Microenvironment-driven intratumoral heterogeneity in head and neck cancers: clinical challenges and opportunities for precision medicine.

Squamous cell carcinoma of the head and neck (SCCHN) is among the most prevalent cancer types worldwide. Despite multimodal therapeutic approaches that include surgical resection, radiation therapy or concurrent chemoradiation, targeted therapy and immunotherapy, SCCHN is still associated with a poor prognosis for patients with locally advanced or recurrent/metastatic (R/M) diseases. Although next-generation sequencing data from thousands of SCCHN patients have provided a comprehensive landscape of the somatic genomic alterations in this disease, genomic-based precision medicine is not implemented yet in routine clinical use since no satisfactory genetic biomarker has been identified for diagnosis, patient outcome prediction and selection of tailored therapeutic options. The lack of significant improvement in SCCHN patient survival over the last decades stresses the need for reliable predictive biomarkers and new therapeutic strategies for personalized clinical management of SCCHN patients. Targeting the SCCHN-associated microenvironment or the interaction of the latter with cancer cells may represent such paradigm shift in the development of new strategies to treat SCCHN patients, as exemplified by the recent implementation of immune checkpoint inhibitors to improve clinical outcomes by increasing anti-tumor immune responses in SCCHN patients. Several clinical trials are in progress in SCCHN patients to evaluate the activity of monoclonal antibodies and small-molecule inhibitors targeting the tumor microenvironment (TME) at different treatment settings, including combinations with adjuvant surgery, radiation therapy and chemotherapy. This review describes the current knowledge about the influence of the TME on intratumoral heterogeneity and clinical relapse in human SCCHN patients. More precisely, the role of hypoxia as well as the presence of non-cancer cells (e.g. cancer-associated fibroblasts and immune cells) on therapy response of SCCHN cells is highlighted. We also discuss relevant (pre)clinical models that may help integrate the microenvironment-tumor cell interplay in translational research studies for SCCHN. Finally, this review explores potential therapeutic strategies that may exploit the crosstalk between TME and SCCHN cells in order to implement fundamental changes in the tumor treatment paradigm of patients with locally advanced or R/M SCCHN.

[Work Participation after Multimodal Rehabilitation due to Neurological Diseases - Representative Analyses Using Routine Data of the German Pension Insurance]. / Berufliche Teilhabe nach einer medizinischen Rehabilitation aufgrund neurologischer Erkrankungen.

PURPOSE: There is little representative evidence for the German rehabilitation system on occupational reintegration after medical rehabilitation. For persons who have undergone rehabilitation on behalf of the German Pension Insurance (GPI) due to a neurological disease, it is therefore important to determine (a) what socio-medical risks exist prior to rehabilitation, (b) how well persons were able to participate in working life after rehabilitation, and (c) what conditions determine the work participation. METHODS: The study is conducted on the basis of the GPI's database of rehabilitation statistics. Included were all persons, who completed medical rehabilitation in 2016 due to a neurological disease. The analyses were carried out for the entire group and also in a differentiated manner for the 2 main diseases, cerebrovascular diseases (CD) and multiple sclerosis (MS). Work participation was operationalized both via a monthly status variable until 24 months after rehabilitation and as a rate of all persons who were employed at the 12 and 24 months follow up and in the 3 months before, respectively. To analyse the factors influencing stable work participation, multiple logistic regression models with stepwise inclusion were calculated separately for the rates after 12 and 24 months. RESULTS: A total of 42,230 data sets were included in the analysis (CD: n=18,368, 44%; MS: n=6,343, 15%). Patients with neurological diseases were 50 years old on average, 43% were female. We found that approximately15% of patients reported no absenteeism, whereas 17% stated an absence leave of six months or more in the year prior to rehabilitation. Mental and cardiovascular comorbidity was documented in 31 and 44% of the cases respectively. Nearly 48% of patients with CD returned to work two years after rehabilitation. For MS patients, the percentage was slightly higher at 54%. The amount of sick leave of the rehabilitated individual, their gross/net income prior to rehabilitation as well their work capacity prior to admission were the three strongest influencing factors on their return to the labour market. CONCLUSION: About half of all persons with neurological diseases return to sustainable work after medical rehabilitation in Germany. The amount of sick leave and the income before rehabilitation are determining factors as to whether the person will return to work. The analysis provides representative data on occupational reintegration after medical rehabilitation due to a neurological disease for the first time.

BRACHYURY directs histone acetylation to target loci during mesoderm development.

T-box transcription factors play essential roles in multiple aspects of vertebrate development. Here, we show that cooperative function of BRACHYURY (T) with histone-modifying enzymes is essential for mouse embryogenesis. A single point mutation (TY88A) results in decreased histone 3 lysine 27 acetylation (H3K27ac) at T target sites, including the T locus, suggesting that T autoregulates the maintenance of its expression and functions by recruiting permissive chromatin modifications to putative enhancers during mesoderm specification. Our data indicate that T mediates H3K27ac recruitment through a physical interaction with p300. In addition, we determine that T plays a prominent role in the specification of hematopoietic and endothelial cell types. Hematopoietic and endothelial gene expression programs are disrupted in TY88A mutant embryos, leading to a defect in the differentiation of hematopoietic progenitors. We show that this role of T is mediated, at least in part, through activation of a distal Lmo2 enhancer.

Long-term outcome of surgical excision for treatment of cervicofacial granulomatous lymphadenitis in children.

PURPOSE: Granulomatous inflammation is a common cause of subacute cervicofacial lymphadenitis in children. Nontuberculous mycobacterial (NTM) infections and cat-scratch disease (CSD) are the most frequent causes. Optimal treatment, which may include surgery, antibiotic treatment or wait-and-see approach, is debatable. The goal of this study was to compare the short- and long-term outcome of various surgical procedures. METHODS: Case series with a chart review of all children treated by surgical excision of granulomatous lymph nodes in the cervicofacial area from 2000 to 2016 at two tertiary care centers. RESULTS: Forty patients were included in this study. The median age at first symptoms was 3.7 years (13 months-14 years). Mean follow-up was 5.8 years (6 months-15.3 years). 25 patients fit with diagnosis of NTM infection, 6 with CSD while diagnosis remained uncertain in 9 patients. The primary surgical procedure consisted of total excision (n = 27), incision/drainage (n = 9) or incomplete excision (n = 4). None of the patients treated by primary complete excision needed further intervention contrary to the group of patients with incomplete surgical procedures where additional surgical management was required in 54%. At follow-up, all patients were healthy without evidence of recurrence. CONCLUSION: We advocate early surgical intervention with complete excision to reach quick resolution and reduce the need for additional surgery. The long-term outcome was favorable.

Mechanisms of long noncoding RNA function in development and disease.

Since decades it has been known that non-protein-coding RNAs have important cellular functions. Deep sequencing recently facilitated the discovery of thousands of novel transcripts, now classified as long noncoding RNAs (lncRNAs), in many vertebrate and invertebrate species. LncRNAs are involved in a wide range of cellular mechanisms, from almost all aspects of gene expression to protein translation and stability. Recent findings implicate lncRNAs as key players of cellular differentiation, cell lineage choice, organogenesis and tissue homeostasis. Moreover, lncRNAs are involved in pathological conditions such as cancer and cardiovascular disease, and therefore provide novel biomarkers and pharmaceutical targets. Here we discuss examples illustrating the versatility of lncRNAs in gene control, development and differentiation, as well as in human disease.

Randomized Phase II Study of Cabazitaxel Versus Methotrexate in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck Previously Treated With Platinum-Based Therapy.

LESSONS LEARNED: Cabazitaxel has activity in squamous cell carcinoma of the head and neck (SCCHN) and taxane-resistant cell lines. For the first time, cabazitaxel was investigated in incurable patients with recurrent SCCHN. Patients were randomly assigned to cabazitaxel every 3 weeks or weekly methotrexate.This phase II study did not meet its primary endpoint.Cabazitaxel has low activity in SCCHN.The toxicity profile in this population also was not favorable owing to the high rate of febrile neutropenia observed (17%). BACKGROUND: Cabazitaxel is a second-generation taxane that improves the survival of patients with metastatic castrate-resistant prostate cancer following docetaxel therapy. Cabazitaxel has activity in squamous cell carcinoma of the head and neck (SCCHN) and taxane-resistant cell lines. In this randomized phase II trial, we investigated cabazitaxel in patients with recurrent SCCHN. METHODS: Patients with incurable SCCHN with progression after platinum-based therapy were randomly assigned to cabazitaxel every 3 weeks (cycle 1, 20 mg/m2, increased to 25 mg/m2 for subsequent cycles in the absence of nonhematological adverse events [AEs] greater than grade 2 and hematological AEs greater than grade 3) or methotrexate (40 mg/m2/week). The patients were stratified according to their performance status and previous platinum-based chemotherapy for palliation versus curative intent. The primary endpoint was the progression-free survival rate (PFSR) at 18 weeks. RESULTS: Of the 101 patients, 53 and 48, with a median age of 58.0 years (range, 41-80), were randomly assigned to cabazitaxel or methotrexate, respectively. The PFSR at 18 weeks was 13.2% (95% confidence interval [CI], 5%-25%) for cabazitaxel and 8.3% (95% CI, 2%-20%) for methotrexate. The median progression-free survival was 1.9 months in both arms. The median overall survival was 5.0 and 3.6 months for cabazitaxel and methotrexate, respectively. More patients experienced serious adverse events with cabazitaxel than with methotrexate (54% vs. 36%). The most common drug-related grade 3-4 AE in the cabazitaxel arm was febrile neutropenia (17.3%). CONCLUSION: This study did not meet its primary endpoint. Cabazitaxel has low activity in recurrent SCCHN.

Epigenetic Regulation of Angiogenesis by JARID1B-Induced Repression of HOXA5.

OBJECTIVE: Altering endothelial biology through epigenetic modifiers is an attractive novel concept, which is, however, just in its beginnings. We therefore set out to identify chromatin modifiers important for endothelial gene expression and contributing to angiogenesis. APPROACH AND RESULTS: To identify chromatin modifying enzymes in endothelial cells, histone demethylases were screened by microarray and polymerase chain reaction. The histone 3 lysine 4 demethylase JARID1B was identified as a highly expressed enzyme at the mRNA and protein levels. Knockdown of JARID1B by shRNA in human umbilical vein endothelial cells attenuated cell migration, angiogenic sprouting, and tube formation. Similarly, pharmacological inhibition and overexpression of a catalytic inactive JARID1B mutant reduced the angiogenic capacity of human umbilical vein endothelial cells. To identify the in vivo relevance of JARID1B in the vascular system, Jarid1b knockout mice were studied. As global knockout results in increased mortality and developmental defects, tamoxifen-inducible and endothelial-specific knockout mice were generated. Acute knockout of Jarid1b attenuated retinal angiogenesis and endothelial sprout outgrowth from aortic segments. To identify the underlying mechanism, a microarray experiment was performed, which led to the identification of the antiangiogenic transcription factor HOXA5 to be suppressed by JARID1B. Importantly, downregulation or inhibition of JARID1B, but not of JARID1A and JARID1C, induced HOXA5 expression in human umbilical vein endothelial cells. Consistently, chromatin immunoprecipitation revealed that JARID1B occupies and reduces the histone 3 lysine 4 methylation levels at the HOXA5 promoter, demonstrating a direct function of JARID1B in endothelial HOXA5 gene regulation. CONCLUSIONS: JARID1B, by suppressing HOXA5, maintains the endothelial angiogenic capacity in a demethylase-dependent manner.

Targeting the Tumor Environment in Squamous Cell Carcinoma of the Head and Neck.

OPINION STATEMENT: The survival rate for patients with advanced stages of squamous cell carcinoma of the head and neck (SCCHN) remains poor despite multimodal treatment options. Cetuximab, an anti-EGFR inhibitor, is the only FDA-approved targeted agent for this disease. Recent findings have implicated modifications of the microenvironment and, consequently, phenotypical modifications of the cancer cell, in treatment resistance mechanisms. For many years, cancer research has focused mainly on targetable sites on or inside the cancer cell. Nowadays, in preclinical and clinical studies, a greater emphasis is being placed on drugs that target the tumor microenvironment. Potential targets relate to tumor vascularization, immunology, extracellular matrix components, or cancer-associated fibroblasts. The combination of these new agents with standard treatment options is of particular interest to overcome resistance mechanisms and/or to increase treatment efficacy. Whereas antiangiogenic agents show poor clinical activity, immunotherapy seems to be a more promising tool with an objective response rate (ORR) of 20 % in patients with recurrent and/or metastatic squamous cell carcinoma (R/M SCC). Other targets, located inside the extracellular matrix or on cancer associated fibroblasts, are under preclinical investigation. These new agents all need to be tested in clinical trials alone, or in combination with standard treatment modalities, based on preclinical data. To increase our knowledge of the complex network between the cancer cell and its environment, preclinical studies should consider co-culture models, and clinical studies should incorporate a translational research objective.

The histone demethylase Jarid1b ensures faithful mouse development by protecting developmental genes from aberrant H3K4me3.

Embryonic development is tightly regulated by transcription factors and chromatin-associated proteins. H3K4me3 is associated with active transcription and H3K27me3 with gene repression, while the combination of both keeps genes required for development in a plastic state. Here we show that deletion of the H3K4me2/3 histone demethylase Jarid1b (Kdm5b/Plu1) results in major neonatal lethality due to respiratory failure. Jarid1b knockout embryos have several neural defects including disorganized cranial nerves, defects in eye development, and increased incidences of exencephaly. Moreover, in line with an overlap of Jarid1b and Polycomb target genes, Jarid1b knockout embryos display homeotic skeletal transformations typical for Polycomb mutants, supporting a functional interplay between Polycomb proteins and Jarid1b. To understand how Jarid1b regulates mouse development, we performed a genome-wide analysis of histone modifications, which demonstrated that normally inactive genes encoding developmental regulators acquire aberrant H3K4me3 during early embryogenesis in Jarid1b knockout embryos. H3K4me3 accumulates as embryonic development proceeds, leading to increased expression of neural master regulators like Pax6 and Otx2 in Jarid1b knockout brains. Taken together, these results suggest that Jarid1b regulates mouse development by protecting developmental genes from inappropriate acquisition of active histone modifications.

Jarid1b targets genes regulating development and is involved in neural differentiation.

H3K4 methylation is associated with active transcription and in combination with H3K27me3 thought to keep genes regulating development in a poised state. The contribution of enzymes regulating trimethylation of lysine 4 at histone 3 (H3K4me3) levels to embryonic stem cell (ESC) self-renewal and differentiation is just starting to emerge. Here, we show that the H3K4me2/3 histone demethylase Jarid1b (Kdm5b/Plu1) is dispensable for ESC self-renewal, but essential for ESC differentiation along the neural lineage. By genome-wide location analysis, we demonstrate that Jarid1b localizes predominantly to transcription start sites of genes encoding developmental regulators, of which more than half are also bound by Polycomb group proteins. Virtually all Jarid1b target genes are associated with H3K4me3 and depletion of Jarid1b in ESCs leads to a global increase of H3K4me3 levels. During neural differentiation, Jarid1b-depleted ESCs fail to efficiently silence lineage-inappropriate genes, specifically stem and germ cell genes. Our results delineate an essential role for Jarid1b-mediated transcriptional control during ESC differentiation.

Dynamic contrast-enhanced computed tomography to assess early activity of cetuximab in squamous cell carcinoma of the head and neck.

BACKGROUND: Cetuximab, a monoclonal antibody targeting the Epidermal Growth Factor Receptor (EGFR), has demonstrated activity in various tumor types. Using dynamic contrast-enhanced computed tomography (DCE-CT), we investigated the early activity of cetuximab monotherapy in previously untreated patients with squamous cell carcinoma of the head and neck (SCCHN). METHODS: Treatment-naïve patients with SCCHN received cetuximab for 2 weeks before curative surgery. Treatment activity was evaluated by DCE-CT at baseline and before surgery. Tumor vascular and interstitial characteristics were evaluated using the Brix two-compartment kinetic model. Modifications of the perfusion parameters (blood flow Fp, extravascular space ve, vascular space vp, and transfer constant PS) were assessed between both time points. DCE data were compared to FDG-PET and histopathological examination obtained simultaneously. Plasmatic vascular markers were investigated at different time points. RESULTS: Fourteen patients had evaluable DCE-CT parameters at both time points. A significant increase in the extravascular extracellular space ve accessible to the tracer was observed but no significant differences were found for the other kinetic parameters (Fp, vp or PS). Significant correlations were found between DCE parameters and the other two modalities. Plasmatic VEGF, PDGF-BB and IL-8 decreased as early as 2 hours after cetuximab infusion. CONCLUSIONS: Early activity of cetuximab on tumor interstitial characteristics was detected by DCE-CT. Modifications of plasmatic vascular markers are not sufficient to confirm anti-angiogenic cetuximab activity in vivo. Further investigation is warranted to determine to what extent DCE-CT parameters are modified and to evaluate whether they are able to predict treatment outcome.

The role of neck dissection in squamous cell carcinoma of the head and neck.

ORIGINAL STATEMENT: Lymph node metastases in the neck are a major prognostic factor in patients with head and neck squamous cell carcinoma (HNSCC). Assessment and treatment of lymph nodes in the neck are of utmost importance. Inappropriate management of lymph node metastases can result in regional failure. Radical neck dissection has been and is still considered the "gold standard" for the surgical management of lymph node metastases of HNSCC. However, the philosophy of treatment of the neck has evolved during the last decades. Surgeons progressively realized that extensive neck dissections were associated with a higher morbidity but not always with a better oncologic outcome than more limited procedures. Today, a comprehensive therapeutic approach of the neck is multidisciplinary, taking into account the patient's quality of life without jeopardizing cure and survival. A better understanding of the patterns of lymph node metastasis promoted the use of selective neck dissection in selected patients. Sentinel lymph node biopsy is a reliable diagnostic procedure for staging the neck in node-negative early oral cavity squamous cell carcinoma. With increasing use of chemoradiation in locally advanced HNSCC, paradigms are evolving. Currently, there are strong arguments supporting the position that neck dissection is no longer justified in patients without clinically residual disease in the neck.

Tongue, larynx and esophageal leishmaniosis in an immunocompetent patient: a case report with description of imaging findings and discussion of current literature: A case of multifocal mucosal leishmaniosis.

Mucosal leishmaniosis (ML) is a rare manifestation of leishmaniosis, usually caused by Leishmania brasiliensis in northeast Brazil and by Leishmania infantum and Leishmania donovani in the Mediterranean Europe and Africa. We present the case of a 66-year-old man living between Belgium and Congo, presenting with dysphonia for several months. Imaging work-up with PET-CE, CT scan, and MRI of the tongue, larynx, and esophagus reflected inflammatory and granulomatous tissue, confirmed at the biopsy. The histological examination confirmed the presence of inflammatory granulomatous tissue with Donovan bodies in the tongue, larynx, and esophageal specimens, in keeping with multifocal ML. In conclusion, inflammatory and granulomatous mucosal lesions in individuals leaving or traveling in endemic areas should prompt suspect ML. Imaging can facilitate the appropriate histological and biological examination and nonivasively confirm the response to antiparasitic treatment on follow-up.

Study of the PD-L1 expression, T-cells density and immunoscore in paired baseline tumor biopsies and surgical specimens in squamous cell carcinoma of the oral cavity.

OBJECTIVES: Primary objective was to evaluate the correlation between immune marker expression in baseline tumor biopsies and their respective surgical specimens in squamous cell carcinoma of the oral cavity (OCSCC). Secondary objective was to assess the impact of these markers on overall (OS) and disease-free survival (DFS). MATERIALS AND METHODS: Patients with a histological diagnosis of oral squamous cell carcinoma treated surgically between 2012 and 2020 were included in this retrospective, translational monocentric study. The expression of PD-L1, T-cells markers and an OCSCC-adapted immunoscore were evaluated by multiplex immunohistochemistry. RESULTS: One hundred and four patients (mean: 58 years) were included. Seventy patients had paired samples available. Poor correlation was highlighted for PD-L1-positive surface expression (r = 0.29) and combined positive score (CPS). For CPS ≥ 20 and CPS ≥ 1, correlation coefficient r was 0.24 and 0.46 respectively. T-cells density showed also poor correlation with a r of 0.57 and 0.31 for CD3 and CD8 T-cells, respectively. Univariate survival analyses showed significant better OS and DFS (P < 0.05) for patients with stage III-IV OCSCC with a high compared to a low immunoscore, based on surgical samples only. CONCLUSION: Our study showed poor correlation in PD-L1 expression, CPS, T-cells density and immunoscore between baseline tumor biopsies and surgical resection specimens. In addition, the immunoscore may emerge as a potential prognostic factor in advanced squamous cell carcinoma of the oral cavity. If surgical specimens are available, they may be of interest for clinical practice decision.

Specific erythroid-lineage defect in mice conditionally deficient for Mediator subunit Med1.

The Mediator complex forms the bridge between transcriptional activators and the RNA polymerase II. Med1 (also known as PBP or TRAP220) is a key component of Mediator that interacts with nuclear hormone receptors and GATA transcription factors. Here, we show dynamic recruitment of GATA-1, TFIIB, Mediator, and RNA polymerase II to the ß-globin locus in induced mouse erythroid leukemia cells and in an erythropoietin-inducible hematopoietic progenitor cell line. Using Med1 conditional knockout mice, we demonstrate a specific block in erythroid development but not in myeloid or lymphoid development, highlighted by the complete absence of ß-globin gene expression. Thus, Mediator subunit Med1 plays a pivotal role in erythroid development and in ß-globin gene activation.

Hyoepiglottic Rheumatoid Nodule Mimicking Head and Neck Malignancy on 18 F-FDG PET/CT.

ABSTRACT: A 54-year-old man with a history of tonsillar squamous cell carcinoma treated with chemoradiotherapy and an 18-year history of seropositive rheumatoid arthritis in remission without maintenance therapy presented with right cervical pain and dysphagia for several months. Flexible laryngoscopy did not show any lesion, and MRI revealed a necrotic lesion inside the thyro-hyo-epiglottic space attached to the hyoid bone. 18 F-FDG PET/CT demonstrated a moderately increased metabolic activity of the lesion without any other suspected lesions. Surgical resection was performed, and pathology revealed a necrotizing granuloma compatible with a rheumatoid nodule.

Traumatic ulcerative granuloma with stromal eosinophilia (TUGSE): Case report of a 63-year-old male patient with a rare self-healing oral mucosal lesion.

Traumatic Ulcerative Granuloma with Stromal Eosinophilia (TUGSE)/Riga Fede disease is a rare mucosal and submucosal benign reactive inflammatory process, usually involving the tongue. Trauma is believed to be a major factor amongst the multiple pathogenic mechanisms that have been hypothesized in TUGSE. The lesion presents as an isolated indurated or even ulcerated mass, which may mimic, clinically a squamous cell carcinoma (SCC). We herein report a case of TUGSE in a 63-year-old male referred by his treating physician for high suspicion of tongue malignancy. Histopathological examination confirmed the diagnosis of TUGSE, without any evidence of a neoplasic, infectious or hematologic process. TUGSE occurs in patients with an age range of 41-60 years. Sufficiently deep biopsies with comprehensive immunohistochemical and molecular analyses are mandatory to confirm the benign nature of the lesion and to, definitely, rule out malignancy. This report highlights the need for adequate histological differential diagnosis to avoid inappropriate heavy treatments in a benign condition.

Comparable Accuracy of Quantitative and Visual Analyses of [18F]FDG PET/CT for the Detection of Lymph Node Metastases from Head and Neck Squamous Cell Carcinoma.

BACKGROUND: In head and neck squamous cell carcinoma (HNSCC), [18F]FDG PET/CT is recommended for detecting recurrent disease and in the initial staging for evaluating distant metastases, but its use in detecting cervical lymph metastases remains unclear. The aim of this study is to evaluate and compare the diagnostic accuracy of [8F]FDG-PET/CT using visual and semi-quantitative analyses for detecting the nodal involvement in HNSCC. METHODS: We analyzed consecutive patients who underwent a preoperative [18F]FDG-PET/CT and neck dissection for HNSCC at our tertiary hospital. A blinded evaluation of the [18F]FDG uptake in each neck level was performed using a semi-quantitative approach (SUVmax and SUVR) and a visual grading system (uptake superior to the internal jugular vein for grade 1 and superior to the liver for grade 2). Analyses were compared to the histological results. RESULTS: In our 211 patients, analyses demonstrated similar diagnostic accuracy using a semi-quantitative approach or a visual grading system. Regarding the visual grading system, [18F]FDG-PET/CT detected nodal metastases with a specificity of 83% for lymph nodes classified as grade 1 and 98% for those classified as grade 2. The sensitivity was moderate, ranging from 60 to 63%. CONCLUSIONS: [18F]FDG PET/CT has a high specificity for detecting lymph node metastases in HNSCC and therefore must be considered in the nodal clinical staging.

eHealth for maintenance cardiovascular rehabilitation: a systematic review and meta-analysis.

AIMS: To provide a quantitative analysis of eHealth-supported interventions on health outcomes in cardiovascular rehabilitation (CR) maintenance (phase III) in patients with coronary artery disease (CAD) and to identify effective behavioural change techniques (BCTs). METHODS AND RESULTS: A systematic review was conducted (PubMed, CINAHL, MEDLINE, and Web of Science) to summarize and synthesize the effects of eHealth in phase III maintenance on health outcomes including physical activity (PA) and exercise capacity, quality of life (QoL), mental health, self-efficacy, clinical variables, and events/rehospitalization. A meta-analysis following the Cochrane Collaboration guidelines using Review Manager (RevMan5.4) was performed. Analyses were conducted differentiating between short-term (≤6 months) and medium/long-term effects (>6 months). Effective behavioural change techniques were defined based on the described intervention and coded according to the BCT handbook. Fourteen eligible studies (1497 patients) were included. eHealth significantly promoted PA (SMD = 0.35; 95%CI 0.02-0.70; P = 0.04) and exercise capacity after 6 months (SMD = 0.29; 95%CI 0.05-0.52; P = 0.02) compared with usual care. Quality of life was higher with eHealth compared with care as usual (SMD = 0.17; 95%CI 0.02-0.32; P = 0.02). Systolic blood pressure decreased after 6 months with eHealth compared with care as usual (SMD = -0.20; 95%CI -0.40-0.00; P = 0.046). There was substantial heterogeneity in the adapted BCTs and type of intervention. Mapping of BCTs revealed that self-monitoring of behaviour and/or goal setting as well as feedback on behaviour were most frequently included. CONCLUSION: eHealth in phase III CR is effective in stimulating PA and improving exercise capacity in patients with CAD while increasing QoL and decreasing systolic blood pressure. Currently, data of eHealth effects on morbidity, mortality, and clinical outcomes are scarce and should be investigated in future studies. REGISTRATION: PROSPERO: CRD42020203578.

KEY FINDINGS: • eHealth interventions in cardiovascular rehabilitation maintenance may be used to increase physical activity and exercise capacity as well as quality of life while reducing systolic blood pressure.• Effective behavioural change techniques used in eHealth interventions may include self-monitoring of behaviour, goal setting, and feedback on behaviour; thus, future studies are needed to define effective eHealth components based on behavioural change theories and associated behavioural change techniques to assist patients with coronary artery disease.

• This paper reviews the impact of eHealth-supported interventions on health outcomes during cardiovascular rehabilitation maintenance phase III for patients with coronary artery disease, with a meta-analysis performed to differentiate between short-term (≤6 months) and medium/long-term effects (>6 months).

Tumor Microenvironment Modifications Induced by Afatinib in Squamous Cell Carcinoma of the Head and Neck: A Window-of-Opportunity Study (EORTC-90111-24111).

PURPOSE: The EORTC-90111-24111 phase II window study evaluated afatinib versus no preoperative treatment in patients with primary squamous cell carcinoma of the head and neck (HNSCC). We investigated afatinib-induced tumor and microenvironment modifications by comparing pre- and posttreatment tumor biopsies. PATIENTS AND METHODS: Thirty treatment-naïve patients with primary HNSCC were randomized. Twenty-five patients received afatinib for 14 days before surgery (40 mg 1×/day) and 5 patients were attributed to the control arm. Biopsies were taken at work-up and during surgery. Good quality RNA samples were used for omics analyses. The control arm was enlarged by samples coming from our previous similar window study. RESULTS: IHC analyses of afatinib-treated tumor biopsies showed a decrease in pEGFR (P ≤ 0.05) and pERK (P ≤ 0.05); and an increase in CD3+ (P ≤ 0.01) and CD8+ (P ≤ 0.01) T-cell infiltration, and in CD3+ (P ≤ 0.05) T-cell density. RNA sequencing analyses of afatinib-treated tumor samples showed upregulation of inflammatory genes and increased expression scores of signatures predictive of response to programmed cell death protein 1 blockade (P ≤ 0.05). In posttreatment biopsies of afatinib-treated patients, two clusters were observed. Cluster 1 showed a higher expression of markers and gene sets implicated in epithelial-to-mesenchymal transition (EMT) and activation of cancer-associated fibroblasts (CAF) compared with cluster 2 and controls. CONCLUSIONS: Short-term treatment with afatinib in primary HNSCC induces CD3+ and CD8+ tumor infiltration and, in some patients, EMT and CAF activation. These results open perspectives to overcome resistance mechanisms to anti-HER therapy and to potentiate the activity of immune checkpoint inhibitors.