Adorján F Kovács | Goethe-Universität Frankfurt am Main (original) (raw)

Papers by Adorján F Kovács

Annals of Surgical Oncology, 2009

Involvement of the cervical lymph nodes is the most important prognostic factor for patients with... more Involvement of the cervical lymph nodes is the most important prognostic factor for patients with oral/ oropharyngeal squamous cell carcinoma (OSCC), and the decision of whether to electively treat patients with clinically negative necks remains a controversial topic. Sentinel node biopsy (SNB) provides a minimally invasive method for determining the disease status of the cervical node basin, without the need for a formal neck dissection. This technique potentially improves the accuracy of histologic nodal staging and avoids overtreating three-quarters of this patient population, minimizing associated morbidity. The technique has been validated for patients with OSCC, and larger-scale studies are in progress to determine its exact role in the management of this patient population. This document is designed to outline the current best practice guidelines for the This article

Background: One neoadjuvant course of intra-arterial high-dose cisplatin (cis-diamminedichloropla... more Background: One neoadjuvant course of intra-arterial high-dose cisplatin (cis-diamminedichloroplatinum [CDDP]) tumor perfusion combined with intravenous sodium thiosulfate (STS) (cisplatin neutralizer) infusion is part of a multimodality concept for treatment of oral cancer. Recently, crystalline cisplatin embolization has been described as a novel treatment variant with increased tumor response rates. Methods: We have compared tumor and plasma concentrations of cisplatin and STS by means of microdialysis in 10 patients with oral cancer treated with intra-arterial cisplatin perfusion (150 mg/m 2 in 500 mL of 0.9% sodium chloride) and 6 patients with oral cancer treated with crystalline cisplatin embolization (150 mg/m 2 in 45-60 mL of 0.9% sodium chloride), respectively. The microdialysis catheter was placed into the tumor, and the intra-arterial catheter into the tumor-feeding artery. Cisplatin was rapidly administered through the intra-arterial catheter and STS (9 g/m 2 ) was infused intravenously to reduce the systemic toxicity of cisplatin. STS infusion was started 10 seconds after the cisplatin infusion was started.

Intra-arterial (IA) chemotherapy for curative treatment of head and neck cancer experienced a rev... more Intra-arterial (IA) chemotherapy for curative treatment of head and neck cancer experienced a revival in the last decade. Mainly, it was used in concurrent combination with radiation in organ-preserving settings. The modern method of transfemoral approach for catheterisation, superselective perfusion of the tumour-feeding vessel, and high-dose (150 mg m À2 ) administration of cisplatin with parallel systemic neutralisation with sodium thiosulphate (9 g m À2 ) made preoperative usage feasible. The present paper presents the results of a pilot study on a population of 52 patients with resectable stage 1 -4 carcinomas of the oral cavity and the oropharynx, who were treated with one cycle of preoperative IA chemotherapy executed as mentioned above and radical surgery. There have been no interventional complications of IA chemotherapy, and acute side effects have been low. One tracheotomy had to be carried out due to swelling. The overall clinical local response has been 69%. There was no interference with surgery, which was carried out 3 -4 weeks later. Pathological complete remission was assessed in 25%. The mean observation time was 3 years. A 3-year overall and disease-free survival was 82 and 69%, respectively, and at 5 years 77 and 59%, respectively. Survival results were compared to a treatment-dependent prognosis index for the same population. As a conclusion, it can be stated that IA high-dose chemotherapy with cisplatin and systemic neutralisation in a neoadjuvant setting should be considered a feasible, safe, and effective treatment modality for resectable oral and oropharyngeal cancer. The low toxicity of this local chemotherapy recommends usage especially in stage 1 -2 patients. The potential of survival benefit as indicated by the comparison to the prognosis index should be controlled in a randomised study.

Osseointegrated dental implants seem to be applicable for anchoring orbital prostheses in cases o... more Osseointegrated dental implants seem to be applicable for anchoring orbital prostheses in cases of previous extended ablative surgery of the orbit including excenteration of an eye. These implants are applied at stage one and connected with abutments at stage two of a two-stage surgical procedure. Nine Caucasian patients with a total of 25 osseointegrated periorbital dental implants were studied in a prospective longitudinal trial to evaluate the integrated (group A; 14 implants) and separate (group B; 11 implants) variant of step-one operation. All implants were stable and orbital prostheses were worn for an average of three years (four group A patients: 11 implants; three group B patients: nine implants). Only one implant was lost due to load stress without signs of inflammation (group B; after three years). During a mean observation time of 36 months there were only slight skin reactions around the transcutaneous abutments. Group A and group B patients did not differ with regard to their implants. The design of regular dental implants seems to be appropriate for retaining craniofacial prostheses for the above mentioned purpose. The results of this preliminary study suggest that dental implants are functional in the orbit regardless as to whether inserted in an integrated or a separate step-one operation. Future studies would have involve more patients and more implants.

Ameloblastomas (ICD-DA-213.XI) are unicentric, nonfunctional, and clinically persistent benign tu... more Ameloblastomas (ICD-DA-213.XI) are unicentric, nonfunctional, and clinically persistent benign tumors, intermittent in growth. The following histologic patterns may be distinguished: spindle cell, acanthomatous, granular cell, follicular (simple), basal cell type, and plexiform. Clinical features (even if combined with radiology or histology findings) are not useful when trying to determine the biological behaviour and therefore the prognosis of an individual ameloblastoma. A long-term course of a plexiform ameloblastoma (ICD-O-9310.0), well documented over 20 years with special regard to its recurrence in the soft tissue of the left cheek, is presented in this paper. Important questions on pathology, molecular biology, and therapy are discussed. In conclusion, a close cooperation of clinicians and surgical pathologists is necessary over a long period of time for the best management of each individual case.

Initial experiences using a new implant based distraction system for alveolar ridge augmentation.... more Initial experiences using a new implant based distraction system for alveolar ridge augmentation. Int.

Patients with cancer of the oral cavity often present with advanced tumor stages, distant metasta... more Patients with cancer of the oral cavity often present with advanced tumor stages, distant metastasis, or severe comorbidities, which render radical surgery infeasible. The purpose of this study was to investigate the response rate, technical feasibility, and safety of intra-arterial (IA) chemotherapy as palliative treatment in this situation.

The aim was to determine the reliability and reproducibility of sentinel node biopsy (SNB) as a s... more The aim was to determine the reliability and reproducibility of sentinel node biopsy (SNB) as a staging tool in head and neck squamous cell carcinoma (HNSCC) for T1/2 clinically N0 patients by means of a standardized technique.

Over decades, local chemotherapy for head and neck cancer was a challenging treatment modality ma... more Over decades, local chemotherapy for head and neck cancer was a challenging treatment modality mainly for palliative use. In the last decade, a reappraisal started due to technical innovations. But a regular and safe clinical use has not been established, nor has a pharmacological rationale for this modality been given for humans. A routine intensification of effectivity by embolization in the region of the head and neck also had been a desideratum. In an unselected patient population of 213 patients suffering from oral and oropharyngeal cancer, the routine usage of intraarterial chemotherapy in a neoadjuvant pre-surgery setting could be demonstrated. Remissions, side effects and survival data are presented. In 88 of these patients, a novel dosage format of cisplatin and clear-cut indications enabled a safe routine execution of chemoembolization. By means of microdialysis, tumor and plasma concentrations of drugs involved could be measured in patients. The results presented prove the therapeutic advantage of intraarterial chemotherapy and, especially, of chemoembolization. The prognostic value of response to local chemotherapy is discussed. Intraarterial chemotherapy is an effective modality with low toxicity and should be used broadly in multi-modality regimens for head and neck cancer.

Aim. The aim of the present FDG PET study was to evaluate the prognostic value of the standardize... more Aim. The aim of the present FDG PET study was to evaluate the prognostic value of the standardized uptake value (SUVmax) of head and neck cancer (HNSCC) with respect to the chemotherapy response and tumor recurrence. Methods. The FDG PET findings of 40 patients with HNSCC were compared with the final histopathology results after removal of the primary tumor and surgical neck dissection. The clinical T staging was based on clinical examinations and computed tomography was used for assessment of bone involvement. The pretreatment baseline SUVmax of the primary tumor were correlated with the intra-arterial chemotherapy response prior to the tumor resection and the frequency of tumor relapse. Results. The median SUVmax of tumors which did not relapse was 3.4, compared to a SUVmax of 4.7 for tumors with local tumor relapse (p=0.36, n.s.). Regarding chemotherapy response, the tumor SUVmax was significantly lower in cases with complete remission (CR) (median 2.6, n=11) compared to those with stable disease (5.8, n=10), (p=0.002). Whereas no tumor with CR after chemotherapy relapsed except stage IV tumors, tumor relapse was observed in both a stage II and a stage IV tumor without chemotherapy response. Conclusion. In patients with HNSCC the tumor SUVmax seems to be a useful prognostic indicator for assessing the clinical chemotherapy response, but did not correlate significantly with the recurrence risk. Thus, in tumors with higher SUVmax alternative chemotherapy regimes have to be discussed. KEY WORDS: Fludeoxyglucose, F18 -Tomography, emission computed -Head and neck neoplasms -Prognosis -Standardized uptake value.

Background: To examine the feasibility and efficacy of weekly docetaxel with concurrent radiation... more Background: To examine the feasibility and efficacy of weekly docetaxel with concurrent radiation as postoperative treatment in a multimodality approach to oral and oropharyngeal cancer. Patients and Methods: 94 patients with primary resectable squamous cell carcinoma of the oral cavity and oropharynx (UICC stage I 14%, II 15%, III 18%, IV 53%; ) were treated with a multimodality therapy program consisting of neoadjuvant intra-arterial high-dose chemotherapy (cisplatin 150 mg/m 2 with parallel systemic sodium thiosulfate 9 g/m 2 for neutralization), followed by surgery of the primary and neck, and postoperative concurrent radiation and chemotherapy with weekly docetaxel (20-30 mg/m 2 ; ). Chronic toxicities were followed over a period of 5 years. Results: At a median follow-up of 4 years, the 5-year survival rate for all 94 patients was 80%, and disease-free survival was 73% ). Among patients with advanced disease (stage III and IV), survival was 83 and 59%, respectively ( . Grade 3 and 4 mucositis was the main acute toxicity necessitating supportive care. Long-term toxicity appears to be moderate ( ). The maximum tolerated dose of weekly docetaxel was 25 mg/m 2 . Conclusions: Concurrent radiation and chemotherapy with weekly docetaxel is a feasible postoperative treatment in a multimodality approach to oral and oropharyngeal cancer, resulting in high overall and disease-free survival. This approach warrants further evaluation in prospective randomized trials.

Intensification of intra-arterial chemotherapy with high-dose cisplatin and concomitant reduction... more Intensification of intra-arterial chemotherapy with high-dose cisplatin and concomitant reduction of toxicity under the conditions of the head and neck was aimed at by combination of antineoplastic activity and embolizing effect in the same pharmacon. A cisplatin suspension in normal saline (5 mg in 1 ml) with precipitation of microembolizing cisplatin crystals was prepared. No additional pharmacons. Cisplatin dosage was 150 mg m 72 , maximum absolute dose 300 mg, maximum amount of fluid 60 ml. Thirty patients (UICC-Classification of tumours: I/2 patients, II/6, III/2; IV/20) were treated in a neoadjuvant setting with superselective chemoembolization using the cisplatin suspension. A control group (n=30) with the same tumour and nodal staging was treated with a usual cisplatin solution (150 mg m 72 dissolved in 500 ml saline). In both groups, parallel intravenous infusion of sodium thiosulphate (9 g m 72 ). Endpoints were toxicity and response. Continuation of treatment by surgery or radiation. Overall remission was 70% in the study group and 46.7% in the control group after one cycle respectively. Systemic side-effects were very low (grade I WHO) in both groups. Side-effects were found to be similar to post-embolization syndrome (swelling, mild to moderate pain, leucocytosis without fever) in the study group. Chemoembolization in the head and neck area can be carried out routinely using this method. ) is available in brown glass vials containing a sterile yellowish-white lyophilized powder with 50 mg cisplatin (=pharmacon), 450 mg sodium chloride, 500 mg mannitol and hydrochloric acid

To assess the impact of a diagnostic ladder including [ 18 F]fluorodeoxyglucose positron emission... more To assess the impact of a diagnostic ladder including [ 18 F]fluorodeoxyglucose positron emission tomography (PET) and lymphoscintigraphy guided sentinel node biopsy (LS/SNB) on neck treatment in patients with oral and oropharyngeal squamous cell carcinoma (OOSCC).

Here we report the molecular characterization of the nucleocytoplasmic transport of survivin and ... more Here we report the molecular characterization of the nucleocytoplasmic transport of survivin and its potential implications for tumorigenesis. We identified an evolutionary conserved Crm1-dependent nuclear export signal (NES) in survivin. In dividing cells, the NES is essential for tethering survivin and the survivin/Aurora-B kinase complex to the mitotic machinery, which in turn appears to be essential for proper cell division. In addition, export seems to be required for the cytoprotective activity of survivin, as export-deficient survivin fails to protect tumor cells against chemo-and radiotherapy-induced apoptosis. These findings appear to be clinically relevant since preferential nuclear localization of survivin correlated with enhanced survival in colorectal cancer patients. Targeting survivin's nuclear export by the application of NES-specific antibodies promoted its nuclear accumulation and inhibited its cytoprotective function. We demonstrate that nuclear export is essential for the biological activity of survivin and promote the identification of molecular decoys to specifically interfere with survivin's nuclear export as potential anticancer therapeutics.-Knauer, S. K.,

A 24-year-old patient with C-syndrome and multiple congenital deformities was followed-up for his... more A 24-year-old patient with C-syndrome and multiple congenital deformities was followed-up for his complete lifetime. The patient received extensive interdisciplinary rehabilitation of his complex somatic and craniofacial malformation.

Survivin is described as a bifunctional protein inhibiting apoptosis and regulating mitosis. Howe... more Survivin is described as a bifunctional protein inhibiting apoptosis and regulating mitosis. However, the biological functions and contributions to cancer progression of survivin splice variants are controversially discussed. We here show that the intracellular localization of these splice variants depends on a Crm1-dependent nuclear export signal (NES) present in survivin, survivin -2B and survivin -3B , but absent in survivin -DEx3 and survivin -2a . Survivin isoforms lack an active nuclear import signal and are able to enter the nucleus by passive diffusion. Only survivin -3B but none of the other splice variants is cytoprotective and able to efficiently interact with chromosomal passenger complex (CPC) proteins. The NES together with efficient CPC formation is required for the cytoprotective activity of survivin isoforms, as well as for their correct localization and function during cell division. In the tumours from breast, colorectal, head and neck cancer, lymphoma and leukemia patients, survivin and survivin -2B were found overexpressed. However, survivin was the predominant form detected, and the other survivin isoforms were only expressed at low levels in tumours. Our data provide a molecular rationale for the localization and activity of survivin variants, and conclude that survivin isoforms are unlikely to modulate survivin in trans in cancer patients.

KEY WORDS: primary tumor volume, oral and oropharyngeal cancer, mathematical model analysis no 90... more KEY WORDS: primary tumor volume, oral and oropharyngeal cancer, mathematical model analysis no 90 70,3 Volume (cc) median (range) 11,8 (0,17-211,7)

Annals of Surgical Oncology, 2009