Intravenous Oncolytic Vaccinia Virus Therapy Results in a Differential Immune Response between Cancer Patients.

is an engineered Wyeth-strain vaccinia oncolytic virus (OV), which has been tested extensively in clinical trials, demonstrating enhanced cytotoxic T cell infiltration into tumours following treatment. Favourable immune consequences to include the induction of an interferon (IFN) response, followed by inflammatory cytokine/chemokine secretion. This promotes tumour immune infiltration, innate and adaptive immune cell activation and T cell priming, culminating in targeted tumour cell killing, i.

Effectiveness of Thymoquinone and Fluoridated Bioactive Glass/Nano-Oxide Contained Dentifrices on Abrasion and Dentine Tubules Occlusion: An Ex Vivo Study.

Objectives:  Dentin hypersensitivity (DH) is mainly due to the loss and replenishment of minerals from tooth structure, where the lost minerals can be rehabilitated with a biomimetic approach. The objectives were to determine the relative dentin abrasivity (RDA) of experimental (EXT) dentifrices and to determine the efficacy to occlude dentinal tubules.

Materials And Methods:  Experimental dentifrices contained nano-fluoridated bioactive glass (n-FBG: 1.

Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC): A phase I dose escalating safety study and randomised dose expansion of AZD8931 in combination with oxaliplatin and capecitabine chemotherapy in patients with oesophagogastric adenocarcinoma.

Background: AZD8931 has equipotent activity against epidermal growth factor receptor, erbB2, and erbB3. Primary objectives were to determine the recommended phase II dose (RP2D) of AZD8931 + chemotherapy, and subsequently assess safety/preliminary clinical activity in patients with operable oesophagogastric cancer (OGC).

Methods: AZD8931 (20 mg, 40 mg or 60 mg bd) was given with Xelox (oxaliplatin + capecitabine) for eight 21-day cycles, continuously or with intermittent schedule (4 days on/3 off every week; 14 days on/7 off, per cycle) in a rolling-six design.

Phase II study of TP300 in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma.

Background: TP300, a recently developed synthetic camptothecin analogue, is a highly selective topoisomerase I inhibitor. A phase I study showed good safety and tolerability. As camptothecins have proven active in oesophago-gastric adenocarcinomas, in this phase II study we assessed the efficacy and safety of TP300 in patients with gastric or gastro-oesophageal junction (GOJ) adenocarcinomas.

Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial.

Background: Cisplatin and gemcitabine is the standard first-line chemotherapy regimen for patients with advanced biliary tract cancer; expression of VEGF and its receptors is associated with adverse outcomes. We aimed to assess the effect of the addition of cediranib (an oral inhibitor of VEGF receptor 1, 2, and 3) to cisplatin and gemcitabine on progression-free survival.

Methods: In this multicentre, placebo-controlled, randomised phase 2 study, we recruited patients aged 18 years or older with histologically confirmed or cytologically confirmed advanced biliary tract cancer from hepatobiliary oncology referral centres in the UK.

Phase I study of TP300 in patients with advanced solid tumors with pharmacokinetic, pharmacogenetic and pharmacodynamic analyses.

Background: A Phase I dose escalation first in man study assessed maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended Phase II dose of TP300, a water soluble prodrug of the Topo-1 inhibitor TP3076, and active metabolite, TP3011.

Methods: Eligible patients with refractory advanced solid tumors, adequate performance status, haematologic, renal, and hepatic function. TP300 was given as a 1-hour i.

Cell carriage, delivery, and selective replication of an oncolytic virus in tumor in patients.

Oncolytic viruses, which preferentially lyse cancer cells and stimulate an antitumor immune response, represent a promising approach to the treatment of cancer. However, how they evade the antiviral immune response and their selective delivery to, and replication in, tumor over normal tissue has not been investigated in humans. Here, we treated patients with a single cycle of intravenous reovirus before planned surgery to resect colorectal cancer metastases in the liver.

A first in man, phase I dose-escalation study of PHA-793887, an inhibitor of multiple cyclin-dependent kinases (CDK2, 1 and 4) reveals unexpected hepatotoxicity in patients with solid tumors.

Background: PHA-793887 is an inhibitor of multiple cyclin dependent kinases (CDK) with activity against CDK2, CDK1 and CDK4. The primary objectives of this first in man study were to determine the dose limiting toxicities (DLTs), maximum tolerated dose (MTD) and recommended phase II dose of PHA-793887.

Results: Although toxicity was acceptable at initial dose levels, PHA-793887 was poorly tolerated at doses ≥44 mg/m2.

Severe sequence-specific toxicity when capecitabine is given after Fluorouracil and leucovorin.

Purpose: Options for single-agent fluoropyrimidine adjuvant therapy after bowel cancer resection include intravenous fluorouracil with leucovorin (FU/LV) or oral capecitabine. These treatments have similar efficacy but differ in convenience and toxicity. We therefore wished to compare their overall acceptability to patients.

Monitoring the treatment of carcinoid disease using blood serotonin and plasma 5-hydroxyindoleacetic acid: three case examples.

The results for plasma 5-hydroxyindoleacetic acid (5-HIAA), whole blood serotonin and the chromogranins on three patients following their treatment for carcinoid disease with somatostatin analogues are presented. Two of the patients (a 56-year-old woman and a 55-year-old man) demonstrated a good clinical response following treatment, with initial high blood serotonin and plasma 5-HIAA concentrations showing a significant decline. However, blood serotonin concentrations remained above the reference range during the course of treatment, whereas plasma 5-HIAA remained borderline high or marginally elevated with respect to the clinical cut-off concentration.

A phase I and II study of 2-weekly irinotecan with capecitabine in advanced gastroesophageal adenocarcinoma.

We investigated 2-weekly intravenous irinotecan combined with oral capecitabine in patients with advanced gastroesophageal adenocarcinoma. In phase I, doses were escalated in chemotherapy naïve or pretreated patients to establish maximum tolerated doses (MTD). In phase II, patients were treated at MTD as first-line therapy with the primary end point of RECIST response.

Intravenous irinotecan plus oral ciclosporin.

We previously reported a phase I study of intravenous irinotecan plus oral ciclosporin, in which dose-limiting diarrhoea was not observed, supporting the hypothesis that pharmacokinetic modulation of irinotecan by ciclosporin may improve its therapeutic index. We now report results of a further 34 patients treated at the recommended dose. A low rate of diarrhoea of grade 3 or above (3%) was again seen, with useful anti-tumour activity.

Weekly 5-fluorouracil and leucovorin: achieving lower toxicity with higher dose-intensity in adjuvant chemotherapy after colorectal cancer resection.

Background: Current standard therapy following resection of high-risk colon cancer is intravenous bolus 5-fluorouracil (5-FU) with leucovorin (LV), but there is no consensus on the optimum regimen of these drugs: practice ranges from the high toxicity Mayo Clinic schedule to the very low toxicity weekly QUASAR schedule. We present data for a weekly schedule that aims to provide moderately dose-intense treatment with low toxicity.

Patients And Methods: One hundred and sixty-two patients were studied: 60% male; median age 65 years (36% over 70 years); 94% colorectal primary.

Comparative preclinical pharmacokinetic and metabolic studies of the combretastatin prodrugs combretastatin A4 phosphate and A1 phosphate.

Purpose: Combretastatin A4 phosphate (CA4P) and its structural analog, combretastatin A1 phosphate (CA1P), are soluble prodrugs capable of interacting with tubulin and causing rapid vascular shutdown within tumors. CA4P has completed Phase I clinical trials, but recent preclinical studies have shown that CA1P displays a greater antitumor effect than the combretastatin A4 (CA4) analog at equal doses. The aim of this study, therefore, is to compare pharmacokinetics and metabolism of the two compounds to determine whether pharmacokinetics plays a role in their differential activity.

Bleomycin, vincristine, cisplatin/bleomycin, etoposide, cisplatin chemotherapy: an alternating, dose intense regimen producing promising results in untreated patients with intermediate or poor prognosis malignant germ-cell tumours.

Patients with poor and intermediate prognosis metastatic germ-cell tumours (MGCTs) are at a significant risk of relapse after standard platinum-based chemotherapy. Novel treatment regimens are required to improve survival. Dose intense, alternating combinations of drugs with known activity in germ-cell tumours represents one approach.

DNA: still a target worth aiming at? A review of new DNA-interactive agents.

DNA acts as the final target for most clinically effective cytotoxic agents, but the lack of selectivity for tumor cells has raised questions about the value of developing new DNA-interactive agents. Three new classes of cytotoxic agents are reviewed; each interacts directly with DNA but cytotoxicity appears to be mediated through novel mechanisms, including the interaction with specific proteins by DNA-bound drug molecules. Irofulven is the lead compound of the illudin family of molecules.

A phase II trial of the vitamin D analogue Seocalcitol (EB1089) in patients with inoperable pancreatic cancer.

Inoperable cancer of the exocrine pancreas responds poorly to most conventional anti-cancer agents, and new agents are required to palliate this disease. Seocalcitol (EB1089), a vitamin D analogue, can inhibit growth, induce differentiation and induce apoptosis of cancer cell lines in vitro and can also inhibit growth of pancreatic cancer xenografts in vivo. Thirty-six patients with advanced pancreatic cancer received once daily oral treatment with seocalcitol with dose escalation every 2 weeks until hypercalcaemia occurred, following which patients continued with maintenance therapy.

Inflammatory demyelinating polyneuropathy: a complication of immunotherapy in malignant melanoma.

Paraneoplastic syndromes (PNS) involving the central nervous system are a rare manifestation of malignant disease. As they commonly precede the diagnosis of malignancy their acute manifestations do not often present themselves to oncologists in the first instance. It is currently believed that most, if not all, neurological PNS are autoimmune in nature.

Drug resistance : the clinical perspective.

There are very few tumor types in which the use of chemotherapy can bring about prolonged survival, and possibly cure, for individual patients. The most common reason for this is the development of drug resistance within tumor cells. The laboratory study of resistance to anticancer drugs has resulted in the discovery of numerous mechanisms present within tumor cells that act to reduce their cytotoxic effects.

hMLH1 expression and cellular responses of ovarian tumour cells to treatment with cytotoxic anticancer agents.

Loss of expression of the hMLH1 and hPMS2 subunits of the MutL alpha-mismatch repair complex is a frequent event (9/10) in independent cisplatin resistant derivatives of a human ovarian carcinoma cell line. However, only hMLH1 mRNA is decreased in these MutL alpha-deficient lines. No alterations in the levels of the hMSH2 and hMSH6 (GTBP) subunits of the MutS alpha-complex are observed.

Microsatellite instability, apoptosis, and loss of p53 function in drug-resistant tumor cells.

We have examined microsatellite instability and loss of p53 function in human tumor cell line models of acquired anticancer drug resistance. We observe acquisition of an RER(+) phenotype in cell lines selected for resistance to cisplatin or doxorubicin. The majority of independent cisplatin-resistant sublines are RER(+), whereas the parental line shows no evidence of microsatellite instability.

Colonic adenocarcinoma associated ectopic ACTH secretion: a case history.

A 57-year-old woman developed features of Cushing's syndrome after resection of a Duke's C adenocarcinoma of the sigmoid colon. Biochemical and endocrine investigation indicated ectopic production of adrenocorticotrophic hormone (ACTH) as the cause for her condition. Hepatic metastases were detected by computed tomography (CT) scan.

On temporal structure of human hiccups: ethology and chronobiology.

During a study on the phylogeny and ontogeny of human hiccups, essentially all hiccups to occur over continuous periods of 3m - lly were recorded from 20 healthy people of either sex and various ages. Hiccups displayed considerable structure in time. If more than a few occurred together, they became "established" and a hiccup bout ensued, which did not stop until a certain "minimum" number of hiccups had occurred.