Purpose African Americans (AAs) have the highest incidence of colorectal cancer (CRC) compared to other US populations and more proximal CRCs. The objective is to elucidate the basis of these cancer disparities. . Experimental design 566 AA and 328 Non-Hispanic White (NHW) CRCs were ascertained in five Chicago hospitals. Clinical and exposure data were collected. Microsatellite instability and BRAF (V600E) and KRAS mutations were tested. Statistical significance of categorical variables was tested by Fisher's exact test or logistic regression and age by Mann-Whitney U test. Results Over a ten-year period, the median age at diagnosis significantly decreased for both AAs (68 to 61; P<0.01) and NHWs (64.5 to 62; P=0.04); more AA patients were diagnosed before age 50 than NHWs (22% vs 15%; P=0.01). AAs had more proximal CRC than NHWs (49.5% vs. 33.7%; P<0.01), but overall frequencies of microsatellite instability, BRAF and KRAS mutations were not different nor were they different by location in the colon. Proximal CRCs often presented with lymphocytic infiltrate (P<0.01) and were diagnosed at older ages (P=0.02). Smoking, drinking, and obesity were less common in this group, but results were not statistically significant. Conclusions Patients with CRC have gotten progressively younger. The excess of CRC in AAs predominantly consists of more proximal, microsatellite stable tumors, commonly presenting lymphocytic infiltrate and less often associated with toxic exposures or a higher BMI. Younger AAs had more distal CRCs than older ones. These data suggest two different mechanisms driving younger age and proximal location of CRCs in AAs.

Patients with hepatocellular carcinoma who undergo orthotopic liver transplantation (OLT) are at risk for posttransplant tumor recurrence. The aim of this study was to evaluate whether expression of p53 and Ki-67 in hepatocellular carcinoma lesions present in explanted liver tissue was associated with time to tumor recurrence after OLT. Subjects consisted of 20 consecutive patients who underwent OLT and were found to have hepatocellular carcinoma in the liver explant. Immunostaining for p53 and Ki-67 was performed by standard methods. The presence of nuclear immunostaining in 410% of the tumor tissue was considered positive. Time to recurrence of hepatocellular carcinoma after OLT was compared between patients with positive and negative immunostaining by the log rank test. Multivariate analysis was performed using a Cox regression model to control for potentially confounding clinical factors. Time to post-transplant hepatocellular carcinoma recurrence was significantly more rapid in p53 þ (P ¼ 0.0007) and Ki-67 þ cases (P ¼ 0.001). These associations remained significant in multivariate analysis. Furthermore, time to recurrent hepatocellular carcinoma was significantly shorter in patients with a serum alpha feto-protein (AFP) level Z100 ng/ml at time of diagnosis, compared to those with an AFP level o100 ng/ml (P ¼ 0.003). In conclusion, expression of p53 and Ki-67 in hepatocellular carcinoma lesions, and a serum AFP level Z100 ng/ml were associated with more rapid recurrence of hepatocellular carcinoma after OLT. Identification of patients at risk for early post-transplant recurrence could be used to guide surveillance and adjuvant treatment strategies.

African Americans (AAs) have higher incidence and mortality rates of colorectal cancer (CRC) compared to other US populations. They present with more right-sided, microsatellite stable disease and are diagnosed at earlier ages compared to non-Hispanic whites (NHWs). To gain insight into these trends, we conducted exome sequencing (n=45), copy number (n=33), and methylation analysis (n=11) of microsatellite stable AA CRCs. Results were compared to data from The Cancer Genome Atlas (TCGA). Two of the 45 tumors contained POLE mutations. In the remaining 43 tumors, only 27 (63%) contained loss-of-function mutations in APC compared to 80% of TCGA NHW CRCs. APC mutation-negative CRCs were associated with an earlier onset of CRC (p=0.01) and with previous cancer (p=0.06). They were also associated with lower overall mutation burden, fewer copy number variants, and a DNA methylation signature that was distinct from the CpG island methylator phenotype characterized in microsatellite unstable disease. Three of the APC mutation-negative CRCs had loss-of-function mutations in BCL9L. Mutations in driver genes identified by TCGA exome analysis were less frequent in AA colorectal cancer cases than TCGA NHWs. Genes that regulate the WNT signaling pathway, including SOX9, GATA6, TET1, GLIS1, and FAT1, were differentially hypermethylated in APC mutation-negative CRCs, suggesting a novel mechanism for cancer development in these tumors. In summary, we have identified a subtype of CRC that is associated with younger age of diagnosis, lack of APC mutation, microsatellite and chromosome stability, lower mutation burden, and distinctive methylation changes.

SummaryChanges in spleen size postallogeneic haematopoietic stem cell transplantation (HSCT) in patients with primary myelofibrosis have been poorly characterized. We analysed 10 patients with myelofibrosis and splenomegaly following a reduced-intensity allogeneic HSCT. All patients fully engrafted donor cells including five patients with extensive splenomegaly. Extensive splenomegaly was associated with a prolonged time to neutrophil and platelet recovery. In all 10 patients, a progressive reduction of splenomegaly was documented within 12 months posttransplant and paralleled the reduction of marrow fibrosis. These findings suggest that myelofibrosis patients with extensive splenomegaly may proceed with allogeneic HSCT without prior splenectomy.