Outcomes of surgical versus non-surgical treatment of resectable T4a laryngeal and hypopharyngeal carcinoma.

OBJECTIVE: Surgery is the recommended treatment for resectable T4a laryngeal and hypopharyngeal carcinoma. Non-surgical treatment is an option in a select few patients. METHOD: This retrospective study was undertaken to assess the treatment outcomes in patients with resectable T4a carcinoma of the larynx and hypopharynx who received either surgical or non-surgical treatment at our institute and to assess factors influencing these outcomes. RESULTS: A total of 120 patients were included in the study. They were divided into groups A, B and C based on the presence of extralaryngeal spread through laryngeal membrane, cartilage or both. The overall survival was better among patients who received surgery than those who received non-surgical treatment in the three groups. The factor influencing overall survival was the treatment given in the form of surgical versus non-surgical treatment. CONCLUSION: Surgery is the preferred treatment for T4a laryngeal and hypopharyngeal carcinoma, even in patients with extralaryngeal spread without cartilage erosion.

Longitudinal health utilities, symptoms and toxicities in patients with ALK-rearranged lung cancer treated with tyrosine kinase inhibitors: a prospective real-world assessment.

Background: Tyrosine kinase inhibitors (tkis) have dramatically improved the survival of patients with ALK-rearranged (ALK+) non-small-cell lung cancer (nsclc). Clinical trial data can generally compare drugs in a pair-wise fashion. Real-world collection of health utility data, symptoms, and toxicities allows for the direct comparison between multiple tki therapies in the population with ALK+ nsclc. Methods: In a prospective cohort study, outpatients with ALK+ recruited between 2014 and 2018, treated with a variety of tkis, were assessed every 3 months for clinico-demographic, patient-reported symptom and toxicity data and EQ-5D-derived health utility scores (hus). Results: In 499 longitudinal encounters of 76 patients with ALK+ nsclc, each tki had stable longitudinal hus when disease was controlled, even after months to years: the mean overall hus for each tki ranged from 0.805 to 0.858, and longitudinally from 0.774 to 0.912, with higher values associated with second- or third-generation tkis of alectinib, brigatinib, and lorlatinib. Disease progression was associated with a mean hus decrease of 0.065 (95% confidence interval: 0.02 to 0.11). Health utility scores were inversely correlated to multiple symptoms or toxicities: rho values ranged from -0.094 to -0.557. Fewer symptoms and toxicities were associated with the second- and third-generation tkis compared with crizotinib. In multivariable analysis, only stable disease state and baseline Eastern Cooperative Oncology Group performance status were associated with improved hus. Conclusions: There was no significant decrease in hus when patients with ALK+ disease were treated longitudinally with each tki, as long as patients were clinically stable. Alectinib, brigatinib, and lorlatinib had the best toxicity profiles and exhibited high mean hus longitudinally in the real-world setting.

Revision PCL Reconstruction Review/Update.

PURPOSE OF REVIEW: The primary goal of this review is to update recent literature on revision PCL reconstruction and to discuss factors relevant to surgical failure, surgical indications and goals, patient evaluation, surgical decision-making, graft selection, surgical technique, associated surgical procedures, postoperative rehabilitation, and revision PCL reconstruction results. RECENT FINDINGS: Specifically, it is paramount to consider and treat posteromedial and posterolateral instability. Success in revision surgery focuses on appropriate graft choice and precise tunnel placement at anatomical attachment sites. Furthermore, correct tensioning of the graft, secondary or backup fixation and well-designed PT and rehab protocols are integral components. The factors causing failure of the primary reconstruction should be identified, as revision surgery must address the errors and follow strict surgical principals to be successful. There are many variables that play a role in successful revision posterior cruciate ligament (PCL) reconstruction. In general, as in most ligament reconstruction surgery, it is important to identify and address all associated pathology such as lower extremity malalignment and additional instability.

Assessing impact of organised breast screening across small residential areas-development and internal validation of a prediction model.

Monitoring screening mammography effects in small areas is often limited by small numbers of deaths and delayed effects. We developed a risk score for breast cancer death to circumvent these limitations. Screening, if effective, would increase post-diagnostic survivals through lead-time and related effects, as well as mortality reductions. Linked cancer and BreastScreen data at four hospitals (n = 2,039) were used to investigate whether screened cases had higher recorded survivals in 13 small areas, using breast cancer deaths as the outcome (M1), and a risk of death score derived from TNM stage, grade, histology type, hormone receptor status, and related variables (M2). M1 indicated lower risk of death in screened cases in 12 of the 13 areas, achieving statistical significance (p < .05) in 5. M2 indicated lower risk scores in screened cases in all 13 areas, achieving statistical significance in 12. For cases recently screened at diagnosis (<6 months), statistically significant reductions applied in 8 areas (M1) and all 13 areas (M2). Screening effects are more detectable in small areas using these risk scores than death itself as the outcome variable. An added advantage is the application of risk scores for providing a marker of screening effect soon after diagnosis.

Fine Needle Aspiration Cytology vs. the Postoperative Histology - the Continuing Need for Multi-Disciplinary Approach?

We set out to investigate the concordance rates that were observed between fine needle aspiration cytology (FNA) compared with that of the post operative histology obtained for thyroid nodules over an 8 year period at a large university hospital.A retrospective analysis of 355 cases was conducted; patients operated for hyperthyroidism were excluded for the purposes of this study. We identified malignancy in a total of 101 cases (28%) The chance of malignancy with 2 Thy1 specimens was 5% in this study and 9% was observed in those with a Thy 2 FNA. On the converse, 7% of patient had malignant cytology on FNA though post-operative histology turned out to be benign.This therefore highlights the potential for discordance between thyroid FNA cytology and post-operative histology in the assessment of any thyroid nodule and thus reinforcing the need for a multidisciplinary approach in the assessment of all thyroid nodules.

Effectiveness and cost-effectiveness of sentinel lymph node biopsy compared with axillary node dissection in patients with early-stage breast cancer: a decision model analysis.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is less invasive than axillary lymph node dissection (ALND) for staging early breast cancer, and has a lower risk of arm lymphoedema and similar rates of locoregional recurrence up to 8 years. This study estimates the longer-term effectiveness and cost-effectiveness of SLNB. METHODS: A Markov decision model was developed to estimate the incremental quality-adjusted life years (QALYs) and costs of an SLNB-based staging and management strategy compared with ALND over 20 years' follow-up. The probability and quality-of-life weighting (utility) of outcomes were estimated from published data and population statistics. Costs were estimated from the perspective of the Australian health care system. The model was used to identify key factors affecting treatment decisions. RESULTS: The SLNB was more effective and less costly than the ALND over 20 years, with 8 QALYs gained and $883,000 saved per 1000 patients. The SLNB was less effective when: SLNB false negative (FN) rate >13%; 5-year incidence of axillary recurrence after an SLNB FN>19%; risk of an SLNB-positive result >48%; lymphoedema prevalence after ALND <14%; or lymphoedema utility decrement <0.012. CONCLUSION: The long-term advantage of SLNB over ALND was modest and sensitive to variations in key assumptions, indicating a need for reliable information on lymphoedema incidence and disutility following SLNB. In addition to awaiting longer-term trial data, risk models to better identify patients at high risk of axillary metastasis will be valuable to inform decision-making.

A newborn with unilateral limb enlargement.

On routine neonatal examination, a newborn term male was noted to have unilateral enlargement of the right lower limb, loose thickened red skin over the palm and widening of all the fingers on the right hand. His body was pinker and warmer on the right side compared with the left and he had a right undescended testicle and hypoplastic scrotum. Radiological examination of the lower limbs demonstrated the enlargement of the soft tissue of the right lower limb compared to the left (Fig. 1). Therefore, the diagnosis was unclear from this constellation of findings and an ophthalmic assessment was requested.

Chronic kidney disease in long duration type 1 diabetes lasting more than 50 years.

OBJECTIVE: There is evidence that microalbuminuria and overt nephropathy may progress more slowly in long duration (> 20 years) type 1 diabetes (T1DM). To explore this further, we examined the characteristics of chronic kidney disease (CKD) in a large cohort of long duration T1DM in the United Kingdom (UK). RESEARCH DESIGN AND METHODS: We studied the UK 'Golden Years' cohort--a group of 400 patients from various parts of the UK with T1DM > 50 years duration. Demographic and clinical information were obtained. HbA(1c), lipids, creatinine and urinary albumin-creatinine ratio (ACR) were measured. Microalbuminuria was defined as 2.5-25.0 mg/mmol for males and 3.5-25.0 mg/mmol for females; macroalbuminuria was defined as an ACR > 25.0 mg/mmol for both sexes. RESULTS: Mean age was 69 years and duration of diabetes 55 years. Nine percent had macroalbuminuria and 27% microalbuminuria. No patient had stage 5 CKD. Microalbuminuria was associated significantly with increased diabetes duration (p = 0.02), male sex (p = 0.02), smoking (p = 0.002), higher HbA(1c) (p < 0.0001), raised triglycerides (p = 0.04), and peripheral vascular disease (PVD) (p < 0.0001). Macroalbuminuria had significant associations with smoking (p = 0.02), raised triglycerides (p = 0.01), raised creatinine (p = 0.02), PVD (p = 0.01) and hypertension (p = 0.01). CONCLUSIONS: We conclude that microalbuminuria and CKD are common, even at long duration (> 50 years) of T1DM, and have similar characteristics and associations as they do with shorter disease duration. There is a striking absence, however, of stage 5 CKD, but selection bias may be an important confounder since patients with advanced disease may have not survived.

Diabetic complications and glycaemic control in remote North Africa.

BACKGROUND: Delivery of diabetes services in resource-poor areas of Africa is difficult. Control is often poor and complications are common. However, adequate robust surveys are uncommon, particularly in remote rural areas. This makes needs assessment difficult and health-care planning impossible. AIM: To accurately assess the glycaemic control and burden of complications in a group of diabetic patients from a remote area of a resource-limited north African country. DESIGN: Prospective cohort study. METHODS: Over a 6-week period, all patients attending the diabetic clinic at Mekelle Hospital in northern Ethiopia were intensively assessed, using imported western technology as necessary. Glycated haemoglobin (HbA(1c)), lipid profile, serum creatinine and urinary albumin-creatinine ratio were measured. Complications were assessed as accurately as possible, including examination of fundi by an ophthalmic specialist, and biosthesiometry for neuropathy. RESULTS: There were 105 patients, mean (+/- SD) age 41 +/- 16 years and diabetes duration 7 +/- 6 years. There were 74 (70%) males, and 69 (66%) on insulin. Median body mass index was low at 20.6 kg/m(2), but mean HbA(1c) high at 11.3 +/- 2.8% (68% had an HbA(1c) over 10.0%). Cataract (12%), retinopathy (21%), neuropathy (41%) and microalbuminuria (51%) were common; but nephropathy (2%) was rare, as was large vessel disease (6% had peripheral vascular disease, and none had coronary artery disease or cerebrovascular disease). Risk factors such as hypertension (5%) and smoking (2%) were uncommon, and lipid profiles were generally good. DISCUSSION: We conclude that in this severely resource-limited area of North Africa, glycaemic control amongst diabetic patients is very poor. Neuropathy, retinopathy and microalbuminuria are common; but large vessel disease risk factors are beneficial, and macroangiopathy prevalence is low. Scattered populations, shortage of drugs and insulin and lack of diabetes team care are major factors behind these serious issues of diabetic control and complications.

Population screening and intensity of screening are associated with reduced breast cancer mortality: evidence of efficacy of mammography screening in Australia.

BACKGROUND: Efficacy of breast screening may differ in practice from the results of randomized trials. We report one of the largest case-control evaluations of a screening service. METHODS: Subjects included 491 breast-cancer deaths affecting 45-80-year-old South Australian females during 2002-2005 (diagnosed after BreastScreen commencement) and 1,473 live controls (three per death) randomly selected from the State Electoral Roll after birth-date matching. Cancer Registry and BreastScreen records provided cancer and screening details. Risk estimates were calculated by BreastScreen participation, using conditional logistic regression. Interpretation was assisted by a population survey of risk factor prevalence by BreastScreen participation in 1,684 females aged > or =40 years. RESULTS: The relative odds (OR) (95% confidence limits) of breast-cancer death in BreastScreen participants compared with non-participants were 0.59 (0.47, 0.74). Compared with non-participants, the OR was 0.70 (0.47, 1.05) for women last screened through BreastScreen more than 3 years before diagnosis of the index case, and 0.57 (0.44, 0.72) for women screened more recently. The OR of 0.47 (0.34, 0.65) for women screened more frequently in the pre-diagnosis phase was lower than the 0.64 (0.50, 0.82) for other screened women. The overall OR of 0.59 approximated 0.70 when corrected for the screening self-selection bias observed in five randomized trials. However, multivariable analysis of survey data did not indicate a lower prevalence of breast-cancer risk factors among BreastScreen participants, suggesting that this correction may be inappropriate. CONCLUSIONS: Participation in screening was associated with a breast-cancer mortality reduction of between 30 and 41%, depending on assumptions about screening self-selection bias. A downward mortality risk by recency of last screen prior to cancer diagnosis, and frequency of recent screening, is consistent with a screening effect.

The LIM-only factor LMO4 regulates expression of the BMP7 gene through an HDAC2-dependent mechanism, and controls cell proliferation and apoptosis of mammary epithelial cells.

The nuclear LIM-only protein 4 (LMO4) is upregulated in breast cancer, especially estrogen receptor-negative tumors, and its overexpression in mice leads to hyperplasia and tumor formation. Here, we show that deletion of LMO4 in the mammary glands of mice leads to impaired lobuloalveolar development due to decreased epithelial cell proliferation. With the goal of discovering potential LMO4-target genes, we also developed a conditional expression system in MCF-7 cells for both LMO4 and a dominant negative (DN) form of its co-regulator, cofactor of LIM domains (Clim/Ldb/Nli). We then used DNA microarrays to identify genes responsive to LMO4 and DN-Clim upregulation. One of the genes common to both data sets was bone morphogenic protein 7 (BMP7), whose expression is also significantly correlated with LMO4 transcript levels in a large dataset of human breast cancers, suggesting that BMP7 is a bona fide target gene of LMO4 in breast cancer. Inhibition of BMP7 partially blocks the effects of LMO4 on apoptosis, indicating that BMP7 mediates at least some functions of LMO4. Gene transfer studies show that LMO4 regulates the BMP7 promoter, and chromatin immunoprecipitation studies show that LMO4 and its cofactor Clim2 are recruited to the BMP7 promoter. Furthermore, we demonstrate that HDAC2 recruitment to the BMP7 promoter is inhibited by upregulation of LMO4 and that HDAC2 knockdown upregulates the promoter. These studies suggest a novel mechanism of action for LMO4: LMO4, Clim2 and HDAC2 are part of a transcriptional complex, and increased LMO4 levels can disrupt the complex, leading to decreased HDAC2 recruitment and increased promoter activity.

Feasibility study on the MammoSite in early-stage breast cancer: initial experience.

The aims of this study were to evaluate the feasibility, practicality, efficacy and safety of the delivery of accelerated partial breast irradiation using the MammoSite for the boost phase. Six patients aged 53-69 years with stage T1N0, T2N0, Grade I-II invasive ductal carcinoma received 9-10 Gy prescribed at 1 cm from the MammoSite balloon surface in two fractions of 4.5-5 Gy 6 h apart. The MammoSite was inserted 20-37 days postoperatively. External beam radiation therapy to the whole breast commenced 1-5 days after accelerated partial breast irradiation. The maximum skin dose ranged from 3 to 9 Gy. The skin-cavity distance ranged from 7 to 19 mm. Local discomfort resolved as the scar healed spontaneously within 3-5 days. No Grade III or higher acute toxicity or local infection was recorded. The ease of insertion and accuracy of dosimetry makes the MammoSite suitable for use in properly selected women with early-stage breast cancer in a trial setting.

Uteroplacental insufficiency affects epigenetic determinants of chromatin structure in brains of neonatal and juvenile IUGR rats.

Intrauterine growth retardation (IUGR) increases the risk of neuroendocrine reprogramming. In the rat, IUGR leads to persistent changes in cerebral mRNA levels. This suggests lasting alterations in IUGR cerebral transcriptional regulation, which may result from changes in chromatin structure. Candidate nutritional triggers for these changes include altered cerebral zinc and one-carbon metabolite levels. We hypothesized that IUGR affects cerebral chromatin structure in neonatal and postnatal rat brains. Rats were rendered IUGR by bilateral uterine artery ligation; controls (Con) underwent sham surgery. At day of life 0 (d0), we measured cerebral DNA methylation, histone acetylation, expression of chromatin-affecting enzymes, and cerebral levels of one-carbon metabolites and zinc. At day of life 21 (d21), we measured cerebral DNA methylation and histone acetylation, as well as the caloric content of Con and IUGR rat breast milk. At d0, IUGR significantly decreased genome-wide and CpG island methylation, as well as increased histone 3 lysine 9 (H3/K9) and histone 3 lysine 14 (H3/K14) acetylation in the hippocampus and periventricular white matter, respectively. IUGR also decreased expression of the chromatin-affecting enzymes DNA methyltransferase 1 (DNMT1), methyl-CpG binding protein 2 (MeCP2), and histone deacetylase (HDAC)1 in association with increased cerebral levels of zinc. In d21 female IUGR rats, cerebral CpG DNA methylation remained lower, whereas H3/K9 and H3/K14 hyperacetylation persisted in hippocampus and white matter, respectively. In d21 male rats, IUGR decreased acetylation of H3/K9 and H3/K14 in these respective regions compared with controls. Despite these differences, caloric, fat, and protein content were similar in breast milk from Con and IUGR dams. We conclude that IUGR results in postnatal changes in cerebral chromatin structure and that these changes are sex specific.

Leprosy in Britain: 50 years experience in Liverpool.

BACKGROUND: Leprosy is a chronic infection that presents with varying dermal and neurological symptoms, and which can lead to extensive disability and morbidity, often with accompanying social stigma. AIM: To review the patients presenting to the Liverpool School of Tropical Medicine (LSTM) between 1946 and 2003, looking specifically at country of birth and of infection, details of clinical presentation, diagnosis, management and reactions. DESIGN: Retrospective record review. METHODS: We retrieved all available clinical records for patients seen between 1946 and 2003 (n = 50), consisting of letters, hospital and LSTM casenotes, and some radiographs and photographs. Any history of tuberculosis or diabetes was recorded. RESULTS: Most patients (64%) were born in the Indian subcontinent, and most were thought to have contracted the disease there (62%). Features at presentation included anaesthetic skin lesions in 19 (36%), hypopigmentation in 15 (30%), and peripheral nerve enlargement in 25 (50%). Diagnoses were made by a combination of clinical data and biopsy (60%), and slit skin smears were positive for acid-fast bacilli in 61% of multibacillary patients. Initial presentation was with a leprosy reaction in five cases (10%), and reactions were documented in 42% of all patients. Treatments were varied, progressing from traditional Eastern medicine to the WHO-approved multidrug therapy in use today, with prophylaxis for children and close contacts. DISCUSSION: Leprosy remains an important diagnosis to consider in patients with a history of work or travel in the tropics, and is a diagnosis with far-reaching medical, social and emotional consequences.

Awareness and use of smoking cessation treatments among diabetic patients.

AIMS: To investigate awareness of pharmacotherapeutic aids to smoking cessation in diabetic cigarette smokers. METHODS: A structured questionnaire-based interview was held by a research nurse individually with consecutively attending cigarette smokers. RESULTS: Of 597 diabetic patients attending a routine clinic, 100 (17%) were current cigarette smokers. Mean (+/-sd) age was 58+/-11 years, 58% were male, and 96% Type 2 diabetic patients. Mean daily cigarette consumption was 16/day, for a mean duration of 35 years. There were 34% who had never heard of nicotine replacement therapy (NRT), and of those who had, only 49% considered it safe with diabetes. Bupropion (Zyban) was unknown to 46%, and of those who knew of it, 39% thought it unsafe in diabetic patients. Only 31% of the group had been previously offered NRT, and 14% bupropion. The NHS Quitline was known of by 84%, but only 8% had used it. CONCLUSIONS: Cigarette smokers with diabetes have poor uptake, awareness and knowledge of NRT and bupropion as aids to smoking cessation. They comprise a high-risk group, for large and small vessel disease, and these findings are therefore of concern. More active education and support for these patients by medical and nursing staff is needed.

A British Second World War veteran with disseminated strongyloidiasis.

A case is described of a 78-year-old British veteran of the Second World War (1939-45) who was stationed in Southeast Asia and who developed a recurrent pneumonia with blood eosinophilia. He was treated with steroids, and eventually died with a severe Pseudomonas pneumonia. Just prior to death, larvae of Strongyloides stercoralis were identified in his sputum, and a specific serum ELISA test was later positive. At autopsy no other organs were involved, but bronchoalveolar carcinoma was found. Longstanding (57 years) chronic strongyloidiasis in a veteran who served in Southeast Asia but who was not a prisoner of war is very unusual. The pattern of dissemination was also not that of a true hyperinfection syndrome, and the case demonstrates the continued need for diagnostic vigilance amongst former soldiers who were based in the Far East.

Diabetes in a high secure hospital.

AIMS: To determine the prevalence of diabetes mellitus and its possible causes and to assess its control in a high secure hospital. METHODS: A cross sectional survey and a prospective cohort study were conducted. The cross sectional survey included 408 patients admitted under the Mental Health Act, and the prospective study included 22 patients with known diabetes followed up for 24 months. The outcome measures evaluated were drug treatment, status of microvascular and macrovascular complications, glycated haemoglobin, and body mass index. RESULTS: In the cross sectional survey, 35 out of 408 patients (8.6%; 95% confidence interval 5.9% to 11.3%) had known diabetes, and all of these had type 2 diabetes. Obesity, cigarette smoking, schizophrenia, and antipsychotic drug use were frequent, and weight gain was common after hospital admission. Glycaemic control was variable, and, although a majority of patients were above recommended treatment targets, control remained stable over the follow up period. CONCLUSIONS: Type 2 diabetes was common in this hospital. Both its prevalence and the suboptimal glycaemic control in some patients probably relate to sedentary life, dietary factors, smoking, and perhaps widespread use of antipsychotic drugs. However, regular multidisciplinary input enabled most patients to maintain relatively stable glycaemic control, with good control of blood pressure and lipids, at levels similar to those seen in community and hospital diabetic clinics. Further modification of lifestyle risk factors is probably needed to reduce the prevalence and impact of diabetes in this patient group.

Surgeons-Take care of pre and par-Surgical rituals.

Surgeons must become convinced regarding the strict adherence to a meticulous operating room ritual and an equally careful aseptic technique for the pre and post opcrative care Surgeons have lived with the risk of contracting potentially fatal vual diseases for the last three decades The author reviens here, the hazards of blood exposure and the measures that ought to be taken.

Characteristics of Type 1 diabetes of over 50 years duration (the Golden Years Cohort).

BACKGROUND: Type 1 diabetes mellitus is associated with high levels of premature morbidity and mortality. Prolonged survival is possible, however, and some patients appear to be protected from the long-term complications of this condition. METHODS: Diabetes UK awards medals to patients who have had Type 1 diabetes for 50 years or more. By examining medal-holders, we have established the clinical and biochemical features of a group of 400 subjects (54% male) with Type 1 diabetes of long duration. RESULTS: Mean age of the subjects was 68.9 years and mean age-at-onset of diabetes 13.7 years. Features of long duration diabetes in this cohort include normal body mass (mean BMI 25.0 kg m-2), low insulin dose (mean 0.52 units kg-2) and greatly elevated HDL-cholesterol (mean 1.84 mmol/l). Mean HbA1c was 7.6% (normal range 3.8-5.0%) and no patient had a normal HbA1c at the time of venesection. As a group, they have long-lived parents and consume moderate amounts of alcohol. Medical contact has often been sporadic. A significant proportion (29%) were taking anti-hypertensive medication. Screening for micro- and macroalbuminuria was positive in 35.7%. CONCLUSIONS: Patients with long-duration (> 50 years) Type 1 diabetes are relatively protected from clinical diabetic nephropathy and large vessel disease; our data are consistent with protection possibly being genetically determined in part via elevated HDL-cholesterol levels. An abnormal urinary albumin/creatinine ratio is common in these patients, despite their low risk of significant renal deterioration; this may have implications for microalbuminuria screening programmes.