Transforming mental well-being for people with diabetes: research recommendations from Diabetes UK's 2019 Diabetes and Mental Well-Being Workshop.

AIMS: To identify key gaps in the research evidence base that could help to improve the mental well-being of people with diabetes, and to provide recommendations to researchers and research funders on how best to address them. METHODS: A 2-day international research workshop was conducted, bringing together research experts in diabetes and in mental health, people living with diabetes and healthcare professionals. RESULTS: The following key areas needing increased financial investment in research were identified: understanding the mechanisms underlying depression; understanding the multifactorial impact of social stigma; improving the language used by healthcare professionals; supporting people who find it difficult to engage with their diabetes; supporting significant others; supporting people with diabetes and eating disorders; improving models of care by learning from best practice; the potential benefits of screening and managing diabetes distress in routine diabetes care pathways; primary prevention of mental health issues at the time of diagnosis of diabetes; establishing the effectiveness of diabetes therapies on mood and other mental health issues; and understanding the impact of current diabetes technologies on mental health. Research recommendations as to how to address each of these priority areas were also developed. CONCLUSIONS: This inaugural position statement outlines recommendations to address the urgent unmet need related to the mental well-being of people living with diabetes, and calls on the research community and funders to develop research programmes and strategies to reduce this need.

Thrombosis in ovarian cancer: a case control study.

BACKGROUND: Thrombotic events are common in cancer patients and have been associated with an adverse prognosis in large registry-based studies. METHODS: A retrospective cohort of 417 patients with ovarian cancer treated at a tertiary cancer centre between 2006 and 2009 was studied to identify the incidence and risk factors for thrombotic events and the prognostic impact of thrombosis. Patient outcomes were evaluated against a matched control group without thrombosis. RESULTS: Ninety-nine thrombotic events occurred in 90 patients (21.6%) from 8 months before diagnosis to 56 months following diagnosis, peaking in the 4 months following diagnosis. Patients with thrombosis were older (mean 65 vs 61 years, P=0.007), had a worse performance status (PS ≥2: 29.9% vs 9.5%, P<0.0001) and had a more advanced FIGO stage (FIGO III/IV 75.6% vs 56.9%, P<0.0001) than patients without thrombosis. Shorter overall survival was seen in patients with pulmonary embolism and pelvic/lower limb deep vein thrombosis than without thrombosis (P=0.001). When the control group was matched for stage and PS, no survival difference was seen (P=0.91). CONCLUSION: Ovarian cancer patients with thrombotic events had a shorter survival. However, when matched for prognostic factors (PS and FIGO stage), thrombosis did not impact upon prognosis.

Expression of hypoxia-inducible factor-1α predicts benefit from hypoxia modification in invasive bladder cancer.

BACKGROUND: The addition of carbogen and nicotinamide (CON) to radiotherapy (RT) improves overall survival in invasive bladder cancer. We explored whether expression of the hypoxia marker hypoxia-inducible factor-1α (HIF-1α) alone or in combination with other markers predicted benefit from CON. METHODS: A retrospective study was carried out using material from patients with high-grade invasive bladder carcinoma enrolled in the BCON phase III trial of RT alone or with CON (RT+CON). HIF-1α expression was studied in 137 tumours using tissue microarrays and immunohistochemistry. Data were available from other studies for carbonic anhydrase IX and glucose transporter 1 protein and gene expression and tumour necrosis. RESULTS: Patients with high HIF-1α expression had improved 5-year local relapse-free survival with RT+CON (47%) compared with RT alone (21%; hazard ratio (HR) 0.48, 95% CI 0.26-0.8, P=0.02), no benefit was seen with low HIF-1α expression (HR 0.81, 95% CI 0.43-1.50, P=0.5). Combinations of markers including necrosis also predicted benefit but did not improve on prediction using necrosis alone. CONCLUSIONS: HIF-1α may be used to predict benefit from CON in patients with bladder cancer but does not improve on use of necrosis.

Insufficiency fractures in patients treated with pelvic radiotherapy and chemotherapy for uterine and cervical cancer.

Insufficiency fractures are recognised consequences of radiotherapy in gynaecological malignancy with reported incidences between 2.7% and 89%. We aimed to determine the incidence and risk factors for insufficiency fractures in patients receiving radical pelvic radiotherapy for uterine and cervical cancer. A case-note review was undertaken of patients treated between January 2007 and December 2008. Insufficiency fractures were identified from radiographs, computed tomography and magnetic resonance images. Chi-squared and Mann-Whitney tests were performed to determine associations between insufficiency fractures and chemotherapy, steroids and age. A total of 285 patients received pelvic radiotherapy, 137 with uterine and 148 with cervical cancer. Mean age was 59 years. A total of 144 patients received chemotherapy, 101 concurrently and 35 adjuvantly. Bone abnormalities affected 67 patients, 33 had pelvic insufficiency fractures, 12 had multiple fractures and 3 patients developed femoral head avascular necrosis. Use of chemotherapy was not associated with development of fractures (P = 0.949). However, cervical cancer patients had a significantly higher incidence of insufficiency fractures (P = 0.018) and bone pain (P = 0.03) compared with uterine cancer patients. This suggests concurrent chemotherapy may be a significant factor in increasing insufficiency fractures and bone morbidity in these patients and highlights a need for further research to identify, prevent and reduce these long-term complications.

CT scan does not predict optimal debulking in stage III-IV epithelial ovarian cancer: a multicentre validation study.

Our aim was to design and validate a model of CT findings that predict suboptimal cytoreduction in primary surgery (PS) for Stage III-IV epithelial ovarian cancer (EOC). We performed a retrospective review of preoperative CT scans of patients undergoing PS for EOC in a cancer centre in London, UK, between November 1995 and October 2003 (n = 91). Radiological features predictive of suboptimal cytoreduction were identified and the model tested in a second cohort undergoing PS in Manchester, June 2005 - March 2007 (n = 35). In the London cohort, liver surface disease and infrarenal para-aortic lymph node involvement predicted suboptimal cytoreduction with 80% accuracy. Accuracy of these predictors dropped to 63% when applied to the Manchester cohort. We concluded that CT prediction of suboptimal cytoreduction is unreliable and may not be reproducible. In the absence of favourable data from larger, prospective trials, it should not be used to guide management.

Cisplatin plus capecitabine as first-line chemotherapy for recurrent or metastatic head and neck squamous cell cancer: experience outside of a trial setting.

PURPOSE: Cisplatin/5-fluorouracil (5-FU) is an accepted palliative chemotherapy treatment for head and neck squamous cell carcinoma, improving quality of life but not overall survival. Capecitabine in place of 5-FU removes the morbidity of an infusional regime with potential benefit in patient well-being. This study looks at outcomes for cisplatin plus capecitabine (PX) outside of a trial setting. METHODS: Consecutive patients receiving this treatment in a single centre were retrospectively analysed. Cisplatin (mean dose 75 mg/m²) was given on day 1 of a 3-week cycle and capecitabine (mean dose 808 mg/m² twice daily) on days 1-14, for up to 6 cycles. RESULTS: Sixty-five patients (median age 58.6 years) received a median of 4 cycles of chemotherapy. The overall response rate was 30.7%, with a median overall survival of 7.3 months. Treatment was well tolerated with a 10.7% grade 3 and a 1.5% grade 4 neutropenia rate, with no other grade 4 toxicities. One patient died of neutropenic sepsis whilst on treatment. Twenty-seven percent of patients stopped treatment early due to chemotherapy-related side effects. CONCLUSION: PX is well tolerated outside the trial setting with outcomes similar to historical published literature. Ease of administration and benefit to patient convenience make it an attractive alternative to standard palliative treatment.

Gastrointestinal symptoms after pelvic radiotherapy: a national survey of gastroenterologists.

PURPOSE: Seventeen thousand patients receive treatment with radical pelvic radiotherapy annually in the UK. Up to 50% develop significant gastrointestinal symptoms. The National Cancer Survivorship Initiative has identified access to specialist medical care for those with complications after cancer as one of their four key needs. We aimed to determine the current practice of British gastroenterologists with regards to chronic gastrointestinal symptoms after pelvic radiotherapy. METHODS: A questionnaire was developed and sent up to a maximum of five times to all UK consultant gastroenterologists. RESULTS: Eight hundred sixty-six gastroenterologists were approached and 165 (20%) responded. Sixty-one percent saw one to four patients annually with bowel symptoms after radiotherapy. Eighteen percent rate the current treatments as effective "often" or "most of the time". Forty-seven percent of gastroenterologists consider themselves "confident with basic cases", with 11% "confident in all cases". Fifty-nine percent thinks a gastroenterologist with a specialist interest should manage these patients. Although only 29% thinks a specific service is required for these patients, 34% rates the current service as inadequate. The ideal service was considered to be gastroenterology-led, multidisciplinary and regional. Low referral rates, poor evidence-base and poor funding are cited as reasons for the current patchy services. CONCLUSIONS: The low response rate contrasts with that from a parallel survey of clinical oncologists. This may reflect the opinion that radiation-induced bowel toxicity is not a significant issue, which may be because only a small proportion of patients are referred to gastroenterologists. The development of new, evidence-based gastroenterology-led services is considered the optimal way to meet the needs of these patients.

Clinical features of oral chemotherapy: results of a longitudinal prospective study of breast and colorectal cancer patients receiving capecitabine in the UK.

The aim was to describe the clinical sequelae of patients treated with capecitabine in terms of adverse events, treatment modifications and therapy cessation throughout the treatment trajectory. A total of 1232 toxicity assessments were undertaken on colorectal and breast cancer patients receiving palliative and adjuvant treatment prior to treatment and at days 7, 14 and 21 for six cycles of chemotherapy. Most common adverse events were diarrhoea, nausea, palmar-plantar erythrodysesthesia (PPE), fatigue and pain which were experienced by over 80% of subjects. Grades 2 and 3 adverse events were common (n= 916 and n= 113) but their development into grade 4 was uncommon (n= 2). There was a downward trend in the percentage incidence of toxicity; however, PPE increased. Almost 60% of subjects completed six cycles, or planned treatment. Some 40% of subjects commenced treatment on a dose reduction (<1250 mg/m(2)), and this increased to 70% at cycle 6. In total, 2.8-11.6% of subjects experienced toxicity-related treatment deferrals. While adverse events are common with capecitabine the lack of grade 4 adverse events support the efficacy of current clinical management strategies. The deferral and dose reduction data indicate that cycles 1 and 2 are important and require careful management and clinical interventions in order to prevent high-grade adverse events.

Symptoms experienced by cancer patients during the first year from diagnosis: patient and informal caregiver ratings and agreement.

OBJECTIVE: The aim of this study was to explore the symptom experience of patients with cancer, identify changes in symptoms over time, and explore the congruence of symptom reports between patients and their informal caregivers. METHOD: This was a prospective longitudinal evaluation of symptoms over 1 year from start of treatments (T1) using the Memorial Symptom Assessment Scale. Assessments and follow up took place at 3 months (T2), 6 months (T3) and 12 months (T4). A heterogeneous sample of 100 patients with cancer participated, providing 325 assessments over time. Furthermore, 82 caregivers also participated, providing 238 dyadic patient-caregiver assessments over the same time. RESULTS: The most commonly occurring, and by far most distressing, symptom was "lack of energy." Common symptoms reported were lack of concentration, difficulties sleeping, shortness of breath, cough, pain, dry mouth, and feeling drowsy. Symptom occurrence and distress improved over time, particularly from T2 to T3 (p < 0.05), but the "chronicity" of some generic symptoms was notable. Caregivers tended to overestimate occurrence and distress compared to patients, particularly in symptoms of psychological nature; κ statistics had a highest coefficient of 0.45, suggesting moderate agreement between patients and caregivers at best. SIGNIFICANCE OF RESULTS: More attention needs to be paid to the commonly reported symptoms by patients, as they have the potential of impacting on quality of life (QOL). As patient-caregiver reports had moderate agreement, effort should be directed to improving this agreement, as caregivers are often communicating patient symptoms to clinicians.

The impact of radiotherapy late effects on quality of life in gynaecological cancer patients.

The aims of this study were to assess changes in quality of life (QoL) scores in relation to radical radiotherapy for gynaecological cancer (before and after treatment up to 3 years), and to identify the effect that late treatment effects have on QoL. This was a prospective study involving 225 gynaecological cancer patients. A QoL instrument (European Organisation for the Research and Treatment of Cancer QLQ-C30) and late treatment effect questionnaire (Late Effects Normal Tissues - Subjective Objective Management Analysis) were completed before and after treatment (immediately after radiotherapy, 6 weeks, 12, 24 and 36 months after treatment). Most patients had acute physical symptoms and impaired functioning immediately after treatment. Levels of fatigue and diarrhoea only returned to those at pre-treatment assessment after 6 weeks. Patients with high treatment toxicity scores had lower global QoL scores. In conclusion, treatment with radiotherapy for gynaecological cancer has a negative effect on QoL, most apparent immediately after treatment. Certain late treatment effects have a negative effect on QoL for at least 2 years after radiotherapy. These treatment effects are centred on symptoms relating to the rectum and bowel, for example, diarrhoea, tenesmus and urgency. Future research will identify specific symptoms resulting from late treatment toxicity that have the greatest effect on QoL; therefore allowing effective management plans to be developed to reduce these symptoms and improve QoL in gynaecological cancer patients.

Preoperative downstaging chemoradiation with concurrent irinotecan and capecitabine in MRI-defined locally advanced rectal cancer: a phase I trial (NWCOG-2).

BACKGROUND: The aim of this study was to investigate the safety of neoadjuvant chemoradiation using radiotherapy (RT) combined with concurrent capecitabine and irinotecan for locally advanced rectal cancer before surgery. METHODS: Forty-six patients were recruited and treated on the basis that MRI scanning had shown poor-risk tumours with threatening (< or =1 mm) or involvement of the mesorectal fascia. Conformal RT was given using 3 or 4 fields at daily fractions of 1.8 Gy on 5 days per week to a total dose of 45 Gy. Concurrently oral capecitabine was given twice daily throughout radiotherapy continuously from days 1 to 35 and intravenous irinotecan was given once per week during weeks 1 to 4 of RT. Dose levels were gradually escalated as follows. Dose level 1: capecitabine 650 mg m(-2) b.i.d. and irinotecan 50 mg m(-2); Dose level 2: capecitabine 650 mg m(-2) b.i.d. and irinotecan 60 mg m(-2); Dose level 3: capecitabine 825 mg m(-2) b.i.d. and irinotecan 60 mg m(2); Dose level 4: capecitabine 825 mg m(-2) b.i.d. and irinotecan 70 mg m(-2). RESULTS: Diarrhoea (grade 3, no grade 4) was the main serious acute toxicity with lesser degrees of fatigue, neutropenia, anorexia and palmar-plantar erythrodysesthesia. The recommended dose for future study was dose level 2 at which 3 of 14 patients (21%) developed grade 3 diarrhoea. Postoperative complications included seven pelvic or wound infections and two anastomotic and two perineal wound dehiscences. There were no deaths in the first 30 days postoperatively. Of 41 resected specimens, 11 (27%) showed a pathological complete response (pCR) and five (12%) showed an involved circumferential resection margin (defined as < or =1 mm). The 3-year disease-free survival (intent-to-treat) was 53.2%. CONCLUSION: In patients with poor-risk MRI-defined locally advanced rectal cancer threatening or involving the mesorectal fascia, preoperative chemoradiation based on RT at 45 Gy in 25 daily fractions over 5 weeks with continuous daily oral capecitabine at 650 mg m(-2) b.i.d. days 1-35 and weekly IV irinotecan at 60 mg m(-2) weeks 1-4, provides acceptable acute toxicity and postoperative morbidity with encouraging response and curative resection rates.

The UK national breast cancer screening programme for survivors of Hodgkin lymphoma detects breast cancer at an early stage.

BACKGROUND: Supradiaphragmatic radiotherapy (SRT) to treat Hodgkin's lymphoma (HL) at a young age increases the risk of breast cancer (BC). A national notification risk assessment and screening programme (NRASP) for women who were treated with SRT before the age of 36 years was instituted in the United Kingdom in 2003. In this study, we report the implementation and screening results from the largest English Cancer Network. METHODS: A total of 417 eligible women were identified through cancer registry/hospital databases and from follow-up (FU) clinics. Screening results were collated retrospectively, and registry searches were used to capture BC cases. RESULTS: Of the 417 women invited for clinical review, 243 (58%) attended. Of these 417 women, 23 (5.5%) have been diagnosed with BC, a standardised incidence ratio of 2.9 compared with the age-matched general population. Of five invasive BCs diagnosed within the NRASP, none involved axillary lymph nodes compared with 7 of 13 (54%) diagnosed outside the programme (P<0.10). The mean latency for BC cases was 19.5+/-8.35 years and the mean FU duration for those unaffected by BC was 14.6+/-9.11 years (P<0.01), suggesting that those unaffected by BC remain at high risk. Recall and negative biopsy rates were acceptable (10.5 and 0.8%, respectively). CONCLUSIONS: The NRASP appears to detect BC at an early stage with acceptable biopsy rates, although numbers are small. Determination of NRASP results on a national basis is required for the accurate evaluation of screening efficacy in women previously treated with SRT.

Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: a multicentre randomised phase II study - The UK ABC-01 Study.

BACKGROUND: We assessed the activity of gemcitabine (G) and cisplatin/gemcitabine (C/G) in patients with locally advanced (LA) or metastatic (M) (advanced) biliary cancers (ABC) for whom there is no standard chemotherapy. METHODS: Patients, aged > or =18 years, with pathologically confirmed ABC, Karnofsky performance (KP) > or =60, and adequate haematological, hepatic and renal function were randomised to G 1000 mg m(-2) on D1, 8, 15 q28d (Arm A) or C 25 mg m(-2) followed by G 1000 mg m(-2) D1, 8 q21d (Arm B) for up to 6 months or disease progression. RESULTS: In total, 86 patients (A/B, n=44/42) were randomised between February 2002 and May 2004. Median age (64/62.5 years), KP, primary tumour site, earlier surgery, indwelling biliary stent and disease stage (LA: 25/38%) are comparable between treatment arms. Grade 3-4 toxicity included (A/B, % patients) anaemia (4.5/2.4), leukopenia (6.8/4.8), neutropenia (13.6/14.3), thrombocytopenia (9.1/11.9), lethargy (9.1/28.6), nausea/vomiting (0/7.1) and anorexia (2.3/4.8). Responses (WHO criteria, % of evaluable patients: A n=31 vs B n=36): no CRs; PR 22.6 vs 27.8%; SD 35.5 vs 47.1% for a tumour control rate (CR+PR+SD) of 58.0 vs 75.0%. The median TTP and 6-month progression-free survival (PFS) (the primary end point) were greater in the C/G arm (4.0 vs 8.0 months and 45.5 vs 57.1% in arms A and B, respectively). CONCLUSION: Both regimens seem active in ABC. C/G is associated with an improved tumour control rate, TTP and 6-month PFS. The study has been extended (ABC-02 study) and powered to determine the effect on overall survival and the quality of life.

Clinical outcome for chemoradiotherapy in carcinoma of the cervix.

AIMS: Two recent meta-analyses have shown a survival advantage for the addition of concurrent chemotherapy to radiotherapy in the treatment of cervical cancer. However, there is insufficient information available on late toxicity and few data from UK practice. The aims of this study were to examine treatment outcomes (survival and toxicity) in patients with cervical cancer treated with chemoradiation and to compare these with outcomes in patients treated with radiation alone. MATERIALS AND METHODS: Between July 2000 and December 2003, 75 patients with cervical cancer were treated with chemoradiation. Case notes were reviewed retrospectively. Acute and late toxicity were recorded, with late toxicity graded using the Franco-Italian glossary. The median age was 47 years. All patients were staged with examination under anaesthesia and magnetic resonance imaging scans. Forty-two patients were treated with concurrent chemoradiation alone and 33 patients were treated with a combination of neoadjuvant and concurrent chemoradiation. This was due to waiting list problems. The chemotherapy used was cisplatin 40 mg/m(2) weekly with radiotherapy, (the neoadjuvant dose was 60 mg/m(2) 3 weekly). External beam radiotherapy was given to the pelvis (40-45 Gy/20 fractions/4 weeks) followed by low dose rate brachytherapy (22.5-32.5 Gy to point A). Patients who were unable to have brachytherapy were given an external beam boost (15-20 Gy/8-10 fractions). RESULTS: The 3-year overall survival rate was 70%, with an estimated 5-year overall survival rate of 60%. The 3-year disease-free survival was 63.6%, with an estimated 5-year disease-free survival rate of 55%. Compared with the cohort of 183 patients from the Christie Hospital in a 1993 audit, there was a trend towards improved overall survival from 49 to 60% (P=0.06), which may become significant with longer follow-up. There were seven patients (9.3%) with grade 3 toxicity and no cases of grade 4 toxicity. In comparison with patients treated in the 1993 audit, the late toxicity rate has increased from 3.4 to 9.3%, but this was not statistically significant (P=0.14). CONCLUSION: There was a trend towards improved survival with concurrent chemoradiation in this cohort of patients that may become significant with longer follow-up.

Ultrasound imaging to assess inter- and intra-fraction motion during bladder radiotherapy and its potential as a verification tool.

AIMS: Organ motion is the principle source of error in bladder cancer radiotherapy. The aim of this study was to evaluate ultrasound bladder volume measurement as a surrogate measure of organ motion during radiotherapy: (1) to assess inter- and intra-fraction bladder variation and (2) as a potential treatment verification tool. MATERIALS AND METHODS: Twenty patients receiving radical radiotherapy for bladder cancer underwent post-void ultrasound bladder volume measurement at the time of radiotherapy treatment planning (RTP), and immediately before (post-void) and after receiving daily fractions. RESULTS: Ultrasound bladder volume measurement was found to be a simple and acceptable method to estimate relative bladder volume changes. Six patients showed significant changes to post-void bladder volume over the treatment course (P<0.05). The mean inter-fraction post-void bladder volume of five patients exceeded their RTP ultrasound bladder volume by more than 50%. Intra-fraction bladder volume increased on 275/308 (89%) assessed fractions, with the mean intra-fraction volume increases of seven patients exceeding their RTP ultrasound bladder volume by more than 50%. CONCLUSIONS: Both day-to-day bladder volume variation and bladder filling during treatment should be considered in RTP and delivery. Ultrasound may provide a practical daily verification tool by: supporting volume limitation as a method of treatment margin reduction; allowing detection of patients who may require interventions to promote bladder reproducibility; and identifying patients with prominent volume changes for the selective application of more advanced adaptive/image-guided radiotherapy techniques.

A phase II study evaluating the use of concurrent mitomycin C and capecitabine in patients with advanced unresectable pseudomyxoma peritonei.

Pseudomyxoma peritonei (PMP) is a rare neoplastic process characterised by progressive intra-abdominal dissemination of mucinous tumour, and generally considered resistant to systemic chemotherapy. A phase II study in patients with advanced unresectable PMP was undertaken to evaluate the combination of systemic concurrent mitomycin C (7 mg m(-2) i.v. on day 1) and capecitabine (1250 mg m(-2) b.d. on days 1-14) in a 3-weekly cycle (MCap). Response was determined by semiquantitative assessment of disease volume on serial computed tomographic (CT) scans and serum tumour marker (CEA, CA125, CA19-9) changes at 12 weeks. Between 2003 and 2006, 40 patients were recruited through a national centre for the treatment of peritoneal surface tumours. At baseline, 23 patients had progressive disease and 17 had stable disease. Of 39 assessable patients, 15 (38%, 95% confidence intervals (CIs): 25, 54%) benefited from chemotherapy in the form of either reductions in mucinous deposition or stabilisation of progressive pretreatment disease determined on CT scan. Notably, two patients, originally considered unresectable, following MCap and re-staging underwent potentially curative cytoreductive surgery. Grade 3/4 toxicity rates were low (6%, 95% CIs: 4, 9%). Twenty out of 29 assessed patients (69%, 95% CIs: 51, 83%) felt that their Global Health Status improved during chemotherapy. This is the first trial to demonstrate an apparent benefit of systemic chemotherapy in patients with advanced unresectable PMP.

Alternating irinotecan with oxaliplatin combined with UFT plus leucovorin (SCOUT) in metastatic colorectal cancer.

Tegafur-uracil (UFT) plus leucovorin (LV, folinic acid) with alternating irinotecan and oxaliplatin were effective and well tolerated in patients with metastatic colorectal cancer (mCRC) in a phase I study. This study expanded the maximum tolerated dose group. Patients aged >or=18 years had histologically confirmed, inoperable, previously untreated, measurable mCRC. Patients received irinotecan 180 mg m(-2) on day 1, oxaliplatin 100 mg m(-2) on day 15 and UFT 250 mg m(-2) plus LV 90 mg on days 1-21 every 28 days. The phase I/II study comprised 45 patients, 29 at the maximum tolerated dose (MTD). The response rate in 38 evaluable patients was 63% (95% confidence interval (CI): 49-80). Median time to progression and overall survival were 8.7 months (95% CI: 7.9-10.4) and 16.8 months (95% CI: 9.6-25.3), respectively. In the MTD group, one patient had grade 3 leucopenia; one had grade 3 neutropaenia; three had grade 3 diarrhoea; and one had grade 3 neurotoxicity. No hand-foot syndrome grade >1 was seen. In total, 67% of eligible patients received second-line therapy. UFT plus LV with alternating irinotecan and oxaliplatin is an efficacious first-line treatment for mCRC, with minimal neurotoxicity and hand-foot syndrome.

Acquisition of biologically relevant gene expression data by Affymetrix microarray analysis of archival formalin-fixed paraffin-embedded tumours.

Robust protocols for microarray gene expression profiling of archival formalin-fixed paraffin-embedded tissue (FFPET) are needed to facilitate research when availability of fresh-frozen tissue is limited. Recent reports attest to the feasibility of this approach, but the clinical value of these data is poorly understood. We employed state-of-the-art RNA extraction and Affymetrix microarray technology to examine 34 archival FFPET primary extremity soft tissue sarcomas. Nineteen arrays met stringent QC criteria and were used to model prognostic signatures for metastatic recurrence. Arrays from two paired frozen and FFPET samples were compared: although FFPET sensitivity was low ( approximately 50%), high specificity (95%) and positive predictive value (92%) suggest that transcript detection is reliable. Good agreement between arrays and real time (RT)-PCR was confirmed, especially for abundant transcripts, and RT-PCR validated the regulation pattern for 19 of 24 candidate genes (overall R(2)=0.4662). RT-PCR and immunohistochemistry on independent cases validated prognostic significance for several genes including RECQL4, FRRS1, CFH and MET - whose combined expression carried greater prognostic value than tumour grade - and cmet and TRKB proteins. These molecules warrant further evaluation in larger series. Reliable clinically relevant data can be obtained from archival FFPET, but protocol amendments are needed to improve the sensitivity and broad application of this approach.

No relationship between 18F-fluorodeoxyglucose positron emission tomography and expression of Glut-1 and -3 and hexokinase I and II in high-grade glioma.

The purpose of this study was to compare glucose metabolism, measured using 18F-fluorodeoxyglucose positron emission tomography ([18F]FDG-PET), with the expression of Glut-1 and -3 and hexokinase I (Hex I) and II in high-grade glioma. The retrospective study involved 27 patients with WHO classification grade III and IV glioma, with either newly diagnosed or recurrent tumours. Patients underwent dynamic and static [18F]FDG-PET to glucose metabolic rate (MRGlu) and standardised uptake value (SUV), respectively. Tumour biopsies were obtained and stained using immunohistochemistry for the expression of Glut-1, -3, Hex I and II. Relationships between variables were studied using Spearman's rank correlation test. Results showed that the expression of Glut-1, Glut-3, Hex I and Hex II varied between and within the tumour samples. The mean of MRGlu was 0.2 (range 0.09-0.25) micromol/min/ml and that of SUV was 4.2 (range 3.2-5.2). There were no significant relationships among the tumour expression of any of the proteins studied with either MRGlu or SUV (p>0.21 for all). In conclusion, the lack of relationship between the immunohistochemical expression of Glut-1, -3, Hex I or II and glucose metabolism measured using [18F]FDG-PET in patients with high-grade glioma may be due to the tissue heterogeneity and presence of necrosis in high-grade tumours.

Estimation of renal function -- what is appropriate in cancer patients?

AIMS: To compare the accuracy of renal assessment in patients with cancer using radioisotope glomerular filtration rate (GFR), urine collection for creatinine clearance, Cockroft-Gault, Modification of Diet in Renal Disease (MDRD) and Wright formulae. MATERIALS AND METHODS: Measurements of isotope GFR from 367 patients were compared with estimates from the described methods (Cockroft-Gault, MDRD, Wright). An analysis including a further 252 patients with an isotope GFR < or = 50 ml/min was also carried out. RESULTS: The Wright formula was the most accurate form of estimating renal function for the first study group. The formulae were similar in accuracy in the second study group. CONCLUSIONS: The Wright formula is the most accurate form of estimation of renal function in comparison with the isotope GFR for cancer patients. When there is a large proportion of patients with a low isotope GFR (< or = 50 ml/min), the formulae have similar accuracy.