Dominik Horn

Phosphorylation of AKT(Ser473) serves as an independent prognostic marker for radiosensitivity in advanced head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is frequently characterized by high resistance to radiotherapy, which critically depends on both altered signaling pathways within tumor cells and their dynamic interaction with the tumor microenvironment. This study evaluated the prognostic value of the phosphorylation status of AKT on Ser473 and Thr308 for the clinical outcome of patients with advanced HNSCC on radiotherapy. Furthermore, we investigated the impact of AKT(Ser473) phosphorylation [p‐AKT(Ser473)] in the context of radioresistance using ex vivo tissue cultures that resemble the complex tissue architecture and paracrine interaction with the tumor microenvironment. In a cohort of 120 patients with advanced HNSCC, who were treated with primary or adjuvant radiotherapy, a significant association was found between relative p‐AKT(Ser473) levels and overall survival (p = 0.006) as well as progression‐free survival (p = 0.021), while no significant correlation was revealed for relative p‐AKT(Thr308) levels. In ex vivo tissue cultures p‐AKT(Ser473) levels were increased upon irradiation and treatment with the PI3K inhibitor LY294002 inhibited both basal and irradiation induced AKT(Ser473) phosphorylation. Strikingly, pretreatment with LY294002 sensitized tissue cultures derived from primary and recurrent tumors to radiotherapy as determined by impaired tumor cell proliferation and enhanced DNA damage. In conclusion, phosphorylation status of AKT(Ser473) in tumor specimens serves as a novel biomarker to identify patients with advanced HNSCC at high risk for treatment failure following radiotherapy, and our data from ex vivo tissue cultures support the assumption that pharmacological inhibition of AKT(Ser473) phosphorylation might circumvent radioresistance to improve efficiency and reduce toxicity of current treatment modalities.

Targeting EGFR-PI3K-AKT-mTOR signaling enhances radiosensitivity in head and neck squamous cell carcinoma.

Introduction: Head and neck squamous cell carcinoma (HNSCC) is frequently characterized by high resistance to radiotherapy, which critically depends on both altered signaling pathways within tumor cells and their dynamic interaction with the tumor microenvironment. Areas covered: This review covers EGFR-phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT)-mechanistic target of rapamycin (mTOR) signaling in HNSCC. The role of each pathway node in radioresistance is discussed. Preclinical and clinical innovative aspects of targeting EGFR-PI3K-AKT and mTOR are demonstrated. Ongoing clinical trials and future perspectives are presented. Expert opinion: Different cellular signaling pathways seem to mediate radioresistance in advanced HNSCC and various molecular targeted therapies are currently being investigated to sensitize tumor cells to radiotherapy. Recently, new insights in the mutational landscape of HNSCC unraveled critical alterations in putative oncogenes and tumor suppressor genes and have emphasized the importance of PI3K and the corresponding upstream and downstream signaling pathways in pathogenesis and treatment response. The frequent activation of the EGFR-PI3K-AKT-mTOR pathway in HNSCC and its implication in the context of radiosensitivity make this pathway one of the most promising targets in the therapy of HNSCC patients. Clinical studies targeting EGFR and mTOR in combination with radiotherapy are under investigation.

A comparison of free anterolateral thigh and latissimus dorsi flaps in soft tissue reconstruction of extensive defects in the head and neck region.

Tailoring the most suitable reconstructive approach to each patient remains challenging especially in the head and neck region. To compare the applicability of the latissimus dorsi (LD) and anterolateral thigh (ALT) flap, we retrospectively analyzed patients who had reconstruction of extensive and/or bulky composite tissue defects in the head and neck area. We performed 85 free tissue transfers (44 LD and 41 ALT flaps). LD mean flap surface was 115.8 cm(2). ALT mean flap surface was 67.0 cm(2). Pedicle length ranged from 8 to 16 cm in LD and 11-16 cm in ALT flaps. The survival rate was 93% in ALT and 91% in LD flaps. Donor site morbidity occurred in 5% (ALT) and 7% (LD). A Two-team-approach was possible in 24% of the LD group, whereas all ALT flaps were raised in a Two-team-approach. Both flaps present excellent opportunities for the reconstruction of extensive and/or bulky defects. They largely meet the requirements of an ideal soft tissue flap in terms of versatility, skin texture and tissue stock. Both flaps can be raised with a double skin paddle. The advantages and disadvantages of each flap have to be weighed up against each other and both flaps should be in the repertoire of every microvascular surgeon.

Reconstruction of a near-total nasal defect using a precontoured titanium mesh with a converse scalping flap.

The reconstruction in case of large nasal defects, especially affecting the cartilaginous portion, is a surgical and aesthetic challenge. The result has to fulfill functional and aesthetic aspects concerning shape, texture, and nasal breathing, which requires accurate reproduction of nasal lining, support, and coverage. Here, we describe nasal reconstruction in a 36-year-old woman after near-total nasal resection due to a malignant peripheral nerve sheath tumor in the glabellar and nasal regions. After tumor resection, the cartilaginous and bone structures were reconstructed using a dynamic titanium mesh, which was precontoured on a three-dimensional-print model of the preoperative situation. Soft tissue defects were covered as a 2-stage procedure using a Converse scalp flap. We achieved an adequate long-term functional and aesthetic and oncological result. Titanium mesh in combination with Converse flap proved to be an alternative in extensive composite midfacial defects.

The value of tranexamic acid during fronto-orbital advancement in isolated metopic craniosynostosis.

Craniofacial surgery in infants still harbors the risk of significant blood loss and the need for red blood cell (RBC) transfusion. Hence, the aim of the present study was to investigate the antifibrinolytic effect of tranexamic acid (TXA) on intraoperative blood loss and RBC transfusion rates during fronto-orbital advancement (FOA) in isolated metopic synostosis. A total of 33 children with metopic synostosis were operated on using standardized FOA, of which 16 patients (48.5%) were treated without intraoperative TXA (non-TXA group) and 17 patients (51.5%) received TXA intraoperatively (TXA group). To accurately evaluate the calculated blood loss (CBL) we analyzed the values for pre- and postoperative hematocrit and the volume of the RBC transfusion. The mean CBL and the mean weight-adjusted CBL was significantly lower for patients receiving TXA compared with the non-TXA group (158.8 ml vs. 198.5 ml, p = 0.0001; and 19.1 ml/kg vs. 22.3 ml/kg, p = 0.0293, respectively). In addition, the mean RBC transfusion and the mean weight-adjusted RBC transfusion was significantly lower for the TXA group (252.2 ml vs. 280.0 ml, p = 0.0001; and 27.9 ml/kg vs. 31.3 ml/kg, p = 0.0345, respectively). The mean duration of the surgical procedure did not differ statistically between the groups (132 min vs. 136 min, p = 0.4081), hence the lower CBL in the TXA-group was not related to a shorter cutting-suture time. As the use of intraoperative TXA minimizes blood transfusion volumes in children who undergo FOA, antifibrinolytics, such as TXA, should be considered for routine use in pediatric craniofacial surgery.

Regulation and function of Myb-binding protein 1A (MYBBP1A) in cellular senescence and pathogenesis of head and neck cancer

Myb-binding protein 1A (MYBBP1A) is a nucleolar protein implicated in stress response and carcinogenesis; however, its functional contribution to senescence remains elusive. In this study we show decreased MYBBP1A protein levels in tumor cells after treatment with etoposide, a potent inducer of DNA damage. Although silencing of MYBBP1A expression was not sufficient to induce senescence, it significantly increased the relative abundance of senescent cells after DNA damage. We found an inverse regulation of MYBBP1A and AKT phosphorylation (pAKT(Ser473)), which was characteristic for the pre-senescent state after etoposide administration in vitro. Tissue microarrays with tumor specimens from primary oropharyngeal squamous cell carcinoma (OPSCC) patients (n = 61) by immunohistochemistry revealed a significant correlation between MYBBP1A(low)pAKT(Ser473)(high) staining pattern and shorter progression-free (p = 0.007) or overall survival (p < 0.001). Multivariate analysis showed that MYBBP1A(low)pAKT(Ser473)(high) staining pattern is an independent prognosticator for OPSCC. Taken together, our study points to a critical role of MYBBP1A in the regulation of senescence under genotoxic stress and that a MYBBP1A(low)AKT(Ser473)(high) staining pattern serves not only as a marker for the pre-senescent stage but also as an indicator of OPSCC patients at high risk for treatment failure.

Upregulation of pAKT(Ser473) expression in progression of HPV-positive oropharyngeal squamous cell carcinoma

PIK3CA alterations have been shown to be a frequent event in oropharyngeal squamous cell cancer (SCC), especially in human papillomavirus (HPV)‐related tumors.

Free Vastus Intermedius Muscle Flap: A Successful Alternative for Complex Reconstruction of the Neurocranium in Preoperated Patients

Abstract The reconstruction of large cranial and scalp defects is a surgical and esthetic challenge. Single autologous tissue transfer can be insufficient due to the defect size and the anatomic complexity of the recipient site. Alloplastic patient-specific preformed implants can be used to recover hard tissue defects of the neurocranium. Nevertheless, for long-term success adequate soft tissue support is required. In this brief clinical study, the authors describe calvarian reconstruction in a 33-year-old patient with wound healing disorder after an initial resection of ependymoma. The patient suffered from osteonecrosis and wound breakdown in the fronto-parietal region. An alloplastic polymethylmethacrylate implant for hard tissue support was manufactured based on 3-dimensional visualization of a computed tomography scan. After the resection of remaining pathologic bone from earlier surgical procedures, the alloplastic implant was inserted to achieve functional coverage of the brain. Due to anatomic variation of donor site vessels during anterolateral thigh flap preparation, the authors performed a vastus intermedius free flap as a new muscular flap for craniofacial reconstruction. The authors achieved excellent functional and esthetic results. The muscular vastus intermedius free flap in combination with a split skin graft proves to be a new alternative to the anterolateral thigh flap for soft tissue reconstruction of the neurocranium.

Outcome of heavily pretreated recurrent oral squamous cell carcinoma after salvage resection: A monocentric retrospective analysis

PURPOSE The goals of the present study were to analyze survival data of patients who received salvage surgery due to recurrent oral squamous cell carcinoma (OSCC) of the oral cavity with curative intent, and to investigate the feasibility of microvascular flap reconstruction in a heavily pretreated patient cohort. MATERIAL AND METHODS A total of 32 patients who received salvage surgery due to recurrent OSCC were included. The cohort was analyzed in regard to relevant clinical and pathological features. Survival was estimated by using Kaplan-Meier analysis and verified in a multivariate Cox regression model. RESULTS All patients recovered well from surgery. The most common severe complication was free flap failure in 7 patients (24.1%). R0-resection was achieved in 16 patients (50%). Univariate Kaplan-Meier analysis showed that the estimated overall survival and disease-free survival of all patients after 24 months were 37.8% and 30.9%, respectively. Multivariate testing identified R1-resection was the only independent predictor of treatment failure. CONCLUSION Salvage surgery is the only potential curative treatment option in recurrent OSCC. Microvascular reconstruction is feasible in heavily pretreated patients, but it is associated with a higher free flap failure rate. Recurrent OSCC in heavily pretreated patients shows different biological behavior. Further prospective clinical and molecular studies are needed to develop a better molecular understanding of recurrent OSCC and the best and safest individual therapeutic strategy.