Modular skeletal evolution in sticklebacks is controlled by additive and clustered quantitative trait Loci.

Understanding the genetic architecture of evolutionary change remains a long-standing goal in biology. In vertebrates, skeletal evolution has contributed greatly to adaptation in body form and function in response to changing ecological variables like diet and predation. Here we use genome-wide linkage mapping in threespine stickleback fish to investigate the genetic architecture of evolved changes in many armor and trophic traits. We identify >100 quantitative trait loci (QTL) controlling the pattern of serially repeating skeletal elements, including gill rakers, teeth, branchial bones, jaws, median fin spines, and vertebrae. We use this large collection of QTL to address long-standing questions about the anatomical specificity, genetic dominance, and genomic clustering of loci controlling skeletal differences in evolving populations. We find that most QTL (76%) that influence serially repeating skeletal elements have anatomically regional effects. In addition, most QTL (71%) have at least partially additive effects, regardless of whether the QTL controls evolved loss or gain of skeletal elements. Finally, many QTL with high LOD scores cluster on chromosomes 4, 20, and 21. These results identify a modular system that can control highly specific aspects of skeletal form. Because of the general additivity and genomic clustering of major QTL, concerted changes in both protective armor and trophic traits may occur when sticklebacks inherit either marine or freshwater alleles at linked or possible "supergene" regions of the stickleback genome. Further study of these regions will help identify the molecular basis of both modular and coordinated changes in the vertebrate skeleton.

Floxin, a resource for genetically engineering mouse ESCs.

We describe a method for the highly efficient and precise targeted modification of gene trap loci in mouse embryonic stem cells (ESCs). Through the Floxin method, gene trap mutations were reverted and new DNA sequences inserted using Cre recombinase and a shuttle vector, pFloxin. Floxin technology is applicable to the existing collection of 24,149 compatible gene trap cell lines, which should enable high-throughput modification of many genes in mouse ESCs.

Intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer and outcome of radical treatment: a retrospective analysis of two randomised radiotherapy trials and one surgical cohort study.

BACKGROUND: Expression of intrinsic markers of tumour hypoxia and angiogenesis are important predictors of radiotherapeutic, and possibly surgical, outcome in several cancers. Extent of tumour hypoxia in localised prostate cancer is comparable to that in other cancers, but few data exist on the association of extent of tumour hypoxia with treatment outcome. We aimed to study the predictive value of intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer, both in patients treated with radiotherapy and in those treated surgically. METHODS: We applied a new, needle biopsy tissue microarray (TMA) technique to study diagnostic samples from men with localised, previously untreated prostate cancer treated in two randomised controlled trials of radiotherapy-dose escalation. Multivariate analysis by Cox proportional hazards was done to assess the association between clinical outcome, in terms of biochemical control, and immunohistochemical staining of hypoxia inducible factor-1 alpha (HIF-1 alpha), vascular endothelial growth factor (VEGF), and osteopontin expression. The analysis was repeated on an independent series of men with localised, previously untreated prostate cancer treated by radical prostatectomy. The main outcome was time to biochemical (ie, prostate-specific antigen [PSA]) failure. FINDINGS: Between Oct 12, 1995, and Feb 5, 2002, 308 patients were identified from two prospective, randomised trials at the Royal Marsden Hospital, London and Sutton, UK, for the radiotherapy cohort and diagnostic biopsies were available for 201 of these patients. Between June 6, 1995, and Nov 4, 2005, 329 patients were identified from the Aarhus University Hospital, Skejby, Denmark, for the prostatectomy cohort; of these, 40 patients were excluded because the tumour was too small to sample (19 patients), because the paraffin block was too thin (19 patients), or because the blocks were missing (two patients), leaving 289 patients for analysis. For patients treated with radiotherapy, increased staining for VEGF (p=0.008) and HIF-1 alpha (p=0.02) expression, but not increased osteopontin expression (p=0.978), were significant predictors of a shorter time to biochemical failure on multivariate analysis, independent of clinical tumour stage, Gleason score, serum PSA concentration, and dose of radiotherapy. For patients treated with surgery, increased staining for VEGF (p<0.0001) and HIF-1 alpha (p<0.0001) expression, and increased osteopontin expression (p=0.0005) were each significantly associated with a shorter time to biochemical failure on multivariate analysis, independent of pathological tumour stage, Gleason score, serum PSA concentration, and margin status. INTERPRETATION: To our knowledge, this is the largest study of intrinsic markers of hypoxia and angiogenesis in relation to the outcome of radical treatment of localised prostate cancer. Increased expression of VEGF, HIF-1 alpha, and, for patients treated with surgery, osteopontin, identifies patients at high risk of biochemical failure who would be suitable for enrolment into trials of treatment intensification.

Predicting the probability of deferred radical treatment for localised prostate cancer managed by active surveillance.

OBJECTIVES: Outcome data from a prospective study of active surveillance of localised prostate cancer were analysed to identify factors, present at the time of diagnosis, that predict subsequent radical treatment. METHODS: Eligible patients had clinical stage T1-T2a, N0-Nx, M0-Mx adenocarcinoma of the prostate with serum PSA<15 ng/ml, Gleason score 1 ng/ml/yr) or histological progression (primary Gleason grade >or= 4, or %pbc > 50%). Multivariate Cox regression analysis of baseline variables was performed with respect to time to radical treatment. RESULTS: The 326 men recruited from 2002 to 2006 have been followed for a median of 22 mo. Median age was 67 yr, and median initial PSA (iPSA) 6.4 ng/ml. Sixty-five patients (20%) had deferred radical treatment, 16 (5%) changed to watchful waiting because of increasing comorbidity, 7 (2%) died of other causes, and 238 (73%) remain on surveillance. On multivariate Cox regression analysis, the free/total PSA ratio (p<0.001) and clinical T stage (p=0.006) were independent determinants of time to radical treatment. CONCLUSIONS: In addition to established prognostic factors, the free/total PSA ratio may predict time to radical treatment in patients with untreated, localised prostate cancer managed by active surveillance. This possibility warrants further study.

Clinical implications of introducing a new PSA assay.

BACKGROUND: A number of different prostate-specific antigen (PSA) assays are in common use. There has been little consideration of the possible clinical implications of interassay variation. The availability of two assays in the same laboratory provided an opportunity to audit the clinical implications of the interassay variation in PSA levels. METHODS: The same serum samples from patients with prostate cancer on follow-up were analyzed for PSA by the Abbott AxSYM assay and by the Abbott ARCHITECT assays. To assess within-patient reproducibility of the interassay variation, repeat analysis of PSA by both assays was conducted in a second sample obtained at least 1 month after the first. RESULTS: Samples from 156 cases were analyzed. The mean ratio of serum PSA values by the two assays (AxSYM assay/ARCHITECT assay) was 0.89 (range 0.5-2.27). The interassay coefficient of variation was 20%. In a subgroup of 50 cases with repeat samples available, the correlation coefficient, r, of the interassay variation in PSA between the first and second samples was 0.441. CONCLUSIONS: Interassay variation in serum PSA is clinically significant, both between patients and on repeated measurement within the same patient. Clinicians should be aware that simple correction factors may not accurately control for variation between PSA assays. Ideally, patients on follow-up for prostate cancer should be monitored using a single PSA assay.

Long-term effects of a short course of neoadjuvant luteinizing hormone-releasing hormone analogue and radical radiotherapy on the hormonal profile in patients with localized prostate cancer.

OBJECTIVE: To assess whether a long-term follow-up shows any reduction in the level of luteinizing hormone (LH) secretion, which could result in declining testosterone levels in men with localized prostate cancer, as most (96%) men have testosterone levels within the normal range by 1 year after treatment with a short course of LH-releasing hormone analogue (LHRHa) and radiotherapy, and LH and follicle stimulating hormone (FSH) remain high at 1 year after treatment, maintaining the testosterone levels. PATIENTS AND METHODS: We prospectively evaluated 55 patients who previously had a short course of LHRHa (median 97 days, range 28-167) and radiotherapy for localized prostate cancer. Eligible patients had documented normal testosterone, LH and FSH levels at baseline and at 1-3 years after radiotherapy. LH, FSH and testosterone were then measured at 5 years after treatment. RESULTS: The mean hormone levels before, at 1-3 years and at 5 years after treatment, respectively, were: testosterone (nmol/L), 15.33, 13.98, 12.97; LH (U/L), 5.51, 9.95, 6.95; and FSH (U/L), 7.95, 22.40, 17.00. The decrease in testosterone level at 5 years vs 1-3 years was not statistically significant and was of little clinical relevance (P = 0.057). LH and FSH levels were higher at 1-3 years than at baseline and decreased significantly (P < 0.001) at 5 years towards the baseline value. The decrease in FSH level was less marked than for LH. CONCLUSION: After a short course of LHRHa and radiotherapy, the testosterone level was maintained at 5 years. LH levels decreased towards the baseline value, suggesting recovery of Leydig cell function. FSH levels remained high, suggesting persistent Sertoli cell damage from treatment.

Diagnostic accuracy of rim and segmental MRI enhancement of colorectal hepatic metastasis after administration of mangafodipir trisodium.

OBJECTIVE: The purpose of this study was to determine the diagnostic accuracy of rim and segmental MRI enhancement of hepatic metastasis of colorectal cancer after administration of mangafodipir trisodium (MnDPDP). SUBJECTS AND METHODS: Sixty-one patients with a potentially resectable hepatic metastasis of colorectal cancer consecutively underwent breath-hold T1-weighted MRI in the axial and coronal planes 30 minutes and 24 hours after administration of MnDPDP. For each lesion, the presence or absence of rim enhancement and segmental enhancement 30 minutes and 24 hours after contrast administration was recorded. These features were evaluated separately for lesions 10 mm in diameter or larger and lesions smaller than 10 mm. The nature of each lesion was determined at histopathologic examination (n = 29) and on follow-up imaging (n = 32). RESULTS: Two hundred thirty lesions were identified at MRI: 210 lesions were metastatic, and 20 were benign. Rim enhancement was observed around 22 of 210 (10%) of the metastatic lesions at 30 minutes and 199 of 210 (95%) of metastatic lesions at 24 hours. Rim enhancement at 24 hours had 94.8% (95% CI, 91.8-97.8%) sensitivity, 90.0% (68.3-98.8%) specificity, 99.0% (97.6-100%) positive predictive value, 62.1% (42.3-79.3%) negative predictive value, and 94.3% (91.4-97.3%) diagnostic accuracy for metastasis. Segmental enhancement was infrequently seen (34/210; 16%) at 24 hours but had 100% (89.7-100%) positive predictive value for metastasis. CONCLUSION: Rim and segmental enhancement at MRI 24 hours after MnDPDP administration enabled accurate characterization of hepatic colorectal metastasis. These features may aid in preoperative mapping of hepatic tumor burden and disease distribution in patients with colorectal cancer.

Treating stage I nonseminomatous germ cell tumours with a single cycle of chemotherapy.

OBJECTIVE: To estimate the rate of relapse in men with stage I nonseminomatous germ cell tumours (NSGCT) of the testis treated with one cycle of chemotherapy instead of the usual two cycles. PATIENTS AND METHODS: Between 1992 and 1996, 22 men with stage I NSGCT who had normalized tumour markers after orchidectomy and negative findings on computed tomography, and who were at moderate risk of relapse, were treated with one cycle of platinum-containing chemotherapy (bleomycin and etoposide with either cisplatin or carboplatin). RESULTS: At a median follow-up of 10.2 years, none of the patients have relapsed with malignant GCTs. CONCLUSION: The results after one cycle of chemotherapy are no worse than after two cycles. The present study needs to be replicated in a larger cohort of patients to define the relapse risk more accurately. This approach is soon to be tested in a large multicentre trial randomizing patients between one and two cycles.

Variability of bladder filling in patients receiving radical radiotherapy to the prostate.

BACKGROUND AND PURPOSE: Patients receiving radical radiotherapy to the prostate are requested to maintain a full bladder to displace the dome of the bladder and small bowel from the target volume. This study investigated patients' ability to consistently maintain a full bladder throughout planning and treatment before (Study 1) and after (Study 2) the introduction of a patient information sheet. PATIENTS AND METHODS: Bladder volumes were measured on 41 patients at CT scanning, simulation and once weekly during treatment using a portable ultrasound device, BladderScan BVI 3000. Patients were asked their assessment of bladder fullness, time since last urination and the volume of fluid drank. A patient information sheet on bladder filling was then introduced and the study repeated on 25 patients (Study 2). The ultrasound bladder volumes measured at CT were compared to the CT scan data. RESULTS: There was a strong correlation between the ultrasound and CT bladder volumes r = 0.88 (P < 0.01). There was a significant decrease between the volume at CT (mean 362 ml, SD 229 ml) and treatment (mean 251 ml, SD 171 ml) in Study 1 (P = 0.002). In Study 2 the mean volume at CT was 286 ml (SD 164 ml) compared to a mean of 312 ml (SD 196 ml) during treatment. The measured volume correlated with patient self-assessment (r = 0.47, P < 0.01). The median volume drank by patients in Study 2 was 350 ml (range 50-825 ml) compared to 450 ml (range 75-1500 ml) in Study 1. CONCLUSIONS: Our initial results showed patients were unable to maintain a constant bladder volume during planning and treatment. Implementation of written bladder filling instructions was shown to improve bladder volume consistency.

Intensity-modulated radiotherapy in patients with locally advanced rectal cancer reduces volume of bowel treated to high dose levels.

PURPOSE: To investigate the potential for intensity-modulated radiotherapy (IMRT) to spare the bowel in rectal tumors. METHODS AND MATERIALS: The targets (pelvic nodal and rectal volumes), bowel, and bladder were outlined in 5 patients. All had conventional, three-dimensional conformal RT and forward-planned multisegment three-field IMRT plans compared with inverse-planned simultaneous integrated boost nine-field equally spaced IMRT plans. Equally spaced seven-field and five-field and five-field, customized, segmented IMRT plans were also evaluated. RESULTS: Ninety-five percent of the prescribed dose covered at least 95% of both planning target volumes using all but the conventional plan (mean primary and pelvic planning target volume receiving 95% of the prescribed dose was 32.8 +/- 13.7 Gy and 23.7 +/- 4.87 Gy, respectively), reflecting a significant lack of coverage. The three-field forward planned IMRT plans reduced the volume of bowel irradiated to 45 Gy and 50 Gy by 26% +/- 16% and 42% +/- 27% compared with three-dimensional conformal RT. Additional reductions to 69 +/- 51 cm(3) to 45 Gy and 20 +/- 21 cm(3) to 50 Gy were obtained with the nine-field equally spaced IMRT plans-64% +/- 11% and 64% +/- 20% reductions compared with three-dimensional conformal RT. Reducing the number of beams and customizing the angles for the five-field equally spaced IMRT plan did not significantly reduce bowel sparing. CONCLUSION: The bowel volume irradiated to 45 Gy and 50 Gy was significantly reduced with IMRT, which could potentially lead to less bowel toxicity. Reducing the number of beams did not reduce bowel sparing and the five-field customized segmented IMRT plan is a reasonable technique to be tested in clinical trials.

A modified inflammatory bowel disease questionnaire and the Vaizey Incontinence questionnaire are more sensitive measures of acute gastrointestinal toxicity during pelvic radiotherapy than RTOG grading.

PURPOSE: Simple scales with greater sensitivity than Radiation Therapy Oncology Group (RTOG) grading to detect acute gastrointestinal toxicity during pelvic radiotherapy, could be clinically useful. METHODS AND MATERIALS: Do questionnaires used in benign gastrointestinal diseases detect toxicity in patients undergoing radiotherapy? The patient-completed Inflammatory Bowel Disease (IBDQ) and Vaizey Incontinence questionnaires were compared prospectively at baseline and at Week 5 to physician-completed RTOG grading. RESULTS: A total of 107 patients, median age 63 years, were recruited. After 5 weeks of treatment, patients with gynecologic and gastrointestinal cancer were more symptomatic than urologic patients (p = 0.012; p = 0.014). Overall, 94% had altered bowel habits, 80% loose stool, 74% frequency, 65% difficult gas, 60% pain, >48% distress, 44% tenesmus, >40% restrictions in daily activity, 39% urgency, 37% fecal incontinence, and 40% required antidiarrheal medication. The median RTOG score was 1 (range, 0-2), median IBDQ score 204.5 (range, 74-224), and median Vaizey score 5 (range, 0-20). Chemotherapy preceding radiotherapy increased fecal incontinence (p = 0.002). RTOG scores stabilized after 3 weeks, IBDQ scores peaked at Week 4, and Vaizey scores worsened throughout treatment. IBDQ and Vaizey scores distinguished between groups with different RTOG scores. CONCLUSION: The IBDQ and Vaizey questionnaires are reliable and sensitive, offering greater insight into the severity and range of symptoms compared with RTOG grading.

Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor-risk rectal cancer.

PURPOSE: To evaluate neoadjuvant capecitabine/oxaliplatin before chemoradiotherapy (CRT) and total mesorectal excision (TME) in newly diagnosed patients with magnetic resonance imaging (MRI) -defined poor-risk rectal cancer. PATIENTS AND METHODS: MRI criteria for poor-risk rectal cancer were tumors within 1 mm of mesorectal fascia (ie, circumferential resection margin threatened), T3 tumors at or below levators, tumors extending > or = 5 mm into perirectal fat, T4 tumors, and T1-4N2 tumors. Patients received 12 weeks of neoadjuvant capecitabine/oxaliplatin followed by concomitant capecitabine and radiotherapy. TME was planned 6 weeks after CRT. Postoperatively, patients received another 12 weeks of capecitabine. RESULTS: Between November 2001 and August 2004, 77 eligible patients were recruited. After neoadjuvant capecitabine/oxaliplatin, the radiologic response rate was 88%. In addition, 86% of patients had symptomatic responses in a median of 32 days (ie, just over one cycle of capecitabine/oxaliplatin). After CRT, the tumor response rate was increased to 97%. Three patients remained inoperable. Sixty-seven patients proceeded to TME, and all but one patient had R0 resection. Pathologic complete response was observed in 16 patients (24%; 95% CI, 14% to 36%), and in an additional 32 patients (48%), only microscopic tumor foci were found on surgical specimens. Four deaths occurred during neoadjuvant capecitabine/oxaliplatin therapy as a result of pulmonary embolism, ischemic heart disease, sudden death with history of chest pain, and neutropenic colitis. CONCLUSION: Capecitabine/oxaliplatin before synchronous CRT and TME results in substantial tumor regression, rapid symptomatic response, and achievement of R0 resection.

Recovery of serum testosterone after neoadjuvant androgen deprivation therapy and radical radiotherapy in localized prostate cancer.

OBJECTIVE: To prospectively evaluate the time-course of recovery of serum testosterone levels after a short course of luteinizing hormone-releasing hormone analogue (LHRHa) and radical radiotherapy to the prostate. PATIENTS AND METHODS: Testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were sequentially measured prospectively in 59 men who received short-course LHRHa treatment and radiotherapy for localized prostate cancer. Measurements were made before treatment (baseline), during LHRHa treatment, and at 6, 12, 18, 24 and >40 weeks after the last LHRHa injection. RESULTS: The median (range) time from the first to last LHRHa injection was 116 (54-194) days. The mean (95% confidence interval) testosterone levels (in nmol/L) at baseline, during treatment and at 6, 12, 18, 24 and >40 weeks afterward were 12.0 (10.8-13.1), 0.6 (0.5-0.7), 1.4 (0.6-2.2), 11.4 (9.7-13), 12.2 (10.5-14), 10.4 (8.9-12) and 11.7 (10.5-13). Four men had low baseline testosterone levels (<6.1 nmol/L). At 6 weeks after the last LHRHa injection, no men had testosterone levels in the 'normal' range; 35% were in the normal range at 12 weeks, 85% at 18 weeks, 89% at 24 weeks, and 96% at 1 year. CONCLUSION: After LHRHa treatment and radiotherapy, the testosterone levels of most men had recovered to normal by 18-24 weeks after the last LHRHa injection.

The palatability of milk-based and non-milk-based nutritional supplements in gastrointestinal cancer and the effect of chemotherapy.

INTRODUCTION: Oral nutritional supplements may have a role in the management of weight loss in patients with cancer. Information on preference for different types of nutritional supplements and the influence of taste changes and chemotherapy is limited. AIMS AND METHODS: This study aimed, in patients with gastrointestinal (GI) cancer, to determine the short-term preference for commonly used nutritional supplements compared with controls, to examine whether preference is altered by chemotherapy and to assess the reproducibility of taste assessments conducted using a Visual Analogue Scale (VAS). Patients with GI cancer and controls were asked to rate the acceptability of three oral nutritional supplements on a VAS before starting chemotherapy and after 6 weeks of chemotherapy. Supplements were presented in a random order in sealed containers and subjects were blinded to the type of product. One supplement was repeated at random within each set (four cups) to assess the reproducibility of responses. RESULTS: Sixty patients and 63 controls were included in the study, 47 patients and 47 controls were available for follow-up. Before the start of chemotherapy, patients had a higher mean preference for Calshake (5.9 cm) than Ensure plus (5.1 cm) and Fortijuce (3.2 cm) (P=0.025 and P<0.001). Calshake was the most preferred supplement in the control group (mean 6.6 cm), with no significant differences in preferences between patients and controls. There were no changes in preference for patients after 6 weeks of chemotherapy. The results for the control group similarly showed no change after 6 weeks. No significant differences were found between scores assigned to the supplement repeated in the random order for any product at either timepoint. DISCUSSION: Patients with GI cancers prefer the taste of fresh milk-based supplements and short-term preferences are not changed by chemotherapy. Preferences are similar between patients with GI cancers and people without cancer. A VAS is a reliable tool to assess taste preference. Further studies are needed to assess the patient compliance over longer periods and the reasons for non-compliance with prescriptions for nutritional supplements.

Vertebrate Smoothened functions at the primary cilium.

The unanticipated involvement of several intraflagellar transport proteins in the mammalian Hedgehog (Hh) pathway has hinted at a functional connection between cilia and Hh signal transduction. Here we show that mammalian Smoothened (Smo), a seven-transmembrane protein essential for Hh signalling, is expressed on the primary cilium. This ciliary expression is regulated by Hh pathway activity; Sonic hedgehog or activating mutations in Smo promote ciliary localization, whereas the Smo antagonist cyclopamine inhibits ciliary localization. The translocation of Smo to primary cilia depends upon a conserved hydrophobic and basic residue sequence homologous to a domain previously shown to be required for the ciliary localization of seven-transmembrane proteins in Caenorhabditis elegans. Mutation of this domain not only prevents ciliary localization but also eliminates Smo activity both in cultured cells and in zebrafish embryos. Thus, Hh-dependent translocation to cilia is essential for Smo activity, suggesting that Smo acts at the primary cilium.

Longitudinal quality of life and quality adjusted survival in a randomised controlled trial comparing six months of bolus fluorouracil/leucovorin vs. twelve weeks of protracted venous infusion fluorouracil as adjuvant chemotherapy for colorectal cancer.

Longitudinal quality of life (QOL) assessment is infrequently made in adjuvant therapy for colorectal cancer (CRC). This analysis aims to assess QOL and quality adjusted survival (QAS) in patients receiving adjuvant 5-FU for stage II and III CRC. We performed a multicentre study in which 801 patients were randomised to 6 months of bolus 5-FU/leucovorin (LV n = 404) or 12 weeks of protracted venous infusion (PVI) 5-FU (n = 397). There were significant differences in the deterioration of QOL scores at week 2 with bolus 5-FU/LV compared to PVI 5-FU (P < 0.001), coinciding with toxicity peak during the first cycle. Following week 12, global QOL recovered to baseline when PVI 5-FU was stopped but this was delayed with bolus 5-FU/LV until completion at week 24. QOL scores significantly improved in both arms during follow-up (P < 0.001) and reached a plateau by year 1 without incremental improvement between years 2 and 5. There was a trend towards better QAS with PVI 5-FU. Twelve weeks of adjuvant PVI 5-FU was associated with significantly better QOL during treatment and faster time to recovery compared to 6 months of bolus 5-FU/LV.

Gastrointestinal symptoms after pelvic radiotherapy: role for the gastroenterologist?

PURPOSE: To analyze the cause of GI symptoms after pelvic radiotherapy (RT) in a consecutive series of patients with symptoms beginning after RT. A striking lack of evidence is available concerning the optimal treatment for the 50% of patients who develop permanent changes in bowel habits affecting their quality of life after pelvic RT. As a result, in the UK, most such patients are never referred to a gastroenterologist. METHODS AND MATERIALS: All diagnoses were prospectively recorded from a consecutive series of patients with symptoms that started after RT and who were referred during a 32-month period to a gastroenterology clinic. Patients either underwent direct access flexible sigmoidoscopy or were investigated in a standard manner by one gastroenterologist after first being seen in the clinic. RESULTS: A total of 265 patients referred from 15 institutions were investigated. They included 90 women (median age, 61.5 years; range, 22-84 years) and 175 men (median age, 70 years; range, 31-85 years). RT had been completed a median of 3 years (range, 0.1-34 years) before the study in the women and 2 years (range, 0-21 years) before in the men. Of the 265 patients, 171 had primary urologic, 78 gynecologic, and 16 GI tumors. The GI symptoms included rectal bleeding in 171, urgency in 82, frequency in 80, tenesmus, discomfort, or pain in 79, fecal incontinence in 79, change in bowel habit in 42, weight loss in 19, vomiting without other obstructive symptoms in 18, steatorrhea in 7, nocturnal defecation in 8, obstructive symptoms in 4, and other in 24. After investigation, significant neoplasia was found in 12%. One-third of all diagnoses were unrelated to the previous RT. More than one-half of the patients had at least two diagnoses. Many of the abnormalities diagnosed were readily treatable. The symptoms were generally unhelpful in predicting the diagnosis, with the exception of pain, which was associated with neoplasia (p < 0.001). CONCLUSION: The results of our study have shown that radiation enteritis is not a single disease entity. More than one-half of the patients had more than one GI diagnosis contributing to their symptoms. After pelvic RT, specific GI symptoms were not a reliable measure of the underlying diagnoses, and the evaluation of new GI symptoms is worthwhile. An algorithm for this purpose is proposed.

The frequency and pattern of cardiotoxicity observed with capecitabine used in conjunction with oxaliplatin in patients treated for advanced colorectal cancer (CRC).

We examined the cardiotoxicity in 153 patients treated with capecitabine and oxaliplatin in two prospective trials for advanced colorectal cancer. Ten patients (6.5%) developed cardiac events. One patient (0.7%) had sudden death, one patient developed cardiac failure with raised troponin I while another developed ventricular tachycardia (VT). The remaining seven patients (4.6%) experienced angina and three of the seven patients had raised troponin I, one of which developed ventricular fibrillation. Eight events occurred within cycle 1 (median cycle 1 day 10). Four patients with angina and one patient with VT recovered on stopping capecitabine, four patients required additional medical management and the remaining patient died suddenly at home. Patients with ischaemic heart disease appeared to be at increased risk. Physicians and patients need to be aware of these complications, so that prompt discontinuation of treatment and appropriate interventions may be instituted.

Sixty-day all-cause mortality rates in patients treated for gastrointestinal cancers, in randomised trials, at the Royal Marsden Hospital.

The aim of this study was to determine the 60-day all-cause mortality rate, during chemotherapy, for patients with oesophagogastric, pancreatic, and colorectal cancer. We analysed 1720 patients that were treated within randomised trials. The minimum follow-up period was > 60 days. Sixty-day mortality and 95% Confidence Intervals (CI) were calculated from the Kaplan-Meier survival curves. Causes of death were classified as treatment-related, disease-related or vascular syndrome-induced deaths. Patients with oesophagogastric cancer that could not tolerate a cis-platinum-containing regimens were treated with infused 5-fluorouracil (5FU)+/-mitomycin-C (MMC). The 60-day mortality rate depends upon the site of the primary tumour and the disease status (adjuvant versus advanced). The rate of treatment- and vascular syndrome-induced deaths was

Retrospective study of resection of pulmonary metastases in patients with advanced colorectal cancer: the development of a preoperative chemotherapy strategy.

Considerable data are available to support the resection of hepatic metastases in patients with colorectal cancer, but there are relatively few studies on the role of pulmonary metastectomy. The small number of such studies is mainly noncontemporaneous and predates the use of preoperative neoadjuvant chemotherapy. A retrospective analysis of 31 patients with pulmonary metastases from colorectal cancer treated with surgery and perioperative chemotherapy between 1995 and 2003 was performed. Twenty patients (65%) proceeded directly to surgery and 5 of these received postoperative chemotherapy. Eleven patients (35%) received preoperative chemotherapy, which consisted of a fluoropyrimidine in combination with oxaliplatin or mitomycin-C, except for 1 patient who received single agent irinotecan. Nine of 11 patients (82%) had a partial response and 2 patients (18%) had stable disease. A total of 39 thoracic surgeries (6 bilateral and 1 incomplete) were performed. There were no postoperative deaths. Four of 20 patients (20%) who had initial surgery had postoperative complications, compared with 18% of the preoperative chemotherapy group. Overall 3- and 5-year survival rates after the first thoracic surgery were 65.2% (95% CI, 35.1%-83.9%) and 26.1% (95% CI, 4.3%-56.2%), respectively. Based on the limited data from this study, disease-free interval, number of pulmonary metastases, previous resection of hepatic metastases, prethoracotomy carcinoembryonic antigen levels, and preoperative chemotherapy were not found to be significant prognostic factors for survival. Therefore, surgical resection of lung metastases is associated with low morbidity and mortality and results in long-term survival for 20%-30% of patients. Moreover, preoperative chemotherapy produced a high response rate, with no patients experiencing disease progression before surgery.