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Joshua B. Brown, Reetesh K. Pai, Melissa A. Burgess, Jennifer Chennat, and Amer H. Zureikat

Gastrointestinal stromal tumors (GISTs) represent 1% of alimentary tract neoplasms. Up to 90% of GISTs are driven by activating mutations in tyrosine kinase KIT or PDGFRα genes. Imatinib mesylate is a tyrosine kinase inhibitor that has recently been used in a neoadjuvant role for locally advanced GIST. Pathologic complete response (pCR) to imatinib, however, is rare and may be limited to patients with certain mutations. We report on a 71-year-old woman with a large advanced gastric GIST near the gastroesophageal junction initially involving the pancreas, spleen, adrenal, and aortic wall. The tumor harbored a KIT exon 11 deletion mutation in codon 558, which predicts a favorable response to imatinib. After 6 months of neoadjuvant imatinib therapy, the tumor was downstaged to allow partial gastric resection without the need for total gastrectomy reconstruction. The patient underwent partial gastrectomy, distal pancreatectomy, and splenectomy, and histologic examination showed a margin-negative resection with a near-pCR, with <5% viable tumor. Prolonged neoadjuvant therapy was undertaken based on the prognostic significance of a KIT exon 11 deletion mutation in codon 558, which facilitated an R0 resection while minimizing the surgical extent of the resection. A near-pCR of a large gastric GIST after neoadjuvant imatinib therapy remains a rare occurrence. Molecular testing should be undertaken before neoadjuvant therapy, because specific mutations can identify patients who will respond to imatinib and those likely to achieve significant downstaging and pCR.

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Ahmad Hamad, Aatur D. Singhi, Nathan Bahary, Kevin McGrath, Rula Amarin, Herbert J. Zeh, and Amer H. Zureikat

Overexpression of HER2 protein and amplification of the ERBB2 gene has been observed in various adenocarcinomas, providing a therapeutic target that can be used to extend the survival of a select cohort of patients. Anti-HER2 therapy has been successfully applied to gastric and colorectal cancers, but its use and potential benefit in small intestinal carcinomas is not well characterized. We applied anti-HER2 therapy to an ERBB2-amplified advanced duodenal adenocarcinoma, adding trastuzumab to FOLFOX in the neoadjuvant setting. A 61-year-old woman with an advanced duodenal cancer harboring an ERBB2 amplification received preoperative trastuzumab and FOLFOX. Restaging revealed significant tumor downstaging with no metastasis. After multidisciplinary assessment, she underwent pancreaticoduodenectomy. Final pathologic analysis revealed no residual invasive adenocarcinoma, consistent with a complete neoadjuvant treatment response. This case report emphasizes the need for further molecular characterization of small bowel cancers; genetic alterations may provide therapeutic targets to improve the prognosis of these rare and aggressive malignancies.

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Quisette P. Janssen, Jacob L. van Dam, Laura R. Prakash, Deesje Doppenberg, Christopher H. Crane, Casper H.J. van Eijck, Susannah G. Ellsworth, William R. Jarnagin, Eileen M. O’Reilly, Alessandro Paniccia, Marsha Reyngold, Marc G. Besselink, Matthew H.G. Katz, Ching-Wei D. Tzeng, Amer H. Zureikat, Bas Groot Koerkamp, Alice C. Wei, and for the Trans-Atlantic Pancreatic Surgery (TAPS) Consortium

Background: The value of neoadjuvant radiotherapy (RT) after 5-fluorouracil with leucovorin, oxaliplatin, and irinotecan, with or without dose modifications [(m)FOLFIRINOX], for patients with borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) is uncertain. Methods: We conducted an international retrospective cohort study including consecutive patients with BR PDAC who received (m)FOLFIRINOX as initial treatment (2012–2019) from the Trans-Atlantic Pancreatic Surgery Consortium. Because the decision to administer RT is made after chemotherapy, patients with metastases or deterioration after (m)FOLFIRINOX or a performance score ≥2 were excluded. Patients who received RT after (m)FOLFIRINOX were matched 1:1 by nearest neighbor propensity scores with patients who did not receive RT. Propensity scores were calculated using sex, age (≤70 vs >70 years), WHO performance score (0 vs 1), tumor size (0–20 vs 21–40 vs >40 mm), tumor location (head/uncinate vs body/tail), number of cycles (1–4 vs 5–8 vs >8), and baseline CA 19-9 level (≤500 vs >500 U/mL). Primary outcome was overall survival (OS) from diagnosis. Results: Of 531 patients who received neoadjuvant (m)FOLFIRINOX for BR PDAC, 424 met inclusion criteria and 300 (70.8%) were propensity score–matched. After matching, median OS was 26.2 months (95% CI, 24.0–38.4) with RT versus 32.8 months (95% CI, 25.3–42.0) without RT (P=.71). RT was associated with a lower resection rate (55.3% vs 72.7%; P=.002). In patients who underwent a resection, RT was associated with a comparable margin-negative resection rate (>1 mm) (70.6% vs 64.8%; P=.51), more node-negative disease (57.3% vs 37.6%; P=.01), and more major pathologic response with <5% tumor viability (24.7% vs 8.3%; P=.006). The OS associated with conventional and stereotactic body RT approaches was similar (median OS, 25.7 vs 26.0 months; P=.92). Conclusions: In patients with BR PDAC, neoadjuvant RT following (m)FOLFIRINOX was associated with more node-negative disease and better pathologic response in patients who underwent resection, yet no difference in OS was found. Routine use of RT cannot be recommended based on these data.