EZH2 Expression in Head-and-Neck Squamous Cell Cancer in Young Patients.

EZH2 (Enhancer of zeste homolog 2) promotes tumor growth and survival through numerous mechanisms and is a promising target for novel therapeutic approaches. We aimed to characterize the expression of EZH2 in the tumors of young head-and-neck squamous cell cancer (HNSCC) patients in comparison with the general HNSCC patient population. We used formalin-fixed, paraffin-embedded tissue blocks from 68 random young HNSCC patients (≤39 years, median age: 36 years; diagnosed between 2000 and 2018), which were compared with the samples of 58 age- and gender-matched general HNSCC subjects (median age: 62 years; all diagnosed in the year 2014). EZH2 and p53 expression of the tumors was detected using immunohistochemical staining. Lower EZH2 expression was found to be characteristic of the tumors of young HNSCC patients as opposed to the general population (median EZH2 staining intensity: 1 vs. 1.5 respectively, p < 0.001; median fraction of EZH2 positive tumor cells: 40% vs. 60%, respectively, p = 0.003, Mann-Whitney). Cox analysis identified a more advanced T status (T3-4 vs. T1-2), a positive nodal status, and alcohol consumption, but neither intratumoral EZH2 nor p53 were identified as predictors of mortality in the young patient group. The lower EZH2 expression of young HNSCC patients' tumors discourages speculations of a more malignant phenotype of early-onset tumors and suggests the dominant role of patient characteristics. Furthermore, our results might indicate the possibility of an altered efficacy of the novel anti-EZH2 therapies in this patient subgroup.

Dosimetric comparison of postoperative interstitial high-dose-rate brachytherapy and modern external beam radiotherapy modalities in tongue and floor of the mouth tumours in terms of doses to critical organs.

BACKGROUND: The aim of the study was to dosimetrically compare interstitial high-dose-rate (HDR) brachytherapy (BT) and modern external beam radiotherapy modalities, as volumetric modulated arc therapy (VMAT) and stereotactic radiotherapy with Cyberknife (CK) of tumours of the tongue and floor of the mouth in terms of dose to the critical organs. PATIENTS AND METHODS: In National Institute of Oncology, Budapest, between March 2013 and August 2022 twenty patients (11 male/9 female) with stage T1-3N0M0 tongue (n = 14) and floor of mouth (n = 6) tumours received postoperative radiotherapy because of close/positive surgical margin and/or lymphovascular and/or perineural invasion. High-dose-rate interstitial brachytherapy applying flexible plastic catheters with a total dose of 15 × 3 Gy was used for treatment. In addition to BT plans VMAT and stereotactic CK plans were also made in all cases, using the same fractionation scheme and dose prescription. As for the organs at risk, the doses to the mandible, the ipsilateral and the contralateral salivary glands were compared. RESULTS: The mean volume of the planning target volume (PTV) was 12.5 cm3, 26.5 cm3 and 17.5 cm3 in BT, VMAT and CK techniques, respectively, due to different safety margin protocols. The dose to the mandible was the most favourable with BT, as for the salivary glands (parotid and submandibular) the CK technique resulted in the lowest dose. The highest dose to the critical organs was observed with the VMAT technique. The mean values of D2cm3 and D0.1cm3 for the critical organs were as follows for BT, VMAT and CK plans: 47.4% and 73.9%, 92.2% and 101.8%, 68.4% and 92.3% for the mandible, 4.8% and 6.7%, 7.3% and 13.8%, 2.3% and 5.1% for the ipsilateral parotid gland, 3.5% and 4.9%, 6.8% and 10.9%, 1.5% and 3.3% for the contralateral parotid gland, 7.3% and 9.4%, 9.0% and 14.3%, 3.6% and 5.6% for the contralateral submandibular gland. CONCLUSIONS: The present results confirm that BT, despite being an invasive technique, is dosimetrically clearly beneficial in the treatment of oral cavity tumours and is a modality worth considering when applying radiotherapy, not only as definitive treatment, but also postoperatively. The use of the CK in the head and neck region requires further investigation.

Malignant Transformation and Long-Term Outcome of Oral and Laryngeal Leukoplakia.

BACKGROUND: Oral or laryngeal leukoplakia has an increased risk for malignant transformation but the risk of the two anatomical sites has not been compared to each other yet. MATERIALS AND METHODS: Clinical data of 253 patients with leukoplakia (oral = 221 or laryngeal = 32) enrolled from January 1996 to January 2022 were analyzed. One hundred and seventy underwent biopsy and 83 did not. The mean follow-up time was 148.8 months. Risk factors for the malignant transformation of leukoplakia were identified using Cox proportional hazard models. RESULTS: In the oral or laryngeal group, the rate of cancer was 21.7% and 50% (p = 0.002), respectively. The 10-year estimated malignant transformation was 15.1% and 42% (p < 0.0001), respectively. The laryngeal group had an increased risk of malignant transformation (p < 0.0001). The 5-year estimated survival with leukoplakia-associated cancer for the oral or laryngeal group was 40.9% and 61.1% (p = 0.337), respectively. Independent predictors of malignant transformation in the oral group were dysplasia and the grade of dysplasia of the leukoplakia, and in the laryngeal group, dysplasia had a significant impact. The malignant transformation rate was low for oral patients without biopsy or with no dysplasia, 3.9% and 5.1%, respectively. The malignant transformation occurred over 10 years. CONCLUSIONS: Patients with dysplastic leukoplakia have an increased risk of malignant transformation, but the risk is higher with laryngeal than with oral leukoplakia. There is no significant difference between the groups regarding survival with leukoplakia-associated cancer. Oral patients with no dysplastic lesions have a low risk of malignant transformation. A complete excision and long-term follow up are suggested for high-risk patients to diagnose cancer in an early stage and to control late (over 10 years) malignant events.

The characteristics of head and neck squamous cell cancer in young adults: A retrospective single-center study.

We aimed to characterize clinical and prognostical factors of primary head and neck squamous cell carcinoma (HNSCC) in 85 young patients (≤39 years, median age: 37 years; between 2000-2018) in comparison with 140 institutional general HNSCC patients (median age: 61.5 years). The patient's medical records were collected from the institutional database. The prevalence of smoking and alcohol consumption (65.8% and 48.1%) in the young group exceeded the regional population average but was below the institutional (86.4% and 55%) general HNSCC patient population. Primary tumor sites in the group of young patients were as follows: oral cavity (56.4%), oropharynx (17.6%), hypopharynx (11.7%), and larynx (14.1%). Cumulative five-year overall survival was 44.2% in the young group, but significantly better with early T (T1-2 vs. T3-4: 52.6% vs. 26.7%; p = 0.0058) and N0 status (N0 vs. N+: 65.2% vs. 32.3%; p = 0.0013). Young age, abstinence, earlier stage and laryngeal tumor site might predict a better prognosis. The age distribution and the high prevalence of traditional risk factors among the young patients as well as the predominance of oral cavity tumor localization suggest that the early onset of tumor development could be originated from the premature failure of the intrinsic protective mechanisms.

Results of sole postoperative interstitial, high-dose-rate brachytherapy of T1-2 tongue tumours.

PURPOSE: To describe the results of treating tongue cancer patients with single postoperative interstitial, high-dose-rate (HDR) brachytherapy (BT) after resection. METHODS: Between January 1998 and April 2019, 45 patients with squamous cell histology, stage T1-2N0-1M0 tongue tumours were treated by surgery followed by a single HDR BT in case of negative prognostic factors (close or positive surgical margin, lymphovascular and/or perineural invasion). The average dose was 29 Gy (range: 10-45 Gy) and rigid metal needles were used in 11 (24%) and flexible plastic catheters in 34 cases (76%). Survival parameters, toxicities and the prognostic factors influencing survival were analysed. RESULTS: During a mean follow-up of 103 months (range: 16-260 months) for surviving patients, the 10-year local and regional control (LC, RC), overall survival (OS), and disease-specific survival (DSS) probabilities were 85, 73, 34 and 63%, respectively. The incidence of local grade 1, 2 and 3 mucositis was 23, 73 and 4%, respectively. As a serious (grade 4), late side effect, soft tissue necrosis developed in 3 cases (7%). In a univariate analysis, there was a significant correlation between lymphovascular invasion and RC (p = 0.0118) as well as cervical recurrence and DSS (p < 0.0001). CONCLUSION: Sole postoperative HDR brachytherapy can be an effective method in case of negative prognostic factors in the treatment of early, resectable tongue tumours. Comparing the results of patients treated with postoperative BT to those who were managed with surgery or BT alone known from the literature, a slightly more favourable LC can be achieved with the combination therapy, demonstrating the potential compensating effect of BT on adverse prognostic factors, while the developing severe, grade 4 toxicity rate remains low.

The role of brachytherapy in the curative treatment of oral cavity tumors / A brachytherapia szerepe az ajak-szájüregi daganatok kuratív ellátásában.

Összefoglaló. A szájüregi daganatok kuratív kezelésében az elsodlegesen választandó mutét mellett a sugárterápiának is jelentos szerepe van. A lokális tumormentesség biztosításához azonban dóziseszkaláció szükséges. Ennek külso besugárzással való megvalósítása a környezo normálszövetek fölösleges dózisterhelésével és az ebbol következo mellékhatások elofordulásának emelkedésével jár. A brachytherapia (BT) - amelynek során radioaktív sugárforrást/sugárforrásokat juttatunk a tumorba vagy annak közelébe - lehetové teszi a helyileg magasabb dózis leadását a környezo ép szövetek kímélésével. A BT a korai, T1-2N0 stádiumú szájüregi tumoroknál - kedvezo prognosztikai faktorok mellett - akár kizárólagosan vagy mint posztoperatíve egyedül alkalmazott terápiás modalitás jön szóba. Kedvezotlenebb prognózis esetén vagy elorehaladottabb stádiumban (T3-4 vagy N+) a mutétet és/vagy a percutan irradiációt kiegészíto eljárásként alkalmazható kedvezo sugárfizikai tulajdonságai miatt. A kis dózisteljesítményu (low-dose-rate, LDR) BT-t már évtizedek óta alkalmazzák a terápiában, de ezt kezdi kiszorítani a nagy dózisteljesítményu (high-dose-rate, HDR), illetve a pulzáló dózisteljesítményu (pulse-dose-rate, PDR) BT. A jelen áttekinto tanulmány célja irodalmi adatok alapján a BT szerepének és indikációjának ismertetése a szájüregi daganatok kuratív kezelésében, alrégiókra lebontva. Orv Hetil. 2021; 162(37): 1471-1479. Summary. Radiation therapy plays a significant role in the curative treatment of oral cavity tumors, in addition to the primary choice of surgery. However, dose escalation is required to ensure local tumor control. Its implementation with external irradiation is accompanied by an unnecessary dose exposure to the surrounding normal tissues and an increase in the incidence of consequent side effects. Brachytherapy (BT), in which a radiation source/sources is/are placed inside or close to the tumor, allows a higher dose to be delivered locally, sparing the surrounding intact tissues. In addition to favorable prognostic factors in early T1-2N0 stage oral cavity tumors, BT is considered either exclusively or as a sole postoperative therapeutic modality. At less favorable prognosis or at a more advanced stage (T3-4 or N+), BT can be used as a complementary procedure after surgery and/or percutaneous irradiation based on its favorable radio-physical properties. Low-dose-rate (LDR) BT has been used in the therapy for decades, but recently it has been replaced by high-dose-rate (HDR) and pulse-dose-rate (PDR) BT. The purpose of this review is to describe the role and indications of BT in the treatment of oral cavity tumors categorized into subregions, based on the literature data. Orv Hetil. 2021; 162(37): 1471-1479.

Results of postoperative interstitial brachytherapy of resectable floor of mouth tumors.

PURPOSE: The purpose of this study was to describe the results of postoperative sole interstitial brachytherapy (BT) in patients with resectable floor of mouth tumors. METHODS AND MATERIALS: Between January 1998 and December 2017, 44 patients with squamous cell histology, stage T1-3N0-1M0 floor of mouth tumor were treated by excision of the primary lesion with or without neck dissection followed by sole high-dose-rate tumor bed BT with an average dose of 22.7 Gy (10-45 Gy) using rigid metal needles (n = 14; 32%) or flexible plastic catheters (n = 30; 68%). RESULTS: During a median followup time of 122 months for surviving patients, the probability of 5- and 10-year local and regional tumor control, overall survival (OS), and disease-specific survival (DSS) was 89% and 89%, 73% and 67%, 52% and 32%, 66% and 54%, respectively. In univariate analysis, lymphovascular invasion was a negative predictor of regional tumor control (p = 0.0062), DSS (p = 0.0056), and OS (p = 0.0325), whereas cervical recurrence was associated with worse DSS (p < 0.0001) and OS (p < 0.0001). The incidence of local Grade 1, 2, and 3 mucositis was 25%, 64%, and 11%, respectively. Grade 4 side effect, that is soft tissue necrosis occurred in four cases (9%). CONCLUSIONS: Results of postoperative sole high-dose-rate BT of floor of mouth tumors are comparable with those reported with low-dose-rate BT, and this method could improve local tumor control and DSS compared with exclusive surgical treatment.

Image guided high-dose-rate brachytherapy versus volumetric modulated arc therapy for head and neck cancer: A comparative analysis of dosimetry for target volume and organs at risk.

Background The aim of the study was to present dosimetric comparison of image guided high-dose-rate brachytherapy (IGBT) with volumetric modulated arc therapy (VMAT) for head and neck cancer regarding conformity of dose distribution to planning target volume (PTV) and doses to organs at risk (OARs). Patients and methods Thirty-eight consecutive patients with T1-4 mobile tongue, floor of mouth and base of tongue cancer treated with IGBT were selected. For these patients additional VMAT treatment plans were also prepared using identical computed tomography data. OARs and PTV related parameters (e.g. V98, D0.1cm3, Dmean, etc.) were compared. Results Mean V98 of the PTV was 90.2% vs. 90.4% (p > 0.05) for IGBT and VMAT, respectively. Mean D0.1cm3 to the mandible was 77.0% vs. 85.4% (p < 0.05). Dmean to ipsilateral and contralateral parotid glands was 4.6% vs. 4.6% and 3.0% vs. 3.9% (p > 0.05). Dmean to ipsilateral and contralateral submandibular glands was 16.4% vs. 21.9% (p > 0.05) and 8.2% vs. 16.9% (p < 0.05), respectively. Conclusions Both techniques showed excellent target coverage. With IGBT dose to normal tissues was lower than with VMAT. The results prove the superiority of IGBT in the protection of OARs and the important role of this invasive method in the era of new external beam techniques.

[Application of CyberKnife stereotactic radiosurgery in the treatment of head and neck cancer]. / A CyberKnife sztereotaxiás sugárterápia alkalmazásának lehetõsége fej-nyaki daganatok kezelésében.

The treatment of squamous cell carcinoma of the head and neck is multimodal, including surgery, chemotherapy, and radiotherapy, or the combination of those. Though aggressive treatment results in complete tumor remission in many patients even in locally advanced stages, unfortunately local relapse is not uncommon. For patients not candidate for salvage surgery, chemotherapy and conventional fractionated external beam irradiation can be applied. However, for patients previously treated with full-dose radiotherapy, the deliverable reirradiation dose is limited, considering the elevated risk of toxicity caused by cumulative doses. CyberKnife is a highly conformal radiosurgical technology which can successfully treat this subset of patients. In addition, it can be applied for hardly resectable rare tumors of the skull base and the head and neck region like chordoma, chondrosarcoma and paragangliomas. The CyberKnife stereotacic radiosurgery technology is now available in Hungary, in the National Institute of Oncology.