Patrick J. Schuler

Phase I Dendritic Cell p53 Peptide Vaccine for Head and Neck Cancer

Background: p53 accumulation in head and neck squamous cell carcinoma (HNSCC) cells creates a targetable tumor antigen. Adjuvant dendritic cell (DC)–based vaccination against p53 was tested in a phase I clinical trial. Experimental Methods: Monocyte-derived DC from 16 patients were loaded with two modified HLA-class I p53 peptides (Arm 1), additional Th tetanus toxoid peptide (Arm 2), or additional Th wild-type (wt) p53-specific peptide (Arm 3). Vaccine DCs (vDC) were delivered to inguinal lymph nodes at three time points. vDC phenotype, circulating p53-specific T cells, and regulatory T cells (Treg) were serially monitored by flow cytometry and cytokine production by Luminex. vDC properties were compared with those of DC1 generated with an alternative maturation regimen. Results: No grade II–IV adverse events were observed. Two-year disease-free survival of 88% was favorable. p53-specific T-cell frequencies were increased postvaccination in 11 of 16 patients (69%), with IFN-γ secretion detected in four of 16 patients. Treg frequencies were consistently decreased (P = 0.006) relative to prevaccination values. The phenotype and function of DC1 were improved relative to vDC. Conclusion: Adjuvant p53-specific vaccination of patients with HNSCC was safe and associated with promising clinical outcome, decreased Treg levels, and modest vaccine-specific immunity. HNSCC patients DC required stronger maturation stimuli to reverse immune suppression and improve vaccine efficacy. Clin Cancer Res; 20(9); 2433–44. ©2014 AACR.

Effects of Adjuvant Chemoradiotherapy on the Frequency and Function of Regulatory T Cells in Patients with Head and Neck Cancer

Purpose: Regulatory T cells (Treg) accumulate in tumor tissues and the peripheral blood of cancer patients and may persist after therapies. This cross-sectional study examines effects of adjuvant chemoradiotherapy (CRT) on Treg numbers and function in head and neck squamous cell carcinoma (HNSCC) patients. Experimental Design: The frequency and absolute numbers of CD4+, ATP-hydrolyzing CD4+CD39+ and CD8+ T cells, and expression levels of CD39, CD25, TGF-β–associated LAP and GARP on Treg were measured by flow cytometry in 40 healthy donors (NC) and 71 HNSCC patients [29 untreated with active disease (AD); 22 treated with surgery; 20 treated with CRT]. All treated subjects had no evident disease (NED) at the time of phlebotomy. In an additional cohort of 40 subjects with AD (n = 15), NED (n = 10), and NC (n = 15), in vitro sensitivity of CD4+ T-cell subsets to cisplatin and activation-induced cell death (AICD) was tested in Annexin V–binding assays. Results: CRT decreased the frequency of circulating CD4+ T cells (P < 0.002) but increased that of CD4+CD39+ Treg (P ≤ 0.001) compared with untreated or surgery-only patients. Treg frequency remained elevated for >3 years. CRT increased surface expression of LAP, GARP, and CD39 on Treg. In vitro Treg were resistant to AICD or cisplatin but conventional CD4+ T cells (Tconv) were not. CRT-induced Treg from AD or NC subjects upregulated prosurvival proteins whereas Tconv upregulated proapoptotic Bax. Conclusions: Highly suppressive, cisplatin-resistant Treg increase in frequency and persist after CRT and could be responsible for suppression of antitumor immune responses and recurrence in HNSCC. Clin Cancer Res; 19(23); 6585–96. ©2013 AACR.

Comparative analysis of resection tools suited for transoral robot-assisted surgery

Introduction of transoral robot-assisted surgery (TORS) has a strong potential to facilitate surgical therapy of head and neck squamous cell cancer (HNSCC) by decreasing the indication for an external surgical approach. However, the availability of resection tools is limited and comparative studies in the context of TORS are not available. In the context of the newest da Vinci Si HD® robotic system, various dissection methods were compared in a surgical animal model using porcine tongue at three different sites representing mucosal, muscular and lymphatic tissue. Resection methods included (a) CO2 laser tube, (b) flexible fiber Tm:YAG laser, (c) monopolar blade, and (d) radio frequency (RF) needle. Specimens were formalin-fixed, paraffin-embedded, cut, and stained with haematoxylin–eosin. Dissected tissue was examined for the width of the incision as well as the individual coagulation zone of each tool at various tissue sites. In addition, instrument costs and performance were determined. The incisions made by the RF needle had the most favourable cutting width and also smaller coagulation defects, as opposed to other tools, granting the best preservation of tumour-adjacent structures and improved pathological assessment. Instrument performance was best evaluated for CO2 laser and RF needle, whereas financial expenses were lowest for RF needle and monopolar blade. Improvement and modification of resection tools for TORS become a relevant criterion in order to facilitate routine usage in the surgical therapy of HNSCC. A consequent decrease in surgical mortality and improved precision of surgical tumour resection could lead to a significant clinical growth potential of TORS.

First use of a computer-assisted operator-controlled flexible endoscope for transoral surgery.

Transoral robotic surgery (TORS) has become an accepted treatment option for head and neck cancer. However, anatomical limitations and a relevant financial burden require alternative developments in this field. To this end, a patient presenting with a T2 squamous cell carcinoma of the lower lateral oropharyngeal wall was effectively treated with a new Conformité Européene–certified, computer‐assisted, operator‐controlled flexible endoscope (Flex). Intraoperative visualization and tissue handling were acceptable and safe. Transoral surgery with the flexible endoscope was safely conducted in a clinical setting. The introduction of alternative TORS systems will increase competition, drive scientific improvement, and reduce financial expenses. Laryngoscope, 125:645–648, 2015

Effect of C1-Esterase-inhibitor in angiotensin-converting enzyme inhibitor-induced angioedema.

The study objective was to generate pilot data to evaluate the effectiveness and safety of C1‐esterase‐inhibitor concentrate (C1‐INH) compared to standard treatment in patients with angiotensin‐converting enzyme inhibitor (ACEi)‐induced angioedema affecting the upper aerodigestive tract.

Potential Advantages of a Single-Port, Operator-Controlled Flexible Endoscope System for Transoral Surgery of the Larynx

Introduction: Transoral surgery of the larynx is commonly performed with a rigid laryngoscope, a microscope, and a laser. We investigated the potential utility of a flexible, single-port, robot-assisted and physician-controlled endoscopic system to enable easy, transoral surgical access to the larynx. Methods: Transoral laryngeal surgery was performed in human cadavers (n = 4) using the Flex System and compatible flexible instruments. Anatomical landmarks were identified, and mock surgical procedures were performed. Results: Standard laryngeal surgical procedures were completed successfully in a human cadaver model. The built-in HD digital camera enabled high-quality visualization of the larynx. Epiglottectomy, as well as posterior cordectomy, were performed by laser and radio-frequency resection. The flexible design of the compatible tools enabled a nontraumatic approach. Conclusion: The Flex System has the potential to improve surgical access to the larynx, especially in patients with challenging anatomy. The associated flexible instruments enabled completion of surgical procedures in the larynx in a human cadaveric model. Further clinical studies, as well as the development of supplemental technology and tools, are recommended for future clinical applications.

Recent advances in robot-assisted head and neck surgery.

This article reviews current clinical applications and experimental developments for robotic surgery in the head and neck with special focus on financial challenges, current clinical trials, and the controversial aspect of haptic and tactile feedback.

A single-port operator-controlled flexible endoscope system for endoscopic skull base surgery

ObjectiveIn a human cadaver study, a single-port operator-controlled flexible endoscope (Flex® System), facilitated with a high-definition camera and two accessory channels was tested for skull base surgery.DesignSkull base surgery was performed on human cadavers (nu2009=u20094) using the Flex® System. A modified surgical midfacial approach, performed by rigid standard tools, was used for access to the sinus system, the skull base, and the middle cranial fossa.ResultsEndoscopic skull base visualization with the Flex® System is feasible. Surgical procedures performed included extended sinus surgery, anterior skull base approach, and visualization of the brain stem in the posterior cranial fossa. Important landmarks of the anterior skull base were visualized and manipulated by flexible compatible tools.ConclusionThe Flex® System allows for manipulation of the anterior skull base and visualization of the posterior cranial fossa in a preclinical setting. Further studies as well as development of supplemental tools are in progress.ZusammenfassungZielIm Rahmen einer menschlichen Kadaverstudie wurde ein flexibles bedienergesteuertes Single-Port-Endoskopsystem für die endoskopische Schädelbasischirurgie (Flex®-System), das mit einer hochauflösenden Kamera und 2xa0Zusatzkanälen ausgestattet war, für die Schädelbasischirurgie getestet.StudiendesignSchädelbasisoperationen wurden an menschlichen Leichen (nu2009=u20094) mit dem Flex®-System durchgeführt. Ein modifizierter chirurgischer Zugang zum Mittelgesicht mit starren Standardinstrumenten diente dazu, die Sinus, die Schädelbasis und die mittlere Schädelgrube zu erreichen.ErgebnisseDie endoskopische Darstellung der Schädelbasis ist mit dem Flex®-System machbar. Zu den durchgeführten operativen Maßnahmen gehörten eine ausgedehnte Sinusoperation, der Zugang zur vorderen Schädelbasis und die Darstellung des Hirnstamms in der hinteren Schädelgrube. Wichtige Landmarken der vorderen Schädelbasis wurden dargestellt und hierzu geeignete flexible Instrumente eingesetzt.SchlussfolgerungDas Flex®-System ermöglicht in einem präklinischen Rahmen das Operieren an der vorderen Schädelbasis und die Darstellung der hinteren Schädelgrube. Derzeit wird an weiteren Studien sowie an der Entwicklung ergänzender Instrumente gearbeitet.

Demonstration of nasopharyngeal surgery with a single port operator‐controlled flexible endoscope system

Nasopharyngeal surgery is commonly performed with a rigid endoscope using a transnasal or transoral approach. Here, we demonstrate a flexible single port computer‐assisted endoscopic system enabling easy transoral access to the nasopharynx.

Hybrid procedure for total laryngectomy with a flexible robot‐assisted surgical system

Total laryngectomy is a standard procedure in head‐and‐neck surgery for the treatment of cancer patients. Recent clinical experiences have indicated a clinical benefit for patients undergoing transoral robot‐assisted total laryngectomy (TORS‐TL) with commercially available systems. Here, a new hybrid procedure for total laryngectomy is presented.