Study protocol: multi-centre, randomised controlled clinical trial exploring stromal targeting in locally advanced pancreatic cancer; STARPAC2.

Background: Pancreatic cancer (PDAC: pancreatic ductal adenocarcinoma, the commonest form), a lethal disease, is best treated with surgical excision but is feasible in less than a fifth of patients. Around a third of patients presentlocally advanced, inoperable, non-metastatic (laPDAC), whose stadrd of care is palliative chemotherapy; a small minority are down-sized sufficiently to enable surgical excision. We propose a phase II clinical trial to test whether a combination of standard chemotherapy (gemcitabine & nab-Paclitaxel: GEM-NABP) and repurposing All Trans Retinoic Acid (ATRA) to target the stroma may extend progression-free survival and enable successful surgical resection for patients with laPDAC, since data from phase IB clinical trial demonstrate safety of GEM-NABP-ATRA combination to patients with advanced PDAC with potential therapeutic benefit.

The impact of chemotherapy on cognitive performance post-surgery in patients with colorectal cancer: A prospective cohort study.

Objectives: Subjective reports of cognitive impairment following chemotherapy are frequent in cancer patients. Objective cognitive impairment has been observed in cancer patients regardless of treatment regimen suggesting the relationship between cognitive impairment and chemotherapy is not clear cut. Little research has explored the effects of chemotherapy on cognition following surgery in colorectal cancer (CRC).

PANTHER: AZD8931, inhibitor of EGFR, ERBB2 and ERBB3 signalling, combined with FOLFIRI: a Phase I/II study to determine the importance of schedule and activity in colorectal cancer.

Background: Epidermal growth factor receptor (EGFR) is a therapeutic target to which HER2/HER3 activation may contribute resistance. This Phase I/II study examined the toxicity and efficacy of high-dose pulsed AZD8931, an EGFR/HER2/HER3 inhibitor, combined with chemotherapy, in metastatic colorectal cancer (CRC).

Methods: Treatment-naive patients received 4-day pulses of AZD8931 with irinotecan/5-FU (FOLFIRI) in a Phase I/II single-arm trial.

A Therapeutically Actionable Protumoral Axis of Cytokines Involving IL-8, TNFα, and IL-1β.

Unlabelled: Interleukin-8 (CXCL8) produced in the tumor microenvironment correlates with poor response to checkpoint inhibitors and is known to chemoattract and activate immunosuppressive myeloid leukocytes. In human cancer, IL8 mRNA levels correlate with IL1B and TNF transcripts. Both cytokines induced IL-8 functional expression from a broad variety of human cancer cell lines, primary colon carcinoma organoids, and fresh human tumor explants.

Autoimmune Encephalitis With mGluR1 Antibodies Presenting With Epilepsy, but Without Cerebellar Signs: A Case Report.

Objective: To describe the unique case history of a patient with mGluR1 antibodies, with mainly limbic and without cerebellar symptoms.

Methods: A 50-year-old woman initially presented with focal seizures with epigastric rising and déjà-vu sensations, next to cognitive complaints, and musical auditory hallucinations. MRI, EEG, and neuronal autoantibody tests were performed.

Harnessing cytokines and chemokines for cancer therapy.

During the past 40 years, cytokines and cytokine receptors have been extensively investigated as either cancer targets or cancer treatments. A strong preclinical rationale supports therapeutic strategies to enhance the growth inhibitory and immunostimulatory effects of interferons and interleukins, including IL-2, IL-7, IL-12 and IL-15, or to inhibit the inflammatory and tumour-promoting actions of cytokines such as TNF, IL-1β and IL-6. This rationale is underscored by the discovery of altered and dysregulated cytokine expression in all human cancers.

Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer.

Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress pancreatic ductal adenocarcinoma (PDAC) growth. Here, in a phase Ib, dose escalation and expansion, trial for patients with advanced, unresectable PDAC (n = 27), ATRA is re-purposed as a stromal-targeting agent in combination with gemcitabine-nab-paclitaxel chemotherapy using a two-step adaptive continual re-assessment method trial design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D, primary outcome) is the FDA/EMEA approved dose of gemcitabine-nab-paclitaxel along-with ATRA (45 mg/m orally, days 1-15/cycle).

Scheduling nab-paclitaxel combined with gemcitabine as first-line treatment for metastatic pancreatic adenocarcinoma.

Background: Nab-paclitaxel plus gemcitabine (nabP+gemcitabine) offers modest survival gains for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Sequential scheduling of nabP+gemcitabine in a PDAC mouse model improved efficacy; this hypothesis was tested in a clinical trial.

Methods: Patients with previously untreated metastatic PDAC were randomised to receive nabP+gemcitabine administered either concomitantly on the same day, or sequentially, with gemcitabine administered 24 h after nabP.

3-month versus 6-month adjuvant chemotherapy for patients with high-risk stage II and III colorectal cancer: 3-year follow-up of the SCOT non-inferiority RCT.

Background: Oxaliplatin and fluoropyrimidine chemotherapy administered over 6 months is the standard adjuvant regimen for patients with high-risk stage II or III colorectal cancer. However, the regimen is associated with cumulative toxicity, characterised by chronic and often irreversible neuropathy.

Objectives: To assess the efficacy of 3-month versus 6-month adjuvant chemotherapy for colorectal cancer and to compare the toxicity, health-related quality of life and cost-effectiveness of the durations.

SCOT: a comparison of cost-effectiveness from a large randomised phase III trial of two durations of adjuvant Oxaliplatin combination chemotherapy for colorectal cancer.

Background: The Short Course Oncology Therapy (SCOT) study is an international, multicentre, non-inferiority randomised controlled trial assessing the efficacy, toxicity, and cost-effectiveness of 3 months (3 M) versus the usually given 6 months (6 M) of adjuvant chemotherapy in colorectal cancer.

Methods: In total, 6088 patients with fully resected high-risk stage II or stage III colorectal cancer were randomised and followed up for 3-8 years. The within-trial cost-effectiveness analysis from a UK health-care perspective is presented using the resource use data, quality of life (EQ-5D-3L), time on treatment (ToT), disease-free survival after treatment (DFS) and overall survival (OS) data.

Switchable CAR-T cells mediate remission in metastatic pancreatic ductal adenocarcinoma.

Objective: Pancreatic ductal adenocarcinoma (PDAC) is a disease of unmet medical need. While immunotherapy with chimeric antigen receptor T (CAR-T) cells has shown much promise in haematological malignancies, their efficacy for solid tumours is challenged by the lack of tumour-specific antigens required to avoid on-target, off-tumour effects. Switchable CAR-T cells whereby activity of the CAR-T cell is controlled by dosage of a tumour antigen-specific recombinant Fab-based 'switch' to afford a fully tunable response may overcome this translational barrier.

The VAR2CSA malaria protein efficiently retrieves circulating tumor cells in an EpCAM-independent manner.

Isolation of metastatic circulating tumor cells (CTCs) from cancer patients is of high value for disease monitoring and molecular characterization. Despite the development of many new CTC isolation platforms in the last decade, their isolation and detection has remained a challenge due to the lack of specific and sensitive markers. In this feasibility study, we present a method for CTC isolation based on the specific binding of the malaria rVAR2 protein to oncofetal chondroitin sulfate (ofCS).

3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial.

Background: 6 months of oxaliplatin-containing chemotherapy is usually given as adjuvant treatment for stage 3 colorectal cancer. We investigated whether 3 months of oxaliplatin-containing chemotherapy would be non-inferior to the usual 6 months of treatment.

Methods: The SCOT study was an international, randomised, phase 3, non-inferiority trial done at 244 centres.

Intrinsic Charge Dynamics in High-T_{c} AFeAs(O,F) Superconductors.

We report the first determination of the in-plane complex optical conductivity of 1111 high-T_{c} superconducting iron oxypnictide single crystals PrFeAs(O,F) and thin films SmFeAs(O,F) by means of conventional and microfocused infrared spectroscopy, ellipsometry, and time-domain THz transmission spectroscopy. A strong itinerant contribution is found to exhibit a dramatic difference in coherence between the crystal and the film. Using extensive temperature-dependent measurements of THz transmission, we identify a previously undetected 2.

Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial.

Background: Erlotinib is an EGFR tyrosine kinase inhibitor that has shown a significant but only marginally improved median overall survival when combined with gemcitabine in patients with locally advanced and metastatic pancreatic cancer. Vandetanib is a novel tyrosine kinase inhibitor of VEGFR2, RET, and EGFR, all of which are in involved in the pathogenesis of pancreatic cancer. We investigated the clinical efficacy of vandetanib when used in combination with gemcitabine in patients with advanced pancreatic cancer.

Remodelling of microRNAs in colorectal cancer by hypoxia alters metabolism profiles and 5-fluorouracil resistance.

Solid tumours have oxygen gradients and areas of near and almost total anoxia. Hypoxia reduces sensitivity to 5-fluorouracil (5-FU)-chemotherapy for colorectal cancer (CRC). MicroRNAs (miRNAs) are hypoxia sensors and were altered consistently in six CRC cell lines (colon cancer: DLD-1, HCT116 and HT29; rectal cancer: HT55, SW837 and VACO4S) maintained in hypoxia (1 and 0.

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.

Relative telomere lengths in tumor and normal mucosa are related to disease progression and chromosome instability profiles in colorectal cancer.

Telomeric dysfunction is linked to colorectal cancer (CRC) initiation. However, the relationship of normal tissue and tumor telomere lengths with CRC progression, molecular features and prognosis is unclear. Here, we measured relative telomere length (RTL) by real-time quantitative PCR in 90 adenomas (aRTL), 419 stage I-IV CRCs (cRTL) and adjacent normal mucosa (nRTL).

Weak-coupling superconductivity in a strongly correlated iron pnictide.

Iron-based superconductors have been found to exhibit an intimate interplay of orbital, spin, and lattice degrees of freedom, dramatically affecting their low-energy electronic properties, including superconductivity. Albeit the precise pairing mechanism remains unidentified, several candidate interactions have been suggested to mediate the superconducting pairing, both in the orbital and in the spin channel. Here, we employ optical spectroscopy (OS), angle-resolved photoemission spectroscopy (ARPES), ab initio band-structure, and Eliashberg calculations to show that nearly optimally doped NaFe0.

A randomised, open-label phase II trial of afatinib versus cetuximab in patients with metastatic colorectal cancer.

Purpose: This randomised phase II trial aimed to compare efficacy of the irreversible ErbB family blocker, afatinib, with cetuximab in patients with KRAS wild-type metastatic colorectal adenocarcinoma (mCRC) with progression following oxaliplatin- and irinotecan-based regimens. Efficacy in patients with KRAS mutations was also evaluated.

Patients And Methods: Patients with KRAS wild-type tumours were randomised 2:1 to afatinib (40 mg/day, increasing to 50 mg/day if minimal toxicity) or cetuximab weekly (400 mg/m2 loading dose, then 250 mg/m2/week) according to number of previous chemotherapy lines.

Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial.

Background: We aimed to assess the efficacy and safety of sequential or simultaneous telomerase vaccination (GV1001) in combination with chemotherapy in patients with locally advanced or metastatic pancreatic cancer.

Methods: TeloVac was a three-group, open-label, randomised phase 3 trial. We recruited patients from 51 UK hospitals.