The upper limb of Paranthropus boisei from Ileret, Kenya.

Paranthropus boisei was first described in 1959 based on fossils from the Olduvai Gorge and now includes many fossils from Ethiopia to Malawi. Knowledge about its postcranial anatomy has remained elusive because, until recently, no postcranial remains could be reliably attributed to this taxon. Here, we report the first associated hand and upper limb skeleton (KNM-ER 47000) of P. boisei from 1.51 to 1.53 Ma sediments at Ileret, Kenya. While the fossils show a combination of primitive and derived traits, the overall anatomy is characterized by primitive traits that resemble those found in Australopithecus, including an oblique scapular spine, relatively long and curved ulna, lack of third metacarpal styloid process, gracile thumb metacarpal, and curved manual phalanges. Very thick cortical bone throughout the upper limb shows that P. boisei had great upper limb strength, supporting hypotheses that this species spent time climbing trees, although probably to a lesser extent than earlier australopiths. Hand anatomy shows that P. boisei, like earlier australopiths, was capable of the manual dexterity needed to create and use stone tools, but lacked the robust thumb of Homo erectus, which arguably reflects adaptations to the intensification of precision grips and tool use. KNM-ER 47000 provides conclusive evidence that early Pleistocene hominins diverged in postcranial and craniodental anatomy, supporting hypotheses of competitive displacement among these contemporaneous hominins.

An observational study to compare the utilisation of computed tomography colonography with optical colonoscopy as the first diagnostic imaging tool in patients with suspected colorectal cancer.

AIM: To evaluate the clinical and cost implications of using computed tomography colonography (CTC) compared to optical colonoscopy (OC) as the initial colonic investigation in patients with low-to-intermediate risk of colorectal cancer (CRC). MATERIALS AND METHODS: A non-randomised, prospective single-centre study recruited 180 participants to compare the cost implications of two clinical pathways used in the diagnosis of low-to-intermediate risk of CRC that differ in the initial diagnostic test, either CTC or OC. Costs were compared using generalised linear models (GLM) and combined with quality-adjusted life years (QALYs, based on the EQ-5D-5L) to estimate cost-effectiveness at 6 months post-recruitment. Secondary outcomes assessed access to care and patient satisfaction. RESULTS: Mean (SD, n) cost at 6 months post-recruitment per participant was £991 (£316, n=105) for the OC group and £645 (£607, n=68) for the CTC group, leading to an estimated cost difference of -£370 (95% CI: -£554, -£185, p<0.001). Assuming a £20,000 willingness-to-pay per QALY threshold, there was a 91.4% probability of CTC being cost-effective at month 6. The utilisation of CTC led to improved access to care, with a shorter mean time from referral from primary care to results (6.3 days difference, p=0.005). No differences in patient satisfaction were detected between both groups. CONCLUSION: The utilisation of CTC as the first-line investigation for patients with low-to-intermediate risk of CRC has the potential to release OC capacity, of pivotal importance for patients more likely to benefit from an invasive diagnostic approach.

Malignancy and mesenteric panniculitis.

AIM: Mesenteric panniculitis (MP) is a chronic inflammatory process of the small bowel mesentery that has been reported in conjunction with malignancy. The objectives of the present study were to identify the frequency and type of cancers that may coexist with MP and whether these can be seen on the initial diagnostic computerised tomography (CT). METHOD: A prospective database was kept of patients diagnosed with MP in the Canterbury region of New Zealand between 1 January 2003 and 31 December 2014. CT scans were independently reviewed. Clinical records were reviewed and family doctors were contacted for additional information. RESULTS: There were 302 patients with possible MP identified and 259 in whom it was confirmed on review. Seventy-eight patients had a diagnosis of malignancy, with 54 having a current cancer (59 total cancers), 33 a past cancer and nine both. Of the 59 current cancers the most common primary sites were colorectum (19), lymph nodes (17), kidney (six) and prostate (four). Fifty-four were at sites included on an abdominal CT scan. At all sites [except prostate (0/4)] there were high rates of detection on CT with 44/54 cancers visible including 20/23 gastrointestinal tract, 14/17 lymphomas and 9/9 non-prostate urogenital tract malignancies. Six people were subsequently diagnosed with cancer after the index CT. CONCLUSION: When MP occurs in association with malignancy, the commonest primary sites are large bowel, the lymph nodes and the urogenital tract. In those with MP on imaging, any cancer except prostate can usually be seen on the index CT. Further extensive investigation in asymptomatic patients is therefore likely to be of low yield.

Agreement and consistency in the triaging of musculoskeletal primary care referrals by vetting clinicians using a knowledge-based triage tool.

BACKGROUND: Primary care referrals received by secondary care services are vetted or triaged to pathways best suited for patients' needs. If knowledge-based triaging is used by vetting clinicians, accuracy is required to avoid incorrect decisions being made. With limited evidence to support best practice, we aimed to evaluate consistency across vetting clinicians' decisions and their agreement with a criterion decision. METHODS: Twenty-nine trained vetting clinicians (18 female) representative of pay grades independently triaged five musculoskeletal physiotherapy referral cases into one of 10 decisions using an internally developed triage tool. Agreement across clinicians' decisions between and within cases was assessed using Fleiss's kappa overall and within pay grade. Proportions of triage decisions consistent with criterion decisions were assessed using Cochran's Q test. RESULTS: Clinician agreement was fair for all cases (κ = 0.385) irrespective of pay grade but varied within clinical cases (κ = -0.014-0.786). Proportions of correct triage decisions were significantly different across cases [Q(4) = 33.80, P < 0.001] ranging from 17% to 83%. CONCLUSIONS: Agreement and consistency in decisions were variable using the tool. Ensuring referrer information is accurate is vital, as is developing, automating and auditing standards for certain referrals with clear pathways. But we argue that variable vetting outcomes might represent healthy pathway abundance and should not simply be automated in response to perceived inefficiencies.

Accuracy of hepatocellular carcinoma detection on multidetector CT in a transplant liver population with explant liver correlation.

AIM: To evaluate the diagnostic accuracy of multidetector computed tomography (MDCT) for hepatocellular carcinoma (HCC) in cirrhotic patients undergoing liver transplantation. Secondary aims were to examine the effect of radiologist experience and lesion size on diagnostic accuracy. MATERIALS AND METHODS: Thirty-nine patients (72% male with a mean age of 56.5 years) underwent liver transplantation following preoperative triple-phase MDCT examination of the liver. MDCT examinations were retrospectively independently reviewed by three radiologists for the presence and location of suspected HCCs, with the diagnostic confidence recorded using a five-point confidence scale. MDCT examinations were compared with explant specimens for histopathological correlation. RESULTS: Histopathological results demonstrated 46 HCCs in 29 of the 39 patients. Analysis demonstrated a sensitivity of 65-75% and specificity of 47-88% for detection of HCC lesions. The sensitivity dropped to 48-57% for lesions of size ≤20mm. As the diagnostic confidence increased, there was a further decrease in the sensitivity (4-26%). The radiologist with the greatest number of years experience was found to have a significantly higher accuracy of detection of HCC lesions compared with the least experienced radiologist. CONCLUSION: Larger lesion size of HCC and greater number of years experience of the radiologist resulted in significantly higher accuracy of HCC lesion detection. The overall sensitivity and specificity results for MDCT detection of HCC are comparable to previous helical CT imaging.

Two-year audit of computed tomographic colonography in a teaching hospital: are we meeting the standard?

OBJECTIVE: We aimed to determine whether adopting the published recommendations has led to successful implementation of computed tomographic colonography (CTC) in a teaching hospital setting outside the context of a clinical trial. METHOD: An audit of all the CTC examinations between April 2005 and June 2007 was conducted to determine the following: adequacy of bowel preparation, CTC indications and findings (compared with available colonoscopy), complications and experience of reporting radiologist. RESULTS: The most common indications for the 111 CTC patients reviewed included exclusion of synchronous colonic tumours, incomplete colonoscopy and altered bowel habit. Only 16% of ascending colon/caecal segments was clear of faecal or fluid contamination. The rectum and sigmoid colon were free of contamination in 78% and 74% of cases respectively. Appropriately trained radiologists reported 91% of studies. Thirty-two percent of studies were normal. The most common positive findings were diverticular disease or a rectal tumour. Sensitivity, specificity and positive predictive value were 89%, 94% and 90% respectively (all polyps) with a sensitivity of 98.5% for lesions > 5 mm in size. Twenty-five percent of patients had extra colonic abnormalities. There were no recorded complications. CONCLUSION: Our CTC practice is within accepted published guidelines. Bowel preparation is suboptimal in a significant proportion of cases and faecal tagging is being implemented.

Acetazolamide and exercise hypoxia.

Acetazolamide is useful for acclimatizing to high altitude. How long it should be taken, and the physiological consequences of stopping it have not been thoroughly studied. We investigated the effect of acetazolamide cessation on exercise oxygenation at different altitudes and durations of use. Three groups were studied: group 1 acclimatized to 4,060 m for 6 days while taking acetazolamide 250 mg three times a day. On day 7 acetazolamide was stopped, then resumed on day 8. Standardized exercise oximetry was performed each day. The protocol for group 2 was identical to group 1, except acclimatization occurred over 14 days to 4 120 m. The protocol for group 3 was identical to group 2, except subjects acclimatized to 4,770 m. Multivariate regression revealed a negative effect of stopping acetazolamide on exercise oxygenation (p=0.028). At 4,100 m cessation of acetazolamide after one week resulted in a 11% drop in exercise oxygenation (p=0.008); after two weeks acclimatization to this altitude there was an non-significant drop in exercise oxygenation (2.5% p=0.064). At 4 770 m acetazolamide cessation resulted in an increase in exercise oxygenation (7% p=0.027). We conclude that exercise oxygenation after acetazolamide cessation is dependent both on duration of acclimatization/drug administration, and acclimatization altitude.

Requirement for B cell linker protein (BLNK) in B cell development.

Linker proteins function as molecular scaffolds to localize enzymes with substrates. In B cells, B cell linker protein (BLNK) links the B cell receptor (BCR)-activated Syk kinase to the phosphoinositide and mitogen-activated kinase pathways. To examine the in vivo role of BLNK, mice deficient in BLNK were generated. B cell development in BLNK-/- mice was blocked at the transition from B220+CD43+ progenitor B to B220+CD43- precursor B cells. Only a small percentage of immunoglobulin M++ (IgM++), but not mature IgMloIgDhi, B cells were detected in the periphery. Hence, BLNK is an essential component of BCR signaling pathways and is required to promote B cell development.

The role of a consultant radiologist--are patients still in the dark?

Little is known regarding public awareness of the roles and responsibilities of a consultant radiologist. Between 1 April and 20 May 2008, 916 outpatients attending our radiology department completed a questionnaire addressing this issue. We found public perception variable. Thirty-six percent of respondents thought we were responsible for choosing appropriate imaging; only 65% perceived that we reported studies. Another 38% felt that we did not play an important role in their treatment, and 38% considered that we were not part of their medical team. Thirty-two percent of respondents preferred their hospital consultant to give them their imaging results, with 17% preferring this to come from the radiologist. There is significant under-appreciation of the roles and responsibilities of a consultant radiologist. It is important that we educate the public to ensure that future health policy reflects the increasingly central role imaging plays in health-care delivery.

Cysts, cavities, and honeycombing in multisystem disorders: differential diagnosis and findings on thin-section CT.

Pulmonary cysts, cavities, and honeycombing are seen in a number of systemic disorders. The purpose of this review is to discuss the findings on thin-section computed tomography (CT) in both congenital and acquired multisystem conditions that give rise to multiple cystic spaces in the lungs. Conditions discussed include lymphangioleiomyomatosis, Langerhan's cell histiocytosis, lymphocytic interstitial pneumonia, and Birt-Hogg-Dubé syndrome, with reference to specific features that may be helpful in the differentiation of these conditions on CT.

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

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

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

CT and histopathological correlation of congenital cystic pulmonary lesions: a common pathogenesis?

AIM: To determine whether similarities exist in both the imaging and histopathological features of congenital cystic lung lesions and whether a more appropriate classification would be to adopt the theory of "malinosculation". MATERIAL AND METHODS: From the histopathology and computed tomography (CT) database, 24 patients (16 male, median age 3 years) with congenital cystic lung lesions were identified. CT studies were reviewed for site and characteristics of the lesions, parenchymal features, bronchial anatomy, and the presence of a feeding systemic vessel. Individual histopathological parameters were also correlated with CT data. RESULTS: There were five type 1 congenital cystic adenomatoid malformations (CCAMs), six type 2 CCAMs, one type 4 CCAM, one bronchial atresia, four pleuropulmonary blastomas (PPBs), and seven sequestrations. CCAMs (types 1, 2 and 4), sequestrations and PPBs appeared as cystic lesions, with cyst size less than 2 cm in type 2 CCAMs. Sequestrations were distinguished radiologically from CCAMs by systemic vessels. Reduced pulmonary attenuation was seen in bronchial atresia, type 2 CCAMs and in sequestrations. Histopathology showed an overlap in entities with sequestrations demonstrating CCAM type 2 histology and segmental atresia noted in both type 2 CCAMs and sequestrations. PPBs showed histological and imaging overlap with type 4 CCAMs and were distinguished on histology by the presence of blastematous proliferation. CONCLUSIONS: This study demonstrates overlap in the CT appearances of congenital cystic lesions. The similarity in CT and histopathology findings across the spectrum of developmental lesions supports the hypothesis of a common aetiology.

High resolution imaging of the knee on 3-Tesla MRI: a pictorial review.

The recent introduction of 3-Tesla MRI offers substantial advances in musculoskeletal applications. High resolution images can now be obtained with shorter data acquisition times. This article provides a pictorial review of 3-Tesla imaging in the knee with descriptions of both normal anatomy and the more common lesions involving the menisci, ligaments, and articular cartilage. A discussion of the issues associated with imaging at higher field strengths is also included.

Cross-sectional geometric analysis of a foot bone assemblage from Mangaia, Cook Islands.

This study describes a human foot bone assemblage from prehistoric Mangaia, Cook Islands in the context of diaphyseal cross-sectional strength measures. We use this sample to test the hypothesis that habitually unshod individuals who walk over rugged terrain will have stronger foot bones than a sample of habitually shod industrialized people. Specifically, we examine whether the Mangaian sample has a stronger size-adjusted metatarsal (MT) and phalangeal cross-sectional properties than the industrial sample, drawn from the Terry Collection. Contrary to expectations, residual analyses showed that most values of cross-sectional area (CA) and torsional resistance (J) of MTs 1-4 and the hallucal proximal phalanx (HPP) of the Mangaians are among those in the lower range of the Terry Collection sample. However, the bending strength ratios (Zy/Zx) of the Mangaian HPP are significantly greater than those of the Terry Collection. While characteristics such as forefoot shape variation between the sexes and among geographic populations cannot be ruled out as influential factors, cross-sectional properties of the hallucal proximal phalanges, but not the MTs, indicate terrain complexity in prehistoric populations.

From laboratory to Phase I/II cancer trials with recombinant biotherapeutics.

Many promising recombinant cancer medicines are generated by academic research and increasing the number of these products that are translated into the clinic will increase the pipeline of new therapies. Recombinant proteins for use in Phase I/II cancer trials must be produced to standards of Good Manufacturing Practice (GMP) in compliance with EU law. This can be a major obstacle for translating experimental products to clinical reality especially when there is no established process or prior experience with GMP. Here, we illustrate the principals of GMP with a step-by-step guide and we show that GMP can be achieved on a relatively small scale in the researchers own institution. The process is exemplified with an antibody-based therapeutic expressed in the yeast Pichia pastoris. The purified product has been used safely in patients and the principles are applicable to any recombinant protein required for Phase I/II cancer trials.

Patterns of recurrence in oesophageal cancer following oesophagectomy in the era of neoadjuvant chemotherapy.

BACKGROUND: Tumour recurrence following oesophagectomy for oesophageal cancer is common despite neoadjuvant treatment. Understanding patterns of recurrence and risk factors associated with locoregional and systemic recurrence might influence future treatment strategies. METHODS: This was a cohort study involving patients undergoing resection for adenocarcinoma or squamous cell carcinoma of the oesophagus between 2000 and 2014. Clinicopathological factors associated with locoregional and systemic recurrence were analysed using multivariable logistic regression to determine odds ratios (ORs) and 95 per cent confidence intervals. RESULTS: Some 698 patients were identified. Lymphovascular invasion (OR 2·09, 95 per cent c.i. 1·18 to 3·71) and preoperative stenting (OR 3·70, 1·34 to 10·23) were independent risk factors for isolated locoregional recurrence. Pathological nodal disease in patients with pT1-2 (pN1: OR 2·72, 1·35 to 5·48; pN2-3: OR 5·00, 2·35 to 10·66) or pT3-4 (pN1: OR 3·03, 1·51 to 6·07; pN2-3: OR 5·75, 3·15 to 10·49) disease predisposed to systemic recurrence. Poor or no response to chemotherapy was also an independent risk factor for isolated systemic recurrence (OR 1·85, 1·05 to 3·26). A positive resection margin (R1 resection) was not associated with a significantly increased risk of isolated locoregional recurrence (OR 1·37, 0·81 to 2·33). CONCLUSION: These findings confirm that oesophageal adenocarcinoma is frequently a systemic disease. Understanding the key predictors of local and systemic recurrence may facilitate the tailoring of oncological therapies to the individual patient.

The posterior pituitary regulates prolactin, but not adrenocorticotropin or gonadotropin, secretion in the sheep.

The aim of this study was to determine the role of the posterior pituitary gland in the control of PRL, LH, FSH, and ACTH secretion in sheep. Posterior pituitary function was removed in ovariectomized ewes by electrical lesioning of the hypothalamo-neurohypophysial tract immediately posterior to the stalk-median eminence (LESION); controls were subjected to sham surgery (SHAM). LESION caused a 2-fold increase in plasma PRL concentrations on days 1-3 after surgery. Thereafter, concentrations gradually declined until they were similar to those in SHAM ewes. There was no change in plasma concentrations of LH, FSH, or ACTH after LESION. Plasma PRL responses to insulin in SHAM ewes were completely abolished, and the plasma PRL response to chlorpromazine was reduced to almost half by LESION. In contrast, audiovisual stress (barking dog) and serotonin challenge caused an immediate release of PRL in both LESION and SHAM ewes, with the amplitude of the responses indistinguishable between groups. LESION had no effect on the plasma ACTH responses to audiovisual stress, insulin, or serotonin. We conclude that the posterior pituitary gland is involved in the regulation of PRL under some circumstances, but not of LH, FSH, or ACTH secretion in the sheep. Accordingly, changes in PRL release after hypothalamopituitary disconnection in this species may reflect a loss of posterior lobe function rather than the removal of hypothalamic inputs. In addition, the PRL response to insulin is dependent on a functional posterior pituitary gland, whereas responses to audiovisual stress and serotonin appear to rely on inputs to the pituitary gland via the median eminence and the long hypothalamo-hypophysial portal blood vessels.

Antibodies raised by gastrimmune inhibit the spontaneous metastasis of a human colorectal tumour, AP5LV.

Both precursor forms of gastrin and mature amidated gastrin peptides can enhance proliferation of colorectal tumours and may regulate growth in an autocrine manner. The purpose of this study was to evaluate the effect of neutralization of precursor and amidated gastrin on primary and secondary in vivo growth of a human colorectal tumour. The human colorectal cell line, AP5LV, when injected into the muscle layer of the abdominal wall of severe combined immunodeficient (SCID) mice, grows as a well-vascularized primary tumour and metastasis to the lung. AP5LV expressed the precursor gastrin forms; progastrin and glycine-extended gastrin and gastrin/CCKB receptors, as assessed by immunocytochemistry. Gastrimmune is a gastrin immunogen in which the amino terminus of the gastrin-17 molecule is linked to diphtheria toxoid and induces antibodies which neutralise the amidated and glycine-extended forms of gastrin-17. Rabbit antiserum, raised against Gastrimmune, was administered intravenously into SCID mice bearing AP5LV tumours. Control animals were treated with antiserum raised against diphtheria toxoid only. Antibodies raised against Gastrimmune significantly limited the growth of primary AP5LV tumours, as assessed by median cross-sectional area (controls = 244 mm2; antibody-treated = 179 mm2; P = 0.033). In addition Gastrimmune-induced antiserum limited the growth of lung metastasis as assessed by nodule number (controls = 3.5; antibody-treated = 1.0; P = 0.0001) and nodule cross-sectional as assessed by image analysis (controls = 11.9 mm2; antibody-treated = 3.75 mm2; P = 0.0064). In conclusion in vivo neutralization of gastrin forms, which may potentially be fueling growth by an autocrine pathway, inhibited both primary growth and, to a greater degree, lung metastasis of a human colorectal tumour cell line. Immunization against tumour-associated gastrin forms may provide an effective therapy for advanced colorectal cancer.

A pilot study of the safety and effects of the matrix metalloproteinase inhibitor marimastat in gastric cancer.

The aim of this study was to evaluate the safety and tolerability of 4 weeks administration of marimastat, and to seek evidence of biological activity as observed by changes in the endoscopic appearance of the gastric tumours. 35 patients with advanced, inoperable gastric or gastro-oesophageal tumours were recruited. The dose of marimastat was reduced from the starting dose of 50 mg twice daily (6 patients) to 25 mg once daily (29 patients). 31 completed the 28 day study period. Marimastat was generally well tolerated, with the principal treatment-related toxicity being pain and stiffness of the musculoskeletal system. These symptoms occurred more frequently at the higher-dose, and increased to involve a total of 13 patients (37%) with longer-term treatment. The events were usually rapidly reversible on drug discontinuation. 3 patients receiving prolonged treatment experienced more severe symptoms, with the development of skin thickening and contractures in the hands. At endoscopy, 10 patients showed an increased fibrotic cover of the tumour, 8 had decreased haemorrhagic appearance, and in at least 2 cases where comparative tumour histology was assessable, there was evidence of increased stromal fibrotic tissue.

Direct pituitary inhibition of prolactin secretion by dopamine and noradrenaline in sheep.

The effects of dopamine, noradrenaline and 3,4-dihydroxyphenylacetic acid (DOPAC) on the release of prolactin were examined in ovariectomized ewes. Infusion of dopamine (0.5 or 1 microgram/kg per min for 2 h i.v.) reduced plasma prolactin concentrations in a dose-dependent manner, whereas DOPAC (5 or 10 micrograms/kg per min for 2 h i.v.) had no effect. In a further series of experiments, ovariectomized hypothalamopituitary disconnected ewes were given dopamine or noradrenaline (each at 0.5 or 1 microgram/kg per min for 2 h i.v.), and both amines reduced mean plasma concentrations of prolactin with similar potency in a dose-dependent manner. These effects were blocked by treatment with pimozide and prazosin respectively. During the infusion of dopamine, the peripheral plasma concentrations of DOPAC and 3,4-dihydroxyphenylethyleneglycol (DHPG) were increased (DOPAC, 22 +/- 7 (S.E.M.) to 131 +/- 11 nmol/l; DHPG, 2.9 +/- 0.3 to 6.4 +/- 0.2 nmol/l), but plasma concentrations of dopamine and noradrenaline did not change. Finally, administration of domperidone, a specific dopamine receptor antagonist that does not cross the blood-brain barrier, resulted in a sustained increase in plasma prolactin concentrations in ovariectomized ewes. We conclude that the secretion of prolactin from the pituitary gland is under dual inhibitory regulation by both dopamine and noradrenaline in the sheep.