The impact of tumor budding and single-cell invasion on survival in patients with stage III/IV locally advanced oral squamous cell carcinoma- results from a prospective cohort study.

Introduction: Tumor budding (TB) refers to the presence of small clusters of tumor cells at the invasive front of a malignant tumor. Single tumor cell invasion (SCI) is an extreme variant of TB, in which individual loose tumor cells are present at the invasive front. Both TB and SCI are important histomorphologic risk factors postulated to indicate loss of cellular cohesion. In this study, we investigated the influence of TB and SCI on different survival outcomes in patients with locally advanced oral squamous cell carcinoma (OSCC). Methods: We included 129 patients with locally advanced OSCC (pT3-4) from a single-center, prospectively maintained cohort. We examined the association of TB and SCI with the presence of occult lymph node metastasis using a logistic regression model. Survival probabilities were estimated using the Kaplan-Meier method and cumulative incidence functions. The association of TB and SCI on overall survival (OS), oral cancer-specific survival (OCSS), and local recurrence-free survival (LRFS) was investigated using Cox's proportional hazards regression models. Results: TB was detected in 98 (76%) of the tumors, while SCI was observed in 66 (51%) patients. There was a significant association between TB and the occurrence of occult lymph node metastasis (OR=3.33, CI: 1.21-10.0). On multivariate analysis, TB had no detectable impact on survival outcomes. However, SCI showed a higher risk for local recurrence (Hazards ratio (HR): 3.33, CI: 1.19 - 9.27). Discussion: This study demonstrates that TB and SCI in locally advanced OSCC function as an independent risk factor for occult lymph node metastases, as well as local recurrences. Both histomorphologic risk factors could serve as an additional parameter for stratifying therapy and escalating multimodal treatment approaches.

Protective impact of nicotinamide mononucleotide (NMN) and platelet-rich fibrin (PRF) on replicative and radiation-induced senescence of human osteoblasts.

The aim of this study was to investigate the cellular changes induced by spontaneous/replicative senescence and radiation in human osteoblasts (OBs), and the impact of cultivation with nicotinamide mononucleotide (NMN) and platelet-rich fibrin (PRF) on apoptosis, senescence-associated ß-galactosidase staining (SA ß-gal), and senescence-related gene expression using RT2 Profiler PCR array. The results showed that replicative OB aging follows a different pattern from that of radiation-induced cellular senescence. SA ß-gal intensity score showed a significant elevation after spontaneous replicative aging of OB (agiT1) 7 days following the start of the experiment, compared with their initial control condition (T0) (T0 = 2.1 ± 0.47; agiT1 = 9.60 ± 1.56; p = 0.001). Concurrent treatment by NMN and PRF showed a protective effect on OBs undergoing replicative senescence, and reduced SA ß-gal staining significantly (agiT1 = 9.60 ± 1.56; agiT1+PRF = 3.19 ± 0.52; agiT1+NMN = 3.38 ± 0.36; p < 0.001). These results provide evidence for the potential clinical implications of systematic NMN administration and local PRF application to prevent age-related bone disturbances in elderly patients.

Chemoradiation with Cisplatin vs. Carboplatin for Squamous Cell Carcinoma of the Head and Neck (SCCHN).

Cisplatin is the standard for the chemoradiation of squamous cell carcinoma of the head and neck (HNSCC). Many patients cannot receive cisplatin due to impaired renal function. This study investigated carboplatin as an alternative option. In total, 131 patients assigned to two courses of cisplatin (20 mg/m2/d1--5 or 25 mg/m2/d1-4) were matched to 45 patients not suitable for cisplatin and receiving carboplatin (AUC 1.0/d1-5 or AUC 1.5/d1-4). The endpoints included loco-regional control (LRC), metastases-free survival (MFS), overall survival (OS), toxicities, and the completion of chemotherapy. The patients in the carboplatin group were significantly older and had more G3 tumors. Otherwise, the baseline characteristics were balanced. The LRC rates at 2 and 3 years were 77% and 76% in the cisplatin group vs. 69% and 65% in the carboplatin group (p = 0.21). The MFS rates were 83% and 78% vs. 78% and 74% (p = 0.34) and the OS rates 83% and 79% vs. 83% and 75% (p = 0.64), respectively. The outcomes were not significantly different in the subgroups receiving definitive or adjuvant chemoradiation. No significant differences were found regarding toxicities. Non-significantly more patients in the carboplatin group completed their chemotherapy (78% vs. 66%, p = 0.15). Carboplatin was associated with similar outcomes and toxicities as cisplatin, although these patients had worse renal function, more aggressive tumors, and were older. Given the limitations of this study, carboplatin appears an option for patients not suitable for cisplatin.

A New Prognostic Instrument for Predicting the Probability of Completion of Cisplatin during Chemoradiation for Head and Neck Cancer.

Many head and neck cancer patients assigned to definitive or adjuvant chemoradiation treatment do not complete the concurrent cisplatin dose. We determined corresponding risk factors and developed a prognostic instrument to help identify these patients. Ten pre-treatment characteristics were retrospectively analyzed in 154 patients with head and neck cancer who were treated via chemoradiation with cisplatin. These pre-treatment characteristics included age, sex, Karnofsky performance score, tumor site, primary tumor stage, nodal stage, histologic grade, upfront surgery, human papilloma virus status, and history of smoking. The characteristics significantly associated with the completion of cisplatin-based treatment, the receipt of ≥80% cisplatin, or showing a strong trend of association after multivariate analyses were used for the prognostic instrument. For each characteristic, 0 points were assigned for worse outcomes, and 1 point was assigned for better outcomes. Patients' scores were calculated by adding these points. Age ≤ 60 years and a Karnofsky performance score of 90-100 were significantly associated with both endpoints after multivariate analysis, and male gender showed a trend for association with the receipt of ≥80% cisplatin. Patient scores were 0, 1, 2, and 3 points. The corresponding rates of completion of cisplatin-based treatment were 14%, 41%, 62%, and 72%, respectively (p = 0.004). The rates of receipt of ≥80% cisplatin were 29%, 54%, 72%, and 94%, respectively (p < 0.001). This new prognostic instrument helps to predict whether head and neck cancer patients scheduled for chemoradiation will receive cisplatin as planned.

First Results of Concurrent Chemoradiation with Two Courses of 5 × 25 mg/m2 Cisplatin for Locally Advanced Head and Neck Cancer.

Many patients with squamous cell carcinoma of the head and neck (SCCHN) receive cisplatin-based chemoradiation. Cisplatin 100 mg/m2 every three weeks is toxic and alternative cisplatin regimens are desired. Two courses of 20 mg/m2/day 1-5 (cumulative 200 mg/m2) were shown to be similarly effective and better tolerated than 100 mg/m2 every three weeks. Previous studies suggested that cumulative doses >200 mg/m2 may further improve outcomes. In this study, 10 patients (group A) receiving two courses of 25 mg/m2/day 1-5 (cumulative 250 mg/m2) in 2022 were retrospectively matched and compared to 98 patients (group B) receiving two courses of 20 mg/m2/day 1-5 or 25 mg/m2/day 1-4 (cumulative 200 mg/m2). Follow-up was limited to 12 months to avoid bias. Group A achieved non-significantly better 12-month loco-regional control (100% vs. 83%, p = 0.27) and metastases-free survival (100% vs. 88%, p = 0.38), and similar overall survival (89% vs. 88%, p = 0.90). No significant differences were found regarding toxicities, completion of chemotherapy, and interruption of radiotherapy. Given the limitations of this study, chemoradiation with two courses of 25 mg/m2/day 1-5 appears an option for carefully selected patients as a personalized treatment approach. Longer follow-up and a larger sample size are needed to properly define its role.

Emotional Distress in Head-and-neck Cancer Patients Scheduled for Chemoradiation or Radiotherapy Alone.

BACKGROUND/AIM: Radiotherapy for head-and-neck cancer is often associated with significant toxicities, which may cause emotional distress. We evaluated prevalence and risk factors for pre-treatment emotional problems in patients irradiated for head-and-neck cancer. PATIENTS AND METHODS: Twelve characteristics were retrospectively investigated in 213 patients for associations with emotional problems (worry, fear, sadness, depression, nervousness, loss of interest). After Bonferroni adjustment, p-values <0.0042 were regarded significant. RESULTS: At least one emotional problem was reported by 131 patients (61.5%). Specific prevalence for emotional problems ranged between 10% and 44%. Physical complaints showed significant associations with all six emotional problems (p<0.0001) and female sex with sadness (p=0.0013). Trends were found for associations between female sex and fear (p=0.0097), history of another tumor and sadness (p=0.043), worse performance status and nervousness (p=0.012), and cancer site (oropharynx/oral cavity) and nervousness (p=0.063). CONCLUSION: More than 60% of patients reported emotional distress prior to radiotherapy for head-and-neck cancer. Patients with risk factors likely require near-term psycho-oncological assistance.

Comparison of Two Cisplatin Regimens for Chemoradiation in Patients With Squamous-cell Carcinoma of the Head and Neck.

BACKGROUND/AIM: Many patients with squamous-cell carcinoma of the head and neck receive cisplatin-based chemoradiation. This retrospective study compared two chemoradiation programs to help identify the optimal cisplatin-regimen. PATIENTS AND METHODS: Forty-one patients assigned to chemoradiation with two cycles of 20 mg/m2/days(d)1-5 were compared to 78 patients assigned to chemoradiation with two cycles of 25 mg/m2/d1-4. Groups were compared for toxicity, loco-regional control (LRC), and survival. RESULTS: Both treatments were associated with similar rates of oral mucositis, radiation dermatitis, xerostomia, nausea, decreased renal function, and hematotoxicity. The cisplatin-regimen had no significant impact on LRC (p=0.41) or survival (p=0.85). Survival was significantly worse with radiotherapy interruptions (>1 week) or discontinuation (p<0.001) and administration of <80% of the planned cisplatin dose (p<0.001). CONCLUSION: Both cisplatin-regimens did not differ significantly regarding toxicities, LRC, and survival. It is important to avoid interruption or discontinuation of radiotherapy and to administer ≥80% of planned cisplatin.

Evaluation of the Impact of Smoking and Alcohol Consumption on Toxicity and Outcomes of Chemoradiation for Head and Neck Cancer.

BACKGROUND/AIM: Smoking and alcohol abuse may impair outcomes of chemoradiation for squamous cell head and neck cancer (SCCHN). Potential associations with toxicity, loco-regional control (LRC), and overall survival (OS) were investigated. PATIENTS AND METHODS: Ninety-six patients were retrospectively analyzed for impacts of pre-radiotherapy (pre-RT) smoking history, smoking during radiotherapy, and pre-RT alcohol abuse on toxicity, LRC, and OS. RESULTS: A trend was found for associations between pre-RT smoking history and grade ≥2 dermatitis. Smoking during radiotherapy was significantly associated with grade ≥3 mucositis and showed trends regarding grade ≥2 mucositis and dermatitis. On univariate analyses, smoking during radiotherapy was negatively associated with LRC and OS, pre-RT alcohol abuse with OS, and >40 pack years with LRC and OS. In multivariate analyses, smoking during radiotherapy remained significant for decreased OS, and pack years showed a trend. CONCLUSION: Smoking during radiotherapy was an independent predictor of OS and associated with increased toxicity. Thus, it is important to stop smoking prior to the start of radiotherapy.

Impact of a mobile application (reminder app) on acute toxicity during radiotherapy of head-and-neck cancer - results of a randomized phase III trial (RAREST-02).

BACKGROUND: Radiotherapy of head-and-neck cancer (SCCHN) is often associated with acute toxicity. In a previous trial, daily reminders by staff members to perform skin care resulted in less dermatitis. This randomized trial investigated whether a mobile application can replace these reminders. METHODS: Patients were stratified according to tumor site, treatment and center. Fifty-three patients were eligible for per-protocol-set (25 with, 28 without app). Primary endpoint was grade ≥ 2 dermatitis until 60 Gy. Secondary endpoints included dermatitis grade ≥ 2 until end of radiotherapy (EOT), dermatitis grade ≥ 3, and mucositis grade ≥ 2 and ≥ 3. RESULTS: After an interim analysis, the study was terminated (delayed and slow accrual). Until 60 Gy, grade ≥ 2 dermatitis rates were 72% with vs. 82% without app (p = 0.38), grade ≥ 3 dermatitis rates 20% vs. 11% (p = 0.45). Until EOT, grade ≥ 2 and ≥ 3 dermatitis rates were 72% vs. 86% (p = 0.22) and 24% vs. 18% (p = 0.58). Until 60 Gy, grade ≥ 2 and ≥ 3 mucositis rates were 76% vs. 82% (p = 0.58) and 20% vs. 36% (p = 0.20). Until EOT, corresponding mucositis rates were 76% vs. 82% (p = 0.58) and 28% vs. 43% (p = 0.26). CONCLUSION: Given the limitations of this trial, the reminder app led to non-significant reduction of grade ≥ 2 dermatitis, grade ≥ 2 mucositis and ≥ 3 mucositis. Additional studies are required to define the value of reminder apps during radiotherapy for SCCHN.

Impact of Dose-Volume Parameters of Parotid Glands on Xerostomia in Patients Irradiated for Head-and-Neck Cancer.

BACKGROUND/AIM: Optimal planning of radiotherapy for head-and-neck cancers should consider the risk of xerostomia. This study investigated the prognostic value of dosevolume parameters of the parotid glands. PATIENTS AND METHODS: Dose-volume parameters were evaluated for xerostomia in 145 patients including D40 (minimum dose to 40% of corresponding parotid volume), D60 (minimum dose to 60%), D80 (minimum dose to 80%), and mean dose of ipsilateral, contralateral, and bilateral parotid glands. RESULTS: Grade ≥2 xerostomia was significantly associated with D40 of ipsilateral and all parameters of bilateral glands; trends were found for all other parameters. Grade ≥3 xerostomia was significantly associated with D80 of bilateral glands; trends were found for other parameters of ipsilateral and bilateral glands. CONCLUSION: Since grade ≥2 xerostomia was associated with all parameters, D40, D60, and D80 did not provide additional information to mean doses. D80 of bilateral glands is a new factor and more predictive than mean dose regarding grade ≥3 xerostomia.

Current Trends in the Reconstruction and Rehabilitation of Jaw following Ablative Surgery.

The reconstruction and rehabilitation of jaws following ablative surgery have been transformed in recent years by the development of computer-assisted surgery and virtual surgical planning. In this narrative literature review, we aim to discuss the current state-of-the-art jaw reconstruction, and to preview the potential future developments. The application of patient-specific implants and the "jaw-in-a-day technique" have made the fast restoration of jaws' function and aesthetics possible. The improved efficiency of primary reconstructive surgery allows for the rehabilitation of neurosensory function following ablative surgery. Currently, a great deal of research has been conducted on augmented/mixed reality, artificial intelligence, virtual surgical planning for soft tissue reconstruction, and the rehabilitation of the stomatognathic system. This will lead to an even more exciting future for the functional reconstruction and rehabilitation of the jaw following ablative surgery.

Prognostic Factors for Complete Recovery From Xerostomia After Radiotherapy of Head-and-Neck Cancers.

BACKGROUND/AIM: Radiotherapy of head-and-neck cancers can cause xerostomia. This study investigated potential prognostic factors for complete recovery from this complication. PATIENTS AND METHODS: Eighty head-and-neck cancer patients with radiation-induced xerostomia were retrospectively evaluated. Thirteen characteristics were analyzed for complete recovery (to grade 0) from xerostomia including age, sex, tumor site and stage, nodal stage, upfront surgery, mean dose to ipsilateral, contralateral and both parotid glands, chemotherapy, radiation type and dose, and initial grade of xerostomia. RESULTS: Fifteen patients (18.8%) experienced complete recovery of xerostomia. Significant associations with complete recovery were found for initial grade 1 xerostomia (p<0.001), mean dose to contralateral parotid gland of <20 Gy (p=0.034), and radiation treatment without chemotherapy (p=0.047). CONCLUSION: Almost every fifth patient experienced complete recovery of xerostomia. Prognostic factors were identified that can guide radiation oncologists during the process of treatment planning.

Smoking-, Alcohol-, and Age-Related Alterations of Blood Monocyte Subsets and Circulating CD4/CD8 T Cells in Head and Neck Cancer.

Head and neck squamous cell carcinoma (HNSCC) represents a heterogeneous malignant disease of the oral cavity, pharynx, and larynx. Although cigarette smoking, alcohol abuse, and aging are well-established associated factors for HNSCC, their respective influence on immunologic alterations of monocyte subsets or T-cell compositions in the peripheral blood has not yet been fully unveiled. Using flow cytometry, whole blood measurements of CD14/CD16 monocyte subsets and analyses of T-cell subsets in isolated PBMC fractions were carried out in 64 HNSCC patients in view of their tobacco and alcohol consumption, as well as their age, in comparison to healthy volunteers. Flow cytometric analysis revealed significantly increased expression of monocytic CD11b, as well as significantly decreased expression levels of CX3CR1 on classical and intermediate monocyte subsets in smoking-related and in alcohol-related HNSCC patients compared to healthy donors. Peripheral monocytes revealed an age-correlated significant decrease in PD-L1 within the entirety of the HNSCC cohort. Furthermore, we observed significantly decreased abundances of CD8+ effector memory T cells in active-smoking HNSCC patients and significantly increased percentages of CD8+ effector T cells in alcohol-abusing patients compared to the non-smoking/non-drinking patient cohort. Our data indicate an enhanced influence of smoking and alcohol abuse on the dynamics and characteristics of circulating monocyte subsets and CD4/CD8 T-cell subset proportions, as well as an age-related weakened immunosuppression in head and neck cancer patients.

The First Prognostic Tool to Estimate the Risk of Late Grade ≥3 Xerostomia in Patients Irradiated for Head-and-Neck Cancer.

BACKGROUND/AIM: Xerostomia is a serious complication following radiotherapy of head-and-neck cancers. A prognostic tool was developed for estimating its risk. PATIENTS AND METHODS: In our previous study, age, tumor site, bilateral lymph node involvement, definitive radiotherapy, and addition of systemic therapies showed significant associations with grade ≥3 late xerostomia or trends. In additional analyses, mean radiation dose to ipsilateral parotid gland was significant (p=0.011). These six factors were included in the prognostic tool. Scoring points of 0 (lower risk) or 1 (higher risk) were assigned to each factor and added for each patient. RESULTS: Patient scores ranged between 0 and 6; Grade ≥3 xerostomia rates were 0%, 8%, 24%, 26%, 25%, 42%, and 100%, respectively. Three groups were designed (0-1, 2-4, and 5-6 points) with grade ≥3 xerostomia rates of 5%, 25%, and 50%, respectively (p<0.001). CONCLUSION: This new tool helps estimating the risk of radiation-induced grade ≥3 xerostomia. It can support physicians and other medical staff members during treatment planning.

Risk Factors for Xerostomia Following Radiotherapy of Head-and-Neck Cancers.

BACKGROUND/AIM: Many head-and-neck cancer patients receive radiotherapy, which may be associated with significant toxicities. Xerostomia is considered one of the most debilitating late adverse events. This study was performed to identify risk factors for xerostomia. PATIENTS AND METHODS: Several characteristics were investigated for associations with late xerostomia in 159 patients irradiated for head-and-neck cancer including age, sex, tumor site and size, underlying pathology, histologic grading, upfront resection, systemic treatment, and type and dose of radiotherapy. RESULTS: Ninety (57%) and 35 (22%) patients experienced grade ≥2 and ≥3 xerostomia, respectively. Grade ≥2 xerostomia was significantly associated with tumor site (nasopharynx/oropharynx/oral cavity/floor of mouth, p=0.049). Grade ≥3 xerostomia was significantly associated with age ≥61 years (p=0.035); trends were found for tumor site (p=0.088), bilateral nodal involvement (p=0.093), definitive treatment (p=0.082), and systemic treatment (p=0.055). CONCLUSION: Risk factors for xerostomia following radiotherapy of head-and-neck cancers were identified including older age, unfavorable tumor site, bilateral involvement of lymph nodes, definitive treatment, and addition of systemic therapies. For patients with risk factors, sparing of the salivary glands is particularly important.

Impact of PRP and PRF on Viability of Zoledronic Acid Treated Osteoblasts in 2D and 3D Cell Culture.

BACKGROUND/AIM: Zoledronic acid (ZA) treatment of in vitro cultured osteoblasts (OB) results in reduction in viability, proliferation and differentiation. These effects are slightly attenuated when platelets-rich fibrin and plasma (PRF and PRP) are added. However, it is still unknown whether application of PRP/PRF on ZA-treated OB in a 3D-environment would influence the viability in relation to 2D-cultivation. MATERIALS AND METHODS: Non-treated and ZA-treated OB were cultivated in 2D conditions or seeded in a 3D collagen scaffold with and without PRP/PRF. MTT test was carried out after 5 days of colonization. 4,6-diamidino-2'-phenylindole, dihydrochloride (DAPI)-staining was performed in OB grown in 3D scaffolds to ensure spatial distribution of OB. RESULTS: ZA led to a significant reduction in cell viability compared to the control group. Addition of either PRF or PRP to the 3D colonized and ZA-treated OB significantly enhanced their survival and viability in relation to 2D monolayer cultivation. CONCLUSION: The use of 3D-scaffolds has a positive effect on OB viability, and stimulation by PRF and PRP may provide a therapeutic approach to transfer these results into clinical routine for the treatment of patients with bisphosphonate related osteonecrosis of the jaw (BR-ONJ).

The Benefit of Postoperative Radiotherapy and Extending Neck Dissection in pT1-2 Oral Squamous Cell Carcinoma With a Single Ipsilateral Cervical Lymph Node Metastasis (pN1).

BACKGROUND/AIM: We compared postoperative radiotherapy (PORT) to surgery only (SO), and supraomohyoidal neck dissection (SOHND) to modified radical neck dissection (MRND) in patients with pT1-T2 squamous cell carcinomas of the oral cavity (OSCC) and a single cervical lymph node metastasis (pN1) in terms of overall survival (OS), oral cancer specific survival (OCSS), and regional recurrence-free survival (RRFS), in a prospective cohort study. PATIENTS AND METHODS: We included patients with pT1-T2 pN1 OSCC with no distant metastasis and estimated the survival probabilities using the Kaplan-Meier method and calculated hazards ratios (HR) for PORT vs. SO and MRND vs. SOHND using adjusted Cox regression models. RESULTS: A total of 51 patients (26 SO vs. 25 PORT, 9 SOHND vs. 42 MRND) were evaluated. Patients who received PORT were more likely to be younger and healthier. OS at 5 years was 41% and 87% in the SO and PORT groups, respectively. OS at 5 years was 52% and 67% in the in the SOHND and MRND groups, respectively. Both OCSS and RRFS were improved by PORT. Extending neck dissection was not associated with improved OS (HR = 0.83). CONCLUSION: PORT is associated with preferable OS, OCSS, and RRFS in pT1-2 pN1 oral cancer and should be recommended regularly.

The sub-fascial pattern of the myocutaneous platysma flap - The anatomical basis and preliminary cases for oral reconstruction.

To verify the feasibility of the SF-MPF for oral reconstruction, the anatomic, sonographic and histologic features of the SF-MPF were investigated and the outcome in a series of patients was evaluated. The sonographic and histologic results showed a supra-fascial arterio-venous vascular blood supply to the sub-fascial design of the MPF. The clinical course of 12 consecutive patients who underwent oral reconstruction using the SF-MPF along with ipsi- or lateral neck dissection for treatment of oral cancer showed sufficient pedicle length and reliable blood supply. The SF-MPF is a reliable and safe pedicled myocutaneous flap. Therefore, it should be considered being an additional option when a pedicled flap has to be selected.