Evaluation of a new score associated with acute kidney injury in patients treated with cisplatin based EXTREME regimen.

BACKGROUND: This study evaluates the association of diuresis and hydration through a new monitoring indicator called U sen and the risk of acute kidney injury in patients treated with cisplatin based-EXTREME regimen. METHODS: We retrospectively reviewed all the cycles of patients with recurrent and/or metastatic head and neck cancer who received cisplatin based-EXTREME regimen from June 2008 to July 2022. Hydration regimen, urine output and concomitant treatments data were collected on the day of cisplatin infusion and the following day of each course received. RESULTS: Of the 110 courses received by 46 patients, 38 (34.5%) results in AKI. No patient characteristics showed a significant difference between AKI (70%) and non-AKI (30%) group. In univariate analysis, dose reduction of cisplatin (odds ratio = 0.166 [0.04; 0.75], p = 0.01)) and U sen >8 (odds ratio = 0.316 [0.133; 0.755], p = 0.015) and cardiac treatments (odds ratio = 3.24 [1.26; 8.52], p = 0.02) were significantly associated with AKI risk. In multivariate analysis, cisplatin dose reduction (odds ratio = 0.129 [0.0241; 0.687], p = 0.016) and U sen >8 (odds ratio = 0.184 [0.0648; 0.523], p = 0.0015) were associated with a risk reduction of cisplatin-related AKI. Concomitant administration of cardiac treatments (odds ratio = 3.18 [1.1; 9.22], p = 0.033) showed an increased risk of cisplatin-related AKI. CONCLUSION: The combination of diuresis and i.v. hydration through the U sen composite score was shown to be associated with cisplatin-induced AKI risk in patients treated with cisplatin based EXTREME regimen. It could be used as a practical indicator to trigger specific clinical management to limit the risk of cisplatin induced AKI.

Pembrolizumab-based first-line treatment for PD-L1-positive, recurrent or metastatic head and neck squamous cell carcinoma: a retrospective analysis.

BACKGROUND: The KEYNOTE-048 trial showed that pembrolizumab-based first-line treatment for R/M HNSCC led to improved OS in the PD-L1 CPS ≥ 1 population when compared to the EXTREME regimen. However, the R/M HNSCC real-world population is generally frailer, often presenting with multiple comorbidities, worse performance status and older age than the population included in phase III clinical trials. METHODS: This is a retrospective, single-centre analysis of patients with R/M HNSCC treated with pembrolizumab-based first-line treatment. RESULTS: From February 2021 to March 2023, 92 patients were treated with pembrolizumab-based first-line treatment. Patients treated with pembrolizumab-based chemoimmunotherapy had better ECOG PS and younger age than those treated with pembrolizumab monotherapy. Median PFS and OS were 4 months and 8 months, respectively. PFS was similar among patients treated with pembrolizumab-based chemoimmunotherapy and pembrolizumab monotherapy, while patients treated with pembrolizumab monotherapy had worse OS (log-rank p =.001, HR 2.7). PFS and OS were improved in patients with PD-L1 CPS > = 20 (PFS: log-rank p =.005, HR 0.50; OS: log-rank p =.04, HR 0.57). Patients with higher ECOG PS scores had worse PFS and OS (PFS, log-rank p =.004; OS, log-rank p = 6e-04). In multivariable analysis, ECOG PS2 was associated with worse PFS and OS. CONCLUSIONS: PFS in our real-world cohort was similar to the KEYNOTE-048 reference while OS was numerically inferior. A deeper understanding of clinical variables that might affect survival outcomes of patients with R/M HNSCC beyond ECOG PS and PD-L1 CPS is urgently needed.

Neoadjuvant chemo-immunotherapy with camrelizumab plus nab-paclitaxel and cisplatin in resectable locally advanced squamous cell carcinoma of the head and neck: a pilot phase II trial.

Neoadjuvant chemoimmunotherapy has emerged as a potential treatment option for resectable head and neck squamous cell carcinoma (HNSCC). In this single-arm phase II trial (NCT04826679), patients with resectable locally advanced HNSCC (T2‒T4, N0‒N3b, M0) received neoadjuvant chemoimmunotherapy with camrelizumab (200 mg), nab-paclitaxel (260 mg/m2), and cisplatin (60 mg/m2) intravenously on day one of each three-week cycle for three cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included pathologic complete response (pCR), major pathologic response (MPR), two-year progression-free survival rate, two-year overall survival rate, and toxicities. Here, we report the perioperative outcomes; survival outcomes were not mature at the time of data analysis. Between April 19, 2021 and March 17, 2022, 48 patients were enrolled and received neoadjuvant therapy, 27 of whom proceeded to surgical resection and remaining 21 received non-surgical therapy. The ORR was 89.6% (95% CI: 80.9, 98.2) among 48 patients who completed neoadjuvant therapy. Of the 27 patients who underwent surgery, 17 (63.0%, 95% CI: 44.7, 81.2) achieved a MPR or pCR, with a pCR rate of 55.6% (95% CI: 36.8, 74.3). Treatment-related adverse events of grade 3 or 4 occurred in two patients. This study meets the primary endpoint showing potential efficacy of neoadjuvant camrelizumab plus nab-paclitaxel and cisplatin, with an acceptable safety profile, in patients with resectable locally advanced HNSCC.

Risk Factors of Cetuximab-Induced Hypomagnesemia and the Effect of Magnesium Prophylaxis in Patients with Head and Neck Cancer: A Retrospective Study.

Hypomagnesemia is a characteristic adverse event of cetuximab in patients with head and neck cancer (HNC). However, there is limited information about its prevalence, risk factors, and preventive strategies. This study aimed to investigate the risk factors of hypomagnesemia and examine the preventive effects of prophylactic magnesium (Mg) administration. We initially investigated HNC patients treated with cetuximab between 2013 and 2019. Our institute started prophylactic Mg treatment (20-mEq Mg sulfate administration before cetuximab) in practice during this period. We retrospectively assess the preventive efficacy by comparing patients before and after its implementation. In total, 109 patients were included. In 60 patients without prophylaxis, all-grade and grade ≥2 hypomagnesemia at 3 months occurred in 61.7 and 15.0% of patients. The incidence of hypomagnesemia was not affected by regimens and concomitant medications. In 49 patients treated with prophylactic Mg treatment, there was no significant decrease in the cumulative incidence of hypomagnesemia. However, the preventive Mg treatment eliminated the need for additional Mg repletion to maintain Mg levels in patients treated with paclitaxel + cetuximab. A risk factor in patients without prophylaxis was a low Mg level at pre-treatment (≤2.0 mg/dL) (odds ratio: 6.03, 95% confidence interval: 1.78-20.4, p = 0.004), whereas that in patients with prophylaxis was the number of cetuximab doses (≥10) (odds ratio: 5.50, 95% confidence interval: 1.52-19.87, p = 0.009). In conclusion, a low pre-treatment Mg level was the only risk factor that could be avoided by prophylactic Mg administration. This preventive intervention is recommended for managing cetuximab-induced hypomagnesemia.

A bioconvergence study on platinum-free concurrent chemoradiotherapy for the treatment of HPV-negative head and neck carcinoma.

Locally advanced head and neck squamous cell carcinoma (LA-HNSCC) is characterized by high rate of recurrence, resulting in a poor survival. Standard treatments are associated with significant toxicities that impact the patient's quality of life, highlighting the urgent need for novel therapies to improve patient outcomes. On this regard, noble metal nanoparticles (NPs) are emerging as promising agents as both drug carriers and radiosensitizers. On the other hand, co-treatments based on NPs are still at the preclinical stage because of the associated metal-persistence.In this bioconvergence study, we introduce a novel strategy to exploit tumour chorioallantoic membrane models (CAMs) in radio-investigations within clinical equipment and evaluate the performance of non-persistent nanoarchitectures (NAs) in combination with radiotherapy with respect to the standard concurrent chemoradiotherapy for the treatment of HPV-negative HNSCCs. A comparable effect has been observed between the tested approaches, suggesting NAs as a potential platinum-free agent in concurrent chemoradiotherapy for HNSCCs. On a broader basis, our bioconvergence approach provides an advance for the translation of Pt-free radiosensitizer to the clinical practice, positively shifting the therapeutic vs. side effects equilibrium for the management of HNSCCs.

Nanoparticle-mediated Photodynamic Therapy as a Method to Ablate Oral Cavity Squamous Cell Carcinoma in Preclinical Models.

Photodynamic therapy (PDT) is a tissue ablation technique able to selectively target tumor cells by activating the cytotoxicity of photosensitizer dyes with light. PDT is nonsurgical and tissue sparing, two advantages for treatments in anatomically complex disease sites such as the oral cavity. We have previously developed PORPHYSOME (PS) nanoparticles assembled from chlorin photosensitizer-containing building blocks (∼94,000 photosensitizers per particle) and capable of potent PDT. In this study, we demonstrate the selective uptake and curative tumor ablation of PS-enabled PDT in three preclinical models of oral cavity squamous cell carcinoma (OCSCC): biologically relevant subcutaneous Cal-33 (cell line) and MOC22 (syngeneic) mouse models, and an anatomically relevant orthotopic VX-2 rabbit model. Tumors selectively uptake PS (10 mg/kg, i.v.) with 6-to 40-fold greater concentration versus muscle 24 hours post-injection. Single PS nanoparticle-mediated PDT (PS-PDT) treatment (100 J/cm2, 100 mW/cm2) of Cal-33 tumors yielded significant apoptosis in 65.7% of tumor cells. Survival studies following PS-PDT treatments demonstrated 90% (36/40) overall response rate across all three tumor models. Complete tumor response was achieved in 65% of Cal-33 and 91% of MOC22 tumor mouse models 14 days after PS-PDT, and partial responses obtained in 25% and 9% of Cal-33 and MOC22 tumors, respectively. In buccal VX-2 rabbit tumors, combined surface and interstitial PS-PDT (200 J total) yielded complete responses in only 60% of rabbits 6 weeks after a single treatment whereas three repeated weekly treatments with PS-PDT (200 J/week) achieved complete ablation in 100% of tumors. PS-PDT treatments were well tolerated by animals with no treatment-associated toxicities and excellent cosmetic outcomes. SIGNIFICANCE: PS-PDT is a safe and repeatable treatment modality for OCSCC ablation. PS demonstrated tumor selective uptake and PS-PDT treatments achieved reproducible efficacy and effectiveness in multiple tumor models superior to other clinically tested photosensitizer drugs. Cosmetic and functional outcomes were excellent, and no clinically significant treatment-associated toxicities were detected. These results are enabling of window of opportunity trials for fluorescence-guided PS-PDT in patients with early-stage OCSCC scheduled for surgery.

Model-Informed Selection of the Recommended Phase III Dose of the Inhibitor of Apoptosis Protein Inhibitor, Xevinapant, in Combination with Cisplatin and Concurrent Radiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck.

Xevinapant, an oral inhibitor of apoptosis protein (IAP) inhibitor, demonstrated efficacy in combination with chemoradiotherapy in a randomized phase II study (NCT02022098) in patients with locally advanced squamous cell carcinoma of the head and neck at 200 mg/day on days 1-14 of a 3-week cycle. To confirm 200 mg/day as the recommended phase III dose (RP3D), we integrated preclinical, clinical, pharmacokinetic/pharmacodynamic (PK/PD), and exposure-response modeling results. Population PK/PD modeling of IAP inhibition in peripheral blood mononuclear cells in 21 patients suggested the pharmacologically active dose range was 100-200 mg/day, with a trend for more robust inhibition at the end of the dosing interval at 200 mg/day based on an indirect response model. Additionally, the unbound average plasma concentration at 200 mg/day was similar to that associated with efficacy in preclinical xenograft models. Logistic regression exposure-response analyses of data from 62 patients in the phase II study showed exposure-related increases in probabilities of locoregional control at 18 months (primary end point), overall response, complete response, and the radiosensitization mechanism-related composite safety end point "mucositis and/or dysphagia" (P < 0.05). Exposure-response relationships were not discernible for 12 of 13 evaluated safety end points, incidence of dose reductions, and time to first dose reduction. Quantitative integration of all available data, including model-derived target inhibition profiles, positive exposure-efficacy relationships, and lack of discernible exposure-safety relationships for most safety end points, supports selection of xevinapant 200 mg/day on days 1-14 of a 3-week cycle as the RP3D, allowing for successive dose reductions to 150 and 100 mg/day to manage adverse events.

Preconditioning with Photobiomodulation as an Effective Method in Preventing Chemotherapy-Induced Oral Mucositis: A Systematic Review.

Background: Given the suffering experienced by cancer patients, effective solutions must be found to prevent the most painful and debilitating side effects of anticancer treatment. The use of photobiomodulation (PBM) with specific parameters has been proposed to prevent oral mucositis in adults undergoing hematopoietic stem cell transplantation as well as in head and neck cancer patients receiving radiotherapy alone without chemotherapy. No recommendations were possible for patients undergoing chemotherapy alone. This systematic review aims to analyze the effectiveness of preconditioning by PBM in preventing chemotherapy-induced oral mucositis. Methods: This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, PRISMA, Checklist and registered at the International Prospective Register of Systematic Reviews (PROSPERO). We searched and identified articles of the subsequent bibliographic databases: PubMed and Cochrane. Revised Cochrane risk-of-bias tool for randomized trials (RoB 2.0) was used to assess the risk of bias of studies included in this review. Results: There were only six clinical trials examining the efficacy of PBM therapy in the primary prevention of chemotherapy-induced oral mucositis. All of the studies used lasers, except for one study that compared lasers with light-emitting diodes. The wavelength ranges from 630 to 830 nm. Irradiation parameters varied among the included studies. All studies showed good results for the use of PBM in the prevention of oral mucositis except for one study that found no benefit for the laser application. Conclusions: PBM has been shown to be effective in preventing oral mucositis when applied to healthy tissues. Finding the optimal protocol has been difficult due to the variability between studies, and therefore, further well-designed, controlled, blinded studies are recommended to precisely determine irradiation parameters and the number of sessions. This review has been registered at the International Prospective Register of Systematic Reviews (PROSPERO) under number CRD42023397771.

Low dose cisplatin weekly versus high dose cisplatin every three weeks in primary chemoradiotherapy in head and neck cancer patients with low skeletal muscle mass: The CISLOW-study protocol.

Chemoradiotherapy with cisplatin in a triweekly regimen of 100 mg/m2 body surface area, is used to treat locally advanced head and neck squamous cell carcinoma (HNSCC) with curative intent. Cisplatin dose limiting toxicity (CDLT) occurs often and impedes obtaining the planned cumulative cisplatin dose. A cumulative cisplatin dose of 200 mg/m2 or more is warranted for better survival and locoregional control. Patients with a low skeletal muscle mass (SMM) have a three-fold higher risk of developing CDLT than patients with a normal SMM. SMM can be assessed through measurements on routinely performed diagnostic head and neck CT- or MRI-scans. A weekly regimen of 40 mg/m2 body surface area cisplatin is proposed as a less toxic schedule, which possibly decreases the risk of developing CDLT and enables reaching a higher cumulative cisplatin dose. The aim of this multicenter randomized clinical trial (NL76533.041.21, registered in the Netherlands Trial Register) is to identify whether a regimen of weekly cisplatin increases compliance to the planned chemotherapy scheme in HNSCC patients with low SMM. The primary outcome is the difference in compliance rate, defined as absence of CDLT, between low SMM patients receiving either the weekly or triweekly regimen. Secondary outcomes consist of toxicities, the cumulative cisplatin dose, time to recurrence, incidence of recurrence at two years of follow-up, location of recurrence, 2-year overall, disease free and disease specific survival, quality of life, patient's experiences, and cost-effectiveness.

Low skeletal muscle mass is predictive of dose-limiting toxicities in head and neck cancer patients undergoing low-dose weekly cisplatin chemoradiotherapy.

BACKGROUND: The dose-limiting effect of CT-assessed low skeletal muscle mass (LSMM) measured at the level of the third cervical vertebra has been found in head and neck cancer patients receiving high-dose cisplatin chemoradiotherapy. The aim of this study was to investigate the predictive factors for dose-limiting toxicities (DLTs) using low-dose weekly chemoradiotherapy. MATERIALS AND METHODS: Head and neck cancer patients receiving definite chemoradiotherapy with weekly 40 mg/m2 body surface area (BSA) cisplatin or paclitaxel 45 mg/m2 BSA and carboplatin AUC2 were consecutively included and retrospectively analysed. Skeletal muscle mass was assessed using the muscle surface at the level of the third cervical vertebra in pretherapeutic CT scans. After stratification for LSMM DLT, acute toxicities and feeding status during the treatment were examined. RESULTS: Dose-limiting toxicity was significantly higher in patients with LSMM receiving cisplatin weekly chemoradiotherapy. For paclitaxel/carboplatin, no significance regarding DLT and LSMM could be found. Patients with LSMM had significantly more dysphagia before treatment, although feeding tube placement before treatment was equal in patients with and without LSMM. CONCLUSIONS: LSMM is a predictive factor for DLT in head and neck patients treated with low-dose weekly chemoradiotherapy with cisplatin. For paclitaxel/carboplatin, further research must be carried out.

GPR68 limits the severity of chemical-induced oral epithelial dysplasia.

Head and neck cancer is the sixth most common malignancy, and there is an urgent need to identify physiological processes contributing to tumorigenesis. Extracellular acidification caused by aerobic glycolysis within tumor microenvironments can stimulate proton-sensing receptors. GPR68, or ovarian cancer G protein-coupled receptor 1, responds to extracellular acidity and is highly expressed in head and neck squamous cell carcinoma (HNSCC) as well as normal esophageal tissue. To study the role of GPR68 in oral dysplasia, wild-type and GPR68-/- mice were treated with 4-Nitroquinoline N-oxide (4NQO) in drinking water for 11-13 weeks, followed by normal water for 11-12 weeks. 4NQO treatment resulted in 45 percent of GPR68-/- mice developing severe dysplasia or squamous cell carcinoma compared to only 10.5 percent of GPR68+/+ mice. This correlated with increased frequencies of regulatory T cells in the spleens of male GPR68-/- mice. Dysplastic regions of the tongue had increased CD31 staining compared to normal regions in both GPR68-/- and GPR68+/+ mice, suggesting that angiogenesis was GPR68-independent. RNA knockdown studies using HNSCC cell lines demonstrated no direct effect of GPR68 on survival or growth. Overall, we demonstrate that GPR68-deficiency worsens the severity of chemical-induced oral dysplasia, suggesting a protective role for this gene in tumorigenesis.

A Retrospective Service- Evaluation of Implant Success, Survival, Periimplant Health and Prosthetic Complications in a Cohort of Head and Neck Cancer Patients.

OBJECTIVES: To determine the success, survival, peri-implant health and prosthetic complications in head and neck cancer patients receiving oral rehabilitation utilising dental implants between 2008 and the present day. MATERIALS AND METHODS: Service evaluation. Survival Group: Retrospective review of records to determine implant survival and prosthetic complications. Success Group: Examination to determine implant success and health. RESULTS: Survival Group: 260 implants in 81 individuals, median follow up 49.2 months. 89.3% implant survival at 96 months, no further failures up to 133 months. 40.9% individuals required repair or remake of prosthesis by 72 months - mostly denture re-lines. Success group: 164 implants in 48 individuals, median follow up 56 months. Peri-implant mucositis detected in 22% of fixtures (37.5% individuals); peri-implantitis in 12.8% (25% individuals); 33.3% fixtures exhibiting periimplantitis at 120 months. Previous smoking significantly associated with development of peri-implantitis (HR 2.372, p=0.032, 95CI:1.232, 93.317). Compromised survival (e.g. peri-implantitis), absolute (not in mouth) or clinical failure estimated to occur in 28.1% fixtures at 101 months, mostly due to peri-implantitis. CONCLUSIONS: There is a large burden of ongoing care in this cohort, requiring interventions to improve peri-implant health and maintain complex prostheses. Oral rehabilitation and ongoing maintenance in this cohort is complex and multi-disciplinary.

Oral Squamous Cell Carcinoma Following Acute Methotrexate Toxicity in a Psoriasis Patient: A Causal Association or Mere Co-Incidence.

BACKGROUND: Methotrexate is an antimetabolite anticancer drug frequently used in the treatment of extensive chronic plaque psoriasis. Psoriasis patients on treatment with immunosuppressants have an increased risk of developing malignancies. OBJECTIVE: To present a rare case of Oral Squamous Cell Carcinoma (OSCC) in a psoriasis patient postacute methotrexate toxicity. CASE REPORT: A 47-year-old female, a known case of chronic plaque psoriasis for which she was on 15 mg/ week methotrexate therapy and accidentally consumed 15 mg for 7 consecutive days. She was successfully treated for methotrexate toxicity and 45 days later she presented with exophytic growth on the tongue. Histopathology confirmed the diagnosis of squamous cell carcinoma and the patient underwent surgical resection. CONCLUSION: There could be a causal association between psoriasis and OSCC in the setting of acute methotrexate toxicity, as in the present case.

MOVIE: a phase I, open-label, multicenter study to evaluate the safety and tolerability of metronomic vinorelbine combined with durvalumab plus tremelimumab in patients with advanced solid tumors.

BACKGROUND: Anti-programmed cell death protein 1 (PD1)/programmed death-ligand 1 (PD-L1) agents have only moderate antitumor activity in some advanced solid tumors (AST), including breast cancer (BC), prostate cancer (PC), cervical cancer (CC), and head and neck cancer (HNC). Combining anti-PD-L1 with anti-cytotoxic T-lymphocyte-associated protein (CTLA) and chemotherapy may significantly improve efficacy. PATIENTS AND METHODS: MOVIE is a multicohort phase I/II study examining the combination of anti-PD-L1 durvalumab (Durv; 1500 mg IV Q4W) plus anti-CTLA tremelimumab (Trem; 75 mg IV Q4W) with metronomic vinorelbine (MVino; 20-40 mg orally daily) in various AST resistant to conventional therapies. The primary objective of the phase I part was to determine the maximum tolerated dose (MTD) and recommended dose for phase II (RP2D). RESULTS: Among the 14 patients enrolled during phase I, including 13 women and 1 man, 9 had BC, 1 PC, 2 CC, and 2 miscellaneous cancers with high mutational loads. Median age was 53 years. A total of 12 patients were assessable for the dose-escalation part in which only one dose-limiting toxicity (DLT) was observed [one neutropenia without fever, grade (G) 4]. Two (14.3%), four (28.6%), and four (28.6%) patients had G ≥3 adverse events (AEs) related to MVino, Durv, and Trem, respectively. Treatment-related events included mostly clinical AEs with asthenia (eight G2; three G3), colitis (one G2, one G3), diarrhea (one G3), nausea (two G2), dry skin (two G2), maculopapular rash (one G3), and hyperthyroidism (three G2). No toxic death was reported. Preliminary data showed one patient (CC) who presented a complete response and four patients with stable disease (SD). CONCLUSIONS: MTD was not reached and dose level 2 (MVino 40 mg, Durv 1500 mg, Trem 75 mg) was selected as RP2D. The safety profile of the combination was manageable and consistent with previous reports of Trem + Durv or MVino. Phase II is currently ongoing in BC, PC, CC, HNC, and miscellaneous cohorts.

Genomic signature of Fanconi anaemia DNA repair pathway deficiency in cancer.

Fanconi anaemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink repair resulting in chromosome breakage1-3. The FA repair pathway protects against endogenous and exogenous carcinogenic aldehydes4-7. Individuals with FA are hundreds to thousands fold more likely to develop head and neck (HNSCC), oesophageal and anogenital squamous cell carcinomas8 (SCCs). Molecular studies of SCCs from individuals with FA (FA SCCs) are limited, and it is unclear how FA SCCs relate to sporadic HNSCCs primarily driven by tobacco and alcohol exposure or infection with human papillomavirus9 (HPV). Here, by sequencing genomes and exomes of FA SCCs, we demonstrate that the primary genomic signature of FA repair deficiency is the presence of high numbers of structural variants. Structural variants are enriched for small deletions, unbalanced translocations and fold-back inversions, and are often connected, thereby forming complex rearrangements. They arise in the context of TP53 loss, but not in the context of HPV infection, and lead to somatic copy-number alterations of HNSCC driver genes. We further show that FA pathway deficiency may lead to epithelial-to-mesenchymal transition and enhanced keratinocyte-intrinsic inflammatory signalling, which would contribute to the aggressive nature of FA SCCs. We propose that the genomic instability in sporadic HPV-negative HNSCC may arise as a result of the FA repair pathway being overwhelmed by DNA interstrand crosslink damage caused by alcohol and tobacco-derived aldehydes, making FA SCC a powerful model to study tumorigenesis resulting from DNA-crosslinking damage.

A Study of Patients with Recurrent or Metastatic Head and Neck Cancer Treated with Pembrolizumab.

BACKGROUND/AIM: In December 2019, pembrolizumab was approved in Japan for the treatment of head and neck cancer with recurrence or distant metastasis, making it a new option for first-line treatment. However, there are still many unanswered questions about Overall survival (OS), Progression free survival (PFS), adverse events including immune-related adverse events (irAEs), and biomarkers. AIMS/OBJECTIVES: The aim of this study was to retrospectively review first-line treatment of head and neck cancer with recurrence or distant metastasis treated with pembrolizumab and to determine whether Combined positive score (CPS) is still useful as a biomarker in the clinical practice. MATERIAL AND METHODS: We retrospectively reviewed clinical records of 20 patients who received pembrolizumab as first-line treatment for head and neck cancer with recurrence or distant metastasis between December 2019 and March 2021. RESULTS: Age ranged from 45 to 83 years (median 66 years), 17 male patients and 3 female patients. The response rate was 40%, and the disease control rate was 60%. OS and PFS in patients with CPS < 1 were significantly worse than those with CPS ≤ 1 (CPS-positive patients). The OS and PFS of patients with CPS < 1 were s ignificantly worse than those of p atients with 1 < = CPS (CPS-positive p atients), and there was no significant difference between the group with CPS between 1 and 20 and the group with CPS over 20. And we experiences several CR cases with high CPS. CONCLUSION: CPS is a useful biomarker for pembrolizumab. SIGNIFICANCE: There are no reported cases of CR after two courses of pembrolizumab in head and neck cancer. There are no reports of pembrolizumab in patients with head and neck cancer in Japan.

Effect of intravenous lidocaine on pain after head and neck cancer surgery (ELICO trial): A randomised controlled trial.

BACKGROUND: Treatment of postoperative pain after ear, nose and throat (ENT) cancer surgery is mainly morphine administration. Additional systemic lidocaine has shown promising results in some surgical procedures. OBJECTIVE: The main objective was to evaluate morphine consumption in the first 48 postoperative hours after intra-operative lidocaine infusion during major ENT cancer surgery. DESIGN: A randomised, double-blind, placebo-controlled trial. SETTING: Bicentric study including a university hospital and a major cancer centre, conducted from December 2016 to December 2019. PATIENTS: A total of 144 patients undergoing major ENT cancer surgery were included. INTERVENTION: The patients were randomly assigned to receive intravenous lidocaine or placebo during surgery and in the recovery room. MAIN OUTCOME MEASURES: Endpoints were postoperative morphine consumption in the first 24 and 48 h postoperatively, intra-operative remifentanil consumption, adverse events occurrence and assessment 3 to 6 months after surgery with the McGill pain questionnaire. RESULTS: A total of 118 patients were included (lidocaine n  = 57; placebo n  = 61, 26 patients were excluded). There was no significant difference in morphine consumption during the first 48 postoperative hours in the lidocaine group compared with the placebo group with a median [IQR] of 0.60 [0.30 to 1.03] mg kg -1 vs. 0.57 [0.37 to 0.96] mg kg -1 , total dose 44 [21 to 73.3] mg vs. 38 [23.3 to 56.5] mg, P  = 0.92.There was no significant difference between the two groups in any of the other endpoints, including at follow up 3 to 6 months after surgery. CONCLUSION: Intravenous lidocaine in ENT cancer surgery did not show any additional analgesic or morphine-sparing effect 48 h after surgery. Three to six months after surgery, there was no significant difference in pain scores or consumption of analgesics. Patients treated pre-operatively with opioids were not evaluated in the study. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02894710 and EUDRACT number 2015-005799-90.

Predictive significance of body composition indices in patients with head and neck squamous cell carcinoma treated with nivolumab: A multicenter retrospective study.

BACKGROUND: The identification of predictive factors is imperative for identifying patients with optimal responses to nivolumab. We aimed to determine whether body composition parameters can predict treatment outcomes in patients with head and neck squamous cell carcinoma (HNSCC) treated with nivolumab. METHOD: We performed a multicenter retrospective chart review of patients with recurrent and/or metastatic HNSCC treated with nivolumab between 2017 and 2020. Computed tomography images and anthropometric measures were used to determine the skeletal muscle index (SMI), subcutaneous adipose index, visceral adipose index (VAI), and body mass index. Objective response, overall survival (OS), progression-free survival (PFS), and severe immune-related adverse events (irAEs) were the main outcomes. Odds ratios (ORs) and hazard ratios (HRs) for low-index groups compared with high-index groups were calculated for these outcomes. RESULTS: Our study comprised 114 patients with a median follow-up period of 23.1 months. Low SMI and low VAI were significantly associated with poor disease control [OR: 0.39, 95% confidence interval (CI): 0.15-0.97] and poor response (OR: 0.38, 95% CI: 0.15-0.94), respectively. Low SMI independently predicted poor OS (HR: 2.06, 95% CI: 1.16-3.67), poor PFS (HR: 1.74, 95% CI: 1.04-2.92), and increased incidence of irAEs (OR: 6.00, 95% CI: 1.04-34.61). Low VAI independently predicted poor PFS (HR 2.07, 95% CI: 1.15-3.73). CONCLUSION: The SMI and VAI are predictive factors of nivolumab therapy in patients with HNSCC. Body composition indices should be assessed before nivolumab treatment for achieving optimal responses to nivolumab.

Drug-Eluting Embolics Chemoembolization for the Management of Recurrent or Advanced Head and Neck Cancer.

PURPOSE: To characterize the safety, tolerability, and efficacy of chemoembolization using drug-eluting embolic (DEE) microspheres in patients with recurrent and advanced head and neck cancer. MATERIALS AND METHODS: In this retrospective study, 32 patients (mean age, 57.2 years ± 2.8; 17 women) with recurrent (n = 16) and advanced (n = 16) head and neck cancer were treated with chemoembolization using DEE microspheres loaded with doxorubicin. Treatment response, overall survival, local progression-free survival, and adverse events were evaluated. RESULTS: At 6 months after the procedure, the objective response and disease control rates were 25% and 69%, respectively. The median overall survival and local progression-free survival were 14.5 and 13.6 months, respectively. Seven (22%) patients experienced adverse events after the chemoembolization procedure. All the adverse events were related to postembolization syndrome, including vomiting and nausea (n = 1), pyrexia (n = 2), and localized pain (n = 7). No severe adverse events or procedure-related deaths were observed. CONCLUSIONS: Chemoembolization using DEE microspheres was safe and tolerable in patients with recurrent and advanced head and neck cancer.

Topical Xerostomia Treatment with Hyaluronate Sheets Containing Pilocarpine.

Sjogren's syndrome and radiation therapy for head and neck cancers are often accompanied by xerostomia. Oral pilocarpine (PCP) to treat xerostomia produces systemic side effects, such as runny nose and lacrimation. To improve the therapeutic efficacy of PCP and reduce the aforementioned side effects, we developed a topical delivery system for PCP using freeze-dried sheets of hyaluronic acid (HA). The advantages of HA sheets over conventional oral formulations were examined through in vivo pharmacokinetic and pharmacodynamic studies after their application to oral tissues and salivary glands. The concentration of PCP in the submucosal tissue of the oral cavity was determined using the microdialysis (MD) method after buccal application of HA sheets containing PCP to hamsters. The concentration of PCP in the MD outflow was quite low after gastric administration, whereas the PCP concentration in plasma was high. In contrast, after buccal application of HA sheets containing PCP, the concentration of the drug in the MD outflow increased, despite the negligible concentration in plasma. These findings indicated that both enhancement of saliva secretion and the avoidance of systemic side effects could be achieved through buccal administration of PCP-loaded HA sheets. In addition, the pharmacodynamic study showed that when compared with intravenous and gastric administration, salivary application of HA sheets containing PCP resulted in similar volumes of saliva secretion and reduced lacrimal secretions. In conclusion, freeze-dried HA sheets allow for the development of a novel buccal delivery system with enhanced therapeutic efficacy and safety to treat xerostomia.