Purpose We initiated a personalized medicine program in the context of early clinical trials, using targeted agents matched with tumor molecular aberrations. Herein, we report our observations. Patient and Methods Patients with advanced cancer were treated in the Clinical Center for Targeted Therapy. Molecular analysis was conducted in the MD Anderson Clinical Laboratory Improvement Amendments (CLIA) -certified laboratory. Patients whose tumors had an aberration were treated with matched targeted therapy, when available. Treatment assignment was not randomized. The clinical outcomes of patients with molecular aberrations treated with matched targeted therapy were compared with those of consecutive patients who were not treated with matched targeted therapy. Results Of 1,144 patients analyzed, 460 (40.2%) had 1 or more aberration. In patients with 1 molecular aberration, matched therapy (n = 175) compared with treatment without matching (n = 116) was associated with a higher overall response rate (27% vs. 5%; P < 0.0001), longer time-to-treatment failure (TTF; median, 5.2 vs. 2.2 months; P< 0.0001), and longer survival (median, 13.4 vs. 9.0 months; P= 0.017). Matched targeted therapy was associated with longer TTF compared with their prior systemic therapy in patients with 1 mutation (5.2 vs. 3.1 months, respectively; P < 0.0001). In multivariate analysis in patients with 1 molecular aberration, matched therapy was an independent factor predicting response (P = 0.001) and TTF (P = 0.0001). Conclusion Keeping in mind that the study was not randomized and patients had diverse tumor types and a median of 5 prior therapies, our results suggest that identifying specific molecular abnormalities and choosing therapy based on these abnormalities is relevant in phase I clinical trials.

Inflammation and microbiota are critical components of intestinal tumorigenesis. To dissect how the microbiota contributes to tumor distribution, we generated germ-free (GF) ApcMin/+ and ApcMin/+;Il10−/− mice and exposed them to specific-pathogen-free (SPF) or colorectal cancer-associated bacteria. We found colon tumorigenesis significantly correlated with inflammation in SPF housed ApcMin/+;Il10−/−, but not ApcMin/+ mice. In contrast, small intestinal neoplasia development significantly correlated with age in both ApcMin/+;Il10−/− and ApcMin/+ mice. GF ApcMin/+;Il10−/− mice conventionalized by an SPF microbiota had significantly more colon tumors compared to GF mice. Gnotobiotic studies revealed that while Fusobacterium nucleatum clinical isolates with FadA and Fap2 adhesins failed to induce inflammation and tumorigenesis, pks+ Escherichia coli promoted tumorigenesis in the ApcMin/+;Il10−/− model in a colibactin-dependent manner, suggesting colibactin is a driver of carcinogenesis. Our results suggest a distinct etiology of cancers in different locations of the gut, where colon cancer is primarily driven by inflammation and the microbiome, while age is a driving force for small intestine cancer.

Mucus-invasive bacterial biofilms are identified on the colon mucosa of approximately 50% of colorectal cancer (CRC) patients and approximately 13% of healthy subjects. Here, we test the hypothesis that human colon biofilms comprise microbial communities that are carcinogenic in CRC mouse models. Homogenates of human biofilm-positive colon mucosa were prepared from tumor patients (tumor and paired normal tissues from surgical resections) or biofilm-positive biopsies from healthy individuals undergoing screening colonoscopy; homogenates of biofilm-negative colon biopsies from healthy individuals undergoing screening colonoscopy served as controls. After 12 weeks, biofilm-positive, but not biofilmnegative, human colon mucosal homogenates induced colon tumor formation in 3 mouse colon tumor models (germ-free Apc MinΔ850/+ ;Il10-/or Apc MinΔ850/+ and specific pathogen-free Apc MinΔ716/+ mice). Remarkably, biofilm-positive communities from healthy colonoscopy biopsies induced colon inflammation and tumors similarly to biofilm-positive tumor tissues. By 1 week, biofilm-positive human tumor homogenates, but not healthy biopsies, displayed consistent bacterial mucus invasion and biofilm formation in mouse colons. 16S rRNA gene sequencing and RNA-Seq analyses identified compositional and functional microbiota differences between mice colonized with biofilm-positive and biofilm-negative communities. These results suggest human colon mucosal biofilms, whether from tumor hosts or healthy individuals undergoing screening colonoscopy, are carcinogenic in murine models of CRC.

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a relatively rare but life-threatening disease with confusing clinical manifestations, rapidly deteriorating health, high morbidity and mortality.MethodsTo improve the recognition as well as understanding of this disorder, we analyzed clinical characteristics and prognostic factors from 85 adult patients diagnosed with HLH in our hospital from April 2005 to June 2014.ResultsPatients with HLH displayed variable clinical markers across a wide spectrum. These included fever and hyperferritinemia (100%), elevated lactate dehydrogenase (LDH) (98.8%), two or three cytopenia (92.2%), splenomegaly (72.9%), hypofibrinogenemia (69.4%), hypertriglyceridemia (64.7%), hemophagocytosis (51.7%), and hepatomegaly (24.7%). Patients with active Epstien-Barr Virus (EBV) infection had a median overall survival (OS) of 65 days. Those displaying malignancy had very poor survival (median OS: 40 days). However, patients in rheumatic and non-EBV infection groups had relatively superior prognosis (not reached). Univariate analysis showed that Fibrinogen (Fbg) <1.5 g/L, platelet number (PLT) <40 × 109/L and LDH ≥1000 U/L were factors that negatively affected survival (P = 0.004, 0.000, 0.002). Multivariate analysis showed that PLT <40 × 109/L was the independent adverse factor (HR = 0.350, 95% CI: 0.145-0.844, P = 0.019).ConclusionsHLH had very complex clinical manifestations and high death rate. Patients with active EBV infection, malignancy, Fbg <1.5 g/L, PLT <40 × 109/L and LDH ≥1000 U/L had high risk of death as well as inferior survival, and these patients require systemic targeted treatments as early as possible.

Various forms of cancer have been linked to the carcinogenic activities of microorganisms1–3. The virulent gene island polyketide synthase (pks) produces the secondary metabolite colibactin, a genotoxic molecule(s) causing double-stranded DNA breaks4 and enhanced colorectal cancer development5,6. Colibactin biosynthesis involves a prodrug resistance strategy where an N-terminal prodrug scaffold (precolibactin) is assembled, transported into the periplasm and cleaved to release the mature product7–10. Here, we show that ClbM, a multidrug and toxic compound extrusion (MATE) transporter, is a key component involved in colibactin activity and transport. Disruption of clbM attenuated pks+ E. coli-induced DNA damage in vitro and significantly decreased the DNA damage response in gnotobiotic Il10−/− mice. Colonization experiments performed in mice or zebrafish animal models indicate that clbM is not implicated in E. coli niche establishment. The X-ray structure of ClbM shows a structural motif common to the recently described MATE family. The 12-transmembrane ClbM is characterized as a cation-coupled antiporter, and residues important to the cation-binding site are identified. Our data identify ClbM as a precolibactin transporter and provide the first structure of a MATE transporter with a defined and specific biological function.