Integrative genomic characterization and a genomic staging system for gastrointestinal stromal tumors

BACKGROUND:

Gastrointestinal stromal tumors (GISTs) historically were grouped with leiomyosarcomas (LMSs) based on their morphologic similarities; however, recently, GIST was established unequivocally as a distinct type of sarcoma based on its molecular features and response to imatinib treatment.

METHODS:

To gain further insight into the genomic differences between GISTs and LMSs, the authors mapped gene copy number aberrations (CNAs) in 42 GISTs and 30 LMSs and integrated the results with gene expression profiles.

RESULTS:

Distinct patterns of CNAs were revealed between GISTs and LMSs. Losses in 1p, 14q, 15q, and 22q were significantly more frequent in GISTs than in LMSs (P < .001); whereas losses in chromosomes 10 and 16 and gains in 1q, 14q, and 15q (P < .001) were more common in LMSs. By integrating CNAs with gene expression data and clinical information, the authors identified several clinically relevant CNAs that were prognostic of survival in patients with GIST. Furthermore, GISTs were categorized into 4 groups according to an accumulating pattern of genetic alterations. Many key cellular pathways were expressed differently in the 4 groups, and the patients in each group had increasingly worse prognoses as the extent of genomic alterations increased.

CONCLUSIONS:

Based on the current findings, the authors proposed a new tumor‐progression genetic staging system termed genomic instability stage to complement the current prognostic predictive system based on tumor size, mitotic index, and v‐kit Hardy‐Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) mutation. Cancer 2011. © 2010 American Cancer Society.     

Controlled trial of medical therapy for active upper gastrointestinal bleeding and prevention of rebleeding

This multicentered, placebo-controlled trial evaluated the efficacy of medical therapy to stop bleeding in 285 patients with active upper gastrointestinal bleeding (bleeding phase) and 194 patients who had ceased gastrointestinal bleeding and in whom therapy was instituted to prevent rebleeding during the same hospitalization (prevention phase). Patients in the bleeding phase were given cimetidine (300 mg every six hours) or intravenous placebo. There was no significant overall difference between intravenous cimetidine (71 percent) and placebo (77 percent) in stopping acute upper gastrointestinal bleeding. There was also no significant difference noted between intravenous cimetidine and placebo when specific bleeding lesions were evaluated. Once gastrointestinal bleeding had stopped, recurrence of bleeding while receiving prevention therapy (cimetidine tablets 300 mg one three times a day and at bedtime, or Mylanta II liquid 30 ml every hour, or cimetidine plus hourly antacids, or placebo) was evaluated in 194 of the patients in the bleeding phase. Twenty-four percent (12 of 51 patients) rebled while receiving cimetidine, 13 percent (five of 39 patients) rebled while receiving hourly antacids, 11 percent (six of 54 patients) rebled while receiving cimetidine plus hourly antacids, and 26 percent (13 of 50 patients) rebled while receiving placebo. None of these prevention regimens reached statistical significance (p = 0.13). Evaluation of specific bleeding lesions within this group also failed to show any significant value of prevention therapy. In conclusion: (1) intravenous cimetidine offers no advantage over placebo in stopping active upper gastrointestinal bleeding; (2) the occurrence of rebleeding during the same hospitalization does not appear to be significantly affected by any of the medical regimens used for prevention. These findings would suggest that the cessation of active bleeding and the prevention of recurrent upper gastrointestinal bleeding during a single hospitalization appear to be unaffected by therapy directed at acid neutralization or reduction.