Curcumin Alone and Combined With PI3K Inhibitors Elicits Positive Effects on Oropharyngeal Cancer Cell Lines Regardless of HPV Status.

BACKGROUND/AIM: Human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is rising in incidence. Compared to HPV-negative (HPV-) OPSCC, HPV+ cases have a better 5-year survival. With its severe side-effects, today's chemoradiotherapy has not improved outcome compared to radiotherapy alone, so new therapies are needed. Mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), fibroblast growth factor receptor 3 (FGFR3) and cell division cycle 27 (CDC27) are found in HPV+ OPSCC, and in vitro targeted therapy combining PI3K and FGFR inhibitors showed synergistic effects. Here the effects of targeting CDC27 with curcumin with/without various inhibitors or cisplatin on OPSCC cell lines were examined. MATERIALS AND METHODS: Curcumin was administered to HPV+ OPSCC cell lines CU-OP-2, CU-OP-3 and CU-OP-20, and HPV- CU-OP-17 with/without PI3K, cyclin-dependent kinase 4/6, FGFR, poly (ADP-ribose) polymerase or WEE1 inhibitors (BYL719, PD-0332991, JNJ-42756493, BMN-673 and MK-1775, respectively), or cisplatin. The cell lines were then assessed for 72 h after treatment for viability, proliferation and cytotoxicity. RESULTS: Curcumin led to dose-dependent responses with reduced viability and proliferation; upon combining it with BYL719, additional positive effects were found for most OPSCC lines grown as monolayers, and these effects were validated in CU-OP-2 cells grown as spheroids. Curcumin with MK-1775 or PD-0332991 also elicited some positive effects on CU-OP-2 and CU-OP-17 cells. CONCLUSION: Curcumin alone led to dose-dependent responses and when combined with BYL719, positive effects were revealed, as they were when it was combined with MK-1775 or PD-0332991, suggesting a potential use of some of these combinations for HPV+ OPSCC.

Primary and adjuvant intensity-modulated radiotherapy in oropharyngeal carcinoma patients from a single institution.

BACKGROUND: To retrospectively access outcome, adverse events and prognostic factors in oropharyngeal carcinoma (OPC) patients treated with intensity-modulated radiotherapy (IMRT). METHODS: Ninety-eight OPC patients were treated between 2000 and 2015. Thirty-three patients received definitive and 65 adjuvant radiotherapy. Seventy-one percent had simultaneous chemotherapy. Patients were systematically followed up (mean 114 months, range 19-197 months). Statistical analysis used Kaplan-Meier method, Cox regression analysis, and log-rank test. Adverse events were classified according to common toxicity criteria version (CTCAE) 4.03. RESULTS: The 1-, 5-, and 10-year overall survival rates in the adjuvant vs. definitive cohort were 90.8% vs. 66.7%, 67.4% vs. 33.1%, and 57.7% vs. 16.5%. Survival in the adjuvant cohort was significantly longer than in the definitive cohort (P < 0.00005). Patients <65 years had a significantly longer survival than older patients. Locoregional tumor control rates after 1-, 5-, and 10 years in the adjuvant vs. definitive cohort were 90.2% vs. 66.7%, 82.2% vs 45.4%, and 72.1% vs. 30.3%. Locoregional tumor control in the adjuvant cohort was significantly longer than in the definite cohort (P < 0.005). Distant metastases were diagnosed in 20.4% of all patients. Most patients had mild CTCAE grade 1 and 2 adverse events and mild late adverse events including xerostomia, dysphagia, and lymphedema. CONCLUSION: Intensity-modulated radiotherapy for OPC is an important part of the treatment algorithm alone and in particular after surgery while the additional benefits of chemotherapy might be age dependent. Despite advanced tumor stages, nearly half of our patients were alive in the long term. The majority of patients had relatively mild chronic adverse events.

Hypoxia-Directed Treatment of Human Papillomavirus-Related Oropharyngeal Carcinoma.

PURPOSE: Standard curative-intent chemoradiotherapy for human papillomavirus (HPV)-related oropharyngeal carcinoma results in significant toxicity. Since hypoxic tumors are radioresistant, we posited that the aerobic state of a tumor could identify patients eligible for de-escalation of chemoradiotherapy while maintaining treatment efficacy. METHODS: We enrolled patients with HPV-related oropharyngeal carcinoma to receive de-escalated definitive chemoradiotherapy in a phase II study (ClinicalTrials.gov identifier: NCT03323463). Patients first underwent surgical removal of disease at their primary site, but not of gross disease in the neck. A baseline 18F-fluoromisonidazole positron emission tomography scan was used to measure tumor hypoxia and was repeated 1-2 weeks intratreatment. Patients with nonhypoxic tumors received 30 Gy (3 weeks) with chemotherapy, whereas those with hypoxic tumors received standard chemoradiotherapy to 70 Gy (7 weeks). The primary objective was achieving a 2-year locoregional control (LRC) of 95% with a 7% noninferiority margin. RESULTS: One hundred fifty-eight patients with T0-2/N1-N2c were enrolled, of which 152 patients were eligible for analyses. Of these, 128 patients met criteria for 30 Gy and 24 patients received 70 Gy. The 2-year LRC was 94.7% (95% CI, 89.8 to 97.7), meeting our primary objective. With a median follow-up time of 38.3 (range, 22.1-58.4) months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 94% and 100%, respectively, for the 30-Gy cohort. The 70-Gy cohort had similar 2-year PFS and OS rates at 96% and 96%, respectively. Acute grade 3-4 adverse events were more common in 70 Gy versus 30 Gy (58.3% v 32%; P = .02). Late grade 3-4 adverse events only occurred in the 70-Gy cohort, in which 4.5% complained of late dysphagia. CONCLUSION: Tumor hypoxia is a promising approach to direct dosing of curative-intent chemoradiotherapy for HPV-related carcinomas with preserved efficacy and substantially reduced toxicity that requires further investigation.

Impact of low skeletal muscle mass in oropharyngeal cancer patients treated with radical chemo-radiotherapy: A mono-institutional experience.

AIMS: Low skeletal muscle mass index (SMI) has recently emerged as an independent prognostic factor in oncological patients and it is linked with poor survival and higher treatment toxicity. The present study aims to determine the possible impact of low SMI on survival and acute toxicity in oropharyngeal patients. METHODS: Seventy-six patients with locally advanced oropharyngeal squamous cell carcinoma (stage III-IVC) were treated in our institution with Helical TomoTherapy® (HT - Accuray, Maddison, WI, USA) between 2005 and 2021. All patients received concomitant platinum-based chemotherapy (CT) (at least 200 mg/m2). The SMI was determined using the calculation of cross-sectional area at C3. Twenty patients (26%) presented pre-treatment low SMI, according to Chargi definitions. RESULTS: All patients concluded the treatment. Thirteen patients with low SMI (65%) and 22 patients with normal SMI (39%) presented acute toxicity greater than or equal to grade 3, but this difference was not statistically significant (p-value = 0.25). Overall survival was analyzed in 65 patients, excluding those who finished CT-RT less than six months before the analysis. Overall survival was significantly lower in low SMI versus normal SMI patients (p-value = 0.035). Same difference was observed in N0-N2a patients, suggesting an important role of SMI also in lower nodal burden and putatively better prognosis. CONCLUSIONS: Although the results are limited to a small population, our case series has the advantage to be very homogeneous in patients and treatment characteristics. In our setting, SMI demonstrated a crucial impact on overall survival. Further investigation with larger samples is necessary to confirm our results to improve patient outcomes.

Impact of mandated drug monitoring on opioid use during highly conformal radiotherapy for oropharynx cancer.

BACKGROUND: Prescription drug monitoring programs (PDMPs) have proliferated due to increasing opioid-related deaths. We evaluated acute opioid use changes for 64 patients treated with highly conformal radiotherapy (RT) following a state-mandated PDMP. METHODS: Patients receiving proton therapy (PT) (n=40), intensity-modulated RT (IMRT) (n=14), or both (n=10) were divided into preintervention (n=26) and postintervention cohorts (n=38); records were reviewed retrospectively under an institutional review board (IRB)-approved tracking protocol. Dosages prescribed during acute therapy (during RT-3 months post-RT) and patient-reported pain (Defense and Veterans Pain Rating Scale) were endpoints. Dosages were treated as responses in Chi-square tests (three-level ordinal response). RESULTS: Overall, 72% (n=46) received opioids; of which 22% (n=10) of all patients and 10% (n=2) of opioid-naive patients continued analgesic management 3 months post-RT. Median total doses were 975 and 1,025 morphine milligram equivalents (MME) in pre- and postintervention groups, with no significant differences in MME prescribed (P=0.8) or uncontrolled pain (P=0.3). Statistically significant factors were tonsil primaries (P<0.01) and alcohol use (P=0.02). Uncontrolled pain episodes during and post-RT did not vary per cohort (P=0.19). CONCLUSIONS: PDMP use was not associated with management changes in patient-reported acute pain during RT (IMRT or PT). Following highly conformal RT, few patients remained on narcotics 3 months post-RT.

The combined HPV16-E2/E6/E7 T cell response in oropharyngeal cancer predicts superior survival.

Tumor-infiltrating HPV16-E2-specific CD8+ T cells have been detected in HPV16-induced oropharyngeal squamous cell carcinoma (OPSCC). Whether intratumoral CD4+ T cells target HPV16 E2 and if HPV16-E2-specific immunity contributes to better clinical outcome is unknown. In a prospective HPV16+ OPSCC cohort, we regularly detect HPV16-E2-specific CD4+ and CD8+ intratumoral T cells, albeit at lower frequencies than the co-infiltrating HPV16-E6/E7-specific T cells. These HPV16-reactive T cells produce multiple cytokines when activated, indicating their polyfunctionality. Importantly, their combined intratumoral presence predicts superior survival, emphasizing the value of HPV16-E2-specific T cells in anti-tumor immunity and suggests its use as a target antigen for immunotherapy.

Conventional Therapies of Oral Cancers: Highlights on Chemotherapeutic Agents and Radiotherapy, Their Adverse Effects, and the Cost Burden of Conventional Therapies.

Oral cancer (OC) is increasing worldwide, and it is mostly present to clinic in the late-stage of disease. Cancer of the lips, tongue, hard palate, upper and lower gingiva, buccal mucosa, and retromolar trigone are all included in the category of oral cavity cancer. Disease symptomatology and pathological grading decides the course of treatment. Several treatment modalities either alone in combinations may be utilized for oral squamous cell carcinoma (OSCC), including surgery, radiotherapy (external beam radiotherapy/brachytherapy), and adjuvant systemic therapy (chemotherapy or immunotherapy). Cancer patients also face a greater risk of oral side effects from chemotherapy, such as slowed tissue healing, bone, and salivary gland damage and disintegration, and disruption of the normal bacterial balance in the mouth. Consequently, the economic burden of the salivary gland, oral cavity, and oropharyngeal cancers must be also known for budget allocation, designing different programs and management strategies targeting oral cancers by any healthcare institutes. This article provides a summary of the most recent research that supports the use of chemotherapy for patients with advanced illness both alone and in conjunction with radiation including its adverse events and cost burden for oral cancers.

Neo-adjuvant chemotherapy and transoral robotic surgery in locoregionally advanced oropharyngeal cancer.

PURPOSE: To analyze the oncological outcomes and patterns of recurrence of patients with locoregionally advanced oropharyngeal squamous cell carcinoma (OPSCC) who underwent neo-adjuvant chemotherapy (NCT) with subsequent transoral robotic surgery (TORS). METHODS: A single-center retrospective cohort study was performed, including 198 patients (mean age: 58.6, SD: 9.2). The primary outcome was disease-free survival (DFS). RESULTS: The median follow-up time was 26.5 months (IQR: 16.0-52.0). Estimated DFS rates (95 % CI) at 1 and 3 years were 86.6 % (81.9-91.7), and 81.4 % (75.7-87.6), respectively. Estimated DSS rates (95 % CI) at 1 and 3 years were 96.7 % (94.1-99.3), and 92.6 % (88.4-97.0), respectively. Estimated OS rates (95 % CI) at 1 and 3 years were 96.2 % (93.4-99.0), and 88.7 % (83.4-94.2), respectively. A total of 31 (15.6 %) patients showed a disease relapse after a median time of 8 months (IQR: 4.0-12.0), but only 12 (6 %) patients died of the disease during the study period. CONCLUSIONS: This study demonstrates that NCT and TORS can obtain excellent tumor control and survival in locoregionally advanced OPSCC. NCT might reduce the need for adjuvant treatments, and randomized clinical trials should be conducted to better define this aspect.

Homologous platelet gel on radiation-induced dermatitis in a patient receiving head and neck radiotherapy plus cetuximab: A case report.

INTRODUCTION: Acute radiodermatitis is a significant complication of cancer radiotherapy, and platelet-based therapies are emerging as potential new treatments. MAIN SYMPTOMS AND IMPORTANT CLINICAL FINDINGS: In this report, we present the case of a patient with head and neck cancer undergoing radiotherapy combined with the monoclonal antibody cetuximab. After 4 weeks of this treatment, the patient developed cutaneous radiation dermatitis. Despite receiving standard treatment with corticosteroids and emollient cream, the lesion did not improve. MAIN DIAGNOSIS: cutaneous radiation dermatitis on head and neck cancer patient. THERAPEUTIC INTERVENTIONS: Topical application of platelet gel was initiated on the wound. From the second week of radiotherapy to the 4th week, homologous platelet-rich plasma was applied on the dermatitis using a bandage, 4 times a day. OUTCOMES: The topical treatment with homologous platelet gel resulted in complete healing of the radiodermatitis, including restoration of the epidermis, reepithelialization, and reduction in associated pain. CONCLUSION: homologous platelet gel might be an alternative to standard treatment of radiation dermatitis.

Investigating Predictive Factors of Dysphagia and Treatment Prolongation in Patients with Oral Cavity or Oropharyngeal Cancer Receiving Radiation Therapy Concurrently with Chemotherapy.

Radiation therapy (RT) treatment for head and neck cancer has been associated with dysphagia manifestation leading to worse outcomes and decrease in life quality. In this study, we investigated factors leading to dysphagia and treatment prolongation in patients with primaries arising from oral cavity or oropharynx that were submitted to radiation therapy concurrently with chemotherapy. The records of patients with oral cavity or oropharyngeal cancer that received RT treatment to the primary and bilateral neck lymph nodes concurrently with chemotherapy were retrospectively reviewed. Logistic regression models were used to analyze the potential correlation between explanatory variables and the primary (dysphagia ≥ 2) and secondary (prolongation of total treatment duration ≥ 7 days) outcomes of interest. The Toxicity Criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) were used to evaluate dysphagia. A total of 160 patients were included in the study. Age mean was 63.31 (SD = 8.24). Dysphagia grade ≥ 2 was observed in 76 (47.5%) patients, while 32 (20%) experienced treatment prolongation ≥ 7 days. The logistic regression analysis showed that the volume in the primary site of disease that received dose ≥ 60 Gy (≥118.75 cc, p < 0.001, (OR = 8.43, 95% CI [3.51-20.26]) and mean dose to the pharyngeal constrictor muscles > 40.6 Gy (p < 0.001, OR = 11.58, 95% CI [4.84-27.71]) were significantly associated with dysphagia grade ≥ 2. Treatment prolongation ≥ 7 days was predicted by higher age (p = 0.007, OR = 1.079, 95% CI [1.021-1.140]) and development of grade ≥ 2 dysphagia (p = 0.005, OR = 4.02, 95% CI [1.53-10.53]). In patients with oral cavity or oropharyngeal cancer that receive bilateral neck irradiation concurrently with chemotherapy, constrictors mean dose and the volume in the primary site receiving ≥ 60 Gy should be kept below 40.6 Gy and 118.75 cc, respectively, whenever possible. Elderly patients or those that are considered at high risk for dysphagia manifestation are more likely to experience treatment prolongation ≥ 7 days and they should be closely monitored during treatment course for nutritional support and pain management.

Nutri-PEITC Jelly Significantly Improves Progression-Free Survival and Quality of Life in Patients with Advanced Oral and Oropharyngeal Cancer: A Blinded Randomized Placebo-Controlled Trial.

TP53 mutation is associated with cancer progression. Novel strategies to reboot p53 are required to stabilize the disease and improve survival. This randomized placebo-controlled trial investigated safety and efficacy of Nutri-PEITC Jelly (a texture-modified nutritious diet fortified with ß-phenethyl isothiocyanate (PEITC) on oral cancer. Seventy-two patients with advanced-staged oral or oropharyngeal cancer were randomly assigned to study and control groups, who consumed 200 g of Nutri-Jelly with and without 20 mg of PEITC, respectively, 5 days/week for 12 weeks. Outcomes, including adverse events, health-related quality of life (HRQOL), progression-free survival (PFS), tumor response, serum p53, and cytochrome c, were measured at 0, 1, and 3 months. Results show that the study group had a higher proportion of participants with improved HRQOL, stable disease, and increased serum p53 levels than those in the control group (p < 0.001). The PFS time in the study group was significantly longer than that of the control group (p < 0.05). Serum cytochrome c levels were non-significantly decreased in the study group. No serious intervention-related adverse events occurred in either group. In conclusion, Nutri-PEITC Jelly intake for 3 months is safe, stabilizes the disease, improves quality of life and progression-free survival, and might re-activate p53 in advanced-stage oral and oropharyngeal cancer patients.

Antimicrobial photodynamic therapy for the treatment of oral mucositis-A comparative study.

OBJECTIVES: The aim was to evaluate the effectiveness of photobiomodulation and antimicrobial photodynamic therapy in the treatment of oral mucositis. BACKGROUND: Oral Mucositis is a frequent complication of oral cavity and oropharynx cancer. Considering the OM aggravation by microorganisms contamination, disinfection provide by antimicrobial photodynamic therapy could be an effective approach. MATERIAL AND METHODS: This comparative study included fourteen patients undergoing radiochemotherapy for oral cavity and oropharynx cancer treatment, who developed oral mucositis. CONTROL GROUP: photobiomodulation. Intervention group: photobiomodulation and antimicrobial photodynamic therapy. The lesion size, duration, pain, and identification of microorganisms were evaluated. RESULTS: The mean reduction in oral mucositis size in the intervention group was 0.70 cm² (±0.35) and 0.30 cm² (±1.10) for the control group. The mean duration of oral mucositis was 18.37 days (±12.12) for the intervention group and 23 days (±14.78) for the control group. The intervention group had a mean reduction of 3.40 points on the pain scale (±2.44), while the control group had 0.17 (±2.28). In the intervention group, the predominant isolated microbiota was featured as mixed culture (n = 4/ 50%), followed of Gram Positive (n = 3/ 37.50%), and Gram Negative (n = 1/ 12.55%). In the control group, mixed culture was also more frequent (n = 4 / 66%), followed by Gram Positive (n = 2 /34%). Gram Negative was not predominantly isolated in the control group. CONCLUSION: No statistical significance was found between PBM-T alone and PBM-T + PDT. However, the better outcomes reached by PBM-T + PDT group would suggest there could be a role for combined treatment in the management of OM lesions.

Loco-Regional Control and Sustained Difference in Serum Immune Protein Expression in Patients Treated for p16-Positive and p16-Negative Head and Neck Squamous Cell Carcinoma.

The main prognostic factors for patients with head and neck cancer are the tumour site and stage, yet immunological and metabolic factors are certainly important, although knowledge is still limited. Expression of the biomarker p16INK4a (p16) in oropharyngeal cancer tumour tissue is one of the few biomarkers for the diagnosis and prognosis of head and neck cancer. The association between p16 expression in the tumour and the systemic immune response in the blood compartment has not been established. This study aimed to assess whether there is a difference in serum immune protein expression profiles between patients with p16+ and p16- head and squamous cell carcinoma (HNCC). The serum immune protein expression profiles, using the Olink® immunoassay, of 132 patients with p16+ and p16- tumours were compared before treatment and one year after treatment. A significant difference in the serum immune protein expression profile was observed both before and one year after treatment. In the p16- group, a low expression of four proteins: IL12RB1, CD28, CCL3, and GZMA before treatment conferred a higher rate of failure. Based on the sustained difference between serum immune proteins, we hypothesise that the immunological system is still adapted to the tumour p16 status one year after tumour eradication or that a fundamental difference exists in the immunological system between patients with p16+ and p16- tumours.

Response to induction chemotherapy predicts survival outcomes in oropharyngeal cancer.

BACKGROUND: The role of induction chemotherapy (IC) in oropharyngeal squamous cell carcinoma (OPSCC) remains controversial. Its interpretation can be confounded by heterogeneity in chemosensitivity and human papillomavirus (HPV) status. This study aimed to investigate the prognostic impact of IC response in HPV-positive and -negative OPSCC. METHODS: Patients with OPSCC who underwent IC and concurrent chemoradiotherapy (CCRT) were retrospectively analyzed. Radiologic response to IC by ≥50% was defined as IC-sensitive (IC-s), while lesser response was deemed as IC-resistant (IC-r). Progression-free survival (PFS) and overall survival (OS) were compared between subgroups. RESULTS: A total of 51 HPV-positive and 57 HPV-negative patients were included. IC-s patients accounted for 55.6%, 62.7%, and 49.1% in the entire cohort, HPV-positive, and HPV-negative subgroup, respectively. Compared with IC-r subgroup, IC-s was associated with better clinical outcomes either in the entire cohort (3y-PFS 91.7%vs.43.7%, P < 0.001; 3y-OS 98.3% vs. 67.4%, P = 0.002), the HPV-positive subgroup (3-year PFS 94.7% vs. 47.9%, P < 0.001; 3-year OS 100% vs. 73.5%, P = 0.055) or the HPV-negative subgroup (3-year PFS 88.2% vs. 40.9%, P = 0.001; 3-year OS 96.4% vs. 63.1%, P = 0.026). Multivariate analysis demonstrated that response to IC represents an independent prognosticator for 3-year PFS (HR, 0.088; 95% CI, 0.027-0.289; P < 0.001) and 3-year OS (HR, 0.100; 95% CI, 0.021-0.477; P = 0.004). CONCLUSIONS: Response to IC exerts a critical predictive effect on prognosis of both HPV-positive and -negative OPSCC. Personalized treatment strategy based on IC response is worthy of further exploration in the future.

Clinical outcomes in relapsed oropharyngeal cancer after definitive (chemo) radiotherapy.

OBJECTIVES: To report clinical outcomes of relapsed oropharyngeal squamous cell carcinoma (OPSCC) after definitive intensity-modulated (chemo)radiotherapy [(C)RT]. MATERIALS AND METHODS: Data for all relapsed patients treated for OPSCC with definitive (C)RT between 2010 and 2016 were collected. Primary end-point was post-failure survival (PFS). RESULTS: Overall, 273 OPSCC patients completed definitive (C)RT. Of these, 42 cases (n = 26 human papilloma virus (HPV)-negative; n = 16 HPV-positive) had relapsed (n = 23 persistent disease; n = 19 recurrent disease) and were included in the final analysis. Two-year PFS for the entire population was 30.6%; 20.5% for HPV-negative and 43.8% for HPV-positive patients. Salvage curative surgery was associated with a significantly higher 2 years PFS rate (56.2%) compared with palliative treatment (22.9%) and best supportive care (0%) (p < 0.001). A positive trend in 2 years PFS was recorded in the early complete response cases (49.5%) versus patients who did not achieve a complete response within 3 months of the end of (C)RT (23.0%) (p = 0.11). CONCLUSION: A higher PFS rate is achieved when relapsed OPSCC cases are treated with salvage curative intent. HPV-positive disease and early complete response within 3 months from the end of (C)RT may be related to better PFS.

The immune microenvironment of HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma: a multiparametric quantitative and spatial analysis unveils a rationale to target treatment-naïve tumors with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICI) are approved for treatment of recurrent or metastatic oropharyngeal head and neck squamous cell carcinoma in the first- and second-line settings. However, only 15-20% of patients benefit from this treatment, a feature increasingly ascribed to the peculiar characteristics of the tumor immune microenvironment (TIME). METHODS: Immune-related gene expression profiling (GEP) and multiplex immunofluorescence (mIF) including spatial proximity analysis, were used to characterize the TIME of 39 treatment-naïve oropharyngeal squamous cell carcinomas (OPSCC) and the corresponding lymph node metastases. GEP and mIF results were correlated with disease-free survival (DFS). HPV-positive tumors disclosed a stronger activation of several immune signalling pathways, as well as a higher expression of genes related to total tumor-infiltrating lymphocytes, CD8 T cells, cytotoxic cells and exhausted CD8 cells, than HPV-negative patients. Accordingly, mIF revealed that HPV-positive lesions were heavily infiltrated as compared to HPV-negative counterparts, with a higher density of T cells and checkpoint molecules. CD8+ T cells appeared in closer proximity to tumor cells, CD163+ macrophages and FoxP3+ cells in HPV-positive primary tumors, and related metastases. In HPV-positive lesions, PD-L1 expression was increased as compared to HPV-negative samples, and PD-L1+ tumor cells and macrophages were closer to PD-1+ cytotoxic T lymphocytes. Considering the whole cohort, a positive correlation was observed between DFS and higher levels of activating immune signatures and T cell responses, higher density of PD-1+ T cells and their closer proximity to tumor cells or PD-L1+ macrophages. HPV-positive patients with higher infiltration of T cells and macrophages had a longer DFS, while CD163+ macrophages had a negative role in prognosis of HPV-negative patients. CONCLUSIONS: Our results suggest that checkpoint expression may reflect an ongoing antitumor immune response. Thus, these observations provide the rationale for the incorporation of ICI in the loco-regional therapy strategies for patients with heavily infiltrated treatment-naïve OPSCC, and for the combination of ICI with tumor-specific T cell response inducers or TAM modulators for the "cold" OPSCC counterparts.

Disease outcome and associated factors after definitive platinum based chemoradiotherapy for advanced stage HPV-negative head and neck cancer.

BACKGROUND: Definitive concomitant cisplatin-based chemoradiotherapy (CRT) is the current gold standard for most patients with advanced stage head and neck squamous cell carcinoma (HNSCC) of the pharynx and larynx. Since previous meta-analysis on CRT outcomes in HNSCC have been reported, advances have been made in radiotherapy techniques and clinical management, while HPV-status has been identified as a strong confounding prognostic factor in oropharyngeal cancer. Here, we present real-world outcome data from a large multicenter cohort of HPV-negative advanced stage HNSCC treated with CRT using contemporary IMRT-based techniques. METHOD: Retrospective data were collected from a multicenter cohort of 513 patients treated with definitive concurrent platinum-based CRT with curative intent between January 2009 and August 2017. Only patients with HPV-negative advanced stage (III-IV) HNSCC were included. A prognostic model for outcome was developed based on clinical parameters and compared to TNM. RESULTS: Nearly half of the 513 patients (49%) had an oropharyngeal tumor, often locally advanced (73.3% T3-T4b) and with involvement of the regional lymph nodes (84%). Most patients (84%) received cisplatin as single agent. In total 66% received the planned number of cycles and 75% reached a cumulative cisplatin dose of ≥200 mg/m2. Locoregional control was achieved in 324 (63%) patients during follow-up, and no association with tumor sites was observed (p = 0.48). Overall survival at 5 year follow-up was 47%, with a better survival for laryngeal cancer (p = 0.02) compared to other sites. A model with clinical variables (gender, high pre-treatment weight loss, N2c/N3-stage and <200 mg/m2 dose of cisplatin) provided a noticeably stronger association with overall survival than TNM-staging (C- index 0.68 vs 0.55). Simultaneous Integrated Boosting (SIB) significantly outperformed Sequential Boosting (SEQ) to reduce the development of distant metastasis (SEQ vs SIB: OR 1.91 (1.11-3.26; p = 0.02). CONCLUSION: Despite advances in clinical management, more than a third of patients with HPV-negative HNSCC do not complete CRT treatment protocols due to cisplatin toxicity. A model that consists of clinical variables and treatment parameters including cisplatin dose provided the strongest association with overall survival. Since cisplatin toxicity is a major obstacle in completing definitive CRT, the development of alternative and less toxic radiosensitizers is therefore warranted to improve treatment results. The association of RT-boost technique with distant metastasis is an important finding and requires further study.

Expression patterns of uPAR, TF and EGFR and their potential as targets for molecular imaging in oropharyngeal squamous cell carcinoma.

The clinical introduction of molecular imaging for the management of oropharyngeal squamous cell carcinoma (OPSCC) relies on the identification of relevant cancer­specific biomarkers. The application of three membrane­bound receptors, namely urokinase­type plasminogen activator receptor (uPAR), tissue factor (TF) and EGFR have been previously explored for targeted imaging and therapeutic strategies in a broad range of solid cancers. The present study aimed to investigate the expression patterns of uPAR, EGFR and TF by immunohistochemistry (IHC) to evaluate their potential for targeted imaging and prognostic value in OPSCC. In a retrospective cohort of 93 patients with primary OPSCC, who were balanced into the 45 human papillomavirus (HPV)­positive and 48 HPV­negative groups, the IHC­determined expression profiles of uPAR, TF and EGFR in large biopsy or tumor resection specimens were analyzed. Using the follow­up data, overall survival (OS) and recurrence­free survival were measured. Specifically, associations between survival outcome, biomarker expression and clinicopathological factors were examined using Cox proportional hazards model and log­rank test following Kaplan­Meier statistics. After comparing the expression pattern of biomarkers within the tumor compartment with that in the adjacent normal tissues, uPAR and TF exhibited a highly tumor­specific expression pattern, whereas EGFR showed a homogeneous expression within the tumor compartment as well as a consistent expression in the normal mucosal epithelium and salivary gland tissues. The positive expression rate of uPAR, TF and EGFR in the tumors was 98.9, 76.3 and 98.9%, respectively. No statistically significant association between biomarker expression and survival outcome could be detected. Higher uPAR expression levels had a trend towards reduced OS according to results from univariate analysis (P=0.07; hazard ratio=2.01; 95% CI=0.92­4.37). Taken together, these results suggest that uPAR, TF and EGFR may be suitable targets for molecular imaging and therapy in OPSCC. In particular, uPAR may be an attractive target owing to their high positive expression rates in tumors and a highly tumor­specific expression pattern.

A preliminary study of suppression of candida infection by miconazole mucoadhesive tablets in oral or oropharyngeal cancer patients undergoing radiotherapy.

Elevated numbers of candida in the oral cavity often lead to oral candidiasis development in patients undergoing radiotherapy for oral or oropharyngeal cancer. This study aimed to verify the effect of miconazole mucoadhesive tablets on suppression of oral candida infection during radiotherapy. For this preliminary interventional study, miconazole mucoadhesive tablets were attached to the oral mucosa for 14 days from when grade 2 oral mucositis appeared in patients with oral or oropharyngeal cancer receiving radiotherapy, and the incidence of oral candidiasis was investigated. Various clinical factors were examined; univariate and multivariate Cox regression analyses were performed to investigate and compare the efficacy of this drug in preventing oral candidiasis with results of our previous study as historical control. Miconazole mucoadhesive tablets were administered to 18 patients, and oral candidiasis was observed in one patient (5.6%) after treatment completion. Among 144 historical control patients, 43 (29.9%) developed oral candidiasis. Multivariate Cox regression showed that miconazole mucoadhesive tablets significantly reduced oral candidiasis development during radiotherapy (p = 0.049, Hazard ratio 0.136, 95% confidence interval 0.019-0.994). This preliminary study suggests the efficacy of miconazole mucoadhesive tablets in preventing oral candidiasis in oral or oropharyngeal cancer patients treated with radiotherapy.Trial registration: Japan Registry of Clinical Trials (jRCT), jRCTs071190023. Registered 3 September, 2019.