Prognosis of HPV-Positive and -Negative Oropharyngeal Cancers Depends on the Treatment Modality.

BACKGROUND: The association between human papilloma virus (HPV) and oropharyngeal carcinoma is a topical issue due mainly to the rapid increase in incidence over recent years. These tumors are etiopathogenetically, epidemiologically, and clinically different from other carcinomas at this location. They have a better prognosis in that they are more chemo-and radiosensitive. Indeed, this has been shown by many extensive retrospective and prospective studies. HPV status is considered an integral part of a standard histopathological examination and is included as a new biological parameter in TNM classification. MATERIALS AND METHODS: The results of 77 patients who were treated non-surgically for locally advanced oropharyngeal carcinoma at a single university ear, nose, and throat clinic were analyzed retrospectively. RESULTS: Overall and specific survival of those with HPV-positive (HPV+) tumors was better that those for HPV negative (HPV-) tumors. With the exception of TNM classification, HPV positivity appeared to be the strongest predictor of local control, and of overall and specific survival, regardless of the type of treatment. However, smoking and p53 positivity were significant negative predictors of overall survival. Patients with HPV-associated tumors had a significantly better prognosis, regardless of treatment type. The difference between treatment modalities was confirmed for the whole group of patients, but not for the HPV+ and HPV-patients specifically, most probably due to the small number of patients enrolled. CONCLUSION: The results obtained herein may constitute the first step toward the concept of treatment de-escalation in those with HPV-associated oropharyngeal carcinoma; however, this decision can be based only on the results of current extensive randomized trials. Specification of the optimal de-escalation scheme, or the choice of treatment modality, for which the difference in treatment results is most pronounced, has yet to be identified. This work was supported by grants of the Ministry of Health of the Czech Republic IGA NT12483-4/2011 and AZV 15-31627A. he authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 21. 9. 2018 Accepted: 14. 5. 2019.

[Reconstruction of Isolated Orbital Floor Fractures by Nasoseptal Cartilage]. / Rekonstrukce izolovaných zlomenin spodiny ocnice nazoseptální chrupavkou.

PURPOSE OF THE STUDY The incidence of isolated orbital floor fractures has an increasing tendency. Their optimal management is not uniform and is still being discussed in the literature. The therapeutic decision as to whether surgical intervention is necessary or conservative approach is adequate vitally depends on clinical and CT findings. Incorrect treatment can lead to serious consequences, especially to persistent diplopia and enophthalmos. The objective of our study was to evaluate the radiological indication criteria for surgery and the clinical outcomes thereafter. MATERIAL AND METHODS The retrospective monocentric study of the group of 53 patients who underwent the isolated orbital floor fracture reconstruction during the period from 1/1/2006 to 31/12/2016 at the Clinic of Otolaryngology and Head and Neck Surgery of the St. Anne's University Hospital, Brno. The ealuated parameters wee the following: trauma cause, clinical symptoms, evaluation of CT parameters (MH index, RF index, MRI index), time interval from injury to surgery, complications. RESULTS Trauma cause: an assault 30/53 (57%), a fall 14/53 (26%), sports 4/53 (7%), a road traffic accident 4/53 (7%), an accident at work 1/53 (2%). Clinical symptoms: eyelid haematoma and/or swelling 53/53 (100%), diplopia 29/53 (55%), emphysema 29/53 (55%), infraorbital nerve hypoesthesia 4/53 (7%). Radiological report of the CT: RF index > 50% (defect length more than a half of the orbital floor length) 49/53 (92%), RF index <50% (defect length less than a half of the orbital floor length) 4/53 (7%). MH index (maximum height of periorbital herniation): mean value 9.0 mm (2.8-14.2 mm), MRI index (rectus inferior muscle index): <1.5 15/53 (28%), ≥ 1.5 38/53 (72%). Time interval from injury to surgery: mean value 11 days (3-21 days). Complications 6 weeks postoperatively: diplopia 4/53 (7%), ectropion 2/53 (4%), enophtalmos 0/53 (0%), visual damage 0/53 (0%). CONCLUSIONS The choice between the surgical and conservative management of the isolated orbital fracture is the key factor to ensure a good therapeutic result. The evaluation of CT findings is crucial for the decision-making process. The key radiological parameters are the standardized assessment of the orbital floor defect size (RF index), orbital tissue herniation (MH index) and the assessment of damage to the intraorbital muscles (MRI index). As demonstrated by the results of our analysis, surgical reconstruction of the orbital floor by nasoseptal cartilage represents a highly effective and safe method. Key words: orbital fractures, blow-out fracture, orbital floor, orbital reconstruction.

[Anticancer Effect of Fish Oil - a Fable or the Truth?]. / Protinádorový efekt rybího oleje -  mýtus, nebo realita?

Omega-3 fatty acids from fish oil have several health benefits for cancer patients. Recent findings indicate that, besides their well-known anti-cachectic effect, they can act synergistically with chemotherapeutic agents and may enhance tumor radio-sensitivity. The mechanisms underlying their anti-tumor effects are complex. The following effects have been reported after administration of omega-3 fatty acids: increased lipid peroxidation during therapy; disturbed tumor receptor signal pathways; lower levels level of pro-inflammatory cytokines that induce tumor cell proliferation; promotion of apoptosis in tumor tissues; immune modulation; and changes in hormonal metabolism. Epidemiological and experimental evidence support the conjecture that fish oil has an anticancer benefit for both animals and humans. However, Western countries have a diet rich in omega-6 fatty acids, which interfere with the health benefits of omega-3 fatty acids because they compete for the same rate-limiting enzymes. For this reason, the consumption of omega-6 fatty acids in Western diet needs to be lowered to observe the anti-tumor effect of omega-3 fatty acids. Some epidemiological studies report conflicting results, which may be explained by inconsistencies in the methodologies employed.

Genetic risk factors of cisplatin induced ototoxicity in adult patients.

Ototoxicity is an important adverse effect of using Cisplatin (cis-diamminedichloroplatinum) (CDDP) as a form of chemotherapy. The clinical picture of CDDP induced ototoxicity includes perceptive hearing impairment (reversible or permanent) and tinnitus. Ototoxicity manifests with considerable variability between patients. The objective of this prospective study was to investigate a possible genetic background to this variability. We assessed ototoxicity induced by therapeutic doses of CDDP in adult patients with germinative testicular tumors, or other tumors treated with an identical CDDP dosage scheme. Audiological examination before, during and after the treatment has shown deterioration in hearing; first in the high-frequencies and with increased CDDP cumulative doses, impairment in other frequencies as well. Occurrence of tinnitus was not dependent on the administered dose of CDDP, or the other risk factors examined in this study. The association of CDDP induced ototoxicity with genetic polymorphisms in candidate genes was examined. Our study has demonstrated an association of early onset of CDDP induced ototoxicity with the presence of two copies of GSTT1 gene (p=0,009) and with T allele of rs9332377 polymorphism in COMT gene (p=0,001).

[Genetic background of cisplatin induced ototoxicity]. / Genetické pozadí ototoxicity cisplatiny.

BACKGROUND: Cisplatin induced ototoxicity is a serious adverse effect of cisplatin therapy. Cisplatin induced ototoxicity shows significant interindividual variability. This variability is probably based on genetic background. Recent papers describe association of cisplatin ototoxicity with allelic variants of glutathion-S-transferase coding genes. PATIENTS AND METHODS: We have analyzed 55 patients treated with cisplatin therapy without any previous hearing impairment. Audiometric examination was performed before the start of cisplatin therapy and then before and after each cycle of cisplatin. DNA isolated from peripheral blood samples was used to analyze genetic polymorphisms of selected genes coding for glutathion-S-transferases. RESULTS: We have demonstrated association of early onset of cisplatin induced hearing impairment with absence of null allele of GSTT1 (p = 0.009). Both GSTM1 gene deletion and single nucleotide polymorphism in GSTP1 gene (rs1695) did not show any association with cisplatin induced ototoxicity. CONCLUSION: Early onset of cisplatin induced hearing impairment is more probable in persons with two functional alleles of GSTT1 gene.

Epidermal growth factor receptor (EGFR) expression and mutations in the EGFR signaling pathway in correlation with anti-EGFR therapy in head and neck squamous cell carcinomas.

UNLABELLED: Epidermal growth factor receptor (EGFR) is an important therapeutic target and a poor prognosis factor in head and neck squamous cell carcinoma (HNSCC). The aim of the study was to analyze EGFR expression and KRAS and EGFR mutational status and to correlate it with treatment response to anti-EGFR therapy combined with radiotherapy in 29 patients with advanced head and neck squamous cell carcinomas (HNSCC).EGFR gene expression normalized to GAPDH and EGFR variant type III (EGFRvIII) was detected in tumor tissue using real time reverse transcription -PCR. The mutational status of the EGFR and KRAS genes was investigated by real time PCR with sequence specific primers.Gene expression median values were 3.1x10(8) GAPDH gene copies per µg of RNA, and 8x10(6) EGFR gene copies per µg of RNA. The median EGFR/GADPH ratio reached 0.14. Patients, who achieved complete response after Cetuximab combined with radiotherapy, had significantly higher expression of the EGFR gene in tumors than patients with partial remission or patient without treatment response. An EGFRvIII mutation was found in 20.7 % of patients and no association was found between this mutation and treatment response. 27 patients (93.1 %) had an EGFR gene wild type tumor, and deletion in exon 19 was found in two patients with a poor clinical outcome. Most of the patients (82.8%) had a KRAS wild type tumor; a p.Gly12Cys was found in three patients and a p.Gly12Val mutation in one. Presence of a p.Gly12Val mutation in the KRAS gene was associated with an absence of response to treatment. CONCLUSION: Our data suggest that KRAS mutation (p.Gly12Val) and somatic EGFR mutation located in exon 19 may contribute to the limited clinical response to therapy with cetuximab + radiotherapy. Higher EGFR gene expression serves as an independent indicator of good clinical response to EGFR-targeted therapy + radiotherapy.

Mutations in EGFR signal pathway in correlation with response to treatment of head and neck cancers.

UNLABELLED: The prognostic and predictive value of the epidermal growth factor receptor (EGFR) expression and some genetic alterations in an EGFR signal pathway, such as the EGFR amplification, the EGFR activating tyrosine kinase domain mutations or the k-ras gene mutation were investigated in our study. The aim of the research was to evaluate the occurrence of the above-mentioned biomarkers in correlation with a therapeutic response and survival in patients with locoregionally advanced spinocellular head and neck cancers. KEYWORDS: Head and neck cancer, EGFR, predictive marker, k-ras, EGFR amplification, EGFR tyrosine kinase domain mutation.

Increased activity of superoxide dismutase in advanced stages of head and neck squamous cell carcinoma with locoregional metastases.

The aim of the study was to investigate relationship between activity of superoxide dismutase (SOD), malondialdehyde (MDA) and tumor necrosis factor alpha (TNFalpha) and between Ala-9Val polymorphism in the gene encoding MnSOD (SOD2) and the initial stage and prognosis of the head and neck squamous cell carcinoma (HNSCC). Prospective study cohort comprised 88 patients who underwent surgical treatment for the diagnosis of HNSCC (53 patients were diagnosed with locoregional metastatic spread (N+) at the time of diagnosis). After the initial surgery subjects were followed for the subsequent period of 26 months during which 14 manifested relapse. Genotypes were detected by the PCR-based methodology. Activity of p-SOD, ery-SOD and TNFalpha were determined by ELISA, and the concentration of MDA by high performance liquid chromatography. Genotype and allele frequencies of the Ala-9Val differed neither between groups defined according to the stage of primary disease (TNM), nor between relapse vs. remission groups after the follow-up (p>0.05). Activity of p-SOD was significantly higher in T3/4 stage compared to T1/2 (p=0.01) and was also higher in N+ compared to N0 patients (p=0.002). Carriers of the Ala/Ala genotype had higher p-SOD activity (p=0.04). There was no significant difference in DFI between SOD2 genotype groups (p>0.05), however, the Ala/Ala group exhibited the shortest median DFI. In conclusion, our results suggest that increased p-SOD at the time of the initial treatment for HNSCC is connected with greater extent and nodal metastatic spread of the initial disease and with an earlier relapse of the disease. Progression of the disease might be further modified by the presence of Ala/Ala genotype of the SOD2. Activity of p-SOD could thus offer diagnostic as well as prognostic value.

Correlation of expression of Ki-67, EGFR, c-erbB-2, MMP-9, p53, bcl-2, CD34 and cell cycle analysis with survival in head and neck squamous cell cancer.

The purpose of this study was to clarify the prognostic significance of flow cytometric analysis of DNA, mitotic, apoptotic indices, Ki-67, EGF-R, c-erb-B2, matrix metalloproteinasis-9 (MMP 9), p53, bcl-2, CD 34 in Head and Neck Carcinomas (HNSCC). The analysis was carried out with a set of 217 patients suffering from HNSCC. The parameters of tumors were related to the overall survival (OS) and the event-free survival (EFS). Clinical stage, ploidy and T-N categories influence both survival measures equally and significantly. Grade score did not significantly contribute to the prediction of EFS and OS when entered to the analysis as single factor. Measure of realized proliferation significantly contributed to the risk prediction both in EFS and OS. Cytokinetic parameters generally strongly correlated with grade score and grade correlates, responsible for the increasing risk in combination with other risk factors like clinical stage and/or ploidy. Positivity in bcl-2 and MMP-9 was significantly related to OS of patients (not to EFS). Positivity of EGFR, c-erbB-2, CD34, p53 did not reached statistically significant value in association to EFS or OS.

[Recommendations for the treatment of tobacco dependence]. / Doporucení pro lécbu závislosti na tabáku.

This first Czech version of guidelines formulated by the working group of mentioned medical associations is based on current literature and international guidelines. They are aimed mainly on clinical medicine and on incorporation of this treatment into the health care system according to WHO recommendations. They should serve to the treatment of tobacco dependence at any level: during any contact with the smoking patient (short intervention), in specialised centres or for the health care providers or health system itself.

Prognostic significance of mitotic and apoptotic index and the DNA cytometry in head and neck cancer.

The lack of suitable criteria to predict the response to chemo- and or radiotherapy for individual patients with squamous cell carcinoma of the head and neck (HNSCC) remains still a major problem. This study was conducted to analyze prognostic significance of mitotic and apoptotic index and the DNA flow cytometric analysis of HNSCC to the recurrence-free survival time and to the overall survival. The analysis was carried out in a set of 56 patients suffering from carcinoma of the pharynx and supraglottis. Most patients (96.7%) underwent neoadjuvant chemotherapy, followed by surgery and postoperative irradiation. Besides routine examinations, flow cytometric analysis was performed, as well as p53 and Ki-67 markers and mitotic and apoptotic index were established by means of immunohistochemistry. Event-free survival (EFS) and overall survival (OS) were accepted as primary endpoints for the prognostic analyses. All the examined potential markers entered standard Kaplan-Meier survival analysis and Cox regression modeling. Statistical significance of prognostic factors was first examined in univariate models and all the parameters subsequently entered multivariate models. The analyses revealed significant prognostic position of advanced clinical stage (III+IV) and increased proliferative activity as primary risk factors (p<0.01) that typically positively correlate with increased mitotic activity and G2/M cell fraction. Better survival results obtained for grade 3-4 as compared to grade 1-2 were caused by molecular parameters that make these samples similar to less risk cases. Cytokinetic parameters and proliferation activity were found as important predictors of the second level (after recognizing stage, grade and DNA status of the tumor). Multivariate combination of these markers contributed namely to the prognosis of early risk event: a ratio S phase cell fraction/G2M cell fraction was found to be the key prognostic factor (p<0.01). Early risk events are associated with increased mitotic activity, decreased apoptic rate, decreased S phase cell fraction and significantly increased G2/M fraction.

[Metal stents in patients with malignant and benign esophageal stenoses]. / Kovové stenty u nemocných s maligní a benigní stenózou jícnu.

The authors used between October 1993 and January 1997 in 131 patients with inoperable malignant or benign stenosis of the oesophagus an expansible metal stent. In 25 patients the stenosis was in the upper third of the oesophagus, in 44 in the medium part, in 53 in the lower third of the oesophagus and in 9 patients in the area of the anastomosis. All patients suffered at the time when the stent was introduced from marked dysphagia (stage 3-4 according to the international classification). In 45 patients the authors introduced more than one stent. 112 patients suffered from malignant stenosis (67 squamous cell carcinoma, 27 adenocarcinoma, 9 pulmonary or bronchogenic carcinoma, in two instances lymphoma, in two instances leiomyosarcoma and in five patients another type of tumour). Seventeen patients suffered from benign stenosis (8 complications of reflux oesophagitis, 3 stenosis in the anastomosis, in two instances corrosion by acid, 2 cases of epidermolysis bullosa oesophagi and one post-radiation stenosis). In these patients repeatedly before introduction of the stent dilatation of the stenosis by means of a balloon dilatation catheter was attempted. In two instances the etiology of the stenosis was obscure. Complications related to the procedure proper or after insertion of the stent were recorded in 49 patients-dislocation of the stent 23x, occlusion of the stent 17x, development of a fistula 6x, ulceration 16x, haemorrhage 4x, hyperplasia of the mucosa 21x, ileus 2x, inadequate expansion of the stent 8x.