Potential immune priming of the tumor microenvironment with FOLFOX chemotherapy in locally advanced rectal cancer

Strategies to enhance tumor immunogenicity may expand the role of immunotherapy beyond the mismatch repair-deficient subtype. In this pilot study, biopsies were performed at baseline and after four cycles of FOLFOX in eight patients receiving neoadjuvant chemotherapy for stage II/III locally advanced rectal cancer. Immunostaining was performed for T cell subsets (CD3+, CD8+, CD45RO+); macrophages (CD163+); T regulatory cells (FOXP3+); and expression of MHC class I, PD-1 and PD-L1. Changes in cell number or intensity were quantified and correlated with treatment response. Pretreatment patterns of immune infiltrates were mixed and did not correlate with treatment response. Posttreatment increases in T cell infiltrates (CD3+, CD8+ and CD45RO+) and MHC-I expression were observed in five patients. CD163+ cell numbers increased in four patients. FOXP3+ cells numbers increased in two patients, decreased in two other patients and remained unchanged in three patients. PD-1 scores increased in seven patients, and PD-L1 scores increased in four patients. Changes in tumor T cell responses did not correlate with treatment response. Changes in FOXP3+ cells were associated with treatment response in some patients: two patients with increases in FOXP3+ cells had poor responses, whereas the patient with the greatest reduction in FOXP3+ cells had a complete response. The patient with a complete clinical response had a much higher increase in MHC-I expression than other patients. These results suggest that chemotherapy can increase immune activity in the tumor microenvironment and could potentially be utilized to prime immune responses prior to immunomodulatory treatments

CD117 expression in diffuse large B-cell lymphomas: Fact or fiction?

CD117 (KIT) is expressed in a variety of hematopoietic neo- plasms but there are a paucity of data regarding its expres- sion in diffuse large B-cell lymphomas (DLBCL). The purpose of the present paper was to describe the authors’ experience of two CD117+ DLBCL (one of follicle center-cell origin and one nasal Epstein–Barr virus (EBV)– plasmablas- tic lymphoma associated with lytic bone lesions), as deter- mined by tissue immunohistochemistry and flow cytometry. The CD117 expression in DLBCL was further evaluated using tissue microarrays and seven additional plasma- blastic lymphomas, using two commercially available anti-CD117 antibodies (Ab-1, Oncogene and A4502, Dako- Cytomation). Membranous ± cytoplasmic staining was seen with Ab-1 in 24/65 (37%) DLBCL, including 21/56 microarray DLBCL, two index cases, and 1/7 additional plasmablastic lymphomas, with persistent staining in 13% of microarray DLBCL despite preincubation with KIT peptide. However, A4502 had only membranous staining of the index cases and one additional EBV– plasmablastic lymphoma with medullary disease. The present study suggests that (i) CD117 expression can be detected sporadically in DLBCL of follicle center-cell origin and a subset of plasmablastic lymphomas; (ii) staining for CD117 might help in identifying EBV– plasmablastic lymphomas associated with bone mar- row involvement; and (iii) CD117 antibodies should be care- fully validated prior to use, because non-specific staining, as observed with Ab-1, could lead to false-positive results

Cytogenetic analysis of B-cell posttransplant lymphoproliferations validates the World Health Organization classification and suggests inclusion of florid follicular hyperplasia as a precursor lesion

Cytogenetic abnormalities in B-cell posttransplant lymphoproliferative disorders (PTLD) have not been well characterized. We thus performed cytogenetic analysis of 28 cases of B-cell PTLD, 1 infectious mononucleosis (IM)–like lesion, 9 polymorphic PTLD, 17 monomorphic PTLD, and 1 classical Hodgkin lymphoma (HL), and correlated the karyotypic findings with the phenotype, Epstein- Barr virus infection status, and clinical outcome. Karyotypes of 19 cases of posttransplant florid follicular hyperplasia (FFH) were also analyzed. Informative karyotypes were obtained in 20 (71.4%) of 28 PTLDs and 18 (94.7%) of 19 FFHs. Clonal karyotypic abnormalities were detected in 13 (65%) of 20 PTLDs, including 9 (75%) of 12 monomorphic PTLDs, 2 (33.3%) of 6 polymorphic PTLDs, 1 IM-like lesion, and 1 HL, and 2 (11.1%) of 18 FFHs. Recurrent chromosome breaks at 1q11-21 (n = 6, including 1 FFH), 14q32 (n = 3, including 1 FFH), 16p13 (n = 3), 11q23-24 (n = 2), and 8q24 (c-MYC) (n = 2); gains of chromosome 7 (n = 4), X (n = 3), 2 (n = 3), 12 (n = 2); and loss of chromosome 22 (n = 2, including 1 IM- like lesion) were identified. The presence of cytogenetic abnormalities did not correlate with PTLD phenotype, Epstein-Barr virus infection, or clinical outcome. We describe novel karyotypic aberrations in PTLD and report clonal cytogenetic abnormalities in posttransplant FFH and an IM-like lesion for the first time. Our findings provide validation of the current World Health Organization classification of PTLD and also suggest incorporation of FFH as the earliest recognizable precursor of PTLD

Mutation location on the RAS oncogene affects pathologic features and survival after resection of colorectal liver metastases

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136316/1/cncr30351_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136316/2/cncr30351.pd

Mutant N-RAS Protects Colorectal Cancer Cells from Stress-Induced Apoptosis and Contributes to Cancer Development and Progression

N-Ras is one member of a family of oncoproteins that are commonly mutated in cancer. Activating mutations in N-Ras occur in a subset of colorectal cancers, but little in known about how the mutant protein contributes to onset and progression of the disease. Using genetically engineered mice, we find that mutant N-Ras strongly promotes tumorigenesis in the context of inflammation. The pro-tumorigenic nature of mutant N-Ras is related to its anti-apoptotic function, which is mediated by activation of a non-canonical MAPK pathway that signals through Stat3. As a result, inhibition of MEK selectively induces apoptosis in autochthonous colonic tumors expressing mutant N-Ras. The translational significance of this finding is highlighted by our observation that NRAS mutation correlates with a less favorable clinical outcome for colorectal cancer patients. These data demonstrate for the first time the important role that N-Ras plays in colorectal cancer.

Radiation Impairs Perineural Invasion by Modulating the Nerve Microenvironment

Perineural invasion (PNI) by cancer cells is an ominous clinical event that is associated with increased local recurrence and poor prognosis. Although radiation therapy (RT) may be delivered along the course of an invaded nerve, the mechanisms through which radiation may potentially control PNI remain undefined. murine sciatic nerve model was used to study how RT to nerve or cancer affects nerve invasion by cancer.Cancer cell invasion of the DRG was partially dependent on DRG secretion of glial-derived neurotrophic factor (GDNF). A single 4 Gy dose of radiation to the DRG alone, cultured with non-radiated cancer cells, significantly inhibited PNI and was associated with decreased GDNF secretion but intact DRG viability. Radiation of cancer cells alone, co-cultured with non-radiated nerves, inhibited PNI through predominantly compromised cancer cell viability. In a murine model of PNI, a single 8 Gy dose of radiation to the sciatic nerve prior to implantation of non-radiated cancer cells resulted in decreased GDNF expression, decreased PNI by imaging and histology, and preservation of sciatic nerve motor function.Radiation may impair PNI through not only direct effects on cancer cell viability, but also an independent interruption of paracrine mechanisms underlying PNI. RT modulation of the nerve microenvironment may decrease PNI, and hold significant therapeutic implications for RT dosing and field design for patients with cancers exhibiting PNI