HPV-associated head and neck cancer is characterized by distinct profiles of CD8+ T cells and myeloid-derived suppressor cells.

Patients with HPV--localized head and neck cancer (HNC) show inferior outcomes after surgery and radiochemotherapy compared to HPV-associated cancers. The underlying mechanisms remain elusive, but differences in immune status and immune activity may be implicated. In this study, we analyzed immune profiles of CD8+ T cells and myeloid-derived suppressor cells (MDSC) in HPV+ versus HPV- disease.The overall frequency of CD8+ T cells was reduced in HNC versus healthy donors but substantially increased after curative therapy (surgery and/or radiochemotherapy). In HPV+ patients, this increase was associated with significant induction of peripheral blood CD8+/CD45RA-/CD62L- effector memory cells. The frequency of HPV-antigen-specific CD8+ cells was low even in patients with virally associated tumors and dropped to background levels after curative therapy. Pre-therapeutic counts of circulating monocytic MDSC, but not PMN-MDSC, were increased in patients with HPV- disease. This increase was accompanied by reduced fractions of terminally differentiated CD8+ effector cells. HPV- tumors showed reduced infiltrates of CD8+ and CD45RO+ immune cells compared with HPV+ tumors. Importantly, frequencies of tumor tissue-infiltrating PMN-MDSC were increased, while percentages of Granzyme B+ and Ki-67+ CD8 T cells were reduced in patients with HPV- disease.We report differences in frequencies and relative ratios of MDSC and effector T cells in HPV- HNC compared with more immunogenic HPV-associated disease. Our data provide new insight into the immunological profiles of these two tumor entities and may be utilized for more tailored immunotherapeutic approaches in the future.

Nonfunctional TGF-ß/ALK1/ENG signaling pathway supports neutrophil proangiogenic activity in hereditary hemorrhagic telangiectasia.

The transforming growth factor ß (TGF-ß)/ALK1/ENG signaling pathway maintains quiescent state of endothelial cells, but at the same time, it regulates neutrophil functions. Importantly, mutations of this pathway lead to a rare autosomal disorder called hereditary hemorrhagic telangiectasia (HHT), characterized with abnormal blood vessel formation (angiogenesis). As neutrophils are potent regulators of angiogenesis, we investigated how disturbed TGF-ß/ALK1/ENG signaling influences angiogenic properties of these cells in HHT. We could show for the first time that not only endothelial cells, but also neutrophils isolated from such patients are ENG/ALK1 deficient. This deficiency obviously stimulates proangiogenic switch of such neutrophils. Elevated proangiogenic activity of HHT neutrophils is mediated by the increased spontaneous degranulation of gelatinase granules, resulting in high release of matrix-degrading matrix metalloproteinase 9 (MMP9). In agreement, therapeutic disturbance of this process using Src tyrosine kinase inhibitors impaired proangiogenic capacity of such neutrophils. Similarly, inhibition of MMP9 activity resulted in significant impairment of neutrophil-mediated angiogenesis. All in all, deficiency in TGF-ß/ALK1/ENG signaling in HHT neutrophils results in their proangiogenic activation and disease progression. Therapeutic strategies targeting neutrophil degranulation and MMP9 release and activity may serve as a potential therapeutic option for HHT.

Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor Improves Leukocyte Energy Metabolism in Hereditary Hemorrhagic Telangiectasia.

The interplay between hypoxia-inducible factors (HIFs) and transforming growth factor beta (TGF-ß) is critical for both inflammation and angiogenesis. In hereditary hemorrhagic telangiectasia (HHT), we have previously observed that impairment of the TGF-ß pathway is associated with downregulation of HIF-1α. HIF-1α accumulation is mandatory in situations of altered energy demand, such as during infection or hypoxia, by adjusting cell metabolism. Leukocytes undergo a HIF-1α-dependent switch from aerobic mitochondrial respiration to anaerobic glycolysis (glycolytic switch) after stimulation and during differentiation. We postulate that the decreased HIF-1α accumulation in HHT leads to a clinically observed immunodeficiency in these patients. Examination of HIF-1α and its target genes in freshly isolated peripheral blood mononuclear cells (PBMCs) from HHT patients revealed decreased gene expression and protein levels of HIF-1α and HIF-1α-regulated glycolytic enzymes. Treatment of these cells with the HIF-prolyl hydroxylase inhibitor, Roxadustat, rescued their ability to accumulate HIF-1α protein. Functional analysis of metabolic flux using a Seahorse FX extracellular flux analyzer showed that the extracellular acidification rate (indicator of glycolytic turnover) after Roxadustat treatment was comparable to non-HHT controls, while oxygen consumption (indicator of mitochondrial respiration) was slightly reduced. HIF stabilization may be a potential therapeutic target in HHT patients suffering from infections.

Nationwide Awareness Campaign and Call for Dental Screening for Hereditary Hemorrhagic Telangiectasia in Germany.

Objectives: Hereditary hemorrhagic telangiectasia (HHT) is a rare disorder encompassing facial and oral telangiectasias and visceral vascular malformations (VMs). Pulmonary VMs can lead to paradoxical embolism of thrombi or bacteria, e.g., due to dental procedures. Early detection can reduce morbidity and mortality and is recommended. However, diagnosis is often delayed for decades. Our study is assessing the feasibility and effect of a nationwide awareness campaign for early diagnosis of HHT addressing all dentists in Germany. Methods: In 2018, one article and two reminders about HHT were published in a nationwide awareness campaign. As a proxy for the effectiveness of the campaign, researchers measured the number of first-time inquiries from patients and physicians about HHT documented by the German HHT self-help group from September 2016 until September 2019. Results: A total of 411 first contacts with the German self-help group were documented, mainly via Internet platforms (Internet forum (n = 130) and Facebook® (n = 189)). For 9% of those patients (n = 36/411), the physician or dentist (physician: (n = 31/36, 86%; dentist: n = 5/36, 14%) informed patients about the disease HHT and the self-help group. Before publishing the first article about HHT, no dentist referred patients to the German self-help group; afterwards, 5 patients received information about HHT from their dentist and contacted the patient organization for the first time. After each publication in June, September, and December 2018, the number of new contacts increased. Contacts via phone and e-mail had the highest relative increase. Conclusions: The repeated call for dental screening for HHT in Germany led to increased awareness of this rare disease; more patients with possible HHT received information about the condition. The authors conclude that targeted campaigns may contribute to a shorter diagnostic latency resulting in increased quality of life and life expectancy in HHT. This trial is registered with CT03549949.

European Reference Network for Rare Vascular Diseases (VASCERN): When and how to use intravenous bevacizumab in Hereditary Haemorrhagic Telangiectasia (HHT)?

Hereditary haemorrhagic telangiectasia (HHT) is a rare vascular multisystemic disease that leads to epistaxis, anaemia due to blood loss, and arteriovenous malformations (AVMs) in organs such as the lungs, liver and brain. HHT prevalence is estimated at 1/6000, i.e. around 85,000 European citizens, and is served by the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN). HHT treatments depend on clinical manifestations, and span multiple different medical, surgical and interventional disciplines. Separate to local treatments in the nose, in severe settings, intravenous bevacizumab has been proposed as treatment option, and the purpose of the current article is to assess the use of intravenous bevacizumab in patients with HHT in 2022 according to available data.

IFNAR1 Deficiency Impairs Immunostimulatory Properties of Neutrophils in Tumor-Draining Lymph Nodes.

Tumor-draining lymph nodes (TDLNs) are the first organs where the metastatic spread of different types of cancer, including head and neck cancer (HNC), occurs and have therefore high prognostic relevance. Moreover, first anti-cancer immune responses have been shown to be initiated in such LNs via tumor-educated myeloid cells. Among myeloid cells present in TDLNs, neutrophils represent a valuable population and considerably participate in the activation of effector lymphocytes there. Tumor-supportive or tumor-inhibiting activity of neutrophils strongly depends on the surrounding microenvironment. Thus, type I interferon (IFN) availability has been shown to prime anti-tumor activity of these cells. In accordance, mice deficient in type I IFNs show elevated tumor growth and metastatic spread, accompanied by the pro-tumoral neutrophil bias. To reveal the mechanism responsible for this phenomenon, we have studied here the influence of defective type I IFN signaling on the immunoregulatory activity of neutrophils in TDLNs. Live imaging of such LNs was performed using two-photon microscopy in a transplantable murine HNC model. CatchupIVM-red and Ifnar1-/- (type I IFN receptor- deficient) CatchupIVM-red mice were used to visualize neutrophils and to assess their interaction with T-cells in vivo. We have evaluated spatiotemporal patterns of neutrophil/T-cell interactions in LNs in the context of type I interferon receptor (IFNAR1) availability in tumor-free and tumor-bearing animals. Moreover, phenotypic and functional analyses were performed to further characterize the mechanisms regulating neutrophil immunoregulatory capacity. We demonstrated that inactive IFNAR1 leads to elevated accumulation of neutrophils in TDLNs. However, these neutrophils show significantly impaired capacity to interact with and to stimulate T-cells. As a result, a significant reduction of contacts between neutrophils and T lymphocytes is observed, with further impairment of T-cell proliferation and activation. This possibly contributes to the enhanced tumor growth in Ifnar1-/- mice. In agreement with this, IFNAR1-independent activation of downstream IFN signaling using IFN-λ improved the immunostimulatory capacity of neutrophils in TDLNs and contributed to the suppression of tumor growth. Our results suggest that functional type I IFN signaling is essential for neutrophil immunostimulatory capacity and that stimulation of this signaling may provide a therapeutic opportunity in head and neck cancer patients.

Altered hypoxia inducible factor regulation in hereditary haemorrhagic telangiectasia.

Patients with hereditary haemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, suffer from the consequences of abnormal vessel structures. These structures can lead to haemorrhages or shunt effects in liver, lungs and brain. This inherited and rare disease is characterized by mutations affecting the transforming growth factor-ß (TGF-ß)/Bone Morphogenetic Protein (BMP) pathway that results in arteriovenous malformations and studies indicate an impaired immune response. The mechanism underlying this altered immune response in HHT patients is still unknown. TGF-ß interacts with hypoxia inducible factors (HIF), which both orchestrate inflammatory and angiogenic processes. Therefore, we analysed the expression of HIF and related genes in whole blood samples from HHT patients. We could show significantly decreased expression of HIF-1α on the mRNA and protein level. However, commonly known upstream regulators of HIF-1α in inflammatory responses were not affected, whereas HIF-1α target genes were significantly downregulated. There was no correlation between HIF1A or HIF2A gene expression and the severity of HHT detected. Our results represent a rare case of HIF-1α downregulation in a human disease, which underlines the relevance of HIFs in HHT. The study indicates an interaction of the known mutation in HHT and the dysregulation of HIF-1α in HHT patients, which might contribute to the clinical phenotype.

Treatment of juvenile recurrent parotitis with irrigation therapy without anesthesia.

PURPOSE: No standardized treatment regimen exists for juvenile recurrent parotitis (JRP). The investigators hypothesized that irrigation with saline only without local anesthesia will be an effective and beneficial option. METHODS: Using a retrospective study design, a series of children with typical symptoms of JRP who were treated with at least one irrigation therapy were evaluated. This treatment consisted of irrigation of the affected gland with 3-10 ml saline solution without any type of anesthesia. The outcome variables were patient/parent satisfaction, frequency and duration of acute JRP episodes, and the need for antibiotics before and after irrigation therapy. RESULTS: The case series was composed of six boys aged 3.3-7.7 years who experienced one to eight sessions of irrigation therapy. The period of follow-up was 9-64 months. We observed a total resolution of symptoms in two children and an improvement in the other four. No relevant side effects were seen. CONCLUSION: Our results suggest that irrigation therapy is a reasonable, simple, and minimally invasive treatment alternative for JRP. In contrast to sialendoscopy or sialography, there is no need for general anesthesia or radiation exposure.

SIRT1-mediated deacetylation of FOXO3a transcription factor supports pro-angiogenic activity of interferon-deficient tumor-associated neutrophils.

Angiogenesis plays an important role during tumor growth and metastasis. We could previously show that Type I interferon (IFN)-deficient tumor-associated neutrophils (TANs) show strong pro-angiogenic activity, and stimulate tumor angiogenesis and growth. However, the exact mechanism responsible for their pro-angiogenic shift is not clear. Here, we set out to delineate the molecular mechanism and factors regulating pro-angiogenic properties of neutrophils in the context of Type I IFN availability. We demonstrate that neutrophils from IFN-deficient (Ifnar1-/- ) mice efficiently release pro-angiogenic factors, such as VEGF, MMP9 or BV8, and thus significantly support the vascular normalization of tumors by increasing the maturation of perivascular cells. Mechanistically, we could show here that the expression of pro-angiogenic factors in neutrophils is controlled by the transcription factor forkhead box protein O3a (FOXO3a), which activity depends on its post-translational modifications, such as deacetylation or phosphorylation. In TANs isolated from Ifnar1-/- mice, we observe significantly elevated SIRT1, resulting in SIRT1-mediated deacetylation of FOXO3a, its nuclear retention and activation. Activated FOXO3a supports in turn the transcription of pro-angiogenic genes in TANs. In the absence of SIRT1, or after its inhibition in neutrophils, elevated kinase MEK/ERK and PI3K/AKT activity is observed, leading to FOXO3a phosphorylation, cytoplasmic transfer and inactivation. In summary, we have found that FOXO3a is a key transcription factor controlling the angiogenic switch of neutrophils. Post-translational FOXO3a modifications regulate its transcriptional activity and, as a result, the expression of pro-angiogenic factors supporting development of vascular network in growing tumors. Therefore, targeting FOXO3a activity could provide a novel strategy of antiangiogenic targeted therapy for cancer.

Restless Leg Syndrome Is Underdiagnosed in Hereditary Hemorrhagic Telangiectasia-Results of an Online Survey.

BACKGROUND: Recurrent bleeding in patients with hereditary hemorrhagic telangiectasia (HHT) can lead to chronic iron deficiency anemia (CIDA). Existing research points to CIDA as a contributing factor in restless leg syndrome (RLS). The association between HHT-related symptoms and the prevalence of RLS was analyzed. METHODS: An online survey was conducted whereby the standardized RLS-Diagnostic Index questionnaire (RLS-DI) was supplemented with 82 additional questions relating to HHT. RESULTS: A total of 474 persons responded to the survey and completed responses for questions pertaining to RLS (mean age: 56 years, 68% females). Per RLS-DI criteria, 48 patients (48/322, 15%; 95% confidence interval (CI): 11-19%) self-identified as having RLS. An analysis of physician-diagnosed RLS and the RLS-DI revealed a relative frequency of RLS in HHT patients of 22% (95% CI: 18-27%). In fact, 8% (25/322; 95% CI: 5-11%) of the HHT patients had RLS which had not been diagnosed before. This equals 35% of the total amount of patients diagnosed with RLS (25/72; 95% CI: 25-46%). HHT patients with a history of gastrointestinal bleeding (prevalence ratio (PR) = 2.70, 95% CI: 1.53-4.77), blood transfusions (PR = 1.90, 95% CI: 1.27-2.86), or iron intake (PR = 2.05, 95% CI: 0.99-4.26) had an increased prevalence of RLS. CONCLUSIONS: Our data suggest that RLS is underdiagnosed in HHT. In addition, physicians should assess CIDA parameters for possible iron supplementation.

[Hereditary hemorrhagic telangiectasia: symptoms and diagnostic latency]. / Hereditäre hämorrhagische Teleangiektasie: Symptome und diagnostische Latenz.

OBJECTIVE: Patients with hereditary hemorrhagic Telangiectasia (HHT) suffer from a rare and systemic disease which is characterized by vascular malformations leading to a variety of different symptoms. MATERIAL AND METHODS: A retrospective review of patients who were referred to our new HHT Center of Excellence (HHT COE) for evaluation and treatment between April 2014 and August 2019 was performed. RESULTS: 235 patients were treated at the West German HHT Center. 83 % of these were diagnosed with definite HHT (235/282, 83 %) and 9 % with possible HHT (26/282). The average latency between first manifestation and definite diagnosis of HHT was 18 years. Several initial symptoms were direct or indirect signs of bleeding (224/241, 93 %). In 83 % of the patients HHT was reported having caused their degree of disability. Older, female patients and those with severe epistaxis suffered from chronic iron deficiency anemia, took iron preparations (148/261, 57 %) and received 9 blood transfusions on average (± standard deviation: 41, minimum - maximum: 0-400, number of patients: 218). 10 % of all patients tolerated anticoagulant or antiplatelet agents. 74 % of patients with HHT used nasal creams/sprays/oils (177/238) and reported fewer bleedings compared to patients without nasal care (ESS: T-Test: 3.193; p = 0.003; anemia: Chi-square: 5.173; p = 0.023). CONCLUSIONS: The diagnostic latency of HHT was almost two decades. Patients with HHT particularly suffered from recurrent epistaxis, which was mostly treated with nasal care and coagulative therapies. Antiplatelet or anticoagulant agents can be used in patients with HHT with caution if indicated.

[Implementation and development of a center for hereditary hemorrhagic telangiectasia]. / Aufbau und Entwicklung eines interdisziplinären Zentrums für hereditäre hämorrhagische Teleangiektasie.

OBJECTIVE: Hereditary Hemorrhagic Telangiectasia (HHT) is a rare and systemic disorder which is characterized by recurrent epistaxis, mucocutaneous telangiectases, and visceral arteriovenous malformations (AVM). An interdisciplinary concept is recommended. MATERIAL AND METHODS: We performed a retrospective review of consecutive patients who were referred to our newly established HHT Center of Excellence (HHT COE) for evaluation and treatment between April 2014 and August 2019. RESULTS: A network of over 20 departments was established at the University Hospital Essen. In 261 of the 282 patients (93 %), who were referred to the hospital's COE, the HHT diagnosis was at least possible. Most patients suffered from several symptoms (epistaxis and / or telangiectasia: > 80 %, visceral involvement: 65 %) and received a variety of treatments, often in a multidisciplinary setting. Alongside this direct treatment, the COE leader manages the coordination of the center and its public relations, which involves more than 900 e-mails per year. International collaboration and exchanges of expertise within the European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) can improve the treatment of patients with HHT particularly where these cases are complex. CONCLUSIONS: An HHT COE provides an interdisciplinary network where highly specialized diagnostic and therapeutic processes can be updated and optimized continuously.

European Reference Network for Rare Vascular Diseases (VASCERN) position statement on cerebral screening in adults and children with hereditary haemorrhagic telangiectasia (HHT).

Hereditary haemorrhagic telangiectasia (HHT) is a multisystemic vascular dysplasia inherited as an autosomal dominant trait. Approximately 10 % of patients have cerebral vascular malformations, a proportion being cerebral arteriovenous malformations (AVMs) and fistulae that may lead to potentially devastating consequences in case of rupture. On the other hand, detection and treatment related-risks are not negligible, and immediate. While successful treatment can be undertaken in individual cases, current data do not support the treatment of unruptured AVMs, which also present a low risk of bleeding in HHT patients. Screening for these AVMs is therefore controversial.Structured discussions, distinctions of different cerebrovascular abnormalities commonly grouped into an "AVM" bracket, and clear guidance by neurosurgical and neurointerventional radiology colleagues enabled the European Reference Network for Rare Vascular Disorders (VASCERN-HHT) to develop the following agreed Position Statement on cerebral screening:1) First, we emphasise that neurological symptoms suggestive of cerebral AVMs in HHT patients should be investigated as in general neurological and emergency care practice. Similarly, if an AVM is found accidentally, management approaches should rely on expert discussions on a case-by-case basis and individual risk-benefit evaluation of all therapeutic possibilities for a specific lesion.2) The current evidence base does not favour the treatment of unruptured cerebral AVMs, and therefore cannot be used to support widespread screening of asymptomatic HHT patients.3) Individual situations encompass a wide range of personal, cultural and clinical states. In order to enable informed patient choice, and avoid conflicting advice, particularly arising from non-neurovascular interpretations of the evidence base, we suggest that all HHT patients should have the opportunity to discuss knowingly brain screening issues with their healthcare provider.4) Any screening discussions in asymptomatic individuals should be preceded by informed pre-test review of the latest evidence regarding preventative and therapeutic efficacies of any interventions. The possibility of harm due to detection of, or intervention on, a vascular malformation that would not have necessarily caused any consequence in later life should be stated explicitly.We consider this nuanced Position Statement provides a helpful, evidence-based framework for informed discussions between healthcare providers and patients in an emotionally charged area.

Trauma Can Induce Telangiectases in Hereditary Hemorrhagic Telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease of the fibrovascular tissue resulting in visceral vascular malformations and (muco-) cutaneous telangiectases with recurrent bleedings. The mechanism behind the disease is not fully understood; however, observations from HHT mouse models suggest that mechanical trauma may induce the formation of abnormal vessels. To assess the influence of environmental trauma (mechanical or light induced) on the number of telangiectases in patients with HHT, the number of telangiectases on the hands, face, and lips were counted on 103 HHT patients possessing at least three out of four Curaçao criteria. They were then surveyed for information concerning their dominant hand, exposure to sunlight, and types of regular manual work. Patients developed more telangiectases on their dominant hand and lower lip (Wilcoxon rank sum test: p < 0.001). Mechanical stress induced by manual work led to an increased number of telangiectases on patients' hands (Mann-Whitney U test: p < 0.001). There was also a positive correlation between sun exposure and the number of telangiectases on the lips (Mann-Whitney U test: 0.027). This study shows that mechanical and UV-induced trauma strongly influence the formation of telangiectases in HHT patients. This result has potential implications in preventive measures and on therapeutic approaches for HHT.

Impaired Release of Neutrophil Extracellular Traps and Anemia-Associated T Cell Deficiency in Hereditary Hemorrhagic Telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by mucocutaneous telangiectases and visceral vascular malformations. Individuals suffering from HHT have a significantly increased risk of bacterial infections, but the mechanisms involved in this are not clear. White blood cell subpopulations were estimated with flow cytometry in 79 patients with HHT and 45 healthy individuals, and association with clinicopathological status was assessed. A prominent decrease in absolute numbers of T cells in HHT was revealed (0.7 (0.5-1.1) vs. 1.3 (0.8-1.6), 106/mL, p < 0.05), and in multivariate regression analysis, hemoglobin level was associated with lymphopenia (OR = 0.625, 95% CI: 0.417-0.937, p < 0.05). Although no changes in absolute numbers of neutrophils and monocytes were observed, we revealed a significant impairment of neutrophil antibacterial functions in HHT (n = 9), compared to healthy individuals (n = 7), in vitro. The release of neutrophil extracellular traps (NETs) against Pseudomonas aeruginosa MOI10 was significantly suppressed in HHT (mean area per cell, mm2: 76 (70-92) vs. 121 (97-128), p < 0.05), due to impaired filamentous actin organization (% of positive cells: 69 (59-77) vs. 92 (88-94), p < 0.05). To conclude, this study reveals the categories of patients with HHT that are prone to immunosuppression and require careful monitoring, and suggests a potential therapeutic strategy based on the functional activation of neutrophils.

Prognostic Role of Blood NETosis in the Progression of Head and Neck Cancer.

Neutrophil extracellular traps (NETs) represent web-like structures consisting of externalized DNA decorated with granule proteins that are responsible for trapping and killing bacteria. However, undesirable effects of NET formation during carcinogenesis, such as metastasis support, have been described. In the present study, we evaluated the correlation between NETosis and disease progression in head and neck cancer (HNC) patients in order to establish a valid biomarker for an early detection and monitoring of HNC progression. Moreover, factors influencing NET release in HNC patients were revealed. We showed a significantly elevated vital NETosis in neutrophils isolated from early T1-T2 and N0-N2 stage patients, as compared to healthy controls. Additionally, in our experimental setting, we confirmed the involvement of tumor cells in the stimulation of NET formation. Interestingly, in advanced cancer stages (T3-4, N3) NETosis was reduced. This also correlated with the levels of granulocyte colony-stimulating factor (G-CSF) in plasma and tumor tissue. Altogether, we suggest that the elevated NETosis in blood can be used as a biomarker to detect early HNC and to predict patients at risk to develop tumor metastasis. Therapeutic disruption of NET formation may offer new roads for successful treatment of HNC patients in order to prevent metastasis.

European Reference Network For Rare Vascular Diseases (VASCERN) Outcome Measures For Hereditary Haemorrhagic Telangiectasia (HHT).

Hereditary haemorrhagic telangiectasia (HHT) is a multisystemic vascular dysplasia that leads to nosebleeds, anaemia due to blood loss, and arteriovenous malformations (AVMs) in organs such as the lungs, liver and brain. HHT is estimated to affect 85,000 European citizens, but most health care providers have limited prior HHT exposure or training.Outcome Measures were developed and implemented by the HHT Working Group of the European Reference Network for Rare Vascular Diseases (VASCERN), in order to maximise the number of patients receiving good care. The measures specifically target areas where optimal management reduces morbidity and mortality in HHT patients, and were designed to be robust to emerging new evidence. Thresholds are the percentage of patients in particular settings who have been recommended screening, or provided with written advice. The 5 Outcome Measures cover (1) pulmonary AVM screening; (2) written nosebleed advice, (3) assessment of iron deficiency; (4) antibiotic prophylaxis prior to dental and surgical procedures for patients with pulmonary AVMs, and (5) written advice on pregnancy. They are not a blueprint for detailed HHT management, but are suitable for all clinicians to be aware of and implement.In summary, these 5 Outcome Measures provide metrics to identify healthcare providers of good care, and encourage care improvement by all healthcare providers.

Clinical Relevance and Suppressive Capacity of Human Myeloid-Derived Suppressor Cell Subsets.

Purpose: Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of pathologically expanded myeloid cells with immunosuppressive activity. In human disease, three major MDSC subpopulations can be defined as monocytic (M-MDSC), granulocytic [polymorphonuclear-MDSC (PMN-MDSC)], and early stage (e-MDSC), which lacks myeloid lineage markers of the former two subsets. The purpose of this study was to determine and compare the immunosuppressive capacity and clinical relevance of each of these subsets in patients with solid cancer.Experimental Design: The frequency of MDSC subsets in the peripheral blood was determined by flow cytometry in a cohort of 49 patients with advanced head and neck cancer (HNC) and 22 patients with urological cancers. Sorted and purified MDSC subsets were tested in vitro for their T-cell-suppressive capacity. Frequency of circulating MDSC was correlated with overall survival of patients with HNC.Results: A high frequency of PMN-MDSC most strongly correlated with poor overall survival in HNC. T-cell-suppressive activity was higher in PMN-MDSC compared with M-MDSC and e-MDSC. A subset of CD66b+/CD11b+/CD16+ mature PMN-MDSC displayed high expression and activity of arginase I, and was superior to the other subsets in suppressing proliferation and cytokine production of T cells in both cancer types. High levels of this CD11b+/CD16+ PMN-MDSC, but not other PMN-MDSC subsets, strongly correlated with adverse outcome in HNC.Conclusions: A subset of mature CD11b+/CD16+ PMN-MDSC was identified as the MDSC subset with the strongest immunosuppressive activity and the highest clinical relevance. Clin Cancer Res; 24(19); 4834-44. ©2018 AACR.