BACKGROUND:Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers. Given the currently limited therapeutic options, the definition of molecular subgroups with the development of tailored therapies remains the most promising strategy. Patients with high-level gene amplification of urokinase plasminogen activator receptor (uPAR/PLAUR) have an inferior prognosis. We analyzed the uPAR function in PDAC to understand this understudied PDAC subgroup's biology better.METHODS:A total of 67 PDAC samples with clinical follow-up and TCGA gene expression data from 316 patients were used for prognostic correlations. Gene silencing by CRISPR/Cas9, as well as transfection of uPAR and mutated KRAS, were used in PDAC cell lines (AsPC-1, PANC-1, BxPC3) treated with gemcitabine to study the impact of these two molecules on cellular function and chemoresponse. HNF1A and KRT81 were surrogate markers for the exocrine-like and quasi-mesenchymal subgroup of PDAC, respectively.RESULTS:High levels of uPAR were correlated with significantly shorter survival in PDAC, especially in the subgroup of HNF1A-positive exocrine-like tumors. uPAR knockout by CRISPR/Cas9 resulted in activation of FAK, CDC42, and p38, upregulation of epithelial makers, decreased cell growth and motility, and resistance against gemcitabine that could be reversed by re-expression of uPAR. Silencing of KRAS in AsPC1 using siRNAs reduced uPAR levels significantly, and transfection of mutated KRAS in BxPC-3 cells rendered the cell more mesenchymal and increased sensitivity towards gemcitabine.CONCLUSIONS:Activation of uPAR is a potent negative prognostic factor in PDAC. uPAR and KRAS cooperate in switching the tumor from a dormant epithelial to an active mesenchymal state, which likely explains the poor prognosis of PDAC with high uPAR. At the same time, the active mesenchymal state is more vulnerable to gemcitabine. Strategies targeting either KRAS or uPAR should consider this potential tumor-escape mechanism.

162 Background: TNT, consisting of preoperative chemoradiation (CRT +5-FU) followed by 3 cycles FOLFOX chemotherapy (cCTX) and total mesorectal excison (TME), was performed in rectal cancer patients (stages UICC ≥ II) according to the TransValid-B-phase-I/II-protocol (WHO-UTN-U1111-1132-0235) at a single site. The aim was to evaluate safety, feasibility, and long-term survival. Furthermore, the impact of postsurgical surrogate-parameters was determined. Methods: 62 patients (15 f, 47 m; median age: 62 years) with resectable LARC of the lower (43.5%; < 6 cm from the anal verge) or mid rectal third (56.5%, ≥ 6 - 12 cm) were included. Staging procedures revealed a positive circumferential resection margin (CRM < 2 mm) in 85.5% and clinical stages II to IV in 3.2%, 88.7% and 8.1%, respectively. TNT was performed by radiation (28x 1.8 Gy; total 50.4 Gy), civ infusion of FU (250 mg/m2/d; d1 - d14 and d22 - d35) and OX (50 mg/m2 on d1, d8, d22 and d29). Four weeks later, 3 FOLFOX cycles were applied with OX (80-100 mg/m2), followed by FA (400 mg/m2) and 5-FU (civ, 2400 mg/m2 over 46h, on d1, d15 and d30). Five to six weeks after cCTx, TME was performed with peri-/postoperative control of the specimen (MERCURY-criteria, 7th TNM/UICC-classification). Acute toxicities were recorded according to NCI-CTC-AE criteria (v4.03). Progression-free (PFS), overall (OS) and cancer-specific survival (CSS) were calculated using Kaplan-Meier estimators, logrank tests and multiparametric Cox proportional-hazards models. Results: During CRT (n = 62) and cCTx (n = 60), CTC-AE grades ≥ 3 occurred in 25.8% and 8.5%, respectively. Complete irradiation, concomitant CTx and consolidation FOLFOX-CTx were administered in 98.4%, 95.2% and 83.3%, respectively. After TNT, preoperative re-assessment showed a shift from stages ≥ III to ≤ II in 65% and from positive to negative CRM in 48,3%. 58 patients (93.5%) underwent TME-surgery with R0, negative CRM and optimal quality of the specimen in 94.8%, 91.4%, and 89.7%, respectively. Postoperatively, stages 0 to IV and complete remission (pCR; T0 N0) were diagnosed in 15.5%, 19%, 31%, 24.1%, 10.3% and 17.2%, respectively. Nearly complete remission (nCR; T1-T2 N0 and TRG 2 or TRG 3) occurred in 17.2%. Median follow-up time was 63 months (mo; quartiles: 48-103 months). Mean PFS and CSS were significantly higher for ypUICC stage ≤ II compared to stage ≥ III (111 ± 7.2 mo vs. 67 ± 12.2 mo; p = 0.006 and 130 ± 3.5 mo vs. 94 ± 10.2 mo; p = 0.004). Mean OS was 117 ± 6.4 mo for stages ≤ II vs. 91 ± 10.1 mo for stages ≥ III (p = 0.087). OS and PFS for patients with good (pCR and nCR) vs. poor response were 125 ± 7.0 mo vs. 101.5 ± 7.8 mo (p = 0.043) and 114 ± 9.6 mo vs. 87.9 ± 9.2 mo (p = 0.083). Conclusions: TNT is a safe, highly feasible and well-tolerated regimen with a good response of the primary rectal cancer and locoregional lymph nodes. Good response (pCR, nCR) or stage ≤ II results in higher rates for PFS, OS, and CSS. Clinical trial information: 2011-004228-37 .

JDDG: Journal der Deutschen Dermatologischen GesellschaftVolume 20, Issue 4 p. 528-530 Clinical LetterOpen Access Response of metastatic acral melanoma with exon 11 BRAF G469A mutation to BRAF/MEK inhibition Katharina Julius, Katharina Julius Department of Dermatology, Venereology, and Allergology, University Medical Center, Göttingen, GermanySearch for more papers by this authorChristian Kromer, Christian Kromer Department of Dermatology, Venereology, and Allergology, University Medical Center, Göttingen, GermanySearch for more papers by this authorViktor Schnabel, Viktor Schnabel Department of Dermatology, Venereology, and Allergology, University Medical Center, Göttingen, GermanySearch for more papers by this authorLyubomira Vlahova, Lyubomira Vlahova Department of Dermatology, Venereology, and Allergology, University Medical Center, Göttingen, GermanySearch for more papers by this authorJulia Kitz, Julia Kitz Institute of Pathology, University Medical Center, Göttingen, GermanySearch for more papers by this authorMichael P. Schön, Michael P. Schön Department of Dermatology, Venereology, and Allergology, University Medical Center, Göttingen, Germany Lower Saxony Institute of Occupational Dermatology, University Medical Center, Göttingen, GermanySearch for more papers by this authorCarsten-Oliver Sahlmann, Carsten-Oliver Sahlmann Institute of Nuclear Medicine, University Medical Center, Göttingen, GermanySearch for more papers by this authorLutz Kretschmer, Corresponding Author Lutz Kretschmer [email protected] Department of Dermatology, Venereology, and Allergology, University Medical Center, Göttingen, Germany Correspondence to Lutz Kretschmer, MD Department of Dermatology University Medical Center Göttingen Robert-Koch-Strasse 40 37075 Göttingen, Germany E-mail: [email protected]Search for more papers by this author Katharina Julius, Katharina Julius Department of Dermatology, Venereology, and Allergology, University Medical Center, Göttingen, GermanySearch for more papers by this authorChristian Kromer, Christian Kromer Department of Dermatology, Venereology, and Allergology, University Medical Center, Göttingen, GermanySearch for more papers by this authorViktor Schnabel, Viktor Schnabel Department of Dermatology, Venereology, and Allergology, University Medical Center, Göttingen, GermanySearch for more papers by this authorLyubomira Vlahova, Lyubomira Vlahova Department of Dermatology, Venereology, and Allergology, University Medical Center, Göttingen, GermanySearch for more papers by this authorJulia Kitz, Julia Kitz Institute of Pathology, University Medical Center, Göttingen, GermanySearch for more papers by this authorMichael P. Schön, Michael P. Schön Department of Dermatology, Venereology, and Allergology, University Medical Center, Göttingen, Germany Lower Saxony Institute of Occupational Dermatology, University Medical Center, Göttingen, GermanySearch for more papers by this authorCarsten-Oliver Sahlmann, Carsten-Oliver Sahlmann Institute of Nuclear Medicine, University Medical Center, Göttingen, GermanySearch for more papers by this authorLutz Kretschmer, Corresponding Author Lutz Kretschmer [email protected] Department of Dermatology, Venereology, and Allergology, University Medical Center, Göttingen, Germany Correspondence to Lutz Kretschmer, MD Department of Dermatology University Medical Center Göttingen Robert-Koch-Strasse 40 37075 Göttingen, Germany E-mail: [email protected]Search for more papers by this author First published: 26 February 2022 https://doi.org/10.1111/ddg.14737Citations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume20, Issue4April 2022Pages 528-530 RelatedInformation

Medical therapy of advanced hepatocellular carcinoma (HCC) remains an emerging subject, but therapeutic sequences together with toxicity management are rarely described. Herein, we report the case of a therapeutic sequence and toxicity management in a 72-year old White male with advanced non-cirrhotic HCC. The HCC of this patient was refractory against treatment with several tyrosine kinase inhibitors, including lenvatinib and cabozantinib or immune combination of pembrolizumab and lenvatinib. Double immune combination of nivolumab and ipilimumab was effective in fourth-line treatment but resulted in immunotherapy-related grade 4 hepatitis. This toxicity responded well to high doses of corticosteroids, and reinduction of dual immune combination remained effective despite continuation of high-dose corticosteroids in a non-cirrhotic HCC. This case demonstrated the efficacy of double immune therapy in higher treatment lines in advanced non-cirrhotic HCC even if the patient was treated with other immune modulatory therapies earlier. Moreover, it can remain effective under concomitant administration of high-dose corticosteroids.

Purpose Preoperative (neoadjuvant) chemoradiotherapy (CRT) and total mesorectal excision is the standard treatment for rectal cancer patients (UICC stage II/III). Up to one-third of patients treated with CRT achieve a pathological complete response (pCR). These patients could be spared from surgery and its associated morbidity and mortality, and assigned to a “watch and wait” strategy. However, reliably identifying pCR based on clinical or imaging parameters remains challenging. Experimental design We generated gene-expression profiles of 175 patients with locally advanced rectal cancer enrolled in the CAO/ARO/AIO-94 and -04 trials. One hundred and sixty-one samples were used for building, training and validating a predictor of pCR using a machine learning algorithm. The performance of the classifier was validated in three independent cohorts, comprising 76 patients from (i) the CAO/ARO/AIO-94 and -04 trials ( n = 14), (ii) a publicly available dataset ( n = 38) and (iii) in 24 prospectively collected samples from the TransValid A trial. Results A 21-transcript signature yielded the best classification of pCR in 161 patients (Sensitivity: 0.31; AUC: 0.81), when not allowing misclassification of non-complete-responders (False-positive rate = 0). The classifier remained robust when applied to three independent datasets ( n = 76). Conclusion The classifier can identify >1/3 of rectal cancer patients with a pCR while never classifying patients with an incomplete response as having pCR. Importantly, we could validate this finding in three independent datasets, including a prospectively collected cohort. Therefore, this classifier could help select rectal cancer patients for a “watch and wait” strategy. Translational relevance Forgoing surgery with its associated side effects could be an option for rectal cancer patients if the prediction of a pathological complete response (pCR) after preoperative chemoradiotherapy would be possible. Based on gene-expression profiles of 161 patients a classifier was developed and validated in three independent datasets ( n = 76), identifying over 1/3 of patients with pCR, while never misclassifying a non-complete-responder. Therefore, the classifier can identify patients suited for “watch and wait”.

JDDG: Journal der Deutschen Dermatologischen GesellschaftVolume 20, Issue 4 p. 527-529 Clinical LetterOpen Access Ansprechen eines metastasierten akrolentiginösen Melanoms mit Exon-11-BRAF-G469A-Mutation auf BRAF/MEK-Inhibition Katharina Julius, Katharina Julius Klinik für Dermatologie, Venerologie und Allergologie, Universitätsmedizin Göttingen, Göttingen, DeutschlandSearch for more papers by this authorChristian Kromer, Christian Kromer Klinik für Dermatologie, Venerologie und Allergologie, Universitätsmedizin Göttingen, Göttingen, DeutschlandSearch for more papers by this authorViktor Schnabel, Viktor Schnabel Klinik für Dermatologie, Venerologie und Allergologie, Universitätsmedizin Göttingen, Göttingen, DeutschlandSearch for more papers by this authorLyubomira Vlahova, Lyubomira Vlahova Klinik für Dermatologie, Venerologie und Allergologie, Universitätsmedizin Göttingen, Göttingen, DeutschlandSearch for more papers by this authorJulia Kitz, Julia Kitz Institut für Pathologie, Universitätsmedizin Göttingen, Göttingen, DeutschlandSearch for more papers by this authorMichael P. Schön, Michael P. Schön Klinik für Dermatologie, Venerologie und Allergologie, Universitätsmedizin Göttingen, Göttingen, Deutschland Niedersächsisches Institut für Berufsdermatologie, Universitätsmedizin Göttingen, Göttingen, DeutschlandSearch for more papers by this authorCarsten-Oliver Sahlmann, Carsten-Oliver Sahlmann Klinik für Nuklearmedizin, Universitätsmedizin Göttingen, Göttingen, DeutschlandSearch for more papers by this authorLutz Kretschmer, Corresponding Author Lutz Kretschmer lkre@med.uni-goettingen.de Klinik für Dermatologie, Venerologie und Allergologie, Universitätsmedizin Göttingen, Göttingen, Deutschland Korrespondenzanschrift Prof. Dr. med. Lutz Kretschmer Klinik für Dermatologie, Venerologie und Allergologie Universitätsmedizin Göttingen Robert-Koch-Strasse 40 37075 Göttingen, Deutschland E-Mail: lkre@med.uni-goettingen.deSearch for more papers by this author Katharina Julius, Katharina Julius Klinik für Dermatologie, Venerologie und Allergologie, Universitätsmedizin Göttingen, Göttingen, DeutschlandSearch for more papers by this authorChristian Kromer, Christian Kromer Klinik für Dermatologie, Venerologie und Allergologie, Universitätsmedizin Göttingen, Göttingen, DeutschlandSearch for more papers by this authorViktor Schnabel, Viktor Schnabel Klinik für Dermatologie, Venerologie und Allergologie, Universitätsmedizin Göttingen, Göttingen, DeutschlandSearch for more papers by this authorLyubomira Vlahova, Lyubomira Vlahova Klinik für Dermatologie, Venerologie und Allergologie, Universitätsmedizin Göttingen, Göttingen, DeutschlandSearch for more papers by this authorJulia Kitz, Julia Kitz Institut für Pathologie, Universitätsmedizin Göttingen, Göttingen, DeutschlandSearch for more papers by this authorMichael P. Schön, Michael P. Schön Klinik für Dermatologie, Venerologie und Allergologie, Universitätsmedizin Göttingen, Göttingen, Deutschland Niedersächsisches Institut für Berufsdermatologie, Universitätsmedizin Göttingen, Göttingen, DeutschlandSearch for more papers by this authorCarsten-Oliver Sahlmann, Carsten-Oliver Sahlmann Klinik für Nuklearmedizin, Universitätsmedizin Göttingen, Göttingen, DeutschlandSearch for more papers by this authorLutz Kretschmer, Corresponding Author Lutz Kretschmer lkre@med.uni-goettingen.de Klinik für Dermatologie, Venerologie und Allergologie, Universitätsmedizin Göttingen, Göttingen, Deutschland Korrespondenzanschrift Prof. Dr. med. Lutz Kretschmer Klinik für Dermatologie, Venerologie und Allergologie Universitätsmedizin Göttingen Robert-Koch-Strasse 40 37075 Göttingen, Deutschland E-Mail: lkre@med.uni-goettingen.deSearch for more papers by this author First published: 21 April 2022 https://doi.org/10.1111/ddg.14737_gAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume20, Issue4April 2022Pages 527-529 RelatedInformation

BACKGROUND: MicroRNAs constitute promising biomarkers. OBJECTIVE: The aim was to investigate diagnostic and prognostic implications of miR-182-5p and miR-205-5p in p16-positive and p16-negative oropharyngeal squamous cell carcinomas (OPSCCs). METHODS: Expression of miR-182-5p, miR-205-5p were determined via quantitative real-time-PCR in fresh frozen tissues of 26 p16-positive, 19 p16-negative OPSCCs and 18 HPV-negative oropharyngeal controls. Associations between miRNA-expression, clinicopathological characteristics and prognosis were analyzed. RESULTS: Higher miR-182-5p expression was associated with significant inferior disease-specific survival for p16-positive OPSCCs (HR = 1.98E+09, 95% CI 0-Inf; P = 0.028) and a similar trend was observed for p16-negative OPSCCs (HR = 1.56E+09, 95% CI 0-Inf; P = 0.051). Higher miR-205-5p expression was associated with an inferior progression-free survival (HR = 4.62, 95% CI 0.98-21.83; P = 0.034) and local control rate (HR = 2.18E+09, 95% CI 0-Inf; P = 0.048) for p16-positive OPSCCs. CONCLUSIONS: Results indicate that miR-182-5p and miR-205-5p can further stratify patients with p16-positive OPSCC into prognostic groups.

Hintergrund Nicht-kodierende, genregulierende MikroRNAs (miR) eröffnen als potentielle Biomarker neue Perspektiven der prognostischen Stratifizierung von Kopf-Hals-Karzinomen. Ziel war es, die diagnostische und prognostische Aussagekraft der miR-182-5p und miR-205-5p bei Oropharynxkarzinomen (OPSCCs) zu untersuchen.

Gastric cancer (GC) represents one of the most fatal neoplasms in gastrointestinal oncology and affected patients can only hope for cure in limited disease. In a metastatic situation however, patients have a worse prognosis finally resulting in cancer-related death. Some improvements were made by using intensified chemotherapy such as the FLOT protocol (5-FU, leucovorin, oxaliplatin and docetaxel). However, a breakthrough in the treatment of advanced GC has been achieved by pre-therapeutical tumor analysis for potentially targetable alterations. Microsatellite instability, PD-L1 expression, Epstein Barr virus, and human epidermal growth factor receptor-2 (HER2) overexpression or amplification are the most beneficial targets, if addressed, can prolong survival in a palliative situation. Whether the combination of these targeted therapeutics with chemotherapy can bring long-term survival or even a chance of cure in a metastatic situation is not clear. Here, we report the case of a 30-year-old man with GC and extensive metastases who was cured by anti-HER2 antibody Trastuzumab combined with the FLOT regime. Initial staging showed an exophytic Siewert type III tumor and extensive hepatic metastases. Histology resulted in gastric adenocarcinoma with HER2 overexpression (2+, FISH positive). Twelve courses of chemotherapy comprising Trastuzumab and FLOT were administered. After treatment, the extensive liver metastases had disappeared with no evidence of residual tumor growth on the CT scans. Monotherapy of Trastuzumab was continued until gastrectomy with D2 lymph node dissection and probing of liver tissue, which revealed no residual tumor cells. Five years after surgery, there is continued complete remission. In conclusion, Trastuzumab in combination with FLOT may have curative potential even for metastatic stages of HER-2-positive GC.

Histological subtype and grading are cornerstones of treatment decisions in soft tissue sarcoma (STS). Due to intratumoral heterogeneity, pretreatment grading assessment is frequently unreliable and may be improved through functional imaging. In this pilot study, 12 patients with histologically confirmed STS were included. Preoperative functional magnetic resonance imaging was fused with a computed tomography scan of the resected specimen after collecting core needle biopsies and placing radiopaque markers at distinct tumor sites. The Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading criteria of the biopsies and apparent diffusion coefficients (ADCs) of the biopsy sites were correlated. Concordance in grading between the specimen and at least one biopsy was achieved in 9 of 11 cases (81.8%). In 7 of 12 cases, fusion imaging was feasible without relevant contour deviation. Functional analysis revealed a tendency for high-grade regions (Grade 2/3 (G2/G3)) (median (range) ± standard deviation: 1.13 (0.78–1.70) ± 0.23 × 10−3 mm2/s) to have lower ADC values than low-grade regions (G1; 1.43 (0.64–2.03) ± 0.46 × 10−3 mm2/s). In addition, FNCLCC scoring of multiple tumor biopsies proved intratumoral heterogeneity as expected. The ADC appears to correlate with the FNCLCC grading criteria. Further studies are needed to determine whether functional imaging may supplement histopathological grading.

Background: Non-coding microRNAs (miR) regulate gene expression on post transcriptional level and open new perspectives of prognostic stratification as potential biomarkers of head and neck cancer. The aim was to investigate diagnostic and prognostic implications of miR-182-5p and miR-205-5p in oropharyngeal squamous cell carcinomas (OPSCCs).

Background: Cancer stem cells (CSC) are cells that exhibit stem cell properties and are pivotal in tumor biology. CSC markers have been described for many tumorous entities. However, to this date, there is no data on CSC markers in respect to squamous cell carcinomas (SCC) of the salivary glands. Methods: Histologic samples from patients with salivary gland SCCs were stained for CSC markers (ALDH-1/BMI-1/SOX-2/CD-44/vimentin) and divided into high and low expression subgroups. These were then correlated with tumor and patient characteristics as well as overall survival (OS), disease-specific survival, recurrence-free survival and local control rates (LCR) after 3 and 5 years. Results: Overall, 31 samples were included. CD-44 and ALDH-1 expression were associated with tumor origin (metastatic/primary disease, p = 0.048 and p = 0.011, respectively). Strong BMI-1 expression was associated with poorer OS (62.9 vs. 27.3%, p = 0.029), strong SOX-2 expression was associated with poorer LCR (62.5 vs. 21.9%, p = 0.007). Conclusion: CD-44 and ALDH-1 may be useful in differentiating between primary SCCs and metastatic disease. BMI-1 and SOX-2 are correlated with poorer prognosis.

VIPoma, a neuroendocrine tumour mostly occurring in the human pancreas and producing high levels of vasoactive intestinal peptide, is a rare disease that presents with a wide spectrum of symptoms, including intense diarrhoea, hypokalaemia, and cardiac complications, with life-threatening consequences. In most cases, metastatic lesions are present at VIPoma diagnosis. Treatment options include symptomatic therapy, chemotherapy, radiation and surgery. Due to its low incidence, there are no evidence-based therapy recommendations to date. Here, we present a case of a 39-year-old woman with severe symptoms due to VIPoma of the pancreas with diffuse hepatic metastasis, who underwent simultaneous resection of the primary tumour, extensive liver resection and radiofrequency ablation. The patient was released in good health and was recurrence-free during 12 months surveillance. According to the existing literature and our own experience, surgical procedures appear to be the most promising therapy option for cases with diffuse hepatic metastasis, offering patients relief from their symptoms and (chemo)therapy-free time.

BACKGROUND:The prognostic impact of hsa-miRNA-182-5p in oral cancer remains unexplored. Therefore, the aim of this study was to investigate the prognostic value of hsa-miRNA-182-5p and its predicted target kinectin 1 (KTN1) in oral squamous cell carcinoma (OSCC). METHOD:Expression level of hsa-miRNA-182-5p was analyzed in tumor tissue (n = 36) and healthy oral mucosal tissue (n = 17) using quantitative real-time polymerase chain reaction. Protein level of the predicted target KTN1 was detected via immunohistochemistry. Results were validated in a cohort of The Cancer Genome Atlas (TCGA). RESULTS:After dividing the data into a subgroup with high and low hsa-miRNA-182-5p expression level, a significant better overall (p = 0.016), recurrence-free (p = 0.009), and progression-free survival (p = 0.004) was observed in an upregulation of hsa-miRNA-182-5p. Staining intensity of KTN1 showed a reciprocal impact on the prognosis. Validation in a TCGA cohort confirmed these results. CONCLUSION:Our results indicate hsa-miRNA-182-5p and KTN1 as potential biomarkers for OSCC.

Treatment of locally advanced, unresectable head and neck squamous cell carcinoma (HNSCC) often yields only modest results with radiochemotherapy (RCT) as standard of care. Prognostic features related to outcome upon RCT might be highly valuable to improve treatment. Monocarboxylate transporters-1 and -4 (MCT1/MCT4) were evaluated as potential biomarkers. A cohort of HNSCC patients without signs for distant metastases was assessed eliciting 82 individuals eligible whereof 90% were diagnosed with locally advanced stage IV. Tumor specimens were stained for MCT1 and MCT4 in the cell membrane by immunohistochemistry. Obtained data were evaluated with respect to overall (OS) and progression-free survival (PFS). Protein expression of MCT1 and MCT4 in cell membrane was detected in 16% and 85% of the tumors, respectively. Expression of both transporters was not statistically different according to the human papilloma virus (HPV) status. Positive staining for MCT1 (n = 13, negative in n = 69) strongly worsened PFS with a hazard ratio (HR) of 3.1 (95%-confidence interval 1.6–5.7, p < 0.001). OS was likewise affected with a HR of 3.8 (2.0–7.3, p < 0.001). Multivariable Cox regression confirmed these findings. We propose MCT1 as a promising biomarker in HNSCC treated by primary RCT.

Infantile-onset RNaseT2 deficient leukoencephalopathy is characterised by cystic brain lesions, multifocal white matter alterations, cerebral atrophy, and severe psychomotor impairment. The phenotype is similar to congenital cytomegalovirus brain infection and overlaps with type I interferonopathies, suggesting a role for innate immunity in its pathophysiology. To date, pathophysiological studies have been hindered by the lack of mouse models recapitulating the neuroinflammatory encephalopathy found in patients. In this study, we generated Rnaset2-/- mice using CRISPR/Cas9-mediated genome editing. Rnaset2-/- mice demonstrate upregulation of interferon-stimulated genes and concurrent IFNAR1-dependent neuroinflammation, with infiltration of CD8+ effector memory T cells and inflammatory monocytes into the grey and white matter. Single nuclei RNA sequencing reveals homeostatic dysfunctions in glial cells and neurons and provide important insights into the mechanisms of hippocampal-accentuated brain atrophy and cognitive impairment. The Rnaset2-/- mice may allow the study of CNS damage associated with RNaseT2 deficiency and may be used for the investigation of potential therapies.

Introduction Oncogenic mutation within the KRAS gene represents a negative predictor for treatment response to anti-epidermal growth factor receptor (EGFR) in patients with colorectal cancer. Recently, we have shown no relevant heterogeneity for KRAS mutation status within and between pre- and posttherapeutic samples from the primary tumor in patients with locally advanced rectal cancer. The aim of this study was to evaluate the intertumoral heterogeneity of KRAS mutation status between the primary tumor and the corresponding metastasis or local recurrence in the similar cohort and to evaluate the ideal representative tissue for KRAS mutation testing. Materials and methods KRAS mutation status was analyzed from 47 patients with locally advanced rectal cancer, which were enrolled in the CAO/ARO/AIO-94 or CAO/ARO/AIO-04 trial. Mutations in KRAS codons 12, 13, and 61 were analyzed by using the KRAS RGQ PCR Kit (therascreen® KRAS test). Six patients needed to be excluded due to incomplete follow up data. 11 patients showed a relapse of the disease during the follow up presented by distant metastases or local recurrence. DNA from representative areas of metastatic tissue was obtained from formalin-fixed paraffin-embedded specimens. Results The mean patient age was 64.13 ± 10.64 years. In total, 19 patients showed a KRAS mutation (46.34%) in the primary tumor. Of the eleven patients with a metastatic disease or local recurrence, five patients showed a KRAS mutation whereas six patients had a KRAS wildtype status. Metastatic localizations included the liver (n = 2), lung (n = 4), local recurrence (n = 1), liver + lung (n = 3), lung + local recurrence (n = 1). For these eleven patients with paired data available for the primary tumor and metastatic tissue, a significant KRAS mutation status concordance was detected in 81.18% (9/11) of the patients (p = 0.03271). Only two patients showed intertumoral heterogeneity, which harbored in one patient a KRAS G12C mutation status in the primary tumor, but a G12V KRAS mutation status in the corresponding lung lesion, and in the other patient a G12A mutation in the primary lesion and a WT in the lung metastasis. Conclusions We show a significant concordance of the KRAS mutation status between tumor samples obtained from the primary tumor and the corresponding metastasis and/ or local recurrence in patients with rectal cancer indicating no relevant intertumoral heterogeneity. Our data suggest that sampling either the primary (pre- or posttherapeutical tumor tissue) or metastatic lesion may be valid for the initial evaluation of KRAS mutation status predicting the response to anti-EGFR treatment and guiding clinical decisions.