Smoothed particle hydrodynamics implementation to enhance vertebral fracture finite element model in a cervical spine segment under compression.

Spinal cord injuries (SCIs) can arise from compression loading when a vertebra fractures and bone fragments are pushed into the spinal canal. Experimental studies have demonstrated the importance of both fracture initiation and post-fracture response in the investigation of vertebral fractures and spinal canal occlusion resulting from compression. Finite element models, such as the Global Human Body Models Consortium (GHBMC) model, focused on predicting the initiation location of fractures using element erosion to model hard tissue fracture. However, the element erosion method resulted in a loss of material and structural support during compression, which limited the ability of the model to predict the post-fracture response. The current study aimed to improve the post-fracture response by combining strain-based element erosion with smoothed particle hydrodynamics (SPH) to preserve the volume of the trabecular bone during compression fracture. The proposed implementation was evaluated using a model comprising two functional spinal units (FSUs) (C5-C6-C7) extracted from the GHBMC 50th percentile male model, and loaded under central compression. The original and enhanced models were compared to experimental force-displacement data and measured occlusion of the spinal canal. The enhanced model with SPH improved the shape and magnitude of the force-displacement response to be in good agreement with the experimental data. In contrast to the original model, the enhanced SPH model demonstrated occlusion on the same order of magnitude as reported in the experiments. The SPH implementation improved the post-fracture response by representing the damaged material post-fracture, providing structural support throughout compression loading and material flow leading to occlusion.

Prediction of a positive circumferential resection margin at surgery following neoadjuvant chemotherapy for adenocarcinoma of the oesophagus.

Background: A positive circumferential resection margin (CRM) has been associated with higher rates of locoregional recurrence and worse survival in oesophageal cancer. The aim of this study was to establish if clinicopathological and radiological variables might predict CRM positivity in patients who received neoadjuvant chemotherapy before surgery for oesophageal adenocarcinoma. Methods: Multivariable analysis of clinicopathological and CT imaging characteristics considered potentially predictive of CRM was performed at initial staging and following neoadjuvant chemotherapy. Prediction models were constructed. The area under the curve (AUC) with 95% confidence intervals (c.i.) from 1000 bootstrapping was assessed. Results: A total of 223 patients were included in the study. Poor differentiation (odds ratio (OR) 2·84, 95 per cent c.i. 1·39 to 6·01) and advanced clinical tumour status (T3-4) (OR 2·93, 1·03 to 9·48) were independently associated with an increased CRM risk at diagnosis. CT-assessed lack of response (stable or progressive disease) following chemotherapy independently corresponded with an increased risk of CRM positivity (OR 3·38, 1·43 to 8·50). Additional CT evidence of local invasion and higher CT tumour volume (14 cm3) improved the performance of a prediction model, including all the above parameters, with an AUC (c-index) of 0·76 (0·67 to 0·83). Variables associated with significantly higher rates of locoregional recurrence were pN status (P = 0·020), lymphovascular invasion (P = 0·007) and poor response to chemotherapy (Mandard score 4-5) (P = 0·006). CRM positivity was associated with a higher locoregional recurrence rate, but this was not statistically significant (P = 0·092). Conclusion: The presence of advanced cT status, poor tumour differentiation, and CT-assessed lack of response to chemotherapy, higher tumour volume and local invasion can be used to identify patients at risk of a positive CRM following neoadjuvant chemotherapy.

Antecedentes: Un margen de resección circunferencial (circumferential resection margin, CRM) positivo se ha asociado con tasas más elevadas de recidiva locorregional y peor supervivencia en el cáncer de esófago. El objetivo de este estudio fue establecer si las variables clínico­patológicas y radiológicas podrían predecir la positividad del CRM en el adenocarcinoma de esófago tras quimioterapia neoadyuvante antes de la cirugía. Métodos: Se realizó un análisis multivariable de las características clínico­patológicas y de la tomografía computarizada (computed tomography, CT) que se consideraron potencialmente predictivas de CRM en la estadificación inicial y tras la quimioterapia neoadyuvante. Se construyeron modelos de predicción. Se evaluó el área bajo la curva (area under curve, AUC) con el i.c. del 95% a partir de 1.000 muestras bootstrap. Resultados: Se incluyeron 223 pacientes en el estudio. Una pobre diferenciación (razón de oportunidades, odds ratio, OR 2,84, i.c. del 95% 1,39­6,01) y un estadio clínico T avanzado (T3­4) (OR 2,93, i.c. del 95% 1,03­9,48) se asociaron de forma independiente con un riesgo aumentado de CRM en el diagnóstico. La falta de respuesta en la CT (estable o enfermedad en progresión) tras la quimioterapia se correspondía de forma independiente con un riesgo aumentado de CRM positivo (OR 3,38, i.c. del 95% 1,43­8,50). Además, la evidencia por CT de invasión local y un mayor volumen del tumor en CT (14 cm3) mejoraron el funcionamiento del modelo predictivo, incluyendo todos los parámetros previamente señalados; con AUC (índice c) de 0,76 (0,68­0,83). Las variables asociadas de forma significativa con tasas más elevadas de recidiva locorregional fueron el estado de los ganglios linfáticos patológicos (P = 0,002), la invasión linfovascular (P = 0,007) y la respuesta pobre a la quimioterapia (Mandard 4 y 5 (P = 0,006)). La positividad del CRM se asoció con una tasa de recidiva locorregional más elevada pero sin alcanzar significación estadística (P = 0,09). Conclusión: La presencia de un estadio clínico T avanzado, tumor pobremente diferenciado, falta de respuesta a la quimioterapia en la TC, mayor volumen del tumor en la TC e invasión local pueden ser utilizados para identificar pacientes en riesgo de un CRM positivo tras quimioterapia neoadyuvante.

The Effect of Long Working Hours and Overtime on Occupational Health: A Meta-Analysis of Evidence from 1998 to 2018.

There has been no subsequent meta-analysis examining the effects of long working hours on health or occupational health since 1997. Therefore, this paper aims to conduct a meta-analysis covering studies after 1997 for a comparison. A total of 243 published records were extracted from electronic databases. The effects were measured by five conditions, namely, physiological health (PH), mental health (MH), health behaviours (HB), related health (RH), and nonspecified health (NH). The overall odds ratio between long working hours and occupational health was 1.245 (95% confidence interval (CI): 1.195-1.298). The condition of related health constituted the highest odds ratio value (1.465, 95% CI: 1.332-1.611). The potential moderators were study method, cut-point for long weekly working hours, and country of origin. Long working hours were shown to adversely affect the occupational health of workers. The management on safeguarding the occupational health of workers working long hours should be reinforced.

Prognostic value of tumour regression grade in locally advanced rectal cancer: a systematic review and meta-analysis.

AIM: The current standard of care for locally advanced rectal cancer involves neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision. There is a spectrum of response to neoadjuvant therapy; however, the prognostic value of tumour regression grade (TRG) in predicting disease-free survival (DFS) or overall survival (OS) is inconsistent in the literature. METHOD: This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search was undertaken using Ovid MEDLINE, Embase and Google Scholar. Inclusion criteria were Stage II and III locally advanced rectal cancer treated with long-course CRT followed by radical surgery. The aim of the meta-analysis was to assess the prognostic implication of each TRG for rectal cancer following neoadjuvant CRT. Long-term prognosis was assessed. The main outcome measures were DFS and OS. A random effects model was performed to pool the hazard ratio (HR) from all included studies. RESULTS: There were 4875 patients from 17 studies, with 775 (15.9%) attaining a pathological complete response (pCR) and 719 (29.9%) with no response. A significant association with OS was identified from a pooled-estimated HR for pCR (HR = 0.47, P = 0.002) and nonresponding tumours (HR = 2.97; P < 0.001). Previously known tumour characteristics, such as ypN, lymphovascular invasion and perineural invasion, were also significantly associated with DFS and OS, with estimated pooled HRs of 2.2, 1.4 and 2.3, respectively. CONCLUSION: In conclusion, the degree of TRG was of prognostic value in predicting long-term outcomes. The current challenge is the development of a high-validity tests to predict pCR.

FOLFOX and intensified split-course chemoradiation as initial treatment for rectal cancer with synchronous metastases.

BACKGROUND: Optimal initial management of rectal carcinoma with synchronous metastases (RCSM) is controversial - both for patients being treated with curative and palliative intent. This study aims to evaluate the use of an upfront treatment strategy combining FOLFOX chemotherapy with split-course pelvic chemoradiation (FOLFOX + CRT) for patients with RCSM. MATERIAL AND METHODS: An analysis of all patients who commenced treatment with FOLFOX + CRT at our institutions between January 2009 and June 2014 was performed. The regimen consisted of a total of 12 weeks of treatment with split-course pelvic chemoradiation (50.4Gy with concurrent oxaliplatin and 5-FU) alternating with FOLFOX chemotherapy. Restaging imaging was performed following treatment, with subsequent management as per local standard of care. RESULTS: 78 patients (15 with resectable liver-only metastases) were identified. 77 (99%) completed at least 45Gy of radiation and 87% completed ≥75% of planned dose intensity of both oxaliplatin and 5FU. Two (2.6%) patients died within 30 days of treatment. Rates of radiological complete or partial response for local and metastatic disease were 90% and 66%, respectively. 24% patients had radiological disease progression of metastatic disease. Median overall survival for patients with unresectable metastatic disease at baseline was 23 months (95%CI: 19-28). 12 patients underwent radical surgery to both the rectum and liver and had an estimated 3-year overall survival rate of 62% (95%CI: 37-100). For those patients who did not proceed to rectal surgery, only 7% required palliative re-irradiation or surgery at a later date and all >20months from initial treatment. CONCLUSIONS: In patients with unresectable metastatic disease, FOLFOX + CRT provides durable pelvic control for the majority without the need for additional local treatment. For patients with an advanced primary tumor and synchronous resectable liver-only metastases, FOLFOX + CRT can be considered a feasible and tolerable upfront treatment option.

A phase Ib/II translational study of sunitinib with neoadjuvant radiotherapy in soft-tissue sarcoma.

BACKGROUND: Preoperative radiotherapy (RT) is commonly used to treat localised soft-tissue sarcomas (STS). Hypoxia is an important determinant of radioresistance. Whether antiangiogenic therapy can 'normalise' tumour vasculature, thereby improving oxygenation, remains unknown. METHODS: Two cohorts were prospectively enrolled. Cohort A evaluated the implications of hypoxia in STS, using the hypoxic tracer (18)F-azomycin arabinoside (FAZA-PET). In cohort B, sunitinib was added to preoperative RT in a dose-finding phase 1b/2 design. RESULTS: In cohort A, 13 out of 23 tumours were hypoxic (FAZA-PET), correlating with metabolic activity (r(2)=0.85; P<0.001). Two-year progression-free (PFS) and overall (OS) survival were 61% (95% CI: 0.44-0.84) and 87% (95% CI: 0.74-1.00), respectively. Hypoxia was associated with radioresistance (P=0.012), higher local recurrence (Hazard ratio (HR): 10.2; P=0.02), PFS (HR: 8.4; P=0.02), and OS (HR: 41.4; P<0.04). In Cohort B, seven patients received sunitinib at dose level (DL): 0 (50 mg per day for 2 weeks before RT; 25 mg per day during RT) and two patients received DL: -1 (37.5 mg per day for entire period). Dose-limiting toxicities were observed in 4 out of 7 patients at DL 0 and 2 out of 2 patients at DL -1, resulting in premature study closure. Although there was no difference in PFS or OS, patients receiving sunitinib had higher local failure (HR: 8.1; P=0.004). CONCLUSION: In STS, hypoxia is associated with adverse outcomes. The combination of sunitinib with preoperative RT resulted in unacceptable toxicities, and higher local relapse rates.

Phase II trial evaluating the feasibility of interdigitating folfox with chemoradiotherapy in locally advanced and metastatic rectal cancer.

BACKGROUND: Patients (pts) with metastatic rectal cancer and symptomatic primary, require local and systemic control. Chemotherapy used during chemoradiotherapy (CRT) is adequate for radiosensitisation, but suboptimal for systemic control. The aim of this phase II study was to assess tolerability, local/systemic benefits, of a novel regimen delivering interdigitating intensive chemotherapy with radical CRT. METHODS: Eligible pts had untreated synchronous symptomatic primary/metastatic rectal cancer. A total of 12 weeks of treatment with split-course pelvic CRT (total 50.4 Gy with concurrent oxaliplatin and 5-FU infusion) alternating with FOLFOX chemotherapy. All pts staged with CT, MRI and FDG-PET pre and post treatment. RESULTS: Twenty-six pts were treated. Rectal primary MRI stage: T3 81% and T4 15%. Liver metastases in 81%. Twenty-four pts (92%) completed the 12-week regimen. All patients received planned RT dose, and for both agents over 88% of patients achieved a relative dose intensity of >75%. Grade 3 toxicities: neutropenia 23%, diarrhoea 15%, and radiation skin reaction 12%. Grade 4 toxicity: neutropenia 15%. FDG-PET metabolic response rate for rectal primary 96%, and for metastatic disease 60%. CONCLUSIONS: Delivery of interdigitating chemotherapy with radical CRT was feasible to treat both primary and metastatic rectal cancer. High completion and response rates were encouraging.

Safety, cost-effectiveness and feasibility of daycase paracentesis in the management of malignant ascites with a focus on ovarian cancer.

BACKGROUND: Paracentesis for malignant ascites is usually performed as an in-patient procedure, with a median length of stay (LoS) of 3-5 days, with intermittent clamping of the drain due to a perceived risk of hypotension. In this study, we assessed the safety of free drainage and the feasibility and cost-effectiveness of daycase paracentesis. METHOD: Ovarian cancer admissions at Hammersmith Hospital between July and October 2009 were audited (Stage 1). A total of 21 patients (Stage 2) subsequently underwent paracentesis with free drainage of ascites without intermittent clamping (October 2010-January 2011). Finally, 13 patients (19 paracenteses, Stage 3), were drained as a daycase (May-December 2011). RESULTS: Of 67 patients (Stage 1), 22% of admissions and 18% of bed-days were for paracentesis, with a median LoS of 4 days. In all, 81% of patients (Stage 2) drained completely without hypotension. Of four patients with hypotension, none was tachycardic or symptomatic. Daycase paracentesis achieved complete ascites drainage without complications, or the need for in-patient admission in 94.7% of cases (Stage 3), and cost £954 compared with £1473 for in-patient drainage. CONCLUSIONS: Free drainage of malignant ascites is safe. Daycase paracentesis is feasible, cost-effective and reduces hospital admissions, and potentially represents the standard of care for patients with malignant ascites.

FDG-PET metabolic response predicts outcomes in anal cancer managed with chemoradiotherapy.

BACKGROUND: The aim was to investigate the correlation between (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) metabolic response to chemoradiotherapy and clinical outcomes in squamous cell carcinoma (SCC) of the anus. METHODS: A total of 48 patients with biopsy-proven anal SCC underwent FDG-PET scans at baseline and post chemoradiotherapy (54 Gy, concurrent 5-FU/mitomycin). Kaplan-Meier analysis was used to determine survival outcomes according to FDG-PET metabolic response. RESULTS: In all, 79% patients (n=38) had a complete metabolic response (CMR) at all sites of disease, 15% (n=7) had a CMR in regional nodes but only partial response in the primary tumour (overall partial metabolic response (PMR)) and 6% (n=3) had progressive distant disease despite CMR locoregionally (overall no response (NR)). The 2-year progression-free survival (PFS) was 95% for patients with a CMR, 71% for PMR and 0% for NR (P<0.0001). The 5-year overall survival (OS) was 88% in CMR, 69% in PMR and 0% in NR (P<0.0001). Cox proportional hazards regression analyses for PFS and OS found significant associations for incomplete (PMR+NR) vs complete FDG-PET response to treatment only, (HR 4.1 (95% CI: 1.5-11.5, P=0.013) and 6.7 (95% CI: 2.1-21.6, P=0.002), respectively). CONCLUSION: FDG-PET metabolic response to chemoradiotherapy in anal cancer is significantly associated with PFS and OS, and in this cohort incomplete FDG-PET response was a stronger predictor than T or N stage.

Metabolic response of rectal cancer assessed by 18-FDG PET following chemoradiotherapy is prognostic for patient outcome.

BACKGROUND: Complete pathological response has proven prognostic benefits in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy. Sequential 18-FDG PET may be an early surrogate for pathological response to chemoradiotherapy. OBJECTIVES: The aim of this study was to identify whether metabolic response measured by FDG PET following chemoradiotherapy is prognostic for tumor recurrence and survival following neoadjuvant therapy and surgical treatment for primary rectal cancer. METHODS: Patients with primary rectal cancer treated by long-course neoadjuvant chemoradiotherapy followed by surgery had FDG PET performed before and 4 weeks after treatment, before surgical resection was performed. Retrospective chart review was undertaken for patient demographics, tumor staging, recurrence rates, and survival. RESULTS: : Between 2000 and 2007, 78 patients were identified (53 male, 25 female; median age, 64 y). After chemoradiotherapy, 37 patients (47%) had a complete metabolic response, 26 (33%) had a partial metabolic response, and 14 (18%) had no metabolic response as assessed by FDG PET (1 patient had missing data). However, only 4 patients (5%) had a complete pathological response. The median postoperative follow-up period was 3.1 years during which 14 patients (19%) had a recurrence: 2 local, 9 distant, and 3 with both local and distant. The estimated percentage without recurrence was 77% at 5 years (95% CI 66%-89%). There was an inverse relationship between FDG PET metabolic response and the incidence of recurrence within 3 years (P = .04). Kaplan-Meier analysis of FDG PET metabolic response and overall survival demonstrated a significant difference in survival among patients in the 3 arms: complete, partial, and no metabolic response (P = .04); the patients with complete metabolic response had the best prognosis. CONCLUSION: Complete or partial metabolic response on PET following neoadjuvant chemoradiotherapy and surgery predicts a lower local recurrence rate and improved survival compared with patients with no metabolic response. Metabolic response may be used to stratify prognosis in patients with rectal cancer.

Chemoradiotherapy in the management of primary squamous-cell carcinoma of the rectum.

AIM: To assess the efficacy of chemoradiotherapy in the management of primary squamous-cell carcinoma of the rectum. METHOD: Nine patients with primary squamous-cell carcinoma of the rectum were treated with chemoradiotherapy from 1985 to 2007. All patients were female, with a mean age of 54 years (range 41-72 years). The mean distance of the tumour from the anal verge was 6 cm (range 4-10 cm). Seven patients were treated with curative intent (two postoperative, three preoperative, two chemoradiotherapy alone). Clinical stages for the curative group were T1N0M0 (1), T3N0M0 (3), T3N1M0 (1) and T4N0M0 (2). Chemoradiotherapy consisted of pelvic radiation 45-54 Gy in 1.8 Gy/fraction and concurrent 5-fluorouracil and mitomycin C. The mean follow-up duration for the curative group was 39 months (range 15-120 months). RESULTS: All seven patients treated with curative intent achieved local control. A complete pathological response was seen in all patients after preoperative chemoradiotherapy. Two patients did not have surgery and remained free of disease. One patient with gross residual disease after surgery achieved local control. 18-Fluorodeoxyglucose (FDG) avidity was detected in all patients who had FDG-PET scans. Both primary and metastatic tumours demonstrated FDG-avidity. CONCLUSION: Primary squamous-cell carcinoma of the rectum appears to be very sensitive to chemoradiotherapy. The high complete response rate suggests that chemoradiotherapy alone with salvage surgery for local failure should be further explored. FDG-PET scan may have a role to play in the management of this disease.

Phase I trial of docetaxel, cisplatin and concurrent radical radiotherapy in locally advanced oesophageal cancer.

BACKGROUND: Locally advanced oesophageal cancer (LAEC) is associated with poor survival and more effective treatments are needed. The aim of this phase I trial was to assess the maximum tolerated dose (MTD) of a novel weekly docetaxel and cisplatin regimen concurrent with radical radiotherapy. METHODS: Patients with unresectable, non-metastatic LAEC were eligible. Treatment comprised docetaxel 15-30 mg m(-2) per week and cisplatin 15-30 mg m(-2) per week in six planned dose levels (DLs) in 3-6 patient cohorts with 50 Gy radiotherapy in 25 fractions. Maximum tolerated dose was based on defined dose-limiting toxicities (DLTs) during therapy and 2 weeks post therapy. RESULTS: A total of 24 patients were enrolled. There were two DLTs: grade 3 fever in DL1 (docetaxel 15 mg m(-2), cisplatin 15 mg m(-2)) and grade 3 nausea in DL2 (20 mg m(-2), 15 mg m(-2)). These DLs were each expanded to six patients without further DLTs. The most common acute toxicity was grade 3 radiation oesophagitis (37.5%). There were no grade 4 toxicities, and haematologic toxicity was minimal. Cisplatin and docetaxel dose intensity was 100% at the highest dose level (DL6). A MTD was not reached in this trial. Tumour overall response rate was 50% (33% complete, 17% partial). CONCLUSION: Cisplatin and docetaxel each 30 mg m(-2) per week concurrent with 50 Gy radiotherapy is recommended for use in phase II clinical trials in oesophageal cancer.

The significance of size change of soft tissue sarcoma during preoperative radiotherapy.

AIM: To assess the significance of change in tumour size during preoperative radiotherapy in patients with soft tissue sarcoma (STS). METHODS: A retrospective review of 91 cases with STS was performed. Inclusion criteria were localised extremity and truncal STS with measurable disease, older than 18 years, treated with preoperative radiotherapy and wide local excision, in the period between January 1966 and December 2005. Patients with head and neck STS, or who received neoadjuvant chemotherapy were excluded. A difference in excess of 10% of the greatest tumour diameter of the pre-radiotherapy and the post-radiotherapy MRI scans was considered as change in tumour size. RESULTS: Increase in tumour size was noted in 28 patients (31%) (Group 1). No change or decrease in size was observed in 63 patients (Group 2). There were no significance differences in local control or overall survival rates between the 2 groups. The estimated overall actuarial local recurrence free, event-free and overall survival rates were 90.5%, 64.4%, 62.9% in Group 1, and 85.7%, 60.8%, 68.9% in Group 2 respectively. CONCLUSION: Increase in tumour size during preoperative radiotherapy for soft tissue sarcoma does not seem to associate with inferior local tumour control or compromise survival. Lack of reduction in tumour size is not necessarily a sign of lack of response to preoperative radiotherapy.

Intraoperative radiotherapy and colorectal cancer.

Intraoperative radiotherapy (IORT) is a highly specialized component of multidisciplinary management of advanced and recurrent colorectal cancer. The aim of this review was to assess its role and effectiveness in the management of colorectal cancer. A literature search was performed using Medline, Embase, Ovid and Cochrane to identify English language studies which have used IORT in the multidisciplinary management of primary and recurrent colon and rectal cancers. Improved survival and local control in patients with involved surgical margins treated with IORT have been shown in many studies, but these results have been mainly from retrospective studies. There is associated morbidity from IORT. IORT does have a role in the management of colorectal cancer. Further research needs to be performed to optimize the application of this therapy.

Radiation therapy in the treatment of desmoid tumours reduces surgical indications.

BACKGROUND: While several modalities have been proposed for the treatment of desmoid tumour/aggressive fibromatosis, high local recurrence rates have been reported. We present a retrospective study of including patients treated with radiation therapy, some of them in combination with surgical resection. PATIENTS AND METHODS: Thirty-four consecutive patients were included (mean age 40+/-16 years, 9 male). Complete follow-up was available in 31 patients (51+/-36 months). Seventeen patients (50%) were treated with radiation therapy alone, 17 patients with radiation therapy and surgery. Radiation therapy (external beam) was applied in most cases to a total dose of 50.4 Gy in 28 fractions. The lesion was located in the upper extremity in 11 patients, in the lower extremity in 14 cases and on the trunk in 9 cases. RESULTS: Overall recurrence/progression free survival was 88.5% at 5 years and 77.5% at 10 years. Recurrence free survival of the subset of patients undergoing combined treatment with radiation therapy and surgical resection was 83.6% at 5 years and 10 years. In patients who did not receive surgery but only radiation therapy, MRI showed a complete response in 20%, a partial response in 20%, and stable disease in 53% of cases. In this subset, two-third of patient had a metabolic response to radiotherapy (i.e. decrease uptake on the thallium-210 scan after radiotherapy compared to pre-therapy levels). CONCLUSION: Low recurrence rates can be achieved with the use of radiation therapy alone in selected cases. Patients with a metabolic response (decrease) to radiotherapy may be treated with a non-surgical approach. Surgery might be considered in patients with a poor metabolic response to radiotherapy.

Microarray coupled to quantitative RT-PCR analysis of androgen-regulated genes in human LNCaP prostate cancer cells.

The androgen receptor (AR) mediates the growth-stimulatory effects of androgens in prostate cancer cells. Identification of androgen-regulated genes in prostate cancer cells is therefore of considerable importance for defining the mechanisms of prostate-cancer development and progression. Although several studies have used microarrays to identify AR-regulated genes in prostate cancer cell lines and in prostate tumours, we present here the results of gene expression microarray profiling of the androgen-responsive LNCaP prostate-cancer cell line treated with R1881 for the identification of androgen-regulated genes. We show that the expression of 319 genes is stimulated by 24 h after R1881 addition, with a similar number (300) of genes being significantly repressed. Expression of the upregulated genes, as well as of 60 of the most robustly downregulated genes, was carried out using quantitative RT-PCR (Q-RT-PCR) over a time-course of R1881 treatment from 0 to 72 h. Q-RT-PCR was also carried out following treatment with other AR agonists (dihydrotestosterone, estradiol and medroxyprogesterone) and antagonists (cyproterone acetate, hydroxyflutamide and bicalutamide). This study provides a comprehensive analysis of androgen-regulated gene expression in the LNCaP prostate cancer cell line, and identifies a number of androgen-regulated genes, not described previously, as candidates for mediating androgen responses in prostate cancer cells.

The impact of 18-fluorodeoxyglucose positron emission tomography on the staging, management and outcome of anal cancer.

Accurate inguinal and pelvic nodal staging in anal cancer is important for the prognosis and planning of radiation fields. There is evidence for the role of 18-fluorodeoxyglucose positron emission tomography (FDG-PET) in the staging and management of cancer, with early reports of an increasing role in outcome prognostication in a number of tumours. We aimed to determine the effect of FDG-PET on the nodal staging, radiotherapy planning and prognostication of patients with primary anal cancer. Sixty-one consecutive patients with anal cancer who were referred to a tertiary centre between August 1997 and November 2005 were staged with conventional imaging (CIm) (including computed tomography (CT), magnetic resonance imaging, endoscopic ultrasound and chest X-ray) and by FDG-PET. The stage determined by CIm and the proposed management plan were prospectively recorded and changes in stage and management as a result of FDG-PET assessed. Patients were treated with a uniform radiotherapy technique and dose. The accuracy of changes and prognostication of FDG-PET were validated by subsequent clinical follow-up. Kaplan-Meier survival analysis was used to estimate survival for the whole cohort and by FDG-PET and CIm stage. The tumour-stage group was changed in 23% (14 out of 61) as a result of FDG-PET (15% up-staged, 8% down-staged). Fourteen percent of T1 patients (3 out of 22), 42% of T2 patients (10 out of 24) and 40% of T3-4 patients (6 out of 15) assessed using CIm, had a change in their nodal or metastatic stage following FDG-PET. Sensitivity for nodal regional disease by FDG-PET and CIm was 89% and 62%, respectively. The staging FDG-PET scan altered management intent in 3% (2 out of 61) and radiotherapy fields in 13% (8 out of 61). The estimated 5-year overall survival (OS) and progression-free survival (PFS) for the cohort were 77.3% (95% confidence interval (CI): 55.3-90.4%) and 72.2% (95% CI: 51.5-86.4%), respectively. The estimated 5-year PFS for FDG-PET and CIm staged N2-3 disease was 70% (95% CI: 42.8-87.9%) and 55.3% (95% CI: 23.3-83.4%), respectively. FDG-PET shows increased sensitivity over CIm for staging nodal disease in anal cancer and changes treatment intent or radiotherapy prescription in a significant proportion of patients.

The role of intraoperative radiotherapy in solid tumors.

BACKGROUND: Combined multimodality therapy is becoming standard treatment for many solid tumors, but the role of intraoperative radiotherapy in the management of solid tumors remains uncertain. The aim is to review the indication, application, and outcomes of intraoperative radiotherapy in the management of nongynecological solid tumors. METHODS: A literature search was performed using Medline, Embase, Ovid, and Cochrane database for studies between 1965 and 2008 assessing intraoperative radiotherapy, using the keywords "intraoperative radiotherapy," "colorectal cancer," "breast cancer," "gastric cancer," "pancreatic cancer," "soft tissue tumor," and "surgery." Only publications in English with available abstracts and regarding adult humans were included, and the evidence was critically evaluated. RESULTS: Our search retrieved 864 publications. After exclusion of nonclinical papers, duplicated papers and exclusion of brachytherapy papers, 77 papers were suitable to assess the current role of intraoperative radiotherapy. The clinical application and evidence base of intraoperative radiotherapy for each cancer is presented. CONCLUSIONS: Current studies in all common cancers show an additional benefit in local recurrence rates when intraoperative radiotherapy is included in the multimodal treatment. However, intraoperative radiotherapy may not improve overall survival and has significant morbidity depending on the site of the tumor. Intraoperative radiotherapy does have a role in the multidisciplinary management of solid tumors, but further studies are required to more precisely determine the extent of benefit.

A phase I trial of Capecitabine+Gemcitabine with radical radiation for locally advanced pancreatic cancer.

Standard chemoradiotherapy with infusional 5FU for locally advanced pancreatic cancer (LAPC) has limited efficacy in this disease. The combination of Capecitabine (Cap) and Gemcitabine (Gem) are synergistic and are potent radiosensitisers. The aim of this phase I trial was thus to determine the highest administered dose of the Cap plus Gem combination with radical radiotherapy (RT) for LAPC. Patients had LAPC, adequate organ function, ECOG PS 0-1. During RT, Gem was escalated from 20-50 mg m(-2) day(-1) (twice per week), and Cap 800-2000 mg m(-2) day(-1) (b.i.d, days 1-5 of each week). Radiotherapy 50.4 Gy/28 fractions/5.5 weeks, using 3D-conformal techniques. Three patients were entered to each dose level (DL). Dose-limiting toxicity(s) (DLTs) were based on treatment-related toxicities. Twenty patients were accrued. Dose level (DL) 1: Cap/Gem; 800/20 mg m(-2) day(-1) (3 patients), DL2: 1000/20 (12 patients), DL3: 1300/30 (5 patients). Dose-limiting toxicities were observed in DL3; grade 3 dehydration (1 patient) and grade 3 diarrhoea and dehydration (1 patient). Dose level 2 was the recommend phase 2 dose. Disease control rate was 75%: PR=15%, SD=60%. Median overall survival was 11.2 months. The addition of Cap and Gem to radical RT was feasible and active and achieved at relatively low doses.

The impact of 18-fluorodeoxyglucose positron emission tomography-computed tomography on the staging and management of primary rectal cancer.

PURPOSE: 18-Fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) has a role in recurrent colorectal cancer. This study was designed to assess the impact of PET-CT on management of primary rectal cancer. METHODS: Eighty-three patients with rectal cancer underwent PET-CT scan between 2002 and 2005. Referring physicians prospectively recorded stage and management plan after conventional imaging before PET-CT scan, which were compared to subsequent stage and management after PET-CT. RESULTS: Staging PET-CT caused a change in stage from conventional imaging in 26 patients (31 percent). Twelve (14 percent) were upstaged (7 change in N stage; 4 change in M stage; 1 change in N and M stage), and 14 (17 percent) were downstaged (10 change in N stage; 3 change in M stage; 1 change in N and M stage). PET-CT scan altered management intent in seven patients (8 percent) (curative to palliative 6 patients; palliative to curative 1 patient). Management was altered in ten patients (12 percent). There was no difference in impact with respect to tumor height. CONCLUSIONS: PET-CT scan impacts the management of patients with primary rectal cancer and influences staging/therapy in a third of patients and should be a component of rectal cancer workup.