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ContextAnaplastic thyroid carcinoma (ATC) represents one of the most aggressive carcinomas with no consistent survival benefit when treated with conventional radiochemotherapy. Approaches targeting “oncogene addiction” of ATC are increasingly explored and first promising results have been reported in single case studies.ObjectiveTo determine the prevalence of mutations in known thyroid oncogenes and signalling pathways amendable to targeted therapy in a large cohort of ATC.ResultsIn 118 ATC (57 male/ 61 female) a total of 165 mutations were found. Genes involved in the MAPK/ERK and PI3K pathway (BRAF 11.0%, HRAS 4.2%, KRAS 7.6%, NRAS 7.6%, PI3KCA 11.8%) were altered in 33%. Targetable receptor tyrosine kinases were mutated in 11%. The most frequently altered genes were TERT in 86/118 (73%) and p53 in 65/118 (55%) cases. No mutations were found analysing ALK, KIT, MET and mTOR.Materials and MethodsNext generation sequencing (NGS) was performed in FFPE samples from 118 ATC using MiSeq (Illumina) and CLC Cancer Research Workbench (CLCbio; Qiagen) for mutation analysis in: ALK, BRAF, CDKN2A, EGFR, ERBB2, HRAS, KIT, KRAS, MET, mTOR, NRAS, PDGFRA, PI3KCA, p53, RB1, RET and TSC2. Sanger sequencing was used to detect TERT promotor mutations.ConclusionsTo our knowledge this is the largest study analysing mutations for targeted therapy of ATC. We found that 33% of ATC harbour mutations in pathways amendable to targeted therapy. Molecular screening in ATC is suggested for targeted therapies since current conventional treatment for ATC proved mainly futile.

ROS1-positive metastatic lung adenocarcinomas frequently harbor concomitant oncogenic driver mutations. Levels of ROS1 FISH-positive events are variable over time. This heterogeneity provides additional therapeutic options if discovered by multiplex biomarker testing and repeat biopsies.

Background and study aims  The ideal treatment strategy for rectal neoplasia extending to the dentate line (RNDL) is not well defined. Endoscopic mucosal resection (EMR) and submucosal dissection (ESD) compete with surgical techniques such as transanal endoscopic microsurgery (TEM). Non-Asian data and prospective data on ESD are lacking. The study aim was to evaluate the role of ESD in treatment of RNDL in a Western center. Patients and methods  Eighty-six patients with rectal adenomas were included. ESD was performed in 86 rectal adenomas including 24 RNDLs (27.9 %) and 62 lesions distant from the dentate line (72.1 %). Results  En bloc resection rate was comparable (91.7 % vs. 93.5 %, P  = 0.670) between ESD for RNDL and non-RNDL. R0 resection rate was significantly lower in ESD for RNDL compared to that for non-RNDL (70.8 % vs 88.7 %; P  = 0.039), but most non-R0 resection was unclear margin (Rx) and was not obvious positive margin (R1). Accordingly, the recurrence rate after ESD for RNDL (4.5 %) was not statistically different from that for non-RNDL (0 %, P  = 0.275) and was lower than that previously reported for EMR. Median procedure time was 127 vs. 110 minutes ( P  = 0.182). Risk of delayed bleeding (20.8 % vs. 0 %, P  = 0.001) and postinterventional pain (33.3 % vs. 14.5 %, P  = 0.07) increased in RNDL cases, but they were managed conservatively. Incidence of stricture (4.2 % vs. 1.6 %, P  = 0.483) and perforation (0 % vs. 1.6 %, P  = 1.000) were similar. Conclusions  ESD is a feasible and safe resection technique for RNDLs. A randomized controlled trial comparing ESD to other methods (EMR or transanal surgery) is warranted.

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The International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS), and the European Respiratory Society (ERS) proposed a classification for lung adenocarcinomas (ADC) based on the predominant growth pattern. This classification has been shown to have prognostic and maybe even predictive impact. However, until now, the reproducibility of this classification has not been sufficiently demonstrated. Digital images of 40 selected ADC cases were shown twice to members of the Pulmonary Pathology Working Group of the German Society of Pathology. Each time a teledialogue-based survey on the classification was performed. Between the voting procedures, salient features of the novel classification were presented and discussed in detail by its members. The mean percentages of consensual votes per pattern ranged between 59.6 and 75 %, with lepidic and solid being the pattern with the most discordant and concordant votes, respectively. The other patterns ranged in between (papillary 65.8 %; acinar 67.8 %; micropapillary 74.2 %). The extent of disagreement decreased after the educational session. This decrease, however, was heterogeneous for the different patterns with acinar being the pattern with the strongest improvement. The overall number of abstentions decreased significantly after the educational session (p < 0.001) as well. The IASLC/ATS/ERS classification of lung ADC can be applied with reasonable consensus even for difficult cases in a nationwide context. The reproducibility evidently improves following educational sessions, even among experienced lung pathologists. Worldwide harmonization is clearly the next step on the way to a clinically meaningful, internationally accepted use of this novel prognostic and potentially predictive tool in lung pathology.

Infection with human papillomaviruses (HPVs) characterizes a distinct subset of head and neck squamous cell cancers (HNSCCs). HPV-positive HNSCC preferentially affect the oropharynx and tonsils. Localized HPV-positive HNSCCs have a favorable prognosis and treatment outcome. However, the impact of HPV in advanced or metastatic HNSCC remains to be defined. In particular, it is unclear whether HPV modulates the response to cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), which is a mainstay of treatment of advanced HNSCC. To this end, we have examined the sensitivity of HPV-positive and -negative HNSCC models to cetuximab and cytotoxic drugs in vitro and in vivo. In addition, we have stably expressed the HPV oncogenes E6 and E7 in cetuximab-sensitive cancer cell lines to specifically investigate their role in the antibody response. The endogenous HPV status or the expression of HPV oncogenes had no significant impact on cetuximab-mediated suppression of EGFR signaling and proliferation in vitro. Cetuximab effectively inhibited the growth of E6- and E7-expressing tumors grafted in NOD/SCID mice. In support, formalin-fixed, paraffin-embedded tumor samples from cetuximab-treated patients with recurrent or metastatic HNSCC were probed for p16INK4a expression, an established biomarker of HPV infection. Response rates (45.5% versus 45.5%) and median progression-free survival (97 versus 92 days) following cetuximab-based therapy were similar in patients with p16INK4A-positive and p16INK4A-negative tumors. In conclusion, HPV oncogenes do not modulate the anti-EGFR antibody response in HSNCC. Cetuximab treatment should be administered independently of HPV status.

CLAUDIN-1 belongs to the family of transmembrane tight junction proteins tightening the paracellular cleft of epithelial cells. In human malignancies, CLAUDIN-1 is often dysregulated and located in subcellular compartments, particularly in the nucleus where it may influence cellular behaviour. Here, we studied CLAUDIN-1 in relation to the biological characteristics of follicular thyroid carcinoma (FTC). CLAUDIN-1 immuno-staining showed loss of membrane expression and increased nuclear CLAUDIN-1 localization in FTC metastases. CLAUDIN-1 function was further investigated in two different follicular thyroid carcinoma cell lines: FTC-133 isolated from a regional lymph node metastasis and FTC-238 derived from a lung metastasis. In both cell lines CLAUDIN-1 expression was demonstrated in the cell nuclei with a significantly higher protein expression in FTC-238 compared to FTC-133 cells. Interestingly, in vitro scratch assay revealed enriched nuclear CLAUDIN-1 expression near the scratch. Furthermore, the increase of the pathogenic character of FTC-133 cells by RASV12 transfection was associated with elevated CLAUDIN-1 expression and enhanced cell migration, invasion and proliferation. Likewise over-expression of nuclear CLAUDIN-1 in FTC-133 cells resulted in increased cell migration and invasion. Conversely, CLAUDIN-1 downregulation in FTC-238 cells by siRNA resulted in decreased cell migration and invasion and was accompanied by reduced phosphoPKC expression. Moreover, activation and inhibition of PKC resulted in CLAUDIN-1 up-and downregulation in FTC cells respectively. These data suggest an impact of CLAUDIN-1 on follicular thyroid carcinoma aggressiveness, which could potentially be influenced by PKC activity.