Matthew David Hale

Tumour-microenvironment interactions: role of tumour stroma and proteins produced by cancer-associated fibroblasts in chemotherapy response

BackgroundCytotoxic chemotherapy improves survival for some, but not all, cancer patients. Non-responders may experience unnecessary toxicity and cancer progression, thus creating an urgent need for biomarkers that can predict the response to chemotherapy. So far, the search for such biomarkers has primarily been focused on the cancer cells and less on their surrounding stroma. This stroma is known to act as a key regulator of tumour progression and, in addition, has been associated with drug delivery and drug efficacy. Fibroblasts represent the major cell type in cancer-associated stroma and they secrete extracellular matrix proteins as well as growth factors. This Medline-based literature review summarises the results from studies on epithelial cancers and aimed at investigating relationships between the quantity and quality of the intra-tumoral stroma, the cancer-associated fibroblasts, the proteins they produce and the concomitant response to chemotherapy. Biomarkers were selected for review that are known to affect cancer-related characteristics and patient prognosis.ResultsThe current literature supports the hypothesis that biomarkers derived from the tumour stroma may be useful to predict response to chemotherapy. This notion appears to be related to the overall quantity and cellularity of the intra-tumoural stroma and the predominant constituents of the extracellular matrix.ConclusionIncreasing evidence is emerging showing that tumour-stroma interactions may not only affect tumour progression and patient prognosis, but also the response to chemotherapy. The tumour stroma-derived biomarkers that appear to be most appropriate to determine the patient’s response to chemotherapy vary by tumour origin and the availability of pre-treatment tissue. For patients scheduled for adjuvant chemotherapy, the most promising biomarker appears to be the PLAU: SERPINE complex, whereas for patients scheduled for neo-adjuvant chemotherapy the tumour stroma quantity appears to be most relevant.

Xanthogranulomatous cholecystitis: a European and global perspective.

INTRODUCTION Xanthogranulomatous cholecystitis (XGC) is often mistaken for, and may predispose to, gallbladder carcinoma (GB Ca). This study reviews the worldwide variation of the incidence, investigations, management and outcome of patients with XGC. METHODS Data from 29 studies, cumulatively containing 1599 patients, were reviewed and results summarized by geographical region (Europe, India, Far East and Americas) with 95% confidence intervals (CIs) to present variability within regions. The main study outcomes were incidence, association with GB Ca and treatment of patients with XGC. RESULTS Overall, the incidence of XGC was 1.3-1.9%, with the exception of India where it was 8.8%. The incidence of GB Ca associated with XGC was lowest in European studies (3.3%) varying from 5.1-5.9% in the remaining regions. Confusion with or undiagnosed GB Ca led to 10.2% of patients receiving over or under treatment. CONCLUSIONS XGC is a global disease and is associated with GB Ca. Characteristic pathological, radiological and clinical features are shared with GB Ca and contribute to considerable treatment inaccuracy. Tissue sampling by pre-operative endoscopic ultrasound or intra-operative frozen section is required to accurately diagnose gallbladder pathology and should be performed before any extensive resection is performed.

Biopsy proportion of tumour predicts pathological tumour response and benefit from chemotherapy in resectable oesophageal carcinoma: results from the UK MRC OE02 trial

Background Neoadjuvant chemotherapy followed by surgery is the standard of care for UK patients with locally advanced resectable oesophageal carcinoma (OeC). However, not all patients benefit from multimodal treatment and there is a clinical need for biomarkers which can identify chemotherapy responders. This study investigated whether the proportion of tumour cells per tumour area (PoT) measured in the pre-treatment biopsy predicts chemotherapy benefit for OeC patients. Patients and methods PoT was quantified using digitized haematoxylin/eosin stained pre-treatment biopsy slides from 281 OeC patients from the UK MRC OE02 trial (141 treated by surgery alone (S); 140 treated by 5-fluorouracil/cisplatin followed by surgery (CS)). The relationship between PoT and clinicopathological data including tumour regression grade (TRG), overall survival and treatment interaction was investigated. Results PoT was associated with chemotherapy benefit in a non-linear fashion (test for interaction, P=0.006). Only patients with a biopsy PoT between 40% and 70% received a significant survival benefit from neoadjuvant chemotherapy (N=129; HR (95%CI):1.94 (1.39-2.71), unlike those with lower or higher PoT (PoT<40%, N=39, HR:1.25 (0.66-2.35); PoT>70% (N=28, HR:0.65 (0.36-1.18)). High pre-treatment PoT was related to lack of primary tumour regression (TRG 4 or 5), P=0.0402. Conclusions This is the first study to identify in a representative subgroup of OeC patients from a large randomized phase III trial that the proportion of tumour in the pre-chemotherapy biopsy predicts benefit from chemotherapy and may be a clinically useful biomarker for patient treatment stratification.

Endoscopic biopsies from gastrointestinal carcinomas and their suitability for molecular analysis: a review of the literature and recommendations for clinical practice and research

Endoscopic biopsies (EBs) are the gold standard for diagnosing gastrointestinal carcinoma yet no guidelines address EB use for prognostic and predictive molecular testing. This review summarizes the reported quantity and quality of EBs, their relationship with molecular test failure rates and the resultant concordance between EB and resection specimen. Studies reporting molecular testing on gastrointestinal carcinoma EBs published between 2002 and 2014 were identified. Details regarding EB quantity, quality, tumour content, molecular test failure rates as well as causes and concordance with resection specimens were reviewed. Seventy‐five studies were identified. Eighteen (24%) reported the mean EB number per patient (median: 2.1, range: 1–6.6 EBs). Sixty‐one (81%) reported the frequency of test failure (median: 0%, range: 0–100%). Twenty‐two (29%) investigated EB and resection specimen concordance (range: 0–100%). EB quantity and quality affected neither concordance nor failure rate. In summary, few studies currently report EB quantity, EB quality or EB and resection specimen concordance. Reliable molecular testing in EBs appears achievable, and can be representative of resection specimens. Concordance depends upon the testing methodology and biomarker heterogeneity within the tumour. To improve patient care, EB sampling, processing and reporting requires standardization and needs optimization for each biomarker individually.

A Novel Functional Magnetic Resonance Imaging Paradigm for the Preoperative Assessment of Auditory Perception in a Musician Undergoing Temporal Lobe Surgery

BACKGROUND Presurgical evaluation for temporal lobe epilepsy routinely assesses speech and memory lateralization and anatomic localization of the motor and visual areas but not baseline musical processing. This is paramount in a musician. Although validated tools exist to assess musical ability, there are no reported functional magnetic resonance imaging (fMRI) paradigms to assess musical processing. We examined the utility of a novel fMRI paradigm in an 18-year-old left-handed pianist who underwent surgery for a left temporal low-grade ganglioglioma. METHODS Preoperative evaluation consisted of neuropsychological evaluation, T1-weighted and T2-weighted magnetic resonance imaging, and fMRI. Auditory blood oxygen level-dependent fMRI was performed using a dedicated auditory scanning sequence. Three separate auditory investigations were conducted: listening to, humming, and thinking about a musical piece. RESULTS All auditory fMRI paradigms activated the primary auditory cortex with varying degrees of auditory lateralization. Thinking about the piece additionally activated the primary visual cortices (bilaterally) and right dorsolateral prefrontal cortex. Humming demonstrated left-sided predominance of auditory cortex activation with activity observed in close proximity to the tumor. CONCLUSIONS This study demonstrated an fMRI paradigm for evaluating musical processing that could form part of preoperative assessment for patients undergoing temporal lobe surgery for epilepsy.

Abstract 3958: The importance of co-localized resting CD8+ T cells and proliferating tumor cells in gastric cancer

Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. With the advent of immunotherapies, there is a need to characterize the phenotype of tumor infiltrating immune cells and co-localized cancer cells. We have shown previously that high density of CD45R0+ T cells is related to better prognosis in Japanese GC. However, the variation of T-cell infiltration in GC is still not understood. We hypothesized that an increased CD8+ T-cell infiltration is related to T-cell activation (high T cell Ki67 proliferation index). Purpose: To establish the frequency of co-occurrence of Ki67+ and CD8+ in T cells and their co-localization with tumor cells and evaluate the relationship with clinicopathological variables including survival. Patients and Methods: Immunohistochemistry for T cells (CD8), proliferation (Ki67), and epithelial cells (CK) was performed on tissue microarrays (TMAs) from 213 GC from the Kanagawa Cancer Centre Hospital (Yokohama, Japan). Stained slides were scanned, quality controlled, and analyzed using Tissue Phenomics (Definiens, Munich, Germany) for cell/nuclei segmentation and automatic co-registration of consecutive sections. The TMA cores were subdivided into tiles of size 64 µm2 to count co-localized positive cells. Average ratio of CD8+ cells and Ki67+ cells per tile/patient was used for statistical analyses. The relationship with pT, pN and histological tumor type was assessed using the Kruskal-Wallis test. Prognostic features were determined by univariate stratification which optimizes Kaplan-Meier p-value using 50 independent pre-validations with 3 folds and ranked by the median pre-validation p-values. P-values Results: 60887 tiles were analyzed in total. Median (range) number of tiles analyzed per patient was 291 (81-345). Median (range) CD8+/Ki67+ ratio was 0.39 (0.01-0.92). Manual inspection of selected image tiles showed that CD8+ cells are rarely Ki67+. Median (range) % of tiles/patient where CD8+Ki67- cells co-localized with Ki67+ tumor cells was 17% (0%-93%). Significant difference of ratio was observed between histological subtypes (p=0.0096). There was no significant relationship between CD8+/Ki67+ and pT or pN. A high CD8+/Ki67+ ratio was related to better survival (p=0.012). Conclusions: This is the first study to suggest that the majority of CD8+ T cells in GC appear to be resting (Ki67-) T cells rejecting our hypothesis that high numbers of intratumoral T cells are due to high intratumoral T cell proliferation. The co-localization of CD8+ T cells and Ki67+ tumor cells seems to be clinically relevant and characterize certain histological phenotypes in GC. However, the potential underlying biological mechanisms of interaction between T cells and tumor cells are currently unknown. Further studies are needed to validate our findings and characterize the interface between tumor and immune cells. Citation Format: Mehmet Yigitsoy, Sophie Earle, Armin Meier, Nathalie Harder, Matthew Hale, Aleksandra Zuraw, Takaki Yoshikawa, Gunter Schmidt, Ralf Huss, Heike I. Grabsch. The importance of co-localized resting CD8+ T cells and proliferating tumor cells in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3958. doi:10.1158/1538-7445.AM2017-3958

All UK trains should carry automated external defibrillators (AEDs).

One of us (DB) was recently involved in a medical emergency on a mainline train and was surprised to find that no automated external defibrillator (AED) was carried.1 AEDs require minimal training to use, are designed for use by non-medical operators, and often include both audio and visual instructions to …