Client and stakeholder perceptions of a novel, nurse practitioner-led alcohol and other drug ambulatory withdrawal service.

INTRODUCTION: Despite recommendations for ambulatory withdrawal programs appearing in many contemporary alcohol and other drug treatment guidelines, to date there have been few studies exploring such programs from client and service stakeholder perspectives. The aim of this study was to explore both individual and service stakeholder perceptions of a nurse practitioner-led ambulatory withdrawal service on the Gold Coast, Queensland, Australia. METHODS: Data were obtained from three groups: clinicians with knowledge of the service (n = 6); relatives of clients who had used the service (n = 2); and clients who had used the service (n = 10) using a Qualitative Descriptive design. Saldaña's (Saldaña, The coding manual for qualitative researchers. 2013) structural coding framework was used to analyse and code data into themes, with the study reported in accordance with the Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist (Tong et al. Int J Qual Health Care 2017;19:349-57). RESULTS: Participants noted advantages of the nurse practitioner-led ambulatory withdrawal service, including rapid availability of admission to the service and a person-centred approach. Compared with other ambulatory withdrawal options, clients valued the ability to remain in their own environment, however participants suggested greater follow-up after withdrawal, with the potential of a home visiting service for greater client engagement and treatment retention. DISCUSSION AND CONCLUSIONS: Findings provide evidence to suggest that nurse practitioner-led ambulatory withdrawal services are an acceptable option for a proportion of clients who need rapid access to services when they wish to make changes to their alcohol and/or other drug use. Furthermore, they can provide person-centred care for comorbid physical and mental ill health occurring in addition to psychosocial issues associated with alcohol and/or other drug use.

Human umbilical cord-derived mesenchymal stromal cells improve myocardial fibrosis and restore miRNA-133a expression in diabetic cardiomyopathy.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a serious health-threatening complication of diabetes mellitus characterized by myocardial fibrosis and abnormal cardiac function. Human umbilical cord mesenchymal stromal cells (hUC-MSCs) are a potential therapeutic tool for DCM and myocardial fibrosis via mechanisms such as the regulation of microRNA (miRNA) expression and inflammation. It remains unclear, however, whether hUC-MSC therapy has beneficial effects on cardiac function following different durations of diabetes and which mechanistic aspects of DCM are modulated by hUC-MSC administration at different stages of its development. This study aimed to investigate the therapeutic effects of intravenous administration of hUC-MSCs on DCM following different durations of hyperglycemia in an experimental male model of diabetes and to determine the effects on expression of candidate miRNAs, target mRNA and inflammatory mediators. METHODS: A male mouse model of diabetes was induced by multiple low-dose streptozotocin injections. The effects on severity of DCM of intravenous injections of hUC-MSCs and saline two weeks previously were compared at 10 and 18 weeks after diabetes induction. At both time-points, biochemical assays, echocardiography, histopathology, polymerase chain reaction (PCR), immunohistochemistry and enzyme-linked immunosorbent assays (ELISA) were used to analyze blood glucose, body weight, cardiac structure and function, degree of myocardial fibrosis and expression of fibrosis-related mRNA, miRNA and inflammatory mediators. RESULTS: Saline-treated diabetic male mice had impaired cardiac function and increased cardiac fibrosis after 10 and 18 weeks of diabetes. At both time-points, cardiac dysfunction and fibrosis were improved in hUC-MSC-treated mice. Pro-fibrotic indicators (α-SMA, collagen I, collagen III, Smad3, Smad4) were reduced and anti-fibrotic mediators (FGF-1, miRNA-133a) were increased in hearts of diabetic animals receiving hUC-MSCs compared to saline. Increased blood levels of pro-inflammatory cytokines (IL-6, TNF, IL-1ß) and increased cardiac expression of IL-6 were also observed in saline-treated mice and were reduced by hUC-MSCs at both time-points, but to a lesser degree at 18 weeks. CONCLUSION: Intravenous injection of hUC-MSCs ameliorated key functional and structural features of DCM in male mice with diabetes of shorter and longer duration. Mechanistically, these effects were associated with restoration of intra-myocardial expression of miRNA-133a and its target mRNA COL1AI as well as suppression of systemic and localized inflammatory mediators.

Amelioration of diabetic nephropathy in mice by a single intravenous injection of human mesenchymal stromal cells at early and later disease stages is associated with restoration of autophagy.

BACKGROUND AND AIMS: Mesenchymal stromal cells (MSCs) a potentially effective disease-modulating therapy for diabetic nephropathy (DN) but their clinical translation has been hampered by incomplete understanding of the optimal timing of administration and in vivo mechanisms of action. This study aimed to elucidate the reno-protective potency and associated mechanisms of single intravenous injections of human umbilical cord-derived MSCs (hUC-MSCs) following shorter and longer durations of diabetes. METHODS: A streptozotocin (STZ)-induced model of diabetes and DN was established in C57BL/6 mice. In groups of diabetic animals, human (h)UC-MSCs or vehicle were injected intravenously at 8 or 16 weeks after STZ along with vehicle-injected non-diabetic animals. Diabetes-related kidney abnormalities was analyzed 2 weeks later by urine and serum biochemical assays, histology, transmission electron microscopy and immunohistochemistry. Serum concentrations of pro-inflammatory and pro-fibrotic cytokines were quantified by ELISA. The expression of autophagy-related proteins within the renal cortices was investigated by immunoblotting. Bio-distribution of hUC-MSCs in kidney and other organs was evaluated in diabetic mice by injection of fluorescent-labelled cells. RESULTS: Compared to non-diabetic controls, diabetic mice had increases in urine albumin creatinine ratio (uACR), mesangial matrix deposition, podocyte foot process effacement, glomerular basement membrane thickening and interstitial fibrosis as well as reduced podocyte numbers at both 10 and 18 weeks after STZ. Early (8 weeks) hUC-MSC injection was associated with reduced uACR and improvements in multiple glomerular and renal interstitial abnormalities as well as reduced serum IL-6, TNF-α, and TGF-ß1 compared to vehicle-injected animals. Later (16 weeks) hUC-MSC injection also resulted in reduction of diabetes-associated renal abnormalities and serum TGF-ß1 but not of serum IL-6 and TNF-α. At both time-points, the kidneys of vehicle-injected diabetic mice had higher ratio of p-mTOR to mTOR, increased abundance of p62, lower abundance of ULK1 and Atg12, and reduced ratio of LC3B to LC3A compared to non-diabetic animals, consistent with diabetes-associated suppression of autophagy. These changes were largely reversed in the kidneys of hUC-MSC-injected mice. In contrast, neither early nor later hUC-MSC injection had effects on blood glucose and body weight of diabetic animals. Small numbers of CM-Dil-labeled hUC-MSCs remained detectable in kidneys, lungs and liver of diabetic mice at 14 days after intravenous injection. CONCLUSIONS: Single intravenous injections of hUC-MSCs ameliorated glomerular abnormalities and interstitial fibrosis in a mouse model of STZ-induced diabetes without affecting hyperglycemia, whether administered at relatively short or longer duration of diabetes. At both time-points, the reno-protective effects of hUC-MSCs were associated with reduced circulating TGF-ß1 and restoration of intra-renal autophagy.

The strategic use of biopsy in the diagnosis of coeliac disease in adults.

BACKGROUND: The paediatric guidelines support the use of the 'No Biopsy Approach' in the diagnosis of coeliac disease (CD). We aimed to determine the correlation between anti tissue transglutaminase (anti-TTG serology) ≥10 times the upper limit of normal (ULN), using the Celikey ® ELiA assay and histological findings. Our secondary aim was to determine the safety of this approach in our centre. METHODS: A retrospective analysis of adult patients referred to a tertiary referral centre with raised anti-TTG titres and/or histological changes of coeliac on D2 biopsies between 2014 - 2019. Excluded patients were those who did not have a biopsy performed, or whose biopsy was unavailable for review, selective IgA deficiency, and gluten elimination prior to biopsy. Biopsies were classified according to Marsh, by two independent pathologists, blinded to the anti-TTG titre. RESULTS: 164 patients had positive anti-TTG serology and duodenal biopsy in our centre prior to starting a gluten free diet (GFD) in the period 2014 - 2019. Of these 164 patients (median age 40yrs, 62% female), 68 (33%) had an anti-TTG titre ≥10 x ULN, 99% of which had a Marsh grading ≥ 3 and 1% had a Marsh of 2 on biopsy. 91% had either a normal index gastroscopy or findings of mild gastritis/oesophagitis. CONCLUSIONS: We found a 98.5% positive predictive value (PPV) of determining CD (i.e., Marsh ≥ 3) in those with an anti-TTG ≥10 x ULN. In those with moderate to high-risk clinical suspicion of CD we propose that duodenal biopsy is unnecessary for diagnosis.

Targeting stromal cell sialylation reverses T cell-mediated immunosuppression in the tumor microenvironment.

Immunosuppressive tumor microenvironments (TMEs) reduce the effectiveness of immune responses in cancer. Mesenchymal stromal cells (MSCs), precursors to cancer-associated fibroblasts (CAFs), promote tumor progression by enhancing immune cell suppression in colorectal cancer (CRC). Hyper-sialylation of glycans promotes immune evasion in cancer through binding of sialic acids to their receptors, Siglecs, expressed on immune cells, which results in inhibition of effector functions. The role of sialylation in shaping MSC/CAF immunosuppression in the TME is not well characterized. In this study, we show that tumor-conditioned stromal cells have increased sialyltransferase expression, α2,3/6-linked sialic acid, and Siglec ligands. Tumor-conditioned stromal cells and CAFs induce exhausted immunomodulatory CD8+ PD1+ and CD8+ Siglec-7+/Siglec-9+ T cell phenotypes. In vivo, targeting stromal cell sialylation reverses stromal cell-mediated immunosuppression, as shown by infiltration of CD25 and granzyme B-expressing CD8+ T cells in the tumor and draining lymph node. Targeting stromal cell sialylation may overcome immunosuppression in the CRC TME.

A case report of mucinous tubular and spindle cell carcinoma of the kidney.

Mucinous tubular and spindle cell carcinoma (MTSCC) is a rare type of kidney tumor that has only recently been described, with less than eighty cases in the literature. This was only recognized as a specific entity in the World Health Organization 2004 classification of Renal Cell Carcinoma (RCC). MTSCCs are polymorphic renal neoplasms characterized by small, elongated tubules lined by cuboidal cells with cords of spindled cells separated by pale mucinous stroma. We report the case of a 57 year old lady who had an incidental finding of a mass in her right kidney. The radiological features were consistent with a RCC and following a multidisciplinary team discussion she underwent a laparoscopic radical nephrectomy. Macroscopic examination revealed a well circumscribed 6.5 × 6 × 6.5 cm right lower pole mass. Histologically it was composed of elongated tubules, small tubules and papillary structures with a necrotic centre. The cells demonstrated cuboidal and spindle cell morphology. Histological grade was Fuhrman grade 2. The majority of MTSCCs are indolent, and there are only two reports of distant metastases which responded favorably to adjuvant sunitinib. To date there is no international consensus on long term surveillance of these patients. Due of the favorable prognosis with this type of tumor, MTSCC must be differentiated from papillary renal cell carcinoma to avoid administration of excessive adjuvant treatment to patients.

Plaque burden estimated from optical coherence tomography with deep learning: In vivo validation using co-registered intravascular ultrasound.

OBJECTIVES: The objective of the present study was to compare plaque burden (PB) calculated from optical coherence tomography (OCT) using deep learning (DL) with PB derived from co-registered intravascular ultrasound (IVUS). BACKGROUND: A DL algorithm was developed for automated plaque characterization and PB quantification from OCT images. However, the performance of this algorithm for PB quantification has not been validated. METHODS: Five-year follow-up OCT and IVUS images from 15 patients implanted with bioresorbable vascular scaffold (BVS) at baseline were analyzed. Precise co-registration for 72 anatomical slices was achieved utilizing unique BVS radiopaque markers. PB derived from OCT DL and IVUS were compared. OCT cross-sections were divided into four subgroups with different media visibility level. The impact of media visibility on the numerical difference between OCT-derived and IVUS-derived PB was investigated. The stent sizes selected by OCT DL and IVUS were compared. RESULTS: Sixty-four paired OCT and IVUS cross-sections were compared. OCT DL showed good concordance with IVUS for PB assessment (ICC = 0.81, difference = -3.53 ± 6.17%, p < 0.001). The numerical difference between OCT DL-derived PB and IVUS-derived PB was not substantially impacted by missing segments of media visualization (p = 0.21). OCT DL showed a diagnostic accuracy of 92% in identifying PB > 65%. The stent sizes selected by OCT DL were smaller compared to the ones selected by IVUS (difference = 0.30 ± 0.34 mm, p < 0.001). CONCLUSIONS: The DL algorithm provides a feasible and reliable method for automated PB estimation from OCT, irrespective of media visibility. OCT DL showed good diagnostic accuracy in identifying PB > 65%, revealing its potential to complement conventional OCT imaging.

Case report of the duplex vermiform appendix: A rare presentation in an elderly patient.

INTRODUCTION AND IMPORTANCE: Duplex appendix is a rare anatomical entity with incidence rate of 0.004 and 0.009%. Diagnosis is often missed despite growth in radiological investigations. Missed appendiceal anomalies can lead to undesirable medicolegal implications. CASE PRESENTATION: Here we discuss a case of a 76-year-old-male who initially presented to his primary care physician with right-sided abdominal pain for several weeks. A colonoscopy was performed and demonstrated a lesion arising from the appendicular orifice. The patient underwent staging imaging including Computerised Tomography of the abdomen and pelvis which demonstrated a dilated appendix. The patient underwent a laparoscopic right hemicolectomy. He made an uneventful recovery post-operatively and at his follow-up review at 4 weeks and 2 months. DISCUSSION: While duplex appendix has been reported in the literature, to our knowledge this is the first case report to describe duplicated appendix presenting as a colonic mass in an elderly patient. CONCLUSION: Intra-operative examination of the cecum is paramount to rule out appendiceal anomalies and prevent medicolegal complications.

Inflammation-specific targeted carriers for local drug delivery to inflammatory bowel disease.

Delivering drugs directly to the inflamed intestinal sites to treat inflammatory bowel disease (IBD), particularly Crohn's and ulcerative colitis, is highly challenging. Recent advances in colitis therapy medications are expanding opportunities for improving local on-site drug availability by minimising the associated systemic side-effects. Drug delivery with targeted carrier systems has shown the potential to increase site-specificity, stability, and therapeutic efficacy. Herein, we report the development of a strong anionic charged inflammation targeted nanocarriers (IT-NCs) loaded with an immunosuppressant model drug. This system showed preferential adhesion on a charge-modified surface in vitro, and in both dextran sulfate sodium (DSS) and TNBS colitis mice in vivo models. IT-NCs showed improved colitis phenotype therapeutic efficacy in both animal models compared to free drug. Furthermore, ex vivo study of colon tissue biopsies from patients with colitis revealed that IT-NCs adhered preferentially to inflamed biopsies compared to normal. Together, our results suggest that IT-NCs have promising therapeutic potential as delivery carriers' in colitis management.

Comparison of Single and Repeated Dosing of Anti-Inflammatory Human Umbilical Cord Mesenchymal Stromal Cells in a Mouse Model of Polymicrobial Sepsis.

Mesenchymal stromal cells (MSCs) ameliorate pre-clinical sepsis and sepsis-associated acute kidney injury (SA-AKI) but clinical trials of single-dose MSCs have not indicated robust efficacy. This study investigated immunomodulatory effects of a novel MSC product (CD362-selected human umbilical cord-derived MSCs [hUC-MSCs]) in mouse endotoxemia and polymicrobial sepsis models. Initially, mice received intra-peritoneal (i.p.) lipopolysaccharide (LPS) followed by single i.p. doses of hUC-MSCs or vehicle. Next, mice underwent cecal ligation and puncture (CLP) followed by intravenous (i.v.) doses of hUC-MSCs at 4 h or 4 and 28 h. Analyses included serum/plasma assays of biochemical indices, inflammatory mediators and the AKI biomarker NGAL; multi-color flow cytometry of peritoneal macrophages (LPS) and intra-renal immune cell subpopulations (CLP) and histology/immunohistochemistry of kidney (CLP). At 72 h post-LPS injections, hUC-MSCs reduced serum inflammatory mediators and peritoneal macrophage M1/M2 ratio. Repeated, but not single, hUC-MSC doses administered at 48 h post-CLP resulted in lower serum concentrations of inflammatory mediators, lower plasma NGAL and reversal of sepsis-associated depletion of intra-renal T cell and myeloid cell subpopulations. Hierarchical clustering analysis of all 48-h serum/plasma analytes demonstrated partial co-clustering of repeated-dose hUC-MSC CLP animals with a Sham group but did not reveal a distinct signature of response to therapy. It was concluded that repeated doses of CD362-selected hUC-MSCs are required to modulate systemic and local immune/inflammatory events in polymicrobial sepsis and SA-AKI. Inter-individual variability and lack of effect of single dose MSC administration in the CLP model are consistent with observations to date from early-phase clinical trials.

A pre-clinical animal study of a novel mechanical-only ablation device treatment for superficial venous disease.

OBJECTIVE: Current minimally invasive techniques for ablation in superficial venous reflux are limited to thermal based systems requiring tumescent anesthesia, non-thermal chemical sclerosants and permanent glue implantation. The aim of this feasibility study was to determine the safety and efficacy of a novel mechanical-only ablation (MOA) device called EnVena, in a recognised large animal model with chronic follow up. METHODS: Venous ablation of six lateral saphenous veins in three sheep was performed using the EnVena device. Luminal patency and vein wall fibrosis were evaluated by histologic analysis at 51 and 89 days. RESULTS: All treated veins demonstrated fibrotic occlusion in contiguous segments at 51 and 89 days on histological analysis. From 45 consecutive segments spanning the treatment length across the six treated veins, 26 (57%) were fully occluded, 7 (16%) were impinged or partially occluded and 12 (27%) were open. There were no device related complications during the follow up period. CONCLUSIONS: A purely mechanical approach to superficial venous ablation demonstrated safety and efficacy in a recognized large animal model based on histological findings.

Ki-67 as a Prognostic Biomarker in Invasive Breast Cancer.

The advent of molecular medicine has transformed breast cancer management. Breast cancer is now recognised as a heterogenous disease with varied morphology, molecular features, tumour behaviour, and response to therapeutic strategies. These parameters are underpinned by a combination of genomic and immunohistochemical tumour factors, with estrogen receptor (ER) status, progesterone receptor (PgR) status, human epidermal growth factor receptor-2 (HER2) status, Ki-67 proliferation indices, and multigene panels all playing a contributive role in the substratification, prognostication and personalization of treatment modalities for each case. The expression of Ki-67 is strongly linked to tumour cell proliferation and growth and is routinely evaluated as a proliferation marker. This review will discuss the clinical utility, current pitfalls, and promising strategies to augment Ki-67 proliferation indices in future breast oncology.

Practical guide for the comparison of two next-generation sequencing systems for solid tumour analysis in a universal healthcare system.

AIMS: Although there have been excellent reports in the literature of validating next-generation sequencing, comparisons between two systems are not often published due to cost and time. We set out to establish that targetable mutations could be reliably detected with different gene panels and different chemistries using a common bioinformatics pipeline for meaningful comparisons to be made. METHODS: After running selected formalin-fixed, paraffin-embedded samples through QPCR, Sanger sequencing and the 50 gene hotspot v2 panel from Life Technologies to determine standard-of-care variants, we compared the Oncomine panel from Life Technologies performed on a Personal Genome Machine (PGM) and the eight-gene actionable panel from Qiagen performed on a MiSeq platform. We used a common bioinformatics program following the creation of respective VCF files. RESULTS: Both panels were accurate to above 90%, the actionable panel workflow was easier to perform but the lowest effective starting DNA load was obtained on the Oncomine workflow at 4 ng. Such minimal DNA can help with samples where there is limited material such as those for lung cancer molecular studies. We also discuss gene panel content and propose that increasing the gene profile of a panel will not benefit clinical laboratories where standard-of-care testing is all that is required. CONCLUSIONS: Once recognised, it may be cost-effective for such laboratories to begin validation with an appropriate bioinformatics pipeline for targeted multigene hotspot molecular testing.

Automated Tumour Recognition and Digital Pathology Scoring Unravels New Role for PD-L1 in Predicting Good Outcome in ER-/HER2+ Breast Cancer.

The role of PD-L1 as a prognostic and predictive biomarker is an area of great interest. However, there is a lack of consensus on how to deliver PD-L1 as a clinical biomarker. At the heart of this conundrum is the subjective scoring of PD-L1 IHC in most studies to date. Current standard scoring systems involve separation of epithelial and inflammatory cells and find clinical significance in different percentages of expression, e.g., above or below 1%. Clearly, an objective, reproducible and accurate approach to PD-L1 scoring would bring a degree of necessary consistency to this landscape. Using a systematic comparison of technologies and the application of QuPath, a digital pathology platform, we show that high PD-L1 expression is associated with improved clinical outcome in Triple Negative breast cancer in the context of standard of care (SoC) chemotherapy, consistent with previous findings. In addition, we demonstrate for the first time that high PD-L1 expression is also associated with better outcome in ER- disease as a whole including HER2+ breast cancer. We demonstrate the influence of antibody choice on quantification and clinical impact with the Ventana antibody (SP142) providing the most robust assay in our hands. Through sampling different regions of the tumour, we show that tumour rich regions display the greatest range of PD-L1 expression and this has the most clinical significance compared to stroma and lymphoid rich areas. Furthermore, we observe that both inflammatory and epithelial PD-L1 expression are associated with improved survival in the context of chemotherapy. Moreover, as seen with PD-L1 inhibitor studies, a low threshold of PD-L1 expression stratifies patient outcome. This emphasises the importance of using digital pathology and precise biomarker quantitation to achieve accurate and reproducible scores that can discriminate low PD-L1 expression.

IHC-based subcellular quantification provides new insights into prognostic relevance of FLIP and procaspase-8 in non-small-cell lung cancer.

In this study, we developed an image analysis algorithm for quantification of two potential apoptotic biomarkers in non-small-cell lung cancer (NSCLC): FLIP and procaspase-8. Immunohistochemical expression of FLIP and procaspase-8 in 184 NSCLC tumors were assessed. Individual patient cores were segmented and classified as tumor and stroma using the Definiens Tissue Studio. Subsequently, chromogenic expression of each biomarker was measured separately in the nucleus and cytoplasm and reported as a quantitative histological score. The software package pROC was applied to define biomarker thresholds. Cox proportional hazards analysis was applied to generate hazard ratios (HRs) and associated 95% CI for survival. High cytoplasmic expression of tumoral (but not stromal) FLIP was associated with a 2.5-fold increased risk of death in lung adenocarcinoma patients, even when adjusted for known confounders (HR 2.47, 95% CI 1.14-5.35). Neither nuclear nor cytoplasmic tumoral procaspase-8 expression was associated with overall survival in lung adenocarcinoma patients; however, there was a significant trend (P for trend=0.03) for patients with adenocarcinomas with both high cytoplasmic FLIP and high cytoplasmic procaspase-8 to have a multiplicative increased risk of death. Notably, high stromal nuclear procaspase-8 expression was associated with a reduced risk of death in lung adenocarcinoma patients (adjusted HR 0.31, 95% CI 0.15-0.66). On further examination, the cells with high nuclear procaspase-8 were found to be of lymphoid origin, suggesting that the better prognosis of patients with tumors with high stromal nuclear procaspase-8 is related to immune infiltration, a known favorable prognostic factor. No significant associations were detected in analysis of lung squamous cell carcinoma patients. Our results suggest that cytoplasmic expression of FLIP in the tumor and nuclear expression of procaspase-8 in the stroma are prognostically relevant in non-small-cell adenocarcinomas but not in squamous cell carcinomas of the lung.

Eosinophilic Angiocentric Fibrosis as a Stenosing Lesion in the Subglottis.

Subglottic Eosinophilic Angiocentric Fibrosis (EAF) is an extremely rare disease of an elusive aetiology. It is chronically progressive benign condition that causes narrowing of the subglottic region leading to dysphonia and airway compromise. The diagnosis is historical and imaging is nonspecific. We report a case xc of 56-year-old lady referred to our institution with globus sensation, hoarseness, and mild stridor. Incidental subglottic mass was found at time of diagnostic microlaryngoscopy and biopsy confirmed subglottic EAF. All laboratory investigations were unremarkable. Lesion was removed with laryngeal microdebrider and three courses of intravenous dexamethasone were administered. Patient's postoperative period was uneventful and had remained disease free for 1 year. To date, no consensus has been reached on the optimal treatment of subglottic EAF. We recommend regular follow-up to detect early recurrence.

Back to the future: routine morphological assessment of the tumour microenvironment is prognostic in stage II/III colon cancer in a large population-based study.

AIMS: Both morphological and molecular approaches have highlighted the biological and prognostic importance of the tumour microenvironment in colorectal cancer (CRC). Despite this, microscopic assessment of the tumour microenvironment has not been adopted into routine practice. The study aim was to identify those tumour microenvironmental features that are most likely to provide prognostic information and be feasible to use in routine pathology reporting practice. METHODS AND RESULTS: On the basis of existing evidence, we selected specific morphological features relating to peritumoral inflammatory and stromal responses, agreed criteria for scoring, and assessed these in representative haematoxylin and eosin (H&E)-stained whole tumour sections from a population-based cohort of 445 stage II/III colon cancer cases. Moderate/severe peritumoral diffuse lymphoid inflammation and Crohn's disease-like reaction were associated with significantly reduced risks of CRC-specific death [adjusted hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.31-0.76, and HR 0.60, 95% CI 0.42-0.84, respectively]. The presence of >50% tumour stromal percentage, as assessed by global evaluation of tumour area, was associated with a significantly increased risk of CRC-specific death (HR 1.60 95% CI 1.06-2.41). A composite 'fibroinflammatory score' (0-3), combining dichotomized scores of these three features, showed a highly significant association with survival outcomes. Those with a score of ≥2 had an almost 2.5-fold increased risk of CRC-specific death (HR 2.44, 95% CI 1.56-3.81) as compared with those scoring zero. These associations were stronger in microsatellite instability (MSI)-high tumours, potentially identifying a subset of MSI-high colon cancers that lack characteristic morphological features and have an associated worse prognosis. CONCLUSIONS: In summary, reporting on H&E staining of selected microscopic features of the tumour microenvironment, independently or in combination, offers valuable prognostic information in stage II/III colon cancer, and may allow morphological correlation with developing molecular classifications of prognostic and predictive relevance.

Tissue-based next generation sequencing: application in a universal healthcare system.

In the context of solid tumours, the evolution of cancer therapies to more targeted and nuanced approaches has led to the impetus for personalised medicine. The targets for these therapies are largely based on the driving genetic mutations of the tumours. To track these multiple driving mutations the use of next generation sequencing (NGS) coupled with a morphomolecular approach to tumours, has the potential to deliver on the promises of personalised medicine. A review of NGS and its application in a universal healthcare (UHC) setting is undertaken as the technology has a wide appeal and utility in diagnostic, clinical trial and research paradigms. Furthermore, we suggest that these can be accommodated with a unified integromic approach. Challenges remain in bringing NGS to routine clinical use and these include validation, handling of the large amounts of information flow and production of a clinically useful report. These challenges are particularly acute in the setting of UHC where tests are not reimbursed and there are finite resources available. It is our opinion that the challenges faced in applying NGS in a UHC setting are surmountable and we outline our approach for its routine application in diagnostic, clinical trial and research paradigms.

Resolution of idiopathic granulomatous orbital inflammation with intraorbital triamcinolone.

A 77-year-old man presented with a right lower eyelid swelling. Biopsy and histopathology of the lesion identified idiopathic granulomatous orbital inflammation. Clinical resolution of this patient's orbital mass was achieved with injection of 40 mg triamcinolone acetonide, perilesionally, at three sites in the right orbit. Such treatment may thus form an alternative to oral corticosteroid therapy in the management of granulomatous orbital inflammation.