Circulating pre-treatment T-cell receptor repertoire as a predictive biomarker in advanced or metastatic non-small-cell lung cancer patients treated with pembrolizumab alone or in combination with chemotherapy.

BACKGROUND: The circulating T-cell receptor (TCR) repertoire is a dynamic representation of overall immune responses in an individual. MATERIALS AND METHODS: We prospectively collected baseline blood from patients treated with first-line pembrolizumab monotherapy or in combination with chemotherapy. TCR repertoire metrics were correlated with clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS) and immune-related adverse events (irAEs). We built a logistic regression classifier by fitting all four TCR-ß repertoire metrics to the immune checkpoint inhibitor (ICI) CBR data. In the subsequent receiver operating characteristic (ROC) analysis of the resulting logistic regression model probabilities, the best cut-off value was selected to maximise sensitivity to predict CBR to ICI. RESULTS: We observed an association between reduced number of unique clones and CBR among patients treated with pembrolizumab monotherapy (cohort 1) [risk ratio = 2.86, 95% confidence interval (CI) 1.04-8.73, P = 0.039]. For patients treated with pembrolizumab plus chemotherapy (cohort 2), increased number of unique clones [hazard ratio (HR) = 2.96, 95% CI 1.28-6.88, P = 0.012] and Shannon diversity (HR = 2.73, 95% CI 1.08-6.87, P = 0.033), and reduced evenness (HR = 0.43, 95% CI 0.21-0.90, P = 0.025) and convergence (HR = 0.41, 95% CI 0.19-0.90, P = 0.027) were associated with improved PFS, while only an increased number of unique clones (HR = 4.62, 95% CI 1.52-14.02, P = 0.007) were associated with improved OS. Logistic regression models combining the TCR repertoire metrics improved the prediction of CBR (cohorts 1 and 2) and were strongly associated with PFS (cohort 1, HR = 0.38, 95% CI 0.19-0.78, P = 0.009) and OS (cohort 2, HR = 0.20, 95% CI 0.05-0.76, P < 0.0001). Reduced TCR conversion was associated with increased frequency of irAEs needing systemic steroid treatment. CONCLUSION: Combined pre-treatment circulating TCR metrics might serve as a predictive biomarker for clinical outcomes among patients with advanced non-small-cell lung cancer treated with pembrolizumab alone or in combination with chemotherapy.

An update on oral cavity cancer: epidemiological trends, prevention strategies and novel approaches in diagnosis and prognosis.

In the UK, the incidence of oral cavity cancer continues to rise, with an increase of around 60% over the past 10 years. Many patients still present with advanced disease, often resulting in locoregional recurrence and poor outcomes, which has not changed significantly for over four decades. Changes in aetiology may also be emerging, given the decline of smoking in developed countries. Therefore, new methods to better target prevention, improve screening and detect recurrence are needed. High-throughput 'omics' technologies appear promising for future individual-level diagnosis and prognosis. However, given this is a relatively rare cancer with significant intra-tumour heterogeneity and variation in patient response, reliable biomarkers have been difficult to elucidate. From a public health perspective, implementing these novel technologies into current services would require substantial practical, financial and ethical considerations. This may be difficult to justify and implement at present, therefore focus remains on early detection using new patient-led follow-up strategies. This paper reviews the latest evidence on epidemiological trends in oral cavity cancer to help identify at risk groups, population-based approaches for prevention, in addition to potential cutting-edge approaches in the diagnosis and prognosis of this disease.

Variation in chemotherapy prescribing rates and mortality in early breast cancer over two decades: a national data linkage study.

BACKGROUND: Regional variation in clinical practice may identify differences in care, reveal inequity in access, and explain inequality in outcomes. The study aim was to measure geographical variation in Scotland for adjuvant chemotherapy use and mortality in early-stage breast cancer. PATIENTS AND METHODS: In this retrospective cohort study using population cancer registry-based data linkage, patients with surgically treated early breast cancer between 2001 and 2018 were identified from the Scottish Cancer Registry. Geographical regions considered were based on NHS Scotland organisational structure including 14 territorial Health Boards as well as three regional Cancer Networks. Regional variation in the proportion receiving chemotherapy, breast cancer mortality and all-cause mortality was investigated. Inter-regional comparisons of chemotherapy use were adjusted for differences in case mix using logistic regression. Comparison of breast cancer-specific mortality and all-cause mortality used regression with a parametric survival model. Time trends were assessed using moving average plots. RESULTS: Chemotherapy use ranged from 35% to 46% of patients across Health Boards without adjustment. Variation reduced between 2001 and 2018. Following adjustment for clinical case mix, variation between cancer networks was within 3 percentage points, but up to 10 percentage points from the national average in some Health Boards. Differences in breast cancer mortality and all-cause mortality between cancer networks were modest, with hazard ratios of between 0.933 (95% confidence interval 0.893-0.975) and 1.041 (1.002-1.082) compared with the national average. Survival improved over the time period studied. CONCLUSION: With adequate case mix adjustment, variation in adjuvant chemotherapy use for early breast cancer in Scotland is small, with a trend towards greater convergence in practice and improved mortality outcomes in more recent cohorts. This suggests very limited regional inequity in access and convergence of clinical practice towards risk-stratified treatment recommendations. Outliers require assessment to understand the reasons for variance.

Risk of missing colorectal cancer with a COVID-adapted diagnostic pathway using quantitative faecal immunochemical testing.

BACKGROUND: COVID-19 has brought an unprecedented challenge to healthcare services. The authors' COVID-adapted pathway for suspected bowel cancer combines two quantitative faecal immunochemical tests (qFITs) with a standard CT scan with oral preparation (CT mini-prep). The aim of this study was to estimate the degree of risk mitigation and residual risk of undiagnosed colorectal cancer. METHOD: Decision-tree models were developed using a combination of data from the COVID-adapted pathway (April-May 2020), a local audit of qFIT for symptomatic patients performed since 2018, relevant data (prevalence of colorectal cancer and sensitivity and specificity of diagnostic tools) obtained from literature and a local cancer data set, and expert opinion for any missing data. The considered diagnostic scenarios included: single qFIT; two qFITs; single qFIT and CT mini-prep; two qFITs and CT mini-prep (enriched pathway). These were compared to the standard diagnostic pathway (colonoscopy or CT virtual colonoscopy (CTVC)). RESULTS: The COVID-adapted pathway included 422 patients, whereas the audit of qFIT included more than 5000 patients. The risk of missing a colorectal cancer, if present, was estimated as high as 20.2 per cent with use of a single qFIT as a triage test. Using both a second qFIT and a CT mini-prep as add-on tests reduced the risk of missed cancer to 6.49 per cent. The trade-off was an increased rate of colonoscopy or CTVC, from 287 for a single qFIT to 418 for the double qFIT and CT mini-prep combination, per 1000 patients. CONCLUSION: Triage using qFIT alone could lead to a high rate of missed cancers. This may be reduced using CT mini-prep as an add-on test for triage to colonoscopy or CTVC.

A meta-analysis comparing the diagnostic performance of abbreviated MRI and a full diagnostic protocol in breast cancer.

AIM: To undertake a meta-analysis of the diagnostic performance of abbreviated (ABB) magnetic resonance imaging (MRI) and full diagnostic protocol MRI (FDP-MRI) in breast cancer. MATERIALS AND METHODS: This meta-analysis was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis for Diagnostic Test Accuracy (PRISMA-DTA) guidelines. The PubMed and EMBASE databases were searched through August 2019 for studies comparing the diagnostic performance of ABB-MRI and FDP-MRI in the breast. Studies were reviewed by two authors independently according to eligibility and exclusion criteria and split into two subgroups (screening population studies and studies using cohorts enriched with known cancers) to avoid bias. Quality assessment and bias for diagnostic accuracy was determined with Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). The diagnostic accuracy for each subgroup was pooled using a bivariate random effects model and summary receiver operating characteristic (sROC) curves produced. Sensitivities and specificities were compared using a paired t-test. RESULTS: Five screening (62/2,588 cancers/patients) and eight enriched cohort (540/1,432 cancers/patients) studies were included in the meta-analysis. QUADAS-2 assessment showed a low risk of bias in most studies. The pooled sensitivity/specificity/area under the receiver operating characteristic curve (AUC) for screening studies was 0.90/0.92/0.94 for ABB-MRI and 0.92/0.95/0.97 for FDP-MRI. The pooled sensitivity/specificity/AUC for enriched cohort studies was 0.93/0.83/0.94 for ABB-MRI and 0.93/0.84/0.95 for FDP-MRI. There was no significant difference in sensitivity or specificity using ABB-MRI or FDP-MRI (p=0.18 and 0.27, p=0.18 and 0.93, respectively). CONCLUSION: The diagnostic performances of the ABB-MRI and FDP-MRI protocols used in either screening or enriched cohorts were comparable. There was a large variation in patient population, study methodology, and abbreviated protocols reported.

Stopping targeted therapy for complete responders in advanced BRAF mutant melanoma.

BRAF inhibitors revolutionised the management of melanoma patients and although resistance occurs, there is a subgroup of patients who maintain durable disease control. For those cases with durable complete response (CR) it is not clear whether it is safe to cease therapy. Here we identified 13 patients treated with BRAF +/- MEK inhibitors, who cease therapy after prolonged CR (median = 34 months, range 20-74). Recurrence was observed in 3/13 (23%) patients. In the remaining 10 patients with sustained CR off therapy, the median follow up after discontinuation was 19 months (range 8-36). We retrospectively measured ctDNA levels using droplet digital PCR (ddPCR) in longitudinal plasma samples. CtDNA levels were undetectable in 11/13 cases after cessation and remained undetectable in patients in CR (10/13). CtDNA eventually became detectable in 2/3 cases with disease recurrence, but remained undetectable in 1 patient with brain only progression. Our study suggests that consideration could be given to ceasing targeted therapy in the context of prolonged treatment, durable response and no evidence of residual disease as measured by ctDNA.

A standardised protocol for the evaluation of small extracellular vesicles in plasma by imaging flow cytometry.

Flow cytometry provides robust, multi-parametric and quantitative information on single cells which also exhibits enormous potential as a tool for small particle characterisation. Small extracellular vesicle (sEV) detection by flow cytometry remains compromised due to the high prevalence of swarm detection, which is defined by the simultaneous illumination of more than one sEV, recorded as a single event. Detection of sEVs by imaging flow cytometry presents a major advantage by having the ability to resolve single particles from swarm detection based on the image features recorded for each event. In this study, we provide a simplified protocol that facilitates the removal of both swarm events and aggregated particles to improve the accuracy of sEV analysis. Our results indicate that imaging flow cytometry should be at the forefront as a robust and sensitive technique for sEV characterisation.

Improved White Matter Cerebrovascular Reactivity after Revascularization in Patients with Steno-Occlusive Disease.

BACKGROUND AND PURPOSE: One feature that patients with steno-occlusive cerebrovascular disease have in common is the presence of white matter (WM) lesions on MRI. The purpose of this study was to evaluate the effect of direct surgical revascularization on impaired WM cerebrovascular reactivity in patients with steno-occlusive disease. MATERIALS AND METHODS: We recruited 35 patients with steno-occlusive disease, Moyamoya disease (n = 24), Moyamoya syndrome (n = 3), atherosclerosis (n = 6), vasculitis (n = 1), and idiopathic stenosis (n = 1), who underwent unilateral brain revascularization using a direct superficial temporal artery-to-MCA bypass (19 women; mean age, 45.8 ± 16.5 years). WM cerebrovascular reactivity was measured preoperatively and postoperatively using blood oxygen level-dependent (BOLD) MR imaging during iso-oxic hypercapnic changes in end-tidal carbon dioxide and was expressed as %Δ BOLD MR signal intensity per millimeter end-tidal partial pressure of CO2. RESULTS: WM cerebrovascular reactivity significantly improved after direct unilateral superficial temporal artery-to-middle cerebral artery (STA-MCA) bypass in the revascularized hemisphere in the MCA territory (mean ± SD, -0.0005 ± 0.053 to 0.053 ± 0.046 %BOLD/mm Hg; P < .0001) and in the anterior cerebral artery territory (mean, 0.0015 ± 0.059 to 0.021 ± 0.052 %BOLD/mm Hg; P = .005). There was no difference in WM cerebrovascular reactivity in the ipsilateral posterior cerebral artery territory nor in the vascular territories of the nonrevascularized hemisphere (P < .05). CONCLUSIONS: Cerebral revascularization surgery is an effective treatment for reversing preoperative cerebrovascular reactivity deficits in WM. In addition, direct-STA-MCA bypass may prevent recurrence of preoperative symptoms.

Melanoma circulating tumor cells: Benefits and challenges required for clinical application.

The implementation of novel therapeutic interventions has improved the survival rates of melanoma patients with metastatic disease. Nonetheless, only 33% of treated cases exhibit long term responses. Circulating tumor cell (CTC) measurements are currently of clinical value in breast, prostate and colorectal cancers. However, the clinical utility of melanoma CTCs (MelCTCs) is still unclear due to challenges that appear intrinsic to MelCTCs (i.e. rarity, heterogeneity) and a lack of standardization in their isolation, across research laboratories. Here, we review the latest developments, pinpoint the challenges in MelCTC isolation and address their potential role in melanoma management.

Sympathetic hyper-excitation in obesity and pulmonary hypertension: physiological relevance to the 'obesity paradox'.

BACKGROUND: Within the lung, sympathetic nerve activity (SNA) has an important role in facilitating pulmonary vasodilation. As SNA is elevated in obesity, we aimed to assess the impact of sympathetic hyper-excitation on pulmonary vascular homeostasis in obesity, and its potential role in ameliorating the severity of pulmonary hypertension (PH); the well-documented 'obesity paradox' phenomenon. METHODS: Zucker obese and lean rats were exposed to normoxia or chronic hypoxia (CH-10% O2) for 2 weeks. Subsequently, pulmonary SNA (pSNA) was recorded (electrophysiology), or the pulmonary microcirculation was visualized using Synchrotron microangiography. Acute hypoxic pulmonary vasoconstriction (HPV) was assessed before and after blockade of ß1-adrenergic receptors (ARs) (atenolol, 3 mg kg(-1)) and ß1+ß2-adrenergic (propranolol, 2 mg kg(-1)). RESULTS: pSNA of normoxic obese rats was higher than lean counterparts (2.4 and 0.5 µV s, respectively). SNA was enhanced following the development of PH in lean rats, but more so in obese rats (1.7 and 6.8 µV s, respectively). The magnitude of HPV was similar for all groups (for example, ~20% constriction of the 200-300 µm vessels). Although ß-blockade did not modify HPV in lean rats, it significantly augmented the HPV in normoxic obese rats (ß1 and ß2 blockade), and more so in obese rats with PH (ß2-blockade alone). Western blots showed, while the expression of pulmonary ß1-ARs was similar for all rats, the expression of ß2-ARs was downregulated in obesity and PH. CONCLUSIONS: This study suggests that sympathetic hyper-excitation in obesity may have an important role in constraining the severity of PH and, thus, contribute in part to the 'obesity paradox' in PH.

Autoantibody Production in Cancer--The Humoral Immune Response toward Autologous Antigens in Cancer Patients.

A link between autoimmune responses and cancer via autoantibodies was first described in the 1950s. Since, autoantibodies have been studied for their potential use as cancer biomarkers, however the exact causes of their production remain to be elucidated. This review summarizes current theories of the causes of autoantibody production in cancer, namely: 1) defects in tolerance and inflammation, 2) changes in protein expression levels, 3) altered protein structure, and 4) cellular death mechanisms. We also highlight the need for further research into this field to improve our understanding of autoantibodies as biomarkers for cancer development and progression.

Cost-effectiveness of 3-year vs 1-year adjuvant therapy with imatinib in patients with high risk of gastrointestinal stromal tumour recurrence in the Netherlands; a modelling study alongside the SSGXVIII/AIO trial.

BACKGROUND: Surgical resection of gastrointestinal stromal tumour (GIST) is rarely curative in patients at high risk of tumour recurrence and therefore 1 year of post-surgery adjuvant imatinib therapy has been recommended in this sub-group. Recently, adjuvant imatinib therapy administered for 3 years has been demonstrated to further increase recurrence-free survival and overall survival. The goal of this study was to assess the economic value of extending the duration of adjuvant imatinib therapy in high-risk patients in the Netherlands. METHODS: A multistate Markov model was developed to simulate how patients' clinical status after GIST excision evolves over time until death. The model structure encompassed four primary health states: free of recurrence, first GIST recurrence, second GIST recurrence, and death. Transition probabilities between the health states, data on medical care costs, and quality-of-life were obtained from published sources and from expert opinion. RESULTS: The expected number of life years (or quality-adjusted life years, QALYs) was higher in the 3-year group than in the 1-year group, 8.91 (6.55) and 7.04 (5.18) years, respectively. In the 3-year and 1-year group, the expected total costs amounted to €120,195 and €79,361, of which, €74,631 (62%) and €27,619 (35%) were adjuvant therapy drug costs, respectively. The difference in health benefits, that is 1.87 life years or 1.37 QALYs, and costs, €40,835, resulted in incremental cost-effectiveness ratios (ICER) of €21,865 per life year gained, and €29,872 per QALY gained. LIMITATIONS: A limitation of the study was inherently related to the uncertainty around the predictions of RFS. Scenario analyses were conducted to test the sensitivity of different RFS predictions on the results. CONCLUSIONS: Delayed recurrence due to treatment with longer-term adjuvant imatinib therapy represents a cost-effective treatment option with an ICER below the generally accepted threshold in the Netherlands.

Effects of apoptosis and lipid peroxidation on T-lymphoblastoid phospholipid-dependent procoagulant activity.

BACKGROUND: Coagulation has an absolute requirement for macromolecular complexes to be assembled on a negatively charged phospholipid (PL) surface. Previously, we reported that malignant T-lymphoblastoid cells have the ability to support procoagulant activity (PCA) independently of tissue factor by providing such a surface. OBJECTIVE: To explore the effect of two pathophysiologic processes, apoptosis and lipid peroxidation (LP), on this PL-dependent PCA. METHODS: Three different assays for PL-dependent PCA (factor IXa-initiated FXa and thrombin generation and prothrombinase activity) were used to investigate this PCA after exposing three T-lymphoblastoid cell lines to either apoptotic stimuli (1 microM staurosporine) or oxidative stress (4 mm H(2)O(2) and 40 microM CuSO(4)). Surface exposure of anionic PL was measured by flow cytometry using annexin A5(FITC) and an antibody (3G4) specific for native, but not oxidized, phosphatidylserine (PS). RESULTS AND CONCLUSIONS: Both apoptosis and LP significantly enhanced the PCA of cells, to a level that was greater than that observed following calcium ionophore treatment, suggesting that the increased activity was not solely due to anionic PL exposure. Whereas cells undergoing apoptosis bound both annexin A5(FITC) and 3G4, only annexin A5(FITC) bound to cells undergoing LP. This implies that apoptosis increases PCA by causing the translocation of oxidized/native PS to the outer membrane, whereas LP appears to increase the PCA, possibly due to malondialdehyde adducts altering the net charge on the cell surface, which allows PLs other than PS to participate in thrombin generation.

Alemtuzumab pre-conditioning with tacrolimus monotherapy in pediatric renal transplantation.

We employed antibody pre-conditioning with alemtuzumab and posttransplant immunosuppression with low-dose tacrolimus monotherapy in 26 consecutive pediatric kidney transplant recipients between January 2004 and December 2005. Mean recipient age was 10.7 +/- 5.8 years, 7.7% were undergoing retransplantation, and 3.8% were sensitized, with a PRA >20%. Mean donor age was 32.8 +/- 9.2 years. Living donors were utilized in 65% of the transplants. Mean cold ischemia time was 27.6 +/- 6.4 h. The mean number of HLA mismatches was 3.3 +/- 1.3. Mean follow-up was 25 +/- 8 months. One and 2 year patient survival was 100% and 96%. One and 2 year graft survival was 96% and 88%. Mean serum creatinine was 1.1 +/- 0.6 mg/dL, and calculated creatinine clearance was 82.3 +/- 29.4 mL/min/1.73 m(2). The incidence of pre-weaning acute rejection was 11.5%; the incidence of delayed graft function was 7.7%. Eighteen (69%) of the children were tapered to spaced tacrolimus monotherapy, 10.5 +/- 2.2 months after transplantation. The incidence of CMV, PTLD and BK virus was 0%; the incidence of posttransplant diabetes was 7.7%. Although more follow-up is clearly needed, antibody pre-conditioning with alemtuzumab and tacrolimus monotherapy may be a safe and effective regimen in pediatric renal transplantation.

Information from the Internet: attitudes of Australian oncology patients.

BACKGROUND: Patients require accurate information about their illness to make informed decisions. Many sources of information exist, although reliability is variable. Our objective was to investigate information seeking behaviour and attitudes toward health-related information from the Internet in a sample of Australian oncology patients. METHOD: During their outpatient attendance, 109 patients completed a self-administered paper-pen format questionnaire. They were required to have a recent cancer diagnosis (<6 months ago) adequate English and no cognitive impairment. RESULTS: Seventy-four per cent of questionnaires were returned. The majority of patients (78%) wanted as much information about their cancer diagnosis as possible and 90% reported receiving adequate information from their treating team. Despite this, more than half actively searched for additional information, with 77% using the Internet. Patients were trusting of information obtained from the Internet. More than half of information searchers discussed information obtained in their search with a health professional. The majority of patients did not believe that information searching adversely affected the doctor-patient relationship. CONCLUSION: Information searching is common in ambulatory Australian oncology patients, with the Internet being a frequently used resource. To ensure patients find reliable and relevant information and to minimize the risk of harm, health professionals involved in treating oncology patients should provide guidance in finding information sources and assistance in interpreting the information obtained.

A novel bacteriocin, thuricin 17, produced by plant growth promoting rhizobacteria strain Bacillus thuringiensis NEB17: isolation and classification.

AIMS: The aim of this study was to identify and characterize a compound produced by the plant growth promoting bacterium, Bacillus thuringiensis non-Bradyrhizobium Endophytic Bacterium 17. METHODS AND RESULTS: The bacterial peptide was analysed and purified via HPLC. Using the disk diffusion assay this peptide inhibited the growth of 16/19 B. thuringiensis strains, 4/4 Bacillus cereus strains, among others, as well as a Gram-negative strain Escherichia coli MM294 (pBS42). Both bactericidal and bacteristatic effects were observed on B. cereus ATCC 14579 and bactericidal effects were observed on B. thuringiensis ssp. thuringiensis Bt1267. The molecular weight of the peptide was estimated via SDS-PAGE and confirmed with Matrix Assisted Laser Desorption Ionization Quadrapole Time of Flight mass spectrometry; its weight is 3162 Da. The peptide is biologically active after exposure to 100 degrees C for 15 min, and within the pH range 1.00-9.25. Its activity disappeared when treated with proteinase K and protease, but not with alpha-amylase or catalase. CONCLUSIONS: We conclude that this is the first report of a bacteriocin produced by a plant growth promoting rhizobacteria (B. thuringiensis) species and have named the bacteriocin thuricin 17. SIGNIFICANCE AND IMPACT OF THE STUDY: Our work has characterized a bacteriocin produced by a plant growth promoting bacterium. This strain is previously reported to increase soya bean nodulation.

Characterization of the cell-surface procoagulant activity of T-lymphoblastoid cell lines.

The procoagulant activity (PCA) of four T-lymphoblastoid cell lines (CEM-CCRF, Jurkat, Molt-4 and A3.01) at different stages of differentiation has been characterized and compared with that of a monocytoid cell line (THP-1). Four assay systems were employed; the activated partial thromboplastin time (APTT); prothrombin time/tissue factor (TF) activity; a purified factor (F)Xa generation system and cancer procoagulant. High levels of TF activity were seen only with the monocytic cells. However the more differentiated of the T-lymphoblastoid cells (Molt-4 and A3.01) were more active than monocytic cells in supporting FXa generation. This pattern was not repeated for the APTT assay, which was related to cell-surface TF activity, since it was partially inhibited by antiTF antibody. Annexin V totally inhibited the activity observed in all three assay systems, indicating that the PCA of T-lymphoblastoid cells is primarily due to expression of negatively charged phospholipids. However, antiphosphatidylserine antibody even at a high concentration gave only partial inhibition of the activity observed in the APTT and FXa generation systems for the cells compared with almost total inhibition for the phospholipid standard, suggesting either that cellular phosphatidylserine (PS) is less accessible to the antibody, or that PS is not the sole negatively charged phospholipid responsible for this activity. Flow cytometry studies using propidium iodide and annexin V showed that the PCA, although linked to PS exposure, was not the result of apoptosis.

Sacrococcygeal teratomas: the UK Children's Cancer Study Group's experience. I. Neonatal.

The aim of this study was to review the United Kingdom Children's Cancer Study Group (UKCCSG) experience of sacrococcygeal teratomas (SCT) including histological presentation, response to surgery and chemotherapy, and long term effects of the tumour and treatment. This paper presents the results for those children diagnosed during the neonatal period. Children aged up to 4 weeks with biopsy proven localised or metastatic sacrococcygeal germ cell tumours were eligible. From 1st January 1989 to 31st December 1997 (9 years), 15 UKCCSG centres registered 51 neonates with SCT into GC 8901. Surgery alone was performed in all and the prognosis was good - except for 1 baby who died from massive haemorrhage at the initial operation and 1 who died from the complications of prematurity. Seven of the 51 children (14%) who had teratomas in the neonatal period (5 mature, two immature) had yolk sac tumour (YST) recurrence at: 4, 12, 15, 20, 20, 28 and 32 months of age. These children received chemotherapy in the form of etoposide/bleomycin/carboplatin (JEB) and are alive and well at review. These results emphasise the need for oncological follow-up of SCT and the good response to JEB chemotherapy of malignant teratomas and YST.

Antithrombin: a new look at the actions of a serine protease inhibitor.

Antithrombin (AT) is a plasma-derived, single-chain glycoprotein with a molecular weight of 58 kDa. It is a serine protease inhibitor (serpin), sharing about 30% homology in amino acid sequence with other serpins. AT is a complex molecule with multiple biologically important properties. It is a potent anticoagulant that has been demonstrated to provide benefit in animal models and small cohorts of patients with coagulation disorders. AT also has remarkable anti-inflammatory properties, several of which result from its actions in the coagulation cascade. Activated coagulation proteases like activated factor X and thrombin contribute to inflammation; for instance, by the release of pro-inflammatory mediators. Inhibition of these proteases by AT prevents their specific interaction with cells and subsequent reactions. Anti-inflammatory properties of AT independent of coagulation involve direct interactions with cells leading to the release of, for instance, prostacyclin. Binding of AT to a recently identified cellular receptor, syndecan-4, leads to the interference with the intracellular signal induced by mediators like lipopolysaccharides and, thereby, to a down-modulation of the inflammatory response. AT has been shown to be effective in prospective and well-controlled small-scale studies of patients with inflammatory conditions, including sepsis. Although AT did not decrease overall patient mortality in a double-blind, placebo-controlled, phase III trial of patients with sepsis, it is important to note that AT improved the survival of individuals in this study not receiving heparin as a prophylactic regimen, which can be explained by the impaired interaction of AT with its cellular receptor in the presence of heparin, resulting in the reduction of the anti-inflammatory properties. Accordingly, the supplementation of AT without concomitant heparin may be beneficial in disorders with inflammatory characteristics, which has to be demonstrated in further clinical studies. Finally, recent results suggest that latent AT can induce apoptosis of endothelial cells by disrupting cell-matrix interactions. Further investigations will have to demonstrate whether latent and/or cleaved AT are physiological means to control angiogenesis. A potential prophylactic or therapeutic use as an anti-angiogenic and antitumor agent merits further exploration, including whether the growth of vessels in tumor tissues or close to tumors can be controlled by latent AT without affecting the formation of blood vessels during wound healing processes.

Fecal calprotectin: validation as a noninvasive measure of bowel inflammation in childhood inflammatory bowel disease.

BACKGROUND: Calprotectin is an abundant neutrophil protein, which is extremely stable in feces. This study aimed to validate fecal calprotectin as a marker of bowel inflammation against invasive measures in children with inflammatory bowel disease (IBD), including colitis and small bowel Crohn disease. METHODS: Fecal calprotectin was measured using a simple enzyme-linked immunosorbent assay in 36 spot stool samples from 22 children before colonoscopy and from 14 children before technetium-99 (99Tc) scanning. Using standard scoring systems, the severity of inflammation was assessed macroscopically and histologically at six standard sites in those who underwent colonoscopy and also at six standard sites in those who underwent 99Tc scanning. The subscores from each site were summated to give combined severity and extent scores for macroscopic and for histologic inflammation in the group undergoing colonoscopy and total inflammation in the group undergoing 99Tc scanning. RESULTS: In the 22 children who underwent colonoscopy, median fecal calprotectin was 4.9 mg/L (0.1-272.5 mg/L) (range). Disease groups included six normal cases, nine ulcerative colitis cases, two isolated Crohn colitis cases, two indeterminate colitis cases, and three allergic colitis cases. Fecal calprotectin correlated closely with colonic macroscopic inflammation (r = 0.75, P < 0.001) and histologic inflammation (r = 0.85, P < 0.001). Of the 14 children undergoing 99Tc scanning, 10 had Crohn disease, 3 had ulcerative colitis, and 1 had allergic colitis. Median fecal calprotectin was 9.1 mg/L (0.3-141.7 mg/L), and this correlated closely with the 99Tc scanning score (r = 0.80, P = 0.001). CONCLUSION: Fecal calprotectin correlates closely with the best invasive measures of colonic and small bowel inflammation in childhood inflammatory bowel disease. As a sensitive objective measure of bowel inflammation that is risk-free and noninvasive, fecal calprotectin lends itself particularly to the monitoring of and assessment of therapeutic interventions in children with inflammatory bowel disease.