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Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial

BACKGROUND No treatments are presently available to increase survival in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy. We aimed to assess efficacy and safety of zalutumumab, a human IgG1 monoclonal antibody targeting the epidermal growth factor receptor, for overall survival in such patients. METHODS In our open-label, parallel-group, phase 3, randomised trial, we randomly allocated patients with squamous-cell carcinoma of the head and neck who were regarded as incurable with standard therapy, a WHO performance status of 0-2, and progressive disease within 6 months of platinum-based therapy in a 2:1 ratio to receive zalutumumab plus best supportive care (zalutumumab group) or best supportive care with optional methotrexate (control group) at medical centres in Europe, Brazil, and Canada. Randomisation was done via a centralised interactive voice-response system, stratified by performance status. Data were analysed when the randomisation code was broken, after the completion of the accrual and cleaning of the relevant data. An independent review committee, masked to treatment assignment, assessed tumour response and disease progression according to response evaluation criteria in solid tumours. Zalutumumab was given weekly by individual dose titration on the basis of skin rash. After a prespecified 231 deaths, we included all randomised patients in the survival analyses and all patients receiving at least one session of therapy in the safety analysis. The primary endpoint was overall survival, although progression-free survival was also assessed. This trial is registered with ClinicalTrials.gov, NCT00382031. FINDINGS We randomly allocated 191 (67%) of 286 eligible patients to the zalutumumab group and 95 (33%) to the control group. Median overall survival was 6.7 months (95% CI 5.8-7.0) in the zalutumumab group and 5.2 months (4.1-6.4) in the control group (hazard ratio [HR] for death, stratified by WHO performance status, was 0.77, 97.06% CI 0.57-1.05; unadjusted p=0.0648). Progression-free survival was longer in the zalutumumab group than in the control group (HR for progression or death, stratified by WHO performance status, was 0.63, 95% CI 0.47-0.84; p=0.0012). 189 patients given zalutumumab and 94 controls were included in the safety analysis. The most common grade 3-4 adverse events were rash (39 [21%] patients in the zalutumumab group vs none in the control group), anaemia (11 [6%] vs five [5%]), and pneumonia (nine [5%] vs two [2%]). 28 (15%) patients in the zalutumumab group had grade 3/4 infections compared with eight (9%) in the control group. The most common serious adverse events were tumour haemorrhage (28 [15%] patients given zalutumumab vs 13 [14%] controls), pneumonia (13 [7%] vs three [3%]), and dysphagia (11 [6%] vs two [2%]). INTERPRETATION Although zalutumumab did not increase overall survival, progression-free survival was extended in patients with recurrent squamous-cell carcinoma of the head and neck who had failed platinum-based chemotherapy. Zalutumumab dose titration on the basis of rash is safe. FUNDING Genmab.

The pathogenesis of nasal polyposis by immunoglobulin E and interleukin-5 is completed by transforming growth factor-β1

Objectives/Hypothesis Nasal polyps are benign mucosal protrusions into the nasal cavity of multifactorial origin and are characterized by chronic mucosal inflammation. The suggested multifactorial pathological mechanisms comprise several factors including cytokines and immunoglobulin E (IgE). The study was designed to examine the suggested roles of IgE, interleukin‐5 (IL‐5), and transforming growth factor‐β1 (TGF‐β1) in the pathogenesis of nasal polyposis.

Progression of head and neck squamous cell cancer

Squamous cell cancer in the head and neck region (HNSC) is unique concerning its progression since it remains locoregional for long time and visceral metastases develop only in a later stage of the disease. Accordingly, molecular markers of the local invasion and the lymphatic dissemination both have critical importance. HNSC progression is associated with deregulated control of cell proliferation and apoptosis but it seems equally significant the disregulation of the proteolytic machineries. Here we outline the lymphatic metastatic cascade for HNSC to depict key molecular determinants as possible prognostic factors or therapeutic targets identifying immunological selection as a major feature. Unlike in local spreading, invasive potential of cancer cells seems to be less significant during lymphatic dissemination due to the anatomical properties of the lymphatic vessels and tissues. There is a general believe that HNSC is one disease however, data indicate that the anatomical localization of the tumor (the “soil”) such as oral, lingual, glottic or pharyngeal has a significant effect on the gene expression profile and corresponding biological behavior of HNSC. Furthermore, even the endocrine milieu of the host was proved to be influential in modulating the progression of HNSC. Gene expression profiling techniques combined with proteomics could help to define and select usefull genetic and biomarkers of progression of HNSC, some of them could well be potential novel therapeutic target.

Neoadjuvant Immunotherapy of Oral Squamous Cell Carcinoma Modulates Intratumoral CD4/CD8 Ratio and Tumor Microenvironment: A Multicenter Phase II Clinical Trial

PURPOSE To investigate the clinicopathologic effects of local neoadjuvant Leukocyte Interleukin Injection (LI) regimen in oral squamous cell carcinoma (OSCC) patients. Treatment regimen included LI 800 IU/d as interleukin-2 (IL-2), administered half peritumorally and half perilymphatically five times per week for 3 weeks; low-dose cyclophosphamide; indomethacin; zinc; and multivitamins. PATIENTS AND METHODS Thirty-nine patients diagnosed with T2-3N0-2M0 OSCC participated in the pathology portion of this phase II multicenter study (19 LI-treated patients and 20 historical controls). Clinical responses were determined by imaging. Paraffin-embedded tumor samples were obtained at surgery for all patients. Surgery for the LI-treated group was performed between days 14 and 54 after the end of treatment. Histologic evaluation, pathologic staging, necrosis, and American Joint Committee on Cancer grading were performed from hematoxylin and eosin sections. Immunohistochemistry and morphometry determined cellular infiltrate. RESULTS Two pathologically complete, two major (> 50%), and four minor responses (> 30% but < 50%) resulted from LI treatment (overall response rate, 42%). Histopathology showed that the intratumoral CD4+:CD8+ ratio was low (< 1) in patients not treated with LI (controls). An increase in tumor-infiltrating CD4+ and a decrease of CD8+ T cells was observed in LI-treated patients, leading to a significantly (P < .05) higher intratumoral CD4+:CD8+ ratio (> 2.5). This was paralleled by dendritic cell transition from tumor surface toward stromal interface (P < .05), with macrophage decrease and neutrophil accumulation, multifocal microscopic necrosis, and significant (P < .05) increase in tumor stroma of LI-treated patients compared with controls. CONCLUSION LI-treated OSCC patients were characterized by a markedly altered composition of tumor-infiltrating mononuclear cells, increased CD4+:CD8+ ratio, and increased tumor stroma to epithelial ratio, all of which were distinct from controls.

Apoptosis in the human inner ear: Detection by in situ end-labeling of fragmented DNA and correlation with other markers

The aim of this study was to obtain baseline data on the recently described special form of single cell death, apoptosis, in normal human inner ears. For this purpose, in situ end-labeling of the fragmented DNA was applied, in conjunction with apoptosis-related markers, to detect cellular elements showing programmed cell death in decalcified and paraffin-embedded tissues. Over 20 specimens were analyzed which were obtained from autopsy cases with no history of acoustic lesions confirmed by histopathology. Based on staining results, we saw no apoptotic signs in the majority of normal adult inner ears. An apoptotic cell captured in the Reissners membrane of the cochlea from an old patient may, however, indicate an age-related subtle cell loss with the process of apoptosis. Nevertheless, the fact that more apoptosis was not found in our cases suggests that this phenomenon does not contribute significantly to the tissue homeostasis in the adult inner ear under normal conditions. These data are in accordance with our immunohistochemical findings on the p53 nucleoprotein, and proliferating cell nuclear antigen expression since there was no staining in any of the cellular elements, including the mesenchymal cells. This reflects a stationary and stable condition of cells of the vestibular and the cochlear structures, probably to maintain their integrity and the fine sensory functions. As opposed to the above findings, during inner ear development, the epithelial cells lining the cochlear lumen, the ossifying cartilage of the temporal bone, and the mesenchymal cells show different degrees of proliferation in combination with single cell death as signs of maturation of the vestibular and the cochlear apparatus. In addition, apoptosis has been demonstrated in cells of the cochlear stria vascularis from an adult patient treated with high doses of cisplatin, vinblastine and bleomycin prior to death. Furthermore, a wide range of apoptosis could be induced experimentally in a normal ear by an external perfusion of actinomycin D (ActD), which is known to produce programmed cell death in many cell types of different origins. The potential role of cytostatic agents in the apoptotic process of the inner ear needs, however, to be confirmed in large-scale specimens from patients treated with genotoxins. The fact, however, that apoptotic cells are also seen in association with ActD indicates that the fine sensory structure of the cochlea may also be a target for certain chemotherapeutic agents when administered in high doses.

Cochlear Implantation Influences Contralateral Hearing and Vestibular Responsiveness

A cochlear implant program has been carried out at the ORL Clinic of Semmelweis University in Budapest since 1985. Different devices and techniques have been used in pre- and postlingual children and adults. Over the last 6 years contralateral hearing improvement has been observed in 18 patients. This phenomenon can usually be demonstrated 6 months after the operation. Since our first observation several other authors have confirmed this phenomenon. However, the underlying mechanism is still obscure; both the efferent innervation and the plasticity of the brain may be important factors. The vestibular function of cochlear implant candidates was checked routinely pre- and postoperatively and changes in vestibular responsiveness were observed. Over the last 3 years air-caloric stimulation has been performed by means of a computer-based ENG system. In most patients the vestibular function was unchanged after the implantation. but in some cases a significant improvement in vestibular responsiveness was noted. Here we briefly describe cases of re-implantation carried out at the clinic. All the patients obtained better speech discrimination scores after having been implanted with intracochlear devices. None of the patients suffered any inner ear abnormality due to the first implant.

Expression of invasion markers CD44v6/v3, NM23 and MMP2 in laryngeal and hypopharyngeal carcinoma

Twelve laryngeal squamous cell carcinoma cases (7 laryngeal and 5 hypopharyngeal cancer; 15 samples) were analysed by immunohistochemistry for the expression of invasion markers CD44v6/v3, NM23 and matrix metalloproteinase, MMP2. The laryngeal epithelium showed CD44v6+v3+NM23- /MMP2- phenotype. When tumors were grouped into TNM categories the phenotype of the T2 and T3 tumors was similar, characterised by decreased CD44v3+ and lack of MMP2 expressions. Meanwhile the NM23 expression was more frequent in T3 tumors. In T4 stage the frequency of NM23 and MMP2 positive cases increased (5/6 and 4/6, respectively) but there was no correlation with the appearence of lymph node metastasis. Comparison of the phenotype of laryngeal and hypopharyngeal tumors, irrespective of the TNM stages, revealed characteristic differences: T2 stage laryngeal tumors showed decreased CD44v3 and occasional NM23 and MMP2 positivity, while in T3 stage these tumors were characterised by increased frequency of NM23 positivity. The phenotype of the hypopharyngeal tumors was significantly different with a high frequency of MMP2 positive cases (5/6) and NM23+1ow CD44v3+ phenotype. The sharp differences in the phenotypes of laryngeal and hypopharyngeal carcinomas were connected to the differences in their invasive capacity unlike to the size of the tumors, since the T4 stage hypopharyngeal tumors had a significantly smaller size than laryngeal ones, even at lower stages.

Cochlear dopamine release is modulated by group II metabotropic glutamate receptors via GABAergic neurotransmission

Dopamine (DA), released from the lateral olivocochlear efferent fibers, is suggested to be neuroprotective against ischemia and noise exposure in the mammalian cochlea because it can reduce the postsynaptic excitotoxic effect of glutamate on the dendrite of the afferent auditory neuron. Using in vitro microvolume superfusion method on isolated guinea pig cochlea preparation, we found that the selective mGluR2/3 agonist (2R,4R)-aminopyrrolidine-2,4-dicarboxylic acid (2R,4R-APDC) significantly increased the release of DA in a dose-dependent manner. Other mGluR agonists, acting on groups I and III receptors (3,5-dihydroxyphenylglycine, amino-4-phosphonobutyric acid) and antagonists (2-methyl-6-(phenylethynyl)pyridine), (2S)-2-amino-2-(1S,2S-2-carboxycyclopronan-1-yl-3-(xanth9-yl)propanoic acid, alpha-methylserine-O-phosphate), were ineffective. The GABA(A) antagonist bicuculline (10microM) could antagonize the effect of 2R,4R-APDC suggesting that the mGluR-mediated enhancement of DA release was most likely attributable to a disinhibitory mechanism involving local GABAergic fibers. Bicuculline alone could also elevate the DA outflow indicating that cochlear GABA controls local DA release tonically. Our findings expand the view on the local effects of glutamate in the cochlea by showing the ability of the excitatory neurotransmitter to alleviate its own action on type I afferents via mGluRs and initiate a neuroprotective mechanism.

Chromosomal imbalances in laryngeal and hypopharyngeal cancers detected by comparative genomic hybridization

The prognostic divergence of laryngeal and hypopharyngeal carcinomas is well known. Hypopharyngeal tumors are characterized by frequent metastasis formation and local recurrence, which is the source of the unfavorable prognosis of this subtype. The aim of this study was to define chromosomal alterations associated with the aggressive behavior of hypopharyngeal tumors.

Characteristic distribution patterns of tenascin in laryngeal and hypopharyngeal cancers

Objectives: Progression of malignant neoplasias is accompanied by alteration of the extracellular matrix (ECM) composition. Tenascin is known as a member of the adhesion‐modulating family of ECM macromolecules; thus its expression and distribution may have significant influence on tumor cell proliferation and invasiveness.