PURPOSE This is a phase Ib trial of regorafenib plus nivolumab for gastric and colorectal cancer. PATIENTS AND METHODS Enrolled patients received regorafenib plus nivolumab in a dose-finding part to estimate the maximum tolerated dose. Additional patients were enrolled in a dose-expansion part. Regorafenib of 80-160 mg was administered once daily for 21 days on/7 days off with nivolumab 3 mg/kg every 2 weeks. The primary end point was dose-limiting toxicity (DLT) during the first 4 weeks to estimate the recommended dose. RESULTS Fifty patients (25 each with gastric and colorectal cancer) were enrolled. All patients had received ≥ 2 previous lines of chemotherapy, including anti-angiogenetic inhibitors in 96% of patients. Seven patients with gastric cancer had previously been treated with immune checkpoint inhibitors. One patient had microsatellite instability–high colorectal cancer, whereas the remaining patients had microsatellite stable or mismatch repair–proficient tumors. Three DLTs (grade 3 colonic perforation, maculopapular rash, and proteinuria) were observed with regorafenib 160 mg; none were observed with 80 or 120 mg. During the dose-expansion part, regorafenib dose was reduced from 120 to 80 mg because of frequent maculopapular rash. The common grade ≥ 3 treatment-related adverse events were rash (12%), proteinuria (12%), and palmar-plantar erythrodysesthesia (10%). Objective tumor response was observed in 20 patients (40%), including 11 with gastric cancer (44%) and 9 with colorectal cancer (36%). Median progression-free survival was 5.6 and 7.9 months in patients with gastric and colorectal cancer, respectively. CONCLUSION The combination of regorafenib 80 mg plus nivolumab had a manageable safety profile and encouraging antitumor activity in patients with gastric and colorectal cancer, which warrants additional investigations in larger cohorts.

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During hematopoiesis, myeloid progenitor cells give rise to granulocytes and macrophages. To study the role for ICSBP, a hematopoietic cell-specific transcription factor in myeloid cell development, the gene was introduced into myeloid progenitor cells established from ICSBP-/- mice. ICSBP retrovirus-transduced cells differentiated into mature macrophages with phagocytic activity, which coincided with the induction of specific target DNA binding activity. Similar to macrophages in vivo, ICSBP-transduced cells were growth arrested, expressed many macrophage-specific genes, and responded to macrophage activation signals. Contrary to this, ICSBP transducion led to repression of granulocyte-specific genes and inhibited G-CSF-mediated granulocytic differentiation in these and other myeloid progenitor cells. Together, ICSBP has a key role in the myeloid cell lineage selection and macrophage maturation.

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In GC, PD-L1 expression was associated with distinct clinicopathological features, including high densities of TILs, MMR deficiency, and EBV positivity, but was not a prognostic factor.

PCAF plays a role in transcriptional activation, cell-cycle arrest, and cell differentiation in cultured cells. PCAF contributes to transcriptional activation by acetylating chromatin and transcription factors through its intrinsic histone acetylase activity. In this report, we present evidence for the in vivo function of PCAF and the closely related PCAF-B͞GCN5. Mice lacking PCAF are developmentally normal without a distinct phenotype. In PCAF null-zygous mice, protein levels of PCAF-B͞GCN5 are drastically elevated in lung and liver, where PCAF is abundantly expressed in wild-type mice, suggesting that PCAF-B͞GCN5 functionally compensates for PCAF. In contrast, animals lacking PCAF-B͞GCN5 die between days 9.5 and 11.5 of gestation. Normally, PCAF-B͞GCN5 mRNA is expressed at high levels already by day 8, whereas PCAF mRNA is first detected on day 12.5, which may explain, in part, the distinct knockout phenotypes. These results provide evidence that PCAF and PCAF-B͞GCN5 play distinct but functionally overlapping roles in embryogenesis.H uman (h)PCAF (p300͞CBP associated factor; ref. 1) is a transcriptional coactivator with intrinsic histone acetylase activity, which contributes to transcriptional activation by modifying chromatin and transcriptional factors (for reviews, see refs. 2-5). Although an exact mechanism of how acetylation of histones contribute to transcriptional activation has not been clarified, it has been thought that acetylation of nucleosomal histones leads to relaxation of chromatin structure such that various transcription factors can gain access and function onto chromatin DNA. Although histones are physiologically relevant substrates for PCAF, PCAF also acetylates transcriptional activators p53 (6, 7) and MyoD (8), as originally demonstrated by p300 acetylase (9), and stimulates DNA binding.PCAF is present in a stable multisubunit complex consisting of more than 20 distinct polypeptides, whose molecular masses range from 10 to 400 kDa (10). Although recombinant PCAF per se cannot efficiently acetylate histones in nucleosomal contexts, the PCAF complex that we purified can, strongly suggesting that subunits in the PCAF complex could stimulate acetylation of relevant substrates (10). Moreover, characterization of subunits of the PCAF complex has revealed that they are TATA boxbinding protein-associated factors (TAFs), which were originally found in TFIID; TAF-related PAF65␣ and ␤; human homologs of yeast transcriptional cofactors ADA2, ADA3, and Spt3 as well as PAF400, which exhibits sequence similarity to members of the ATM superfamily (10, 11). Importantly, TAF80, TAF-like PAF65␣, and TAF20͞15 bear sequence similarities to core histones (10) and thus may form a histone octamer-like structure in the PCAF complex, as has been proposed for TFIID (12)(13)(14). Furthermore, TAF-like PAF65␤ has WD40-repeats, motifs often found in factors that target chromatin (10).The second family member is hPCAF-B͞GCN5 (5, 15). PCAF and PCAF-B͞GCN5 are well conserved over their entire sequence, and both exhibit p...

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Background Hyperprogressive disease (HPD) during treatment with anti-programmed death-1/programmed death-ligand 1 monoclonal antibodies has anecdotally been reported in some types of cancers, but is not well-characterized in patients with advanced gastric cancer (AGC). Methods Total 62 AGC patients treated with nivolumab in a single institution from September 2017 to April 2018 were enrolled in this study. Tumor responses were assessed according to Response Evaluation Criteria in Solid Tumors version 1.1, and HPD was defined as ≥ two fold increase in tumor growth rate. Clinicopathological and molecular characteristics associated with HPD were also investigated. Results Thirteen of 62 patients (21%) developed HPD after nivolumab treatment. Overall survival (OS) and progression-free survival (PFS) were significantly shorter in patients with HPD than in patients without HPD (median OS: 2.3 months vs. not reached, P < 0.001; median PFS: 0.7 months vs. 2.4 months, P < 0.001). Liver metastases (77% vs. 41%), Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or 2 (77% vs. 29%), and a large sum of target lesion diameters at baseline (median 104.2 mm vs. 44.9 mm) were significantly associated with HPD. Absolute neutrophil count (ANC) and C-reactive protein (CRP) level significantly increased in the first 4 weeks in only patients with HPD. Conclusions HPD was observed in AGC patients treated with nivolumab and correlated with some clinicopathological characteristics. Elevations in ANC and CRP levels upon treatment might indicate HPD.