Activated naïve γδ T cells accelerate deep molecular response to BCR-ABL inhibitors in patients with chronic myeloid leukemia.

Tyrosine kinase inhibitors (TKIs) that target BCR-ABL are the frontline treatments in chronic myeloid leukemia (CML). Growing evidence has shown that TKIs also enhance immunity. Since gamma-delta T (γδT) cells possess the potent anticancer capability, here we investigated the potential involvement of γδT cells in TKI treatments for CML. We characterized γδT cells isolated from chronic-phase CML patients before and during TKI treatments. γδT expression increased significantly in CML patients who achieved major molecular response (MMR) and deep molecular response (DMR). Their Vδ2 subset of γδT also expanded, and increased expression of activating molecules, namely IFN-γ, perforin, and CD107a, as well as γδT cytotoxicity. Mechanistically, TKIs augmented the efflux of isopentenyl pyrophosphate (IPP) from CML cells, which stimulated IFN-γ production and γδT expansion. Notably, the size of the IFN-γ+ naïve γδT population in TKI-treated CML patients was strongly correlated with their rates to reach DMR and with the duration on DMR. Statistical analysis suggests that a cutoff of 7.5% IFN-γ+ naïve subpopulation of γδT in CML patients could serve as a determinant for MR4.0 sustainability. Our results highlight γδT cells as a positive regulator for TKI responses in CML patients.

NKG2A Down-Regulation by Dasatinib Enhances Natural Killer Cytotoxicity and Accelerates Effective Treatment Responses in Patients With Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) is a hematological malignancy characterized by the presence of t(9;22) chromosomal translocation that results in BCR-ABL fusion gene. ABL tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, and dasatinib, are currently the front-line treatment options for CML. Recently, natural killer (NK) cell activation and expansion have been shown to be associated with optimal treatment responses for CML. To investigate the effects and mechanisms of these TKIs on NK cells, here we characterized activating and inhibitory NK receptors in CD3-CD16+CD56dim NK cells isolated from CML patients in chronic phase (CP). The expressions of activating NK receptors, such as NKG2D, natural cytotoxicity receptor (NCR) and DNAM-1, rebounded after successful TKI treatments for CML. In contrast, among the three surveyed inhibitory receptors (NKG2A, KIR2DL1, and KIR3DL1), only the expression of NKG2A was reverted and suppressed to a very low level by dasatinib, and not by imatinib or nilotinib. CML patients treated with dasatinib indeed expressed fewer NKG2A+ NK cells, which send negative signals for induction of NK cytotoxicity. For these dasatinib-treated patients, the duration to reach major molecular response (MMR) was shorter, and significantly correlated with individual's NKG2A+ NK cell number. This clinical relevance to NKG2A was not observed in treatments with imatinib or nilotinib. In line with dasatinib-specific down-regulation of NKG2A, NK cytotoxicity evaluated by the killing assay was also significantly higher in patients treated with dasatinib than in those treated with imatinib or nilotinib. The lower NK cytotoxicity from imatinib or nilotinib treatments could be reverted by NKG2A blockade using anti-NKG2A antibody. Further in vitro experiments revealed mechanistically that dasatinib could inactivate p38 mitogen-activated protein kinase (MAPK), and consequently affect nuclear import of GATA-3 and GATA-3 transcriptional activities for NKG2A. Our results highlight the dual effects of dasatinib in direct inhibition of ABL kinase and in immunomodulation through NKG2A down-regulation, contributing to accelerated molecular responses (MR) in CML.

CIP2A is a predictor of poor prognosis in colon cancer.

PURPOSE: The cancerous inhibitor of protein phosphatase 2A (CIP2A) oncoprotein is overexpressed in colon cancer tissue compared to normal colon mucosa. We investigated the impact of CIP2A on colon cancer. METHODS: A tissue microarray consisting of 167 colon cancer specimens was investigated. The association between CIP2A and clinicopathological parameters was analyzed using the χ(2) test. Survival was analyzed using the Kaplan-Meier method. The impact of CIP2A on proliferation and drug resistance was evaluated using the 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide test. An anchorage-independent colony formation assay was also performed. RESULTS: CIP2A was an independent prognostic factor in colon cancer after controlling for other clinical confounding factors, such as stage and lymphovascular invasion, particularly in stages III and IV (hazard ratio = 2.974, P < 0.001). The knockdown of CIP2A reduced the proliferation and anchorage-independent colony formation of colon cancer cells. Knockdown of CIP2A decreased the resistance of the cells to 5-fluorouracil, oxaliplatin, and SN38 (an active metabolite of irinotecan). Treatment with 5-fluorouracil, oxaliplatin, and SN38 decreased CIP2A expression. CONCLUSIONS: CIP2A is a prognostic factor in colon cancer. The knockdown of CIP2A reduced proliferation and anchorage-independent colony formation and increased 5-fluorouracil, oxaliplatin, and SN38 efficacy in colon cancer cell lines.

A new classification scheme for recurrent or metastatic colon cancer after liver metastasectomy.

BACKGROUND: Metastasectomy is the standard treatment for patients with resectable liver metastasis from colon cancer. This study aimed to determine the impact of initial stage on overall survival (OS) after metastasectomy. METHODS: A retrospective analysis of 2804 patients diagnosed with colon cancer between 1999 and 2008. RESULTS: Of the cohort, 38.1% of the patients were stage IV or had recurrence after curative surgery, and 131 received liver metastasectomy. The 5-year survival rate for patients after liver metastasectomy was 42.1%. The 5-year survival rates after metastasectomy for initial stage I disease, stage II disease, stage III disease, and stage IV disease were 100%, 82.5%, 31.8%, and 36.9%, respectively (p = 0.014). When patients were grouped as initial stage I/II and stage III/IV, the 5-year survival rate after liver metastasectomy differed significantly (83.9% vs. 35.7%, p = 0.006). Patients with initial stage I/II disease after liver metastasectomy had a significantly better 5-year progression-free period compared to those with stage III/IV disease (60% vs. 28%, p = 0.021), which was due to the lower recurrence rate in the stage I/II group. CONCLUSION: Our results suggest that patients who receive liver metastasectomy for metastatic colon cancer should be grouped into two groups: those with initial stages I and II disease, and those with stages III and IV disease, since the progression-free survivals (PFS) and OS after metastasectomy in these two groups differ significantly.

Liver abscess after liver metastasectomy is a poor prognostic factor in patients with colorectal cancer.

PURPOSE: More and more complications of extensive hepatic resection are being encountered in patients treated for liver metastases from colorectal cancer. This study aimed to determine the impact of liver abscess after hepatic resection on overall survival (OS) and the role of adjuvant chemotherapy. METHODS: This is a retrospective study of 252 patients treated by liver metastasectomy between 2001 and 2010. RESULTS: The 5-year survival rate was 55.8%. Twenty-one (8.3%) patients developed liver abscess after liver metastasectomy. Multivariate analysis identified the size of liver metastasis, surgical margin, and the presence of liver abscess as significant prognostic factors. Patients (whether or not they developed liver abscess after hepatic resection) had similar progression-free survival (median, 9.8 vs. 12.4 months, P = 0.476), but patients who developed liver abscess had significantly shorter OS (26.6 vs. 76.0 months, P = 0.004). Subsequent adjuvant therapy significantly improved OS in these patients (16.9 vs. 38.5 months, P = 0.032). CONCLUSIONS: Liver abscess after liver metastasectomy is an independent prognostic factor, and adjuvant chemotherapy is warranted in those patients who develop liver abscess.

Effect of allogeneic hematopoietic stem cell transplantation from matched siblings or unrelated donors during the first complete remission in patients with cytogenetically normal acute myeloid leukemia.

We retrospectively examined the impact of hematopoietic stem cell transplantation (HSCT) during the first complete remission (CR1) in 81 patients with cytogenetically normal acute myeloid leukemia (CN-AML). Eligible patients were divided into three subgroups: HSCT recipients with allogeneic sibling or matched unrelated donors (MUD) (allogeneic HSCT, n = 47), recipients of autologous HSCT (n = 12), and patients receiving chemotherapy alone (n = 22). We examined factors associated with overall survival (OS) in these patients, focusing particularly on the effect of allogeneic HSCT. Comparing to those receiving chemotherapy alone, patients in the allogeneic HSCT group had significantly better OS, which was independent of the presence of comorbidities. Furthermore, patients who received allogeneic sibling HSCT had the best OS and disease-free survival (DFS). Patients who received MUD HSCT also had significant advantage in DFS but not in OS, when compared with patients in the chemotherapy group. The study results suggest that patients with CN-AML in CR1 who are eligible for HSCT may have a survival benefit from HSCT, especially the allogeneic HSCT. We suggest that future studies employ molecular classification of AML to better define the benefits of HSCT during CR1 in patients with CN-AML.

Idiopathic hyperammonemia after chemotherapy with vinorelbine, topotecan, and cisplatin in a patient with acute lymphocytic leukemia.

Idiopathic hyperammonemia (IHA) had been reported in some patients with hematological malignancy after receiving intensive chemotherapy, following bone marrow transplantation, or after using 5-fluorouracil for some solid tumors. The chemotherapeutic agents involved include cytarabine, daunomycin, cyclophosphamide, vincristine, amsacrine, etoposide, asparaginase, busulfan, and methotraxate, all used for treating hematological malignancies. No previous reports have described the association between idiopathic hyperammonemia and combined chemotherapy with vinorelbine, topotecan, and cisplatin. We describe a 20-year-old girl with normal liver function and relapsed precursor B-lymphoblastic leukemia receiving the modified TVTG (topotecan, vinorelbine, thiotepa, dexamethasone, and gemcitabine) protocol to control her disease. We used cisplatin (30 mg/m2/day) to replace thiotepa on day 3 because thiotepa was not available in Taiwan. The patient developed acute idiopathic hyperammonemia after 5 days of chemotherapy and died 9 days after chemotherapy. To our knowledge, this patient is the first report of the association of hyperammonemia and chemotherapy with vinorelbine, topotecan, and cisplatin in the English literature.

Adjuvant oxaliplatin- or irinotecan-containing chemotherapy improves overall survival following resection of metachronous colorectal liver metastases.

PURPOSE: Adjuvant systemic 5-fluorouracil (5-FU)-based chemotherapy improves survival after resection of synchronous colorectal liver metastases (CLMs), but not metachronous. We retrospectively examined if adjuvant chemotherapy with new regimen containing oxaliplatin or irinotecan improved survivals after resection of metachronous CLMs. METHODS: Between 2000 and 2007, 52 patients having undertaken resection of metachronous CLMs with curative intent were identified from Taipei Veterans General Hospital hospitalization registry. One patient with perioperative mortality and another being lost to follow-up within 3 months after metastasectomy were excluded. Thirty-one patients experienced six to 12 cycles of FOLFOX or FOLFIRI chemotherapy while 19 patients with 5-FU/leucovorin (LV)-based chemotherapy following CLM resection. The primary end point was disease-free survival (DFS) and secondary end point, overall survival (OS). RESULTS: By the univariate analysis, median DFS was 34.3 months in the FOLFOX/FOLFIRI group vs 14.2 months in the 5-FU/LV group (P = 0.022). The median OS and 5-year survival rates were longer than 57.7 months (not reached, with median follow-up of 35.5 months) and 54.0%, respectively, in the FOLFOX/FOLFIRI group compared to 49 months and 34.6% in the 5-FU/LV group (P = 0.027). FOLFOX/FOLFIRI chemotherapy was shown by multivariate analyses to be an independent factor predicting a better DFS (hazard ratio [HR] = 0.37; 95% CI: 0.15-0.94; P = 0.036) and a better OS (HR = 0.27; 95% CI: 0.083-0.86, P = 0.026) than 5-FU/LV-based. CONCLUSIONS: Adjuvant FOLFOX/FOLFIRI chemotherapy following resection of metachronous CLMs is demonstrated to have better DFS and OS than 5-FU/LV chemotherapy.