Safety and Antitumor Activity of the Anti-Programmed Death-1 Antibody Pembrolizumab in Patients With Advanced Esophageal Carcinoma.

Purpose The anti-programmed death-1 antibody pembrolizumab was evaluated in KEYNOTE-028, a multicohort, phase IB study of patients with programmed death ligand-1 (PD-L1)-positive advanced solid tumors. Results from the esophageal carcinoma cohort are reported herein. Patients and Methods Eligible patients with squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction in whom standard therapy failed and who had PD-L1-positive tumors received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed disease progression or intolerable toxicity.

Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial.

Background: Expression of PD-L1 has been shown to be upregulated in some patients with gastric cancer. As part of the phase 1b KEYNOTE-012 study, we aimed to assess the safety and activity of the anti-PD-1 antibody pembrolizumab in patients with PD-L1-positive recurrent or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction.

Methods: This study was a multicentre, open-label, phase 1b trial done at 13 cancer research centres in the USA, Israel, Japan, South Korea, and Taiwan.

Role of GLI1 and NDRG1 in Increased Resistance to Apoptosis Induction.

We examined the effects of GLI1 expression in PW mouse embryo fibroblasts and H441 lung carcinoma cells. Ectopic expression of GLI1 in PW cells induced anchorage-independent growth and increased resistance to staurosporine-induced apoptosis, and overexpression of GLI1 in H441 cells caused resistance to apoptosis induced by staurosporine and etoposide. GLI1 expression in both H441 and PW cells was associated with increased expression of NDRG1, a gene known to be downregulated by the MYC family of proteins, indicating that upregulation of NDRG1 by GLI1 is not cell-type specific.

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.

Background: Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade.

Methods: We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti-programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency.

Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial.

Background: Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, prolonged survival in patients with advanced gastric cancer.

Methods: We did an international, randomised, double-blind, placebo-controlled, phase 3 trial between Oct 6, 2009, and Jan 26, 2012, at 119 centres in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa.

Effect of biliary drainage on chemotherapy in patients with biliary tract cancer: an exploratory analysis of the BT22 study.

Background/purpose: Complications from biliary drainage in biliary tract cancer (BTC) may influence the relative dose intensity of chemotherapy or increase adverse events during chemotherapy. BT22 was a randomized phase II trial, the results of which were consistent with those of a phase III trial in non-Japanese that demonstrated the effectiveness of gemcitabine plus cisplatin combination therapy (GC) in BTC. The purpose of this exploratory analysis of the BT22 study was to identify the possible effects of biliary drainage on the efficacy and safety of GC or gemcitabine monotherapy (G).

Phase I study of LY2469298, an Fc-engineered humanized anti-CD20 antibody, in patients with relapsed or refractory follicular lymphoma.

Patients with follicular lymphoma (FL), where position 158 of FcγR-IIIa is heterozygous valine/phenylalanine or homozygous phenylalanine (F-carriers), have natural killer cells with lower binding affinity to IgG than valine homozygote patients. In addition, F-carriers show less efficacy with rituximab treatment than patients homozygous for valine. LY2469298 is a humanized IgG1 monoclonal antibody targeting CD20, with human germline framework regions, and specific amino acid substitutions engineered into the Fc region to increase effector function in antibody-dependent cell-mediated cytotoxicity.

Lessons from the comparison of two randomized clinical trials using gemcitabine and cisplatin for advanced biliary tract cancer.

There had been no standard chemotherapy established for advanced biliary tract cancer (BTC) until 2009, when the combination of cisplatin and gemcitabine (GC) was adopted as a first line standard chemotherapy option based on the results from two randomized studies: ABC-02, a UK investigator-initiated trial and the largest randomized phase III study in this tumor type with 410 patients; and BT22, a Japanese, industry-sponsored, randomized phase II study with 83 patients. In this review, investigators from both studies collaborated to compare protocols, patient characteristics, and outcomes of both studies including sub-analyses of study results. Although both studies showed GC combination therapy to be more effective than monotherapy, a detailed comparison revealed disparities between efficacy and safety end-points between the studies, which did not necessarily arise from different populations but from differences in protocol design.

Phase I dose escalation and pharmacokinetic study of oral enzastaurin (LY317615) in advanced solid tumors.

Enzastaurin is an oral serine/threonine kinase inhibitor that targets the protein kinase C (PKC) and phosphoinositide 3-kinase/AKT pathways to induce apoptosis and suppress proliferation of various cancer cell lines. This phase I study evaluated the tolerability and pharmacokinetics of enzastaurin in Japanese patients with advanced solid tumors and determined the recommended dose for phase II. Eligible patients had advanced solid tumors and an Eastern Cooperative Oncology Group performance status of 0-2.

A phase I study of enzastaurin combined with pemetrexed in advanced non-small cell lung cancer.

Introduction: Enzastaurin is an oral serine/threonine kinase inhibitor, which suppress signaling through protein kinase C-beta and the phosphatidylinositol 3-kinase/AKT pathway. Preclinical studies suggested synergic antitumor activity of enzastaurin and pemetrexed. We conducted this phase I study to evaluate the safety, pharmacokinetics, and clinical activity of this combination in patients with previously treated advanced non-small cell lung cancer.

[Drug interactions in medical oncology].

Cytotoxic anti-neoplastic drugs are some of the strongest acting drugs. They have a complex pharmacological profile, narrow therapeutic window, steep dose-toxicity curve, and many pharmacokinetic and pharmacodynamic differences both within and between patients. This makes it difficult to avoid adverse effects.

A landmark point analysis with cytotoxic agents for advanced NSCLC.

Introduction: As a result of recent publications, we hypothesized that period of 8 weeks after initiation of treatment is a useful landmark point for cytotoxic agents for advanced non-small cell lung cancer (NSCLC). To test this hypothesis, we conducted landmark analyses with clinical trials employing cytotoxic agents. Our goal was to assess the proper design of clinical trials with cytotoxic agents for NSCLC for maximizing patients' benefit.

Hypoxic suppression of the cell cycle gene CDC25A in tumor cells.

Hypoxia, a key microenvironmental factor for tumor development, not only stimulates angiogenesis and glycolysis for tumor expansion, but also induces cell cycle arrest and genetic instability for tumor progression. Several independent studies have shown hypoxic blockade of cell cycle progression at the G1/S transition, arising from the inactivation of S-phase-promoting cyclin E-CDK2 kinase complex. Despite these findings, the biochemical pathways leading to the cell cycle arrest remain poorly defined.

Correlation of N-myc downstream-regulated gene 1 expression with clinical outcomes of colorectal cancer patients of different race/ethnicity.

Aim: To evaluate the role of N-myc downstream-regulated gene 1 (NDRG1) expression in prognosis and survival of colorectal cancer patients with different ethnic backgrounds.

Methods: Because NDRG1 is a downstream target of p53 and hypoxia inducible factor-1 alpha (HIF-1 alpha), we examined NDRG1 expression together with p53 and HIF-1 alpha by immunohistochemistry. A total of 157 colorectal cancer specimens including 80 from Japanese patients and 77 from US patients were examined.

Genetic instability: the dark side of the hypoxic response.

Under low oxygen tension, the activated transcription factor HIF-1alpha upregulates an array of hypoxia-inducible genes via heterodimerization with ARNT and binding to the hypoxia-responsive element in the promoter. Alternatively, HIF-1alpha regulates hypoxia-responsive genes by functionally antagonizing the oncoprotein Myc via protein-protein interactions. This so-called HIF-1alpha-Myc mechanism apparently not only accounts for the gene upregulation, but also for the gene downregulation during hypoxia, depending upon the activating and repressive nature of Myc in gene expression.

HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression.

Hypoxia promotes genetic instability by undefined mechanisms. The transcription factor HIF-1alpha is crucial for the cellular response to hypoxia and is frequently overexpressed in human cancers, resulting in the activation of genes essential for cell survival. Here, we demonstrate that HIF-1alpha is responsible for genetic instability at the nucleotide level by inhibiting MSH2 and MSH6, thereby decreasing levels of the MSH2-MSH6 complex, MutSalpha, which recognizes base mismatches.

Tumor suppressor p53 represses transcription of RECQ4 helicase.

RECQ4 is a member of the RecQ helicase family, which has been implicated in the regulation of DNA replication, recombination and repair. p53 modulates the functions of RecQ helicases including BLM and WRN. In this study, we demonstrate that p53 can regulate the transcription of RECQ4.

Dynamic balancing of the dual nature of HIF-1alpha for cell survival.

In hypoxic cells, HIF-1alpha escapes from oxygen-dependent proteolysis and binds to the hypoxia-responsive element (HRE) for transcriptional activation of target genes involved in angiogenesis and glycolysis. We recently demonstrated that the G(1) checkpoint gene p21(cip1)is activated by HIF-1alpha with a novel mechanism that involves the HIF-1alpha PAS domains to displace Myc binding from p21(cip1) promoter. This HIF-1alpha-Myc pathway may account for up- and down-regulation of other hypoxia-responsive genes that lack the HRE.

Leu-574 of human HIF-1alpha is a molecular determinant of prolyl hydroxylation.

Hypoxia-inducible factor (HIF)-1alpha, a master regulator of oxygen homeostasis, regulates genes crucial for cell growth and survival. In normoxia, HIF-1alpha is constantly degraded via the ubiquitin-proteasome pathway. The von Hippel-Lindau (VHL) E3 ubiquitin ligase binds HIF-1alpha through specific recognition of hydroxylated Pro-402 or Pro-564, both of which are modified by the oxygen-dependent HIF prolyl hydroxylases (PHDs/HPHs).

HIF-1alpha induces cell cycle arrest by functionally counteracting Myc.

Hypoxia induces angiogenesis and glycolysis for cell growth and survival, and also leads to growth arrest and apoptosis. HIF-1alpha, a basic helix-loop-helix PAS transcription factor, acts as a master regulator of oxygen homeostasis by upregulating various genes under low oxygen tension. Although genetic studies have indicated the requirement of HIF-1alpha for hypoxia-induced growth arrest and activation of p21(cip1), a key cyclin-dependent kinase inhibitor controlling cell cycle checkpoint, the mechanism underlying p21(cip1) activation has been elusive.

Genetic alterations in normal epithelium of colorectal cancer patients may be a useful indicator for subsequent metachronous tumor development.

Background: We attempted to identify areas of microsatellite alterations specific to histologically normal colorectal epithelium and to clarify the correlations among those molecular events and clinicopathologic features.

Methods: We conducted a prospective observation study on 51 colorectal cancer patients. Preoperative blood and microdissected histologically normal colorectal epithelium and neoplastic tissues were collected.

Microsatellite analysis of fecal DNA for colorectal cancer detection.

Background And Objectives: The advent of noninvasive methods of testing for colorectal cancer that have a high level of specificity and sensitivity is eagerly awaited.

Methods: Thirty patients with sporadic colorectal cancer and 11 patients with hereditary nonpolyposis colon cancer (HNPCC) enrolled in this study. We analyzed the loss of heterozygosity (LOH) in matched genomic DNA extracted from blood and surgical specimens (tumor and tumor-free colonic mucosa), and the corresponding oral rinse and stool specimens using seven microsatellite loci (APC, p53, DCC, hMLH1, D9S162, D9S171, and IFNA).