High PD-L1 expression on immune cells along with increased density of tumor-infiltrating lymphocytes predicts a favorable survival outcome for patients with loco-regionally advanced head and neck cancer: early results from a prospective study.

Introduction: In the era of personalized medicine and treatment optimization, use of immune biomarkers holds promise for estimating the prognosis of patients with head and neck squamous cell carcinoma (HNSCC) undergoing definitive treatment. Methods: To evaluate the prognostic potential of immune biomarkers, we conducted a prospective monocentric cohort study with loco-regionally advanced HNSCC patients indicated for definitive radiotherapy/radiochemotherapy at the Department of Oncology, Ostrava University Hospital, Czech Republic, between June 2020 and August 2023. We focused on the expression of programmed death ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs) relative to overall survival (OS) and specific survival rates. Associations between biomarkers and survival rates were assessed by crude and adjusted hazard ratios (cHR, aHR, respectively) obtained from Cox proportional hazards regression. Results: Among a total of 55 patients within a median follow-up of 19.7 months, there were 21 (38.2%) all-cause deaths and 15 (27.3%) cancer-related deaths. An overall survival (OS) rate of 61.8% and a disease-specific survival (DSS) rate of 72.7% were recorded. A significant association between survival rates and a ≥10% difference in PD-L1 expression on immune versus tumor cells (high PD-L1IC expression) was documented regardless of the type of analysis (univariate or multivariate). In addition, a stronger association was confirmed for OS and the composite biomarker high PD-L1IC expression along with either median-higher CD8+ TIL count or increased TIL density ≥30%, as indicated by an aHR of 0.08 (95% CI, 0.01 to 0.52) and 0.07 (95% CI, 0.01 to 0.46), respectively. Similar results were demonstrated for other specific survival rates. Discussion: The early outcomes of the present study suggest the utility of a strong prognostic factor involving a composite biomarker high PD-L1IC expression along with increased TIL density in HNSCC patients undergoing definitive radiotherapy and radiochemotherapy. Trial registration: The study is registered with Clinicaltrials.gov. - NCT05941676.

Programmed Cell Death Ligand 1 Expression on Immune Cells and Survival in Patients With Nonmetastatic Head and Neck Cancer: A Systematic Review and Meta-analysis.

Importance: The failure or success of radical treatment in patients with head and neck squamous cell carcinoma (HNSCC) is associated with many known and unknown factors; hence, there is a search for further prognostic markers to help optimize therapeutic strategy and improve treatment outcomes. Objective: To assess the association of programmed cell death ligand 1 (PD-L1) expression on immune or tumor cells, including its composite expression on both cell types, with overall survival (OS) or specific survival. Data Sources: MEDLINE, Embase, PQSciTech, and HCAPlus databases were systematically searched for cohort studies focused on the prognostic role of PD-L1 expression in patients with HNSCC in curative stages of the disease. Search results generated publications from January 1, 2010, to January 6, 2023. Study Selection: Of 3825 publications identified, a total of 17 cohort studies in the English language met inclusion criteria of this systematic review and meta-analysis. Eligible studies reported adjusted hazard ratios (aHRs) with 95% CIs for the association of PD-L1 expression levels with OS and arbitrary specific survival. Data Extraction and Synthesis: Data from studies were extracted independently by 2 researchers strictly adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guidelines and recommendations. The risk of bias was assessed using the Quality in Prognosis Studies tool and Newcastle-Ottawa Scale. Pooled effect estimates were obtained using a random-effect or fixed-effect model based on homogeneity of studies. Main Outcomes and Measures: The primary outcome was to investigate whether there was an association between PD-L1 expression on immune or tumor cells and OS. Results: In 17 cohort studies of the association of PD-L1 expression with survival in 3190 patients with HNSCC, high PD-L1 expression on immune cells was associated with a favorable OS (pooled aHR, 0.39; 95% CI, 0.25-0.59). There was no association between composite PD-L1 expression on immune and tumor cells and OS (pooled aHR, 0.79; 95% CI, 0.55-1.14) or between PD-L1 expressed only on tumor cells and OS (pooled aHR, 1.22; 95% CI, 0.87-1.70). A high level of PD-L1 expression on immune cells was associated with favorable specific survival (pooled aHR, 0.52; 95% CI, 0.38-0.72). There were no interactions between tumor location or type of primary treatment (ie, surgery vs radiotherapy or radiochemotherapy) and the association between PD-L1 expression and OS. Conclusions and Relevance: This study's findings suggest that PD-L1 expression on immune cells may serve as a new prognostic biomarker in patients with HNSCC. However, future studies may be warranted to verify this potential role given the limited number of studies on this topic conducted and published to date.

HPV and RAD51 as Prognostic Factors for Survival in Inoperable Oral and Oropharyngeal Cancer in Patients Unfit for Chemotherapy Treated with Hyperfractionated Radiotherapy.

INTRODUCTION: The incidence of advanced oral cavity and oropharyngeal cancers is generally high. Treatment outcomes for patients, especially those unfit for comprehensive cancer treatment, are unsatisfactory. Therefore, the search for factors to predict response to treatment and increase overall survival is underway. OBJECTIVE: This study aimed to analyze the presence of 32 HPV genotypes in tumor samples of 34 patients and the effect of HPV status and RAD51 on overall survival. METHOD: Tumor samples of 34 patients with locally advanced oropharyngeal or oral cavity cancer treated with accelerated radiotherapy in monotherapy were analyzed using reverse hybridization and immunohistochemistry for the presence of HPV and RAD51. Its effect on overall survival was examined. RESULTS: Only two types of HPV were identified-HPV 16 (dominant) and HPV 66 (two samples). The HPV positivity was associated with a borderline insignificant improvement in 2-year (p = 0.083), 5-year (p = 0.159), and overall survival (p = 0.083). Similarly, the RAD51 overexpression was associated with borderline insignificant improvement in 2-year (p = 0.083) and 5-year (p = 0.159) survival. CONCLUSION: We found no statistically significant differences but detected trends toward improvement in the survival of HPV-positive and RAD51 overexpressing patients unfit for surgical treatment or chemotherapy treated with hyperfractionated radiotherapy. The trends, however, indicate that in a larger group of patients, the effects of these two parameters would likely be statistically significant.

Enhancing oral squamous cell carcinoma prediction: the prognostic power of the worst pattern of invasion and the limited impact of molecular resection margins.

Objective: Oral squamous cell carcinoma (OSCC) originates from the mucosal lining of the oral cavity. Almost half of newly diagnosed cases are classified as advanced stage IV disease, which makes resection difficult. In this study, we investigated the pathological features and mutation profiles of tumor margins in OSCC. Methods: We performed hierarchical clustering of principal components to identify distinct patterns of tumor growth and their association with patient prognosis. We also used next-generation sequencing to analyze somatic mutations in tumor and marginal tissue samples. Results: Our analyses uncovered that the grade of worst pattern of invasion (WPOI) is strongly associated with depth of invasion and patient survival in multivariable analysis. Mutations were primarily detected in the DNA isolated from tumors, but several mutations were also identified in marginal tissue. In total, we uncovered 29 mutated genes, mainly tumor suppressor genes involved in DNA repair including BRCA genes; however none of these mutations significantly correlated with a higher chance of relapse in our medium-size cohort. Some resection margins that appeared histologically normal harbored tumorigenic mutations in TP53 and CDKN2A genes. Conclusion: Even histologically normal margins may contain molecular alterations that are not detectable by conventional histopathological methods, but NCCN classification system still outperforms other methods in the prediction of the probability of disease relapse.

FMISO-Based Adaptive Radiotherapy in Head and Neck Cancer.

Concurrent chemoradiotherapy represents one of the most used strategies in the curative treatment of patients with head and neck (HNC) cancer. Locoregional failure is the predominant recurrence pattern. Tumor hypoxia belongs to the main cause of treatment failure. Positron emission tomography (PET) using hypoxia radiotracers has been studied extensively and has proven its feasibility and reproducibility to detect tumor hypoxia. A number of studies confirmed that the uptake of FMISO in the recurrent region is significantly higher than that in the non-recurrent region. The escalation of dose to hypoxic tumors may improve outcomes. The technical feasibility of optimizing radiotherapeutic plans has been well documented. To define the hypoxic tumour volume, there are two main approaches: dose painting by contour (DPBC) or by number (DPBN) based on PET images. Despite amazing technological advances, precision in target coverage, and surrounding tissue sparring, radiation oncology is still not considered a targeted treatment if the "one dose fits all" approach is used. Using FMISO and other hypoxia tracers may be an important step for individualizing radiation treatment and together with future radiomic principles and a possible genome-based adjusting dose, will move radiation oncology into the precise and personalized era.

Stereotactic radiotherapy for spinal hemangioblastoma - disease control and volume analysis in long-term follow up.

Background: This retrospective analysis evaluated the long-term outcome of spinal stereotactic body radiotherapy (SBRT) treatment for hemangioblastomas. Materials and methods: Between 2010 and 2018, 5 patients with 18 Von-Hippel Lindau-related pial-based spinal hemangioblastomas were treated with fractionated SBRT. After precisely registering images of all relevant datasets, we delineated the gross tumor volume, spinal cord (including intramedullary cysts and/or syrinxes), and past radiotherapy regions. A sequential optimization algorithm was used for dose determinations, and patients received 25-26 Gy in five fractions or 24 Gy in three fractions. On-line image guidance, based on spinal bone structures, and two orthogonal radiographs were provided. The actuarial nidus control, surgery-free survival, cyst/syrinx changes, and progression-free survival were calculated with the Kaplan-Meier method. Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Results: The median follow-up was 5 years after SBRT. Patients displayed one nidus progression, one need of neurosurgery, and two cyst/syrinx progressions directly connected to symptom worsening. No SBRT-related complications or acute adverse radiation-related events occurred. However, one asymptomatic radiological sign of myelopathy occurred two years after SBRT. All tumors regressed; the one-year equivalent tumor volume reduction was 0.2 mL and the median volume significantly decreased by 28% (p = 0.012). Tumor volume reductions were not correlated with the mean (p = 0.19) or maximum (p = 0.16) dose. Conclusions: SBRT for pial-based spinal hemangioblastomas was an effective, safe, viable alternative to neurosurgery in asymptomatic patients. Escalating doses above the conventional dose-volume limits of spinal cord tolerance showed no additional benefit.

Prostate deformation during hypofractionated radiotherapy: an analysis of implanted fiducial marker displacement.

BACKGROUND: To report prostate deformation during treatment, based on an analysis of fiducial marker positional differences in a large sample. MATERIAL AND METHODS: This study included 144 patients treated with prostate stereotactic body radiation therapy after implantation in each of 4 gold fiducial markers (FMs), which were located and numbered consistently. The center of mass of the FMs was recorded for every pair of X-ray images taken during treatment. The distance between each pair of fiducials in the live X-ray images is calculated and compared with the respective distances as determined in the CT volume. The RBE is the difference between these distances. Mean RBE and intrafraction and interfraction RBE were evaluated. The intrafraction and intefraction RBE variability were defined as the standard deviation, respectively, of all RBE during 1 treatment fraction and of the mean daily RBE over the whole treatment course. RESULTS: We analyzed 720 treatment fractions comprising 24,453 orthogonal X-ray image acquisitions. We observed a trend to higher RBE related to FM4 (apex) during treatment. The fiducial marker in the prostate apex could not be used in 16% of observations, in which RBE was > 2.5 mm. The mean RBEavg was 0.93 ± 0.39 mm (range 0.32-1.79 mm) over the 5 fractions. The RBEavg was significantly lower for the first and second fraction compared with the others (P < .001). The interfraction variability of RBEavg was 0.26 ± 0.16 mm (range 0.04-0.74 mm). The mean intrafraction variability of all FMs was 0.45 ± 0.25 mm. The highest Pearson correlation coefficient was observed between FM2 and FM3 (middle left and right prostate) (R = 0.78; P < .001). Every combination with FM4 yielded lower coefficients (range 0.66-0.71; P < .001), indicating different deformation of the prostate apex. CONCLUSIONS: Ideally, prostate deformation is generally small, but it is very sensitive to rectal and bladder filling. We observed RBE up to 11.3 mm. The overall correlation between FMs was affected by shifts of individual fiducials, indicating that the prostate is not a "rigid" organ. Systematic change of RBE average between subsequent fractions indicates a systematic change in prostate shape.

Negative pressure therapy in the orofacial region in oncological patients - two case reports.

BACKGROUND: Chronic wounds and their problematic healing is a widely discussed topic in all branches of medicine. In recent years, vacuum therapy appears to be a very successful non-invasive method supporting the healing of these wounds. The aim of this paper is to demonstrate the possibility of utilizing a vacuum system in the orofacial area where other conservative and surgical procedures have failed. CASES: The case reports demonstrate the use of vacuum therapy in non-healing postoperative wounds in cancer patients. CONCLUSION: Vacuum therapy has limited use in the orofacial area, but based on our experience, we can conclude that it has a very positive effect on the healing of chronic wounds. Thanks to this treatment, it was possible to reduce the frequency of dressings and significantly shorten the length of hospital stay. Despite these advantages, however, it is necessary to adhere to the conditions for the application of vacuum treatment.

Dose escalation in advanced floor of the mouth cancer: a pilot study using a combination of IMRT and stereotactic boost.

PURPOSE: We evaluated the efficiency and toxicity of stereotactic hypofractionated boost in combination with conventionally fractionated radiotherapy in the treatment of advanced floor of the mouth cancer. METHODS: Thirty-seven patients with advanced stage of the floor of the mouth cancer, histologically confirmed squamous cell carcinoma (p16 negative) ineligible for surgical treatment, were indicated for radiochemotherapy or hyperfractionated accelerated radiotherapy (HART). The radiotherapy protocol combined external beam radiotherapy (EBRT) and a stereotactic hypofractionated boost to the primary tumor. The dose delivered from EBRT was 70-72.5 Gy in 35/50 fractions. The hypofractionated boost followed with 10 Gy in two fractions. For the variables-tumor volume, stage and grade a multivariate analysis was performed to find the relationship between overall survival, local progression and metastasis. Toxicity was evaluated according to CTCAE scale version 4. RESULTS: After a median follow-up of 16 months, 23 patients (62%) achieved complete remission. The median time to local progression and metastasis was 7 months. Local control (LC) at 2 and 5-years was 70% and 62%, respectively. Progression-free survival (PFS) and overall survival (OS) were 57% and 49% at 2 years and 41% and 27% at 5 years, respectively. Statistical analysis revealed that larger tumors had worse overall survival and a greater chance of metastasis. Log-Rank GTV > 44 ccm (HR = 1.96; [95% CI (0.87; 4.38)]; p = 0.11). No boost-related severe acute toxicity was observed. Late osteonecrosis was observed in 3 patients (8%). CONCLUSION: The combination of EBRT and stereotactic hypofractionated boost is safe and seems to be an effective option for dose escalation in patients with advanced floor of the mouth tumors who are ineligible for surgical treatment and require a non-invasive approach.