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Carcinoma of Unknown Primary presenting primarily as hepatic metastases encompasses a dismal subgroup of tumors with a median survival of 5.9 months. Adenocarcinoma is the most common histological subtype identified upon biopsy and the primary tumor remains undetectable in the majority of cases despite extensive workup. It is important to have a validated and standardized algorithm to follow these tumors to avoid unnecessary tests, as the wishes and health status of the patient represent the principal concerns. The purpose of this paper is to briefly review the current literature on carcinoma of unknown primary with hepatic metastases and propose a standardized diagnostic approach.

The poultry industry in Tanzania has grown steadily over the past decade. We surveyed 121 chicken farming households along an intensification gradient from backyard to semi-intensive and intensive production systems based on rearing system and assumed purpose and poultry breed in the Iringa region. About 30% of households had more than one breed and/or rearing system combination. The subdivision of poultry systems was refined by adding the size of the flocks to highlight variation in scale of operations. On this basis we distinguished 3 main types: 1) subsistence small-scale free-range chicken production; 2) market-oriented small to medium scale semi-intensive and 3) small to medium-large scale intensive systems. ‘Intensification’ involves the transition from keeping indigenous chickens to improved dual-purpose and exotic breeds driven by greater productivity and potential for income generation. The more intensive the production system, the more the intensity and diversity of diseases identified by farmers as their main problem, which was partly attributed to the greater sensitivity of the improved breeds, poor veterinary measures, and the high chicken density facilitating disease spread. Based on the survey we constructed a problem tree to classify the underlying constraints and their interrelations, and to identify common root causes, based on which we propose practical solutions to improve chicken production. Development of medium-large scale systems is particularly constrained by a limited supply of 1-day-old chicks and theft. By contrast, intensification of small-scale systems is constrained by limited access to quality feed, vaccines and medicines, capital, and lack of a reliable market, partly due to the absence of farmer organization. These constraints can be addressed through formation of producer groups and promotion of outgrower and enterprise development models. Enterprise development appears to be the most promising business model for smallholder chicken farmers given that it allows farmers more freedom in decision-making and management while strengthening linkages with input suppliers and output markets to ensure a viable and profitable business.

Background: The interim analysis of the multicentre New EPOC trial in patients with resectable colorectal liver metastasis showed a significant reduction in progression-free survival in patients allocated to cetuximab plus chemotherapy compared with those given chemotherapy alone. The focus of the present analysis was to assess the effect on overall survival. Methods: New EPOC was a multicentre, open-label, randomised, controlled, phase 3 trial. Adult patients (aged ≥18 years) with KRAS wild-type (codons 12, 13, and 61) resectable or suboptimally resectable colorectal liver metastases and a WHO performance status of 0–2 were randomly assigned (1:1) to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done centrally with minimisation factors of surgical centre, poor prognosis cancer, and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m 2 administered intravenously over 2 h, l-folinic acid (175 mg flat dose administered intravenously over 2 h) or d,l-folinic acid (350 mg flat dose administered intravenously over 2 h), and fluorouracil bolus 400 mg/m 2 administered intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m 2 repeated every 2 weeks (regimen one), or oxaliplatin 130 mg/m 2 administered intravenously over 2 h and oral capecitabine 1000 mg/m 2 twice daily on days 1–14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m 2 intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given intravenously, 500 mg/m 2 every 2 weeks with regimen one and three or a loading dose of 400 mg/m 2 followed by a weekly infusion of 250 mg/m 2 with regimen two. The primary endpoint of progression-free survival was published previously. Secondary endpoints were overall survival, preoperative response, pathological resection status, and safety. Trial recruitment was halted prematurely on the advice of the Trial Steering Committee on Nov 1, 2012. All analyses (except safety) were done on the intention-to-treat population. Safety analyses included all randomly assigned patients. This trial is registered with ISRCTN, number 22944367. Findings: Between Feb 26, 2007, and Oct 12, 2012, 257 eligible patients were randomly assigned to chemotherapy with cetuximab (n=129) or without cetuximab (n=128). This analysis was carried out 5 years after the last patient was recruited, as defined in the protocol, at a median follow-up of 66·7 months (IQR 58·0–77·5). Median progression-free survival was 22·2 months (95% CI 18·3–26·8) in the chemotherapy alone group and 15·5 months (13·8–19·0) in the chemotherapy plus cetuximab group (hazard ratio [HR] 1·17, 95% CI 0·87–1·56; p=0·304). Median overall survival was 81·0 months (59·6 to not reached) in the chemotherapy alone group and 55·4 months (43·5–71·5) in the chemotherapy plus cetuximab group (HR 1·45, 1·02–2·05; p=0·036). There was no significant difference in the secondary outcomes of preoperative response or pathological resection status between groups. Five deaths might have been treatment-related (one in the chemotherapy alone group and four in the chemotherapy plus cetuximab group). The most common grade 3–4 adverse events reported were: neutrophil count decreased (26 [19%] of 134 in the chemotherapy alone group vs 21 [15%] of 137 in the chemotherapy plus cetuximab group), diarrhoea (13 [10%] vs 14 [10%]), skin rash (one [1%] vs 22 [16%]), thromboembolic events (ten [7%] vs 11 [8%]), lethargy (ten [7%] vs nine [7%]), oral mucositis (three [2%] vs 14 [10%]), vomiting (seven [5%] vs seven [5%]), peripheral neuropathy (eight [6%] vs five [4%]), and pain (six [4%] vs six [4%]). Interpretation: Although the addition of cetuximab to chemotherapy improves the overall survival in some studies in patients with advanced, inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of overall survival. Cetuximab should not be used in this setting. Funding: Cancer Research UK.

Summary Background 30-day mortality might be a useful indicator of avoidable harm to patients from systemic anticancer treatments, but data for this indicator are limited. The Systemic Anti-Cancer Therapy (SACT) dataset collated by Public Health England allows the assessment of factors affecting 30-day mortality in a national patient population. The aim of this first study based on the SACT dataset was to establish national 30-day mortality benchmarks for breast and lung cancer patients receiving SACT in England, and to start to identify where patient care could be improved. Methods In this population-based study, we included all women with breast cancer and all men and women with lung cancer residing in England, who were 24 years or older and who started a cycle of SACT in 2014 irrespective of the number of previous treatment cycles or programmes, and irrespective of their position within the disease trajectory. We calculated 30-day mortality after the most recent cycle of SACT for those patients. We did logistic regression analyses, adjusting for relevant factors, to examine whether patient, tumour, or treatment-related factors were associated with the risk of 30-day mortality. For each cancer type and intent, we calculated 30-day mortality rates and patient volume at the hospital trust level, and contrasted these in a funnel plot. Findings Between Jan 1, and Dec, 31, 2014, we included 23 228 patients with breast cancer and 9634 patients with non-small cell lung cancer (NSCLC) in our regression and trust-level analyses. 30-day mortality increased with age for both patients with breast cancer and patients with NSCLC treated with curative intent, and decreased with age for patients receiving palliative SACT (breast curative: odds ratio [OR] 1·085, 99% CI 1·040–1·132; p

The use of intensity-modulated radiotherapy (IMRT) in breast cancer reduces clinician-assessed breast tissue toxicity including fibrosis, telangectasia and sub-optimal cosmesis. Patient reported outcome measures (PROMs) are also important as they provide the patient's perspective. This longitudinal study reports on (a) the effect of forward planned field-in-field IMRT (∼simple IMRT) on PROMs compared to standard RT at 5 years after RT, (b) factors affecting PROMs at 5years after RT and (c) the trend of PROMs over 5 years of follow up.PROMs were assessed at baseline (pre-RT), 6, 24 and 60 months after completion of RT using global health (EORTC QLQ C30) and 4 breast symptom questions (BR23). Also, 4 breast RT-specific questions were included at 6, 24 and 60 months: change in skin appearance, firmness to touch, reduction in breast size and overall change in breast appearance since RT. The benefits of simple IMRT over standard RT at 5 years after RT were assessed using standard t-test for global health and logistic regression analysis for breast symptom questions and breast RT-specific questions. Clinical factors affecting PROMs at 5 years were investigated using a multivariate analysis. A repeated mixed model was applied to explore the trend over time for each of PROMs.(89%) 727/815, 84%, 81% and 61% patients completed questionnaires at baseline, 6, 24 and 60 months respectively. Patients reported worse toxicity for all four BR23 breast symptoms at 6 months, which then improved over time (p0.0001). They also reported improvement in skin appearance and breast hardness over time (p0.0001), with no significant change for breast shrinkage (p=0.47) and overall breast appearance (p=0.13). At 5years, PROMs assessments did not demonstrate a benefit for simple IMRT over standard radiotherapy. Large breast volume, young age, baseline surgical cosmesis and post-operative infection were the most important variables to affect PROMs.This study was unable to demonstrate the benefits of IMRT on PROMs at 5years. PROMs are influenced by non-radiotherapy factors and surgical factors should be optimised to improve patients' outcome. Only a small proportion of patients report moderate-severe breast changes post radiotherapy, with most PROMs improving over time. The difference in clinician assessment and PROMs outcome requires further investigation.

Purpose To evaluate the role of high-dose-rate endorectal brachytherapy (HDREBT) in the preoperative and definitive management of operable rectal cancer in terms of clinical outcomes and toxicities using a systematic review. Methods and Materials A review of published articles from January 1990 to December 2016 was conducted using the PubMed, Embase, and Scopus databases using the search terms “rectal” or “rectum” in combination with “brachytherapy,” “high dose rate,” “HDR,” and “endorectal.” Additional publications were identified by scanning references. Only studies published in English reporting clinical outcomes with ≥30 patients treated with HDREBT were included. Results The search identified 1688 articles, of which 22 met our inclusion criteria. Twelve studies were included in this systematic review. Following preoperative HDREBT with chemoradiation therapy (CRT), the pathologic complete response (pCR) rate ranged between 18% and 31% (weighted mean rate, 22.2%); R0 resection rate, between 80% and 99% (weighted mean rate, 95.5%); and sphincter-preservation rate, between 29% and 54% (weighted mean rate, 46.4%). The weighted mean 2-year progression-free survival and overall survival (OS) rates were 68.1% and 81.5%, respectively. After preoperative HDREBT alone, the pCR rate ranged between 10.4% and 27% (weighted mean rate, 23.8%), the R0 rate was 96.5% (1 study), and the sphincter-preservation rate ranged between 53.8% and 75.8% (weighted mean rate, 59.4%). The weighted mean 5-year progression-free survival and OS rates were 66.6% and 70.8%, respectively. There was only 1 study of HDREBT for nonsurgical management of rectal cancer, which reported a 2-year OS rate of 100%. Conclusions Preoperative HDREBT either alone or in combination with CRT may result in a better pCR but may not necessarily translate into better survival, which is similar to outcomes seen following preoperative CRT alone. There were significant variations across studies in terms of patient selection, treatment approaches, and evaluation of clinical outcomes, suggesting the need for an international consensus on the dosimetric parameters and techniques of HDREBT, timing and methods of response assessment, definitions and assessment of toxicities, and optimal timing of surgery before further prospective studies. Future studies should include evaluation of the role of HDREBT in the nonsurgical curative treatment of screen-detected early cancers and organ preservation in lower rectal cancers.

To review the current research on trauma-informed child-serving systems. Research on this topic, although sparse, is critically important because most children who come into contact with systems, including the child welfare and juvenile justice systems, have experienced at least one traumatic event.Very little research has actually been done on this topic area. Although it makes intuitive sense to integrate a trauma-informed approach into child-serving systems, much more research needs to be conducted in order to determine the efficacy of trauma-informed thinking in child-serving systems.A number of research studies have been conducted that focus on adults with co-occurring disorders who have received trauma-informed treatment. These results suggest that a 'trauma-informed' approach is a helpful and effective way to implement services. These same principles may be applied to work with children in order to create a 'trauma-informed child-serving system'. Twelve literature-supported and research-supported components of such a system are introduced in this review, ranging from the importance of specialized knowledge about trauma to trauma assessment and the value of trauma-informed policy.

INTRODUCTION The risk of ipsilateral breast tumour recurrence (IBTR) following breast conservation surgery (BCS) for invasive breast cancer (IBC) and radiotherapy is dependent on patient-, tumour- and treatment-related variables. In the Cambridge Breast Unit, breast conserving surgery has been performed with a target radial margin of 5 mm for IBC, in combination with 40-Gy hypofractionated (15 fractions) breast radiotherapy, since 1999. PATIENTS AND METHODS An audit was performed of cases treated between 1999 and 2004. A total of 563 patients underwent BCS for invasive breast cancer with 90.4% receiving radiotherapy (RT) and 60.4% of patients receiving boost RT (3 fractions of 3-Gy). RESULTS After a median follow-up of 58 months, five of the 563 (0.9%) patients developed IBTR. The 5-year actuarial IBTR rate was 1.1%. In terms of distant disease recurrence (DDR), 29 of the 563 (5.2%) had DDR during follow-up, giving a 5-year actuarial DDR rate of 5.4%. The 5-year breast cancer specific survival was 95%, with the poorer NPI groups having worse breast cancer specific survival (Log-rank, P < 0.0001). More importantly, patients with IBTR had a shorter breast cancer-specific survival than those who were IBTR-free (Log-rank, P < 0.0001). CONCLUSIONS Our treatment regimen, combining BCS with a 5-mm target margin and hypofractionated 40-Gy RT, results in an extremely low rate of IBTR, and compares favourably with the target IBTR rate of < 5% defined by the Association of Breast Surgeons (ABS) at BASO guidelines.

Introduction Accurate tumour bed (TB) localisation is a key requirement for the UK IMPORT (Intensity Modulated Partial Organ Radiotherapy) trial. We audited the value of titanium clips for TB localisation following breast conserving surgery (BCS) in breast radiotherapy (RT) planning. Patients and methods At surgery, paired clips were positioned around the TB as follows: 1. Medial, lateral, superior and inferior: half-way between skin and fascia; 2. Posterior: at the pectoral fascia; 3. Anterior: close to the suture line. Thirty consecutive patients with clips inserted were audited at the time of RT planning. Audit standards were set as follows: (i) 5/6 pairs of clips identified on RT planning computed tomography (CT) scan – 100%; (ii) possible clip migration: 50%. Inter- and intra-observer variability in clinician outlining of the TB was studied in a subset of 12 randomly selected patients to see if this impacted on positioning of radiotherapy field borders. Results Five or six pairs of clips were identified in all 30 cases. The TB could be successfully identified using CT seroma alone in only 8/30 (27%) patients. Clips were essential for the TB localisation of the other 22/30 (73%) patients. There was no evidence of clip migration. TB localisation led to modified RT field borders in 18/30 (60%) patients. Five of these patients had highly visible seromas, so the addition of clips modified field borders in 13/30 (43%) patients. Both inter- and intra-observer variability was reasonable and did not impact on positioning of radiotherapy field borders. Conclusion Titanium clips provide an accurate and reliable method of TB localisation following BCS. We anticipate that the audit results will lead to clips being adopted as best practice by the Association of Breast Surgeons (ABS) at BASO (British Association of Surgical Oncology).

To determine the incidence of capsular contracture (CC) requiring revisional surgery in patients receiving postoperative radiotherapy (RT) or no RT following mastectomy and immediate breast reconstruction.One hundred and seventy-eight immediate breast reconstructions performed at the Cambridge Breast Unit between 1.1.2001 and 31.12.2005 were identified. RT was delivered using a standard UK scheme of 40 Gray in 15 fractions over 3 weeks. The influence of hormones and chemotherapy as well as postoperative RT on time to development of severe CC after implant-based reconstruction was explored in univariate and multivariate analysis.One hundred and ten patients had implant-based reconstructions with a median follow-up of 51 months. In the RT group (41 patients), there were 8 patients with severe CC requiring revisional surgery, a crude rate of 19.5%, with actuarial rates of 0%, 5%, 5%, 21%, 30% and 30% at 1, 2, 3, 4, 5 and 6 years follow-up. In the unirradiated group, there were no cases of severe CC. This difference is highly significant (p0.001). Hormones and chemotherapy were not significantly associated with severe CC.This series showed a significantly higher rate of severe CC with postoperative RT. This finding has important clinical implications, when counselling patients for immediate breast reconstruction.

Background: Pyridoxine is frequently used to treat capecitabine-induced hand–foot syndrome (HFS), although the evidence of benefit is lacking. We performed a randomised placebo-controlled trial to determine whether pyridoxine could avoid the need for capecitabine dose modifications and improve outcomes. Methods: A total of 106 patients planned for palliative single-agent capecitabine (53 in each arm, 65%/ 35% colorectal/breast cancer) were randomised to receive either concomitant pyridoxine (50 mg po) or matching placebo three times daily. Results: Compared with placebo, pyridoxine use was associated with an increased rate of avoiding capecitabine dose modifications (37% vs 23%, relative risk 0.59, 95% CI 0.29, 1.20, P=0.15) and fewer grade 3/4 HFS-related adverse events (9% vs 17%, odds ratio 0.51, 95% CI 0.15–1.6, P=0.26). Use of pyridoxine did not improve response rate or progression-free survival. Conclusion: Pyridoxine may reduce the need for capecitabine dose modifications and the incidence of severe HFS, but does not impact on antitumour effect.

BACKGROUND AND PURPOSE:\ud Post mastectomy radiotherapy (PMRT) reduces loco-regional recurrence (LRR) and has been associated with survival benefit. It is recommended for patients with T3/T4 tumours and/or ⩾ 4 positive lymph nodes (LN). The role of PMRT in 1-3 positive LN and LN negative patients is contentious. The C-PMRT index has been designed for selecting PMRT patients, using independent prognostic factors for LRR. This study reports a 10 year experience using this index.\ud \ud MATERIALS AND METHODS:\ud The C-PMRT index was constructed using the following prognostic factors (a) number of positive LN/lymphovascular invasion, (b) tumour size (c) margin status and (d) tumour grade. Patients were categorised as high (H) risk, intermediate (I) risk and low (L) risk. PMRT was recommended for H and I risk patients. The LRR, distant metastasis and overall survival (OS) rates were measured from the day of mastectomy.\ud \ud RESULTS:\ud From 1999 to 2009, 898 invasive breast cancers in 883 patients were treated by mastectomy (H: 323, I: 231 and L: 344). At a median follow up of 5.2 years, 4.7% (42/898) developed LRR. The 5-year actuarial LRR rates were 6%, 2% and 2% for the H, I and L risk groups, respectively. 1.6% (14/898) developed isolated LRR (H risk n = 4, I risk group n = 0 and L risk n = 10). The 5-year actuarial overall survival rates were 67%, 77% and 90% for H, I and L risk groups, respectively.\ud \ud CONCLUSION:\ud Based on published literature, one would have expected a higher LRR rate in the I risk group without adjuvant RT. We hypothesise that the I risk group LRR rates have been reduced to that of the L risk group by the addition of RT. Apart from LN status and tumour size, other prognostic factors should also be considered in selecting patients for PMRT. This pragmatic tool requires further validation.

Previous studies have shown that SRP19 promotes association of the highly conserved signal peptide-binding protein, SRP54, with the signal recognition particle (SRP) RNA in both archaeal and eukaryotic model systems. In vitro characterization of this process is now reported using recombinantly expressed components of SRP from the hyperthermophilic, sulfate-reducing archaeon Archaeoglobus fulgidis. A combination of native gel mobility shift, filter binding, and Ni-NTA agarose bead binding assays were used to determine the binding constants for binary and ternary complexes of SRP proteins and SRP RNA. Archaeal SRP54, unlike eukaryotic homologues, has significant intrinsic affinity for 7S RNA (K(D) approximately 15 nM), making it possible to directly compare particles formed in the presence and absence of SRP19 and thereby assess the precise role of SRP19 in the assembly process. Chemical modification studies using hydroxyl radicals and DEPC identify nonoverlapping primary binding sites for SRP19 and SRP54 corresponding to the tips of helix 6 and helix 8 (SRP19) and the distal loop and asymmetric bulge of helix 8 (SRP54). SRP19 additionally induces conformational changes concentrated in the proximal asymmetric bulge of helix 8. Selected nucleotides in this bulge become modified as a result of SRP19 binding but are subsequently protected from modification by formation of the complete complex with SRP54. Together these results suggest a model for assembly in which bridging the ends of helix 6 and helix 8 by SRP19 induces a long-range structural change to present the proximal bulge in a conformation compatible with high-affinity SRP54 binding.

Objective To determine the selection factors for and results of second resections performed to treat recurrent glioblastoma multiforme (GM), we studied 301 patients with GM who were treated from the time of diagnosis using two prospective clinical protocols. Methods The patients were prospectively followed from the time of diagnosis, using clinical and radiographic criteria after maximal surgical resection and external beam radiotherapy with or without adjuvant chemotherapy. Resection of recurrent GM was performed at the recommendation of the treating clinicians. The results of the second resections were retrospectively reviewed and analyzed using multivariate logistic regression, Kaplan-Meier-Turnbull survival analysis, Cox regression, and propensity score stratification. Results Forty-six patients underwent second resections during the study period. The actuarial rate of the second resections was 15% of the patients 1 year after diagnosis and 31% 2 years after diagnosis. Younger age (P = 0.01) and more extensive initial resection (P = 0.02), but not Karnofsky Performance Scale (KPS) score at the time of diagnosis or recurrence, predicted a higher chance of selection for reoperation after initial tumor recurrence. Twenty-eight percent of the patients had improved KPS scores after undergoing reoperation, 49% were stable, and 23% had declines in KPS scores of 10 to 30 points. There was no operative mortality. After reoperation, 85% of the patients received chemotherapy, 11% received brachytherapy or underwent stereotactic radiosurgery, and 17% underwent third resections. The median survival period after reoperation was 36 weeks. Higher preoperative KPS scores predicted longer survival periods after reoperation (P = 0.03). Age and interval since diagnosis were not significant prognostic factors. The median high-quality survival period (KPS score, > or =70) was 18 weeks. The median survival period after first tumor progression was 23 weeks for 130 patients treated using the same protocols who did not undergo reoperations. Patients who did undergo reoperations experienced clinically and statistically significantly longer survival periods. However, this was determined to be partially because of selection bias. Conclusion Survival after resection of recurrent GM remains poor despite advances in imaging, operative technique, and adjuvant therapies. High-quality survival after resection of recurrence to treat GM seems to have increased significantly since an earlier report from our institution.

Venous bleeding during transsphenoidal surgery for resection of pituitary tumors is a common problem that interferes with the performance of the surgical procedure. In this study, data were collected prospectively from 50 patients to determine whether there were pre- or intraoperative factors (e.g., patient demographics, type and grade of pituitary tumor, intraoperative hemodynamics) associated with venous bleeding which might be used to predict its occurrence. In addition, central venous pressure (CVP), and cavernous sinus pressure (CSP) were measured in 13 patients to evaluate the relationship of these pressures to each other and to the severity of venous bleeding. During resection of the pituitary tumor, the severity of venous bleeding was graded as minimal, moderate, or severe, the latter two grades requiring therapeutic intervention. Moderate bleeding requiring intervention occurred in 15 of the 50 patients, and resolved in all cases. Moderate bleeding was not related to CSP or CVP, and no specific associated factor was observed. CSP was not correlated with CVP, and was higher than that predicted from the CVP and the position of the patient or the hydrostatic gravitational pressure gradient. These results suggest that it is not possible to predict in advance which patients will have problems with venous bleeding, but that simple therapeutic maneuvers are effective.

Most multiple case families of young onset breast cancer and ovarian cancer are thought to be due to highly penetrant mutations in the predisposing genes BRCA1 and BRCA2. However, these mutations are uncommon in the population and they probably account for only a few percent of all breast cancer incidence. A much larger fraction of breast cancer might, in principle, be due to common variants which confer more modest individual risks. There are several common polymorphisms in the BRCA1 gene which generate amino acid substitutions. We have examined the frequency of four of these polymorphisms: Gln356Arg, Pro871Leu, Glu1038Gly and Ser1613Gly in large series of breast and ovarian cancer cases and matched controls. Due to strong linkage disequilibrium, these four sites generate only three haplotypes with a frequency > 1.3%. The most common haplotypes, defined by the alleles Gln356Pro871Glu1038Ser1613 and Gln356Leu871Gly1038Gly1613, have frequencies of 0.57 and 0.32 respectively, and these frequencies do not differ significantly between patient and control groups. Thus the most common polymorphisms of the BRCA1 gene do not make a significant contribution to breast or ovarian cancer risk. However, our data suggest that the Arg356 allele may have a different genotype distribution in breast cancer patients from that in controls (Arg356 homozygotes are more frequent in the control groups, P = 0.01), indicating that it may be protective against breast cancer. If this finding can be confirmed, it may provide an insight into the structural features of the BRCA1 protein that are important for its function.

Purpose There are few randomized controlled trial data to confirm that improved homogeneity with simple intensity-modulated radiotherapy (IMRT) decreases late breast tissue toxicity. The Cambridge Breast IMRT trial investigated this hypothesis, and the 5-year results are reported. Patients and Methods Standard tangential plans of 1,145 trial patients were analyzed; 815 patients had inhomogeneous plans (≥ 2 cm3 receiving 107% of prescribed dose: 40 Gy in 15 fractions over 3 weeks) and were randomly assigned to standard radiotherapy (RT) or replanned with simple IMRT; 330 patients with satisfactory dose homogeneity were treated with standard RT and underwent the same follow-up as the randomly assigned patients. Breast tissue toxicities were assessed at 5 years using validated methods: photographic assessment (overall cosmesis and breast shrinkage compared with baseline pre-RT photographs) and clinical assessment (telangiectasia, induration, edema, and pigmentation). Comparisons between different groups were analyzed using polychotomous logistic regression. Results On univariate analysis, compared with standard RT, fewer patients in the simple IMRT group developed suboptimal overall cosmesis (odds ratio [OR], 0.68; 95% CI, 0.48 to 0.96; P = .027) and skin telangiectasia (OR, 0.58; 95% CI, 0.36 to 0.92; P = .021). No evidence of difference was seen for breast shrinkage, breast edema, tumor bed induration, or pigmentation. The benefit of IMRT was maintained on multivariate analysis for both overall cosmesis (P = .038) and skin telangiectasia (P = .031). Conclusion Improved dose homogeneity with simple IMRT translates into superior overall cosmesis and reduces the risk of skin telangiectasia. These results are practice changing and should encourage centers still using two-dimensional RT to implement simple breast IMRT.

Summary Background Chemoradiation became the standard of care for anal cancer after the ACT I trial. However, only two-thirds of patients achieved local control, with 5-year survival of 50%; therefore, better treatments are needed. We investigated whether replacing mitomycin with cisplatin in chemoradiation improves response, and whether maintenance chemotherapy after chemoradiation improves survival. Methods In this 2×2 factorial trial, we enrolled patients with histologically confirmed squamous-cell carcinoma of the anus without metastatic disease from 59 centres in the UK. Patients were randomly assigned to one of four groups, to receive either mitomycin (12 mg/m 2 on day 1) or cisplatin (60 mg/m 2 on days 1 and 29), with fluorouracil (1000 mg/m 2 per day on days 1–4 and 29–32) and radiotherapy (50·4 Gy in 28 daily fractions); with or without two courses of maintenance chemotherapy (fluorouracil and cisplatin at weeks 11 and 14). The random allocation was generated by computer and patients assigned by telephone. Randomisation was done by minimisation and stratified by tumour site, T and N stage, sex, age, and renal function. Neither patients nor investigators were masked to assignment. Primary endpoints were complete response at 26 weeks and acute toxic effects (for chemoradiation), and progression-free survival (for maintenance). The primary analyses were done by intention to treat. This study is registered at controlled-trials.com, number 26715889. Findings We enrolled 940 patients: 472 were assigned to mitomycin, of whom 246 were assigned to no maintenance, 226 to maintenance; 468 were assigned to cisplatin, of whom 246 were assigned to no maintenance, 222 to maintenance. Median follow-up was 5·1 years (IQR 3·9–6·9). 391 of 432 (90·5%) patients in the mitomycin group versus 386 of 431 (89·6%) in the cisplatin group had a complete response at 26 weeks (difference −0·9%, 95% CI −4·9 to 3·1; p=0·64). Overall, toxic effects were similar in each group (334/472 [71%] for mitomycin vs 337/468 [72%] for cisplatin). The most common grade 3–4 toxic effects were skin (228/472 [48%] vs 222/468 [47%]), pain (122/472 [26%] vs 135/468 [29%]), haematological (124/472 [26%] vs 73/468 [16%]), and gastrointestinal (75/472 [16%] vs 85/468 [18%]). 3-year progression-free survival was 74% (95% CI 69–77; maintenance) versus 73% (95% CI 68–77; no maintenance; hazard ratio 0·95, 95% CI 0·75–1·21; p=0·70). Interpretation The results of our trial—the largest in anal cancer to date—show that fluorouracil and mitomycin with 50·4 Gy radiotherapy in 28 daily fractions should remain standard practice in the UK. Funding Cancer Research UK.

To illustrate the wider potential scope of image-guided intensity-modulated radiotherapy (IG-IMRT), outside of the "standard" indications for IMRT.Nine challenging clinical cases were selected. All were treated with radical intent, although it was accepted that in several of the cases the probability of cure was low. IMRT alone was not adequate owing to the close proximity of the target to organs at risk, the risk of geographical miss, or the need to tighten planning margins, making image-guided radiotherapy an essential integral part of the treatment. Discrepancies between the initial planning scan and the daily on-treatment megavoltage CT were recorded for each case. The three-dimensional displacement was compared with the margin used to create the planning target volume (PTV).All but one patient achieved local control. Three patients developed metastatic disease but benefited from good local palliation; two have since died. A further patient died of an unrelated condition. Four patients are alive and well. Toxicity was low in all cases. Without daily image guidance, the PTV margin would have been insufficient to ensure complete coverage in 49% of fractions. It was inadequate by3 mm in 19% of fractions, and by5 mm in 9%.IG-IMRT ensures accurate dose delivery to treat the target and avoid critical structures, acting as daily quality assurance for the delivery of complex IMRT plans. These patients could not have been adequately treated without image guidance.IG-IMRT can offer improved outcomes in less common clinical situations, where conventional techniques would provide suboptimal treatment.

This article describes a community assessment process designed to evaluate a specific child welfare jurisdiction based on the current definition of trauma-informed child welfare and its essential elements. This process has recently been developed and pilot tested within three diverse child welfare systems in the United States. The purpose of the assessment is to identify strengths and barriers related to trauma and child welfare in each site, to make tailored recommendations to help the sites better understand, and to address the impact of trauma on the families served and on the child welfare system itself. The specific components of the assessment process will be explained, and a summary of some of the findings that were common across sites will be provided. Recommendations for future work will also be discussed.

This paper will provide information on a recent Breakthrough Series Collaborative (BSC) conducted by the National Child Traumatic Stress Network on Using Trauma-Informed Child Welfare Practice to Improve Foster Care Placement Stability. Information on this particular BSC will be provided, followed by initial findings gathered from an evaluation of the BSC and metrics gathered by each of the nine participating teams throughout the BSC process. Specific trauma-informed promising strategies adopted by teams are presented along with recommendations for next steps.

Purpose This study directly compares four dosimetric techniques for balloon-based partial breast brachytherapy: single source, standard line source, and both forward planned and inverse planned multilumen (ML). A standard line source plan is presented to be used in a single catheter or as a starting point for forward planned ML. Methods and Materials The study population consists of 12 patients previously treated with a single lumen. Inverse plans were created for 7 patients and used to create a standard line source plan. ML plans were created on the same patient data sets. The dosimetric aims were as follows: PTV_EVAL (planning target volume for evaluation) D95 (dose received [%] by 95% of PTV_EVAL volume) ≥ 95% of the prescribed dose (PD), the maximum skin and rib dose ≤125% of prescription dose, breast V150 (volume [cc] receiving 150% of the PD) ≤ 50 cc, and V200 (volume [cc] receiving 200% of the PD) ≤ 10 cc. Results The number of patients fulfilling all dosimetric constraints went from 1 patient of 12 with a single catheter to 6 patients of 12 with inverse planned ML and 7 patients of 12 with forward planned ML. PTV_EVAL D95 increased significantly with the standard line source plans and ML plans when compared with the single-source plans. Forward planning took, on average, 7 min longer than inverse planning. Conclusion Multiple sources in a single catheter improve coverage at catheter ends, whereas ML can further improve coverage and reduce dose to organs at risk. Using a standard line source as a starting point for forward planning ML means increase in planning time is kept to a minimum, making it a practicable option for centers without inverse planning software. Patients previously ineligible for treatment with a single catheter may be treated using ML.

✓ The authors retrospectively analyzed 140 patients treated at the University of California, San Francisco, from 1967 to 1990 to evaluate the results of radiation therapy (median 5400 cGy) given as an adjuvant to subtotal resection of intracranial meningioma. Of the 140 meningiomas, 117 were benign and 23 were malignant. The median follow-up period was 40 months. The overall survival rate at 5 years was 85% for the benign and 58% for the malignant tumor groups (p = 0.02); the 5-year progression-free survival rates were 89% and 48%, respectively (p = 0.001). For patients with benign meningioma, the 10-year overall and progression-free survival rates were 77%. An improved progression-free survival rate in that group was not related to tumor size but was associated with a younger age (p = 0.01) and treatment after 1980 with innovative technologies (p = 0.002); none of those variables affected the progression-free survival rate in the patients with malignant meningioma. Increased progression-free survival in the benign tumor group was also significantly associated with increasing the minimum radiation dose (p = 0.04). The 5-year progression-free survival rate for patients with benign meningioma treated after 1980 (when computerized tomography or magnetic resonance imaging was used for planning therapy) was 98%, as compared with 77% for patients treated before 1980 (p = 0.002). There were no second central nervous system tumors. Morbidity (3.6%) included sudden blindness or cerebral necrosis and death. When total resection of benign meningioma is not feasible, subtotal resection combined with precise treatment planning techniques and adjuvant radiation therapy can achieve results comparable to those of total resection.

Inhaled anesthetics can alter the arrhythmogenicity of exogenously administered epinephrine. Although swine anesthetized with desflurane or isoflurane do not differ in their arrhythmic response to exogenous epinephrine, the relative effect of epinephrine in the presence of these anesthetics in humans is untested.The authors compared the arrhythmogenicity of submucosally administered epinephrine in 36 ASA physical status 1 and 2 patients undergoing transsphenoidal resection of pituitary tumors who were randomly assigned to receive 1.0-1.3 MAC desflurane or isoflurane anesthesia. A surgeon, blinded to the administered anesthetic and the concentration of epinephrine, injected 1:50,000, 1:75,000, or 1:100,000 (20, 13.3, or 10 micrograms/ml) epinephrine in saline of volumes sufficient for surgical need. The authors defined a positive response as three or more premature ventricular contractions (PVCs) in the 5 min after starting the injection.No patient given either anesthetic developed any PVCs with epinephrine doses less than 7.0 micrograms/kg. Greater doses of epinephrine (7.0-13.0 micrograms/kg) produced positive responses at equal frequencies in the two anesthetic groups.The authors concluded that isoflurane and desflurane do not differ in their sensitization of human myocardium to the arrhythmogenic effects of exogenously administered epinephrine.

The effect of patient- and treatment-related factors in the development of late normal tissue toxicity after radiotherapy is not yet fully established. The aim of this study was to elucidate the relative importance of such factors in the development of late toxicity after breast-conserving surgery and adjuvant breast radiotherapy.Patient- and treatment-related factors were analysed in 1014 patients who had received adjuvant radiotherapy to the breast in the Cambridge Breast Intensity-modulated Radiotherapy (IMRT) Trial. Late toxicity data were collected using photographic and clinical assessments and patient-reported questionnaires at 2 years after radiotherapy.On multivariate analysis, a larger breast volume was statistically significantly associated with the development of breast shrinkage assessed by serial photographs (odds ratio per litre increase in breast volume = 1.98, 95% confidence interval 1.41, 2.78; P0.0005), telangiectasia (odds ratio = 3.94, 95% confidence interval 2.49, 6.24; P0.0005), breast oedema (odds ratio = 3.65, 95% confidence interval 2.54, 5.24; P0.0005) and pigmentation (odds ratio = 1.75, 95% confidence interval 1.21, 2.51; P = 0.003). Current smokers had an increased risk of developing pigmentation (odds ratio = 2.09, 95% confidence interval 1.23, 3.54; P = 0.006). Patients with a moderate or poor post-surgical cosmesis had a greatly increased risk of moderate or poor overall cosmesis (odds ratio = 38.19; 95% confidence interval 21.9, 66.7; P0.0005). Postoperative infection requiring antibiotics was associated with increased risk of telangiectasia (odds ratio = 3.39, 95% confidence interval 1.94, 5.91; P0.0005) and breast oversensitivity (odds ratio = 1.78, 95% confidence interval 1.27, 2.49; P = 0.001).In this study, the greatest risk factors for the development of late toxicity 2 years after breast-conserving surgery and adjuvant radiotherapy were larger breast volume, baseline pre-radiotherapy surgical cosmesis, postoperative infection and possibly smoking. These factors seem to be more important than relatively small differences in dose inhomogeneity and the addition of boost radiotherapy at 2 years after the completion of radiotherapy. The modification of potentially preventable risk factors, such as postoperative infection and smoking, may limit the development of late toxicity after breast radiotherapy.

Objective To evaluate institutional experiences regarding laparoscopic salpingo-oophorectomy in breast cancer patients and to compare the technique with gonadotropin-releasing hormone (GnRH) analogs among premenopausal women with hormone-sensitive breast cancer. Methods Between 2004 and 2009, 103 women with breast cancer underwent laparoscopic salpingo-oophorectomy at Addenbrooke's Hospital, Cambridge, UK. All relevant medical records—including reasons for salpingo-oophorectomy, peri-operative events, and subsequent follow-up—were reviewed. Results In the study period, 3 (2.9%) women experienced a recurrence of breast cancer but none had primary peritoneal/ovarian cancer within a median follow-up interval of 34 months (range, 0–70 months). No operative complications were noted among these women and all of them went home on the day of their operation. Conclusion Laparoscopic salpingo-oophorectomy seems to be a safe, permanent, and cost-effective method of ovarian ablation compared with the use of GnRH analogs. Salpingo-oophorectomy also considerably reduces the risk of subsequent ovarian/fallopian tube malignancy in this high-risk population.

Purpose This single-center randomized trial was designed to investigate whether intensity-modulated radiotherapy (IMRT) reduces late toxicity in patients with early-stage breast cancer. Methods and Materials The standard tangential plans of 1,145 nonselected patients were analyzed. The patients with inhomogeneous plans were randomized to a simple method of forward-planned IMRT or standard radiotherapy (RT). The primary endpoint was serial photographic assessment of breast shrinkage. Results At 2 years, no significant difference was found in the development of any photographically assessed breast shrinkage between the patients randomized to the interventional or control group (odds ratio, 1.51; 95% confidence interval, 0.83–1.58; p = .41). The patients in the control group were more likely to develop telangiectasia than those in the IMRT group (odds ratio, 1.68; 95% confidence interval 1.13–2.40; p = .009). Poor baseline surgical cosmesis resulted in poor overall cosmesis at 2 years after RT. In patients who had good surgical cosmesis, those randomized to IMRT were less likely to deteriorate to a moderate or poor overall cosmesis than those in the control group (odds ratio, 0.63; 95% confidence interval, 0.39–1.03, p = .061). Conclusions IMRT can lead to a significant reduction in telangiectasia at comparatively early follow-up of only 2 years after RT completion. An important component of breast induration and shrinkage will actually result from the surgery and not from the RT. Surgical cosmesis is an important determinant of overall cosmesis and could partially mask the longer term benefits of IMRT at this early stage.

✓ Embolization with polyvinyl alcohol (PVA) is an accepted method of rendering complex arteriovenous malformations (AVM's) more amenable to surgery, but its effects on human vascular tissues have not been adequately documented. The authors reviewed the histopathology of 66 intracranial AVM's resected 1 to 76 days after embolization with PVA. The mean age of the patients was 36 years, and their AVM's were located in the cerebral hemispheres (92%), the cerebellum (6%), or the corpus callosum (2%). In 79% of cases, at least one vessel contained PVA particles; in most cases, the vessel was filled with sharp, angular PVA particles in a serpiginous pattern. Polyvinyl alcohol particles indented the endothelium in 69% of cases but were rarely found subendothelially. Clotted blood and fibroblasts were present among the particles, and abundant intraluminal mononuclear and polymorphonuclear inflammatory cells were found in all vessels containing PVA particles. Foreign-body giant cells appeared 2 to 14 days after embolization in the majority of cases. Patchy mural angionecrosis and necrotizing vasculitis were found in 39% of the cases. Recanalized lumina were seen in 18% of PVA-embolized vessels. Foreign materials resembling cotton fibers and other particulate substances, which were probably contaminants of the contrast solution or the embolic material, were found in 65% of the cases. These findings suggest a specific chain of events in the interaction between PVA and vessel wall components and may explain some important sequelae of embolization therapy.

✓ The authors report the cases of three patients with epidermoid cysts which insinuated themselves into the brain stem. In all three patients, the tumor occupied the pons, although in one it was predominantly located in the medulla. The cyst contents and nonadherent tumor capsule were removed in all three patients, but no attempt was made to remove tumor densely adherent to the brain stem. One patient's cyst was removed in one operation, but maximal resection in the other two required two operations. After surgery, sixth nerve function completely returned in one patient; another patient had a stable pontine gaze palsy but developed new facial weakness; and the third patient had stable cranial nerve deficits with a diminished hemiparesis. The last patient developed a pseudomeningocele and communicating hydrocephalus, and required a lumboperitoneal shunt. In all three patients, computerized tomography scans demonstrated hypodense tumors not enhanced by contrast material. Magnetic resonance imaging was performed on two patients; in both, the tumors showed increased signal intensity relative to brain on T1-weighted images and decreased signal intensity relative to brain on T2-weighted studies. Magnetic resonance imaging, the most accurate modality for localizing these lesions and determining their extent, was also invaluable for postoperative monitoring and follow-up evaluation. Safe and adequate resection includes decompression of cyst contents and removal of nonadherent portions of the cyst capsule. Cyst wall adherent to the brain stem, however, should not be removed.

This large trial was designed to investigate whether correction of dose inhomogeneities using intensity-modulated radiotherapy (IMRT) reduces late toxicity and improves quality of life in patients with early breast cancer. This paper reports baseline characteristics of trial participants and dosimetry results.Standard tangential plans of 1145 trials were analysed. Patients with inhomogeneous plans, defined by ICRU recommendations, were randomised to forward-planned IMRT or standard radiotherapy.Twenty-nine percentage of patients had adequate dosimetry with standard 2D radiotherapy. In the randomised patients, the decreases in mean volumes receiving greater than 107% (Vol107) and less than 95% (Vol95) of the prescribed dose in the IMRT compared with the control group were 34.0 cm(3) (95% CI 26.4-41.6; P0.0001) and 48.1 cm(3) (95% CI 34.4-61.9; P0.0001), respectively. In this study, 90% of patients who had a breast separation greateror = 21 cm had Vol1072 cm(3) on standard radiotherapy plans.This large trial, in which patients with all breast sizes were eligible, confirmed that breast dosimetry can be significantly improved with a simple method of forward-planned IMRT and has little impact on radiotherapy resources. It is shown that patients with larger breasts are more likely to have dose inhomogeneities and breast separation gives some indication of this likelihood. Photographic assessment of patients at 2 years after radiotherapy, as the next part of this randomised controlled trial, will show whether these results for IMRT translate into improved cosmetic outcome in patients with early breast cancer. This would provide impetus for the widespread adoption of 3D planning and IMRT.

This article promotes integrating assessment and evidence-based practice in the treatment of traumatized children through a review of two newly developed trauma assessment tools: (1) the Child Welfare Trauma Referral Tool (CWT), and (2) Assessment-Based Treatment for Traumatized Children: A Trauma Assessment Pathway Model (TAP). These tools use pathways and algorithms to increase understanding of individual child trauma victims, and assist professionals working with children to make appropriate referral and treatment decisions within both child welfare and mental health contexts.

✓ In a prospective randomized trial designed to study the effectiveness of adjuvant chemotherapy following standard surgical treatment and radiation therapy, 233 eligible patients with medulloblastoma were treated by members of the Childrens Cancer Study Group and the Radiation Therapy Oncology Group. Eligible patients were randomly assigned to receive radiation therapy with or without adjuvant chemotherapy consisting of 1-(2-chloroethyl)-3-cyclohexyl-nitrosourea (CCNU), vincristine, and prednisone. The estimated 5-year event-free survival probability was 59% for patients treated with radiation therapy and chemotherapy and 50% for patients treated with radiation therapy alone, a difference which is not statistically significant. The 5-year survival probability was 65% for both groups. Although the treatment difference was not statistically significant when all patients were combined, in the small number of patients with more extensive tumors, event-free survival was better in the group receiving chemotherapy (48% vs. 0%, p = 0.006). In these latter patients the survival time is also significantly prolonged. Extent of disease (as measured by the M staging criteria described by Chang) and age at diagnosis were significantly associated with outcome; advanced disease and young age had a worse prognosis. The extent of tumor resection was not an independent prognostic factor. It is concluded that chemotherapy does not benefit patients with low-stage medulloblastoma, but may benefit those with more advanced stages of disease.

✓ The authors report the case of a patient harboring a posterior fossa neuroepithelial cyst who presented with positional facial weakness and syncope. The patient recovered rapidly after cyst fenestration and placement of an internal cyst-cisternal shunt. The pathogenesis and principles of diagnosis and management of these rare lesions are reviewed.

BACKGROUND: We evaluated the potential for radiofrequency (RF) transponder microchips to standardize and document key steps in the blood collection and transfusion process. STUDY DESIGN AND METHODS: Using the blood center's standard operating procedures for blood collections, we programmed a laptop computer and 10 multiwrite 256-byte RF microchips to prompt operators to enter data for key steps in blood collection. Before collections, RF microchips were attached to blood collection sets at the blood center. In parallel with actual collections, we added data to the microchips with the computer and a hand-held scanner-programmer. After labeling, we shipped the RF microchip-tagged blood units to the hospital where unit-related data (whole blood number, ABO and Rh, expiration date, special laboratory test results) were uploaded from the RF microchip to the transfusion service's information system. The microchip was subsequently used as a cross-match label for blood unit–recipient matching. RESULTS: Data were successfully uploaded to the RF microchip at key steps during blood collections. Software programs in the laptop computer and hand-held scanner-programmer successfully prompted operators to enter key data. At any stage in a blood collection, authorized operators were able to review electronic records of prior steps using the laptop computer or by scanning the microchip attached to the blood bag. Unit-related data were successfully transferred to the hospital transfusion service through the RF microchip. These data were successfully incorporated in the RF microchip cross-match label, which was used to confirm recipient–blood unit matching at the bedside. CONCLUSION: RF microchips can collect key data during blood collections, facilitate information transfer from the blood center to the hospital, and confirm recipient–blood unit matching at the bedside before transfusions.

Aptamers are short oligonucleotides that fold into well-defined three-dimensional architectures thereby enabling specific binding to molecular targets such as proteins. To be successful as a novel therapeutic modality, it is important for aptamers to not only bind their targets with high specificity and affinity, but also to exhibit favorable properties with respect to in vivo stability, cost-effective synthesis, and tolerability (i.e., safety). We describe methods for generating aptamers comprising 2 - deoxy purines and 2 -O-methyl pyrimidines (dRmY) that broadly satisfy many of these additional constraints. Conditions under which dRmY transcripts can be efficiently synthesized using mutant T7 RNA polymerases have been identified and used to generate large libraries from which dRmY aptamers to multiple target proteins, including interleukin (IL)-23 and thrombin, have been successfully discovered using the SELEX process. dRmY aptamers are shown to be highly nuclease-resistant, long-lived in vivo, efficiently synthesized, and capable of binding protein targets in a manner that inhibits their biologic activity with K(D) values in the low nM range. We believe that dRmY aptamers have considerable potential as a new class of therapeutic aptamers.

Aptamers (protein binding oligonucleotides) have potential as a new class of targeted therapeutics. For applications requiring chronic systemic administration, aptamers must achieve high-affinity target binding while simultaneously retaining high in vivo stability, tolerability, and ease of chemical synthesis. To this end, we describe a method for generating aptamers composed entirely of 2'-O-methyl nucleotides (mRmY). We present conditions under which 2'-O-methyl transcripts can be generated directly and use these conditions to select a fully 2'-O-methyl aptamer from a library of 3 x 10(15) unique 2'-O-methyl transcripts. This aptamer, ARC245, is 23 nucleotides in length, binds to vascular endothelial growth factor (VEGF) with a Kd of 2 nM, and inhibits VEGF activity in cellular assays. Notably, ARC245 is so stable that degradation cannot be detected after 96 hr in plasma at 37 degrees C or after autoclaving at 125 degrees C. We believe ARC245 has considerable potential as an antiangiogenesis therapeutic.

To compare the efficacy of continuous infusional 5-fluorouracil (5-FU)-based chemotherapy against conventional bolus chemotherapy in the preoperative treatment of patients with large operable early breast cancer.Four hundred and twenty-six women with histologically proven 3 cm invasive early breast cancer were randomised to receive pre-operative infusional 5-FU 200 mg/m(2) by daily 24 h continuous infusion via a Hickman line for 18 weeks with epirubicin 60 mg/m(2) intravenous (i.v.) bolus on day 1 and cisplatin 60 mg/m(2) i.v. bolus on day 1, both repeating 3-weekly (infusional ECisF), or conventional bolus doxorubicin 60 mg/m(2) i.v. on day 1 and cyclophosphamide 600 mg/m(2) i.v. on day 1, both repeating 3-weekly (AC), both schedules for six courses. Patients subsequently had local therapy (surgery or radiotherapy or both) and tamoxifen 20 mg orally daily as appropriate.The 5 year results for AC and infusional ECisF, respectively, were as follows: overall response, 75% and 77%; complete clinical remission, 31% and 34%; pathological complete remission (pathCR), 16% for both; and pathCR with residual ductal carcinoma in situ (DCIS), 25% and 24%. Mastectomy rates were 37% and 34%, respectively. Five-year overall survival was 74% for AC and 82% for infusional ECisF (hazard ratio 0.76, 95% confidence interval 0.51-1.13; P = 0.18). Both treatments were well tolerated. Grade III/IV lethargy, vomiting, alopecia and plantar-palmar erythema were significantly greater for infusional ECisF; grade III/IV leucopenia was significantly greater for AC.Preoperative continuous infusional 5-FU-based chemotherapy is no more active than conventional AC for early breast cancer; with a median 5 year follow-up, the infusion-based schedule shows a non-significant trend towards improved survival.

A subset of children referred due to suspected sexual abuse require more than one interview for professionals to reach an opinion about the veracity of allegations. The National Children's Advocacy Center's forensic evaluation model was designed for that specific group of children. The multisite study of the model reported here followed a 2-year pilot study. Professionals in 12 states adopted the model and collected data for 2 years on a total of 147 participants. In 44.5% of the cases, a credible disclosure was obtained, with 73% of these cases supported in the legal system. The forensic evaluation procedure yielded clear information to be used in child protection and prosecutory decisions in 64% of the cases (combining cases with credible disclosures and abuse unlikely findings). Finally, the study examined the effects of the length of the evaluation and of the case and child characteristics on evaluation outcomes.

✓ The authors present a rare entity, an intrasellar cavernous hemangioma that on neuroimages mimicked a nonfunctioning pituitary macroadenoma in a patient with a known orbital hemangioma. Such lesions can grow extraaxially within the dural sinuses, particularly the cavernous sinus, and present like tumors. A better understanding of the neuroimaging, clinical, and anatomical features of these lesions may prevent difficulties in management.

The molecular basis for function of the mammalian H19 as a tumor suppressor is poorly understood. Large, conserved open reading frames (ORFs) are absent from both the human and mouse cDNAs, suggesting that it may act as an RNA. Contradicting earlier reports, however, recent studies have shown that the H19 transcript exists in polysomal form and is likely translated. To distinguish between possible functional roles for the gene product, we have characterized the sequence requirements for H19-mediated in vitro suppression of tumor cell clonogenicity and analyzed the sequence of the gene cloned from a range of mammals. A cDNA version of the human gene, lacking the unusually short introns characteristic of imprinted genes, is as effective as a genomic copy in blocking anchorage-independent growth by G401 cells. The first 710 nucleotides of the gene can be deleted with no effect on in vitro activity. Further truncations from either the 5'- or 3'-end, however, cause a loss of suppression of clonogenicity. Using conserved sequences within the H19 gene as PCR primers, genomic DNA fragments were amplified from a range of mammalian species that span the functional domain defined by deletion analysis. Sequences from cat, lynx, elephant, gopher and orangutan complement the previous database of sequences from human, mouse, rat and rabbit. Hypothetical translation of the resulting sequences shows an absence of conserved ORFs of any size. Free energy and covariational analysis of the RNA sequences was used to identify potential helical pairings within the H19 transcript. A set of 16 helices are supported by covariation (i.e. conservation of base pairing potential in the absence of primary sequence conservation). The predicted RNA pairings consist largely of local hairpins but also include several long range interactions that bridge the 5'- and 3'-ends of the functional domain. Given the evolutionary conservation of structure at the RNA level and the absence of conservation at the protein level, we presume that the functional product of the H19 gene is a structured RNA.

We describe a computational method for the prediction of RNA secondary structure that uses a combination of free energy and comparative sequence analysis strategies. Using a homology-based sequence alignment as a starting point, all favorable pairings with respect to the Turner energy function are identified. Each potentially paired region within a multiple sequence alignment is scored using a function that combines both predicted free energy and sequence covariation with optimized weightings. High scoring regions are ranked and sequentially incorporated to define a growing secondary structure. Using a single set of optimized parameters, it is possible to accurately predict the foldings of several test RNAs defined previously by extensive phylogenetic and experimental data (including tRNA, 5 S rRNA, SRP RNA, tmRNA, and 16 S rRNA). The algorithm correctly predicts approximately 80 % of the secondary structure. A range of parameters have been tested to define the minimal sequence information content required to accurately predict secondary structure and to assess the importance of individual terms in the prediction scheme. This analysis indicates that prediction accuracy most strongly depends upon covariational information and only weakly on the energetic terms. However, relatively few sequences prove sufficient to provide the covariational information required for an accurate prediction. Secondary structures can be accurately defined by alignments with as few as five sequences and predictions improve only moderately with the inclusion of additional sequences.

Pituitary adenomas are common tumors that account for about 10% of intracranial neoplasms. Most arise from the adenohypophysis and are confined to the region of the sella turcica. Other sites may be involved as a result of extension, infiltration, or ectopic location. However, posterior extension or ectopic involvement of the clivus of the sphenoid and occipital bones is rare. Seven patients with destructive clival masses were referred to our institution with presumptive diagnoses of chordomas. In all cases, histologic workup revealed pituitary adenomas. Because they represent a subset of adenomas, the histologic features of the tumors were studied, and the clinical histories of the patients were reviewed. Five of the patients were men, aged 31 to 67 years, and two were women, aged 55 and 67 years. Four patients had extremely high plasma concentrations of prolactin (8,132-22,424 ng/ml, nl < 15). Four tumors resembled usual sellar adenomas; however, three exhibited nuclear pleomorphism, mitotic figures, and other morphologic features, suggesting alternate diagnoses. Three required immunoperoxidase stains in addition to those for pituitary hormones, and three required electron microscopy for diagnosis. Destructive invasion of the clivus by pituitary adenomas is rare, and anaplastic features of some of the tumors may lead to difficult diagnoses.

Anesthetics can alter the dose of exogenously administered epinephrine that causes cardiac arrhythmias. The purpose of this study was to test the hypothesis that in humans anesthetized with sevoflurane, the arrhythmic response to epinephrine is not different from the response in humans anesthetized with isoflurane.We determined the arrhythmogenicity of submucosally administered epinephrine in 40 ASA physical status 1 or 2 patients who were to undergo transsphenoidal surgery. Patients were assigned randomly to be given 1.0-1.3 minimum alveolar concentration sevoflurane or isoflurane. A surgeon, blinded to the anesthetic and the concentration of epinephrine, injected into the nasal submucosa epinephrine 10, 13.3, or 20 micrograms/ml in saline of volume sufficient for surgical need. We defined a "positive" response as three or more premature ventricular contractions within 5 min after initiation of injection. Responses between anesthetic groups within each dose range of epinephrine were compared by chi-squared analysis.No patient given either anesthetic developed premature ventricular contractions with doses of epinephrine less than 5 micrograms/kg. At larger doses of epinephrine (5-9.9 and 10-14.9 micrograms/kg), the frequency of arrhythmias did not differ between patients given sevoflurane and patients given isoflurane. Patients anesthetized with 1.2 minimum alveolar concentration sevoflurane had blood pressure similar to and heart rate less than those of patients anesthetized with similar concentrations of isoflurane. Blood pressure and heart rate were increased similarly in both groups after laryngoscopy and tracheal intubation and after epinephrine injection.Sevoflurane and isoflurane do not differ in their sensitization of the human myocardium to the arrhythmogenic effect of exogenously administered epinephrine.

✓ Although meningiomas are known to be induced by low doses of cranial irradiation, such as those given to treat tinea capitis, little experience has been reported on the induction of meningiomas by high-dose cranial irradiation. The authors describe a series of 10 patients with meningiomas and a previous history of high-dose radiation therapy, usually given for a primary brain tumor. Of the 10 patients, eight were female, three had multiple meningiomas, and the majority had other stigmata of previous radiation therapy. Eight meningiomas were examined pathologically and one-half were classified as either aggressive or atypical, or were noted to have a high bromodeoxyuridine labeling index. The average time from radiation therapy to diagnosis of a meningioma was 24 years (range 5 to 40 years), a shorter interval than that previously reported for meningiomas induced by lower doses of irradiation. Within this series, patient age at irradiation was significantly correlated with tumor latency; individuals who were younger at the time of radiation therapy had a shorter time to meningioma formation. The latency of meningioma formation is therefore influenced by both the radiation dose and the age of the patient at irradiation.

✓ Four patients with chiasmal syndromes were found to have intrachiasmal hematomas. Computerized tomography scans showed high-density suprasellar masses in all cases. Cryptic vascular anomalies were presumed to be responsible for spontaneous bleeding into the chiasm in three of the cases. In the remaining case, hemorrhage was due to an occult optic glioma. Surgical evacuation of clotted blood resulted in improved visual function in three of the four cases.

✓ Primary cerebral neuroblastoma is a distinct pathological and clinical entity that differs from other primitive neuroectodermal tumors. To characterize the clinical course of this lesion, the authors performed a retrospective analysis in 11 patients who ranged in age from 17 months to 26 years. The tumor had no predilection for either sex. Signs and symptoms were mostly those associated with increased intracranial pressure. The lesions commonly involved the parietal and occipital lobes. Computerized tomography scans of nine patients showed five solid and four cystic lesions; calcifications were found more commonly in the solid lesions. Contrast enhancement was seen in all tumors, yet angiograms typically showed an avascular mass. Total removal of tumor was possible in only two patients, both with cystic tumors. The remaining nine underwent subtotal resection of a solid lesion (in five) or a cystic lesion (in four). All 11 patients underwent postoperative irradiation that included the spinal axis in two cases; only one received adjuvant chemotherapy (solid tumor). Four patients, all with solid tumors that initially were subtotally resected, had evidence of tumor recurrence. The only patient with a subtotally resected solid lesion who did not have recurrence received adjuvant chemotherapy. The six patients who had cystic lesions are free of recurrent tumor at 26 to 109 months after surgery. Based on follow-up analysis of the 11 patients, recommendations are proposed for the treatment of primary cerebral neuroblastomas.