Search

In this era of information technology, big data analysis is entering biomedical sciences. But what is big data, where do they come from and what can we do with it? In this commentary, the main sources of big data are explained, especially in (head and neck) oncology. It also touches upon the need to integrate various sources of clinical, pathological and quality-of-life data. It discusses some initiatives in linking of such datasets on a nation-wide scale in the Netherlands. Finally, it touches upon important issues regarding governance, FAIRness of data and the need to bring into place the necessary infrastructures needed to fully exploit the full potential of big data sets in head and neck cancer. [ABSTRACT FROM AUTHOR]

Introduction In oral squamous cell carcinoma (OSCC) the differentiation grade of the tumor is determined on the biopsy and the resection specimen. The relation between tumor grade, nodal metastasis and survival is debatable. The aims of this study were to determine the correlation between differentiation grade of the biopsy and the resection specimen. Furthermore, we wanted to correlate tumor differentiation grade with nodal stage and survival. Patients and methods One-hundred and forty-five patients with OSCC staged as T1-2, N0 of the tongue, floor of mouth or cheek with primary resection of the tumor were examined. Biopsy and resection specimen were histologically re-assessed with regard to differentiation grade, as well as infiltrative, peri-neural and vascular invasive growth. Results This study showed a poor correlation between differentiation grade in the incisional biopsy and the resection specimen of the same tumor. No significant relation between differentiation grade of the resection specimen and nodal involvement, as well as overall and disease-specific survival was found. Conclusion In early OSCC the differentiation grade determined by biopsy is of little predictive value for the grading of the resection specimen. Poor differentiation grade could not be related to the presence of nodal metastasis or survival and seems not to have any prognostic value concerning outcome. Treatment planning must be related to these findings. [ABSTRACT FROM AUTHOR]

Objectives: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) is used for detection and (re)staging of prostate cancer. However, healthy salivary, seromucous, and lacrimal glands also have high PSMA-ligand uptake. This study aimed to describe physiologic PSMA-ligand uptake distribution characteristics in the head and neck to aid in PSMA PET/CT interpretation and to identify possible new clinical applications for PSMA-ligand imaging.Study Design: Thirty consecutive patients who underwent PSMA PET/CT for prostate cancer were evaluated. Tracer maximum standardized uptake values (SUVmax) in the salivary, seromucous, and lacrimal glands were determined visually and quantitatively. Overall and intraindividual variations were reported.Results: All gland locations had increased tracer uptake. The mean SUVmax ± standard deviation varied: parotid 12.3 ± 3.9; submandibular 11.7 ± 3.5; sublingual 4.5 ± 1.9; soft palate 2.4 ± 0.5; pharyngeal wall 4.3 ± 1.3; nasal mucosa 3.4 ± 0.9; supraglottic larynx 2.7 ± 0.7; and lacrimal 6.2 ± 2.2. The parotid had the largest overall variation in SUVmax (5.2-22.9), and the sublingual glands had the largest mean intraindividual difference (18.1%).Conclusions: Major and minor salivary and seromucous glands consistently have high PSMA-ligand uptake. Minor gland locations can be selectively visualized by this technique for the first time. This provides potential new applications such as quantification of present salivary gland tissues and individualization of radiotherapy for head and neck cancer or lutetium-177-PSMA radionuclide treatment. [ABSTRACT FROM AUTHOR]

Purpose: Stereotactic body radiation therapy (SBRT) is a highly effective and potentially ablative treatment for complex spinal metastases. Recent data have suggested radiobiologic effects of SBRT that expand beyond the traditional concept of DNA damage. Antitumor immunity, vascular damage leading to tumor necrosis, and increased rates of tumor apoptosis have been implied; however, in-human evidence remains scarce. The present study reports unique pathologic confirmation of SBRT-induced biological effects within spinal metastases treated with preoperative SBRT.Methods and Materials: Ten patients with spinal metastases secondary to various solid tumors were treated with preoperative single-fraction SBRT (18 Gy) to the magnetic resonance imaging-defined macroscopic metastasis, followed by spinal stabilization within 24 hours. Perioperative samples of spinal metastases were obtained, and 6 patients also had a pre-SBRT biopsy specimen available for a matched comparison. The samples were stained for tumor necrosis on routine hematoxylin-eosin-stained slices and, subsequently, immunohistochemical staining for T cells (CD3+, CD4+, CD8+), natural killer cells (CD56+), endothelium (CD31+), and apoptotic activity (caspase-3).Results: Perioperative biopsy specimens were obtained ∼6 hours (range 4.5-7.5) or 21 hours (range 18.5-22.5) after SBRT. Necrosis was observed in 83% of the 21-hour post-SBRT samples (5 of 6) compared with 0% of pre-SBRT biopsies (0 of 6) and 6-hour post-SBRT biopsies (0 of 4). Tumor cell apoptosis had increased greatly in the 21-hour post-SBRT samples compared with before and 6 hours after SBRT. The CD31+ vessel counts decreased after SBRT, as did mitotic activity. Both of the renal cell metastases displayed major decreases in vessel density. Desmoplastic reaction was visible in 67% (4 of 6) of the pre-SBRT samples compared with 100% (10 of 10) the post-SBRT samples. The T-cell and natural killer cell counts were relatively unaffected.Conclusions: High-dose single-fraction SBRT induced tumor necrosis, desmoplasia, and tumor apoptosis and decreased tumor vessel density within 24 hours, even in renal cell metastases. The role of immune cells seems limited in this early phase. These first-in-human results imply direct vascular and DNA damage mechanisms important in the clinical efficacy specific to spinal SBRT. [ABSTRACT FROM AUTHOR]

Objectives: Tumor infiltrating lymphocytes (TILs) correlate with both better and worse prognosis in solid tumors. As therapeutic modalities for nasopharyngeal carcinoma (NPC) are limited, immunotherapy could be a potential alternative. Up till now there is limited prognostic data on the role of TILs in NPC, so we assessed the prognostic role of TILs in Epstein-Barr-virus (EBV) positive and negative NPC.Methods: Tissue of 92 NPCs was assessed for CD3, CD4, CD8, PD1 and PDL1 expression in the tumor's micro-environment. Correlations between clinicopathological characteristics was assessed using the Pearson X2 test, Fisher's exact test and ANOVA. Survival was analyzed with the Kaplan-Meier method and Cox regression. Differences in CD3, CD4, CD8, PD1, PDL1 counts/(co)expression between EBV positive and negative NPCs were evaluated using the Mann-Whitney U test. Two-tailed P values below 0.05 were considered statistically significant.Results: EBV positive NPC contains significantly more CD3, CD4 and CD8 TILs than EBV negative NPC. In the whole NPC group, increased CD8 count is associated with better overall survival (OS) (HR 0.219 (95%CI 0.075-0.640)), but also in cases with PDL1 co-expression (HR 0.073 (95%CI 0.010-0.556)). In EBV positive NPC co-expression of CD8 and PDL1 showed better disease free survival (HR 0.407 (95%CI 0.195-0.850)) and OS (HR 0.170 (95%CI 0.037-0.787)).Conclusions: Although TILs are significantly different between EBV positive and negative NPCs, it is especially composition of the infiltrate which determines prognosis. Effects of PD1 and CD8 need more study, because these findings show much potential in using immunotherapeutic modalities in NPC treatment. [ABSTRACT FROM AUTHOR]

Summary The Nucleosome Remodeling and Deacetylase (NURD) complex is a key regulator of cell differentiation that has also been implicated in tumorigenesis. Loss of the NURD subunit Deleted in Oral Cancer 1 (DOC1) is associated with human oral squamous cell carcinomas (OSCCs). Here, we show that restoration of DOC1 expression in OSCC cells leads to a reversal of epithelial-mesenchymal transition (EMT). This is caused by the DOC1-dependent targeting of NURD to repress key transcriptional regulators of EMT. NURD recruitment drives extensive epigenetic reprogramming, including eviction of the SWI/SNF remodeler, formation of inaccessible chromatin, H3K27 deacetylation, and binding of PRC2 and KDM1A, followed by H3K27 methylation and H3K4 demethylation. Strikingly, depletion of SWI/SNF mimics the effects of DOC1 re-expression. Our results suggest that SWI/SNF and NURD function antagonistically to control chromatin state and transcription. We propose that disturbance of this dynamic equilibrium may lead to defects in gene expression that promote oncogenesis. [ABSTRACT FROM AUTHOR]

Summary Most BRAF ( V600E ) mutant melanomas are sensitive to selective BRAF inhibitors, but BRAF mutant colon cancers are intrinsically resistant to these drugs because of feedback activation of EGFR. We performed an RNA-interference-based genetic screen in BRAF mutant colon cancer cells to search for phosphatases whose knockdown induces sensitivity to BRAF inhibition. We found that suppression of protein tyrosine phosphatase non-receptor type 11 ( PTPN11 ) confers sensitivity to BRAF inhibitors in colon cancer. Mechanistically, we found that inhibition of PTPN11 blocks signaling from receptor tyrosine kinases (RTKs) to the RAS-MEK-ERK pathway. PTPN11 suppression is lethal to cells that are driven by activated RTKs and prevents acquired resistance to targeted cancer drugs that results from RTK activation. Our findings identify PTPN11 as a drug target to combat both intrinsic and acquired resistance to several targeted cancer drugs. Moreover, activated PTPN11 can serve as a biomarker of drug resistance resulting from RTK activation. [ABSTRACT FROM AUTHOR]

Summary: Objectives: The treatment strategy of early stage oral squamous cell carcinoma’s (OSCC) resected with close or involved margins is a returning point of discussion. In this study we reviewed the consequences of re-resection (RR), postoperative radiotherapy (PORT) or watchful waiting (WW). Patients and methods: Two-hundred patients with a primary resected Stage 1–2 OSCC of the tongue, floor of the mouth and cheek were included and retrospectively analysed. Local recurrence ratio was related to margin status, unfavourable histological parameters (spidery infiltrative, peri-neural and vascular-invasive growth) and postoperative treatment modality. 3-year overall survival (OS) and disease-specific survival (DSS) was calculated in relation to margin status. Results: Twenty-two of 200 (11%) patients had pathological positive margins (PM), 126 (63%) close margins (CM), and 52 (26%) free margins (FM). OS and DSS were not significantly different between these groups. Nine of 200 (4.5%) patients developed local recurrent disease. Two (9.1%) had a PM, five (4.0%) a CM and two (3.8%) a FM. Of the nine recurrences, five patients had undergone PORT, one a RR, and three follow-up. Watchful waiting for CM ⩾3mm with ⩽2 unfavourable histological parameters showed, besides margin status no significant differences with the FM group. Conclusion: With this treatment strategy, the local recurrence rate was 4.5%. No evidence was found for local adjuvant treatment in case of close margins ⩾3mm with ⩽2 unfavourable histological parameters. Current data do not support the use of one treatment modality above any other. [ABSTRACT FROM AUTHOR]

• The head and neck cancer incidence was nearly 25% less during the first COVID wave. • The lower incidence was mainly observed in oral cavity and laryngeal cancer. • During COVID, tumor stage and treatment distribution did not differ. • The expected increase in incidence during the remainder of 2020 was not observed. • Time-to-treatment was significantly shorter, regardless of first treatment modality. Inevitably, the emergence of COVID-19 has impacted non-COVID care. Because timely diagnosis and treatment are essential, especially for patients with head and neck cancer (HNC) with fast-growing tumours in a functionally and aesthetically important area, we wished to quantify the impact of the COVID-19 pandemic on HNC care in the Netherlands. This population-based study covered all, in total 8468, newly diagnosed primary HNC cases in the Netherlands in 2018, 2019 and 2020. We compared incidence, patient and tumour characteristics, primary treatment characteristics, and time-to-treatment in the first COVID-19 year 2020 with corresponding periods in 2018 and 2019 (i.e. pre-COVID). The incidence of HNC was nearly 25% less during the first wave (n = 433) than in 2019 (n = 595) and 2018 (n = 598). In April and May 2020, the incidence of oral cavity and laryngeal carcinomas was significantly lower than in pre-COVID years. There were no shifts in tumour stage or alterations in initial treatment modalities. Regardless of the first treatment modality and specific period, the median number of days between first visit to a HNC centre and start of treatment was significantly shorter during the COVID-19 year (26–28 days) than pre-COVID (31–32 days, p < 0.001). The incidence of HNC during the Netherlands' first COVID-19 wave was significantly lower than expected. The expected increase in incidence during the remainder of 2020 was not observed. Despite the overloaded healthcare system, the standard treatment for HNC patients could be delivered within a shorter time interval. [ABSTRACT FROM AUTHOR]

Because the tyrosine kinases c-MET and vascular endothelial growth factor receptors (VEGFR) are often overexpressed in salivary gland cancer (SGC), this study evaluated the efficacy and safety of cabozantinib in patients with recurrent/metastatic (R/M) SGC. A single-centre phase II study was conducted. Patients with immunohistochemical c-MET-positive R/M SGC were included in three cohorts: adenoid cystic carcinoma (ACC); salivary duct carcinoma (SDC) and other miscellaneous SGCs. No prior systemic treatments were required. Patients started cabozantinib 60 mg once daily. The primary outcome was the objective response rate (ORR). Secondary outcomes included survival, safety and quality of life. Per Simon-two-stage design, depending on efficacy, a maximum of 43 patients would be included. In total, 25 patients were included until premature closure owing to severe toxicity. Six patients (24%) had grade 3–5 wound complications, occurring at a median of 7.1 months on cabozantinib treatment (range 2.1–12.6). Remarkably, four of these six patients developed this complication in the area prior exposed to high-dose radiotherapy. Other grade ≥3 adverse events in >1 patient were hypertension (20%), diarrhoea (8%) and dehydration (8%). Twenty-one patients were evaluable for response; 1/15 ACC (ORR: 7%); 1/4 SDC and 0/2 patients with other miscellaneous SGC responded. Median progression-free survival was 9.4 months (95% confidence interval [CI] 7.4–11.4 months), 7.2 months (95%CI 0.0–15.1) and 6.9 months (95%CI 0.0–15.1), respectively. This study showed too many severe cabozantinib-associated wound complications in patients with SGC, especially in prior irradiated areas. Therefore, the study closed prematurely. The efficacy in the limited number of evaluable patients was low to moderate. This trial was registered on ClinicalTrials.gov: NCT03729297. • Phase II study of cabozantinib in patients with salivary gland cancer. • Study closed prematurely owing to severe wound complications. • Wound complications occurred especially in prior irradiated areas. • The efficacy of cabozantinib was low to moderate in this study. • Caution with cabozantinib is advised in patients with prior high-dose radiotherapy. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is an endemic malignancy in Southeast Asia, particularly Southern China. The classical non-keratinising cell type is almost unanimously associated with latent Epstein–Barr virus (EBV) infection. Circulating plasma EBV DNA can be a useful biomarker in various clinical aspects, but comprehensive recommendations and international guidelines are still lacking. We conducted a systematic review of all original articles on the clinical application of plasma EBV DNA for NPC; we further evaluated its strengths and limitations for consideration as standard recommendations. The search terms 'nasopharyngeal OR nasopharynx', and 'plasma EBV DNA OR cell-free EBV OR cfEBV' were used to identify full-length articles published up to December 2020 in the English literature. Three authors independently reviewed the article titles, removed duplicates and reviewed the remaining articles for eligibility. A total of 81 articles met the eligibility criteria. Based on the levels of evidence and grades of recommendation assessed, it is worth considering the inclusion of plasma EBV DNA in screening, pre-treatment work-up for enhancing prognostication and tailoring of treatment strategy, monitoring during radical treatment, post-treatment surveillance for early detection of relapse, and monitoring during salvage treatment for recurrent or metastatic NPC. One major limitation is the methodology of measurement requiring harmonisation for consistent comparability. The current comprehensive review supports the inclusion of plasma EBV DNA in international guidelines in the clinical aspects listed, but methodological issues must be resolved before global application. • Plasma Epstein–Barr virus DNA has been the most reliable and accurate marker in nasopharyngeal carcinoma management. • We provide evidence-based recommendations on its use in various clinical settings. • We support its inclusion in international guidelines in the aspects listed. • Limitations and methodological issues must be resolved before its global application. [ABSTRACT FROM AUTHOR]

• Mesenchymal characteristics are associated with poor prognosis in HPV-negative HNSCC. • Multiple EMT signatures confirm poor prognosis association. • Novel HNSCC-specific EMT prediction models predict patient outcomes. • Early metastatic disease prior to treatment linked to mesenchymal HNSCC. The prognosis of patients with HPV-negative advanced stage head and neck squamous cell carcinoma (HNSCC) remains poor. No prognostic markers other than TNM staging are routinely used in clinic. Epithelial-to-mesenchymal transition (EMT) has been shown to be a strong prognostic factor in other cancer types. The purpose of this study was to determine the role of EMT in HPV-negative HNSCC outcomes. Pretreatment tumor material from patients of two cohorts, totalling 174 cisplatin-based chemoradiotherapy treated HPV-negative HNSCC patients, was RNA-sequenced. Seven different EMT gene expression signatures were used for EMT status classification and generation of HNSCC-specific EMT models using Random Forest machine learning. Mesenchymal classification by all EMT signatures consistently enriched for poor prognosis patients in both cohorts of 98 and 76 patients. Uni- and multivariate analyses show important HR of 1.6–5.8, thereby revealing EMT's role in HNSCC outcome. Discordant classification by these signatures prompted the generation of an HNSCC-specific EMT profile based on the concordantly classified samples in the first cohort (cross-validation AUC > 0.98). The independent validation cohort confirmed the association of mesenchymal classification by the HNSCC-EMT model with poor overall survival (HR = 3.39, p < 0.005) and progression free survival (HR = 3.01, p < 0.005) in multivariate analysis with TNM. Analysis of an additional HNSCC cohort from PET-positive patients with metastatic disease prior to treatment further supports this relationship and reveals a strong link of EMT to the propensity to metastasize. EMT in HPV-negative HNSCC co-defines patient outcome after chemoradiotherapy. The generated HNSCC-EMT prediction models can function as strong prognostic biomarkers. [ABSTRACT FROM AUTHOR]

Rationale: This study evaluates the lymphatic drainage patterns and determines the accuracy of the sentinel lymph node biopsy (SLNB) in patients diagnosed with a cT1-2N0 OSCC and a history of neck surgery or radiotherapy in three Dutch head and neck centers.Materials and Methods: Retrospective analysis of 53 cT1-2N0 OSCC patients, who underwent SLNB between 2007 and 2016, after a history of neck surgery or radiotherapy. Ten patients had previous treatment of the neck only contralateral from the current tumour. These ten patients were not used for the analysis of lymphatic drainage patterns. The 43 patients with previous ipsilateral or bilateral treatment of the neck had a history of ipsilateral SLN extirpation (n = 9; 21%), neck dissection (n = 16; 37%), radiotherapy (n = 10; 23%), or combined neck dissection and radiotherapy (n = 8; 19%).Results: SLNs were detected in 45 patients, resulting in an identification rate of 85% (45/53). Three patients (7%) had at least one positive SLN. One patient (1/45; 2%) was diagnosed with regional recurrence during the follow-up after a negative SLNB (sensitivity 75%, negative predictive value 98%). The first SLN was detected in level I-III in 58% of the patients, unexpected drainage patterns were observed in 30% (first SLN level IV 9% and level V 5% and contralateral neck in well-lateralized tumours 16%). In 12% no lymphatic drainage pattern was visible.Conclusions: SLNB seems to be a reliable procedure for neck staging of cT1-2N0 OSCC patients with a previously treated neck. SLNB determines the individual lymphatic drainage patterns, enabling visualization of unexpected drainage pattern variability in 30% of these patients. [ABSTRACT FROM AUTHOR]

Early oral cancer is preferably treated by surgery. Its complete removal is essential for locoregional control and disease-free survival. Inadequate resection margins require adjuvant therapy such as re-resection or (chemo)radiation, that causes extra morbidity and oral discomfort. Intraoral ultrasonography (US) is reported to be of value in determining tumor thickness. Intraoperative visualization of the tumor may facilitate the resection and ensure adequate surgical margins. Furthermore, accurate prediction of tumor thickness could help determine the treatment strategy of the clinically node-negative neck, as thickness and depth of invasion are predictors of cervical metastasis as well as prognosticators of survival. The 8th edition of the American Joint Committee on Cancer staging system for oral squamous cell carcinoma has included depth of invasion as parameter for cT-stage. The aim of this review is to analyze the accuracy of intraoral US in determining tumor thickness in oral cancer. A systematic search was conducted, and the quality of the included papers was assessed using the QUADAS-2 tool for diagnostic accuracy studies. Subsequently, a meta-analysis was performed on the available individual participant data of 240 patients. Most of the twelve included studies focused on T1-2 tongue cancer (n = 129). Meta-analysis showed a high correlation in tumor thickness within this subgroup as measured by intraoral US and histopathology (r = 0.82, p < .001), with minor overestimation of 0.5 mm on US. It is concluded that intraoral US is very accurate in determining tumor thickness in early oral tongue cancer. [ABSTRACT FROM AUTHOR]

Liquid biopsy is a minimally invasive detection method for molecular biomarkers in body fluids which may serve as a novel tool in management of head and neck cancer. The purpose of this systematic review is to outline the current status of liquid biopsy in head and neck squamous cell carcinoma (HNSCC) patients by systematically identifying and qualifying all published studies on the diagnostic or prognostic value of cell-free nucleic acids detection for posttreatment disease monitoring and/or disease outcome. A search was performed in PubMed, EMBASE, and Cochrane Library. Thirty articles met the inclusion criteria for further analysis. Study and patient characteristics, molecular analysis method and treatment or prognostic outcomes were extracted. Seventeen studies investigated circulating miRNAs in blood. Of these studies, 16 found statistically significant results for a total of 24 different candidate miRNAs for prognostication or treatment monitoring. The remaining studies investigated circulating tumor DNA by targeting somatic mutations, allelic imbalances, hypermethylation, or HPV-DNA. Of these studies, 2 found a statistically significant association between nucleic acid levels (tumor DNA targeted by allelic imbalances and HPV-DNA) in blood and/or saliva and prognostic outcome. One study found significantly different pre- and posttreatment levels of mitochondrial DNA in serum. Despite large differences among these studies in both design and results, individual results are promising and provide ground for more large-scale studies with standardized serial assessment of patient samples in the future. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) is an immunogenic cancer type, and tumor associated macrophages (TAMs) are a major component of the tumor microenvironment (TME). In this systematic review and meta-analysis, studies assessing tumor infiltration with CD68+, iNOS+, HLA-DR+, CD11b+, CD163+, CD206+, and CD204+TAMs were included, and correlation to survival hazard was studied. A low number of CD68+TAMs correlated to better overall survival (OS) in multivariate analysis (HR 1.36 95 %CI (1.07-1.72) P = .01). CD68+TAMs did not correlate to disease free survival (DFS), disease specific survival (DSS), progression free survival (PFS), or recurrence free survival (RFS). A low number of CD163+TAMs correlated to better OS in uni- and multivariate analysis (resp. HR 2.65 95 %CI (1.57-4.46) P = .01 and HR 2.42 95 %CI (1.72-3.41) P < .001). A low number of CD163+TAMs also correlated to better DFS and PFS, whereas a low number of CD204+TAMs only correlated to PFS. While IHC analysis of pan macrophage marker CD68 and M2-like marker CD163 both show prognostic utility in OS, CD163 is a stronger prognosticator, as indicated by multivariate meta-analysis. CD163+TAMs also correlate to DFS and PFS; outcomes that are more relevant to patients, thus showing promising results for future clinical implementation. [ABSTRACT FROM AUTHOR]

Objective: Tumor hypoxia results in worse local control and patient survival. We performed a digital, single-cell-based analysis to compare two biomarkers for hypoxia (hypoxia-inducible factor 1-alpha [HIF-1α] and pimonidazole [PIMO]) and their effect on outcome in laryngeal cancer patients treated with accelerated radiotherapy with or without carbogen breathing and nicotinamide (AR versus ARCON).Materials and Methods: Immunohistochemical staining was performed for HIF-1α and PIMO in consecutive sections of 44 laryngeal cancer patients randomized between AR and ARCON. HIF-1α expression and PIMO-binding were correlated using digital image analysis in QuPath. High-density areas for each biomarker were automatically annotated and staining overlap was analyzed. Kaplan-Meier survival analyses for local control, regional control and disease-free survival were performed to predict a response benefit of ARCON over AR alone for each biomarker.Results: 106 Tissue fragments of 44 patients were analyzed. A weak, significant positive correlation was observed between HIF-1α and PIMO positivity on fragment level, but not on patient level. A moderate strength correlation (r = 0.705, p < 0.001) was observed between the number of high-density staining areas for both biomarkers. Staining overlap was poor. HIF-1α expression, PIMO-binding or a combination could not predict a response benefit of ARCON over AR.Conclusion: Digital image analysis to compare positive cell fractions and staining overlap between two hypoxia biomarkers using open-source software is feasible. Our results highlight that there are distinct differences between HIF-1α and PIMO as hypoxia biomarkers and therefore suggest co-existence of different forms of hypoxia within a single tumor. [ABSTRACT FROM AUTHOR]

Abstract: Histopathological parameters are essential for deciding on adjuvant treatment following breast cancer surgery. We assessed the impact of inter-observer variability on treatment strategy in patients operated for clinically node negative, non-palpable breast carcinomas. In the context of a multicenter randomised controlled trial, clinical and histological data of 310 patients with clinically node negative non-palpable invasive breast cancer were prospectively collected. Histological assessment of the primary tumour and sentinel nodes was first performed in a routine setting, subsequently central review took place. In case of discordance between local en central assessments, we determined the impact on locoregional and systemic treatment strategy. Discordance between local and central review was observed in 13% of the patients for type (kappa 0.60, 95% CI 0.50–0.71), in 12% for grade (k=0.796, 95% CI 0.73–0.86), in 1% for ER status (k=0.898, 95% CI 0.80–1.0), in 2% for PR status (k=0.940 95% CI 0.89–0.99). Discrepancy in the assessment of the sentinel node(s) was seen in 2% of the patients (k=0.954, 95% CI 0.92–0.98). Applying current Dutch Guidelines, central review would have affected locoregional treatment in 2% (7/310), systemic treatment in 5% (16/310) and both in 1% (2/310) of the patients. For the 9 (3%) patients in whom central review would have led to additional systemic treatment, Adjuvant! predicted 10 years mortality and recurrence rate would have decreased with a median of 4.6% and 15%, respectively. Discordance between routine histological assessment and central review of non-palpable breast carcinoma specimens and sentinel nodes was observed in 24% of patients. This inter-observer variation would have impacted locoregional and/or systemic treatment strategies in 8% of the patients. [Copyright &y& Elsevier]

Human papilloma virus (HPV) is a well-established causative factor in a subset of squamous cell carcinomas of the head and neck (HNSCC). Although HPV can be detected in various anatomical subsites, HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) is the most common HPV-related malignancy of the head and neck, and its worldwide incidence is constantly rising. Patients with OPSCC are generally younger, have less co-morbidities and generally have better prognosis due to different biological mechanisms of carcinogenesis. These facts have generated hypotheses on potential treatment modifications, aiming to minimize treatment-related toxicities without compromising therapy efficacy. Numerous randomized clinical trials have been designed to verify this strategy and increasingly real-world evidence data from retrospective, observational studies is becoming available. Until now, the data do not support any modification in contemporary treatment protocols. In this narrative review, we outline recent data provided by both randomized controlled trials and real-world evidence of HPV-positive OPSCC in terms of clinical value. We critically analyze the potential value and drawbacks of the available data and highlight future research directions. This article was written by members and invitees of the International Head and Neck Scientific Group.(www.IHNSG.com). [ABSTRACT FROM AUTHOR]

Objectives: Squamous cell carcinoma of the tongue (SCCT) is preferably treated by surgery. Free resection margins (≥5 mm) provide local control and disease-free survival. However, close (1-5 mm) and positive margins (<1 mm) are frequently encountered. We present our first experience of in-vivo ultrasound (US) guided SCCT resections followed by ex-vivo US control on the resection specimen to obtain free margins. We compare the results with those from a hisorical cohort of 91 conventionally treated SCCT patients.Materials and Methods: Ten patients with SCCT were included in a consecutive US-cohort. We aimed for a 5-10 mm margin during surgery, while we visualized the resection plane on US. Ex-vivo US measurements on the resection specimen determined whether there was any need for an immediate re-resection. US measurements were then compared with histopathology. Histopathological margins were compared with a consecutive cohort of 91 patients who had undergone conventional surgery for a SCCT.Results: In the US cohort, 70% of the margins were free. In the conventional cohort, this figure was 17% (P = 0.005). US predicted minimal histopathological margin distance with a mean ± SD error of 1.9 ± 1.8 mm. The mean ± SD of the histopathological overall submucosal/deep margin distance was 7.9 ± 2.1 mm in the US cohort and 7.0 ± 2.2 mm in the conventional cohort (P = 0.188). Ex-vivo examination through use of US indicated an immediate re-resection, which prevented local adjuvant treatment.Conclusion: Use of US-guided SCCT resection is feasible and improves margin control. [ABSTRACT FROM AUTHOR]

Objectives: Salivary duct carcinoma (SDC) is a rare and aggressive subtype of salivary gland cancer. Androgen receptor (AR) (96%) and HER2 (29-46%) expression, and a high propensity for regional lymph node metastases are hallmarks of the disease. We hypothesized that c-MET, E-cadherin, PSMA tumor and PSMA neovascular expression may be prognostic factors in SDC.Materials and Methods: Expression levels of these proteins were established on tissue microarrays containing 165 primary SDC tumor specimens. Association with survival was studied with Kaplan-Meier curves, and univariable and multivariable Cox regression models. Furthermore, association with lymph node status, AR and HER2 expression, and gender was studied.Results: We found that patients with high PSMA tumor expression showed a significantly longer overall survival (OS) (median 83 vs. 43 months, P = 0.022), a trend towards a longer DFS (median 51 vs. 22 months, P = 0.094), and significantly reduced hazard ratio for death in the univariable Cox regression model (HR 0.46, P = 0.034). In the multivariable model only a high number of tumor-positive lymph nodes and high age (>80) at diagnosis were prognostic for poor OS. High PSMA tumor expression was also significantly associated with low N-stage (P = 0.001) and expression was higher in women versus men (P = 0.029). High PSMA tumor expression and E-cadherin loss were significantly associated with strong and weak AR-expression, respectively (P = 0.033 and P = 0.007). None of the factors were significantly associated with HER2 expression.Conclusion: c-MET, E-cadherin, and tumor and neovascular PSMA expression are no independent prognostic factors in SDC. [ABSTRACT FROM AUTHOR]

Objectives: Complete resection of tongue cancer is necessary to achieve local control. Unfortunately, deep resection margins are frequently inadequate. To improve deep margin control, accurate knowledge of tumour thickness is pivotal. Magnetic resonance imaging (MRI) and intraoral ultrasound (ioUS) are frequently applied for tumour staging. This study explores the accuracy of these techniques to estimate depth of invasion.Materials and Methods: The data of patients with a T1-2 tongue cancer that had been treated surgically between 2014 and 2018 were retrospectively analysed. Measurements that had been taken by either MRI or ioUS were compared with those taken during histopathology.Results: A total of 83 patients with tongue cancer had undergone a pre-operative MRI and 107 had been studied through an ioUS. Tumour thickness measured by MRI (r = 0.72) and ioUS (r = 0.78) correlated significantly (p < 0.001) with histopathological depth of invasion (DOI). In tumours with a DOI of 0-10 mm, MRI has a mean absolute difference with histopathology of 3.1 mm (SD 3.2 mm) and ioUS of 1.6 mm (SD 1.3 mm). In tumours with a DOI greater than 10 mm, MRI has a mean absolute difference of 3.5 mm (SD 3.0 mm) and ioUS of 4.7 mm (SD 3.5 mm).Conclusion: Estimation of histopathological DOI in tongue cancers with DOI till 10 mm is very accurate through use of ioUS. ioUS tends to underestimate DOI in tumors exceeding 10 mm DOI. MRI tends to overestimate DOI in both thin and thick tumours. Since ultrasound measurements can be performed during surgery, ioUS could potentially guide the surgeon in the achievement of adequate resection margins. [ABSTRACT FROM AUTHOR]