Bendamustine has efficacy in multiple myeloma with a toxicity profile limited to myelosuppression. We hypothesized that adding bendamustine to autologous stem cell transplant conditioning in myeloma would enhance response without significant additional toxicity. We conducted a phase 1 trial adding escalating doses of bendamustine to the current standard conditioning of melphalan 200mg/m2. Twenty-five subjects were enrolled onto 6 cohorts. A maximum tolerated dose was not encountered and the highest dose level cohort of bendamustine 225mg/m2 + melphalan 200mg/m2 was expanded to further evaluate safety. Overall, there was no transplant related mortality and only 1 grade 4 dose-limiting toxicity was observed. Median number of days to neutrophil and platelet engraftment was 11 (9-14) and 13 (10-21), respectively. Disease responses at day +100 post-transplant were: progression in 5 (21%), partial response in 1 (4%), very good partial response in 7 (33%), complete response in 1 (4%), and stringent complete response in 9 (38%). Six patients (24%) with preexisting high-risk disease died from progressive myeloma during study follow-up, all at or beyond 100 days after ASCT. Bendamustine up to a dose of 225mg/m2 added to autologous stem cell transplant conditioning with high dose melphalan in multiple myeloma did not exacerbate expected toxicities.
The Muc-1 oncoprotein is a tumor-associated mucin often overexpressed in pancreatic cancer. We report that knockout of Muc-1 reduced the degree of pancreatic inflammation that resulted from infection with Coxsackievirus B3 (CVB3) in a mouse model. CVB3-infected Muc-1-deficient (Muc-1
KO
) mice had significantly reduced infiltration of macrophages into the murine pancreas. We found that Muc-1 signaling through NF-κB increased expression of ICAM-1, a pro-inflammatory mediator that recruits macrophages. Further investigation revealed that bone marrow derived macrophages (BMDM) from the Muc-1
KO
mice exhibited defective migration properties, in part due to low expression of the C-C motif chemokine receptor (CCR2) and the integrin Very Late Antigen 4 (VLA-4). The results presented here provide novel insight into the role of Muc-1 in regulating the inflammatory response and the cellular microenvironment in pancreatitis.
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