Publications

BACKGROUND

Endoscopic necrosectomy is now an established minimally invasive method for treatment of organized pancreatic necrosis.

METHODS

Review of methods and results of endoscopic treatment of pancreatic necrosis.

RESULTS

Reports by multiple groups have demonstrated favorable results of endoscopic necrosectomy. The mortality of critically ill patients undergoing endoscopic treatment in several series is approximately 10%. Some patients will eventually also require surgery for situations such as complete pancreatic duct disruption, but even in these cases endoscopic necrosectomy is useful because pancreatic surgery can often be delayed until the patient is stable.

CONCLUSIONS

Endoscopic necrosectomy will likely assume an increasing role in the treatment of pancreatic necrosis. This should result in reduced morbidity and mortality in these critically ill patients.

PURPOSE

Tipifarnib is a farnesyl transferase (FTase) inhibitor that has activity in metastatic breast cancer and enhances the efficacy of cytotoxic agents in preclinical models. We evaluated the biological effects of tipifarnib in primary breast cancers in vivo, whether adding tipifarnib to preoperative chemotherapy increased the pathologic complete response rate (pCR) at surgery, and determined whether biomarkers predictive of pCR could be identified.

EXPERIMENTAL DESIGN

Forty-four patients with stage IIB-IIIC breast cancer received up to four cycles of neoadjuvant doxorubicin-cyclophosphamide (AC) every 2 weeks plus tipifarnib and filgrastim followed by surgery. Enzymatic assays measuring FTase activity and Western blotting for phospho (p)-signal transducer and activator of transcription 3 (STAT3), phospho-extracellular signal-regulated kinase, p-AKT, and p27 were done in 11 patients who agreed to optional tissue biopsies before therapy and 2 hours after the final dose of tipifarnib during the first cycle, and predictive biomarkers were evaluated by immunohistochemistry in 33 patients. The trial was powered to detect an improvement in breast pCR rate of 10% or less expected for AC alone to 25% for AC-tipifarnib (alpha = 0.05, beta = 0.10).

RESULTS

Eleven patients had a breast pCR (25%; 95% confidence interval, 13-40%). FTase enzyme activity decreased in all patients (median, 91%; range, 24-100%) and p-STAT3 expression decreased in 7 of 9 (77%) patients. Low tumor Ki-67 expression (below the median of 60%) at baseline was significantly associated with resistance to therapy (P = 0.01).

CONCLUSION

Tipifarnib inhibits FTase activity in human breast tumors in vivo, is associated with down-regulation of p-STAT3, and enhances the breast pCR rate, thus meriting further evaluation.

BACKGROUND

The Veterans Health Administration, the American Cancer Society, and the American Geriatrics Society recommend colorectal cancer screening for older adults unless they are unlikely to live 5 years or have significant comorbidity that would preclude treatment.

OBJECTIVE

To determine whether colorectal cancer screening is targeted to healthy older patients and is avoided in older patients with severe comorbidity who have life expectancies of 5 years or less.

DESIGN

Cohort study.

SETTING

Veterans Affairs (VA) medical centers in Minneapolis, Minnesota; Durham, North Carolina; Portland, Oregon; and West Los Angeles, California, with linked national VA and Medicare administrative claims.

PATIENTS

27 068 patients 70 years or older who had an outpatient visit at 1 of 4 VA medical centers in 2001 or 2002 and were due for screening.

MEASUREMENTS

The main outcome was receipt of fecal occult blood testing (FOBT), colonoscopy, sigmoidoscopy, or barium enema in 2001 or 2002, on the basis of national VA and Medicare claims. Charlson-Deyo comorbidity scores at the start of 2001 were used to stratify patients into 3 groups ranging from no comorbidity (score of 0) to severe comorbidity (score > or =4), and 5-year mortality was determined for each group.

RESULTS

46% of patients were screened from 2001 through 2002. Only 47% of patients with no comorbidity were screened despite having life expectancies greater than 5 years (5-year mortality, 19%). Although the incidence of screening decreased with age and worsening comorbidity, it was still 41% for patients with severe comorbidity who had life expectancies less than 5 years (5-year mortality, 55%). The number of VA outpatient visits predicted screening independent of comorbidity, such that patients with severe comorbidity and 4 or more visits had screening rates similar to or higher than those of healthier patients with fewer visits.

LIMITATIONS

Some tests may have been performed for nonscreening reasons. The generalizability of findings to persons who do not use the VA system is uncertain.

CONCLUSION

Advancing age was inversely associated with colorectal cancer screening, whereas comorbidity was a weaker predictor. More attention to comorbidity is needed to better target screening to older patients with substantial life expectancies and avoid screening older patients with limited life expectancies. primary funding source: VA Health Services Research and Development.

PURPOSE

We aim to identify genetic variation, in addition to the UGT1A1*28 polymorphism, that can explain the variability in irinotecan (CPT-11) pharmacokinetics and neutropenia in cancer patients.

PATIENTS AND METHODS

Pharmacokinetic, genetic, and clinical data were obtained from 85 advanced cancer patients treated with single-agent CPT-11 every 3 weeks at doses of 300 mg/m(2) (n = 20) and 350 mg/m(2) (n = 65). Forty-two common variants were genotyped in 12 candidate genes of the CPT-11 pathway using several methodologies. Univariate and multivariate models of absolute neutrophil count (ANC) nadir and pharmacokinetic parameters were evaluated.

RESULTS

Almost 50% of the variation in ANC nadir is explained by UGT1A1*93, ABCC1 IVS11 -48C>T, SLCO1B1*1b, ANC baseline levels, sex, and race (P < .0001). More than 40% of the variation in CPT-11 area under the curve (AUC) is explained by ABCC2 -24C>T, SLCO1B1*5, HNF1A 79A>C, age, and CPT-11 dose (P < .0001). Almost 30% of the variability in SN-38 (the active metabolite of CPT-11) AUC is explained by ABCC1 1684T>C, ABCB1 IVS9 -44A>G, and UGT1A1*93 (P = .004). Other models explained 17%, 23%, and 27% of the variation in APC (a metabolite of CPT-11), SN-38 glucuronide (SN-38G), and SN-38G/SN-38 AUCs, respectively. When tested in univariate models, pretreatment total bilirubin was able to modify the existing associations between genotypes and phenotypes.

CONCLUSION

On the basis of this exploratory analysis, common polymorphisms in genes encoding for ABC and SLC transporters may have a significant impact on the pharmacokinetics and pharmacodynamics of CPT-11. Confirmatory studies are required.