Genetic aberrations involving DNA damage repair (DDR) remain underexplored in gastrointestinal stromal tumors (GISTs). We characterized DDR abnormalities using targeted next-generation sequencing and multiplex ligation-dependent probe amplification, and performed immunofluorescence (IF) and immunohistochemistry (IHC) analyses of γH2AX and 53BP1. Consistent with IF-validated nuclear co-localization, γH2AX and 53BP1 showed robust correlations in expression levels, as did both biomarkers between IF and IHC. Without recurrent pathogenic single-nucleotide variants, heterozygous deletions (HetDels) frequently targeted DNA damage-sensing genes, with CHEK2-HetDel being the most prevalent. Despite their chromosomal proximity, BRCA2 and RB1 were occasionally hit by HetDels and were seldom co-deleted. HetDels of CHEK2 and BRCA2 showed a preference for older age groups, while RB1-HetDel predominated in the non-gastric, high-risk, and 53BP1-overexpressing GISTs. Higher risk levels were consistently related to γ-H2AX or 53BP1 overexpression (all p < 0.01) in two validation cohorts, while only 53BP1 overexpression was associated with the deletion of KIT exon 11 (KITex11-del) among genotyped GISTs. Low expressers of dual biomarkers were shown by univariate analysis to have longer disease-free survival (p = 0.031). However, higher risk levels, epithelioid histology, and KITex11-del retained prognostic independence. Conclusively, IHC is a useful surrogate of laborious IF in the combined assessment of 53BP1 and γ-H2AX to identify potential DDR-defective GISTs, which were frequently aberrated by HetDels and a harbinger of progression.

Direct hepatic invasion is an uncommon presentation of esophageal squamous cell carcinoma (ESCC), and evidence guiding chemoradiotherapy in this setting is limited. A 59-year-old man presented with middle-to-lower thoracic ESCC extending through the esophagogastric junction and gastric cardia, with direct hepatic invasion. Extensive regional nodal disease and a solitary right supraclavicular nonregional nodal metastasis supported cT4bN3M1 stage IVB disease, with high PD-L1 expression. The patient received curative-intent radiotherapy with concurrent cisplatin, paclitaxel, and nivolumab. The planned radiotherapy dose was 50.4 Gy in 28 fractions to the esophageal and regional lymph node volume, with a simultaneous integrated boost to the gross tumor and gross lymph nodes to 56 Gy in 28 fractions, followed by a sequential boost to the supraclavicular lymph node to a total 66 Gy in 33 fractions. After the 25th fraction, computed tomography results demonstrated contained tumor–gastric fistulization without pneumoperitoneum; therefore, the remaining three fractions to the esophageal and regional volumes were not delivered. The delivered doses were 45 Gy to these volumes and 50 Gy to the gross disease, each in 25 fractions. A conservative treatment strategy was initiated, including withholding oral intake, administering intravenous antimicrobial therapy, and continuing jejunal enteral feeding. Maintenance nivolumab with infusional 5-fluorouracil was continued for more than three years as an individualized strategy not based on an established prospective trial regimen. With pathological diagnosis designated as Month 0, positron emission tomography/computed tomography demonstrated complete metabolic response at Month 4, with no recurrent or metastatic disease on follow-up examinations through Month 44 during ongoing maintenance therapy. This case highlights durable disease control after immunotherapy-integrated chemoradiotherapy in advanced ESCC with initial direct liver invasion and the value of individualized treatment adaptation when tumor–gastric fistulization develops.