New Ref-1/APE1 targeted inhibitors demonstrating improved potency for clinical applications in multiple cancer types.

AP endonuclease-1/Redox factor-1 (APE1/Ref-1 or Ref-1) is a multifunctional protein that is overexpressed in most aggressive cancers and impacts various cancer cell signaling pathways. Ref-1's redox activity plays a significant role in activating transcription factors (TFs) such as NFκB, HIF1α, STAT3 and AP-1, which are crucial contributors to the development of tumors and metastatic growth. Therefore, development of potent, selective inhibitors to target Ref-1 redox function is an appealing approach for therapeutic intervention. A first-generation compound, APX3330 successfully completed phase I clinical trial in adults with progressing solid tumors with favorable response rate, pharmacokinetics (PK), and minimal toxicity. These positive results prompted us to develop more potent analogs of APX3330 to effectively target Ref-1 in solid tumors. In this study, we present structure-activity relationship (SAR) identification and validation of lead compounds that exhibit a greater potency and a similar or better safety profile to APX3330. In order to triage and characterize the most potent and on-target second-generation Ref-1 redox inhibitors, we assayed for PK, mouse and human S9 fraction metabolic stability, in silico ADMET properties, ligand-based WaterLOGSY NMR measurements, pharmacodynamic markers, cell viability in multiple cancer cell types, and two distinct 3-dimensional (3D) cell killing assays (Tumor-Microenvironment on a Chip and 3D spheroid). To characterize the effects of Ref-1 inhibition in vivo, global proteomics was used following treatment with the top four analogs. This study identified and characterized more potent inhibitors of Ref-1 redox function (that outperformed APX3330 by 5-10-fold) with PK studies demonstrating efficacious doses for translation to clinic.

Functional or radical surgical treatment of laryngeal chondrosarcoma, analysis of survival and prognostic factors: A REFCOR and NetSarc-ResOs multicenter study of 74 cases.

INTRODUCTION: Laryngeal chondrosarcoma (LCS) is a rare tumor of slow evolution whose treatment is poorly codified. For a long time, a radical treatment by total laryngectomy (TL) was proposed. More recent studies tend to propose a conservative surgical approach of the larynx. The objective of this study was to compare the overall survival (OS) of total laryngectomized patients (TL+) versus non-laryngectomized patients (TL-). The secondary objectives were to analyse the reoperation free survival (RFS), the total laryngectomy free survival (TLFS) and to identify the preoperative factors leading surgeons to propose TL. MATERIALS AND METHODS: A retrospective analysis of prospectively collected incident cases from the REFCOR and NetSarc-ResOs multicenter databases between March 1997 and June 2021 was conducted. A propensity score matching analysis was performed to compare the OS of TL+ and TL-patients. RESULTS: 74 patients were included. After propensity score, the 5-year OS of TL+ and TL-patients was comparable (100 %, p = 1). The 5-year RFS rate was 69.2 % (95 % CI [57.5-83.4]) and the 5-year TLFS was 61.7 % (95 % CI [50.4-75.5]). Cricoid involvement greater than 50 % (HR 3.58; IC 95 % [1.61-7.92] p < 0.001), an ASA score of 3 or 4 (HR 5.07; IC 95 % [1.64-15.67] p = 0.009) and involvement of several cartilages (HR 5.26; IC 95 % [1.17-23.6] p = 0.04) are prognostic factors for TL. Dyspnea caused by the tumour is a prognostic factor for reoperation (HR 2.59; IC 95 % [1.04-6.45] p = 0.03). CONCLUSION: These results demonstrate that conservative treatment should be considered as first-line treatment for laryngeal chondrosarcoma.

Characterization of the Stereoselective Disposition of Bupropion and Its Metabolites in Rat Plasma and Brain.

BACKGROUND AND OBJECTIVES: Bupropion is an atypical antidepressant and smoking cessation aid; its use is associated with wide intersubject variability in efficacy and safety. Knowledge of the brain pharmacokinetics of bupropion and its pharmacologically active metabolites is considered important for understanding the cause-effect relationships driving this variability. METHODS: Brain concentrations from rats administered a 10 mg/kg subcutaneous dose of racemic bupropion were analyzed using a stereoselective LC/MS-MS method. A 2 mg/kg dose of (S,S)-hydroxybupropion, which has comparable pharmacologic potency to bupropion, was administered to a separate group of rats. Plasma exposure and unbound concentrations in both matrices from companion equilibrium dialysis experiments were determined to assess potential carrier-mediated transport at the blood-brain barrier. RESULTS: Exposures to unbound forms of bupropion enantiomers were similar in plasma; this was also true in brain. This trend held for reductive diastereomer metabolite pairs in the two matrices. Unbound (R,R)-hydroxybupropion exposure was 1.5-fold higher than (S,S)-hydroxybupropion exposure in plasma and brain following bupropion administration. Unbound concentration ratios (Kp,uu) of a given molecular form decreased over time: between 4 and 6 h, these were < 1 for the two bupropion enantiomers, and they were ~ 1 for metabolites that formed. Administration of preformed (S,S)-hydroxybupropion also demonstrated a declining Kp,uu. CONCLUSIONS: The temporal shift in Kp,uu among the different molecular forms provides evidence regarding the operation of carrier-mediated transport and/or within-brain metabolism of bupropion, and, thereby, fresh insight regarding the causes of intersubject variability in the safety and efficacy of bupropion therapy.

Effectiveness of Geriatric Assessment-Driven Interventions on Survival and Functional and Nutritional Status in Older Patients with Head and Neck Cancer: A Randomized Controlled Trial (EGeSOR).

This study assesses the efficacy of Geriatric Assessment (GA)-driven interventions and follow-up on six-month mortality, functional, and nutritional status in older patients with head and neck cancer (HNC). HNC patients aged 65 years or over were included between November 2013 and September 2018 by 15 Ear, Nose, and Throat (ENT) and maxillofacial surgery departments at 13 centers in France. The study was of an open-label, multicenter, randomized, controlled, and parallel-group design, with independent outcome assessments. The patients were randomized 1:1 to benefit from GA-driven interventions and follow-up versus standard of care. The interventions consisted in a pre-therapeutic GA, a standardized geriatric intervention, and follow-up, tailored to the cancer-treatment plan for 24 months. The primary outcome was a composite criterion including six-month mortality, functional impairment (fall in the Activities of Daily Living (ADL) score ≥2), and weight loss ≥10%. Among the patients included (n = 499), 475 were randomized to the experimental (n = 238) or control arm (n = 237). The median age was 75.3 years [70.4-81.9]; 69.5% were men, and the principal tumor site was oral cavity (43.9%). There were no statistically significant differences regarding the primary endpoint (n = 98 events; 41.0% in the experimental arm versus 90 (38.0%); p = 0.53), or for each criterion (i.e., death (31 (13%) versus 27 (11.4%); p = 0.48), weight loss of ≥10% (69 (29%) versus 65 (27.4%); p = 0.73) and fall in ADL score ≥2 (9 (3.8%) versus 13 (5.5%); p = 0.35)). In older patients with HNC, GA-driven interventions and follow-up failed to improve six-month overall survival, functional, and nutritional status.

Donor site sequelae and patient satisfaction after head and neck reconstruction with a radial forearm free flap.

PURPOSE: Radial forearm free flap (RFFF) being a workhorse flap in head and neck reconstruction, we investigated its donor site delayed consequences. METHODS: Multicentric case series evaluating 189 patients who underwent RFFF for carcinologic reasons at least 6 months before. Patients and surgeon's appreciation regarding the aesthetic and functional consequences of the flap harvest on their daily life were evaluated by questionnaires using likert scales. Medical data were collected from patients' charts retrospectively. RESULTS: Thirty percent of patients had at least one sequelae. Experiencing a graft necrosis did not worsen long-term results. Cosmetic satisfaction was significantly worst for women, according to patients' and surgeons' opinion. For 81% and 92% patients, respectively, the flap harvest had no impact on daily life nor sport practice. Ratio between the benefits of reconstruction and the sequelae at the donor site was judged "excellent" for 77% patients. CONCLUSIONS: Although objectively important, RFFF morbidity has little impact in head and neck cancer patient's life.

Population model analysis of chiral inversion and degradation of bupropion enantiomers, and application to enantiomer specific fraction unbound determination in rat plasma and brain.

Pharmacologic effects elicited by drugs most directly relate to their unbound concentrations. Measurement of binding in blood, plasma and target tissues are used to estimate these concentrations by determining the fraction of total concentration in a biological matrix that is not bound. In the case of attempting to estimate R- and S-bupropion concentrations in plasma and brain following racemic bupropion administration, reversible chiral inversion and irreversible degradation of the enantiomers were hypothesized to confound attempts at unbound fraction estimation. To address this possibility, a kinetic modeling approach was used to quantify inversion and degradation specific processes for each enantiomer from separate incubations of each enantiomer in the two matrices, and in pH 7.4 buffer, which is also used in binding experiments based on equilibrium dialysis. Modeling analyses indicated that chiral inversion kinetics were two to four-fold faster in plasma and brain than degradation, with only inversion observed in buffer. Inversion rate was faster for S-bupropion in the three media; whereas, degradation rates were similar for the two enantiomers in plasma and brain, with overall degradation in plasma approximately 2-fold higher than in brain homogenate. Incorporation of degradation and chiral inversion kinetic terms into a model to predict enantiomer-specific binding in plasma and brain revealed that, despite existence of these two processes, empirically derived estimates of fraction unbound were similar to model-derived values, leading to a firm conclusion that observed extent of plasma and brain binding are accurate largely because binding kinetics are faster than parallel degradation and chiral inversion processes.

Mucoepidermoid carcinoma of salivary glands: A French Network of Rare Head and Neck Tumors (REFCOR) prospective study of 292 cases.

BACKGROUND: To describe the characteristics of the largest European study of MEC of salivary glands and to determine the prognostic factors for overall and disease free survival. PATIENTS AND METHODS: Patients with MEC were prospectively included in the Réseau d'Expertise Français sur les Cancers ORL Rares (REFCOR, French Network of Rare Head and Neck Tumors) database between 2009 and 2015. RESULTS: A total of 292 patients were included. Tumors were classified as low grade in 175 cases (60%), intermediate in 39 (13%) and high grade in 78 (27%). Median follow-up was 26 months. The 5-year OS and DFS rates were respectively 83% and 69%. In multivariate analysis, age (p = 0.004), diabetes (p = 0.02) and advanced stage (p = 0.03) were found to have a significant negative impact on OS. Diabetes (p = 0.001), alcohol consumption (p = 0.003) and advanced stage (p = 0.001) were found to have a significant negative impact on DFS. Compare to low grade, high grade tended to have a negative impact on OS (p = 0.05) and had a significant effect on DFS (0.002) while intermediate grade had no significant influence on survival. The surgical treatment had a positive impact on both OS (p = 0.00005) and DFS (p = 0.0005). Postoperative radiotherapy had no impact in multivariate analysis. CONCLUSION: Advanced clinical stage, high grade tumor, high age, the impossibility of carrying out a complete surgical resection, and diabetes are the main prognostic factors in this prospective series of patients with MEC. Such findings open new research perspectives on the influence of these components on initial patient care.

Oral and oropharyngeal cancer surgery with free-flap reconstruction in the elderly: Factors associated with long-term quality of life, patient needs and concerns. A GETTEC cross-sectional study.

OBJECTIVES: To assess the factors associated with long-term quality of life (QoL) and patient concerns in elderly oral or oropharyngeal cancer (OOPC) patients after oncologic surgery and free-flap reconstruction. METHODS: Patients aged over 70 years who were still alive and disease-free at least 1 year after surgery were enrolled in this cross-sectional multicentric study. Patients completed the EORTC QLQ-C30, -H&N35 and -ELD14 QoL questionnaires, and the Hospital Anxiety and Depression Scale (HADS). Patient needs were evaluated using the Patient Concerns Inventory (PCI). Factors associated with these clinical outcomes were determined in univariate and multivariate analysis. RESULTS: Sixty-four patients were included in this study. Long-term QoL, functioning scales and patient autonomy were well-preserved. Main persistent symptoms were fatigue, constipation and oral function-related disorders. Salivary and mastication/swallowing problems were the main patient concerns. The mean number of patient concerns increased with the deterioration of their QoL. Psychological distress (HADS score ≥ 15) and patient frailty (G8 score < 15) were significantly associated with poor QoL outcomes. CONCLUSIONS: We found a negative correlation between the number of patient concerns and QoL. Dental rehabilitation and psychological and nutritional supportive measures are of critical importance in the multidisciplinary management of elderly OOPC patients.

Clinical characteristics and prognostic factors of sinonasal undifferentiated carcinoma: a multicenter study.

BACKGROUND: Sinonasal undifferentiated carcinoma (SNUC) is a very rare entity with a poor prognosis. Due to the lack of studies on the subject, evidence is lacking concerning its management. METHODS: A multicenter collaborative study was conducted to assess treatment strategy, oncological outcome, and prognostic factors. RESULTS: Definitive analyses focused on 54 patients with a majority of advanced stage; the 3-year overall survival (OS) and 3-year recurrence-free survival (RFS) rates were, respectively, 62.4% and 47.8%. During the follow-up, 18 patients (33.3%) died, 10 (18.5%) developed metastases, 7 had lymph-node involvement (13%), and 12 (22.2%) showed recurrence or local progression. In univariate analyses, treatment modalities associated with improved RFS were induction chemotherapy (p = 0.02) and intensity-modulated radiotherapy (p = 0.007). In the multivariate analyses, only induction chemotherapy (p = 0.047, hazard ratio [HR] = 0.39) was significantly associated with improved RFS. CONCLUSION: Multimodal therapies including induction chemotherapy and intensity-modulated radiotherapy may improve the prognosis of SNUC; surgery might improve local control. Further multicenter studies are required.

Comparison of negative pressure wound therapy and conventional dressing methods for fibula free flap donor site management in patients with head and neck cancer.

BACKGROUND: Evaluation of the efficacy of negative pressure wound therapy in fibula free flap donor site management in head and neck cancer. METHODS: We conducted a single-center retrospective study from 2007 to 2013 comparing fibula free flap donor site healing time after conventional bolster dressing or negative pressure wound therapy. RESULTS: Thirteen patients were treated by conventional dressing and 16 patients were treated by negative pressure wound therapy. The mean graft loss rate was higher in the bolster group (37%) than in the negative pressure wound therapy group (19%). The mean total healing time was significantly shorter in the negative pressure wound therapy group than in the bolster group (67 days vs 163 days; p = .02). CONCLUSION: The use of negative pressure wound therapy for fibula free flap donor site management facilitates early patient mobilization, ensures better graft acceptance, and significantly decreases the healing time.

Velopharyngeal function after free thoracodorsal artery perforator flap in lateral and superior oropharyngeal cancer.

The purpose of this study was to report our experience with the free thoracodorsal artery perforator flap for reconstruction of the oropharynx and soft palate in head and neck cancer using a retrospective review of the medical charts of all patients undergoing oropharyngeal reconstruction by free thoracodorsal artery perforator flap during the same procedure as cancer resection between January 2011 and April 2013. Evaluation of speech, feeding and the presence of nasal emissions was performed 6 months after treatment in accordance with the Declaration of Helsinki. Nine patients were evaluated. Clear understanding of the patient was reported by the family and the examiner for seven patients, while understanding difficulties were reported for two patients (1 case of flap dehiscence and 1 technical error of flap fixation). The results indicated that, due to its complex anatomy and function, reconstruction of the soft palate remains a delicate procedure. The free thoracodorsal artery perforator flap allows functional soft palate reconstruction, while limiting donor site morbidity.

Cultured allogenic keratinocytes for extensive burns: a retrospective study over 15 years.

UNLABELLED: The aim was to review the use and indications of cultured allogenic keratinocytes (CAlloK) in extensive burns and their efficiency. MATERIALS AND METHODS: This retrospective study comprised 15 years (1997-2012). INCLUSION CRITERIA: all patients who received CAlloK. EXCLUSION CRITERIA: patients who died before complete healing. Evaluation criteria were clinical. Time and success of wound healing after CAlloK use were evaluated. RESULTS: The CAlloK were used for 2 indications - STSG donor sites and deep 2nd degree burns in extensively burned patients. A total of 70 patients were included with severity Baux score of 99.2 (from 51 to 144) and mean percentage of TBSA of 63.49% (from 21 to 96%). Fifty nine patients received CAlloK for STSG donor sites with a mean number of applications of 4 and mean surface of 3800 cm(2) per patient. Treated donor sites were re-harvested 2.5 times. The mean time of complete epithelialization was 7 days. In 11 patients, CAlloK were used for deep 2nd degree burns. The mean percentage of burned surface was 73.7%. The mean surface of CAlloK per patient was 2545 cm(2). Complete healing was achieved in 6.4 days. CONCLUSION: The CAlloK allow rapid healing of STSG donor-sites and deep 2nd second degree burns in extensively burned patients.

Long-term results of surgical treatment of vocal fold nodules.

OBJECTIVES/HYPOTHESIS: To evaluate the long-term outcome of patients with vocal fold nodules treated by surgery alone, or by a combination of surgery and voice therapy and to identify factors associated with long-term recurrent dysphonia. STUDY DESIGN: Retrospective study. METHODS: All patients who had undergone surgery for vocal fold nodules in a tertiary care hospital between 1996 and 2006 were contacted. After giving their consent, they were evaluated by videostroboscopic examination of vocal fold nodules and by a subjective questionnaire including the Voice Handicap Index (VHI). RESULTS: Sixty-two out of 90 patients (69%) (60 women, 2 men with a mean age of 33 years) answered the questionnaire at a mean interval of 9.5 years after surgery. Recurrent dysphonia was observed in 19 patients (30%) at a mean interval of 5.2 years after surgery and new benign vocal fold lesions (nodules or Reinke's edema) were observed in 11 patients (18%). Absence of postoperative voice therapy was significantly associated with a higher recurrence rate (P = 0.02) (56% of recurrent dysphonia without voice therapy versus 22% with voice therapy). CONCLUSIONS: Postoperative voice therapy decreases the risk of recurrence. Vocal fold nodules can recur over a period of 5 years, consequently requiring follow-up for at least 5 years in clinical practice and in future prospective studies.

Orbital morphology in exophthalmos and exorbitism.

BACKGROUND: Exophthalmos is a protrusion of the eyeball due to an increase in orbital contents in a normal bony orbit. Exorbitism is a protrusion of the eyeball due to a decrease in capacity of the orbital container, with a normal orbital content volume such as seen in a congenital form termed nonsyndromic exorbitism. High myopia can enhance proptosis. The purpose of this study was to provide values for orbital measurements from computed tomography and to suggest computed tomography criteria for nonsyndromic exorbitism. METHODS: Seventy-three computed tomography scans were collected (57 of Graves' ophthalmopathy and 16 of nonsyndromic exorbitism). Thirty-two scans from nonproptotic patients constituted a control series. Nine measurements and two indexes, performed on a reference axial computed tomography slice transecting the neuro-ocular plane, were obtained from each scan. RESULTS: The angle between the sagittal axis and the lateral orbital wall, as well as the width of the ethmoid bone (midinterorbital distance), was found to be more open in the nonsyndromic exorbitism population. A lateral orbital wall angle greater than or equal to 42 degrees and a midinterorbital distance greater than 30 mm were chosen as cutpoints. The association of these two criteria allowed the authors to obtain a sensitivity of 62 percent, a specificity of 78 percent, a positive predictive value of 80 percent, and a negative predictive value of 86 percent for nonsyndromic exorbitism. CONCLUSIONS: The different mechanisms of globe protrusion have to be taken into account before an orbital expansion/decompression procedure is planned. Only a preoperative morphological analysis of the orbital shape permits a precise analysis of the relative position of the ocular globe and orbital structures, in addition to clinical examination.

Surgical strategy in the treatment of globe protrusion depending on its mechanism (Graves' disease, nonsyndromic exorbitism, or high myopia).

BACKGROUND: Graves' ophthalmopathy affects orbital contents and eyelids. Protrusion of the globe can also be the result of myopia and/or an abnormal orbit shape, which is responsible for nonsyndromic exorbitism. It is necessary to recognize these components of protrusion to treat patients adequately. The authors present a surgical strategy for treatment of the orbit and lids. METHODS: Files of 84 patients treated from 1984 to 2003 were retrospectively reviewed. Sixty-eight patients were operated on for Graves' ophthalmopathy and 16 for nonsyndromic exorbitism with or without myopia. The surgical strategy was adapted to the degree of emergency, the age of the patient, and the shape of the orbit measured using computed tomography. The accepted standard of treatment was a coronal approach with a two-wall expansion, with or without bone grafts, especially in cases of associated nonsyndromic exorbitism, with or without complementary ablation of the external part of the orbital floor. Lid surgery was performed at a second stage. RESULTS: Nonsyndromic exorbitism patients were successfully treated in one step. No diplopia was present either preoperatively or postoperatively. In contrast, the treatment of the Graves' ophthalmopathy patients justified one to three orbital expansion procedures per patient and/or one to seven procedures for levator palpebrae lengthening or reinsertion. Forty-three percent of preexisting diplopias were improved by the surgery. The overall postoperative incidence of de novo diplopia was 19 percent. In the Graves' ophthalmopathy series, three patients (5 percent) finally underwent strabismus surgery. No major complication occurred. CONCLUSIONS: The treatment of Graves' ophthalmopathy is challenging. A graded approach is justified. Patients have to be informed that several procedures may be necessary and, in cases of nonsyndromic exorbitism or myopia, that facial modifications might occur.