Improvement in Dysphagia Outcomes Following Clinical Target Volume Reduction in the De-ESCALaTE Study.

AIMS: The De-ESCALaTE study showed an overall survival advantage for the administration of synchronous cisplatin chemotherapy with radiotherapy in low-risk oropharyngeal cancer when compared with synchronous cetuximab. During the trial, a radiotherapy quality assurance protocol amendment permitted centres to swap from the original radiotherapy contouring protocol (incorporating the whole oropharynx into the high-dose clinical target volume (CTV); anatomical protocol) to a protocol that incorporated the gross tumour volume with a 10 mm margin into the CTV (volumetric protocol). The purpose of this study was to examine both toxicity and tumour control related to this protocol amendment. MATERIALS AND METHODS: Overall survival and recurrence at 2 years were used to compare tumour control in the two contouring cohorts. For toxicity, the cohorts were compared by both the number of severe (grades 3-5) and all grades acute and late toxicities. In addition, quality of life and swallowing were compared using EORTC-C30 and MD Anderson Dysphagia Inventory, respectively. RESULTS: Of 327 patients included in this study, 185 were contoured according to the anatomical protocol and 142 by the volumetric protocol. The two cohorts were well balanced, with the exception of significantly more patients in the anatomical cohort undergoing prophylactic feeding tube insertion (P < 0.001). With a minimum of 2 years of follow-up there was no significant difference in overall survival or recurrence between the two contouring protocols. Similarly, there was no significant difference in the rate of reported severe or all grades acute or late toxicity and no sustained significant difference in quality of life. However, there was a significant difference in favour of volumetric contouring in several domains of the MD Anderson Dysphagia Inventory questionnaire at 1 year, which persisted to 2 years in the dysphagia functional (P = 0.002), dysphagia physical (P = 0.009) and dysphagia overall function (P = 0.008) domains. CONCLUSION: In the context of the unplanned post-hoc analysis of a randomised trial, measurable improvement in long-term dysphagia has been shown following a reduction in the CTV. Further reductions in the CTV should be subject to similar scrutiny within the confines of a prospective study.

First-in-human study of the safety and efficacy of TOL101 induction to prevent kidney transplant rejection.

TOL101 is a murine IgM mAb targeting the αß TCR. Unlike other T cell targets, the αß TCR has no known intracellular signaling domains and may provide a nonmitogenic target for T cell inactivation. We report the 6-month Phase 2 trial data testing TOL101 in kidney transplantation. The study was designed to identify a dose that resulted in significant CD3 T cell modulation (<25 T cell/mm(3) ), to examine the safety and tolerability of TOL101 and to obtain preliminary efficacy information. Thirty-six patients were enrolled and given 5-10 daily doses of TOL101; 33 patients completed dosing, while three discontinued after two doses due to a self-limiting urticarial rash. Infusion adjustments, antihistamines, steroids and dose escalation of TOL101 reduced the incidence of the rash. Doses of TOL101 above 28 mg resulted in prolonged CD3 modulation, with rapid recovery observed 7 days after therapy cessation. There were no cases of patient or graft loss. Few significant adverse events were reported, with one nosocomial pneumonia. There were five biopsy-confirmed acute cellular rejections (13.9%); however, no donor-specific antibodies were detected. Overall TOL101 was well-tolerated, supporting continued clinical development using the dose escalating 21-28-42-42-42 mg regimen.

ASPIRE registry: assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre.

Pulmonary hypertension (PH) is a heterogeneous condition. To date, no registry data exists reflecting the spectrum of disease across the five diagnostic groups encountered in a specialist referral centre. Data was retrieved for consecutive, treatment-naïve cases diagnosed between 2001 and 2010 using a catheter-based approach. 1,344 patients were enrolled, with a mean follow-up of 2.9 yrs. The 3-yr survival was 68% for pulmonary arterial hypertension (PAH), 73% for PH associated with left heart disease, 44% for PH associated with lung disease (PH-lung), 71% for chronic thromboembolic PH (CTEPH) and 59% for miscellaneous PH. Compared with PAH, survival was inferior in PH-lung and superior in CTEPH (p<0.05). Multivariate analysis demonstrated that diagnostic group independently predicted survival. Within PAH, Eisenmenger's survival was superior to idiopathic PAH, which was superior to PAH associated with systemic sclerosis (p<0.005). Within PH-lung, 3-yr survival in sleep disorders/alveolar hypoventilation (90%) was superior to PH-lung with chronic obstructive pulmonary disease (41%) and interstitial lung disease (16%) (p<0.05). In CTEPH, long-term survival was best in patients with surgically accessible disease undergoing pulmonary endarterectomy. In this large registry of consecutive, treatment-naïve patients identified at a specialist PH centre, outcomes and characteristics differed between and within PH groups. The current system of classification of PH has prognostic value even when adjusted for age and disease severity, emphasising the importance of systematic evaluation and precise classification.

Research-intensive cancer care in the NHS in the UK.

In the late 1990 s, in response to poor national cancer survival figures, government monies were invested to enhance recruitment to clinical cancer research. Commencing with England in 2001 and then rolling out across all four countries, a network of clinical cancer research infrastructure was created, the new staff being linked to existing clinical care structures including multi-disciplinary teams. In parallel, a UK-wide co-ordination of cancer research funders driven by the 'virtual' National Cancer Research Institute, combined to create a 'whole-system approach' linking research funders, researchers and NHS clinicians all working to the same ends. Over the next 10 years, recruitment to clinical trials and other well-designed studies, increased 4-fold, reaching 17% of the incident cancer population, the highest national rate world-wide. The additional resources led to more studies opened, and more patients recruited across the country, for all types of cancers and irrespective of additional clinical research staff in some hospitals. In 2006, a co-ordinated decision was made to increasingly focus on randomized trials, leading to increased recruitment, without any fall-off in accrual to non-randomized and observational studies. The National Cancer Research Network has supported large successful trials which are changing clinical practice in many cancers.

Strengthening clinical cancer research in the United Kingdom.

BACKGROUND: In 1999, 270,000 cases of cancer were registered in the United Kingdom, placing a large burden on the NHS. Cancer outcome data in 1999 suggested that UK survival rates were poorer than most other European countries. In the same year, a Department of Health review noted that clinical trials accrual was poor (<3.5% of incident cases) and hypothesised that increasing research activity might improve outcomes and reduce the variability of outcomes across England. Thus, the National Cancer Research Network (NCRN) was established to increase participation in cancer clinical research. METHODS: The NCRN was established in 2001 to provide a robust infrastructure for cancer clinical research and improvements in patient care. Remit of NCRN is to coordinate, support and deliver cancer clinical research through the provision of research support staff across England. The NCRN works closely with similar networks in Scotland, Wales and the Northern Ireland. A key aim of NCRN is to improve the speed of research and this was also assessed by comparing the speed of study delivery of a subset of cancer studies opening before and after NCRN was established. RESULTS: Patient recruitment increased through NCRN, with almost 32,000 (12% of annual incident cases) cancer patients being recruited each year. Study delivery has improved, with more studies meeting the recruitment target - 74% compared with 39% before NCRN was established. CONCLUSION: The coordinated approach to cancer clinical research has demonstrated increased accrual, wide participation and successful trial delivery, which should lead to improved outcomes and care.

Adjuvant trastuzumab in routine clinical practice and the impact of cardiac monitoring guidelines on treatment delivery.

Trastuzumab delivery and changes in left ventricular ejection fraction (LVEF) in 110 patients receiving adjuvant trastuzumab in routine practice are investigated. The potential impact of new, less stringent UK cardiac monitoring guidelines is examined. 86 patients (78%) completed trastuzumab on schedule. 11 (10%) completed treatment despite delay(s) to allow LVEF recovery, 7 (6%) discontinued trastuzumab because of insufficient LVEF recovery, 2 (2%) of whom developed symptomatic cardiotoxicity. 6 (5%) discontinued trastuzumab for non-cardiac reasons. With the newer guidelines, the value of LVEF lower limit of normal is important in determining the proportion of patients who require angiotensin-converting enzyme inhibitors (ACEIs) and cardiology referral: up to 100% could potentially complete trastuzumab on schedule with up to 60% receiving ACEIs and 25% requiring cardiology referral. Adjuvant trastuzumab was well tolerated overall. The new guidelines potentially allow more patients to complete trastuzumab on schedule but require higher levels of cardiological intervention.

Should we routinely offer a second admission for radioiodine to patients with high-risk differentiated thyroid cancer?

AIMS: To assess whether an elective second admission for radioiodine is useful for patients with high-risk differentiated thyroid cancer (DTC). MATERIALS AND METHODS: A retrospective analysis was carried out on 47 high-risk DTC patients treated with a second admission for radioiodine at our centre during the 2007-2008 period. RESULTS: In 21 patients (45%), the surgeon described an incomplete resection. Twenty-six (55%) had surgical macroscopic complete resection, but cancer cells at the margin of excision histologically. Overall, at the second admission for radioiodine, 27 patients (57%) had a normal post-treatment scan and undetectable thyroid-stimulating hormone (TSH) stimulated thyroglobulin. Twenty patients (43%) had raised stimulated thyroglobulin at second admission for radioiodine, of whom only six (13%) had abnormal uptake (>0.1%) on the post-treatment scan. CONCLUSIONS: A second admission for radioiodine could have been avoided in most patients. Instead, information from stimulated thyroglobulin and a diagnostic radioiodine scan would have been sufficient to guide further management. This study also provides interesting outcome data on incompletely resected DTC.

Orbital apex lesion due to Aspergillosis presenting in immunocompetent patients without apparent sinus disease.

We present two cases in which Aspergillus infection was identified at a late stage in the clinical evaluation as the cause for a painful, progressive and indolent orbital apex syndrome in the absence of any clinical or radiological sign of sinus involvement. Surgical investigation was undertaken with serious subsequent morbidity. Although treatment is often satisfactory, neurological outcome is without exception poor. A review of the literature has revealed that the risk of such investigations is high, and advice is provided to readers which may allow avoidance of such complications in the future.

An evaluation of the effects of Tai Chi Chuan and Chi Kung training in patients with symptomatic heart failure: a randomised controlled pilot study.

OBJECTIVE: To study the effect of Tai Chi on exercise tolerance in patients with moderate heart failure. DESIGN: Randomised parallel group study balanced for baseline variables. SETTING: Cardiology Department, Royal Hallamshire Hospital. PATIENTS AND METHODS: 52 patients (42 men, mean age (68.9 years), range (46-90 years), and 10 women, mean age (70.0 years), range (58-82)) with chronic heart failure (New York Heart Association symptom class II-III) were studied. Patients were randomised to Tai Chi Chuan twice a week for 16 weeks or to standard medical care without exercise rehabilitation. MAIN OUTCOME MEASURES: The primary outcome measure was the change in the distance walked in the shuttle walk test. Secondary outcome measures were changes in symptom scores and quality of life indices. RESULTS: Objective measures of exercise tolerance did not improve significantly with Tai Chi, but patients having Tai Chi exercise had an improvement in symptom scores of heart failure measured by the Minnesota Living with Heart Failure Questionnaire (comparison of deltas, -2.4 control vs -14.9; p = 0.01), and depression scores measured by the SCL-90-R questionnaire (-2.9 vs -6.8; p = 0.12) compared with those patients in the control group. CONCLUSION: In patients with chronic heart failure, 16 weeks of Tai Chi training was safe, with no adverse exercise related problems. It was enjoyed by all taking part and led to significant improvements in symptoms and quality of life.

High incidence of late effects found in Hodgkin's lymphoma survivors, following recall for breast cancer screening.

Assessment of late effects in a cohort of female Hodgkin's lymphoma patients treated with mantle radiotherapy, identified from the DoH breast cancer screening recall showed high mortality and frequent undiagnosed abnormalities in tissues affected by radiotherapy. With increasing age, this patient group may suffer premature cardiac and respiratory morbidity.

Stereotypic behaviors in mice selectively bred for high and low methamphetamine-induced stereotypic chewing.

RATIONALE: At high doses, methamphetamine produces repetitive stereotypic behaviors, and the degree to which this occurs is heritable. OBJECTIVES: Mice of a B6D2F2 genetic background were selectively bred for four generations for high (HMA) and low (LMA) numbers of stereotyped chewing episodes measured for 1 min at 33 min post-injection following 10 mg/kg methamphetamine (changed to 7 mg/kg for the high line and 15 mg/kg for the low line in the third selected generation to avoid ceiling and floor effects, respectively). We sought to determine whether stereotypic behaviors other than number of repetitive chewing episodes were altered by the selective breeding process. METHODS: HMA and LMA mice of the third and fourth selected generations were tested for chewing stereotypy, for a number of other stereotypic behaviors previously observed in rodents, and for several other non-stereotypic responses to methamphetamine. Testing in the third selected generation was conducted by observing behaviors on videotape following 7 mg/kg methamphetamine. In the fourth selected generation, mice were also tested in automated activity monitors following 10 mg/kg methamphetamine and in climbing chimneys following 16 mg/kg methamphetamine. Dose-response curves with doses of 1, 2, 3.5, 7, 10, and 15 mg/kg methamphetamine were constructed for the most commonly observed behaviors. RESULTS: LMA mice, which exhibited low stereotyped chewing, exhibited high stereotyped circling and climbing, and the reverse was true for these behaviors for HMA mice. For most of the other behaviors measured, there were drug effects but no differences between selected lines. CONCLUSIONS: These results suggest that these three stereotyped behaviors, chewing, circling, and climbing, at least partly share the same mechanisms, and therefore are influenced by at least some of the same genes, since animals selectively bred for low methamphetamine-induced stereotyped chewing exhibited high amounts of circling and climbing when given methamphetamine. This also suggests that the other stereotypic behaviors that we measured do not occur by the same genetically determined mechanisms as stereotypic chewing.