Pignat's vertical partial laryngectomy with crico-hyoido-epiglotto-plasty.

PURPOSE: Pignat's partial laryngectomy with crico-hyoido-epiglotto-plasty (CHEPL) is a vertical laryngectomy with resection of the anterior portion of the thyroid cartilage and reconstruction with a wires net and the subhyoid muscles. The aim of this retrospective study was to evaluate and analyze oncologic and functional outcomes in patients affected by laryngeal squamous cell carcinoma and treated with Pignat's partial laryngectomy. METHODS: Seventy patients with cT1-cT3 glottic cancer were surgically treated with Pignat's technique. EXCLUSION CRITERIA: invasion of posterior cricoid arch, more than 3 mm under glottis, of more than one arytenoid, of posterior portion of thyroid cartilage, of the suprahyoid epiglottis. Overall survival, disease free survival, rates of decannulation and enteral feeding were analyzed. RESULTS: 23 (32.9%) pT1, 37 (52.9%) pT2, 5 (7.1%) pT3, 5 (7.1%) pT4a, 64 (91.5%) pN0, 5 (7.1%) pN1, 1 (1.4%) pN2. Adjuvant treatment was administered to 13 patients (18.6%). All patients had tracheotomy. Five year OS and DFS were 81.66 and 77.95%, respectively. A statistically significant DFS difference was observed between early and late stages. Five year local control was 81.16%. Five year larynx preservation rate was 89.16%. Median decannulation time was 12 days. Median duration of enteral nutrition was 16 days. All patients achieved efficient phonation. CONCLUSION: Pignat's partial laryngectomy with CHEPL can represent an alternative to horizontal supracricoid laryngectomy to achieve laryngeal preservation. Good oncologic and functional outcomes are possible as long as indications are followed.

Concise and Practical Asymmetric Synthesis of a Challenging Atropisomeric HIV Integrase Inhibitor.

A practical and efficient synthesis of a complex chiral atropisomeric HIV integrase inhibitor has been accomplished. The combination of a copper-catalyzed acylation along with the implementation of the BI-DIME ligands for a ligand-controlled Suzuki cross-coupling and an unprecedented bis(trifluoromethane)sulfonamide-catalyzed tert-butylation renders the synthesis of this complex molecule robust, safe, and economical. Furthermore, the overall synthesis was conducted in an asymmetric and diastereoselective fashion with respect to the imbedded atropisomer.

Preclinical profile of BI 224436, a novel HIV-1 non-catalytic-site integrase inhibitor.

BI 224436 is an HIV-1 integrase inhibitor with effective antiviral activity that acts through a mechanism that is distinct from that of integrase strand transfer inhibitors (INSTIs). This 3-quinolineacetic acid derivative series was identified using an enzymatic integrase long terminal repeat (LTR) DNA 3'-processing assay. A combination of medicinal chemistry, parallel synthesis, and structure-guided drug design led to the identification of BI 224436 as a candidate for preclinical profiling. It has antiviral 50% effective concentrations (EC50s) of <15 nM against different HIV-1 laboratory strains and cellular cytotoxicity of >90 µM. BI 224436 also has a low, ∼2.1-fold decrease in antiviral potency in the presence of 50% human serum and, by virtue of a steep dose-response curve slope, exhibits serum-shifted EC95 values ranging between 22 and 75 nM. Passage of virus in the presence of inhibitor selected for either A128T, A128N, or L102F primary resistance substitutions, all mapping to a conserved allosteric pocket on the catalytic core of integrase. BI 224436 also retains full antiviral activity against recombinant viruses encoding INSTI resistance substitutions N155S, Q148H, and E92Q. In drug combination studies performed in cellular antiviral assays, BI 224436 displays an additive effect in combination with most approved antiretrovirals, including INSTIs. BI 224436 has drug-like in vitro absorption, distribution, metabolism, and excretion (ADME) properties, including Caco-2 cell permeability, solubility, and low cytochrome P450 inhibition. It exhibited excellent pharmacokinetic profiles in rat (clearance as a percentage of hepatic flow [CL], 0.7%; bioavailability [F], 54%), monkey (CL, 23%; F, 82%), and dog (CL, 8%; F, 81%). Based on the excellent biological and pharmacokinetic profile, BI 224436 was advanced into phase 1 clinical trials.

An effective and well-tolerated strategy in recurrent and/or metastatic head and neck cancer: successive lines of active chemotherapeutic agents.

BACKGROUND: The combination platinum, 5-fluorouracil (5-FU) and cetuximab is the standard first-line regimen of recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC). Due to the toxicity of this treatment, alternative therapies are often offered to patients. The aim of this study was to evaluate the overall survival obtained with a first line chemotherapy adapted to patients functional status and the administration of all active drugs within successive lines of chemotherapy. METHODS: This series included a total of 194 patients with recurrent and/or metastatic HNSCC treated from 2006 to 2011 in a single institution where the administration of successive lines of chemotherapies has been the standard clinical approach. Treatment was administered according to clinical practice guidelines. RESULTS: Most patients received at least two treatment lines. Only 11 patients (6%) were treated with a combination of cisplatin, 5-FU and cetuximab in front line, but most patients received at least one platinum-based regimen (n = 154 patients, 78%); 162 (82%) received taxanes, 36 (18%) received 5-FU, 27 (14%) received capecitabine, 67 (34%) received methotrexate and 134 (68%) received cetuximab. The median overall survival was 9.8 months (95% CI: 8.1-11.4 months) and reached 13.1 months among the subgroup of 131 patients eligible for inclusion in a clinical trial. CONCLUSION: The survival outcomes of patients treated in the first-line setting with chemotherapy regimens adapted to their functional status, followed by several subsequent regimens were comparable with published outcomes of patients treated by platinum, 5-FU and cetuximab.

A pyriform sinus cancer organ preservation strategy comprising induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil, followed by potentiated radiotherapy: a multicenter, retrospective study.

No specific study has evaluated the role of neoadjuvant DCF (docetaxel, cisplatin, 5-fluorouracil) followed by radiotherapy in pyriform sinus cancer, which are often included in studies focusing on laryngeal and hypopharyngeal cancer. We assessed the proportion of patients treated sequentially for a pyriform sinus cancer with a preserved larynx. Overall survival, event-free survival (EFS), survival with 'local control', and treatment tolerance were assessed as well. We retrospectively reviewed 88 patients with advanced pyriform sinus squamous cell carcinoma treated with DCF between 2005 and 2010. After induction, radiation could be potentiated with cetuximab or cisplatin. Most patients (82%) had been treated with organ preservation intent. The response rate to DCF was 85%, including 42% with complete response. Primary tumor was operated in 13 patients (eight with total laryngectomy). Radiotherapy had been delivered to 78 (89%) patients (30 with cisplatin, 39 with cetuximab). Potentiation had been achieved as planned in 52 and 79% of patients treated with cisplatin and cetuximab, respectively. Twenty-three local and three neck recurrences were found. Median overall survival was 16.8 months and 38.3% at 3 years. EFS at 3 years was 29.1% with a hazard ratio for partial responders versus nonresponders of 0.18 (P<0.001), and 0.13 (P<0.001) for complete responders versus nonresponders. Thirty-five percent of patients were alive with their larynx preserved at 3 years. This study confirms the efficacy of induction followed by chemoradiation for pyriform sinus cancer and that response to DCF is predictive of EFS.

Neoadjuvant TPF in locally advanced head and neck cancer can be followed by radiotherapy combined with cisplatin or cetuximab: a study of 157 patients.

Neoadjuvant TPF (docetaxel, cisplatin, 5-fluorouracil), followed by radiotherapy or chemoradiotherapy with weekly carboplatin, increases overall survival and organ preservation. We assessed whether TPF could be used in routine practice and whether radiotherapy potentiated with cisplatin or cetuximab was feasible and could increase survival. We retrospectively reviewed 157 patients with advanced head and neck squamous cell carcinoma treated with TPF in four French institutions between May 2005 and March 2009. After induction, operable patients had undergone surgery and were irradiated, and potentiated in some cases with cetuximab or cisplatin. Most patients (79%) had been treated with organ preservation strategies. The two most common sites were the hypopharynx (34%) and the oropharynx (30%). The response rate to TPF was 84%, including 26% with a complete response. Radiotherapy had been provided to 144 (92%) patients (of whom 17 had received radiotherapy alone, 46 had received q3w cisplatin, 30 had received q1w cisplatin, and 37 had received cetuximab). Potentiation had been achieved as planned in 59, 63, and 62% of patients treated with q3w cisplatin, q1w cisplatin, and cetuximab, respectively. After a median follow-up of 39.9 months, the median overall survival was 43 months. No significant difference was observed in progression-free survival or overall survival according to the type of potentiation. This study confirms the efficacy and tolerability of TPF induction, followed by chemoradiation, with outcomes similar to those for patients irradiated without induction. The best potentiation of radiotherapy after induction has not yet been determined.

Discovery of a novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors.

A novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors were derived from a fragment-based approach using information from X-ray crystallographic analysis of NS5B-inhibitor complexes and iterative rounds of parallel synthesis. Structure-based drug design strategies led to the discovery of potent sub-micromolar inhibitors 11a-c and 12a-c from a weak-binding fragment-like structure 1 as a starting point.

[Adenocarcinoma of minor salivary gland origin: a recently described lesion. A case report]. / L'adénocarcinome cribriforme des glandes salivaires accessoires : une tumeur de description très récente. À propos d'une observation.

Cribriform adenocarcinoma of salivary gland origin is a rare and recently described lesion. In spite of the high incidence of metastatic spread, the prognosis remains very good. We report a case of a 64-year-old man with cribriform adenocarcinoma of salivary gland origin of the ventral tongue without locoregional or distant metastasis. The patient is currently 43-month post treatment without any local or regional recurrence of the disease. This entity should be kept in mind regarding its good prognosis and its resemblances with papillary carcinoma of the thyroid and adenoid cystic carcinoma with which it should not be confused.

Predicting acute severe toxicity for head and neck squamous cell carcinomas by combining dosimetry with a radiosensitivity biomarker: a pilot study.

OBJECTIVE: Radiotherapy (RT) against head and neck squamous cell carcinomas (HNSCC) may lead to severe toxicity in 30-40% of patients. The normal tissue complication probability (NTCP) models, based on dosimetric data refined the normal tissue dose/volume tolerance guidelines. In parallel, the radiation-induced nucleoshuttling (RIANS) of the Ataxia-Telangiectasia Mutated protein (pATM) is a predictive approach of individual intrinsic radiosensitivity. Here, we combined NTCP with RADIODTECT©, a blood assay derived from the RIANS model, to predict RT toxicity in HNSCC patients. METHODS: RADIODTECT© cutoff values (i.e. 57.8 ng/mL for grade⩾2 toxicity and 46 ng/mL for grade⩾3 toxicity) have been previously assessed. Validation was performed on a prospective cohort of 36 HNSCC patients treated with postoperative RT. Toxicity was graded with the Common Terminology Criteria for Adverse Events (CTCAE) scale and two criteria were considered: grade⩾2 oral mucositis (OM2), grade⩾3 mucositis (OM3) and grade⩾2 dysphagia (DY2), grade⩾3 dysphagia (DY3). pATM quantification was assessed in lymphocytes of HNSCC patients. The discrimination power of the pATM assay was evaluated through the Area Under the Receiver Operator Characteristics Curve (AUC-ROC). Two previously described NTCP models were considered, including the dose to the oral cavity and the mean dose to the parotid glands (OM2 and OM3) and the dose to the oral cavity, to the larynx and the volume of pharyngeal constrictor muscles (DY2 and DY3). RESULTS: Combining NTCP models with RADIODTECT© blood test improved the AUC-ROC. Considering the prediction of mucositis, AUC-ROCNTCP+RADIODTECT©=0.80 was for OM2, and AUC-ROCNTCP+RADIODTECT©=0.78 for OM3. Considering the prediction of acute dysphagia, AUC-ROCNTCP+RADIODTECT©=0.71 for DY2 and for DY3. CONCLUSIONS: Combining NTCP models with a radiosensitivity biomarker might significantly improve the prediction of toxicities for HNSCC patients.

Addictions, Social Deprivation and Cessation Failure in Head and Neck Squamous Cell Carcinoma Survivors.

AIM: To evaluate the evolution of addictions (tobacco and alcohol) and social precarity in head and neck squamous cell carcinoma survivors when these factors are addressed from the time of diagnosis. METHODS: Addictions and social precarity in patients with a new diagnosis of HNSCC were assessed through the EPICES score, the Fagerström score, and the CAGE questionnaire. When identified as precarious/dependent, patients were referred to relevant addiction/social services. RESULTS: One hundred and eighty-two patients were included. At the time of diagnosis, an active tobacco consumption was associated with alcohol drinking (Fisher's exact test, p < 0.001). Active smokers were more socially deprived (mean EPICES score = mES = 36.2 [±22.1]) than former smokers (mES = 22.8 [±17.8]) and never smokers (mES = 18.9 [±14.5]; Kruskal-Wallis, p < 0.001). The EPICES score was correlated to the Fagerström score (Kruskal-Wallis, p < 0.001). Active drinkers (mES = 34.1 [±21.9]) and former drinkers (mES = 32.7 [±21]) were more likely to be socially deprived than those who never drank (mES = 20.8 [±17.1]; Krukal-Wallis, p < 0.001). A Fagerström score improvement at one year was associated to a CAGE score improvement (Fisher's exact test, p < 0.001). Tobacco and alcohol consumption were more than halved one year after treatment. Patients who continued to smoke one year after diagnosis were significantly more likely to continue to drink (Fisher's exact test, p < 0.001) and had a significantly higher initial EPICES score (Kruskal-Wallis, p < 0.001). CONCLUSIONS: At one year, addictions and social deprivation tend to improve when taken care of from the diagnosis. The most dependent patients and those with multiple frailties are at highest risk of cessation failure.

Efficacy and safety of capecitabine in heavily pretreated recurrent/metastatic head and neck squamous cell carcinoma.

UNLABELLED: The objective of this study was to evaluate the efficacy and tolerability of capecitabine as a single agent in the treatment of recurrent/metastatic head and neck squamous cell carcinoma. Patients were treated with oral capecitabine according to good clinical practice. Efficacy and safety outcomes were analyzed retrospectively. The response and adverse events rates and their exact confidence intervals (CIs) were calculated. Survival distributions were estimated using the Kaplan-Meier method. Twenty-nine patients were included in the study. Twenty-five patients (86%) had received at least three previous lines of chemotherapy. The disease control rate was 48% (95% CI: 29-67%). The median progression-free survival was 2.0 months (95% CI: 0.1-3.9 months) and the median overall survival was 7.0 months (95% CI: 4.1-9.9 months). Hand-foot syndrome, fatigue, and mucositis were the most frequent severe side effects. No patient died, and only three patients discontinued treatment because of side effects. Capecitabine seems to be an active and well-tolerated regimen, even in heavily pretreated, frail patients. LEVEL OF EVIDENCE: 2C 'Outcomes Research'.

From benzimidazole to indole-5-carboxamide Thumb Pocket I inhibitors of HCV NS5B polymerase. Part 1: indole C-2 SAR and discovery of diamide derivatives with nanomolar potency in cell-based subgenomic replicons.

Replacement of the benzimidazole core of allosteric Thumb Pocket 1 HCV NS5B finger loop inhibitors by more lipophilic indole derivatives provided up to 30-fold potency improvements in cell-based subgenomic replicon assays. Optimization of C-2 substitution on the indole core led to the identification of analogs with EC(50)<100 nM and modulated the pharmacokinetic properties of the inhibitors based on preliminary data from in vitro ADME profiles and in vivo rat PK.

Indole 5-carboxamide Thumb Pocket I inhibitors of HCV NS5B polymerase with nanomolar potency in cell-based subgenomic replicons (part 2): central amino acid linker and right-hand-side SAR studies.

In this part 2, new indole 5-carboxamide Thumb Pocket 1 inhibitors of HCV NS5B polymerase are described. Structure-activity relationships (SAR) were explored at the central amino acid linker position and the right-hand-side of the molecule in an attempt to identify molecules with a balanced overall profile of potency (EC(50)<100 nM), physicochemical properties and ADME characteristics.

Determination of predictive factors of tracheobronchial prosthesis removal: stent brands are crucial.

OBJECTIVES: We sought to describe in a retrospective study our experience in the endoscopic management of tracheobronchial stenoses over 20 years and to determine prognostic factors of stent removal. METHODS: We analyzed the medical records of 166 patients (111 male and 55 female) who underwent the placement of a prosthesis for all causes of tracheobronchial stenosis between 1990 and 2009. RESULTS: Overall, 34% of the patients had their stents removed. The incidence of complications for the first stent was 0.08 per patient-month. One hundred five patients (63%) had no complications. In univariate analysis, stent removal was significantly linked with the stent brand. In multivariate analysis, taking into account the causes of stenosis, the stent brand appeared to be the only factor that significantly influenced stent removal. Finally, stenosis with more than 1 stent replacement was most prone to repeat endoscopies. CONCLUSIONS: Even though endoscopic stent placement is a relatively safe and effective treatment for tracheobronchial stenoses, particularly in cases with malignancy, complications led to stent removal in about one third of cases. The type of stent chosen is crucial.

Prognostic impact of extranodal extension in resected head and neck squamous cell carcinomas in the era of postoperative chemoradiation: A retrospective monocentric study.

BACKGROUND: For patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC), surgery (S) followed by radiotherapy (RT) is a standard of care. Randomized controlled trials have shown that postoperative chemoradiation (CRT) increased the locoregional control (LRC) and overall survival (OS) in patient with R1-resection margin and/or extranodal extension (ENE). ENE has been introduced in the 8th TNM staging classification since its presence has been shown to have an independent adverse prognostic impact. The data supporting this finding were however mainly collected in the pre-CRT era. OBJECTIVES: The objective of this study was to challenge the adverse prognostic factor of ENE in the era of CRT. METHODS: A retrospective cohort study was performed to evaluate patients diagnosed with LAHNSCC and undergoing a treatment by S and postoperative RT or CRT in Centre Léon Bérard, Lyon, France between 2003 and 2018. Patients with oral cavity, oropharyngeal, laryngeal and hypopharyngeal SCC were included. RESULTS: 439 patients were included in the study. For patients with non-oropharyngeal p16-positive tumors without ENE, five-year OS, local control, and regional control (RC) reached 63.7%, 86.1%, and 94.9%, respectively; corresponding figures for patients with ENE reached, 42.6%, 77.5%, and 81.1%, respectively (p-value of 0.0006, 0.167, and 0.0005). In multivariable analysis, for non-oropharyngeal p16-positive tumors, ENE remained a poor prognostic factor for OS (RR = 1.74, 95%, CI = 1.16-2.61, p = 0.0069) and RC (RR 3.60, 95% CI =: 1.64-7.87, p = 0.0013). CONCLUSION: In the era or postoperative chemoradiation, pathological ENE remains an adverse prognostic factor for OS and RC.

Proof of Concept of a Binary Blood Assay for Predicting Radiosensitivity.

Radiation therapy (RT), either alone or in combination with surgery and/or chemotherapy is a keystone of cancers treatment. Early toxicity is common, sometimes leading to discontinuation of treatment. Recent studies stressed the role of the phosphorylated ATM (pATM) protein in RT-toxicity genesis and its ability in predicting individual radiosensitivity (IRS) in fibroblasts. Here we assessed the reliability of the pATM quantification in lymphocytes to predict IRS. A first retrospective study was performed on 150 blood lymphocytes of patients with several cancer types. Patients were divided into 2 groups, according to the grade of experienced toxicity. The global quantity of pATM molecules was assessed by ELISA on lymphocytes to determine the best threshold value. Then, the binary assay was assessed on a validation cohort of 36 patients with head and neck cancers. The quantity of pATM molecules in each sample of the training cohort was found in agreement with the observed Common Terminology Criteria for Adverse Events (CTCAE) grades with an AUC = 0.71 alone and of 0.77 combined to chemotherapy information. In the validation cohort, the same test was conducted with the following performances: sensitivity = 0.84, specificity = 0.54, AUC = 0.70 and 0.72 combined to chemotherapy. This study provides the basis of an easy to perform assay for clinical use.

Discovery of benzimidazole-diamide finger loop (Thumb Pocket I) allosteric inhibitors of HCV NS5B polymerase: Implementing parallel synthesis for rapid linker optimization.

Previously described SAR of benzimidazole-based non-nucleoside finger loop (Thumb Pocket I) inhibitors of HCV NS5B polymerase was expanded. Prospecting studies using parallel synthesis techniques allowed the rapid identification of novel cinnamic acid right-hand sides that provide renewed opportunities for further optimization of these inhibitors. Novel diamide derivatives such as 44 exhibited comparable potency (enzymatic and cell-based HCV replicon) as previously described tryptophan-based inhibitors but physicochemical properties (e.g., aqueous solubility and lipophilicity) have been improved, resulting in molecules with reduced off-target liabilities (CYP inhibition) and increased metabolic stability.

N-Acetamideindolecarboxylic acid allosteric 'finger-loop' inhibitors of the hepatitis C virus NS5B polymerase: discovery and initial optimization studies.

SAR studies at the N(1)-position of allosteric indole-based HCV NS5B inhibitors has led to the discovery of acetamide derivatives with good cellular potency in subgenomic replicons (EC(50) <200 nM). This class of inhibitors displayed improved physicochemical properties and favorable ADME-PK profiles over previously described analogs in this class.

An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus.

Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality. Current interferon-based therapies are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics. The HCV-encoded NS3 protease is essential for viral replication and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.

Management of unilateral head and neck carcinoma of unknown primary: Retrospective analysis of the impact of postoperative radiotherapy target volumes.

BACKGROUND: We compared the outcome of postoperative unilateral cervical nodes radiotherapy (UL-RT) vs bilateral cervical nodes plus total mucosal irradiation (COMP-RT) in the management of head and neck carcinoma of unknown primary (HNCUP). METHODS: HNCUP, defined by the absence of primary despite a PET-CT combined with a panendoscopy, were treated with curative intent by initial ipsilateral neck dissection. Sixty-nine patients with unilateral HNCUP were included: 23 received UL-RT while 46 received COMP-RT. Carcinologic outcomes and long-term quality of life (QOL) according to the QOL Questionnaire for Head and Neck 35 were assessed. RESULTS: Within 6.3 years of median follow-up, there was no significant difference in primary tumor emergence rate (P = .68), cervical node recurrence rate (P = .34), or overall survival (P = .33) between UL-RT and COMP-RT groups. A trend toward QOL improvement was observed in the UL-RT group. CONCLUSION: UL-RT seems to provide similar outcomes as COMP-RT in unilateral HNCUP management.