Exploiting biological and physical determinants of radiotherapy toxicity to individualise treatment.

This is the final version of the article. It first appeared from the British Institute of Radiology via http://dx.doi.org/10.1259/bjr.20150172The recent advances in radiation delivery can improve tumour control probability and reduce treatment related toxicity. The use of intensity-modulated radiotherapy (IMRT) in particular can reduce normal tissue toxicity, an objective in its own right, and can allow safe dose escalation in selected cases. Ideally IMRT should be combined with image guidance to verify the position of the target, since patients, target and organs at risk can move day-to-day. Daily image guidance scans can be used to identify the position of normal tissue structures, and potentially to compute the daily delivered dose. Fundamentally, it is still the tolerance of the normal tissues which limits radiotherapy dose and therefore tumour control. However, the dose response relationships for both tumour and normal tissues are relatively steep, meaning that small dose differences can translate into clinically relevant improvements. Differences exist between individuals in the severity of toxicity experienced for a given dose of radiotherapy. Some of this difference may be the result of differences between the planned dose and the accumulated dose (DA). However, some may be due to intrinsic differences in radiosensitivity of the normal tissues between individuals. This field has been developing rapidly, with the demonstration of definite associations between genetic polymorphisms and variation in toxicity recently described. It might be possible to identify more resistant patients who would be suitable for dose escalation, as well as more sensitive patients for whom toxicity could be reduced or avoided. Daily differences in delivered dose have been investigated within the VoxTox research programme, using the rectum as an example organ at risk. In prostate cancer patients receiving curative radiotherapy, considerable daily variation in rectal position and dose can be demonstrated, although the median position matches the planning scan well. Overall, in 10 patients, the mean difference between planned and accumulated rectal equivalent uniform doses (EUDs) was -2.7 Gy (5%), and a dose reduction was seen in 7/10 cases. If dose escalation were performed to take rectal dose back to the planned level, this should increase the mean tumour control probability (TCP) (as biochemical progression-free survival) by 5%. Combining radiogenomics with individual estimates of DA might identify almost half of patients undergoing radical radiotherapy who might benefit from either dose escalation, suggesting improved tumour cure, or reduced toxicity, or both.JS is supported by Cancer Research UK through the Cambridge Cancer Centre. NGB is supported by the NIHR Cambridge Biomedical Research Centre. The VoxTox Research Programme is funded by Cancer Research UK

Prophylactic radiotherapy against heterotopic ossification following internal fixation of acetabular fractures: a comparative estimate of risk.

OBJECTIVE: Radiotherapy (RT) is effective in preventing heterotopic ossification (HO) around acetabular fractures requiring surgical reconstruction. We audited outcomes and estimated risks from RT prophylaxis, and alternatives of indometacin or no prophylaxis. METHODS: 34 patients underwent reconstruction of acetabular fractures through a posterior approach, followed by a 8-Gy single fraction. The mean age was 44 years. The mean time from surgery to RT was 1.1 days. The major RT risk is radiation-induced fatal cancer. The International Commission on Radiological Protection (ICRP) method was used to estimate risk, and compared with a method (Trott and Kemprad) specifically for estimating RT risk for benign disease. These were compared with risks associated with indometacin and no prophylaxis. RESULTS: 28 patients (82%) developed no HO; 6 developed Brooker Class I; and none developed Class II-IV HO. The ICRP method suggests a risk of fatal cancer in the range of 1 in 1000 to 1 in 10,000; the Trott and Kemprad method suggests 1 in 3000. For younger patients, this may rise to 1 in 2000; and for elderly patients, it may fall to 1 in 6000. The risk of death from gastric bleeding or perforation from indometacin is 1 in 180 to 1 in 900 in older patients. Without prophylaxis risk of death from reoperation to remove HO is 1 in 4000 to 1 in 30,000. CONCLUSION: These results are encouraging, consistent with much larger series and endorse our multidisciplinary management. Risk estimates can be used in discussion with patients. ADVANCES IN KNOWLEDGE: The risk from RT prophylaxis is small, it is safer than indometacin and substantially overlaps with the range for no prophylaxis.NGB is supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. JES is supported by Cancer Research UK through the Cambridge Cancer Centre.This is the accepted manuscript version. The final version is available from the BIR at http://www.birpublications.org/doi/abs/10.1259/bjr.20140398?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed&

Posttraumatic stress symptoms in young people with cancer and their siblings: results from a UK sample

Purpose: This study investigated levels of posttraumatic stress symptoms (PTSS) in children with cancer and their siblings from a British sample. It also examined aspects of the Ehlers and Clark model of posttraumatic stress disorder in the current population. Methods: Sixty participants (34 children with cancer and 26 siblings) aged between 8 and 18 years completed measures of PTSS, maladaptive appraisals, trauma-centered identity, perceived social support and family functioning. Results: Over a quarter of the sample scored above the clinical cutoff on the Impact of Events Scale-Revised. No differences were observed between patients and siblings with respect to levels of PTSS. Maladaptive appraisals and age were found to account for unique variance in levels of PTSS for the overall sample. Conclusions: Rates of PTSS in the sample were relatively high. Support was found for aspects of the Ehlers and Clark model in explaining PTSS for the current population

Delivered dose can be a better predictor of rectal toxicity than planned dose in prostate radiotherapy

$\textbf{BACKGROUND AND PURPOSE}$: For the first time, delivered dose to the rectum has been calculated and accumulated throughout the course of prostate radiotherapy using megavoltage computed tomography (MVCT) image guidance scans. Dosimetric parameters were linked with toxicity to test the hypothesis that delivered dose is a stronger predictor of toxicity than planned dose. $\textbf{MATERIAL AND METHODS}$: Dose-surface maps (DSMs) of the rectal wall were automatically generated from daily MVCT scans for 109 patients within the VoxTox research programme. Accumulated-DSMs, representing total delivered dose, and planned-DSMs, from planning CT data, were parametrised using Equivalent Uniform Dose (EUD) and 'DSM dose-width', the lateral dimension of an ellipse fitted to a discrete isodose cluster. Associations with 6 toxicity endpoints were assessed using receiver operator characteristic curve analysis. $\textbf{RESULTS}$: For rectal bleeding, the area under the curve (AUC) was greater for accumulated dose than planned dose for DSM dose-widths up to 70Gy. Accumulated 65Gy DSM dose-width produced the strongest spatial correlation (AUC 0.664), while accumulated EUD generated the largest AUC overall (0.682). For proctitis, accumulated EUD was the only reportable predictor (AUC 0.673). Accumulated EUD was systematically lower than planned EUD. $\textbf{CONCLUSIONS}$: Dosimetric parameters extracted from accumulated DSMs have demonstrated stronger correlations with rectal bleeding and proctitis, than planned DSMs.LEAS is supported by the University of Cambridge W D Armstrong Trust Fund; AMB, MRR and KH are supported by the VoxTox Programme Grant, which is funded by Cancer Research UK (CRUK); JES was supported by a CRUK Clinical Research Fellowship; DJN is supported by a CRUK Clinical Research Fellowship; NGB is Principle Investigator of the CRUK VoxTox Programme and is supported by the NIHR Cambridge Biomedical Research Centre

The masculine logic of DDR and SSR in the Rwanda Defence Force

Since the 1994 genocide and civil war, the Rwandan government has implemented an externally funded Demobilisation, Demilitarisation and Reintegration (DDR)/Security Sector Reform (SSR) program culminating in the consolidation of armed groups into a new, professionalised Rwanda Defence Force (RDF). Feminists argue that DDR-SSR initiatives that exclude combatant women and girls or ignore gendered security needs fail to transform the political conditions that led to conflict. Less attention has been paid to how gendered relations of power play out through gender sensitive DDR and SSR initiatives that seek to integrate women and transform hyper-masculine militarised masculinities. This article investigates how Rwanda’s DDR-SSR program is governed by an oppressive masculine logic. Drawing on critical studies on men and masculinities and feminist work on peacebuilding, myths and the politics of belonging, it is argued that Rwanda’s locally-owned DDR-SSR program places the military and militarisation at the centre of the nation-building program. Through various ‘boundary construction’ practices, the Rwandan government attempts to stabilise the post-1994 gender order and entrench the hegemony of a new militarised masculinity in Rwandan society. The case study draws on field research conducted in 2014 and 2015 and a discourse analysis of RDF historical accounts, policy documents and training materials

Courtship Initiation Is Stimulated by Acoustic Signals in Drosophila melanogaster

Finding a mating partner is a critical task for many organisms. It is in the interest of males to employ multiple sensory modalities to search for females. In Drosophila melanogaster, vision is thought to be the most important courtship stimulating cue at long distance, while chemosensory cues are used at relatively short distance. In this report, we show that when visual cues are not available, sounds produced by the female allow the male to detect her presence in a large arena. When the target female was artificially immobilized, the male spent a prolonged time searching before starting courtship. This delay in courtship initiation was completely rescued by playing either white noise or recorded fly movement sounds to the male, indicating that the acoustic and/or seismic stimulus produced by movement stimulates courtship initiation, most likely by increasing the general arousal state of the male. Mutant males expressing tetanus toxin (TNT) under the control of Gr68a-GAL4 had a defect in finding active females and a delay in courtship initiation in a large arena, but not in a small arena. Gr68a-GAL4 was found to be expressed pleiotropically not only in putative gustatory pheromone receptor neurons but also in mechanosensory neurons, suggesting that Gr68a-positive mechanosensory neurons, not gustatory neurons, provide motion detection necessary for courtship initiation. TNT/Gr68a males were capable of discriminating the copulation status and age of target females in courtship conditioning, indicating that female discrimination and formation of olfactory courtship memory are independent of the Gr68a-expressing neurons that subserve gustation and mechanosensation. This study suggests for the first time that mechanical signals generated by a female fly have a prominent effect on males' courtship in the dark and leads the way to studying how multimodal sensory information and arousal are integrated in behavioral decision making

Concomitant Active Tuberculosis Prolongs Survival in Non-Small Cell Lung Cancer: A Study in a Tuberculosis-Endemic Country

BACKGROUND: Adjuvant tumor cell vaccine with chemotherapy against non-small cell lung cancer (NSCLC) shows limited clinical response. Whether it provokes effective cellular immunity in tumor microenvironment is questionable. Concomitant active tuberculosis in NSCLC (TBLC) resembles locoregional immunotherapy of tumor cell vaccine; thus, maximally enriches effective anti-tumor immunity. This study compares the survival and immunological cell profile in TBLC over NSCLC alone. METHODS: Retrospective review of NSCLC patients within 1-year-period of 2007 and follow-up till 2010. RESULTS: A total 276 NSCLC patients were included. The median survival of TBLC is longer than those of NSCLC alone (11.6 vs. 8.8 month, p<0.01). Active tuberculosis is an independent predictor of better survival with HR of 0.68 (95% CI, 0.48 ~ 0.97). Squamous cell carcinoma (SCC) (55.8 vs. 31.7%, p<0.01) is a significant risk factor for NSCLC with active TB. The median survival of SCC with active tuberculosis is significantly longer than adenocarcinoma or undetermined NSCLC with TB (14.2 vs. 6.6 and 2.8 months, p<0.05). Active tuberculosis in SCC increases the expression of CD3 (46.4 ± 24.8 vs. 24.0 ± 16.0, p<0.05), CXCR3 (35.1 ± 16.4 vs. 19.2 ± 13.3, p<0.01) and IP-10 (63.5 ± 21.9 vs. 35.5 ± 21.0, p<0.01), while expression of FOXP3 is decreased (3.5 ± 0.5 vs. 13.3 ± 3.7 p<0.05, p<0.05). Survival of SCC with high expression of CD3 (12.1 vs. 3.6 month, p<0.05) and CXCR3 (12.1 vs. 4.4 month, p<0.05) is longer than that with low expression. CONCLUSIONS: Active tuberculosis in NSCLC shows better survival outcome. The effective T lymphocyte infiltration in tumor possibly underlies the mechanism. Locoregional immunotherapy of tumor cell vaccine may deserve further researches

Reduced Myelin Basic Protein and Actin-Related Gene Expression in Visual Cortex in Schizophrenia

Most brain gene expression studies of schizophrenia have been conducted in the frontal cortex or hippocampus. The extent to which alterations occur in other cortical regions is not well established. We investigated primary visual cortex (Brodmann area 17) from the Stanley Neuropathology Consortium collection of tissue from 60 subjects with schizophrenia, bipolar disorder, major depression, or controls. We first carried out a preliminary array screen of pooled RNA, and then used RT-PCR to quantify five mRNAs which the array identified as differentially expressed in schizophrenia (myelin basic protein [MBP], myelin-oligodendrocyte glycoprotein [MOG], β-actin [ACTB], thymosin β-10 [TB10], and superior cervical ganglion-10 [SCG10]). Reduced mRNA levels were confirmed by RT-PCR for MBP, ACTB and TB10. The MBP reduction was limited to transcripts containing exon 2. ACTB and TB10 mRNAs were also decreased in bipolar disorder. None of the transcripts were altered in subjects with major depression. Reduced MBP mRNA in schizophrenia replicates findings in other brain regions and is consistent with oligodendrocyte involvement in the disorder. The decreases in expression of ACTB, and the actin-binding protein gene TB10, suggest changes in cytoskeletal organisation. The findings confirm that the primary visual cortex shows molecular alterations in schizophrenia and extend the evidence for a widespread, rather than focal, cortical pathophysiology

What about N? A methodological study of sample-size reporting in focus group studies

<p>Abstract</p> <p>Background</p> <p>Focus group studies are increasingly published in health related journals, but we know little about how researchers use this method, particularly how they determine the number of focus groups to conduct. The methodological literature commonly advises researchers to follow principles of data saturation, although practical advise on how to do this is lacking. Our objectives were firstly, to describe the current status of sample size in focus group studies reported in health journals. Secondly, to assess whether and how researchers explain the number of focus groups they carry out.</p> <p>Methods</p> <p>We searched PubMed for studies that had used focus groups and that had been published in open access journals during 2008, and extracted data on the number of focus groups and on any explanation authors gave for this number. We also did a qualitative assessment of the papers with regard to how number of groups was explained and discussed.</p> <p>Results</p> <p>We identified 220 papers published in 117 journals. In these papers insufficient reporting of sample sizes was common. The number of focus groups conducted varied greatly (mean 8.4, median 5, range 1 to 96). Thirty seven (17%) studies attempted to explain the number of groups. Six studies referred to rules of thumb in the literature, three stated that they were unable to organize more groups for practical reasons, while 28 studies stated that they had reached a point of saturation. Among those stating that they had reached a point of saturation, several appeared not to have followed principles from grounded theory where data collection and analysis is an iterative process until saturation is reached. Studies with high numbers of focus groups did not offer explanations for number of groups. Too much data as a study weakness was not an issue discussed in any of the reviewed papers.</p> <p>Conclusions</p> <p>Based on these findings we suggest that journals adopt more stringent requirements for focus group method reporting. The often poor and inconsistent reporting seen in these studies may also reflect the lack of clear, evidence-based guidance about deciding on sample size. More empirical research is needed to develop focus group methodology.</p

History of clinical transplantation

The emergence of transplantation has seen the development of increasingly potent immunosuppressive agents, progressively better methods of tissue and organ preservation, refinements in histocompatibility matching, and numerous innovations is surgical techniques. Such efforts in combination ultimately made it possible to successfully engraft all of the organs and bone marrow cells in humans. At a more fundamental level, however, the transplantation enterprise hinged on two seminal turning points. The first was the recognition by Billingham, Brent, and Medawar in 1953 that it was possible to induce chimerism-associated neonatal tolerance deliberately. This discovery escalated over the next 15 years to the first successful bone marrow transplantations in humans in 1968. The second turning point was the demonstration during the early 1960s that canine and human organ allografts could self-induce tolerance with the aid of immunosuppression. By the end of 1962, however, it had been incorrectly concluded that turning points one and two involved different immune mechanisms. The error was not corrected until well into the 1990s. In this historical account, the vast literature that sprang up during the intervening 30 years has been summarized. Although admirably documenting empiric progress in clinical transplantation, its failure to explain organ allograft acceptance predestined organ recipients to lifetime immunosuppression and precluded fundamental changes in the treatment policies. After it was discovered in 1992 that long-surviving organ transplant recipient had persistent microchimerism, it was possible to see the mechanistic commonality of organ and bone marrow transplantation. A clarifying central principle of immunology could then be synthesized with which to guide efforts to induce tolerance systematically to human tissues and perhaps ultimately to xenografts