Health-Related Quality of Life Following Simultaneous Resection for Synchronous Colorectal Cancer Liver Metastases.

INTRODUCTION: Up to 25% of colorectal cancer patients present with synchronous liver metastases that can be treated with two operations or a single 'simultaneous' operation. Morbidity and mortality appear similar between approaches, however changes in health-related quality-of-life following simultaneous resection are not well reported. METHODS: A prospective, feasibility trial for simultaneous resection of synchronous colorectal liver metastases was conducted. Patients completed the European Organization for Research and Treatment of Cancer QLQ-C30 and LMC21 at baseline (preoperatively), and 4 and 12 weeks postoperatively. Week 4 and 12 scores were compared with baseline using t-tests. Minimally important clinical differences were considered as a 10-point difference from baseline. RESULTS: C30 and QLQ-LMC21 were completed at baseline, 4 weeks, and 12 weeks by 39 (95%), 35 (85%) and 34 (83%) patients, and 39 (95%), 33 (80%) and 33 (80%) patients, respectively; 79% and 75% had at least one MICD according to QLQ-C30 at 4 and 12 weeks. At 4 weeks, physical functioning (mean difference (MD) - 11.9%, p = 0.002), role functioning (MD - 23.6, p = 0.007), and pain (MD + 19.7, p = 0.017) had significant worsening from baseline. At 12 weeks postoperatively, role functioning (MD - 19.7, p = 0.011) and fatigue (MD + 14.3, p = 0.03) were the only domains that remained significantly worse. By 12 weeks, pain and physical functioning had returned to baseline. There were no major demographic differences among those with and without an MICD at 12 weeks. CONCLUSIONS: Simultaneous resection of colorectal liver metastases led to clinically significant worsening fatigue and role functioning that persisted at 12 weeks post-surgery.

Effects of combined administration of ACE inhibitor and angiotensin II receptor antagonist are prevented by a high NaCl intake.

BACKGROUND: To prevent the action of angiotensin II by blockade with either an angiotensin converting enzyme inhibitor (ACE I) or an angiotensin receptor antagonist (ARA) is difficult due to the physiological compensations. Combined therapy with both drugs may enable complete blockade, and in rats in high doses this has produced a syndrome that results in death. OBJECTIVE: To determine the effect of combined blockade using losartan (10 mg/kg per day) and perindopril (6 mg/kg per day) on blood pressure, cardiac growth, renal function and behaviour, and to determine how this is influenced by different salt intakes in normotensive Sprague Dawley rats. METHODS: Rats were fed an 0.2 or 4% NaCl diet and received the above drugs intraperitoneally. Blood pressure was measured by telemetry. Cardiac weight was measured after 10 days of therapy. Renal function was assessed by plasma creatinine and electrolytes, plasma renin and angiotensinogen concentrations were measured. RESULTS: On 0.2% NaCl intake, combined blockade lowered blood pressure progressively; at day 7, rats on 0.2% NaCl developed a syndrome of listlessness and failure to eat which led to loss of weight and death. Cardiac size was dramatically reduced. Plasma creatinine was elevated to 50% above normal. There was a polyuria. The syndrome was reversed by adding NaCl to the drinking water or prevented in rats on a 4% NaCl intake. In rats on 0.2% NaCl plasma renin rose dramatically with medication and angiotensinogen became depleted. Haematocrit in all groups of rats did not differ. CONCLUSION: Combined blockade of the renin-angiotensin system can cause death in rats on a reduced NaCl intake. This was prevented by a high salt intake. The syndrome may result from depletion of angiotensinogen and the failure to synthesize sufficient angiotensin II that may be critical for normal cardiac growth and function and critical for survival.

High expression of the trefoil protein TFF1 in interval breast cancers.

Breast cancer screening is important for the early detection of breast cancer. Tumors that become symptomatic in the screening interval are known as interval cancers but the reasons for their rapid progression are unknown. Estrogen receptor expression is lower in interval cancers suggesting that they may have reduced hormonal responsiveness. To investigate this hypothesis we have measured the expression of the estrogen receptor and three estrogen-responsive genes (cathepsin D, progesterone receptor, and TFF1) in screen-detected and interval breast cancers. The expression of the protease cathepsin D was not associated with estrogen receptor in either group of tumor. Progesterone receptor expression was highly correlated with that of the estrogen receptor in both groups of tumors but it was not expressed at significantly different levels in the two groups of tumors. Expression of TFF1, a cellular motogen, was correlated with estrogen receptor in screen-detected but not interval cancers and was expressed at markedly higher levels in interval breast tumors, the group that expresses lower levels of estrogen receptor. Interval cancers are characterized by high levels of expression of TFF1 and/or Ki67 suggesting that cell migration and cell division play important roles in the rapid progression of interval cancers. The observation that TFF1 expression in interval cancers tends to be estrogen-independent and that interval cancers have reduced estrogen receptor expression suggests they may have a reduced response to hormone therapy.

Functional and desensitizing effects of the novel synthetic vanilloid-like agent 12-phenylacetate 13-acetate 20-homovanillate (PPAHV) in the perfused rat hindlimb.

1. In the present study, the effects of the novel vanilloid agonist, 12-phenylacetate 13-acetate 20-homovanillate (PPAHV), on oxygen consumption (VO(2)) and vascular resistance (perfusion pressure, PP) were investigated in the constant flow, perfused rat hindlimb. The acute desensitizing properties of this novel synthetic agent were also examined. 2. Maximum stimulation of VO(2) was produced by 0.2 microM PPAHV (delta VO(2), 0.83+/-0.06 micromol g(-1) h(-1)) and was accompanied by mild vasoconstriction (increase in PP; 8.0+/-1.1 mmHg). The highest concentration of PPAHV tested (2 microM) caused inhibition of VO(2) (delta VO(2), -2.73+/-0.51 micromol g(-1) h(-1)) and strong vasoconstriction (delta PP, 42.0+/-1.2 mmHg). 3. Capsazepine (10 microM) caused a parallel shift to the right of both VO(2) and PP concentration-response curves for PPAHV (pK(b)=5.00), indicative of competitive binding to vanilloid receptors. 4. The stimulation of VO(2) produced by 0.2 microM PPAHV decreased, but was not completely abolished, after repeated infusion of PPAHV (change in VO(2), first infusion, 0.66+/-0.18 micromol g(-1) h(-1); sixth infusion, 0.29+/-0. 08 micromol g(-1) h(-1), P<0.05), an acute tachyphylactic response not previously seen with the repeated infusion of other vanilloid analogues. Conversely, the PP response to repeated PPAHV infusion increased (delta PP, first infusion, 5.8+/-0.7 mmHg; sixth infusion, 9.0+/-0.6 mmHg, P<0.05). 5. In conclusion, PPAHV produces vasoconstriction and a biphasic effect on VO(2) in the perfused rat hindlimb very similar to that induced by naturally occurring vanilloids. Both effects are blocked by the competitive antagonist capsazepine. Since, the metabolic response to low concentrations of PPAHV (stimulation of VO(2)) undergoes tachyphylaxis, the present data suggest that PPAHV desensitizes putative vanilloid receptors in the hindlimb.

Differences in Ki67 and c-erbB2 expression between screen-detected and true interval breast cancers.

Breast cancer screening facilitates the early detection of breast cancer, although a significant number of tumors still arise in the interval between screening. The objective of this study was to measure the expression of five markers of proven prognostic significance in symptomatic breast cancer (estrogen receptor, progesterone receptor, p53, Ki67, and c-erbB2) in screen-detected and interval breast cancers to identify biological markers that may be associated with the emergence of symptomatic breast cancer in the screening interval. The expression of estrogen receptor, progesterone receptor, p53, Ki67, and c-erbB2 was assessed in a series of 51 true interval and 84 screened-detected invasive tumors by immunohistochemistry. Interval cancers tended to be of higher histological grade and were of larger pathological size than screen-detected cancers. Expression of estrogen receptor was 1.7-fold lower (P<0.001), whereas expression of p53 was 2.5-fold (P<0.01), Ki67 2.4-fold (P<0.001), and c-erbB2 3.6-fold higher (P<0.01) in true interval cancers compared with screen-detected invasive cancers. There was no significant difference in progesterone receptor expression. The most important differences identified by multiple logistic regression analysis were in the expression of Ki67 and c-erbB2. The differences in the expression of these markers were more important than clinical features such as pathological grade and size. Using the logistic regression model, 83% of the tumors analyzed in this study could be correctly assigned as interval or screen-detected tumors on the basis of Ki67 and c-erbB2 expression. The importance of high expression of Ki67 in interval cancers compared with screen-detected cancers suggests that tumors may become symptomatic in the screening interval as a result of increased levels of cell proliferation. The inclusion of c-erbB2 in the regression equation suggests that this growth factor receptor may play a significant role in stimulating the rapid growth of interval cancers.

Acute and chronic effects of capsaicin in perfused rat muscle: the role of tachykinins and calcitonin gene-related peptide.

In perfused rat skeletal muscle (hindlimb), capsaicin either stimulates (submicromolar concentrations) or inhibits (micromolar concentrations) oxygen consumption (VO2). Both VO2 effects are associated with vasoconstriction, evident as an increase in perfusion pressure (PP), under constant flow. We have proposed that these effects are mediated by two vanilloid receptor subtypes: VN1 (stimulation of VO2) and VN2 (inhibition of VO2) (; ). In the present study, the role of capsaicin-sensitive neurons and sensory neuropeptides in the VN1/VN2 receptor actions of capsaicin was investigated. The observed maximum stimulation of VO2 by capsaicin (0.4 microM; DeltaVO2, 1.35 +/- 0.14 micromol g-1 h-1) was accompanied by mild vasoconstriction (DeltaPP, 5.8 +/- 0.6 mm Hg). In contrast, 2 microM capsaicin produced strong inhibition of VO2 (DeltaVO2, -2.25 +/- 0.23 micromol g-1 h-1) with pronounced vasoconstriction (DeltaPP, 28.0 +/- 1.3 mm Hg). VO2 stimulation was significantly inhibited (P <.05) by the selective NK1 receptor antagonist CP-99994 (1 microM) and the NK2 receptor antagonist SR 48968 (1 microM) (by 42% and 51%, respectively), but PP was not altered. Infused SP and neurokinin A (NKA) stimulated VO2 (observed maximum DeltaVO2, 0.52 +/- 0.06 and 0.53 +/- 0.08 micromol g-1 h-1, respectively; EC50 values, 269 +/- 23 and 21.2 +/- 3.0 nM, respectively) and induced mild vasoconstriction (4.30 +/- 0.33 and 6. 75 +/- 1.18 mm Hg, respectively; EC50 values, 352 +/- 25.7 and 25.5 +/- 2.7 nM, respectively). Neurokinin B (NKB) also stimulated VO2 (maximum not determined) and vasoconstriction (maximum DeltaPP, 3.40 +/- 0.25 mm Hg; EC50, 34.4 +/- 5.2 nM). The rank order of potency for the tachykinins in this preparation was NKA > NKB > SP, which suggests stimulation primarily of NK2 receptors. Although infused calcitonin gene-related peptide (CGRP) did not alter hindlimb VO2 or PP, the selective CGRP antagonist CGRP(8-37) markedly potentiated the inhibition of VO2 produced by 1 microM capsaicin (84%) and the maximum capsaicin-induced vasoconstriction (57%), which indicates that endogenously released CGRP may act as a vasodilator. Hindlimbs perfused 1 day after capsaicin pretreatment showed attenuation of capsaicin-induced (0.4 microM) stimulation of VO2 (92%) (P <.05) and vasoconstriction (64%), but this returned to normal after 7 days. The inhibition of VO2 by 1 microM capsaicin was significantly (P <. 05) enhanced 7 and 14 days after pretreatment (66% and 140%, respectively), as was the maximum vasoconstriction (64% and 68%, respectively). These data suggest that capsaicin-sensitive neurons, presumably via release of SP and NKA, are involved in VN1 responses and that capsaicin pretreatment potentiates VN2 responses, either by depletion of CGRP reserves or by upregulation of putative VN2 receptors.

Myxoglobulosis, a rare variant of appendiceal mucocele, occurring secondary to an occlusive membrane.

A 77-year-old man presented with altered bowel habit and episodic right lower abdominal discomfort. A barium enema showed a large smooth filling defect in the caecum and at operation his appendix was seen to be hugely distended. Pathological examination showed myxoglobulosis, a rare variant of mucocele of the appendix. The appendiceal orifice was completely occluded by an imperforate membrane with no communication between the appendix and caecum. This is the first published report in the English language of appendiceal myxoglobulosis in association with such an occlusive membrane.

The role of surgery in pseudomembranous enterocolitis.

Pseudomembranous enterocolitis is an inflammatory bowel disorder caused by Clostridium difficile toxins. Classical presentation includes abdominal pain, pyrexia, diarrhoea and leucocytes. The management is mainly conservative but in extreme cases surgery is necessary. Resectional procedures (colectomy) carry a better prognosis than diversion procedures (colostomy). A careful history, a high index of suspicion, and early diagnosis and treatment would reduce the associated morbidity and mortality of this condition. The aetiopathogenesis, pathology, clinical presentation, diagnosis, differential diagnosis, complications, medical and surgical management are reviewed, and three case reports briefly discussed. A management algorithm is also suggested.

Capsaicin-induced biphasic oxygen uptake in rat muscle: antagonism by capsazepine and ruthenium red provides further evidence for peripheral vanilloid receptor subtypes (VN1/VN2).

Previous studies with the vanilloid spice principle capsaicin have demonstrated a biphasic VO2 response, with vasoconstriction, in the perfused rat hindlimb that has led to suggestions of vanilloid receptor subtypes (VN1/VN2) in this preparation (1). In the present study, the known competitive vanilloid antagonist capsazepine inhibited the above capsaicin-mediated effects in a manner that was indicative of binding at specific vanilloid recognition sites. Low concentrations of capsazepine selectively inhibited the increased VO2 produced by the putative VN1 receptor at submicromolar concentrations of capsaicin, while the inhibition of VO2 produced by high concentrations of capsaicin (putative VN2) was enhanced. These observations, showing different susceptibilities to blockade by capsazepine, further support the presence of two vanilloid receptor subtypes in the rat hindlimb. Schild plots of the data yielded variable slopes that approach unity at greater responses to capsaicin (mean KB = 8.44 +/- 2.08 microM and 7.28 +/- 0.78 microM for VO2 and perfusion pressure curves, respectively). Low concentrations of the capsaicin antagonist ruthenium red selectively blocked the putative VN2 receptor-mediated effects produced by high concentrations of capsaicin. The noncompetitive nature of this inhibitor suggests an operation through separate receptor-coupled ion channel complexes at high and low concentrations of the vanilloid. Tetrodotoxin failed to attenuate any changes produced by capsaicin, suggesting that the mechanism of action of capsaicin in the rat hindlimb may differ from other tissues.