Prevalence of pathogenic germline variants in the circulating tumor DNA testing

BACKGROUND: Somatic and germline variants are not distinguishable by circulating tumor DNA (ctDNA) testing without analyzing non-tumor samples. Although confirmatory germline testing is clinically relevant, the criteria for selecting presumed germline variants have not been established in ctDNA testing. In the present study, we aimed to evaluate the prevalence of pathogenic germline variants in clinical ctDNA testing through their variant allele fractions (VAFs). METHODS: A total of consecutive 106 patients with advanced solid tumors who underwent ctDNA testing (Guardant360®) between January 2018 and March 2020 were eligible for this study. To verify the origin of pathogenic variants reported in ctDNA testing, germline sequencing was performed using peripheral blood DNA samples archived in the Clinical Bioresource Center in Kyoto University Hospital (Kyoto, Japan) under clinical research settings. RESULTS: Among 223 pathogenic variants reported in ctDNA testing, the median VAF was 0.9% (0.02-81.8%), and 88 variants with ≥ 1% VAFs were analyzed in germline sequencing. Among 25 variants with ≥ 30% VAFs, seven were found in peripheral blood DNA (BRCA2: n = 6, JAK2: n = 1). In contrast, among the 63 variants with VAFs ranging from 1 to < 30%, only one variant was found in peripheral blood DNA (TP53: n = 1). Eventually, this variant with 15.6% VAF was defined to be an acquired variant, because its allelic distribution did not completely link to those of neighboring germline polymorphisms. CONCLUSION: Our current study demonstrated that VAFs values are helpful for selecting presumed germline variants in clinical ctDNA testing

Magnifying Endoscopy with Blue Laser Imaging Improves the Microstructure Visualization in Early Gastric Cancer: Comparison of Magnifying Endoscopy with Narrow-Band Imaging

Backgrounds. Magnifying endoscopy with blue laser imaging (ME-BLI) for diagnosis of early gastric cancer (EGC) is as effective as magnifying endoscopy with narrow-band imaging (ME-NBI). However, there are different EGCs in microstructure visualization between ME-BLI and ME-NBI. This study aimed to clarify the pathological features of the EGCs, in which microstructure visualization was different between ME-NBI and ME-BLI. Methods. EGCs were classified into groups A (irregular microsurface pattern (MSP) in ME-BLI and absent MSP in ME-NBI), B (irregular MSP in two modalities), or C (absent MSP in two modalities), according to the vessel plus surface classification. We compared the pathological features of EGCs between the three groups. Results. 17, four, and five lesions could be evaluated in detail in groups A, B and C, respectively. Well-differentiated adenocarcinomas with shallow crypts were more frequent in group A than in group B (58.8 and 0%, resp.). The mean crypt depth of group A was significantly shallower than that of group B (56 ± 20, 265 ± 64 μm, resp., P=0.0002). Conclusions. ME-BLI could better visualize the microstructures of the EGCs with shallow crypts compared with ME-NBI. Therefore, ME-BLI could enable a more accurate diagnosis of EGC with shallow crypts

A Case of Squamous Cell Carcinoma of Unknown Primary that Responded to the Multi-Tyrosine Kinase Inhibitor Lenvatinib

Lenvatinib is an oral tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, as well as platelet-derived growth factor receptor α, RET, and KIT. At present, lenvatinib is used in the treatment of thyroid cancer and renal cell carcinoma. We herein report a case of a 67-year-old patient with squamous cell carcinoma of unknown primary who was effectively treated with lenvatinib. The patient was initially diagnosed as having undifferentiated thyroid cancer, and after total thyroidectomy and bilateral lymph node dissection, lenvatinib was administered for the treatment of residual lymph node metastasis. A computed tomography scan after 1 month of lenvatinib administration showed marked regression of the lymph nodes, but interstitial pneumonia was also detected. Because the drug lymphocyte stimulation test for lenvatinib was strongly positive, we concluded that the interstitial pneumonia was induced by lenvatinib. The interstitial pneumonia only improved by the withdrawal of lenvatinib. Finally, his thyroid tumor was diagnosed as a metastasis of squamous cell carcinoma; however, we were unable to identify the primary lesion. This is the first reported case of interstitial pneumonia induced by lenvatinib

Sequential histological findings and clinical response after carbon ion radiotherapy for unresectable sarcoma

Background and purpose: The efficacy of carbon ion radiotherapy (CIRT) for bone and soft tissue sarcomahas been reported recently. Although histological assessment after CIRT requires skilled interpretation,little information is presently available. In this study, we report sequential histological findings aftertreatment with CIRT, and evaluate the association between these findings and clinical response.Material and methods: Seven patients with unresectable sarcoma underwent needle biopsy 12 times at anaverage of 14.3 months after CIRT and were included in this study.Results: One patient underwent two biopsies after CIRT for chordoma. Although a few suspected residualchordoma cells were observed at 19 and 30 months after CIRT, the tumor continued to shrink at 75 months.Immunohistochemical analysis of post-CIRT specimens revealed CK AE1/3, EMA, and S100 expression, as inthe pre-CIRT specimen. In total, viable tumor cells were found in 9 of 12 specimens; however, only 2patients showed recurrent masses on radiological examination. The other 5 patients had stable disease.Conclusions: Viable tumor cells after CIRT did not always cause recurrence. This may be due to observationof dying cells or radiation-induced deformed cells. Histological evaluation after CIRT should be donecarefully

Sequential histological findings and clinical response after carbon ion radiotherapy for unresectable sarcoma

Background and purpose: The efficacy of carbon ion radiotherapy (CIRT) for bone and soft tissue sarcoma has been reported recently. Although histological assessment after CIRT requires skilled interpretation, little information is presently available. In this study, we report sequential histological findings after treatment with CIRT, and evaluate the association between these findings and clinical response. Material and methods: Seven patients with unresectable sarcoma underwent needle biopsy 12 times at an average of 14.3 months after CIRT and were included in this study. Results: One patient underwent two biopsies after CIRT for chordoma. Although a few suspected residual chordoma cells were observed at 19 and 30 months after CIRT, the tumor continued to shrink at 75 months. Immunohistochemical analysis of post-CIRT specimens revealed CK AE1/3, EMA, and S100 expression, as in the pre-CIRT specimen. In total, viable tumor cells were found in 9 of 12 specimens; however, only 2 patients showed recurrent masses on radiological examination. The other 5 patients had stable disease. Conclusions: Viable tumor cells after CIRT did not always cause recurrence. This may be due to observation of dying cells or radiation-induced deformed cells. Histological evaluation after CIRT should be done carefully

Blue Laser Imaging-Bright Improves Endoscopic Recognition of Superficial Esophageal Squamous Cell Carcinoma

Background/Aims. The aim of this study was to evaluate the endoscopic recognition of esophageal squamous cell carcinoma (ESCC) using four different methods (Olympus white light imaging (O-WLI), Fujifilm white light imaging (F-WLI), narrow band imaging (NBI), and blue laser imaging- (BLI-) bright). Methods. We retrospectively analyzed 25 superficial ESCCs that had been examined using the four different methods. Subjective evaluation was provided by three endoscopists as a ranking score (RS) of each image based on the ease of detection of the cancerous area. For the objective evaluation we calculated the color difference scores (CDS) between the cancerous and noncancerous areas with each of the four methods. Results. There was no difference between the mean RS of O-WLI and F-WLI. The mean RS of NBI was significantly higher than that of O-WLI and that of BLI-bright was significantly higher than that of F-WLI. Moreover, the mean RS of BLI-bright was significantly higher than that of NBI. Furthermore, in the objective evaluation, the mean CDS of BLI-bright was significantly higher than that of O-WLI, F-WLI, and NBI. Conclusion. The recognition of superficial ESCC using BLI-bright was more efficacious than the other methods tested both subjectively and objectively