Multifocal Extramedullary Plasmacytoma of the Thyroid With Cervical and Paratracheal Lymph Node Involvement and Progression to Multiple Myeloma.

Extramedullary plasmacytomas without evidence of systemic illness make up less than 5% of all plasma cell neoplasms. The incidence of extramedullary plasmacytoma of the thyroid region is exceedingly rare. This report discusses the case of a 72-year-old male with extramedullary plasmacytoma of the thyroid. The patient underwent a total thyroidectomy for an enlarging right-sided thyroid nodule, and intraoperatively, the plasmacytoma was found to have an extracapsular component with adherence to the regional soft tissue as well as involvement of the right laryngeal nerve and regional lymph nodes. Despite a comprehensive negative workup for multiple myeloma initially, including a bone marrow biopsy and hematologic workup, the disease progressed to multiple myeloma following definitive radiation therapy, as evidenced by the development of hypermetabolic lytic lesions and further pathological examination. The patient's treatment course included systemic chemotherapy and an autologous stem cell transplant, resulting in a favorable treatment response. The progression to multiple myeloma despite established guidelines highlights the need for close observation and the potential for innovative therapeutic strategies to manage this rare entity.

High-Grade Atypical Teratoid/Rhabdoid Tumor in the Pituitary Region.

Atypical teratoid/rhabdoid tumors (AT/RTs) are embryological tumors of the central nervous system (CNS). They are typically found in children, with rare presentations in adults. We describe the presentation of an AT/RT in the pituitary region of a 37-year-old female. The patient presented with a two-week history of intractable cephalgia with sudden onset of monocular diplopia and left-sided cranial nerve VI palsy. The patient underwent transsphenoidal resection of their mass, which revealed the diagnosis. She then underwent systemic therapy with chemotherapy as well as radiation. She ultimately died 14 months after treatment completion due to unrelated events. The case highlights the rarity of AT/RT in adults, emphasizing the challenge of establishing standardized treatment protocols due to its rarity in adult presentations.

Validation of nucleolar protein 4 as a novel methylated tumor suppressor gene in head and neck cancer.

Methylation of CpG islands in the promoter region of genes acts as a significant mechanism of epigenetic gene silencing in head and neck cancer. In the present study, we assessed the association of epigenetic alterations of a panel of 12 genes [nucleolar protein 4 (NOL4), iroquois homeobox 1 (IRX1), SLC5A8, LRRC3B, FUSSEL18, EBF3, GBX2, HMX2, SEPT9, ALX3, SOCS3 and LHX6] with head and neck squamous cell carcinoma (HNSCC) via a candidate gene approach. After the initial screening of methylated CpG islands on the promoter regions by bisulfite sequencing using salivary rinse samples, only two genes had methylated CpG dinucleotides on their promoter regions in tumor samples and absence of methylated CpGs were found in normal salivary rinse samples after bisulfite modification and bisulfite sequencing. We then performed real-time quantitative methylation-specific PCR (QMSP) on 16 salivary rinse and 14 normal mucosal samples from healthy subjects and 33 HNSCC tumor samples for the two genes selected. After validation with QMSP, one gene, NOL4, was highly methylated (91%) in tumor samples and unmethylated in normal salivary rinses and minimally methylated in normal mucosal samples demonstrating cancer-specific methylation in HNSCC tissues. Although the IRX1 gene was observed as methylated in normal mucosal and salivary rinse samples, the methylation values of these normal samples were very low (<10%). In conclusion, we identified NOL4 as a highly specific promoter methylated gene associated with HNSCC. IRX1 may have potential as a biomarker for HNSCC and should be assessed in a larger cohort.

Identification of guanine nucleotide-binding protein γ-7 as an epigenetically silenced gene in head and neck cancer by gene expression profiling.

Silencing of tumor suppressor genes plays a vital role in head and neck carcinogenesis. Aberrant hypermethylation in the promoter region of some known or putative tumor suppressor genes occurs frequently during the development of various types of cancer including head and neck squamous cell carcinoma (HNSCC). In this study we used an expanded mRNA expression profiling approach followed by microarray expression analysis to identify epigenetically inactivated genes in HNSCC. Two HNSCC cell lines were treated with 5-aza-2'-deoxycytidine followed by microarray analysis to identify epigenetically silenced genes in HNSCC. We found 1,960, 614 and 427 genes were upregulated in the HNSCC cell lines JHU-012, JHU-011 and the combination of both cell lines, respectively. HNSCC tumor and normal mucosal samples were used for gene profiling by a 47K mRNA gene expression array and we found 7,140 genes were downregulated in HNSCC tumors compared to normal mucosa, as determined by microarray analysis, and were integrated with cell line data. Integrative analysis defined 126 candidate genes, of which only seven genes showed differential methylation in tumors and no methylation in normal mucosa after bisulfite sequencing. Following validation by QMSP, one gene, guanine nucleotide-binding protein γ-7 (GNG7), was confirmed to be highly methylated in tumors and unmethylated in normal mucosal and salivary rinse samples demonstrating cancer-specific methylation in HNSCC tissues. TXNIP and TUSC2 were partially methylated in tumors and normal salivary rinses but unmethylated in normal mucosa. We concluded that GNG7 is a highly specific promoter methylated gene associated with HNSCC. In addition, TXNIP and TUSC2 are also potential biomarkers for HNSCC.

MAGEB2 is activated by promoter demethylation in head and neck squamous cell carcinoma.

PURPOSE: Although promoter hypermethylation has been an accepted means of tumor suppressor gene inactivation, activation of otherwise normally repressed proto-oncogenes by promoter demethylation has been infrequently documented. EXPERIMENTAL DESIGN: In this study we performed an integrative, whole-genome analysis for discovery of epigenetically activated proto-oncogenes in head and neck cancer tumors. We used the 47K GeneChip U133 Plus 2.0 Affymetrix expression microarray platform to obtain re-expression data from 5-aza treated normal cell line and expression data from primary head and neck squamous cell carcinoma (HNSCC) tumor tissues and normal mucosa tissues. We then investigated candidate genes by screening promoter regions for CpG islands and bisulfite sequencing followed by QUMSP and RT PCR for the best candidate genes. Finally, functional studies were performed on the top candidate gene. RESULTS: From the top 178 screened candidates 96 had CpG islands in their promoter region. Seven candidate genes showed promoter region methylation in normal mucosa samples and promoter demethylation in a small cohort of primary HNSCC tissues. We then studied the demethylation of the top 3 candidate genes in an expanded cohort of 76 HNSCC tissue samples and 17 normal mucosa samples. We identified MAGEB2 as having significant promoter demethylation in primary head and neck squamous cell carcinoma tissues. We then found significantly higher expression of MAGEB2 in tumors in a separate cohort of 73 primary HNSCC tissues and 31 normal tissues. Finally, we found that MAGEB2 has growth promoting effects on minimally transformed oral keratinocyte cell lines but not a definite effect on HNSCC cell lines. CONCLUSION: In conclusion, we identified MAGEB2 as activated by promoter demethylation in HNSCCand demonstrates growth promoting effects in a minimally transformed oral keratinocyte cell line. More studies are needed to evaluate MAGBE2's exact role in HNSCC.

Implementation of a TORS program in an academic medical center.

OBJECTIVES: Transoral robotic surgery (TORS) is rapidly being adopted by many head and neck surgeons for treatment of upper aerodigestive tract tumors. Various obstacles exist to efficiently implement this novel surgical technique in a busy academic center. We present our experience to illustrate one approach to initiating a TORS program. STUDY DESIGN: Prospective cohort study. METHODS: A clear, stepwise approach to introduce TORS in our hospital was devised prior to scheduling the first case. Upon initiation of the program, various time points and surgical outcomes were measured for all patients undergoing TORS. RESULTS: The first 20 cases of TORS at Johns Hopkins Hospital are reviewed. Room setup time averaged 24 minutes (±12). Presurgery time averaged 22 ± 10 minutes. Positioning time averaged 38 ± 13 minutes. Operative time (OT) averaged 71 ± 54 minutes. The total time in room (TTR) averaged 242 ± 84 minutes. There were no significant differences (P > .5) in any of the time measurements above between the first and second 10 cases or the first 15 and last 5 cases. Negative margins (both frozen and permanent) were obtained in all ablative cases. No patient required a tracheotomy and no procedure was aborted secondary to inability to expose the tumor. The average hospitalization time was 1.3 days. All patients were discharged on oral diets. There were no long-term surgical complications. CONCLUSIONS: The introduction of a TORS program in an academic medical center can be a complex and daunting undertaking. We demonstrate that with careful planning, excellent efficiency and safety can be attained immediately.

Utility of panendoscopy for the detection of unknown primary head and neck cancer in patients with a negative PET/CT scan.

We conducted a retrospective review of the records of 23 patients who had been diagnosed with regionally metastatic head and neck squamous cell carcinoma from an unknown primary tumor. Our goal was to assess the utility of panendoscopy in locating the primary tumor in those patients whose positron-emission tomography/computed tomography (PET/CT) findings were negative. Overall, we found that PET/CT had correctly identified the unknown primary in 12 of the 23 patients (52%); panendoscopy confirmed this finding in all 12. Of the remaining 11 patients, however, panendoscopy located the primary tumor in only 1 (9%). In this era of cost containment and ongoing advances in imaging and transnasal esophagoscopy, it is important to revisit the workup of an unknown primary in patients with a negative PET/CT scan. There are various advantages and disadvantages to performing panendoscopy with biopsy in patients with an unknown primary and a negative PET/CT scan, but our results and the findings of others indicate that it will detect the primary in only about 10% of these cases. We recommend careful selection of patients who are to undergo panendoscopy for the routine workup of an unknown primary.

The role of MAGEA2 in head and neck cancer.

OBJECTIVE: To examine the role of MAGEA2 in the tumorigenesis of head and neck squamous cell carcinoma (HNSCC). DESIGN: Primary tissue microarray data and quantitative reverse transcription-polymerase chain reaction (RT-PCR) showed that MAGEA2 is differentially overexpressed in HNSCC. Functional analyses were then performed using MAGEA2 transfections and small-interfering RNA knockdowns with subsequent anchorage-dependent growth studies and cell cycle analyses. Quantitative RT-PCR was used to evaluate expression changes in p53 downstream targets after transfection of MAGEA2 into normal upper aerodigestive cell lines. RESULTS: MAGEA2 is differentially overexpressed in HNSCC. In addition, MAGEA2 promotes growth in normal oral keratinocytes, whereas knockdown of MAGEA2 in HNSCC cells decreases growth. Using the HCT116 p53 wt and null cell line system, transfection of MAGEA2 induced growth in the p53 wt cell line while providing no growth advantage in the p53 mutant cells. Subsequently, transfection of MAGEA2 induced a decrease in messenger RNA expression of the p53 downstream targets CDKN1A and BAX and decreased G1 arrest in cells allowed to remain confluent for longer than 48 hours. CONCLUSIONS: These data suggest that MAGEA2 is differentially expressed in HNSCC and functions, in part, through the p53 pathway by increasing cellular proliferation and abrogating cell cycle arrest. This improved understanding of MAGEA2 function and expression patterns will potentially allow for the improved ability to use MAGEA2 for detection, surveillance, and targeted therapeutics.

Transoral robotic-assisted thyroidectomy: a preclinical feasibility study in 2 cadavers.

BACKGROUND: Technological advances in thyroid surgery have included various "minimally invasive" thyroidectomy techniques, both open and endoscopic. These include not only minimally invasive video-associated approaches but also variations of the transaxillary approach. More recently, a transoral technique using video assistance has been reported for thyroidectomy. Use of the robot was also recently published in a transaxillary approach to the thyroid. We hypothesized that the robot in combination with the previously described transoral technique would facilitate this novel surgical approach. METHODS: In 2 human cadavers the da Vinci robot was used to perform a transoral thyroidectomy. The dissection was performed with successful removal of the thyroid gland through the floor of the mouth. RESULTS: A total thyroidectomy was performed in 2 cadavers using the da Vinci robot transoral technique. The recurrent laryngeal nerve was preserved. CONCLUSIONS: Transoral robotic-assisted thyroidectomy (TRAT) provides an attractive approach to the central compartment for thyroidectomy in a field of "minimally invasive" and "scarless" techniques.

What makes a good flap go bad? A critical analysis of the literature of intraoperative factors related to free flap failure.

OBJECTIVES/HYPOTHESIS: The purpose of this article is to discuss the various factors related to poor outcome in free flap reconstructions of the head and neck (H&N). Free tissue transfer has become the standard reconstruction technique for complex H&N defects. With the evolution of free flap use in H&N surgery, numerous factors have been proposed that adversely affect flap outcome, many with the support of only anecdotal experience. We seek to critically review the literature to assess what evidence exists for the relation of various intraoperative factors to free flap complications. STUDY DESIGN: Literature review. METHODS: A review of the contemporary literature (1995 to present) on free flap reconstruction of the H&N was undertaken. A PubMed search using the terms head and neck, reconstruction, free flap, microvascular, failure, complications, fluids, intraoperative, hypertension, hypotension, nitrous oxide, temperature, and morbidity in various combinations was completed. Appropriate articles were selected and analyzed. RESULTS: Studies report various factors thought to influence flap outcomes, often with divergent conclusions. Nonetheless, the body of evidence implicates several intraoperative factors to contribute to free flap complications including: >7 L intraoperative fluid administration, significant medical comorbidity, and prolonged operative time. There is no evidence supporting hypotension, pressors, colloids, and nitrous use in free flap failure. CONCLUSIONS: Although various dogmas related to the intraoperative care of free flap patients exist, including avoidance of hypotension and pressor use, there is no available clinical evidence to support these practices. Although free flap failure is uncommon, a better understanding of its causes is necessary to avoid this disastrous complication.

Electrical stimulation of post-irradiated head and neck squamous cell carcinoma to improve xerostomia.

OBJECTIVE: We observed a significant improvement in the complaints of dysphagia in patients with head and neck cancer who had received noninvasive neuromuscular electrical stimulation (E-stim) of their pharyngeal muscles. We wanted to determine if the improvement in dysphagia was a result of decreased complaints of xerostomia and increased saliva production, since one of our first patients being treated with E-stim noticed a significant improvement in xerostomia. STUDY DESIGN: Prospective trial to determine the effects of E-stim by evaluating saliva production and dysphagia questionnaires instituted by our speech pathologists on head and neck cancer patients that had received radiotherapy (XRT) and were to undergo E-stim for dysphagia. METHODS: Prior to the initiation of E-stim and one to two months after E-stim, saliva samples were collected and patients were asked to answer a Dysphagia and Xerostomia Index Questionnaire. All patients received E-stim two to four months after completing XRT. Patients received three E-stim treatments per week for a total of one to two months. Four electrodes were placed along anterior neck over pharyngeal muscles. E-stim was initiated using four to 30mA at 80-100 pulse-widths. RESULTS: Five patients that received either postoperative radiation therapy or concomitant chemoradiotherapy had been treated with E-stim. All five patients noticed a significant improvement in dysphagia. Five out of five patients noticed a definite increase in saliva production with symptoms of decreased intake of water with meals, sleeping longer hours at night, and increased moistness of lips. CONCLUSION: E-stim therapy appears to be an effective and approved treatment for dysphagia. Our study shows that it may also be beneficial for xerostomia in the post-irradiated head and neck cancer patients. SIGNIFICANCE: To determine if E-stim will benefit the previously irradiated patient with dysphagia and xerostomia.

Level V involvement in patients with early T-stage, node-positive oropharyngeal carcinoma.

OBJECTIVES/HYPOTHESIS: To assess the risk of level V nodal involvement for early T-stage and node positive oropharyngeal squamous cell carcinoma (ORO-SCC). METHODS: Retrospective analysis performed on patients with ORO-SCC and clinically positive lymph nodes who had undergone upfront elective dissection of level V before definitive chemoradiotherapy. Pathological data collected and prevalence of involvement of level V determined. RESULTS: A total of 119 patients had level V dissection. The prevalence of pathologically positive lymph nodes in level V was 3.4% (4/119). Moreover, it was observed only in the presence of pathological involvement of multiple other nodal levels (4/52 patients, 7.7% vs. 0/67 in patients with a single nodal station involved, chi(2)P = .02). CONCLUSIONS: Subclinical involvement of level V in ORO-SCC is rare, especially in the presence of disease confined to a single nodal level. The present data do not support its dissection after primary chemoradiotherapy.

Comparison of radiosensitizing effects of the mammalian target of rapamycin inhibitor CCI-779 to cisplatin in experimental models of head and neck squamous cell carcinoma.

To determine if the mammalian target of rapamycin (mTOR) inhibitor CCI-779 can sensitize head and neck squamous cell carcinoma (HNSCC) to radiotherapy (XRT) and compare the radiosensitizing effects to cisplatin with its known considerable toxicity. Radiosensitizing effects of CCI-779 were assayed on HNSCC cell lines in vitro. CCI-779 (5 mg/kg), cisplatin (1 mg/kg), and XRT (2 Gy) alone and in combination were evaluated for antitumor activity in mice bearing FaDu and SCC40 xenografts. Effects of CCI-779 on radiation-induced activation of the Akt/mTOR pathway were analyzed. Although CCI-779 did not sensitize HNSCC cells to ionizing radiation in vitro, combination of CCI-779 and XRT significantly augmented the in vivo tumor growth-inhibitory effects of XRT and CCI-779 (P < 0.05). In addition, CCI-779 + XRT suppressed tumor growth more effectively than cisplatin + XRT (P < 0.05). CCI-779 + XRT significantly improved survival compared with XRT alone in both cisplatin-sensitive FaDu (P < 0.01) and cisplatin-resistant SCC40 (P < 0.05) xenograft mice. There were no additional benefits of adding cisplatin to CCI-779 + XRT. CCI-779 significantly attenuated irradiation-induced up-regulation of the mTOR pathway, increased apoptosis and displayed potent antiangiogenic activity in FaDu xenografts that was further enhanced by its combination with XRT (P < 0.05), which may explain the mechanism of its selective radiosensitizing effects in vivo and not in vitro. Antitumor activity of XRT was enhanced when combined with CCI-779 in HNSCC xenograft model. CCI-779 + XRT showed antitumor activity superior to conventional chemoradiotherapy with cisplatin. These results pave the way for clinical trials using molecular targeted therapy with CCI-779 in combination with XRT for HNSCC treatment.

Reflux as a cause of tracheoesophageal puncture failure.

OBJECTIVE: To evaluate the response to empiric reflux management in treatment of tracheoesophageal punctures (TEP) failures. METHODS: A retrospective chart review of patients with failed TEP was performed (n = 37). Only those patients without any documented anatomic cause for failure (n = 22) were then further reviewed to determine if empiric treatment for reflux improved voicing. Evidence of reflux was determined by either using video flexible scope of the neopharynx, barium swallows, 24-hour pH probes, and /or transnasal esophagoscopy (TNE). In 13 of 22 patients who had voicing difficulties and no evidence of reflux on these tests, empiric treatment with antireflux medications had been documented. The 22 patients were closely monitored to determine the role of reflux therapy and subsequent voicing outcomes. RESULTS: Of the 22 patients studied, 9 were noted to have granulation tissue on the tracheal side of the prosthesis. All nine patients had complete resolution of the granulation tissue after antireflux treatment, and seven of nine were able to voice again. Of the patients with no obvious reason for TEP failure who were empirically treated for reflux, 62% (8 of 13) had TEP voice after treatment. Seventy-seven percent of our patients (17 of 22) had a positive response to treatment with aggressive reflux therapy. CONCLUSIONS: Previous studies have demonstrated patients with a total laryngectomy and/or radiation therapy have increased reflux. This study addresses reflux as a potential cause of TEP voicing problems. We noted 41% (9 of 22) of patients with voicing difficulties had granulation tissue surrounding the prosthesis as a result of reflux. Aggressive antireflux therapy proved beneficial in eradicating this problem. Prophylactic antireflux therapy may be warranted for patients undergoing TEP to reduce voicing problems.