Phase II trial of the regulatory T cell-depleting agent, denileukin diftitox, in patients with unresectable stage IV melanoma.

BACKGROUND: We previously found that administration of an interleukin 2/diphtheria toxin conjugate (DAB/IL2; Denileukin Diftitox; ONTAK) to stage IV melanoma patients depleted CD4(+)CD25(HI)Foxp3(+) regulatory T cells and expanded melanoma-specific CD8(+) T cells. The goal of this study was to assess the clinical efficacy of DAB/IL2 in an expanded cohort of stage IV melanoma patients. METHODS: In a single-center, phase II trial, DAB/IL2 (12 µg/kg; 4 daily doses; 21 day cycles) was administered to 60 unresectable stage IV melanoma patients and response rates were assessed using a combination of 2-[(18)F]-fluoro-2-deoxy-glucose (FDG)-positron emission tomography (PET) and computed tomography (CT) imaging. RESULTS: After DAB/IL2 administration, 16.7% of the 60 patients had partial responses, 5% stable disease and 15% mixed responses. Importantly, 45.5% of the chemo/immuno-naïve sub-population (11/60 patients) experienced partial responses. One year survival was markedly higher in partial responders (80 ± 11.9%) relative to patients with progressive disease (23.7 ± 6.5%; p value < 0.001) and 40 ± 6.2% of the total DAB/IL2-treated population were alive at 1 year. CONCLUSIONS: These data support the development of multi-center, randomized trials of DAB/IL2 as a monotherapy and in combination with other immunotherapeutic agents for the treatment of stage IV melanoma. TRIAL REGISTRATION: NCT00299689.

Nucleophilic cationization reagents.

Nucleophilic cationization reagents fitted with aminooxy groups are described. Practical syntheses of mono- and bis-aminooxy tetraalkylammonium iodides including N-hydroxyethyl-functionalized analogs are reported. An oximation example using one of the reagents is presented to illustrate their use in synthesis of cationic materials.

Utility of MRCP in clinical decision making of suspected choledocholithiasis: An institutional analysis and literature review.

BACKGROUND: The ideal treatment algorithm for suspected choledocholithiasis is not yet well defined. Imaging options include magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), and intraoperative cholangiogram (IOC). MRCP is diagnostic, while the other two modalities can also be therapeutic. Each of these modalities for diagnosis and treatment carries its own set of risks, benefits, and institutional costs. We hypothesized that there would be a significant difference between the biochemical profiles and characteristics of patients who undergo ERCP vs. MRCP vs. operative intervention as the initial choice of treatment/imaging modality. METHODS: We performed a retrospective review of the electronic medical records for all patients with a coded diagnosis of choledocholithiasis from 2011 to 2014. The initial diagnostic modality was assessed for each hospital encounter. The statistical characteristics of MRCP as compared to fluoroscopic imaging of the biliary tree (ERCP, IOC) were analyzed. RESULTS: Overall, 527 hospital encounters were identified. Initial intervention included ERCP in 63%, MRCP in 12%, and cholecystectomy in 25% of patients. Patients undergoing cholecystectomy first, compared to MRCP or ERCP, tended to have lower values for alkaline phosphatase (P < 0.001) and AST (P = 0.002) as well as be of younger age (P < 0.0001). Of the patients that underwent MRCP as their initial procedure, 82% subsequently underwent either ERCP or laparoscopic cholecystectomy. In patients who underwent an initial MRCP followed by either ERCP or IOC, the predictive performance of MRCP was as follows: sensitivity = 0.90, specificity = 0.86, positive predictive value = 0.97, negative predictive value = 0.60, agreement (Cohen's Kappa) = 0.64. CONCLUSIONS: There is a significant difference in the laboratory evaluation and demographics of patients undergoing ERCP, MRCP, and laparoscopic cholecystectomy. MRCP was followed with a more invasive test a majority of the time. Since MRCP did not change the management of patients with suspected choledocholithiasis, its utility in this patient population should be questioned. Further research is needed to better define the pretest characteristics which would predict which patients do not need further intervention after MRCP as well as defining the most cost-effective strategy.