Exploring the tumor genomic landscape of aggressive prostate cancer by whole-genome sequencing of tissue or liquid biopsies.

Treatment resistance remains a major issue in aggressive prostate cancer (PC), and novel genomic biomarkers may guide better treatment selection. Circulating tumor DNA (ctDNA) can provide minimally invasive information about tumor genomes, but the genomic landscape of aggressive PC based on whole-genome sequencing (WGS) of ctDNA remains incompletely characterized. Thus, we here performed WGS of tumor tissue (n = 31) or plasma ctDNA (n = 10) from a total of 41 aggressive PC patients, including 11 hormone-naïve, 15 hormone-sensitive, and 15 castration-resistant patients. Across all variant types, we found progressively more altered tumor genomic profiles in later stages of aggressive PC. The potential driver genes most frequently affected by single-nucleotide variants or insertions/deletions included the known PC-related genes TP53, CDK12, and PTEN and the novel genes COL13A1, KCNH3, and SENP3. Etiologically, aggressive PC was associated with age-related and DNA repair-related mutational signatures. Copy number variants most frequently affected 14q11.2 and 8p21.2, where no well-recognized PC-related genes are located, and also frequently affected regions near the known PC-related genes MYC, AR, TP53, PTEN, and BRCA1. Structural variants most frequently involved not only the known PC-related genes TMPRSS2 and ERG but also the less extensively studied gene in this context, PTPRD. Finally, clinically actionable variants were detected throughout all stages of aggressive PC and in both plasma and tissue samples, emphasizing the potential clinical applicability of WGS of minimally invasive plasma samples. Overall, our study highlights the feasibility of using liquid biopsies for comprehensive genomic characterization as an alternative to tissue biopsies in advanced/aggressive PC.

Clinical evaluation of antibiotic regimens in patients with surgically verified parapharyngeal abscess: a prospective observational study.

PURPOSE: We aimed to evaluate the effectiveness of different antibiotic regimens for the treatment of parapharyngeal abscess (PPA) and characterize patients, who suffered potentially preventable complications (defined as death, abscess recurrence, spread of infection, or altered antibiotic treatment because of insufficient progress). METHODS: Sixty adult patients with surgically verified PPA were prospectively enrolled at five Danish Ear-nose-throat departments. RESULTS: Surgical treatment included internal incision (100%), external incision (13%), and tonsillectomy (88%). Patients were treated with penicillin G ± metronidazole (n = 39), cefuroxime ± metronidazole (n = 16), or other antibiotics (n = 5). Compared to penicillin-treated patients, cefuroxime-treated patients were hospitalized for longer (4.5 vs 3.0 days, p = 0.007), were more frequently admitted to intensive care (56 vs 15%, p = 0.006), underwent external incision more frequently (31 vs 5%, p = 0.018), and suffered more complications (50 vs 18%, p = 0.022), including re-operation because of abscess recurrence (44 vs 3%, p < 0.001). Nine patients suffered potentially preventable complications. These patients displayed significantly higher C-reactive protein levels, received antibiotics prior to admission more frequently, underwent external incision more commonly, and were admitted to intensive care more frequently compared to other patients. CONCLUSION: The majority of patients with PPA were effectively managed by abscess incision, tonsillectomy, and penicillin G ± metronidazole. Cefuroxime-treated patients were more severely ill at time of admission and had worse outcome compared to penicillin-treated patients. We recommend penicillin G + metronidazole as standard treatment for patients with PPA, but in cases with more risk factors for potentially preventable complications, we recommend aggressive surgical and broadened antibiotic therapy, e.g. piperacillin-tazobactam.

[The nose can be the focus of treatment and prophylactic approaches against COVID-19].

Infection with SARS-CoV-2 frequently commences in the nasal cavity, yet knowledge about this initial virus-host interaction is sparse. In this review, we update our current understanding of SARS-CoV-2 infection via the nasal epithelium and the associated local immune response. Furthermore, we present considerations to how this interaction may influence the clinical course of COVID-19 and the systemic immune response, and lastly touch upon the potential for intranasal vaccination, intranasal antiviral therapies and immunomodulatory approaches.

Microbiology of parapharyngeal abscesses in adults: in search of the significant pathogens.

We aimed to describe the microbiology of parapharyngeal abscess (PPA) and point out the likely pathogens using the following principles to suggest pathogenic significance: (1) frequent recovery, (2) abundant growth, (3) growth in relative abundance to other microorganisms, (4) percentage of the isolates recovered in both absolute and relative abundance, (5) more frequent recovery in PPA pus compared with tonsillar surface and tissue. Comprehensive bacterial cultures were performed on specimens obtained from adult patients (n = 60) with surgically verified PPA, who were prospectively enrolled at five Danish ear-nose-throat departments. The prevalent isolates (in PPA pus) were unspecified anaerobes (73%), non-hemolytic streptococci (67%), Streptococcus anginosus group (SAG) (40%), Corynebacterium spp. (25%), Neisseria spp. (23%), Fusobacterium spp. (22%), Fusobacterium necrophorum (17%), Prevotella spp. (12%), and Streptococcus pyogenes (10%). The bacteria most frequently isolated in heavy (maximum) growth were unspecified anaerobes (60%), SAG (40%), F. necrophorum (23%), and Prevotella spp. (17%). The predominant microorganisms (those found in highest relative abundance) were unspecified anaerobes (53%), SAG (28%), non-hemolytic streptococci (25%), F. necrophorum (15%), S. pyogenes (10%), and Prevotella spp. (10%). Four potential pathogens were found in both heavy growth and highest relative abundance in at least 50% of cases: F. necrophorum, Prevotella spp., SAG, and S. pyogenes. SAG, Prevotella spp., F. necrophorum, S. pyogenes, and Bacteroides spp. were recovered with the same or higher frequency from PPA pus compared with tonsillar tissue and surface. Our findings suggest that SAG, F. necrophorum, Prevotella, and S. pyogenes are significant pathogens in PPA development.

Acute otitis media and antibiotics - a systematic review.

INTRODUCTION: Although acute otitis media (AOM) is a very frequent illness in children, it remains unclear to what extent children with AOM benefit from antibiotics (ABX). This systematic review aimed to clarify this subject by including randomised clinical trials (RCTs) from the pneumococcal vaccine era only. METHODS: We performed a systematic literature search in four databases from 1 January 2000 to 1 January 2019 for RCTs comparing ABX to placebo in patients with AOM. Pain was registered as the main outcome. Adverse events (AE), development of contralateral otitis media, tympanic membrane perforation, late AOM recurrence, abnormal tympanometry and time to resolution of middle ear effusion were registered as secondary outcomes. RESULTS: Six publications based on five RCTs with 1,862 patients were included. The number needed to treat (NNT) to reduce pain varied from seven (pain at day 7-10) to 28 (pain at day 2-3). The NNT for preventing contralateral otitis was ten. AE were seen in every 13th patient treated with ABX. CONCLUSIONS: ABX appears to have a limited effect on both primary and secondary outcomes compared with placebo. A substantial number of patients experienced AE. New RCTs are needed to further clarify the effect. Ideally, RCTs could be conducted in Danish general practices in collaboration with practicing ear, nose and throat specialists to obtain large unselected populations with high rates of vaccine coverage. Until more evidence is provided, ABX should be considered among children younger than two years of age with severe symptoms of AOM, i.e. fewer and affected well-being.

Circulating HOXA9-methylated tumour DNA: A novel biomarker of response to poly (ADP-ribose) polymerase inhibition in BRCA-mutated epithelial ovarian cancer.

AIM: Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as a novel treatment option in BRCA-mutated ovarian cancer (OC); however, responses are variable and there is a lack of prognostic and predictive biomarkers. We therefore investigated whether homeobox A9 (HOXA9) promoter methylation in circulating tumour DNA (meth-ctDNA) can serve as a biomarker in patients with platinum-resistant BRCA-mutated OC, undergoing treatment with a PARP inhibitor. METHODS: Patients (n = 32) were enrolled as part of a phase II trial testing veliparib in platinum-resistant BRCA-mutated OC. HOXA9 meth-ctDNA was determined at baseline and just before each treatment cycle using digital droplet polymerase chain reaction. Methylation status and change in methylation compared with baseline were correlated with overall survival (OS) and progression-free survival (PFS). RESULTS: Detection of HOXA9 meth-ctDNA during treatment with a PARP inhibitor was associated with worse clinical outcomes. This association was apparent after the first cycle of treatment and maintained throughout treatment. After three treatment cycles, patients with detectable HOXA9 meth-ctDNA had a median PFS of 5.1 months compared with 8.3 months for patients without, and a median OS of 9.5 months compared with 19.4 months (p < 0.0001 and p = 0.002, respectively). Patients with detectable HOXA9 meth-ctDNA at baseline, but subsequent undetectable levels, had the most favourable clinical outcome, followed by patients with undetectable levels throughout. These associations were maintained in multivariate analysis. CONCLUSIONS: Longitudinal monitoring of HOXA9 meth-ctDNA is clinically feasible and is strongly correlated to clinical outcomes (PFS, OS), suggesting that it may serve as a valuable predictive biomarker to inform clinical decision-making in the setting of platinum-resistant BRCA-mutated OC treated with a PARP inhibitor.

A Systematic Review of Phase II Targeted Therapy Clinical Trials in Anaplastic Thyroid Cancer.

Anaplastic thyroid carcinoma (ATC) is a rare, but devastating disease. Despite multimodal approaches combining surgery, chemotherapy and radiation therapy, ATC is associated with a dire prognosis, with a median overall survival of only three to ten months. Novel treatments are thus urgently needed. Recent efforts towards the characterization of the molecular landscape of ATC have led to the identification of pro-oncogenic targetable alterations, lending promise for novel targeted therapeutic approaches. This systematic review summarizes the results of phase II clinical trials of targeted therapy in ATC, providing an overview of efficacy and safety profiles. The majority of trials to date have consisted of small single-arm studies and have presented modest results. However, only a minority of trials have selected or stratified patients by molecular alterations. In the setting of BRAF V600E mutated ATC, dabrafenib/trametinib combination therapy and vemurafenib monotherapy have both demonstrated efficacy. Everolimus has furthermore shown promising results in patients with PI3K/mTOR/AKT pathway alterations. These studies underscore the importance of molecular profiling of tumors for appropriate patient selection and determination of genomic correlates of response. Clinical trials are underway testing additional targeted therapies as monotherapy, or as a part of multimodal treatment, and in combination with immunotherapy.

Management of sore throat in Danish general practices.

BACKGROUND: The national guideline for sore throat, endorsed by the Danish Society of General Medicine, recommends the use of the modified Centor score and streptococcal rapid antigen detection test to guide diagnosis and treatment of sore throat. The aim was to investigate Danish general practitioners (GPs) routine management of sore throat patients with a focus on the modalities used and adherence to the guideline. METHODS: A cross-sectional study. GPs in the Central Denmark Region answered an online questionnaire in October 2017. The main outcome measure was modalities used in the management of sore throat patients. RESULTS: In total, 266 of 500 (53%) GPs answered the survey. Ten percent of participants were adherent or almost adherent to the guideline, while 82% of GPs added one or more extra modalities (general clinical assessment (67%), biochemical parameters (48%), and throat swabs for bacterial culture (18%)) to differentiate viral and bacterial etiology. Sixty-five percent of participants used the Centor Score or modified Centor Score, 96% of GPs used a streptococcal rapid antigen detection test, and all GPs chose narrow-spectrum penicillin as the first-line antibiotic. The most common reasons for non-adherence to the guideline were greater confidence in the clinical assessment (39%), time pressure (33%), and difficulty recalling the guideline (19%). CONCLUSION: Danish GPs rarely adhere to the recommended sore throat management guideline, but use various combinations of different modalities in the assessment of bacterial infection. This practice may increase antibiotic prescription rates.

RAS-MAPK Reactivation Facilitates Acquired Resistance in FGFR1-Amplified Lung Cancer and Underlies a Rationale for Upfront FGFR-MEK Blockade.

The FGFR kinases are promising therapeutic targets in multiple cancer types, including lung and head and neck squamous cell carcinoma, cholangiocarcinoma, and bladder cancer. Although several FGFR kinase inhibitors have entered clinical trials, single-agent clinical efficacy has been modest and resistance invariably occurs. We therefore conducted a genome-wide functional screen to characterize mechanisms of resistance to FGFR inhibition in a FGFR1-dependent lung cancer cellular model. Our screen identified known resistance drivers, such as MET, and additional novel resistance mediators including members of the neurotrophin receptor pathway (NTRK), the TAM family of tyrosine kinases (TYRO3, MERTK, AXL), and MAPK pathway, which were further validated in additional FGFR-dependent models. In an orthogonal approach, we generated a large panel of resistant clones by chronic exposure to FGFR inhibitors in FGFR1- and FGFR3-dependent cellular models and characterized gene expression profiles employing the L1000 platform. Notably, resistant clones had enrichment for NTRK and MAPK signaling pathways. Novel mediators of resistance to FGFR inhibition were found to compensate for FGFR loss in part through reactivation of MAPK pathway. Intriguingly, coinhibition of FGFR and specific receptor tyrosine kinases identified in our screen was not sufficient to suppress ERK activity or to prevent resistance to FGFR inhibition, suggesting a redundant reactivation of RAS-MAPK pathway. Dual blockade of FGFR and MEK, however, proved to be a more powerful approach in preventing resistance across diverse FGFR dependencies and may represent a therapeutic opportunity to achieve durable responses to FGFR inhibition in FGFR-dependent cancers. Mol Cancer Ther; 17(7); 1526-39. ©2018 AACR.

Paediatric Virology and its interaction between basic science and clinical practice (Review).

The 3rd Workshop on Paediatric Virology, which took place on October 7th, 2017 in Athens, Greece, highlighted the role of breast feeding in the prevention of viral infections during the first years of life. Moreover, it focused on the long-term outcomes of respiratory syncytial virus and rhinovirus infections in prematurely born infants and emphasised the necessity for the development of relevant preventative strategies. Other topics that were covered included the vaccination policy in relation to the migration crisis, mother­to­child transmission of hepatitis B and C viruses, vaccination against human papilloma viruses in boys and advances on intranasal live­attenuated vaccination against influenza. Emphasis was also given to the role of probiotics in the management of viral infections in childhood, the potential association between viral infections and the pathogenesis of asthma, fetal and neonatal brain imaging and the paediatric intensive care of children with central nervous system viral infections. Moreover, an interesting overview of the viral causes of perinatal mortality in ancient Greece was given, where recent archaeological findings from the Athenian Agora's bone well were presented. Finally, different continuing medical educational options in Paediatric Virology were analysed and evaluated. The present review provides an update of the key topics discussed during the workshop.

Clinical evaluation of intravenous ampicillin as empirical antimicrobial treatment of acute epiglottitis.

INTRODUCTION: The significant pathogens in acute epiglottitis (AE) are poorly defined in the post Haemophilus influenza type b-vaccine era. Furthermore, there is a lack of clinical evaluations of antibiotic regimens in patients with AE. We aimed to evaluate the effectiveness of empiric intravenous ampicillin in the treatment of patients with AE. MATERIALS & METHODS: All patients admitted with AE to the Ear-Nose-Throat Department, Aarhus University Hospital, Denmark, from 2001 to 2015 were included. RESULTS: In total, 103 (51 males) patients were included in the study. The median duration of hospitalization was four days. There was no statistical significant difference between patients initially treated with intravenous ampicillin (n = 83) or other antibiotics (n = 20) (p = .26). The antibiotic regimen was altered during admission in 11% of patients, without significant difference between antibiotic groups (ampicillin 10% vs non-ampicillin 15%, p = .44). Complications potentially related to insufficient antibiotic treatment were observed in four (5%) patients initially treated with ampicillin, but in none of the patients initially treated with antibiotics other than ampicillin (p = 1.00). Throat swab cultures and blood cultures frequently yielded negative results. CONCLUSIONS: Intravenous ampicillin is efficient as empiric antibiotic therapy for AE patients, leading to a quick recovery and low complication rates.

Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression.

Acquired drug resistance is a major factor limiting the effectiveness of targeted cancer therapies. Targeting tumors with kinase inhibitors induces complex adaptive programs that promote the persistence of a fraction of the original cell population, facilitating the eventual outgrowth of inhibitor-resistant tumor clones. We show that the addition of a newly identified CDK7/12 inhibitor, THZ1, to targeted therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in diverse cellular and in vivo cancer models. We propose that targeted therapy induces a state of transcriptional dependency in a subpopulation of cells poised to become drug tolerant, which THZ1 can exploit by blocking dynamic transcriptional responses, promoting remodeling of enhancers and key signaling outputs required for tumor cell survival in the setting of targeted therapy. These findings suggest that the addition of THZ1 to targeted therapies is a promising broad-based strategy to hinder the emergence of drug-resistant cancer cell populations.Significance: CDK7/12 inhibition prevents active enhancer formation at genes, promoting resistance emergence in response to targeted therapy, and impedes the engagement of transcriptional programs required for tumor cell survival. CDK7/12 inhibition in combination with targeted cancer therapies may serve as a therapeutic paradigm for enhancing the effectiveness of targeted therapies. Cancer Discov; 8(1); 59-73. ©2017 AACR.See related commentary by Carugo and Draetta, p. 17This article is highlighted in the In This Issue feature, p. 1.

ER Stress Signaling Promotes the Survival of Cancer "Persister Cells" Tolerant to EGFR Tyrosine Kinase Inhibitors.

An increasingly recognized component of resistance to tyrosine kinase inhibitors (TKI) involves persistence of a drug-tolerant subpopulation of cancer cells that survive despite effective eradication of the majority of the cell population. Multiple groups have demonstrated that these drug-tolerant persister cells undergo transcriptional adaptation via an epigenetic state change that promotes cell survival. Because this mode of TKI drug tolerance appears to involve transcriptional addiction to specific genes and pathways, we hypothesized that systematic functional screening of EGFR TKI/transcriptional inhibitor combination therapy would yield important mechanistic insights and alternative drug escape pathways. We therefore performed a genome-wide CRISPR/Cas9 enhancer/suppressor screen in EGFR-dependent lung cancer PC9 cells treated with erlotinib + THZ1 (CDK7/12 inhibitor) combination therapy, a combination previously shown to suppress drug-tolerant cells in this setting. As expected, suppression of multiple genes associated with transcriptional complexes (EP300, CREBBP, and MED1) enhanced erlotinib/THZ1 synergy. Unexpectedly, we uncovered nearly every component of the recently described ufmylation pathway in the synergy suppressor group. Loss of ufmylation did not affect canonical downstream EGFR signaling. Instead, absence of this pathway triggered a protective unfolded protein response associated with STING upregulation, promoting protumorigenic inflammatory signaling but also unique dependence on Bcl-xL. These data reveal that dysregulation of ufmylation and ER stress comprise a previously unrecognized TKI drug tolerance pathway that engages survival signaling, with potentially important therapeutic implications.Significance: These findings reveal a novel function of the recently described ufmylation pathway, an ER stress survival signaling in drug-tolerant persister cells, which has important biological and therapeutic implications. Cancer Res; 78(4); 1044-57. ©2017 AACR.

Exome and genome sequencing of nasopharynx cancer identifies NF-κB pathway activating mutations.

Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-κB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-κB signalling, and we observed mutual exclusivity among tumours with somatic NF-κB pathway aberrations and LMP1-overexpression, suggesting that NF-κB activation is selected for by both somatic and viral events during NPC pathogenesis.

Peritonsillar Abscess: Complication of Acute Tonsillitis or Weber's Glands Infection?

OBJECTIVE: To review the literature concerning the 2 primary hypotheses put forth to explain the pathogenesis of peritonsillar abscess: "the acute tonsillitis hypothesis" (peritonsillar abscess is a complication of acute tonsillitis) and "the Weber gland hypothesis" (peritonsillar abscess is an infection of Weber's glands). DATA SOURCES: PubMed, EMBASE. REVIEW METHODS: Data supporting or negating one hypothesis or the other were elicited from the literature. CONCLUSIONS: Several findings support the acute tonsillitis hypothesis. First, the 2 main pathogens in peritonsillar abscess have been recovered from pus aspirates and bilateral tonsillar tissues with high concordance rates, suggesting that both tonsils are infected in patients with peritonsillar abscess. Second, studies report signs of acute tonsillitis in the days prior to and at the time of peritonsillar abscess. Third, antibiotic treatment reduces the risk of abscess development in patients with acute tonsillitis. However, some findings suggest involvement of the Weber's glands in peritonsillar abscess pathogenesis. First, high amylase levels have been found in peritonsillar pus. Second, the majority of peritonsillar abscesses are located at the superior tonsillar pole in proximity of the Weber's glands. We propose a unified hypothesis whereby bacteria initially infect the tonsillar mucosa and spread via the salivary duct system to the peritonsillar space, where an abscess is formed. IMPLICATIONS FOR PRACTICE: Our findings support the rationale for antibiotic treatment of patients with severe acute tonsillitis to reduce the risk of abscess development. Improved understanding of peritonsillar abscess pathogenesis is important for the development of efficient prevention strategies.

Genomic landscape of human papillomavirus-associated cancers.

Recent next-generation sequencing studies have generated a comprehensive overview of the genomic landscape of human papillomavirus (HPV)-associated cancers. This review summarizes these findings to provide insight into the tumor biology of these cancers and potential therapeutic opportunities for HPV-driven malignancies. In addition to the tumorigenic properties of the HPV oncoproteins, integration of HPV DNA into the host genome is suggested to be a driver of the neoplastic process. Integration may confer a growth and survival advantage via enhanced expression of viral oncoproteins, alteration of critical cellular genes, and changes in global promoter methylation and transcription. Alteration of cellular genes may lead to loss of function of tumor suppressor genes, enhanced oncogene expression, loss of function of DNA repair genes, or other vital cellular functions. Recurrent integrations in RAD51B, NR4A2, and TP63, leading to aberrant forms of these proteins, are observed in both HPV-positive head and neck squamous cell carcinoma (HNSCC) and cervical carcinoma. Additional genomic alterations, independent of integration events, include recurrent PIK3CA mutations (and aberrations in other members of the PI3K pathway), alterations in receptor tyrosine kinases (primarily FGFR2 and FGFR3 in HPV-positive HNSCC, and ERBB2 in cervical squamous cell carcinoma), and genes in pathways related to squamous cell differentiation and immune responses. A number of the alterations identified are potentially targetable, which may lead to advances in the treatment of HPV-associated cancers.

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors.

The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.

The interplay between HPV and host immunity in head and neck squamous cell carcinoma.

Persistent infection with human papillomavirus (HPV) type 16 is a major risk factor for the development of head and neck squamous cell carcinoma (HNSCC), in particular oropharyngeal squamous cell carcinoma (OPSCC). The oropharyngeal epithelium differs from the mucosal epithelium at other commonly HPV16-infected sites (i.e., cervix and anogenital region) in that it is juxtaposed with the underlying lymphatic tissue, serving a key immunologic function in the surveillance of inhaled and ingested pathogens. Therefore, the natural history of infection and immune response to HPV at this site may differ from that at other anatomic locations. This review summarizes the literature concerning the adaptive immune response against HPV in the context of HNSCC, with a focus on the T-cell response. Recent studies have shown that a broad repertoire of tumor-infiltrating HPV-specific T-cells are found in nearly all patients with HPV-positive tumors. A systemic response is found in only a proportion of these. Furthermore, the local response is more frequent in OPSCC patients than in cervical cancer patients and HPV-negative OPSCC patients. Despite this, tumor persistence may be facilitated by abnormalities in antigen processing, a skewed T-helper cell response, and an increased local prevalence of T-regulatory cells. Nonetheless, the immunologic profile of HPV-positive vs. HPV-negative HNSCC is associated with a significantly better outcome, and the HPV-specific immune response is suggested to play a role in the significantly better response to therapy of HPV-positive patients. Immunoprofiling may prove a valuable prognostic tool, and immunotherapy trials targeting HPV are underway, providing hope for decreasing treatment-related toxicity.

Parapharyngeal abscess is frequently associated with concomitant peritonsillar abscess.

To characterize patients with parapharyngeal abscess admitted to a Danish tertiary care centre and evaluate our management. This is a retrospective chart review. All records of patients with parapharyngeal abscess admitted to the Ear-Nose-Throat Department at Aarhus University Hospital, Denmark, from January 2001 through December 2011 were reviewed. In total, 63 patients (41 males), aged 4-89 years (median, 45 years) were included in the study. The mean annual incidence of parapharyngeal abscess was 0.9 cases/100,000 population. Thirty-three (52%) patients had concomitant peritonsillar abscess. In two patients the parapharyngeal abscess was accompanied by necrotizing fasciitis. The most frequent surgical approach used was intrapharyngeal incision in combination with tonsillectomy. The most commonly used antibiotic regimen was benzylpenicillin plus metronidazole. Seven (13%) patients returned to the operating theatre due to post-tonsillectomy haemorrhage or insufficient abscess drainage. Tonsillectomy and internal incision of the abscess in combination with a narrow-spectrum intravenous penicillin and metronidazole is a safe and efficient approach for managing parapharyngeal abscesses. This approach, however, carries a relatively high complication rate, requiring close surveillance in the early post-operative period. This is especially true for parapharyngeal abscess patients without peritonsillar abscess. In our series, these patients were more ill, more likely to experience complications, require intensive care, intubation, and tracheotomy, than parapharyngeal abscess patients with concurrent peritonsillar abscess. The frequent co-existence of parapharyngeal abscess and peritonsillar abscess favours careful consideration of addition of tonsillectomy to intrapharyngeal incision.