Impaired Cerebrovascular Reactivity Predicts Recurrent Symptoms in Patients with Carotid Artery Occlusion: A Hypercapnia BOLD fMRI Study.

BACKGROUND AND PURPOSE: A key factor in predicting recurrent ischemic episodes in patients with carotid artery occlusion is the presence of hemodynamic impairment. There is, however, no consensus on how to best assess this risk in terms of imaging modalities or thresholds used. Here we investigated whether a predefined threshold of hemispheric asymmetry in hypercapnia fMRI predicts recurrent symptoms in patients with carotid artery occlusion. MATERIALS AND METHODS: We studied 23 patients (2 women) with a mean age of 67.5 ± 9 years. Patients were assessed for recurrent ischemic events until lost to follow-up, study end, death, or recurrent ischemic event. Hypercapnia fMRI was used to assess the cerebrovascular reserve and quantify the percentage signal change in GM in the MCA territory and the hemispheric asymmetry index. Kaplan-Meier survival analysis and log-rank tests were performed to assess differences between patients with normal or abnormal hemispheric indices. RESULTS: The median follow-up was 20 months. During this period, 8 patients experienced recurrent events, and 15 did not. The percentage signal change in GM in the MCA territory was significantly decreased in those patients with recurrent events compared with those without (2.39 ± 0.22 versus 2.70 ± 0.42, P = .032). The normal hemispheric index predicted event-free survival during follow-up (median, 20 months) for both the combined outcome (recurrent events and/or death, log-rank, P = .034) and recurrent retinal or ipsilateral ischemic events only (log-rank, P = .012). CONCLUSIONS: The hemispheric asymmetry index derived from hypercapnia fMRI showed hemodynamic impairment in more than half of the studied patients with carotid occlusion, and those patients showed a higher risk of recurrent ischemic symptoms.

Stenting of the Cystic Duct in Benign Disease: A Definitive Treatment for the Elderly and Unwell.

PURPOSE: There have been few case reports describing cystic duct stent insertion in the management of acute cholecystitis secondary to benign disease with no case series published to date. We present our series demonstrating the role of cystic duct stents in managing benign gallbladder disease in those patients unfit for surgery. MATERIALS AND METHODS: Thirty three patients unfit for surgery in our institution underwent cystic duct stent insertion for the management of acute cholecystitis in the period June 2008 to June 2013. Patients underwent a mixture of transperitoneal and transhepatic gallbladder puncture. The cystic duct was cannulated with a hydrophilic guidewire which was subsequently passed through the common bile duct and into the duodenum. An 8Fr 12-cm double-pigtail stent was placed with the distal end lying within the duodenum and the proximal end within the gallbladder. RESULTS: Ten patients presented with gallbladder perforation, 21 patients with acute cholecystitis, 1 with acute cholangitis and 1 with necrotising pancreatitis. The technical success rate was 91%. We experienced a 13% complication rate with 3% mortality rate at 30 days. CONCLUSION: Cystic duct stent insertion can be successfully used to manage acute cholecystitis, gallbladder empyema or gallbladder perforations in those unfit for surgery and should be considered alongside external gallbladder drainage as a definitive mid-term treatment option.

Randomized clinical trial of stents versus angioplasty for the treatment of iliac artery occlusions (STAG trial).

BACKGROUND: The management of total iliac artery occlusion is now undertaken routinely using percutaneous techniques but there are no controlled data to indicate whether either balloon angioplasty or stent placement is preferable. This was a multicentre randomized trial to assess whether stents confer any safety or efficacy advantage over balloon angioplasty for complete iliac artery occlusion. METHODS: Six participating centres recruited patients with symptoms of lower limb peripheral arterial disease due to iliac artery occlusion 8 cm or less in length. Patients were assigned randomly to either percutaneous transluminal angioplasty (PTA group) or primary stent placement (stent group) alone after the lesion had been traversed with a guidewire. RESULTS: There were 118 patients recruited to the study; six were excluded from the analysis owing to major protocol violations, leaving a total of 112 patients for analysis. Some 55 patients had PTA and 57 had a primary iliac stent. Technical success was achieved in 46 patients (84 per cent) in the PTA group and 56 (98 per cent) in the stent group (P = 0.007). There were 11 (20 per cent) major procedural complications after PTA compared with three (5 per cent) after primary stenting (P = 0.010). There were no significant differences in primary or secondary patency between the groups after 1 and 2 years. CONCLUSION: Primary stent placement for iliac artery occlusion increased technical success and reduced major procedural complications (predominantly distal embolization) compared with balloon angioplasty. REGISTRATION NUMBER: ISRCTN 48145465 (http://www.controlled-trials.com).

Effect of procedure volume on outcomes after iliac artery angioplasty and stenting.

BACKGROUND: Service reorganization to concentrate complex vascular services in hospitals with high caseload volume aims to reduce mortality and complication rates. The present study assessed the relationship between caseload volume and outcome for iliac artery angioplasty and stenting in England using a routinely available national data set (Hospital Episode Statistics, HES). METHODS: Routine administrative data for iliac artery angioplasty and stent procedures performed in England between 2007 and 2011 were analysed. Associations between centre volume and outcomes (death, complications and duration of hospital stay) were tested and compared for two methods of stratification (quartiles and quintiles) and two statistical tests (odds ratios and the Cochran-Armitage test for trend). Multivariable analysis was also performed. RESULTS: There were 23,308 episodes of care recorded in HES with Office of Population Censuses and Surveys Classification of Surgical Operations and Procedures, fourth revision, codes L54.1 or L54.4 corresponding to iliac artery intervention. There was a gradual increase year by year in number of procedures performed. Univariable and multivariable analysis showed no association between centre volume and either death or complications (multivariable odds ratio, OR 1.00, 95 per cent confidence interval 1.00 to 1.00) for elective and non-elective procedures. Age was associated with higher mortality and complication rates in elective procedures, and with mortality in non-elective procedures. The risk of death after elective iliac angioplasty or stenting was significantly higher in women (multivariable OR 4.98, 2.09 to 13.26). CONCLUSION: There was no association between the outcomes of endovascular iliac artery intervention and centre volume, but outcomes were significantly worse with increasing age and female sex.

United Kingdom carotid artery stent registry: short- and long-term outcomes.

BACKGROUND: Carotid artery stenting (CAS) has evolved to treat carotid artery disease with the intention of prevent stroke. The British Society of Interventional Radiologists developed a voluntary registry to monitor the practice of this novel procedure. We present the data from the United Kingdom (UK) CAS registry for short and long-term outcomes for symptomatic and asymptomatic carotid disease. METHODS: The UK CAS registry collected data from 1998 to 2010 from 31 hospitals across the UK for 1,154 patients. All interventions were enrolled in the registry for both asymptomatic and symptomatic patients. Initial entry forms were completed for each patient entered with data including indications, demographic data, CAS data (including stents and protection device details) and 30-day outcomes. Complications were documented. Follow-up data were collected at yearly intervals. RESULTS: Nine hundred fifty-three (83 %) symptomatic and 201 (17 %) asymptomatic patients were enrolled into the registry. The 30-day all stroke and death rates for symptomatic patients were 5.5 and 2.2 % for those with asymptomatic disease. The 30-day mortality rate was 1.7 % for symptomatic and 0.6 % for asymptomatic patients. For symptomatic patients undergoing CAS, the 7-year all-cause mortality rate was 22.2 % and for asymptomatic patients 18.1 %. The 7-year all-cause mortality and disabling stroke rates were 25.3 and 19.4 %, respectively. CONCLUSION: These data indicate that outside of the tight constraints of a randomised trial, CAS provides effective prophylaxis against stroke and death.

Reliability of skin-type self-assessment: agreement of adolescents' repeated Fitzpatrick skin phototype classification ratings during a cohort study.

BACKGROUND: The Fitzpatrick Skin Phototype Classification (FSPC) is the most commonly used measure of skin type. In questionnaire-based surveys, self-rated FSPC is often used as a measure of respondents' skin type. OBJECTIVE: The objective of this analysis was to assess test-retest reliability of the self-rated FSPC within a 12-month cohort study that examined the psychological sequelae of acne. METHODS: Participants were students aged 14-17 years in four Australian secondary schools; two-government system schools and two private schools. The primary outcomes were a number of psychological measures. The FSPC was assessed by a single concise questionnaire item. Test-retest agreement (as measured by quadratic weighted kappa) of participants' self-rated FSPC at three time-points (baseline, 6 and 12 months) was calculated. RESULTS: Of the 244 participating students, 209 students (86%) completed all three rounds of data collection. A further 26 students (11%) completed two rounds. Quadratic weighted kappa for Rounds 1 and 2 was 0.757 (95% CI 0.663-0.831). For Rounds 2 and 3 it was 0.805 (95% CI 0.659-0.893). Between Rounds 1 and 3 it was 0.767 (95% CI 0.698-0.832). This represents good-to-very-good agreement. Skin type was retained as an independent variable in 8 of the 16 regression models built to explain psychological outcomes in this study. CONCLUSION: Skin type appears to be a significant factor in psychological morbidity in acne. The FSPC is a reliable method for assessing skin phenotype, even when elicited via a concise questionnaire item suitable for assessing skin type as a potential confounder in studies of other outcome factors.

Laser and radiofrequency ablation study (LARA study): a randomised study comparing radiofrequency ablation and endovenous laser ablation (810 nm).

OBJECTIVES: There have been few randomised studies comparing Radiofrequency Ablation(RFA) with other endovenous techniques. The primary aim of this study was to determine whether RFA of the great saphenous vein (GSV) was associated with less pain and bruising than endovenous laser ablation (EVLA). MATERIALS AND METHODS: This trial had two cohorts--patients with bilateral GSV incompetence causing varicose veins (VV) and those with unilateral GSV VVs. In total 87 legs were treated in this study. Limbs in the bilateral group were treated with RFA in one leg and EVLA in the other. In the unilateral group limbs were randomised to RFA or EVLA. RFA was performed using the Celon RFiTT system (Teltow, Germany). EVLA was performed using an 810nm Laser (Biolitec AG, Germany). Phlebectomies were performed as required. Primary endpoints were patient assessed pain and bruising measured by visual analogue scale (VAS). Secondary endpoints were patency assessed by duplex ultrasound at 6 weeks and 6 months. RESULTS: In the bilateral group, RFA resulted in significantly less pain than EVLA on days 2-11 postoperatively. RFA also resulted in significantly less bruising than EVLA on days 3-9. There were no significant differences in mean post operative pain, bruising and activity scores in the unilateral group. Both RFA and EVLA resulted in occlusion rates of 95% at 10 days postoperatively. CONCLUSIONS: RFA was less painful for patients than EVLA and produced less bruising in the postoperative period with comparable success rates but there was no difference in the unilateral group.

Acne's relationship with psychiatric and psychological morbidity: results of a school-based cohort study of adolescents.

BACKGROUND: There is a considerable number of studies linking acne with psychological and psychiatric morbidities, although this literature is not entirely consistent and is largely cross-sectional in methodology. OBJECTIVE: This study aims to establish the relationship of acne and psychological and psychiatric morbidity in adolescents in a community setting and, via a longitudinal methodology, provide evidence for causality in the relationship. METHODS: The study was a 12-month cohort study. Two hundred and forty-four students in Years 8, 9 and 11 (ages 14-17) at four Australian high schools were assessed at baseline 6 months and 12 months. Presence and severity of acne were assessed, along with a number of psychological and psychiatric morbidities and personality traits (depression, anxiety, overall psychiatric morbidity, self-consciousness, neuroticism and introversion/extraversion) and other demographic variables. RESULTS: Of the 244 participating students, 209 (86%) completed all three rounds of data collection. A further 26 (11%) completed two rounds. The study failed to demonstrate an association of the presence of acne or of acne severity with the examined measures of psychological and psychiatric morbidity, and no evidence for an effect of acne in their causation. CONCLUSION: The relationship of acne and psychological morbidities found in previous health care settings was not found in this community sample. This may be due to differences between community and clinical acne populations. Other possible reasons for this finding are attenuation of psychological morbidity in subjects in this study by successful acne treatment, and the role of personality traits in the complex relationship between acne and psychological morbidities. It is suggested that this relationship would be best investigated by means of longer-term cohort studies enlisting subjects at an early age, prior to the onset of acne.

Carotid endarterectomy improves cerebrovascular reserve capacity preferentially in patients with preoperative impairment as indicated by asymmetric BOLD response to hypercapnia.

PURPOSE: In patients with symptomatic carotid artery disease the predominant mechanism causing ischaemic injury is considered to be thromboembolic, however compromise of cerebral haemodynamics is considered to be a significant factor. Removal of the embolic source is accepted as the major benefit from carotid endarterectomy (CEA), however improvement in cerebral haemodynamics may be another beneficial outcome as suggested by transcranial doppler (TCD). Blood oxygen level-dependent (BOLD) hypercapnia functional magnetic resonance imaging (fMRI) can be used to map the cerebrovascular reserve (CVR). The aim of this study was to assess the effects of carotid surgery on cerebral haemodynamics in patients with carotid artery disease using a hypercapnia BOLD fMRI and assessment of hemispheric asymmetry. MATERIALS AND METHODS: Seventeen patients with symptomatic internal carotid artery stenosis were scanned using a clinical 1.5T MR scanner. Scanning was done immediately prior to and between 4 and 8 weeks after CEA. 10% carbon dioxide was administered to achieve transient episodes of hypercapnia. The data was analyzed using FMRIB Software Library (FSL) software to derive percentage signal change (PSC) for the grey matter of the middle cerebral artery (MCA-GM) territory for both hemispheres. MCA-GM PSC was furthermore normalized to the contralateral hemisphere to derive an Hemispheric Asymmetry Index (hAI) for all patients pre- and postoperatively. RESULTS: Ipsilateral GM CVR improved significantly following CEA (2.47% preoperatively vs. 2.73% postoperatively, p=0.038). There was no change in CVR in the contralateral grey and white matter MCA territories (p=0.27, p=0.1). Also, the hAI was significantly more shifted to the ipsilateral hemisphere after CEA (preoperative hAI -0.56, vs. -3.90 postoperatively, p=0.02). Patients with an impaired hAI preoperatively were found to show the greatest improvement in PSC and hAI following CEA (p=0.007). CONCLUSIONS: CEA resulted in improved CVR in patients with carotid artery disease as shown by the absolute and hemispheric asymmetry of BOLD response to hypercapnia.. These findings show that benefits from recanalisation may go beyond removal of the embolic source, by improving the cerebrovascular reserve. Moreover, hypercapnia BOLD fMRI may be a useful clinical tool in predicting this therapeutic potential in patients with severe carotid artery disease.

The importance of anatomical suitability and fitness for the outcome of endovascular repair of ruptured abdominal aortic aneurysm.

INTRODUCTION: Endovascular repair of aortic aneurysm (EVAR) has a lower mortality than open repair. The aim of this study was to assess mortality from EVAR for emergency AAA repair and the impact of fitness for operation and adverse anatomy. METHODS: One-hundred and forty two patients who had EVAR for a ruptured AAA (80, REVAR) or a symptomatic AAA (62, SEVAR) between 1994 and 2007 in a single specialist endovascular centre were reviewed. Fitness for surgery was assessed by Hardman's index (age>76, loss of consciousness, Hb<9.0, Cr>190, ischaemic ECG). CT scans were reviewed, compared with operative images and operation notes for adverse anatomy. Details of perioperative complications, and outcome were recorded. RESULTS: Overall mortality at 24-h, 30-days and one year were, respectively: 17%, 36%, 50% for REVAR and 5%, 8%, 23% for SEVAR. Overall adverse anatomy increased 30-day mortality. Hardman's index of three or more increased mortality HR=2.59 (1.24-5.41), p=0.01. On Cox regression Univariate analysis increasing Hardman's index score and adverse anatomy increased the overall mortality over time. In multivariate Cox regression analysis (controlled for the Hardman's index) adverse anatomy was associated with significant increase in graft related mortality. CONCLUSION: The use of EVAR is feasible in patients who present with a ruptured or acutely symptomatic AAA. Care must be taken not to extend anatomical or clinical guidelines.

Suitability of varicose veins for endovenous treatments.

The aim of the study was to assess the suitability of radiofrequency ablation (RFA), endovenous laser ablation (EVLA), and foam sclerotherapy (FS) for patients with symptomatic varicose veins (VVs). The study comprised 403 consecutive patients with symptomatic VVs. Data on 577 legs from 403 consecutive patients with symptomatic VVs were collected for the year 2006. Median patient age was 55 years (interquartile range 45-66), and 62% patients were women. A set of criteria based on duplex ultrasonography was used to select patients for each procedure. Great saphenous vein (GSV) reflux was present in 77% (446 of 577) of legs. Overall, 328 (73%) of the legs were suitable for at least one of the endovenous options. Of the 114 legs with recurrent GSV reflux disease, 83 (73%) were suitable to receive endovenous therapy. Patients with increasing age were less likely to be suitable for endovenous therapy (P = 0.03). Seventy-three percent of patients with VVs caused by GSV incompetence are suitable for endovenous therapy.

Precision of cerebrovascular reactivity assessment with use of different quantification methods for hypercapnia functional MR imaging.

BACKGROUND AND PURPOSE: Tools for noninvasive mapping of hemodynamic function including cerebrovascular reactivity are emerging and may become clinically useful to predict tissue at hemodynamic risk. One such technique assesses blood oxygen level-dependent (BOLD) MR imaging contrast in response to hypercapnia, but the reliability of its quantification is uncertain. The aim of this study was to prospectively investigate the intersubject and interhemispheric variability and short-term reproducibility of hypercapnia functional MR imaging (fMRI) in healthy volunteers and to assess the effects of different methods of quantification and normalization. MATERIALS AND METHODS: Sixteen healthy volunteers, (7 women and 9 men) underwent hypercapnia fMRI with a clinical 1.5T scanner; 8 underwent scanning twice. We determined BOLD amplitude changes using a visually defined block design or automated regression to end-tidal (ET) carbon dioxide (CO2). Absolute percent signal intensity changes (PSC) were extracted for whole-brain, gray matter, and middle cerebral artery territory, and also normalized to ETCO2 change. Intersubject and intrasubject (between hemispheres and sessions) coefficients of variation (COV) were derived. We assessed the effects of different quantification methods on reproducibility indices using the t test and U tests. RESULTS: The mean change in ETCO2 was 7.8 +/- 3.3 mm Hg. Averaged BOLD increases varied from 2.54% to 2.92%. Short-term reproducibility was good for absolute PSC (4.8% to 10%) but poor for normalized PSC (range, 24% to 27% COV). Intersubject reproducibility varied between 11% and 23% for absolute PSC and, again, was poorer for normalized data (32% to 39%). Interhemispheric reproducibility of absolute PSC was excellent ranging between 1.24 and 2.16% COV. CONCLUSIONS: In conclusion, quantification of cerebrovascular reactivity with use of hypercapnia fMRI was found to have good between-session and very good interhemispheric reproducibility. The technique holds promise as a diagnostic tool, especially for sensitive detection of unilateral disease.

A cross-sectional study of psychological morbidity in patients with acne, psoriasis and atopic dermatitis in specialist dermatology and general practices.

BACKGROUND: There is considerable evidence for an association of skin diseases with psychological morbidity. This relationship is best established for acne, psoriasis and atopic eczema. Previous studies have mostly been performed in specialist dermatological practice, and there is a lack of studies that include patients from general practice and a lack of controlled studies employing multivariate analysis. AIMS/OBJECTIVES: This study aims to examine the relationship of acne, psoriasis and atopic eczema with psychological morbidities in patients recruited from general practice as well as specialist dermatology practice. METHODS AND SUBJECTS: In this cross-sectional study, 108 patients from general and specialist dermatology practices with the three diseases had disease severity assessed and completed measures of minor psychological disturbance (General Health Questionnaire-12), anxiety and depression (Hospital Anxiety and Depression Scale), public self-consciousness and social anxiety (Fenigstein Self-Consciousness Scale), and neuroticism and extraversion/introversion (Eysenck Personality Inventory). Demographic data were also collected, along with self-ratings of disease severity. Control subjects were 96 patients without skin disease recruited from the same general practices as the subjects. RESULTS: On univariate analyses, patients with skin disease had higher levels of minor psychological disturbance, public self-consciousness and neuroticism than did controls. There were no differences in psychological measures between specialist and general practice patients or between patients with different skin diseases. On multivariate analyses, the significant differences did not persist. CONCLUSIONS: This study demonstrates confounding in the relationship of skin diseases with psychological morbidity. The complex relationship of skin disease and psychological morbidity should be re-examined.

Intraplaque haemorrhage mimicking carotid pseudoaneurysm on magnetic resonance angiography.

Contrast-enhanced magnetic resonance angiography (CE-MRA) is a commonly used technique to assess the extracranial carotid arteries. We describe two patients (investigated for carotid artery atherosclerotic disease) who underwent CE-MRA. Results suggested pseudoaneurysms of the extracranial carotid arteries. Magnetic resonance direct thrombus imaging (MRDTI) showed that the appearances were due to intraplaque haemorrhage adjacent to the vessel, with the T1-shortening effect of methaemoglobin within the intraplaque haemorrhage mimicking blood flow on the CE-MRA sequence. The cases presented demonstrate this diagnostic pitfall and illustrate the contribution of simple magnetic resonance plaque imaging to establishing the correct diagnosis.

Evaluation of therapeutic effectiveness using MR imaging in a rabbit model of anterior uveitis.

Magnetic resonance imaging (MRI) has been used to examine conditions that alter the permeability of the blood-retinal barrier. Our goal was to determine if blood-aqueous barrier permeability could be similarly assessed, because MRI offers the theoretical advantage of providing quantitative data directly from inflamed uveal tissues rather than from the aqueous humor into which the inflammatory reaction spills. As an additional challenge, we sought to use MRI to measure differences between the inflamed uveal tissues of corticosteroid-treated and placebo-treated uveitic eyes. Anterior uveitis was induced in one eye of eight rabbits by subcutaneous injection of Mycobacterium tuberculosis, followed after 10 days with intravitreal challenge. One rabbit of each pair was treated with topical 1% prednisolone acetate while control rabbits were treated with artificial tears. Contrast-enhanced MRI studies were performed prior to uveitis induction, one day after induction and then weekly for at least 2 weeks. MR image data were analyzed to determine percent change in peak enhancement of the ciliary body and anterior chamber. The initial rate of change of enhancement of the anterior chamber was also measured. Extensive contrast agent-induced MR image enhancement of both the anterior chamber and the ciliary processes was measured following the induction of uveitis. More rapid improvement was measured for the 1% prednisolone acetate-treated rabbit eyes (P < 0.001). MR signal enhancement data obtained from the ciliary processes proved to be the most reliable indicator of disease activity in this rabbit model of uveitis. Such data can only be obtained using MRI.

Transjugular intrahepatic portosystemic shunt vs. small-diameter prosthetic H-graft portacaval shunt: extended follow-up of an expanded randomized prospective trial.

We report herein the results of extended follow-up of an expanded randomized clinical trial comparing transjugular intrahepatic portosystemic shunt (TIPS) to 8 mm prosthetic H-graft portacaval shunt as definitive treatment for variceal bleeding due to portal hypertension. Beginning in 1993, through this trial, both shunts were undertaken as definitive therapy, never as a "bridge to transplantation." All patients had bleeding esophageal/gastric varices and failed or could not undergo sclerotherapy/banding. Patients were excluded from randomization if the portal vein was occluded or if survival was hopeless. Failure of shunting was defined as inability to shunt, irreversible shunt occlusion, major variceal rehemorrhage, hepatic transplantation, or death. Median follow-up after each shunt was 4 years; minimum follow-up was 1 year. Patients undergoing placement of either shunt were very similar in terms of age, sex, cause of cirrhosis, Child's class, and circumstances of shunting. Both shunts provided partial portal decompression, although the portal vein-inferior vena cava pressure gradient was lower after H-graft portacaval shunt (P < 0.01). TIPS could not be placed in two patients. Shunt stenosis/occlusion was more frequent after TIPS. After TIPS, 42 patients failed (64%), whereas after H-graft portacaval shunt 23 failed (35%) (P < 0.01). Major variceal rehemorrhage, hepatic transplantation, and late death were significantly more frequent after TIPS (P < 0.01). Both TIPS and H-graft portacaval shunt achieve partial portal decompression. TIPS requires more interventions and leads to more major rehemorrhage, irreversible occlusion, transplantation, and death. Despite vigilance in monitoring shunt patency, TIPS provides less optimal outcomes than H-graft portacaval shunt for patients with portal hypertension and variceal bleeding.

Marimastat in patients with advanced pancreatic cancer: a dose-finding study.

Patients with solid tumors, including carcinoma of the pancreas, express high levels of matrix metalloproteinases (MMP), and these enzymes are believed to be important for the growth, spread, and dissemination of most solid malignant tumors. Marimastat is the first orally available MMP inhibitor (MMPI) to be tested in humans and has been shown to inhibit the spread and growth of pancreatic cancer in animal models. The purpose of the present study was to define the toxicities, safety, and tolerance of various doses of marimastat and also to get an early indication of potential biologic activity in patients with advanced pancreatic cancer. The authors prospectively studied 64 patients with advanced carcinoma of the pancreas in whom standard treatments had failed. Eligible patients had a progressive rise in CA 19/9 levels of >25% over the 4-week period preceding their entry into the study. Patients were studied in groups of 8 to 10, with each group receiving escalating dosages ranging from 5 mg twice daily to 75 mg twice daily and 10 to 25 mg daily. Patients were considered for long-term (beyond 4 weeks) continuation treatment if clinical benefit, in the view of the investigator, was derived. Study endpoints were safety, tolerance, and changes in the rate of rise of CA 19/9, which were used as surrogate markers for disease progression. Marimastat was well tolerated. Musculoskeletal pain, stiffness, and tenderness emerged as dose-limiting toxicity. No other dose-related toxicities were observed. A reduced rate of rise of CA 19/9 was observed at dose levels of 5, 10, and 25 mg twice daily. The overall median survival was 160 days, with a 1-year survival of 21%. Marimastat was associated with an acceptable toxicity profile, and these preliminary data suggest that long-term oral administration is feasible and safe. Doses of 5, 10, and 25 mg twice daily were identified as the optimal doses to be tested in larger randomized studies.