An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma.

BACKGROUND: An improved understanding of which gastroesophageal adenocarcinoma (GOA) patients respond to both chemotherapy and immune checkpoint inhibitors (ICI) is needed. We investigated the predictive role and underlying biology of a 44-gene DNA damage immune response (DDIR) signature in patients with advanced GOA. MATERIALS AND METHODS: Transcriptional profiling was carried out on pretreatment tissue from 252 GOA patients treated with platinum-based chemotherapy (three dose levels) within the randomized phase III GO2 trial. Cross-validation was carried out in two independent GOA cohorts with transcriptional profiling, immune cell immunohistochemistry and epidermal growth factor receptor (EGFR) fluorescent in situ hybridization (FISH) (n = 430). RESULTS: In the GO2 trial, DDIR-positive tumours had a greater radiological response (51.7% versus 28.5%, P = 0.022) and improved overall survival in a dose-dependent manner (P = 0.028). DDIR positivity was associated with a pretreatment inflamed tumour microenvironment (TME) and increased expression of biomarkers associated with ICI response such as CD274 (programmed death-ligand 1, PD-L1) and a microsatellite instability RNA signature. Consensus pathway analysis identified EGFR as a potential key determinant of the DDIR signature. EGFR amplification was associated with DDIR negativity and an immune cold TME. CONCLUSIONS: Our results indicate the importance of the GOA TME in chemotherapy response, its relationship to DNA damage repair and EGFR as a targetable driver of an immune cold TME. Chemotherapy-sensitive inflamed GOAs could benefit from ICI delivered in combination with standard chemotherapy. Combining EGFR inhibitors and ICIs warrants further investigation in patients with EGFR-amplified tumours.

CAnceR IN PreGnancy (CARING) - a retrospective study of cancer diagnosed during pregnancy in the United Kingdom.

BACKGROUND: The incidence of cancer diagnosed during pregnancy is increasing. Data relating to investigation and management, as well as maternal and foetal outcomes is lacking in a United Kingdom (UK) population. METHODS: In this retrospective study we report data from 119 patients diagnosed with cancer during pregnancy from 14 cancer centres in the UK across a five-year period (2016-2020). RESULTS: Median age at diagnosis was 33 years, with breast, skin and haematological the most common primary sites. The majority of cases were new diagnoses (109 patients, 91.6%). Most patients were treated with radical intent (96 patients, 80.7%), however, gastrointestinal cancers were associated with a high rate of palliative intent treatment (63.6%). Intervention was commenced during pregnancy in 68 (57.1%) patients; 44 (37%) had surgery and 31 (26.1%) received chemotherapy. Live births occurred in 98 (81.7%) of the cases, with 54 (55.1%) of these delivered by caesarean section. Maternal mortality during the study period was 20.2%. CONCLUSIONS: This is the first pan-tumour report of diagnosis, management and outcomes of cancer diagnosed during pregnancy in the UK. Our findings demonstrate proof of concept that data collection is feasible and highlight the need for further research in this cohort of patients.

Metastatic seminoma with isolated gastric metastases: a case report.

Gastric metastases are a rare occurrence in patients with malignancy. In case reports of these arising from germ cell tumours, the majority were non-seminomatous germ cell tumours and had evidence of retroperitoneal involvement. We present a unique case of a 67-year-old man with metastatic testicular pure seminoma. He presented with dyspepsia and investigation found isolated metastases to the gastric mucosa and sub-mucosa from a right testicular primary. No lymph node involvement was identified. The patient was managed with curative intent with total gastrectomy and inguinal orchidectomy. To date, there is no evidence of disease recurrence.

A quick guide to survey research.

Questionnaires are a very useful survey tool that allow large populations to be assessed with relative ease. Despite a widespread perception that surveys are easy to conduct, in order to yield meaningful results, a survey needs extensive planning, time and effort. In this article, we aim to cover the main aspects of designing, implementing and analysing a survey as well as focusing on techniques that would improve response rates.

Marrow stromal cells from patients affected by MPS I differentially support haematopoietic progenitor cell development.

Bone marrow transplantation is the therapy of choice in patients affected by MPS I (Hurler syndrome), but a high incidence of rejection limits the success of this treatment. The deficiency of alpha-L-iduronidase (EC 1.2.3.76), one of the enzymes responsible for the degradation of glycosaminoglycans, results in accumulation of heparan and dermatan sulphate in these patients. Heparan sulphate and dermatan sulphate are known to be important components of the bone marrow microenvironment and critical for haematopoietic cell development. In this study we compared the ability of marrow stromal cells from MPS I patients and healthy donors to support normal haematopoiesis in Dexter-type long term culture. We found an inverse stroma/supernatant ratio in the number of clonogenic progenitors, particularly the colony-forming unit granulocyte-machrophage in MPS I cultures when compared to normal controls. No alteration in the adhesion of haematopoietic cells to the stroma of MPS I patients was found, suggesting that the altered distribution in the number of clonogenic progenitors is probably the result of an accelerated process of differentiation and maturation. The use of alpha-L-iduronidase gene-corrected marrow stromal cells re-established normal haematopoiesis in culture, suggesting that correction of the bone marrow microenvironment with competent enzyme prior to transplantation might help establishment of donor haematopoiesis.

Poor glycaemic control is associated with reduced serum free radical scavenging (antioxidant) activity in non-insulin-dependent diabetes mellitus.

The diabetic patient is at significantly increased risk of developing vascular disease. Its aetiology may involve oxidative damage by free radicals and protection against such damage can be offered by radical-scavenging antioxidants. We investigated whether there was a relationship between glycaemic control as assessed by measurement of glycated haemoglobin (HbA1c) and serum antioxidant status in a population of 118 diabetic outpatients with either insulin-dependent or non-insulin-dependent diabetes. Amongst patients with non-insulin-dependent diabetes mellitus there was a significant inverse correlation between levels of glycated haemoglobin and total free radical scavenging activity (r = -0.456, P < 0.0001). This association resulted primarily because of a similar correlation with uric acid (r = -0.421, P = 0.0003). There was also a weak inverse correlation with vitamin A but no significant association with vitamin C or vitamin E levels. There were no significant associations found amongst the patients with insulin-dependent diabetes. These results indicate that poor diabetic control is associated with reduced serum free radical scavenging (antioxidant) activity in non-insulin-dependent diabetes mellitus. By implication improved glycaemic control may preserve serum antioxidant status in diabetes.

Antioxidant status in patients with uncomplicated insulin-dependent and non-insulin-dependent diabetes mellitus.

Oxidative damage by free radicals has been implicated in the pathogenesis of vascular disease in diabetes. We compared the radical-scavenging antioxidant activity of serum from 28 patients with insulin-dependent diabetes mellitus and 24 patients with non-insulin-dependent diabetes mellitus uncomplicated by vascular disease with age-matched non-diabetic control subjects. Patients with insulin-dependent diabetes had significantly reduced total antioxidant activity (320.2 +/- 11.3 vs. 427.5 +/- 19.2 mumol L-1; P < 0.001). This was attributable to lower urate (209.4 +/- 10.4 vs. 297.1 +/- 16.7 mumol L-1; P < 0.001) and vitamin C levels (63.6 +/- 6.0 vs. 87.5 +/- 4.9 mumol L-1; P < 0.01). Patients with non-insulin-dependent diabetes had lower total antioxidant activity than age-matched control subjects (433.8 +/- 25.4 vs. 473.9 +/- 30.2 mumol L-1; NS), reflecting lower urate (299.5 +/- 19.4 vs. 324.8 +/- 21.4 mumol L-1; NS) and vitamin C levels (38.6 +/- 5.7 vs. 58.5 +/- 5.3 mumol L-1; P < 0.05). Multiple regression analysis showed that urate, vitamin C and vitamin E were the major contributors to serum total antioxidant activity. These results show that diabetic patients have significant defects of antioxidant protection, which may increase vulnerability to oxidative damage and the development of diabetic complications.

Use of near-infrared spectroscopy to evaluate an active in a film coated tablet.

PURPOSE: To provide a method to rapidly screen tablets in the development of new coating technology. METHODS: Near-Infrared (NIR) reflectance spectroscopy was used to quantitatively analyze tablets which were composed of a drug active encasing an active drug core. Diffuse reflectance NIR scans of 240 individual tablets over the range of 1100-2500 nm were obtained. High Performance Liquid Chromatography (HPLC) was used as the reference method. RESULTS: Both qualitative, Principal Component Analysis, and quantitative results showed a strong agreement between the NIR and HPLC methods. The NIR analysis was non-invasive and allowed subsequent testing of the tablets. The contents of the drug active contained in a drug coating was determined to +/- 4% of the target value using NIR analysis. Over 400 samples were analyzed in less than a month utilizing this technique which allowed the optimization of a new coating technology. CONCLUSIONS: NIR analysis allowed the evaluation of the efficiency of a new drug film coating manufacturing process more quickly and inexpensively. Because the Near-Infrared method was non-invasive the tablets were available for further analysis unlike the chromatography method.

Regulation of myo-inositol transport during the growth and differentiation of thyrocytes: a link with thyroid-stimulating hormone-induced phospholipase A2 activity.

The Vmax of myo-inositol transport increased 3-fold during epidermal growth factor (EGF)-induced growth and thyroid-stimulating hormone. (TSH)-induced differentiation in primary cultures of sheep and human thyrocytes. The Km remained unaltered. This up-regulation required the presence of insulin. The TSH-induced rise in myo-inositol transport commenced 8 to 16 h after the initial stimulus and achieved a plateau at 24 h. In human thyrocytes the change in Vmax was accompanied by an increase in the steady-state levels of mRNA for the myo-inositol transporter following treatment with either ligand. Examination of the metabolites of myo-inositol showed few significant changes after treatment of sheep thyrocytes with EGF for 24 h. This is consistent with maintenance of the intracellular concentration of myo-inositol as the cells enlarge in preparation for cell division. In TSH-treated cells, however, up-regulation of myo-inositol transport was linked with increased myo-inositol cycling across the cell membrane, increased phospholipase A2-mediated turnover of phosphatidylinositol and a concomitant increase in arachidonic acid turnover. Increased levels of myo-inositol phosphates were also noted 24 h after TSH treatment. These results indicate the initiation of secondary signalling events many hours after the primary stimulus.

Acromegaly and transsphenoidal hypophysectomy: a case report.

Anterior pituitary tumors account for nearly 18% of all intracranial tumors. Pituitary adenomas that cause hypersecretion of growth hormone lead to acromegaly in adults. Patients with acromegaly may present unique problems for the anesthetist because of the overgrowth of airway soft tissues; a difficult mask ventilation and challenging intubation can be expected. A careful preoperative assessment of the patient's airway is essential, and an awake oral or fiberoptic bronchoscopy may be necessary. Postoperatively, these patients are at risk for developing airway problems and diabetes insipidus; therefore, they warrant careful observation. A 42-year-old, 75-kg, ASA physical status III, white male presented 8 months after suffering a head injury in which he was knocked unconscious for approximately 3 minutes. He began experiencing severe headaches, visual changes, and a marked increase in the size of his hands and feet. Four months before admission, he underwent bilateral carpal tunnel repairs. The patient was diagnosed with acromegaly after an extensive endocrine and neurosurgical evaluation. This is a case report of a patient with acromegaly who underwent an elective transsphenoidal hypophysectomy.

Radioiodine therapy for hyperthyroidism in young patients--perception of risk and use.

Although radioiodine is increasingly the treatment of choice in hyperthyroidism, there are regional differences in its use which reflect, in part, concerns regarding safety. We investigated attitudes amongst general practitioners and consultant physicians to the role of radioiodine therapy, and reviewed our own radioiodine prescribing in patients aged less than 40 to elucidate any influence of age and/or sex. We surveyed general practitioners in the former Central Birmingham Health District and consultant physicians in the West Midlands Region to investigate treatment preferences in hyperthyroidism and perceived risk from radioiodine of hypothyroidism, carcinogenesis and infertility. Of 230 general practitioner and 130 consultant physician respondents, less than 1% considered radioiodine the treatment of choice in a 25-year-old female presenting with hyperthyroidism. At relapse after antithyroid drug treatment in a 25-year-old female, only 16.5% of general practitioners and 23.9% of physicians advocated radioiodine, the greatest number preferring partial thyroidectomy. For a 65-year-old at presentation, 49.1% of general practitioners and 62.3% of physicians considered radioiodine the treatment of choice. More than 10% failed to note the risk of hypothyroidism following radioiodine, while 11-34% perceived increased risk of malignancy or infertility. Review of our own practice demonstrated that of 100 patients given radioiodine, 94% were cured of hyperthyroidism when reviewed at a mean of 2.4 years from latest treatment, 70% being hypothyroid. Females given radioiodine were treated less promptly following diagnosis of hyperthyroidism than males (2.2 +/- 0.26 years vs. 1.6 +/- 0.4) and were more likely to have received a preceding course of antithyroid drugs (78% vs. 57%).(ABSTRACT TRUNCATED AT 250 WORDS)

Audit of the change from twice daily to basal-bolus insulin regimens in insulin-dependent diabetes.

Basal-bolus insulin regimens have become popular with patients, but clinicians' enthusiasm for their use has been tempered by a number of reports that suggest that these regimens do not improve overall glycemic control when compared with conventional, twice daily, regimens. Indeed, it has been suggested that basal-bolus regimens may be abused by certain patients leading to an increase in body weight and deterioration in glycemic control. This paper reports the results of a retrospective audit of 145 insulin-dependent diabetic patients changed from conventional insulin therapy to a basal-bolus insulin regimen. After 3 months on the basal-bolus regimen, a small but significant fall in total insulin (10%; p < 0.001) and intermediate-acting insulin (50%; p < 0.001) dose was recorded. During this time period serum fructosamine measurements also fell by 10% (p < 0.001) indicating a small but significant improvement in glycemic control. Body-mass index (BMI) and body weight data did not support the view that basal-bolus regimens lead to an increase in body weight. Analysis of the data by gender did not support the view that the basal-bolus insulin regimen is prone to abuse by female patients.