Sabapathy P Balasubramanian

Influence of VEGF-A gene variation and protein levels in breast cancer susceptibility and severity

Vascular endothelial growth factor‐A (VEGF‐A) plays an important role in tumour angiogenesis and cancer progression. VEGF gene variation may influence VEGF levels and therefore cancer susceptibility and progression. We studied the role of VEGF single nucleotide polymorphisms and haplotypes in breast cancer susceptibility and severity. We also studied the relationships of VEGF SNPs with circulating VEGF levels in healthy volunteers and protein expression in breast cancers. Single nucleotide polymorphisms (SNPs) in the regulatory regions of the VEGF gene were genotyped by high throughput methods in ∼500 breast cancer cases and 500 appropriate controls. Haplotype frequencies were inferred using methods based on the Expectation Maximisation algorithm. The effect of VEGF genotypes on serum and plasma VEGF levels were studied in another cohort of healthy individuals. A semi‐quantitative assessment of VEGF protein expression on tissue micro arrays (TMA) constructed from ∼300 breast cancer samples was performed and compared with VEGF genotypes and with histopathological parameters and survival in breast cancer. The −460T/+405C/−7C/936C haplotype in the VEGF gene was found to be associated with decreased breast cancer risk (p = 0.029). The −7C>T polymorphism may influence overall breast cancer survival (p = 0.027). Individual polymorphisms however did not affect breast cancer susceptibility. There was no association between the individual polymorphisms and circulating VEGF levels in healthy volunteers and VEGF expression on the breast cancer micro array. VEGF expression in breast cancers was however associated with high grade (p = 0.002) and ER negative tumours (p = 0.03).

Accuracy of references in general surgical journals — An old problem revisited

BACKGROUND Reference errors in biomedicals journals are well documented. Increasing use of electronic databases and bibliographic software may change the nature and frequency of errors. AIM To study the current incidence of reference errors in four major general surgical journals. METHODS Seventy-five references were randomly selected from original articles published in one issue of each of four general surgical journals. For each reference, ease of retrieval on PubMed and the presence of citation errors were noted. Two observers independently reviewed each reference for quotation errors. RESULTS Of the 300 selected references, 261 from indexed English language biomedical journals were analysed. Retrieval from PubMed was impossible or difficult in six instances, giving a major citation error rate of 2.3%. Overall (major and minor) citation error rate was 11.1%. Of the 258 references that could be retrieved, 20 (7.8%) had quotation errors, 80% of which were considered major. The overall citation error rate was significantly different across the four journals. There was moderate correlation between quotation error rate and number of references in each original article. CONCLUSION Errors in references still appear in current surgical literature. Solutions to address this problem have been discussed.

An audit of the management of soft tissue sarcoma within a health region in the UK

AIMS Soft tissue sarcomas are rare and heterogeneous tumours only occasionally seen by most individual clinicians. Early recognition, appropriate referral and timely investigations markedly improve outcomes. Our aim was to retrospectively assess the referral patterns, investigation, surgery and outcomes of patients with soft tissue sarcoma in the Trent region of the UK. METHODS Two hundred and four patients with soft tissue sarcoma registered with the Trent Cancer Registry in 1995-1997 were first studied. Clinical details, tumour characteristics, presentation, management and follow-up were recorded from the case notes and analysed.A further group of 40 patients referred to a single cancer centre in 1999 were audited to establish whether there had been any improvements/changes over the 2 years, since the completion of the first audit. RESULTS In the first audit, 49.5% were first referred to general surgeons and 16% to orthopaedic surgeons. Only 15% of patients fit for surgery were referred to a surgeon with a specialist sarcoma interest prior to definitive exploration. Of the deep tumours, 64% had a preoperative biopsy and only 68% had a scan before biopsy or definitive surgery. Tumour grade, completeness of excision and site of the sarcoma influenced survival. The second audit performed on patients treated in 1999 showed only a marginal improvement in management when compared to the first audit.

Risk profile of the RET A883F germline mutation: an international collaborative study

Context The A883F germline mutation of the rearranged during transfection (RET) proto-oncogene causes multiple endocrine neoplasia 2B. In the revised American Thyroid Association (ATA) guidelines for the management of medullary thyroid carcinoma (MTC), the A883F mutation has been reclassified from the highest to the high-risk level, although no well-defined risk profile for this mutation exists. Objective To create a risk profile for the A883F mutation for appropriate classification among the ATA risk levels. Design Retrospective analysis. Setting International collaboration. Patients Included were 13 A883F carriers. Intervention The intervention was thyroidectomy. Main Outcome Measures Earliest age of MTC, regional lymph node metastases, distant metastases, age-related penetrance of MTC and pheochromocytoma (PHEO), overall and disease-specific survival, and biochemical cure rate. Results One and three carriers were diagnosed at age 7 to 9 years (median, 7.5 years) with a normal thyroid and C-cell hyperplasia, respectively. Nine carriers were diagnosed with MTC at age 10 to 39 years (median, 19 years). The earliest age of MTC, regional lymph node metastasis, and distant metastasis was 10, 20, and 20 years, respectively. Fifty percent penetrance of MTC and PHEO was achieved by age 19 and 34 years, respectively. Five- and 10-year survival rates (both overall and disease specific) were 88% and 88%, respectively. Biochemical cure for MTC at latest follow-up was achieved in 63% (five of eight carriers) with pertinent data. Conclusions MTC of A883F carriers seems to have a more indolent natural course compared with that of M918T carriers. Our results support the classification of the A883F mutation in the ATA high-risk level.

Long-term treatment-related morbidity in differentiated thyroid cancer: a systematic review of the literature

Background Differentiated thyroid cancer (DTC) occurs in relatively young patients and is associated with a good prognosis and long survival. The management of this disease involves thyroidectomy, radioiodine therapy, and long-term thyroid-stimulating hormone suppression therapy (THST). The long-term effects of the treatment and the interaction between subclinical hyperthyroidism and long-term hypoparathyroidism are poorly understood. This review sought to examine the available evidence. Methods A PubMed search was carried out using the search terms “Thyroid Neoplasms” AND (“Thyroxine” OR “Hypocalcemia” OR “Thyrotropin”). Original English language articles published in the last 30 years studying the morbidity from thyroid-stimulating hormone (TSH) suppression and hypoparathyroidism following a surgery for DTC were retrieved and reviewed by 2 authors. Results Of the 3,000 results, 66 papers including 4,517 patients were selected for the present study. Studies reported on a range of skeletal (included in 34 studies, 1,647 patients), cardiovascular (17 studies, 957 patients), psychological (10 studies, 663 patients), and other outcomes (10 studies, 1,348 patients). Nine of 26 studies on patients who underwent THST showed a reduction in bone density, and 13 of 23 studies showed an increase in bone turnover markers. Skeletal effects were more marked in postmenopausal women. There was no evidence of increased fracture risk, and only little data were available on hypoparathyroidism. Four of five studies showed an increased left ventricular mass index on echocardiography, and one study showed a higher prevalence of atrial fibrillation (AF). There was little difference in basic physiological parameters and limited literature regarding symptoms or significant events. Six studies showed associations between long-term TSH suppression and impaired quality of life. Impaired glucose metabolism and prothrombotic states were also found in DTC patients. Conclusion There is limited literature regarding long-term DTC treatment-related morbidity, particularly regarding the effects of long-term hypocalcemia. Most studies have focused on surrogate markers and not on clinical outcomes. A large prospective study on defined clinical outcomes would help characterize the morbidity of treatment and stimulate research on tailoring treatment strategies.

Epidemiology, management and outcomes of Graves’ disease—real life data.

PurposeTreatment options in Graves’ disease are clearly defined, but management practices and the perceptions of success are varied. The outcomes of treatment in large consecutive cohorts of Graves’ disease have not been well characterised. The study describes the epidemiology, management strategies and medium term outcomes following anti-thyroid drug treatment, radio-iodine ablation and surgery in Graves’ disease.MethodsAll patients (n = 659) who received treatment for a new diagnosis of Graves’ disease in secondary care over a 5 year period were included with a median (interquartile range) follow-up of 42.9 (29–57.5) months.ResultsThe age adjusted incidence of adult onset Graves’ disease in Sheffield, UK was 24.8 per 100,000 per year. Excluding 35 patients lost to follow-up, 93.1% (n = 581) were controlled on anti-thyroid drug treatment. Of these, 73.6% went into remission following withdrawal of anti-thyroid drugs; 5.2% were still undergoing initial therapy; 13.3% lost control whilst on anti-thyroid drugs; and 7.9% went on to have either surgery or radio-iodine ablation whilst controlled on anti-thyroid drugs. Of the 428 patients who achieved remission, 36.7% relapsed.Of 144 patients who had radio-iodine ablation treatment, 5.6% relapsed and needed further treatment. Of 119 patients having surgery, 5.2% had long-term hypoparathyroidism and none had documented long-term recurrent laryngeal nerve palsy.ConclusionsIn the follow-up, 39.9% of patients underwent surgery or radio-iodine ablation with little morbidity. Up to two-thirds of patients who achieved remission did not relapse. Data on effectiveness and risks of treatments for Graves’ disease presented in this study will help clinicians and patients in decision making.

Effects of prolonged exposure to low dose metformin in thyroid cancer cell lines

Background: Thyroid cancer is generally associated with an excellent prognosis, but there is significant long-term morbidity with standard treatment. Some sub-types however have a poor prognosis. Metformin, an oral anti-diabetic drug is shown to have anti-cancer effects in several types of cancer (breast, lung and ovarian cancer). The proposed mechanisms include activation of the Adenosine Mono-phosphate-activated Protein Kinase (AMPK) pathway and inhibition of the mTOR pathway (which promotes growth and proliferation). By inhibiting hepatic gluconeogenesis and increasing glucose uptake by muscles, metformin decreases blood glucose and circulating Insulin levels. Aims: Explore the effect of metformin on the growth and proliferation of thyroid cancer cell lines. Methods: The effects of metformin on thyroid cancer cell lines (FTC-133, K1E7, RO82-W-1, 8305C and TT) and normal thyroid follicular cells (Nthy-ori 3-1) were investigated using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay for cell proliferation; clonogenic assays; FACS analysis for apoptosis and cell cycle, H2A.X phosphorylation (γH2AX) assay for DNA repair and scratch assay for cell migration. Results: Metformin inhibited cell proliferation and colony formation at 0.03 mM and above and inhibited cell migration at 0.3 mM. At concentrations of 0.1 mM and above metformin increased the percentage of apoptotic cells and induced cell cycle arrest in G0/G1 phase at minimum concentration of 0.3 mM. Unlike previous reports, no effect on DNA repair response was demonstrated. Conclusion: Metformin suppressed growth of all thyroid cancer cell lines, at concentrations considered to be within in the therapeutic range for diabetic patients on metformin (<0.3 mM).

A case report on acute severe hyponatraemia following parathyroid surgery for primary hyperparathyroidism—A rare but life threatening complication

Highlights • The need for recording and maintaining fluid balance in the early postoperative period.• Hyponatremia may occur in healthy patients after short, uneventful operations. Women and elderly are a higher risk and are more prone to permanent neurological deficits.• Awareness of hyponatremia as a cause of postoperative seizures and the multiple causes of hyponatremia in these settings.• Care should be taken not to continue with increased water intake following surgical correction of hypercalcaemia.

Study raises five questions

Sandblom and colleagues’ 20 year follow-up study of prostate cancer screening raises five questions.1