Publications by authors named "Christian Simon"

202 Publications

Vaccination with a nanoparticle E7 vaccine can prevent tumor recurrence following surgery in a human papillomavirus head and neck cancer model.

Oncoimmunology 2021 Apr 13;10(1):1912473. Epub 2021 Apr 13.

Department of Urology, Lausanne University Hospital and University of Lausanne, Lausanne, Swizterland.

High-risk human papillomavirus (HPV) encoding E6/E7-HPV oncogenes are responsible for a subgroup of head and neck squamous-cell carcinoma (HNSCC) and thus therapeutic E7-vaccines may be used to control HPVHNSCC tumors. Herein we investigated the effects of an optimized nanoparticle-conjugated E7 long-peptide vaccine adjuvanted with CpG (NP-E7LP) in an orthotopic immunocompetent mouse model of HPVHNSCC which is based on injection of HPV16 E6/E7-expressing mEERL95-cells into the submental space. In absence of surgery, vaccination performed before or after tumor-cell injection decreased tumor growth or prolonged mice survival only marginally, despite the high numbers of vaccine-induced circulating E7-specific IFN-γ-secreting CD8 T-cells. This contrasts with the high-efficacy of NP-E7LP-vaccination reported in the genital and subcutaneous HPV16-E6/E7-expressing TC-1 models. Our data show that in a direct comparison, NP-E7LP-vaccination fully controlled TC-1, but not mEERL95, tumors subcutaneously growing in the flanks. Immune-cell infiltration was 10-fold higher in TC-1-tumors, than in mEERL95-tumors, suggesting that vaccine-induced CD8 T-cells can only poorly infiltrate mEERL95-tumors. Indeed, immunofluorescence staining of orthotopic mEERL95-tumors showed that CD3 T-cells are preferentially located peritumorally. However, when NP-E7LP-vaccination was performed after mEERL95-cell injection, but before resection of primary tumors, no postsurgical recurrence was observed and 100% of the mice survived until the experimental endpoint (day 70) in the NP-E7LP-vaccinated group. In contrast, we observed a 60% recurrence rate and only 35% survival in PBS-vaccinated mice. This suggests that removal of the primary tumor modified the tumor microenvironment, allowing a therapeutic effect of the vaccine-induced anti-tumor response. E7-vaccination combined with surgery may thus benefit patients with HPVHNSCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2021.1912473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049199PMC
April 2021

CD40 Agonist Targeted to Fibroblast Activation Protein α Synergizes with Radiotherapy in Murine HPV-Positive Head and Neck Tumors.

Clin Cancer Res 2021 Apr 26. Epub 2021 Apr 26.

Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland.

Purpose: The incidence of human papillomavirus-associated head and neck squamous cell carcinoma (HPV-HNSCC) is rising worldwide and although current therapeutic modalities are efficient in the majority of patients, there is a high rate of treatment failures. Thus, novel combination approaches are urgently needed to achieve better disease control in patients with HPV-HNSCC. We investigated the safety and therapeutic efficacy of a novel fibroblast activation protein (FAP)-targeted CD40 agonist (FAP-CD40) in combination with local hypofractionated radiation in a syngeneic HPV-HNSCC model.

Experimental Design: Using an established orthotopic model, we treated tumor-bearing mice with local hypofractionated radiotherapy (2 × 6 Gy) alone or in combination with a systemic administration of the FAP-CD40 antibody. Following up the mice, we evaluated the changes in the tumor microenvironment (TME) by immunofluorescence, FACS, and NanoString RNA analysis.

Results: The suboptimal radiotherapy regimen chosen failed to control tumors in the treated mice. The FAP-CD40 administered in monotherapy transiently controlled tumor growth, whereas the combined therapy induced durable complete responses in more than 80% of the tumor-bearing mice. This notable efficacy relied on the radiotherapy-induced remodeling of the TME and activation of the CD8 T-cell-cDC1 axis and was devoid of the systemic toxicity frequently associated with CD40-targeted therapy. Moreover, the robust immunologic memory developed effectively prevented tumor relapses, a common feature in patients with HNSCC.

Conclusions: Our study provides proof of concept, as well as mechanistic insights of the therapeutic efficacy of a bispecific FAP-CD40 combined with local radiotherapy in a FAP-HNSCC model increasing overall survival and inducing long-term antitumor immunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-4717DOI Listing
April 2021

Early diagnosis of HIV-1 and HIV-2 using cobas HIV-1/HIV-2 Qualitative, a novel qualitative nucleic acid amplification test for plasma, serum and dried blood spot specimens.

J Acquir Immune Defic Syndr 2021 Apr 19. Epub 2021 Apr 19.

Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; National Health Laboratory Services, Johannesburg, South Africa Labor Berlin - Charité Vivantes Services GmbH Roche Diagnostics International AG, Rotkreuz, Switzerland Roche Molecular Systems, Inc., Pleasanton, CA, USA Bioscientia Institut für Medizinische Diagnostik, Ingelheim, Germany.

Background: Nucleic acid amplification tests (NATs) minimise time from HIV infection to diagnosis, reducing transmission during acute HIV. NATs are especially useful for diagnosing HIV in children under 18 months, and discriminating between HIV-1 and HIV-2.

Methods: We evaluated the performance of the cobas HIV-1/HIV-2 Qualitative Test ("cobas HIV-1/2 Qual") for use on the on cobas 6800/8800 Systems. Results on adult plasma and serum samples, and paediatric dried blood spots were compared with recomLine HIV-1 & HIV-2 IgG serological test and COBAS AmpliPrep/COBAS TaqMan HIV-1 Qualitative Test, v2.0 ("CAP/CTM"). Genotype inclusivity and limits of detection (LOD) were determined, and sensitivity on seroconversion panels compared to Bio-Rad Geenius HIV 1/2 Confirmatory Assay, Abbott ARCHITECT HIV Ag/Ab Combo serologic test and cobas TaqScreen MPX, v2.0.

Results: Concordance of cobas HIV-1/2 Qual with the comparator serologic test and CAP/CTM was ≥99.6% with all sample types. Reactivity with all HIV genotypes was 100%. LOD in plasma samples was 14.8 copies/mL for HIV-1 group M, 12.6 copies/mL for HIV-1 group O and 27.9 copies/mL for HIV-2, with similar results for serum. Dried blood spots LOD was 255 copies/mL for HIV-1 and 984 copies/mL for HIV-2. HIV infection was detected 18.9 days and 8.5 days earlier than the confirmatory and serologic assays, respectively; and at a similar time to the NAT.

Conclusions: cobas HIV-1/2 Qual test enables early and accurate diagnosis of HIV-1 and HIV-2 in adults and children, across sample types. The assay could help avert transmission during acute HIV, simplify HIV diagnostic algorithms, and promote the survival of HIV-infected children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAI.0000000000002713DOI Listing
April 2021

Impaired prenatal motor axon development necessitates early therapeutic intervention in severe SMA.

Sci Transl Med 2021 Jan;13(578)

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Gene replacement and pre-mRNA splicing modifier therapies represent breakthrough gene targeting treatments for the neuromuscular disease spinal muscular atrophy (SMA), but mechanisms underlying variable efficacy of treatment are incompletely understood. Our examination of severe infantile onset human SMA tissues obtained at expedited autopsy revealed persistence of developmentally immature motor neuron axons, many of which are actively degenerating. We identified similar features in a mouse model of severe SMA, in which impaired radial growth and Schwann cell ensheathment of motor axons began during embryogenesis and resulted in reduced acquisition of myelinated axons that impeded motor axon function neonatally. Axons that failed to ensheath degenerated rapidly postnatally, specifically releasing neurofilament light chain protein into the blood. Genetic restoration of survival motor neuron protein (SMN) expression in mouse motor neurons, but not in Schwann cells or muscle, improved SMA motor axon development and maintenance. Treatment with small-molecule splice modifiers beginning immediately after birth in mice increased radial growth of the already myelinated axons, but in utero treatment was required to restore axonal growth and associated maturation, prevent subsequent neonatal axon degeneration, and enhance motor axon function. Together, these data reveal a cellular basis for the fulminant neonatal worsening of patients with infantile onset SMA and identify a temporal window for more effective treatment. These findings suggest that minimizing treatment delay is critical to achieve optimal therapeutic efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.abb6871DOI Listing
January 2021

Clinicopathologic implications of epithelial cell adhesion molecule expression across molecular subtypes of breast carcinoma.

J Cancer Res Ther 2020 Oct-Dec;16(6):1354-1359

Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India.

Background: Epithelial cell adhesion molecule (EpCAM), a type I transmembrane protein of the epithelial tissues and known cell adhesion molecule, has been demonstrated to have critical role in carcinogenesis. In breast cancer, EpCAM expression has been associated with poor prognosis. The expression pattern of EpCAM across molecular subtypes of breast carcinoma has been studied in patients reporting to a South Indian multispecialty tertiary care hospital. The prognostic significance of EpCAM expression pattern and probable response to therapy has also been addressed.

Materials And Methods: EpCAM expression was assessed by immunohistochemical studies on 200 breast carcinoma tissue samples of different molecular subtypes, including luminal A, luminal B, Her2Neu, and triple-negative breast cancer (TNBC). The expression was scored using the standard scoring system. A correlation was drawn with detailed clinicopathologic annotation and available outcomes data to analyze the influence of EpCAM on prognosis.

Results: EpCAM expression varied significantly in the different intrinsic subtypes of breast carcinoma. Differential expression was also established with different grades of breast carcinoma with varying levels of differentiation. We observed strong EpCAM expression in TNBC among other subtypes.

Conclusion: The differential expression of EpCAM among intrinsic subtypes of breast cancer and the correlation of EpCAM expression with high-grade breast carcinoma shown in the study have important implications in understanding the role of EpCAM and might form the basis for developing targeted therapies in breast cancer in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/jcrt.JCRT_490_20DOI Listing
December 2020

Assessing Preferences in Patients with Head and Neck Squamous Cell Carcinoma: Phase I and II of Questionnaire Development.

Cancers (Basel) 2020 Nov 30;12(12). Epub 2020 Nov 30.

Medical Oncology Unit, ASST Spedali Civili di Brescia and Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, 25123 Brescia, Italy.

Shared-decision making for head and neck squamous cell carcinoma (HNSCC) is challenged by the difficulty to integrate the patient perception of value within the framework of a multidisciplinary team approach. The aim of this study was to develop a questionnaire to assess the preferences of HNSCC patients with respect to the disease trajectory, expected treatment, and toxicities. In accordance with the standardized EORTC Quality of Life Group's methodology for the development of quality of life modules, a phase 1-2 study was envisaged. Following a systematic review of the literature, a consolidated list of 28 issues was administered through a semi-structured interview to 111 patients from 7 institutions in 5 countries. Overall, "cure of disease", "survival", and "trusting in health care professionals" were the 3 most common priorities, being chosen by 87.3%, 73.6% and 59.1% of patients, respectively. When assessing the correlation with the treatment subgroup, the issue of "being thoroughly and sincerely informed about treatments' efficacy and survival expectation" was highly prevalent in an independent manner (71.4%, 75% and 90% of patients in the follow-up, palliative and curative subgroups, respectively). Based on prespecified scoring criteria, a 24-item list was generated. Pending clinical applicability, further testing and validation of the questionnaire are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12123577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760305PMC
November 2020

Chronic Pharmacological Increase of Neuronal Activity Improves Sensory-Motor Dysfunction in Spinal Muscular Atrophy Mice.

J Neurosci 2021 01 20;41(2):376-389. Epub 2020 Nov 20.

Center for Motor Neuron Biology and Disease, Columbia University, New York, New York 10032.

Dysfunction of neuronal circuits is an important determinant of neurodegenerative diseases. Synaptic dysfunction, death, and intrinsic activity of neurons are thought to contribute to the demise of normal behavior in the disease state. However, the interplay between these major pathogenic events during disease progression is poorly understood. Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by a deficiency in the ubiquitously expressed protein SMN and is characterized by motor neuron death, skeletal muscle atrophy, as well as dysfunction and loss of both central and peripheral excitatory synapses. These disease hallmarks result in an overall reduction of neuronal activity in the spinal sensory-motor circuit. Here, we show that increasing neuronal activity by chronic treatment with the FDA-approved potassium channel blocker 4-aminopyridine (4-AP) improves motor behavior in both sexes of a severe mouse model of SMA. 4-AP restores neurotransmission and number of proprioceptive synapses and neuromuscular junctions (NMJs), while having no effects on motor neuron death. In addition, 4-AP treatment with pharmacological inhibition of p53-dependent motor neuron death results in additive effects, leading to full correction of sensory-motor circuit pathology and enhanced phenotypic benefit in SMA mice. Our study reveals that 4-AP-induced increase of neuronal activity restores synaptic connectivity and function in the sensory-motor circuit to improve the SMA motor phenotype. Spinal muscular atrophy (SMA) is a neurodegenerative disease, characterized by synaptic loss, motor neuron death, and reduced neuronal activity in spinal sensory-motor circuits. However, whether these are parallel or dependent events is unclear. We show here that long-term increase of neuronal activity by the FDA-approved drug 4-aminopyridine (4-AP) rescues the number and function of central and peripheral synapses in a SMA mouse model, resulting in an improvement of the sensory-motor circuit and motor behavior. Combinatorial treatment of pharmacological inhibition of p53, which is responsible for motor neuron death and 4-AP, results in additive beneficial effects on the sensory-motor circuit in SMA. Thus, neuronal activity restores synaptic connections and improves significantly the severe SMA phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.2142-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810663PMC
January 2021

Enhancer of Zeste Homolog 2 (EZH2) Mediates Glucolipotoxicity-Induced Apoptosis in β-Cells.

Int J Mol Sci 2020 Oct 29;21(21). Epub 2020 Oct 29.

Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.

Selective inhibition of histone deacetylase 3 (HDAC3) prevents glucolipotoxicity-induced β-cell dysfunction and apoptosis by alleviation of proapoptotic endoplasmic reticulum (ER) stress-signaling, but the precise molecular mechanisms of alleviation are unexplored. By unbiased microarray analysis of the β-cell gene expression profile of insulin-producing cells exposed to glucolipotoxicity in the presence or absence of a selective HDAC3 inhibitor, we identified Enhancer of zeste homolog 2 (EZH2) as the sole target candidate. β-Cells were protected against glucolipotoxicity-induced ER stress and apoptosis by EZH2 attenuation. Small molecule inhibitors of EZH2 histone methyltransferase activity rescued human islets from glucolipotoxicity-induced apoptosis. Moreover, EZH2 knockdown cells were protected against glucolipotoxicity-induced downregulation of the protective non-canonical Nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFκB) pathway. We conclude that EZH2 deficiency protects from glucolipotoxicity-induced ER stress, apoptosis and downregulation of the non-canonical NFκB pathway, but not from insulin secretory dysfunction. The mechanism likely involves transcriptional regulation via EZH2 functioning as a methyltransferase and/or as a methylation-dependent transcription factor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21218016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672588PMC
October 2020

L’ORL, une discipline plurivalente.

Rev Med Suisse 2020 10;16(709):1843

Service d'oto-rhino-laryngologie et de chirurgie cervico-faciale, HUG, Genève.

View Article and Find Full Text PDF

Download full-text PDF

Source
October 2020

Magnetotactic Bacteria Accumulate a Large Pool of Iron Distinct from Their Magnetite Crystals.

Appl Environ Microbiol 2020 10 28;86(22). Epub 2020 Oct 28.

Department of Plant and Microbial Biology, University of California, Berkeley, California, USA

Magnetotactic bacteria (MTB) are ubiquitous aquatic microorganisms that form intracellular nanoparticles of magnetite (FeO) or greigite (FeS) in a genetically controlled manner. Magnetite and greigite synthesis requires MTB to transport a large amount of iron from the environment. Most intracellular iron was proposed to be contained within the crystals. However, recent mass spectrometry studies suggest that MTB may contain a large amount of iron that is not precipitated in crystals. Here, we attempted to resolve these discrepancies by performing chemical and magnetic assays to quantify the different iron pools in the magnetite-forming strain AMB-1, as well as in mutant strains showing defects in crystal precipitation, cultivated at various iron concentrations. All results show that magnetite represents at most 30% of the total intracellular iron under our experimental conditions and even less in the mutant strains. We further examined the iron speciation and subcellular localization in AMB-1 using the fluorescent indicator FIP-1, which was designed for the detection of labile Fe(II). Staining with this probe suggests that unmineralized reduced iron is found in the cytoplasm and associated with magnetosomes. Our results demonstrate that, under our experimental conditions, AMB-1 is able to accumulate a large pool of iron distinct from magnetite. Finally, we discuss the biochemical and geochemical implications of these results. Magnetotactic bacteria (MTB) produce iron-based intracellular magnetic crystals. They represent a model system for studying iron homeostasis and biomineralization in microorganisms. MTB sequester a large amount of iron in their crystals and have thus been proposed to significantly impact the iron biogeochemical cycle. Several studies proposed that MTB could also accumulate iron in a reservoir distinct from their crystals. Here, we present a chemical and magnetic methodology for quantifying the iron pools in the magnetotactic strain AMB-1. Results showed that most iron is not contained in crystals. We then adapted protocols for the fluorescent Fe(II) detection in bacteria and showed that iron could be detected outside crystals using fluorescence assays. This work suggests a more complex picture for iron homeostasis in MTB than previously thought. Because iron speciation controls its fate in the environment, our results also provide important insights into the geochemical impact of MTB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AEM.01278-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642088PMC
October 2020

Minimally important differences for interpreting European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 scores in patients with head and neck cancer.

Head Neck 2020 11 6;42(11):3141-3152. Epub 2020 Jul 6.

European Organisation for Research and Treatment of Cancer (EORTC), Brussels, Belgium.

Background: We aimed to estimate minimally important difference (MID) for interpreting group-level change over time for European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (EORTC QLQ-C30) scores in head and neck cancer.

Methods: Data were derived retrospectively from two published EORTC trials. Clinical anchors were selected using correlation strength and clinical plausibility of the given anchor/QLQ-C30 scale pair. MIDs for within-group and between-group change were estimated via the mean change method and linear regression, respectively. Distribution-based MIDs were also examined. MIDs for two of the scales, dyspnea and nausea/vomiting, are more uncertain considering their low correlations with the anchors.

Results: Anchor-based MIDs could be determined for deterioration in 7 of the 14 QLQ-C30 scales assessed, and in 3 scales for improvement. MIDs varied by scale, direction of change, and anchor. Absolute MID values ranged from 5 to 15 points for within-group change and 4 to 12 for between-group change. Most MIDs were within 4 to 10 points.

Conclusions: Our findings, if confirmed, will aid interpreting changes in selected QLQ-C30 scale scores over time and inform sample size calculations in future clinical trials in head and neck cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hed.26363DOI Listing
November 2020

HBV-RNA Co-amplification May Influence HBV DNA Viral Load Determination.

Hepatol Commun 2020 Jul 26;4(7):983-997. Epub 2020 May 26.

Department of Gastroenterology, Hepatology and Endocrinology Hannover Medical School Hannover Germany.

Despite effective hepatitis B virus (HBV)-DNA suppression, HBV RNA can circulate in patients receiving nucleoside/nucleotide analogues (NAs). Current assays quantify HBV DNA by either real-time polymerase chain reaction (PCR), which uses DNA polymerase, or transcription-mediated amplification, which uses reverse-transcriptase (RT) and RNA polymerase. We assessed the effect of RT capability on HBV-DNA quantification in samples from three cohorts, including patients with quantified HBV RNA. We compared the HBV-DNA levels by real-time PCR (cobas HBV, Roche 6800/8800; Xpert HBV, Cepheid), transcription-mediated amplification (Aptima HBV, Hologic), and real-time PCR with added RT capability (cobas HBV+RT). In the first cohort (n = 45) followed over 192 weeks of NA therapy, on-treatment HBV-DNA levels were higher with cobas HBV+RT than cobas HBV (mean difference: 0.14 log IU/mL). In a second cohort (n = 50) followed over 96 weeks of NA therapy, HBV-DNA viral load was significantly higher with the cobas HBV+RT and Aptima HBV compared with the cobas HBV test at all time points after initiation of NA therapy (mean difference: 0.65-1.16 log IU/mL). A clinically significant difference was not detected between the assays at baseline. In a third cohort (n = 53), after a median of 2.2 years of NA therapy, we detected HBV RNA (median 5.6 log copies/mL) in 23 patients (43.4%). Median HBV-DNA levels by Aptima HBV were 2.4 versus less than 1 log IU/mL in samples with HBV RNA and without HBV RNA, respectively ( = 0.0006). In treated patients with HBV RNA, Aptima HBV measured higher HBV-DNA levels than Xpert HBV and cobas HBV. Tests including an RT step may overestimate HBV DNA, particularly in samples with low viral loads as a result of NA therapy. This overestimation is likely due to amplification of HBV RNA and may have an impact on clinical decisions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep4.1520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327219PMC
July 2020

A new endoscopic surgical approach to the larynx, hypopharynx, and neck lymphatics: The robotic-assisted extended "Sistrunk" approach (RESA).

Head Neck 2020 09 13;42(9):2750-2756. Epub 2020 Jun 13.

Department of Otolaryngology - Head and Neck Surgery, CHUV, University of Lausanne, Lausanne, Switzerland.

Background: We report on the feasibility of a novel robotic-assisted extended "Sistrunk" approach (RESA) to the larynx, hypopharynx, and lateral neck lymphatics.

Methods: Studies were performed using the da Vinci Xi and SP system on three cadavers comprising of three supraglottic laryngectomies, one partial hypopharyngectomy, and four lateral level II to IV neck dissections.

Results: In all resections at first a central common working space overlying the hyoid bone was created. The da Vinci Xi system was used with two vestibular and two submental ports for laryngeal/hypopharyngeal resections, and an additional port through a facelift incision for level II to IV neck dissections. The da Vinci SP system was used with only one submental port.

Conclusions: We describe herein a novel endoscopic robotic approach to the larynx, hypopharynx, and neck based on the traditional "Sistrunk" procedure. The technique should help improving exposure of the primary lesion and reduce access-related morbidity to the neck.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hed.26273DOI Listing
September 2020

Pembrolizumab given concomitantly with chemoradiation and as maintenance therapy for locally advanced head and neck squamous cell carcinoma: KEYNOTE-412.

Future Oncol 2020 Jun 3;16(18):1235-1243. Epub 2020 Jun 3.

Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.

Current treatment guidelines for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) recommend multimodal treatment, including chemoradiation therapy (CRT) or surgery followed by radiation, with or without chemotherapy. The immune checkpoint inhibitor pembrolizumab has previously demonstrated antitumor activity in recurrent and/or metastatic HNSCC in large Phase III trials. For patients with locally advanced disease, Phase Ib data on the use of pembrolizumab in combination with chemoradiation have shown the approach to be safe and feasible. We describe here the design and rationale for KEYNOTE-412, a randomized, double-blind, Phase III trial investigating pembrolizumab or placebo administered concurrently with CRT and as maintenance treatment in patients with locally advanced HNSCC. Clinical Trial Registration: NCT03040999 (ClinicalTrials.gov).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2020-0184DOI Listing
June 2020

Follow-Up of Head and Neck Cancer Survivors: Tipping the Balance of Intensity.

Front Oncol 2020 6;10:688. Epub 2020 May 6.

Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.

The traditional concept of post-treatment surveillance in head and neck cancer patients relies on examinations directed at early detection of disease recurrence and/or second primary tumors. They are usually provided by ear, nose and throat specialists with complementary input from radiation oncologists and medical oncologists. Emerging evidence underscores the importance of monitoring and effective management of late adverse events. One of the major drawbacks is a lack of prospective controlled data. As a result, local institutional policies differ, and practice recommendations are subject to continuing debate. Due to the economic burden and impact on emotional comfort of patients, intensity and content of follow-up visits are a particularly conflicting topic. According to the current evidence-based medicine, follow-up of head and neck cancer patients does not prolong survival but can improve quality of life. Therefore, an approach giving priority to a multidisciplinary care involving a speech and swallowing expert, dietician, dentist, and psychologist may indeed be more relevant. Moreover, on a case-by-case basis, some patients need more frequent consultations supplemented by imaging modalities. Human papillomavirus positive oropharyngeal cancer tends to develop late failures at distant sites, and asymptomatic oligometastatic disease, especially in the lungs, can be successfully salvaged by local ablation, either surgically or by radiation. The deep structures of the skull base related to the nasopharynx are inaccessible to routine clinical examination, advocating periodic imaging supplemented by nasofibroscopy as indicated. Anamnesis of heavy smoking justifies annual low-dose computed tomography screening of the thorax and intensive smoking cessation counseling. Finally, some cancer survivors feel more comfortable with regular imaging, and their voice should be taken into consideration. Future development of surveillance strategies will depend on several variables including identification of reliable predictive factors to select those who could derive the most benefit from follow-up visits, the availability of long-term follow-up data, the results of the first randomized trials, resource allocation patterns, infrastructure density, and the therapeutic landscape of locally advanced and recurrent and/or metastatic disease, which is rapidly changing with the advent of immune checkpoint inhibitors and better utilization of local approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2020.00688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218054PMC
May 2020

Proposal of a timing strategy for cholesteatoma surgery during the COVID-19 pandemic.

Eur Arch Otorhinolaryngol 2020 Sep 15;277(9):2619-2623. Epub 2020 May 15.

Department of Otorhinolaryngology, Head & Neck Surgery, Lausanne University Hospital, Lausanne, Switzerland.

Purpose: The COVID-19 infection is an aggressive viral illness with high risk of transmission during otolaryngology examination and surgery. Cholesteatoma is known for its potential to cause complications and scheduling of surgery during the pandemic must be done carefully. The majority of otological surgeries may be classified as elective and postponed at this time (e.g., stapedotomy, tympanoplasty); whereas, others are emergencies (e.g., complicated acute otitis media, complicated cholesteatoma with cerebral or Bezold's abscess, meningitis, sinus thrombosis) and require immediate intervention. What is the ideal time for the surgical management of Cholesteatoma during the COVID-19 pandemic?

Methods: Senior otologic surgeons from six teaching hospitals from various countries affected by the COVID-19 from around the world met remotely to make recommendations on reorganizing schedules for the treatment of cholesteatoma which has a risk of severe morbidity and mortality. The recommendations are based on their experiences and on available literature.

Results: Due to the high risk of infecting the surgical staff it is prudent to stop all elective ear surgeries and plan cholesteatoma surgery after careful selection of patients, based on the extent of the disease and available resources. Specific precautions including use of appropriate personal protection equipment should be followed when operating on all patients during the pandemic. To facilitate the decision-making in the management of cholesteatoma, timing for surgery can be divided into two categories with 3 and 2 sub-groups based on disease severity.

Conclusions: Evidence on the timing of surgery of patients with cholesteatoma during the COVID-19 pandemic is lacking. This manuscript contains practical tips on how cholesteatoma surgery can be reorganized during this pandemic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00405-020-06037-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225247PMC
September 2020

Emergency changes in international guidelines on treatment for head and neck cancer patients during the COVID-19 pandemic.

Oral Oncol 2020 08 24;107:104734. Epub 2020 Apr 24.

Brazilian Group of Head and Neck Cancer/Latin American Cooperative Group - Head and Neck, Brazil; Head and Neck Surgery Department, University of São Paulo Medical School, Sao Paulo, Brazil; Head and Neck Surgery and Otorhinolaryngology Department, A C Camargo Cancer Center, Sao Paulo, Brazil. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.oraloncology.2020.104734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180373PMC
August 2020

Best Practice in Surgical Treatment of Malignant Head and Neck Tumors.

Front Oncol 2020 12;10:140. Epub 2020 Feb 12.

Department of Otolaryngology, Head and Neck Surgery, University Leipzig, Leipzig, Germany.

Defining the best practice of surgical care for patients affected by malignant head and neck tumors is of great importance. In this review we aim to describe the evolution of "best practice" guidelines in the context of quality-of-care measures and discuss current evidence on "best practice" for the surgical treatment of cancers of the sino-nasal tract, skull base, aero-digestive tract, and the neck. Current evidence based on certain structure and outcome indicators, but mostly based on process indicators already helps defining the framework of "Best practice" for head and neck cancer surgery. However, many aspects of surgical treatment still require in-depth research. While a framework of "Best practice" strategies already exists for the conduction of the surgical treatment of head and neck cancers, many questions still require additional research in particular in case of rare histologies in the head and neck region.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2020.00140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028740PMC
February 2020

Development and validation of a multivariable prediction model for the identification of occult lymph node metastasis in oral squamous cell carcinoma.

Head Neck 2020 08 14;42(8):1811-1820. Epub 2020 Feb 14.

Department of Otolaryngology - Head and Neck Surgery, Geneva University Hospital and Faculty of Medecine of the University of Geneva, Geneva, Switzerland.

Background: There have been few recent advances in the identification of occult lymph node metastases (OLNM) in oral squamous cell carcinoma (OSCC). This study aimed to develop, compare, and validate several machine learning models to predict OLNM in clinically N0 (cN0) OSCC.

Methods: The biomarkers CD31 and PROX1 were combined with relevant histological parameters and evaluated on a training cohort (n = 56) using four different state-of-the-art machine learning models. Next, the optimized models were tested on an external validation cohort (n = 112) of early-stage (T1-2 N0) OSCC.

Results: The random forest (RF) model gave the best overall performance (area under the curve = 0.89 [95% CI = 0.8, 0.98]) and accuracy (0.88 [95% CI = 0.8, 0.93]) while maintaining a negative predictive value >95%.

Conclusions: We provide a new clinical decision algorithm incorporating risk stratification by an RF model that could significantly improve the management of patients with early-stage OSCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hed.26105DOI Listing
August 2020

Stasimon Contributes to the Loss of Sensory Synapses and Motor Neuron Death in a Mouse Model of Spinal Muscular Atrophy.

Cell Rep 2019 12;29(12):3885-3901.e5

Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA. Electronic address:

Reduced expression of the survival motor neuron (SMN) protein causes the neurodegenerative disease spinal muscular atrophy (SMA). Here, we show that adeno-associated virus serotype 9 (AAV9)-mediated delivery of Stasimon-a gene encoding an endoplasmic reticulum (ER)-resident transmembrane protein regulated by SMN-improves motor function in a mouse model of SMA through multiple mechanisms. In proprioceptive neurons, Stasimon overexpression prevents the loss of afferent synapses on motor neurons and enhances sensory-motor neurotransmission. In motor neurons, Stasimon suppresses neurodegeneration by reducing phosphorylation of the tumor suppressor p53. Moreover, Stasimon deficiency converges on SMA-related mechanisms of p53 upregulation to induce phosphorylation of p53 through activation of p38 mitogen-activated protein kinase (MAPK), and pharmacological inhibition of this kinase prevents motor neuron death in SMA mice. These findings identify Stasimon dysfunction induced by SMN deficiency as an upstream driver of distinct cellular cascades that lead to synaptic loss and motor neuron degeneration, revealing a dual contribution of Stasimon to motor circuit pathology in SMA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2019.11.058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956708PMC
December 2019

Linking glycemic dysregulation in diabetes to symptoms, comorbidities, and genetics through EHR data mining.

Elife 2019 12 10;8. Epub 2019 Dec 10.

Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.

Diabetes is a diverse and complex disease, with considerable variation in phenotypic manifestation and severity. This variation hampers the study of etiological differences and reduces the statistical power of analyses of associations to genetics, treatment outcomes, and complications. We address these issues through deep, fine-grained phenotypic stratification of a diabetes cohort. Text mining the electronic health records of 14,017 patients, we matched two controlled vocabularies (ICD-10 and a custom vocabulary developed at the clinical center Steno Diabetes Center Copenhagen) to clinical narratives spanning a 19 year period. The two matched vocabularies comprise over 20,000 medical terms describing symptoms, other diagnoses, and lifestyle factors. The cohort is genetically homogeneous (Caucasian diabetes patients from Denmark) so the resulting stratification is not driven by ethnic differences, but rather by inherently dissimilar progression patterns and lifestyle related risk factors. Using unsupervised Markov clustering, we defined 71 clusters of at least 50 individuals within the diabetes spectrum. The clusters display both distinct and shared longitudinal glycemic dysregulation patterns, temporal co-occurrences of comorbidities, and associations to single nucleotide polymorphisms in or near genes relevant for diabetes comorbidities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.44941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904221PMC
December 2019

Utility of the new cobas HCV test for viral load monitoring during direct-acting antiviral therapy.

PLoS One 2019 18;14(11):e0224751. Epub 2019 Nov 18.

Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany.

Background: The COBAS AmpliPrep/COBAS TaqMan assay HCV (CAP/CTM) is widely used in clinical routine for HCV testing. Recently, the new cobas HCV test was established for high throughput testing with minimal operator intervention. As different assays may yield different quantitative/qualitative results that possibly impact treatment decisions, the aim of this study was to externally evaluate the cobas HCV test performance in comparison to CAP/CTM in a clinically relevant setting.

Methods: Serum samples were obtained from 270 patients who received direct acting antiviral therapy with different treatment regimens at two study sites (Hannover and Frankfurt) in 2016. Overall, 1545 samples (baseline, on-treatment and follow-up) were tested in parallel by both assays.

Results: The mean difference between cobas HCV and CAP/CTM for the quantification of HCV RNA was 0.008 log10 IU/ml HCV RNA (95% limits of agreement: -0.02-0.036) showing excellent agreement of both assays. With respect to clinical cut offs (HCV RNA detectable vs. target not detected and HCV RNA above the lower limit of quantification (LLOQ) vs.
Conclusion: The performance of the new cobas HCV test was comparable to CAP/CTM in a clinical setting representing a large patient population with HCV GT 1 and 3 treated with DAAs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224751PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6860929PMC
April 2020

A Review of Controversial Issues in the Management of Head and Neck Cancer: A Swiss Multidisciplinary and Multi-Institutional Patterns of Care Study-Part 4 (Biomarkers).

Front Oncol 2019 24;9:1128. Epub 2019 Oct 24.

Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

The Head and Neck Cancer Working Group of Swiss Group for Clinical Cancer Research (SAKK) has investigated the level of consensus (LOC) and discrepancy in everyday practice of diagnosis and treatment in head and neck cancer. An online survey was iteratively generated with 10 Swiss university and teaching hospitals. LOC below 50% was defined as no agreement, while higher LOC were arbitrarily categorized as low (51-74%), moderate (75-84%), and high (≥85%). Any LOC was achieved in 62% of topics ( = 60). High, moderate, and low LOC were found in 18, 20, and 23%, respectively. Regarding Head and Neck Surgery, Radiation Oncology, Medical Oncology, and biomarkers, LOC was achieved in 50, 57, 83, and 43%, respectively. Consensus on clinical topics is rather low for surgeons and radiation oncologists. The questions discussed might highlight discrepancies, stimulate standardization of practice, and prioritize topics for future clinical research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2019.01128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822019PMC
October 2019

A Review of Controversial Issues in the Management of Head and Neck Cancer: A Swiss Multidisciplinary and Multi-Institutional Patterns of Care Study-Part 3 (Medical Oncology).

Front Oncol 2019 24;9:1127. Epub 2019 Oct 24.

Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

The Head and Neck Cancer Working Group of Swiss Group for Clinical Cancer Research (SAKK) has investigated the level of consensus (LOC) and discrepancy in everyday practice of diagnosis and treatment in head and neck cancer. An online survey was iteratively generated with 10 Swiss university and teaching hospitals. LOC below 50% was defined as no agreement, while higher LOC were arbitrarily categorized as low (51-74%), moderate (75-84%), and high (≥85%). Any LOC was achieved in 62% of topics ( = 60). High, moderate, and low LOC were found in 18, 20, and 23%, respectively. Regarding Head and Neck Surgery, Radiation Oncology, Medical Oncology, and biomarkers, LOC was achieved in 50, 57, 83, and 43%, respectively. Consensus on clinical topics is rather low for surgeons and radiation oncologists. The questions discussed might highlight discrepancies, stimulate standardization of practice, and prioritize topics for future clinical research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2019.01127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822020PMC
October 2019

A Review of Controversial Issues in the Management of Head and Neck Cancer: A Swiss Multidisciplinary and Multi-Institutional Patterns of Care Study-Part 2 (Radiation Oncology).

Front Oncol 2019 24;9:1126. Epub 2019 Oct 24.

Department of Radiation Oncology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.

The Head and Neck Cancer Working Group of Swiss Group for Clinical Cancer Research (SAKK) has investigated the level of consensus (LOC) and discrepancy in everyday practice of diagnosis and treatment in head and neck cancer. An online survey was iteratively generated with 10 Swiss university and teaching hospitals. LOC below 50% was defined as no agreement, while higher LOC were arbitrarily categorized as low (51-74%), moderate (75-84%), and high (≥85%). Any LOC was achieved in 62% of topics ( = 60). High, moderate, and low LOC were found in 18, 20, and 23%, respectively. Regarding Head and Neck Surgery, Radiation Oncology, Medical Oncology, and biomarkers, LOC was achieved in 50, 57, 83, and 43%, respectively. Consensus on clinical topics is rather low for surgeons and radiation oncologists. The questions discussed might highlight discrepancies, stimulate standardization of practice, and prioritize topics for future clinical research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2019.01126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822015PMC
October 2019

A Review of Controversial Issues in the Management of Head and Neck Cancer: A Swiss Multidisciplinary and Multi-Institutional Patterns of Care Study-Part 1 (Head and Neck Surgery).

Front Oncol 2019 24;9:1125. Epub 2019 Oct 24.

Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

The Head and Neck Cancer Working Group of Swiss Group for Clinical Cancer Research (SAKK) has investigated the level of consensus (LOC) and discrepancy in everyday practice of diagnosis and treatment in head and neck cancer. An online survey was iteratively generated with 10 Swiss university and teaching hospitals. LOC below 50% was defined as no agreement, while higher LOC were arbitrarily categorized as low (51-74%), moderate (75-84%), and high (≥85%). Any LOC was achieved in 62% of topics ( = 60). High, moderate and low LOC were found in 18, 20, and 23%, respectively. Regarding Head and Neck Surgery, Radiation Oncology, Medical Oncology, and biomarkers, LOC was achieved in 50, 57, 83, and 43%, respectively. Consensus on clinical topics is rather low for surgeons and radiation oncologists. The questions discussed might highlight discrepancies, stimulate standardization of practice, and prioritize topics for future clinical research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2019.01125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822016PMC
October 2019

Organ Preservation and Late Functional Outcome in Oropharyngeal Carcinoma: Rationale of EORTC 1420, the "Best of" Trial.

Front Oncol 2019 22;9:999. Epub 2019 Oct 22.

Service d'Oto-Rhino-Laryngologie - Chirurgie Cervico-Faciale, Centre Hospitalier Universitaire Vaudois (CHUV), Université de Lausanne (UNIL), Lausanne, Switzerland.

Dysphagia represents one of the most serious adverse events after curative-intent treatments with a tremendous impact on quality of life in patients with head and neck cancers. Novel surgical and radiation therapy techniques have been developed to better preserve swallowing function, while not negatively influencing local control and/or overall survival. This review focuses on the current literature of swallowing outcomes after curative treatment strategies. Available results from recent studies relevant to this topic are presented, demonstrating the potential role of new treatment modalities for early- and intermediate-stage oropharyngeal cancers. Based on this, we present the rationale and design of the currently active EORTC 1420 "Best of" trial, and highlight the potential of this study to help prioritizing either surgery- or radiation-based treatment modalities for the treatment of oropharyngeal cancer in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2019.00999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817682PMC
October 2019

[Thyroid nodules and thyroid differentiated cancers: an update on diagnosis and surgical management.]

Rev Med Suisse 2019 Oct;15(665):1752-1759

Service d'oto-rhino-laryngologie et chirurgie cervico-faciale, CHUV et Université de Lausanne, 1011 Lausanne.

The incidence of differentiated thyroid cancers has increased in the past 30 years, mainly due to overdiagnosis. It is therefore crucial to adapt diagnostic and therapeutic approaches to avoid overtreatment that exposes patients to unnecessary risks. Accordingly, international guidelines on the subject are regularly updated. Ultrasound and cytology guide the management for thyroid nodules. Some microcarcinomas can now be actively followed without immediate surgery, and some low-risk cancers can be adequately treated with lobo-isthmectomy. The indications for central neck dissection remain controversial. Technological advances allow minimizing specific complications of thyroid surgery and facilitate scarless surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
October 2019

Nouveautés dans les prises en charge des pathologies de la sphère ORL.

Rev Med Suisse 2019 Oct;15(665):1735

Médecin-chef, Service d'ORL et de chirurgie cervico-faciale, HUG, Genève.

View Article and Find Full Text PDF

Download full-text PDF

Source
October 2019