Improving the response to lenvatinib in partial responders using a Constrained-Disorder-Principle-based second-generation artificial intelligence-therapeutic regimen: a proof-of-concept open-labeled clinical trial.

Introduction: The main obstacle in treating cancer patients is drug resistance. Lenvatinib treatment poses challenges due to loss of response and the common dose-limiting adverse events (AEs). The Constrained-disorder-principle (CDP)-based second-generation artificial intelligence (AI) systems introduce variability into treatment regimens and offer a potential strategy for enhancing treatment efficacy. This proof-of-concept clinical trial aimed to assess the impact of a personalized algorithm-controlled therapeutic regimen on lenvatinib effectiveness and tolerability. Methods: A 14-week open-label, non-randomized trial was conducted with five cancer patients receiving lenvatinib-an AI-assisted application tailored to a personalized therapeutic regimen for each patient, which the treating physician approved. The study assessed changes in tumor response through FDG-PET-CT and tumor markers and quality of life via the EORTC QLQ-THY34 questionnaire, AEs, and laboratory evaluations. The app monitored treatment adherence. Results: At 14 weeks of follow-up, the disease control rate (including the following outcomes: complete response, partial response, stable disease) was 80%. The FDG-PET-CT scan-based RECIST v1.1 and PERCIST criteria showed partial response in 40% of patients and stable disease in an additional 40% of patients. One patient experienced a progressing disease. Of the participants with thyroid cancer, 75% showed a reduction in thyroglobulin levels, and 60% of all the participants showed a decrease in neutrophil-to-lymphocyte ratio during treatment. Improvement in the median social support score among patients utilizing the system supports an ancillary benefit of the intervention. No grade 4 AEs or functional deteriorations were recorded. Summary: The results of this proof-of-concept open-labeled clinical trial suggest that the CDP-based second-generation AI system-generated personalized therapeutic recommendations may improve the response to lenvatinib with manageable AEs. Prospective controlled studies are needed to determine the efficacy of this approach.

Management of laryngeal chondroradionecrosis: A single-center experience.

BACKGROUND: Laryngeal chondroradionecrosis (LCRN) is a rare but severe complication of radiation therapy. The study aimed to review the management of LCRN and evaluate the clinical benefit of hyperbaric oxygen therapy (HBOT). METHODS: We retrospectively analyzed all radiation-induced LCRN patients between 2006 and 2019 at a tertiary medical center. Diagnosis was based on signs and symptoms of Chandler's classification, imaging, and/or histopathology report. The primary outcome was improvement in Chandler's grade after HBOT. RESULTS: Of 678 irradiated laryngeal cancer patients, 29 (4.3%) were diagnosed with LCRN. The most common primary management was tracheostomy with intravenous steroids and antibiotics (59%). Ten patients received HBOT (34.5%), and six underwent total laryngectomy (21%). In HBOT-treated patients, Chandler's grade significantly improved from a median of 4 (range 2-4) to 2.5 (range 1-4; p = 0.005). CONCLUSIONS: HBOT may benefit in the management of patients with persistence and unresponsive symptoms of LCRN following radiation therapy for laryngeal SCC.

Extended Follow-Up Outcomes from Pooled Prospective Studies Evaluating Efficacy of Interstitial Alpha Radionuclide Treatment for Skin and Head and Neck Cancers.

The initial favorable efficacy and safety profile for Alpha DaRT have been demonstrated (NCT04377360); however, the longer-term safety and durability of the treatment are unknown. This pooled analysis of four prospective trials evaluated the long-term safety and efficacy of Alpha DaRT for the treatment of head and neck or skin tumors. A total of 81 lesions in 71 patients were treated across six international institutions, with a median follow-up of 14.1 months (range: 2-51 months). Alpha DaRT sources were delivered via a percutaneous interstitial technique and placed to irradiate the tumor volume with the margin. The sources were removed two to three weeks following implantation. A complete response was observed in 89% of treated lesions (n = 72) and a partial response in 10% (n = 8). The two-year actuarial local recurrence-free survival was 77% [95% CI 63-87]. Variables, including recurrent versus non-recurrent lesions, baseline tumor size, or histology, did not impact long-term outcomes. Twenty-seven percent of patients developed related acute grade 2 or higher toxicities, which resolved with conservative measures. No grade 2 or higher late toxicities were observed. These data support the favorable safety profile of Alpha DaRT, which is currently being explored in a pivotal US trial.

Pelvic lymph node mapping in prostate cancer: examining the impact of PSMA PET/CT on radiotherapy decision-making in patients with node-positive disease.

INTRODUCTION: Prostate Specific Membrane Antigen (PSMA) imaging with Positron Emission Tomography (PET) plays a crucial role in prostate cancer management. However, there is a lack of comprehensive data on how PSMA PET/CT (Computed Tomography) influences radiotherapeutic decisions, particularly in node-positive prostate cancer cases. This study aims to address this gap by evaluating two primary objectives: (1) Mapping the regional and non-regional lymph nodes (LNs) up to the aortic bifurcation and their distribution using conventional methods with CT compared to PSMA PET/CT, and (2) assessing the impact of PSMA PET/CT findings on radiotherapeutic decisions. METHODS: A retrospective analysis of 95 node-positive prostate cancer patients who underwent both CT and PSMA PET/CT imaging prior to primary radiotherapy and androgen deprivation therapy (ADT) was conducted. The analysis focused on identifying LNs in various regions including the common iliac, external iliac, internal iliac, obturator, presacral, mesorectal, inguinal, and other stations. Treatment plans were reviewed for modifications based on PSMA PET/CT findings, and statistical analysis was performed to identify predictors for exclusive nodal positivity on PSMA PET/CT scans. RESULTS: PSMA PET/CT identified additional positive nodes in 48% of cases, resulting in a staging shift from N0 to N1 in 29% of patients. The most frequent metastatic LNs were located in the external iliac (76 LNs; 34%), internal iliac (43 LNs; 19%), and common iliac (35 LNs; 15%) stations. In patients with nodes only detected on PSMA PET the most common nodes were in the external iliac (27, 40%), internal iliac (13, 19%), obturator (11, 15%) stations. Within the subgroup of 28 patients exclusively demonstrating PSMA PET-detected nodes, changes in radiotherapy treatment fields were implemented in 5 cases (18%), and a dose boost was applied for 23 patients (83%). However, no discernible predictors for exclusive nodal positivity on PSMA PET/CT scans emerged from the analysis. DISCUSSION: The study underscores the pivotal role of PSMA PET/CT compared to CT alone in accurately staging node-positive prostate cancer and guiding personalized radiotherapy strategies. The routine integration of PSMA PET/CT into diagnostic protocols is advocated to optimize treatment precision and improve patient outcomes.

The Active Tumor Vaccination in Combination With CDK4/6 Inhibitor Treatment: A Case Report.

BACKGROUND: Current standard treatment for metastatic breast cancer (MBC) involves cyclin-dependent kinase 4/6 (CDK4/6) inhibitors with endocrine therapy, showing potential in enhancing anti-tumor immune responses. CASE REPORT: This report details a clinical case of MBC where palbociclib was co-administered with letrozole. The integration of allogeneic tumor vaccination to this treatment led to heightened interferon-γ production, expansion of CD8+ and NK cell populations, and positive delayed-type hypersensitivity reactions, indicating successful development of anti-tumor immunity. The induced production of interferon-γ by tumor vaccination was associated with manageable modulation of sensitivity to palbociclib-letrozole therapy. Administration of the BioNTech/Pfizer Covid-19 vaccine compromised the anti-tumor immune response by reducing cytotoxic cell populations and increasing immunosuppressive cytokine production. The patient undergoing combined treatment achieved a progressive-free survival of 42 months. CONCLUSION: Incorporating active tumor vaccination with CDK4/6 inhibitor therapy presents a feasible approach for metastatic breast cancer. The precise regulation of the microenvironment emerges as a crucial factor and warrants careful consideration.

Outcomes of extracranial stereotactic body radiation therapy for induced oligometastatic non-small cell lung cancer on novel systemic therapy.

Background: Stereotactic body radiation therapy (SBRT) is often delivered in patients with oligometastatic disease (OMD). However, the specific subset of patients with polymetastatic non-small cell lung cancer (NSCLC) on novel systemic therapies who develop induced oligopersistant disease (OpersisD) or oligoprogressive disease (OprogD), as defined by the European Organisation for Research and Treatment of Cancer (EORTC) OMD classification, has not been well described. This study explores the outcomes of patients treated with this strategy. Methods: Patients with stage IV NSCLC being treated with osimertinib or immune checkpoint inhibitors (ICIs) who received extracranial SBRT for OpersisD or OprogD were identified in our retrospective analysis. Outcomes reported include progression-free survival (PFS), time to change of systemic treatment (TTCST), overall survival (OS), local control (LC) and treatment-related toxicity. Results: Forty-nine patients received SBRT for OpersisD (34.7%) or OprogD (65.3%) at a median of 5.8 and 15.3 months after start of systemic therapy, respectively. 55.1% received concurrent osimertinib and 44.9% received ICI. Seventy-seven extracranial lesions were treated with various fractionation schemas. At a median of 18.8 months follow-up from first SBRT, LC was achieved in 92.2% of total lesions treated (71). The 1-year OS was 91.7% for OpersisD and 83.3% for OprogD. OpersisD compared to OprogD had a longer median PFS (18.3 vs. 6.1 months) and longer median TTCST (23.6 vs. 13.5 months), median OS was not reached for either cohort. On multivariate analysis, patients treated with osimertinib had shorter PFS (HR: 2.20; 95% CI: 1.01-4.82; P=0.048) and shorter TTCST (HR: 2.83; 95% CI: 1.09-7.33; P=0.032). One patient (2%) experienced grade 3 pneumonitis after SBRT, and no grade 4-5 toxicities were reported with SBRT treatment. Conclusions: This study indicates that SBRT for OpersisD or OprogD in Stage IV NSCLC patients on osimertinib or ICIs is safe, very well tolerated, and may prolong the time before needing a shift in systemic therapy. Further prospective research is needed to validate and expand upon these findings.

Effect of Radiological Tumor Thickness on Prognosis of Early Glottic-Squamous Cell Carcinoma Treated With Radiation.

OBJECTIVES: Tumor depth of invasion is a known prognostic factor in several head and neck cancers, but data on early laryngeal squamous cell carcinoma (SCC) are sparse. In this study, we aim to determine whether radiological tumor thickness serves as a prognostic factor in early SCC of the glottis treated with radiation. METHODS: One hundred thirty-two adult patients (age >18 years) underwent pretreatment computed tomography (CT) and were treated with radiation for pathologically proven early stage (T1 or T2) glottic SCC. Thirty-eight were excluded because the tumor could not be correctly identified on the CT scan, and an additional three patients because of insufficient data. RESULTS: The final cohort consisted of 91 patients, 84 (90.3%) men and 7 (9.7%) women aged 39.86-86.53 (mean 65.55 ± 12.76) years. Mean tumor thickness was 0.59 ± 0.19 cm in patients with T1 tumors and 0.79 ± 0.21 cm in patients with T2 tumors. The optimal cutoff value for 5-year disease-free survival (DFS), using the Youden index (sensitivity: 81.2%, specificity 65.3%), was 0.7 cm. A significant advantage in 5-year overall survival (OAS) and 5-year DFS for tumor thickness of <0.7 cm (P = 0.01 and P < 0.01, respectively) was found, these findings were consistent also when each stage was examined separately (T1 vs T2). CONCLUSION: Radiological tumor thickness appears to significantly predict OAS and DFS in early glottic SCC patients. IMPLICATION FOR PRACTICE: Tumor thickness may be considered as an auxiliary aid in deciding follow-up time and frequency, proper treatment, and determining prognosis.

Post-radiation middle ear effusion in NPC patients: Analysis of patient, tumour, and radiation factors.

OBJECTIVE: The purpose of this study was to investigate whether patient, tumour and radiation therapy factors are associated with development of middle ear effusion (MEE) in nasopharyngeal carcinoma (NPC) patients. DEIGN, SETTINGS, AND PARTICIPANTS: A retrospective review of NPC patients treated between January 2000 and June 2018 at Rabin Medical Center. Patient factors, tumour factors, radiation doses, and radiation fields were collected and outlined if needed (middle ear, eustachian tube [ET], tensor veli palatini [TVP], and levator palatini [LVP] muscles), then analysed and compared between patients with MEE and those without and between sides in patients with unilateral MEE. MAIN OUTCOME MEASURES AND RESULTS: Seventy-three patients were enrolled. Most were males (71.2%) with advanced-stage diseases (78%). At the time of diagnosis 14 patients (19.2%) presented with MEE. Following radiation, 18 patients, with no evidence of MEE at presentation, developed MEE. Tumour stage, histology, and laterality were not associated with development of MEE. Comparison of mean radiation field dosages including-gross target volume, clinical target volume, and patient target volume showed no association with post-radiation MEE. In addition, no difference was found in the radiation doses to the middle ear, ET or the LVP nor the TVP between ears with and without MEE. CONCLUSIONS: Post-irradiation MEE remains a common adverse effect in NPC patients. Surprisingly, tumour stage, tumour laterality, and histology were not associated with MEE. Similar findings were observed for total radiation doses and specific doses to the middle ear, ET, and ET muscles.

Stereotactic radiosurgery for brain metastases arising from gynecological malignancies: A retrospective treatment outcome analysis.

BACKGROUND: This retrospective study aims to assess the efficacy of stereotactic radiosurgery (SRS) in the treatment of brain metastases (BM) originating from gynecological cancers. It focuses on local control (LC), distant tumor control (DTC), and overall survival (OS). METHODS: The analysis comprised 18 individuals with gynecological-origin BM treated with SRS at the Hadassah Medical Center from 2004 to 2021. Statistical analyses evaluate factors impacting LC, DTC, and OS. RESULTS: A total of 36 BM of gynecological origin underwent SRS. The median age at the first SRS treatment was 60 years, with a median time of 24.5 months from the primary malignancy diagnosis to BM detection. The 12-month LC rate per patient was 84.6 %, and 5.6 % per BM. Only two instances of local recurrence were observed. The DTC at 12 months was 75 %, with a 29 % overall. Non-significant trends indicating a correlation with distant brain failure with increased cumulative volume and the occurrence of craniotomy before SRS. The median OS of the cohort was 16.5 months from SRS treatment. The 6, 12, 18, and 24-month survival rates were 77.8 %, 66.7 %, 50 %, and 22.2 % respectively. Higher number of BM was associated with lower OS (p = 0.046). On multivariate analysis, age was a significant factor for OS (p = 0.03), demonstrating that older age was associated with a more favorable prognosis. CONCLUSION: This study supports SRS effectiveness for treating BM from gynecological cancers and suggests similar outcomes to more common malignancies.

Outcome of radiotherapy for the treatment of laryngeal squamous cell carcinoma in the very elderly population.

BACKGROUND: Treatment selection for squamous cell carcinoma patients aged over 84 years is controversial. This retrospective chart review examined and compared characteristics of laryngeal squamous cell carcinoma in very elderly (over 84 years) and younger patients (approximately 65 years). The secondary objective was to further evaluate the outcome of radiotherapy as a treatment modality in this patient population. METHODS: Of all 23 very elderly patients with laryngeal squamous cell carcinoma treated with radiotherapy, with or without surgery, in the Davidoff Cancer Center, from 1992 to 2012, 19 had sufficient data for analysis, and comprised the study group. RESULTS: Median age at diagnosis was 86 years. Disease stage at diagnosis was I, II, III and IVA in 53 per cent, 21 per cent, 21 per cent and 5 per cent, respectively. Median radiotherapy dose was 60 Gy given in 25 fractions. Three patients had recurrence. No patient discontinued treatment because of toxicity. Median overall survival was 3.6 years (range, 0-10 years). CONCLUSION: Very elderly laryngeal squamous cell carcinoma patients may derive a similar survival advantage as younger counterparts. Modern radiotherapy is effective and safe for treating laryngeal squamous cell carcinoma in this study population. Further, large-scale studies are needed.

Heparanase contributes to pancreatic carcinoma progression through insulin-dependent glucose uptake.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor, which is highly resistant to existing therapies and characterized by one of the lowest survival rates known for solid cancers. Among the reasons for this poor prognosis are unique pathophysiological features of PDAC, such as dense extracellular matrix [ECM] creating barriers to drug delivery, as well as systemically-deregulated glucose metabolism manifested by diabetic conditions (i.e., hyperinsulinemia/hyperglycemia) occurring in the majority of PDAC patients. Moreover, in addition to systemically deregulated glucose homeostasis, intracellular metabolic pathways in PDAC are rewired toward increased glucose uptake/anabolic metabolism by the tumor cells. While the role of oncogene-driven programs in governing these processes is actively studied, mechanisms linking metabolic dysregulation and ECM enzymatic remodeling to PDAC progression/therapy resistance are less appreciated. The aim of the current study was to investigate the action of heparanase (the predominant mammalian enzyme that degrades heparan sulfate glycosaminoglycan in the ECM), as a molecular link between the diabetic state and the intracellular metabolic rewiring in PDAC pathogenesis. Here we show that in PDAC elevated levels of heparanase, coupled with diabetic conditions typical for PDAC patients, promote growth and chemotherapy resistance of pancreatic carcinoma by favoring insulin receptor signaling and GLUT4-mediated glucose uptake into tumor cells. Collectively, our findings underscore previously unknown mechanism through which heparanase acts at the interface of systemic and intracellular metabolic alterations in PDAC and attest the enzyme as an important and potentially modifiable contributor to the chemo-resistance of pancreatic tumors.

Clinical Characteristics, Response to Platinum-Based Chemotherapy and Poly (Adenosine Phosphate-Ribose) Polymerase Inhibitors in Advanced Lung Cancer Patients Harboring BRCA Mutations.

The oncogenic role and clinical relevance of BRCA mutations in NSCLC remain unclear. We aim to evaluate the characteristics and clinical outcomes of patients with NSCLC harboring BRCA mutations treated at Hadassah Medical Center (HMC). We retrospectively assessed all patients with advanced NSCLC who underwent next-generation sequencing (NGS) and were found to have pathogenic somatic BRCA mutations (p-BRCA). We compared clinical outcomes in NSCLC patients with wild-type BRCA (wt-BRCA) matched by age, stage, gender, smoking, PDL-1 and driver mutations. Between 2015 and 2022, we evaluated 598 patients with advanced NSCLC using NGS and found 26 patients with p-BRCA, of whom 17 (65.4%) were carriers of germline BRCA variants and represented 1% of all BRCA carriers HMC. The median age of diagnosis was 67 years old (40-78), 13 patients (50%) had a history of smoking and 9 patients (34.6%) had additional driver mutations (EGFR, ALK, BRAF, MET or ERBB2). Objective response rate and median progression-free survival (PFS) for first-line platinum-based chemotherapy in the p-BRCA group compared to wt-BRCA controls were 72.2% and 16 months (CI 95%, 5-22), compared to 47.4% and 7 months (CI 95%, 5-9), respectively, and HR for PFS was 0.41 (CI 95%, 0.17-0.97). Six patients in the p-BRCA group were treated with advanced-line poly (adenosine-phosphate-ribose) polymerase inhibitors (PARPi), with a durable response observed in four patients (66%). In this cohort, patients with NSCLC harboring p-BRCA exhibit high-sensitivity PARPi and a prolonged response to platinum, suggesting some oncogenic role for BRCA mutations in NSCLC. The results support further prospective trials of the treatment of NSCLC harboring p-BRCA with PARPi.

The different clonal origins of metachronous and synchronous metastases.

BACKGROUND: Metastases are the leading cause of mortality in cancer patients. Linear and parallel are the two prominent models of metastatic progression. Metastases can be detected synchronously along with the primary tumor or metachronously, following treatment of localized disease. The aim of the study was to determine whether synchronous metastases (SM) and metachronous metastases (MM) differ only in lead-time or stem from different biological processes. MATERIALS AND METHODS: We retrospectively studied the chest CTs of 791 patients inflicted by eleven malignancy types that were treated in our institution in the years 2010-2020. Patient's population included 396 with SM and 395 with MM. The diameter of 15,427 lung metastases was measured. Clonal origin was deduced from the linear/parallel ratio (LPR)-a computerized analysis of metastases diameters. LPR of 1 suggests pure linear dissemination and - 1 pure parallel. RESULTS: Patients with MM were significantly older (average of 62.9 vs 60.7 years, p = 0.02), and higher percentage of them were males (58.7% vs 51.1%, p = 0.03). Median overall survival of patients with MM and SM was remarkably similar (23 months and 26 months respectively, p = 0.774) when calculated from the time of metastases diagnosis. Parallel dissemination (LPR ≤ 0) was found in 35.4% of patients with MM compared to only 19.8% of the patients with SM (p < 0.00001). CONCLUSION: Patients with SM and MM differ in demography and in clonal origin. Different therapeutic approaches may be considered in these two conditions.

Long-term complications associated with the management of sinonasal malignancies: a single center experience.

Objective: The aim of this study was to review the long-term complications associated with treatment of patients with sinonasal malignancies (SNMs) and risk factors for these complications. Methods: A retrospective analysis of all patients treated for SNMs at a tertiary care center between 2001 and 2018. A total of 77 patients were included. The primary outcome measure was post-treatment long-term complications. Results: Overall, long-term complications were identified in 41 patients (53%), and the most common were sinonasal (22 patients, 29%) and orbital/ocular-related (18 patients, 23%). In a multivariate regression analysis, irradiation was the only significant predictor of long-term complications (p = 0.001, OR = 18.86, CI = 3.31-107.6). No association was observed between long-term complications and tumour stage, surgical modality, or radiation dose/modality. Mean radiation dose ≥ 50 Gy to the optic nerve was associated with grade ≥ 3 visual acuity impairment (100% vs 3%; p = 0.006). Radiation therapy for disease recurrence was associated with additional long-term complications (56% vs 11%; p = 0.04). Conclusions: Treatment of SNMs has substantial long-term complications, which are significantly associated with radiation therapy.

The effect of gastric fundus radiation dose on postoperative anastomotic leakage in esophageal cancer.

Introduction: Standard-of-care treatment for locally advanced esophageal carcinoma (LAEC) includes neoadjuvant chemoradiotherapy followed by esophagectomy. A potentially catastrophic surgical complication is the development of a postoperative anastomotic leak. To date, the association with radiation dose exposure had been inconclusive. We examined the correlation between radiation exposure to the gastric fundus and risk of postoperative leakage using contemporary radiation doses and fractionation. Methods: A total of 69 consecutive patients with LAEC who underwent neoadjuvant chemoradiotherapy followed by esophagectomy in our tertiary center were prospectively followed (median, 27 months). Neoadjuvant regimen included 50.4 Gy in 28 fractions with 5-fluorouracil and cisplatin and 41.4 Gy in 23 fractions with carboplatin and paclitaxel. The gastric fundus was contoured and dosimetric and radiation technique parameters were retrospectively evaluated. Results: Of the total number of patients, 71% and 29% had esophageal and gastroesophageal junction (GEJ) tumors, respectively. Fourteen patients (20.3%) experienced anastomotic leaks within a median of 2 days postoperatively, 78.6% of whom had lower third esophagus or GEJ primaries. Mean and minimum fundus dose did not significantly differ between those with and those without leakage (p = 0.42, p = 0.51). Mean fundus V25, V30, and V35 doses were numerically but not statistically higher in those with anastomotic leak (p = 0.58, p = 0.39, and p = 0.30, respectively). No correlation with incidence of leakage was seen between 3D and IMRT treatment modalities. Conclusions: In our comparatively large prospectively collected series of patients treated for LAEC, radiation dose to the gastric fundus during neoadjuvant combination therapy prior to surgery did not correlate with the risk of postoperative anastomotic leak.

Effect of Opioid Receptor Activation and Blockage on the Progression and Response to Treatment of Head and Neck Squamous Cell Carcinoma.

Recent studies suggest that opioids have a role in the progression of HNSCC mediated by mu opioid receptors (MOR), however, the effects of their activation or blockage remains unclear. Expression of MOR-1 was explored in seven HNSCC cell lines using Western blotting (WB). XTT cell proliferation and cell migration assays were performed on four selected cell lines (Cal-33, FaDu, HSC-2, and HSC-3), treated with opiate receptor agonist (morphine), antagonist (naloxone), alone and combined with cisplatin. All four selected cell lines display an increased cell proliferation and upregulation of MOR-1 when exposed to morphine. Furthermore, morphine promotes cell migration, while naloxone inhibits it. The effects on cell signaling pathways were analyzed using WB, demonstrating morphine activation of AKT and S6, key proteins in the PI3K/AKT/mTOR axis. A significant synergistic cytotoxic effect between cisplatin and naloxone in all cell lines is observed. In vivo studies of nude mice harboring HSC3 tumor treated with naloxone demonstrate a decrease in tumor volume. The synergistic cytotoxic effect between cisplatin and naloxone is observed in the in vivo studies as well. Our findings suggest that opioids may increase HNSCC cell proliferation via the activation of the PI3K/Akt/mTOR signaling pathway. Moreover, MOR blockage may chemo-sensitize HNSCC to cisplatin.