Metastatic small bowel adenocarcinoma: role of metastasectomy and systemic chemotherapy.

BACKGROUND: Metastatic small bowel adenocarcinoma (SBA) has a poor prognosis. Due to its rarity, high-quality data are lacking to guide treatment. This retrospective analysis was conducted to help characterize the treatment options for patients with metastatic SBA while providing clinically meaningful prognostic information. PATIENTS AND METHODS: In total, 437 patients who initially presented with or developed metastatic SBA between September 1977 and September 2019 were identified from the MD Anderson Tumor Registry. Clinical data were collected from review of the medical record. Overall response rates (ORR), time to progression (TTP), and overall survival (OS) were assessed across various treatments and treatment lines. RESULTS: The median OS from diagnosis of metastatic disease was 15.9 months [95% confidence interval (CI): 14.3-17.9]. Seventy-five patients (17.1%) underwent metastasectomy, which was associated with a median OS of 34.5 versus 17.1 months among patients who received chemotherapy alone (P < 0.001). Fluoropyrimidine plus platinum (n = 164) was the most common first-line chemotherapy, associated with an ORR of 59% and TTP of 8.1 months. Irinotecan with 5-FU (n = 101) was the most common second-line therapy associated with an ORR of 31% and TTP of 4.0 months. Twenty-two patients received immunotherapy; 5 of 6 patients with deficient mismatch repair (dMMR) responded, while 0 of 16 with proficient mismatch repair (pMMR) responded. Taxane-based chemotherapy was given to 34 patients with an ORR of 21% and a median TTP of 2.4 months. Among 11 patients who received anti-epidermal-growth-factor-receptor (EGFR) monotherapy, the best response was stable disease (SD) in 1 patient. CONCLUSIONS: In well-selected patients with SBA, metastasectomy appears to be associated with improved OS. This improvement was seen across metastasectomy sites, including liver, lung and peritoneal. Anti-programmed cell death protein 1 (PD-1) based immunotherapy was active for dMMR SBA but not pMMR SBA. While taxane-based chemotherapy demonstrates therapeutic activity, the activity of anti-EGFR therapy was limited.

Phenotypic heterogeneity associated with the splicing mutation in congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

One mutation frequently identified in 21-hydroxylase deficiency is the intron 2 splicing mutation, in which the normal polymorphic C or A at nucleotide 655 has been converted to G. Using allele-specific oligonucleotide hybridization, single strand conformational polymorphism analysis, and heteroduplex analyses, we identified 38 individuals from 21 different families who had 2 deleterious mutations. All were homozygous or compound heterozygotes for the splicing mutation. Comparison of the phenotypic features with the molecular genotypes shows phenotypic heterogeneity extending from classical salt-losing 21-hydroxylase deficiency to asymptomatic. Single strand conformational polymorphism analysis followed by DNA sequence analysis revealed numerous sequence variations in intron 2, most commonly at nucleotides 601 and 683. Transient transfection experiments show that the 3'-portion of intron 2 is sufficient to transfer the effect of the 655c/a-->g mutation to a chimeric heterologous gene. Clinical correlations and initial transfection studies suggest that sequence variations at nucleotides 601 and 683 do not correlate with clinical severity or substantially affect splicing. In summary, a single nucleotide change, 655c/a-->g, alters the splice acceptor site at the intron 2/exon 3 boundary. The molecular basis of the phenotypic heterogeneity associated with the mutation remains to be elucidated.

Human type II arginase: sequence analysis and tissue-specific expression.

A full-length cDNA encoding type II arginase was isolated from a human kidney cDNA library and its sequence compared to those of vertebrate type I arginases as well as to arginases of bacteria, fungi and plants. The predicted sequence of human type II arginase is 58% identical to the sequence of human type I arginase but is 71% identical to the sequence of Xenopus type II arginase, suggesting that duplication of the arginase gene occurred before mammals and amphibians diverged. Seven residues known to be essential for activity were found to be conserved in all arginases. Type II arginase mRNA was detected in virtually all human and mouse RNA samples tested whereas type I arginase mRNA was found only in liver. At least five mRNA species hybridizing to type II arginase cDNA were found in the human RNA samples whereas only a single type II arginase mRNA species was found in the mouse. This raises the possibility that the multiple type II arginase mRNAs in humans arise from differential RNA processing or usage of alternative promoters.