Genetic Variants of DNA Repair Genes as Predictors of Radiation-Induced Subcutaneous Fibrosis in Oropharyngeal Carcinoma.

PURPOSE: To investigate the impact of genetic variants of DNA repair and pro-fibrotic pathway genes on the severity of radiation-induced subcutaneous fibrosis in patients of oropharyngeal carcinoma treated with radical radiotherapy. MATERIALS AND METHODS: Patients of newly diagnosed squamous cell carcinoma of oropharynx being treated with two-dimensional radical radiotherapy were enrolled in the study. Patients who had undergone surgery or were receiving concurrent chemotherapy were excluded. Patients were followed up at 6 weeks post completion of radiotherapy and every 3 months thereafter for a median of 16 months. Subcutaneous fibrosis was graded according to the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) grading system and the maximum grade was recorded over the length of the patient's follow-up. Patients with severe fibrosis (≥G3), were compared to patients with minor (≤G2) fibrotic reactions. Eight single nucleotide polymorphisms of 7 DNA repair genes and 2 polymorphisms of a single pro-fibrotic pathway gene were analyzed by Polymerase Chain Reaction and Restriction Fragment Length Polymorphism and were correlated with the severity of subcutaneous fibrosis. RESULTS: 179 patients were included in the analysis. Subcutaneous fibrosis was seen in 168 (93.9%) patients. 36 (20.1%) patients had severe (grade 3) fibrosis. On multivariate logistic regression analysis, Homozygous CC genotype of XRCC3 (722C>T, rs861539) (p=0.013*, OR 2.350, 95% CI 1.089-5.382), Homozygous AA genotype of ERCC4 Ex8 (1244G>A, rs1800067) (p=0.001**, OR 11.626, 95% CI 2.490-275.901) and Homozygous TT genotype of XRCC5 (1401G>T, rs828907) (p=0.020*, OR 2.188, 95% CI 1.652-7.334) were found to be predictive of severe subcutaneous fibrosis. On haplotype analysis, the cumulative risk of developing severe fibrosis was observed in patients carrying both haplotypes of variant Homozygous AA genotype of ERCC4 Ex8 (1244G>A, rs1800067) and Homozygous TT genotype of XRCC5 (1401 G>T, rs828907) (p=0.010*, OR 26.340, 95% CI 4.014-76.568). CONCLUSION: We demonstrated significant associations between single nucleotide polymorphisms of DNA repair genes and radiation-induced subcutaneous fibrosis in patients of oropharyngeal carcinoma treated with radiotherapy. We propose to incorporate these genetic markers into predictive models for identifying patients genetically predisposed to the development of radiation-induced fibrosis, thus guiding personalized treatment protocols.

Assoziation hypertropher Post-Akne-Narben mit Einzelnukleotid-Polymorphismus (rs243865) im Matrix-Metalloproteinase-2-Gen.

HINTERGRUND UND ZIEL: Bei Akne wurde eine abweichende Gewebeexpression von Matrix-Metalloproteinasen beobachtet. Ziel unserer Studie war es, die Bedeutung von Polymorphismen einzelner Nukleotide (single nucleotide polymorphisms, SNPs) in MMP-2 (-1306 C/T, rs243865) und TIMP-2 (-418 G/C, rs8179090) bei Akne und Post-Akne-Narben zu untersuchen. PATIENTEN UND METHODEN: 512 Patienten (169 mit Akne ohne Narbenbildung, 319 mit atrophen Aknenarben, 24 mit hypertrophen Aknenarben) und 161 gleichaltrige Kontrollen wurden nach Erhalt der schriftlichen Einwilligungserklärung aus der Ambulanz der Hautklinik in die Studie aufgenommen. Zur Genotypisierung mittels Polymerasekettenreaktion-Restriktionsfragmentlängenpolymorphismus (PCR-RFLP) wurde venöses Blut (5 ml) entnommen. Der Schweregrad von Akne und Akne-bedingter Narbenbildung wurde bestimmt. ERGEBNISSE: Männer hatten ein deutlich erhöhtes Risiko schwere Akne (p = 0,012), Akne außerhalb des Gesichts (p = 0,047) und Aknenarben außerhalb des Gesichts (p = 0,0001) zu entwickeln. Entzündliche Akne korrelierte positiv mit dem Schweregrad der Narbenbildung (p = 0,001). Die Wahrscheinlichkeit für die Bildung hypertropher Narben war bei Personen mit homozygotem CC-Genotyp von MMP-2 (-1306 C/T) gegenüber Kontrollen nicht verändert (Faktor 1,0; p = 0,05; 95 %-KI: 0,7-1,6), jedoch gegenüber Personen mit Akne ohne Narbenbildung um den Faktor 7,8 (p = 0,047; 95 %-KI: 1,0-59,9) und gegenüber Personen mit atrophen Narben um den Faktor 8,2 (p = 0,041; 95 %-KI: 1,1-59,9) erhöht. SCHLUSSFOLGERUNGEN: Es wurde eine signifikante Assoziation zwischen der Bildung hypertropher Post-Akne-Narben und dem CC-Genotyp von MMP-2 (-1306 C/T) beobachtet.

A Celiac Disease Phenotype After Checkpoint Inhibitor Exposure: An Example of Immune Dysregulation After Immunotherapy.

Celiac disease is characterized by duodenal inflammation after exposure to gluten. Checkpoint inhibitors are antibodies that inhibit the inhibitory signals of the cytotoxic T lymphocytes to enhance antitumor responses. A 79-year-old man with an unknown history of celiac disease underwent treatment with pembrolizumab for recurrent left maxillary melanoma. He subsequently developed diarrhea and weight loss. Serology was positive for anti-tissue transglutaminase immunoglobulin A. Upper endoscopy revealed duodenal villous atrophy, which was confirmed on biopsy. A gluten-free diet was not tolerated, and symptoms resolved with withdrawal of pembrolizumab and steroid administration for another medical reason.

Cardiac myxoma causing acute ischemic stroke in a pediatric patient and a review of literature.

BACKGROUND: Ischemic stroke in the pediatric population is a rare occurrence, and its possible causes span a wide differential that includes atrial myxomas. Myxomas are friable cardiac tumors that produce "showers" of emboli resulting in transient neurological deficits, cutaneous eruptions, and ophthalmologic deficits. PATIENT: We present an 11-year-old boy with a months-long history of an intermittent spotted "rash" who presented with acute ischemic stroke caused by a left atrial myxoma. We also review clinical features in all 16 other cases of cardiac myxoma causing pediatric stroke reported in the literature. RESULTS: Our case, along with the review of the literature, highlights the fact that myxomas often initially present as stroke with acute hemiplegia and transient cutaneous eruptions due to fragmentation of the tumor. CONCLUSIONS: Cardiac myxoma should be considered in any child presenting with ischemic stroke, and transient skin findings may provide an important diagnostic clue prior to onset of neurological symptoms.