between preoperative 1,25-dihydroxyvitamin D levels and postoperative calcium levels. CONCLUSIONS: Preoperative 1,25-dihydroxyvitamin D levels were not predictive of postoperative calcium levels. Patients who undergo PAE or TL are at extremely low risk for requiring calcium replacement. Patients who undergo TT or SP with 8-hour postoperative PTH levels greater than or equal to 15 pg/mL (1.6 pmol/L) are at low risk for developing postoperative hypocalcemia, whereas those with PTH levels less than 15 pg/mL (1.6 pmol/L) have a high risk of developing hypocalcemia.

Expression of protein tyrosine kinases in head and neck squamous cell carcinomas.

Protein tyrosine kinases (TKs) are overexpressed in many carcinomas and sarcomas. We studied the expression of the following TKs in head and neck squamous cell carcinoma (HNSCC): platelet-derived growth factor receptor (PDGFR), c-kit, epidermal growth factor receptor (EGFR), and a serine-threonine kinase, Akt. Formalin-fixed, paraffin-embedded tumor blocks from 44 consecutive patients with primary HNSCC and 5 specimens of benign pharyngeal and laryngeal mucosa were retrieved for immunohistochemical analysis. Of the specimens, 38 had enough material to stain for all 4 antibodies. The study included 21 pharyngeal (base of tongue, 14; tonsil, 6; soft palate, 1), 16 laryngeal, and 1 floor of the mouth carcinoma. All 4 kinases in the tumor samples were expressed highly (PDGFR, 95%-100%; EGFR, 38%-43%; c-kit, 50%-86%; p-Akt, 57%-81%), with EGFR, c-kit, and p-Akt significantly higher than in benign samples. None of the kinase expressions correlated with disease-free survival. The expression of the kinases raises the possibility of treatment of HNSCC by tyrosine and serine-threonine kinase inhibitors.

Intracranial spread of Merkel cell carcinoma through intact skull.

We report an unusual case of Merkel cell carcinoma presenting as a frontal scalp mass with apparent invasion into underlying brain parenchyma through grossly intact calvaria. Despite wide local excision, craniectomy, intracranial tumor resection, and postoperative adjuvant irradiation, widespread systemic metastases resistant to chemotherapy developed, and the patient died 9 months after surgery. This case report confirms that Merkel cell carcinoma of the head and neck, already known to be an aggressive tumor, has the capacity for rapid intracranial extension. We propose that in this case, the mechanism of intracranial metastasis was via communicating veins rather than through bone destruction or systemic metastasis. Appropriate preoperative imaging should be carried out to define the extent of this tumor when it is adjacent to the skull. We found contrast-enhanced magnetic resonance imaging to be superior to computed tomography for defining soft tissue extent and marrow space involvement within underlying bone.