Effect of Surgery on the Outcome of Midgut Carcinoid Disease with Lymph Node and Liver Metastases

We have evaluated survival and tumor-related symptoms in the presence of mesenteric lymph node and liver metastases in relation to surgical procedures in 314 patients (148 women, mean age at diagnosis 61 years; 249 with liver metastases) treated for midgut carcinoid tumors. Of the operated patients, 46% presented with severe abdominal pain and intestinal obstruction and were operated on before the diagnosis. Medical treatment (somatostatin analogs, interferon-a) was initiated in 67% and 86%, respectively. Surgical attempts included small intestine or ileocecal/right-sided colon resection with excision of mesenteric lymph node metastases. Most of the patients (n = 286) had mesenteric lymph node metastases; 33% of them had unresectable mesenteric lymph node metastases and underwent surgery without mesenteric dissection. Patients who underwent resection for the primary tumor had a longer survival than those with no resection (median survival 7.4 vs. 4.0 years; p <0.01). Patients who underwent successful excision of mesenteric metastases had a significantly longer survival than those with remaining lymph node metastases. Patients operated on for a primary tumor but with remaining lymph nodes but no liver metastases and who subsequently received interferon and somatostatin analog treatment had a median survival of 7.4 years. Resection of the primary tumor and the mesenteric lymph node metastases led to a significant reduction in tumor-related symptoms. Surgery to remove the primary intestinal tumor including mesenteric lymph node metastases is supported by the present results, even in the presence of liver metastases. Liver metastases and significant preoperative weight loss are identified as major negative prognostic factors for survival.     

Clusterin expression is significantly enhanced in prostate cancer cells following androgen withdrawal therapy

INTRODUCTION AND OBJECTIVES: Progression of prostate cancer to androgen independence (AI) results in part from the upregulation of anti-apoptotic genes following androgen withdrawal, and androgen-independent disease remains the primary obstacle to improved survival. Testosterone-repressed prostate message-2 (TRPM-2) encodes the anti-apoptotic protein clusterin, which is upregulated in response to cellular compromise as observed in normal and malignant tissues undergoing apoptosis. Systemic administration of antisense clusterin oligonucleotides in prostate cancer xenograft models delays progression to AI and enhances chemosensitivity. The objective of this study was to define changes in clusterin expression following neoadjuvant hormone therapy (NHT) in prostate cancer patients. MATERIALS AND METHODS: Archival radical prostatectomy (RP) specimens were obtained for 128 patients who received either no NHT or treatment for 2-8 weeks, 3 months, or 8 months. Paired needle biopsy specimens were acquired for 30 patients and all tissues were subjected to clusterin immunohistochemistry. Western blot analysis was performed on frozen tissue from 5 untreated and 5 treated patients. RESULTS: Clusterin expression in malignant prostatic tissue was significantly greater in patients who underwent preoperative NHT (P < 0.001). Needle biopsies obtained prior to NHT consistently demonstrated lower staining intensity than corresponding RP specimens (P < 0.001). Western blot analysis confirmed clusterin levels increased 17-fold beginning within 4 weeks after androgen withdrawal. CONCLUSIONS: Upregulation of clusterin levels following androgen ablation therapy may represent an adaptive cell survival response following apoptotic signals like androgen withdrawal. These findings support clusterin as a valid therapeutic target in strategies employing novel multimodality therapy for advanced prostate cancer.     

Nephron-sparing surgery in multiple bilateral angiomyolipomas

We report on a 17-year-old white woman with multiple bilateral renal angiomyolipomas (AMLs) in the absence of tuberous sclerosis. Multiple hyperdense lesions were detected in both kidneys by sonography. A computed tomography (CT) scan confirmed mainly fatty tissue. Sparing as much functional tissue as possible, eight AMLs of the right kidney were resected. The largest removed tumour measured 7 x 4 x 2.4 cm. Renal function was completely preserved. An AML is a benign, generally unilateral renal tumour. Treatment is necessary in cases of flank pain, spontaneous bleeding, obstruction by tumour growth and tumours exceeding 4 cm in diameter. Patients who present are often symptomatic due to pain, retroperitoneal bleeding or haematuria. An AML occurs either sporadically or in association with tuberous sclerosis. Bilateral or unilateral multiple AMLs are rare.     

The correlation of the bispectral index monitor with clinical sedation scores during mechanical ventilation in the pediatric intensive care unit

In patients who are mechanically ventilated in the pediatric intensive care unit (PICU), sedative and/or analgesic medications are routinely provided and titrated to effect based on clinical assessment of the patient. The bispectral index (BIS) monitor uses a modified electroencephalogram to quantify the effects of central nervous system-acting drugs on the level of consciousness. To evaluate the usefulness of the BIS monitor to predict clinical sedation levels in the PICU, we compared BIS values with simultaneously obtained clinical sedation scores in 24 mechanically ventilated pediatric patients aged 5.7 plus minus 6.1 yr. For each sedation scale used, the BIS value correlated with increasing depth of sedation (P < 0.0001) and was independent of the drug(s) used for sedation. To differentiate adequate from inadequate sedation, a BIS value <70 had a sensitivity of 0.87--0.89 and a positive predictive value of 0.68--0.84. To differentiate adequate from excessive sedation, a BIS value <50 had a sensitivity of 0.67--0.75 and a positive predictive value of 0.07--0.52. We conclude that the BIS monitor may be a useful adjunct for the assessment of sedation in PICU patients. IMPLICATIONS: We demonstrate the usefulness of the bispectral index monitor for assessing sedation in pediatric intensive care unit patients. The bispectral index monitor correlated with clinically assessed sedation levels and was useful for differentiating adequate from inadequate sedation, which would be of value when the clinical examination is unavailable.     

Use of risedronate to prevent bone loss following a single course of glucocorticoids: findings from a proof-of-concept study in inflammatory bowel disease

Summary

We performed a randomised controlled trial (RCT) to determine whether risedronate 35 mg once weekly prevents bone loss following an 8-week reducing course of prednisolone given for an exacerbation of inflammatory bowel disease (IBD). The greatest change in bone mineral density (BMD) was at Ward’s triangle (WT), which fell by 2.2% in the placebo group, compared with a reduction of 0.8% in the risedronate group.

Introduction

Whether bisphosphonates can prevent bone loss associated with intermittent glucocorticoid (GC) therapy is unknown, reflecting the difficulty in performing RCTs in this context.

Method

To explore the feasibility of RCTs to examine this question, lumbar spine (LS; L2–4) and hip dual X-ray absorptiometry (DXA) scans were performed in 78 patients commencing a GC therapy course for a relapse of IBD. They were then randomised to receive placebo or risedronate 35 mg weekly for 8 weeks, after which the DXA scan was repeated.

Results

For LS BMD, there was no change in the placebo group (0.1?±?0.4, p?=?0.9), but there was an increase after risedronate (0.8?±?0.4, p?=?0.04; mean%?±?SEM by paired Student’s t test). There were small decreases in both groups at the total hip (?0.5?±?0.3, p?=?0.04; ?0.5?±?0.3, p?<?0.05, placebo and risedronate, respectively). At WT, BMD fell after placebo (?2.2?±?0.5, p?=?0.001) but not risedronate (?0.8?±?0.5, p?=?0.09; p?=?0.05 for between-group comparison).

Conclusion

RCTs can be used to examine whether bisphosphonates prevent bone loss associated with intermittent GC therapy, providing metabolically active sites such as WT are employed as the primary outcome.     

Leg Length and Offset Measures with a Pinless Femoral Reference Array during THA

The bony fixation of reference marker arrays used for computer-assisted navigation during total hip arthroplasty (THA) theoretically involves the risk of fracture, infection, and/or pin loosening. We asked whether intraoperative assessment of leg length (LL) and offset (OS) changes would be accurate using a novel pinless femoral reference system in conjunction with an imageless measurement algorithm based on specific realignment of the relationship between a dynamic femoral and pelvis reference array. LL/OS measurements were recorded during THA in 17 cadaver specimen hips. Preoperatively and postoperatively, specimens were scanned using CT. Linear radiographic LL/OS changes were determined by two investigators using visible fiducial landmarks and image processing software. We found a high correlation of repeated measurements within and between (both 0.95 or greater) the two examiners who did the CT assessments. Pinless LL/OS values showed mean differences less than 1 mm and correlations when compared with CT measurements.     

Cost reduction of perioperative coagulation management in cardiac surgery: value of ‘bedside’ thrombelastography (ROTEM)

Objective: Demographic changes and aggressive platelet inhibition have resulted in a marked increase in blood- and coagulation product expenditure and costs in cardiac surgery. We analyzed ‘bedside’ coagulation test (ROTEM) in order to verify clot forming quality for the purpose of finding a cost-effective treatment path. Methods: Annual treatment costs of all cardiosurgical patients were analyzed before (729 patients) and after (693 patients) implementation of ‘bedside’ ROTEM. Cumulative numbers and costs of platelet concentrates (PltC), fresh frozen plasma (FFP), red blood cell units (RBC), and coagulation factors: pooled coagulation concentrates (PCC), recombinant factor VIIa (rFVIIa), factor XIII (FXIII), and fibrinogen were assessed. Average monthly numbers and costs were compared. Number of resternotomies and early mortality was assessed and compared in both periods. Results: After ROMTEM implementation cumulative RBC expenditure showed 25% decrease while PltC exhibited 50% decrease. FFP expenditure remained unchanged. PCC, FXIII were markedly reduced (−80%) while rFVIIa were entirely omitted. Fibrinogen, however, increased two-fold. Cumulative average monthly costs of all blood products decreased from 66,000€ to 45,000€ (−32%). Coagulation factor average monthly costs decreased from 60,000€ to 30,000€ (−50%) yielding combined savings of 44%. In contrast, average monthly costs for ROTEM were 1.580€. Total number of resternotomies decreased from 6.6% to 5.5% while early mortality (5.9%; 6.0%) remained stable. Conclusion: Cumulative costs for treatment of perioperative coagulation disorders can be reduced by ‘bedside’ ROTEM analysis to achieve a selective substitution management. Saved costs for blood- and coagulation products clearly outweighed the expenses of ROTEM. Adequate differential coagulation management can therefore be cost-effective.     

Gender differences in the ratio between humerus width and length are established prior to puberty

Summary On a sample of 1,317 children aged 9.9 years we developed a novel method of measuring humeral dimensions from total body dual-energy X-ray absorptiometry (DXA) scans and showed that gender differences in the ratio between humeral width and length are established prior to puberty. Introduction It is recognised that long bone cross-sectional area is greater in males compared to females, which is thought to reflect more rapid periosteal bone growth in boys. However, it is currently unclear whether these findings reflect gender differences in bone size or shape. In the present study, we investigated whether gender differences exist in the balance between longitudinal and periosteal long bone growth in children, leading to gender differences in bone shape, based on a novel method for evaluating shape of the humerus. We also examined whether these differences are established prior to puberty. Methods Length, area and width of the humerus were estimated from total body DXA scans in 1,317 children aged 9.9 ± 0.33 years, who had participated in a nested case-control study of fractures within the Avon Longitudinal Study of Parents and Children (ALSPAC) (a geographically based birth cohort based in South West England). No differences were observed with respect to parameters of humeral geometry according to fracture history, and so both groups were pooled for further analysis. Aspect ratio (AR) of the humerus was calculated as humeral width divided by length. Total body height and weight were measured at the same time as the DXA scan. Puberty was assessed using self-completion questionnaires. Results Humeral width and length were positively associated with age and height in boys and girls combined (P < 0.001), and with Tanner stage in girls (P < 0.002). In contrast, age, height and Tanner stage were not related to humeral AR. We then examined gender differences in humeral shape according to pubertal stage. In prepubertal children (i.e. Tanner stage 1), humeral length was similar in boys and girls, but width (1.92 vs 1.88 cm, P < 0.001) and area (47.7 vs 46.9 cm², P < 0.001) were greater in boys, resulting in a greater AR (7.78 vs 7.53, P < 0.001). Similar gender differences were observed in early pubertal children (i.e. Tanner stage 2). Conclusion We conclude that the greater periosteal diameter of boys compared to girls reflects differences in the balance between longitudinal and periosteal bone growth. Interestingly, resulting gender differences in humeral AR are established in prepubertal children.     

The Effect of <Emphasis Type="Italic">LRP5</Emphasis> Polymorphisms on Bone Mineral Density Is Apparent in Childhood

Paget’s disease of bone (PDB) can adversely affect quality of life, but relatively little is known about the clinical predictors of reduced quality of life in patients with the disease. Here, we studied quality of life and its determinants in a large cohort of PDB patients who had been enrolled into the PRISM study, a randomized comparative trial of intensive versus symptomatic treatment for PDB. Health-related quality of life was assessed using the Short-Form 36 (SF36) questionnaire and other validated assessment instruments in 1,324 subjects with PDB. Clinical predictors of quality of life were identified by multivariate regression analysis. The physical summary (mean ± standard deviation) score of the SF36 was substantially reduced in PDB to 36.3 ± 11.3 compared with the expected population norm of 50 (P < 0.001). The mental summary score was only slightly reduced, to 48.7 ± 11.8, in PDB; but this was statistically significant (P < 0.001). Bone pain due to PDB, previous bisphosphonate therapy, and increasing age were identified as negative predictors of the SF36 physical summary score (P < 0.001); but serum levels of total alkaline phosphatase (ALP) did not predict physical summary score. We conclude that PDB has a substantial negative impact on health-related quality of life, which mainly affects physical functioning. The lack of correlation between ALP and quality of life observed in this study emphasizes the importance of addressing quality-of-life issues when treating PDB and not just focussing on response of ALP levels. The PRISM Trial Group. Writing Group: Marion K. Campbell, William D. Fraser, Anne L. Langston, Graeme MacLennan, Stuart H. Ralston, Peter L. Selby. Independent Trial Steering Committee: Maarten Boers (chair), Juliet Compston (member), Philip Hannaford (observer, host institution representative), Marilyn McCallum (member), Graham Russell (member). Data Monitoring Committee: Ade Adebajo, Nigel Arden, Howard Bird, Margaret Byron, Alison Carr, Ernest Choy (chair 2001–06), Peter Croft, Vern Farewell, Ian Harvey, Sarah Hewlett, Shabbar Jaffar, Martyn Lewis, Gary MacFarlane (chair 2006), Chris Roberts, Lee Shepstone, Deborah Symmons. Trial Office Team: Gary Adams (data manager), Daniel Barnett (trial programmer), Marie Cameron (research assistant), Janice Cruden (data manager), Magnus McGee (trial statistician), Donna Patterson (data manager), Clare Robertson (research assistant), Allan Walker (trial programmer), Euan Wiseman (trial programmer). Local Trial Investigators (the following people were responsible for the local coordination of the study at the collaborating hospital sites, *lead consultant): Aberdeen Royal Infirmary, UK, Vera Herd, Stuart H. Ralston*; University Hospital Aintree, UK, Rose McIver, Mashood Siddiqi*; Royal National Hospital for Rheumatic Disease, Bath, UK, Ashok Bhalla,* Diana Cochran, Sharon Grieve, Sara Mills; Musgrave Park Hospital, Belfast, UK, Katrina Hughes, Richard Wallace*; Queen Elizabeth Hospital, Birmingham, UK, Neil Gittoes,* Liz McGregor; Royal Bolton Hospital, UK, Keatley R. H. Adams,* Mary Adams; Ninewells Hospital, Dundee, UK, Vera Herd, Graham Leese,* Ellen Malcolm; University Hospital of North Durham, UK, Sarah Hailwood*; Medway Maritime Hospital, Gillingham, UK, Paul Ryan,* Gwen Worcester; Western Infirmary, Glasgow, UK, Alastair McLellan,* Debby Nelson; Huddersfield Royal Infirmary, UK, Allan Fairclough, Richard Reece*; Raigmore Hospital, Inverness, UK, Fiona McGhie, Malcolm Steven*; Airedale Hospital, Keighley, UK, Annie Cooper,* Stuart H. Ralston*; Leicester Royal Infirmary and Leicester General Hospital, UK, Margaret Coe, S. Javed Iqbal,* Geraldine McHugh; Royal Liverpool University Hospital, UK, William D. Fraser,* Ya-Wen Jessica Huang, Margaret Little, Vinita Mishra, Nicola Wherly; Llandudno General Hospital, UK, Merle Maddison, Lyn Vaterlaws*; Guy’s Hospital, London, UK, Ignac Fogelman,* Nina Prescod; King’s College Hospital, London, UK, Rama Chandra, Tina Mangion, Caje Moniz*; Manchester Royal Infirmary, UK, Susan Harrison, Peter L. Selby*; James Cook University Hospital, Middlesbrough, UK, John N. Fordham,* Val Lunn, Dawn Youll; Freeman Hospital, Newcastle, UK, Roger Francis*; Norfolk & Norwich University Hospital, UK, Jane Leeder, David G. I. Scott*; City Hospital, Nottingham, UK, David Hosking,* Pat San; Robert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, UK, Michael Davie,* Teresa Jones, Dawn Pugh; Nuffield Orthopaedic Centre, Oxford, UK, Matthew Brown, Vicky Toghill, John Wass,* Jo Young; Llandough Hospital, Penarth, UK, Roz Broadbent, Mike Stone,* Jane Turton; Derriford Hospital, Plymouth, UK, Charles Hutton,* Maggie Jolly; Poole Hospital, UK, Julia Taylor, Paul Thompson*; Harold Wood Hospital, Romford, UK, Kuntal Chakravarty*; Oldchurch Hospital, Romford, UK, Christine Heron, Christopher Kelsey*; Hope Hospital, Salford, UK, Sylvia Mercer, Terence W. O’Neill*; Northern General Hospital, Sheffield, UK, Jenny Cliffe, Linda Kersh, Eugene McCloskey*; Southampton General Hospital, UK, Trish Byng, Janet Cushnaghan, Cyrus Cooper,* Nick Harvey, Karen Walker-Bone; Royal National Orthopaedic Hospital, Stanmore, UK, Richard Keen,* Maggie Partridge; Great Western Hospital, Swindon, UK, Lynne Kerton, Elizabeth Price*; Queen Elizabeth II Hospital, Welwyn Garden City, UK, Jill Lomas, Peter Winocour*; Arrowe Park Hospital, Wirral, UK, E. George, T. D. Kennedy,* Anthony Lake; Yeovil District Hospital, UK, Nita Beacham, Clare Buckley, Jenny Knight, Lisa Martin, T. G. Palferman.*     

Efficacy and safety of pregabalin in the treatment of generalized anxiety disorder: a 6-week, multicenter, randomized, double-blind, placebo-controlled comparison of pregabalin and venlafaxine

OBJECTIVE: Pregabalin has demonstrated robust, rapid efficacy in reducing symptoms of generalized anxiety disorder (GAD) in 4 placebo-controlled clinical trials. The current study compared the efficacy and safety of pregabalin and venlafaxine in patients diagnosed with moderate to severe GAD. METHOD: The study was conducted from December 21, 1999, to July 31, 2001. Outpatients (N = 421) in primary care or psychiatry settings meeting DSM-IV criteria for GAD were randomly assigned to 6 weeks of double-blind treatment with pregabalin 400 or 600 mg/day, venlafaxine 75 mg/day, or placebo. The primary analysis was change in Hamilton Rating Scale for Anxiety (HAM-A) total score from baseline to last-observation-carried-forward (LOCF) endpoint. Secondary analyses included the change in HAM-A psychic (emotional) and somatic (physical) factor scores, significant improvement at week 1, and week 1 improvement sustained at every visit through endpoint. RESULTS: Pregabalin at both dosages (400 mg/day, p = .008; 600 mg/day, p = .03) and venlafaxine (p = .03) produced significantly-greater improvement in HAM-A total score at LOCF endpoint than did placebo. Only the pregabalin 400-mg/day treatment group experienced significant improvement in all a priori primary and secondary efficacy measures. Pregabalin in both dosage treatment groups (400 mg/day, p < .01; 600 mg/day, p < .001) significantly improved HAM-A total score at week 1, with significant improvement through LOCF endpoint. Statistically significant improvement began at week 2 for venlafaxine. Discontinuation rates due to associated adverse events were greatest in the venlafaxine treatment group: venlafaxine, 20.4%; pregabalin 400 mg/day, 6.2%; pregabalin 600 mg/day, 13.6%; placebo, 9.9%. CONCLUSION: Pregabalin was safe, well tolerated, and rapidly efficacious across the physical-somatic as well as the emotional symptoms of GAD in the majority of patients studied in primary care and psychiatric settings.