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Abstract Background Myxoid liposarcoma is a relatively common malignant soft tissue tumor, characterized by a (12;16) translocation resulting in a FUS-DDIT3 fusion gene playing a pivotal role in its tumorigenesis. Treatment options in patients with inoperable or metastatic myxoid liposarcoma are relatively poor though being developed and new hope is growing. Results Using kinome profiling and subsequent pathway analysis in two cell lines and four primary cultures of myxoid liposarcomas, all of which demonstrated a FUS-DDIT3 fusion gene including one new fusion type, we aimed at identifying new molecular targets for systemic treatment. Protein phosphorylation by activated kinases was verified by Western Blot and cell viability was measured before and after treatment of the myxoid liposarcoma cells with kinase inhibitors. We found kinases associated with the atypical nuclear factor-kappaB and Src pathways to be the most active in myxoid liposarcoma. Inhibition of Src by the small molecule tyrosine kinase inhibitor dasatinib showed only a mild effect on cell viability of myxoid liposarcoma cells. In contrast, inhibition of the nuclear factor-kappaB pathway, which is regulated by the FUS-DDIT3 fusion product, in myxoid liposarcoma cells using casein kinase 2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) showed a significant decrease in cell viability, decreased phosphorylation of nuclear factor-kappaB pathway proteins, and caspase 3 mediated apoptosis. Combination of dasatinib and TBB showed an enhanced effect. Conclusion Kinases associated with activation of the atypical nuclear factor-kappaB and the Src pathways are the most active in myxoid liposarcoma in vitro and inhibition of nuclear factor-kappaB pathway activation by inhibiting casein kinase 2 using TBB, of which the effect is enhanced by Src inhibition using dasatinib, offers new potential therapeutic strategies for myxoid liposarcoma patients with advanced disease.

Accurate, consistent and reproducible grading by pathologists is of key‐importance for identification of individual patients with invasive breast cancer (IBC) that will or will not benefit from adjuvant systemic treatment. We studied the laboratory‐specific grading variation using nationwide real‐life data to create insight and awareness in grading variation. Synoptic pathology reports of all IBC resection‐specimens, obtained between 2013 and 2016, were retrieved from the nationwide Dutch Pathology Registry (PALGA). Absolute differences in laboratory‐proportions of Grades I–III were compared to the national reference. Multivariable logistic regression provided laboratory‐specific odds ratios (ORs) for high‐ vs. low‐grade IBC. 33,792 IBC pathology reports of 33,043 patients from 39 laboratories were included, of which 28.1% were reported as Grade I (range between laboratories 16.3–43.3%), 47.6% as Grade II (38.4–57.8%), and 24.3% as Grade III (15.5–34.3%). Based on national guidelines, the indication for adjuvant chemotherapy was dependent on histologic grade in 29.9% of patients. After case‐mix correction, 20 laboratories (51.3%) showed a significantly deviant OR. Significant grading differences were also observed among pathologists within laboratories. In this cohort of 33,043 breast cancer patients, we observed substantial inter‐ and intra‐laboratory variation in histologic grading. It can be anticipated that this has influenced outcome including exposure to unnecessary toxicity, since choice of adjuvant chemotherapy was dependent on grade in nearly a third of patients. Better standardization and training seems warranted. What's new? Histologic grade serves a critical prognostic role in invasive breast cancer (IBC) and is used to guide therapeutic decisions. Evidence indicates, however, that IBC grading varies considerably. Here, grading variation in clinical practice was evaluated using real‐life data from laboratories in the nationwide Dutch Pathology Registry. Laboratories varied in IBC grade I, II, and III reporting. Among grading components, nuclear polymorphism showed the greatest difference between laboratories. Within laboratories, one‐third of pathologists deviated significantly from national proportions for IBC grade I. Despite deployment of uniform guidelines across laboratories, IBC histologic grading is not necessarily performed in a consistent manner. [ABSTRACT FROM AUTHOR]

Objective: Most studies that report on salvage surgery after primary radiotherapy for head and neck squamous cell carcinoma (HNSCC) are small and heterogeneous. Subsequently, some relevant questions remain unanswered. We specifically focused on (1) difference in prognosis per tumor subsite, corrected for disease stage, and (2) differences in prognosis after salvage surgery for local, regional, and locoregional recurrences.Study Design: Retrospective analysis.Setting: Single-center study (2000-2016).Subjects and Methods: Patients treated with salvage surgery for HNSCC recurrence after (chemo)radiotherapy.Results: In total, 189 patients were included. Five-year overall survival (OS) was 33%, and median OS was 18 (95% confidence interval [CI], 11-26) months. Treatment-related mortality was 2%. Larynx carcinoma was associated with more favorable local (adjusted hazard ratio [HR] = 4.02; 95% CI, 1.46-11.10; P = .007) and locoregional control (adjusted HR = 5.34; 95% CI, 1.83-15.61; P = .002) than pharyngeal carcinoma. American Society of Anesthesiologists (ASA) score (≥3 vs 1-2: adjusted HR = 3.04; 95% CI, 1.17-7.91; P = .023), pT stage (3-4 vs 1-2: adjusted HR = 4.41; 95% CI, 1.65-11.82; P = .003), and salvage surgery for locoregional recurrences (locoregional vs local: adjusted HR = 3.81; 95% CI, 1.13-11.82; P = .021) were independent predictors for disease-free survival (DFS).Conclusion: Salvage surgery for larynx carcinoma, regardless of disease stage and other prognostic factors, results in more favorable loco(regional) control but not favorable DFS than pharyngeal carcinoma. The observed difference in DFS between salvage surgery for local and regional recurrences was not significant after correction for confounders. However, survival following salvage surgery for locoregional disease is significantly worse. For this subgroup, we propose to consider T status and comorbidity for clinical decision making, as high pT stage and ASA score are independent predictors for worse DFS. [ABSTRACT FROM AUTHOR]

Purpose: A considerable part of ductal carcinoma in situ (DCIS) lesions may never progress into invasive breast cancer. However, standard treatment consists of surgical excision. Trials aim to identify a subgroup of low-risk DCIS patients that can safely forgo surgical treatment based on histologic grade, which highlights the importance of accurate grading. Using real-life nationwide data, we aimed to create insight and awareness in grading variation of DCIS in daily clinical practice.Methods: All synoptic pathology reports of pure DCIS resection specimens between 2013 and 2016 were retrieved from PALGA, the nationwide Dutch Pathology Registry. Absolute differences in proportions of grade I-III were visualized using funnel plots. Multivariable analysis was performed by logistic regression to correct for case-mix, providing odds ratios and 95% confidence intervals for high-grade (III) versus low-grade (I-II) DCIS.Results: 4952 DCIS reports from 36 laboratories were included, of which 12.5% were reported as grade I (range 6.1-24.4%), 39.5% as grade II (18.2-57.6%), and 48.0% as grade III (30.2-72.7%). After correction for case-mix, 14 laboratories (38.9%) reported a significantly lower (n = 4) or higher (n = 10) proportion of high-grade DCIS than the reference laboratory. Adjusted ORs (95%CI) ranged from 0.52 (0.31-0.87) to 3.83 (1.42-10.39). Significant grading differences were also observed among pathologists within laboratories.Conclusion: In this cohort of 4901 patients, we observed substantial inter- and intra-laboratory variation in DCIS grading, not explained by differences in case-mix. Therefore, there is an urgent need for nationwide standardization of grading practices, especially since the future management of DCIS may alter significantly depending on histologic grade. [ABSTRACT FROM AUTHOR]

Purpose: Medullary thyroid carcinoma (MTC) derives from the parafollicular C-cells of the thyroid gland. Somatostatin receptors (SSTRs) are expressed in various neuroendocrine tumours including MTC. The aim of this study was to evaluate SSTR2A as a prognostic factor for MTC, to study distribution of SSTR2A expression within tumours and to compare expression of SSTR2A between primary tumours and corresponding lymph node metastases.Methods: Patients who underwent surgery between 1988 and 2014 for MTC from five tertiary referral centres in The Netherlands were included. In total, primary tumours of 114 patients and lymph node metastases of 34 patients were analysed for expression of SSTR2A using a tissue microarray, and correlated with clinicopathological variables and survival.Results: The mean age of patients was 45.5 years (SD 16.2), 55 patients were male (49.5%). Primary tumours of 58 patients (50.9%) showed SSTR2A expression. In multivariate Cox-regression analysis, SSTR2A positivity correlated independently with better overall survival (OS) (HR 0.3; 95% CI 0.1-1.0). In stage IV MTC patients, 10-year survival rates for SSTR2A-negative and positive patients were 43% and 96%, respectively. In 53.9% of patients with lymph node metastases, expression in primary tumour and lymph node metastases differed.Conclusion: SSTR2A expression is correlated with longer OS in MTC, especially for stage IV patients, suggesting that SSTR2A expression might be a useful prognostic factor in MTC. The SSTR2A status of the primary MTC does not predict expression in lymph node metastases. [ABSTRACT FROM AUTHOR]

Introduction: Accurate assessment of cervical lymph node status is essential in patients with head and neck squamous cell carcinoma (HNSCC) as it influences prognosis and treatment decisions. During patient workup, lymph node status is often examined by ultrasound guided fine needle aspiration cytology (USgFNAC). 18F-Fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG PET-CT) is frequently used to assess primary tumor and distant metastases but provides information on lymph node status as well. It is possible that FDG PET-CT (if already made for abovementioned indications) can predict the results of USgFNAC in subgroups of lymph nodes based on FDG-uptake and size. The objective of this study is to identify maximum standardized uptake (SUVmax) and short axis diameter cutoff values of lymph nodes at which FDG PET-CT can reliably predict USgFNAC results. Methods: One hundred and seventeen patients with HNSCC were retrospectively analyzed. Patients were included when FDG PET-CT and USgFNAC were available. SUVmax measurements were performed and compared to the USgFNAC results. Results: Using USgFNAC as a reference standard, the area under the curve of the receiver operating curve was 0.91. At an SUVmax cutoff value of 4.9, the accuracy of FDG PET-CT was the highest (85%). Lymph nodes with short axis diameter ≥1.0 cm and SUVmax ≥4.9 were in 91% positive on USgFNAC. If SUVmax was below 2.2, no nodes were positive on USgFNAC. Of all lymph nodes 52% either had a short axis diameter ≥1.0 cm and SUVmax ≥4.9 or an SUVmax <2.2. FDG PET-CT and USgFNAC results were very similar in these nodes. Conclusions: By measuring SUVmax values and minimal axial diameters of lymph nodes and using appropriate cutoff values, FDG PET-CT can predict the results of USgFNAC examinations in half of the examined lymph nodes. This information may lead to a reduction of USgFNAC examinations in HNSCC patients if FDG PET-CT is already performed for other indications. [ABSTRACT FROM AUTHOR]

Biphenotypic sinonasal sarcoma (BSNS) is a recently recognized type of sarcoma arising exclusively in the sinonasal tract displaying unique clinical course, histopathology, and genetics. Due to its rarity, only case series and case reports are available. In order to provide an overview of the current understanding of this disease, we present a comprehensive review of the literature and present three previously unreported cases of BSNS. A total of 55 genetically characterized and 41 cases without molecular data were identified in the literature. Two-thirds of patients were female and the peak incidence was in the fifth decade. Fatal outcome was rare (two cases with intracranial extension) and local recurrence occurred in 31.6%, all occurring within 5 years after initial treatment. Histologically, BSNS is highly cellular in the majority of cases and composed of fascicles of spindle cells, with entrapped hyperplastic surface epithelium being a frequent finding. The immunohistochemical profile is characteristic due to the biphasic nature of this lesion, with shared features of both myogenic and neural origin. Rhabdomyoblastic differentiation is apparent in a subset of cases. The most common genetic event is the PAX3-MAML3 fusion (58.6%) but isolated PAX3 rearrangement (19.2%), absence of rearrangements (9.1%), PAX3-FOXO1 (8.1%), PAX3-NCOA1 (4%), and isolated MAML3 rearrangement (2%) have also been reported. In conclusion, the recognition of BSNS is crucial due to its relatively indolent clinical course. A selected immunohistochemical panel and/or molecular confirmation can be used to aid in appropriate diagnosis and consequently in prognostication and to avoid overtreatment with chemotherapy regimens used in its mimics. [ABSTRACT FROM AUTHOR]