Showing papers by "St Bartholomew's Hospital published in 2005"

Complications of the COX-2 Inhibitors Parecoxib and Valdecoxib after Cardiac Surgery

Abstract: background Valdecoxib and its intravenous prodrug parecoxib are used to treat postoperative pain but may involve risk after coronary-artery bypass grafting (CABG). We conducted a randomized trial to assess the safety of these drugs after CABG. methods In this randomized, double-blind study involving 10 days of treatment and 30 days of follow-up, 1671 patients were randomly assigned to receive intravenous parecoxib for at least 3 days, followed by oral valdecoxib through day 10; intravenous placebo followed by oral valdecoxib; or placebo for 10 days. All patients had access to standard opioid medications. The primary end point was the frequency of predefined adverse events, including cardiovascular events, renal failure or dysfunction, gastroduodenal ulceration, and wound-healing complications. results As compared with the group given placebo alone, both the group given parecoxib and valdecoxib and the group given placebo and valdecoxib had a higher proportion of patients with at least one confirmed adverse event (7.4 percent in each of these two groups vs. 4.0 percent in the placebo group; risk ratio for each comparison, 1.9; 95 percent confidence interval, 1.1 to 3.2; P=0.02 for each comparison with the placebo group). In particular, cardiovascular events (including myocardial infarction, cardiac arrest, stroke, and pulmonary embolism) were more frequent among the patients given parecoxib and valdecoxib than among those given placebo (2.0 percent vs. 0.5 percent; risk ratio, 3.7; 95 percent confidence interval, 1.0 to 13.5; P=0.03). conclusions The use of parecoxib and valdecoxib after CABG was associated with an increased incidence of cardiovascular events, arousing serious concern about the use of these drugs in such circumstances.

Patterns of home mechanical ventilation use in Europe: results from the Eurovent survey

Abstract: The study was designed to assess the patterns of use of home mechanical ventilation (HMV) for patients with chronic respiratory failure across Europe. A detailed questionnaire of centre details, HMV user characteristics and equipment choices was sent to carefully identified HMV centres in 16 European countries. A total of 483 centres treating 27,118 HMV users were identified. Of these, 329 centres completed surveys between July 2001 and June 2002, representing up to 21,526 HMV users and a response rate of between 62% and 79%. The estimated prevalence of HMV in Europe was 6.6 per 100,000 people. The variation in prevalence between countries was only partially related to the median year of starting HMV services. In addition, there were marked differences between countries in the relative proportions of lung and neuromuscular patients using HMV, and the use of tracheostomies in lung and neuromuscular HMV users. Lung users were linked to a HMV duration of or =6 yrs. In conclusion, wide variations exist in the patterns of home mechanical ventilation provision throughout Europe. Further work is needed to monitor its use and ensure equality of provision and access.

The use of iodinated and gadolinium contrast media during pregnancy and lactation.

Abstract: The use of iodinated or gadolinium-based contrast media in pregnant or lactating women often causes concerns in the radiology department because of the principle of not exposing a fetus or neonate to any drugs. Because of the uncertainty about the use of contrast media during pregnancy and lactation, the Contrast Media Safety Committee of the European Society of Urogenital Radiology decided to review the literature and draw up guidelines. An extensive literature search was carried out and summarized in a report. Based on the limited information available, simple guidelines have been drawn up. The report and guidelines were discussed at the 11th European Symposium on Urogenital Radiology in Santiago de Compostela, Spain. Mutagenic and teratogenic effects have not been described after administration of gadolinium or iodinated contrast media. Free iodide in radiographic contrast medium given to the mother has the potential to depress fetal/neonatal thyroid function. Neonatal thyroid function should be checked during the 1st week if iodinated contrast media have been given during pregnancy. No effect on the fetus has been seen after gadolinium contrast media. Only tiny amounts of iodinated or gadolinium-based contrast medium given to a lactating mother reach the milk, and only a minute proportion entering the baby's gut is absorbed. The very small potential risk associated with absorption of contrast medium may be considered insufficient to warrant stopping breast-feeding for 24 h following either iodinated or gadolinium contrast agents.

Hyperemesis gravidarum, a literature review

Abstract: Hyperemesis gravidarum (HG) is a condition causing severe nausea and vomiting in early pregnancy often resulting in hospital admission. The incidence of HG is approximately 0.5% of live births, said to be higher in multiple pregnancies, hydatidiform mole and other conditions associated with increased pregnancy hormone levels. Both the aetiology and pathogenesis of HG remain unknown. We conducted a literature review (1966-now) to summarize the current evidence on the aetiology and pathogenesis of HG. The potential role of pregnancy-related hormones such as progesterone, estrogen and HCG has been widely studied; however, various other hormones such as leptin, placental growth hormone, prolactin, thyroid and adrenal cortical hormones have been implicated in the aetiology of HG. In addition to endocrinological hypotheses, the rationale and evidence considering infectious, immunological, psychological, metabolic and anatomical causes for HG have been analysed here. Many studies suffer from the low number of patients included, the variable definition used for HG and varying assay methodology used in studies of hormone measurement. This review highlights the need for more extensive studies addressing the pathogenesis and aetiology of HG.

A HIF1α Regulatory Loop Links Hypoxia and Mitochondrial Signals in Pheochromocytomas

Abstract: Pheochromocytomas are neural crest-derived tumors that arise from inherited or sporadic mutations in at least six independent genes. The proteins encoded by these multiple genes regulate distinct functions. We show here a functional link between tumors with VHL mutations and those with disruption of the genes encoding for succinate dehydrogenase (SDH) subunits B (SDHB) and D (SDHD). A transcription profile of reduced oxidoreductase is detected in all three of these tumor types, together with an angiogenesis/hypoxia profile typical of VHL dysfunction. The oxidoreductase defect, not previously detected in VHL-null tumors, is explained by suppression of the SDHB protein, a component of mitochondrial complex II. The decrease in SDHB is also noted in tumors with SDHD mutations. Gain-of-function and loss-of-function analyses show that the link between hypoxia signals (via VHL) and mitochondrial signals (via SDH) is mediated by HIF1alpha. These findings explain the shared features of pheochromocytomas with VHL and SDH mutations and suggest an additional mechanism for increased HIF1alpha activity in tumors.

C1 inhibitor deficiency: consensus document

Abstract: Summary We present a consensus document on the diagnosis and management of C1 inhibitor deficiency, a syndrome characterized clinically by recurrent episodes of angio-oedema. In hereditary angio-oedema, a rare autosomal dominant condition, C1 inhibitor function is reduced due to impaired transcription or production of non-functional protein. The diagnosis is confirmed by the pres- ence of a low serum C4 and absent or greatly reduced C1 inhibitor level or function. The condition can cause fatal laryngeal oedema and features indis- tinguishable from gastrointestinal tract obstruction. Attacks can be precipi- tated by trauma, infection and other stimulants. Treatment is graded according to response and the clinical site of swelling. Acute treatment for severe attack is by infusion of C1 inhibitor concentrate and for minor attack attenuated androgens and/or tranexamic acid. Prophylactic treatment is by attenuated androgens and/or tranexamic acid. There are a number of new products in trial, including genetically engineered C1 esterase inhibitor, kal- likrein inhibitor and bradykinin B2 receptor antagonist. Individual sections provide special advice with respect to diagnosis, management (prophylaxis and emergency care), special situations (childhood, pregnancy, contracep- tion, travel and dental care) and service specification.

The clinical significance of invasion of veins by rectal cancer.

Abstract: A histopathological study of 703 surgical specimens from patients with adenocarcinoma of the rectum revealed invasion of veins by primary growth in almost 52 per cent. Follow-up studies on the patients showed that the corrected 5-year survival rate was significantly worse and liver metastases developed more frequently when venous invasion was present. Invasion of extramural veins was particularly significant whereas spread confined to intramural veins was less important. Invasion of large (thick-walled) veins was of greater consequence than invasion of small (thin-walled) veins and spread into thick-walled extramural veins had the greatest adverse influence of all. Venous spread of tumour takes place in parallel with local spread as measured by the Dukes' stage but exerts an influence on prognosis independent of the Dukes' stage. Similarly, vein invasion parallels the number of lymph node metastases but appears to exert an independent influence on prognosis. Observation of venous spread provides a precise assessment of the likely behaviour of rectal carcinoma and supplements, but does not replace indices such as the Dukes' stage or the number of lymph node metastases in routine use. The implications for surgical technique and management are discussed.

Diagnostic Performance of Nanoparticle-Enhanced Magnetic Resonance Imaging in the Diagnosis of Lymph Node Metastases in Patients With Endometrial and Cervical Cancer

Abstract: Purpose Lymph node metastases affect management and prognosis of patients with gynecologic malignancies. Preoperative nodal assessment with computed tomography or magnetic resonance imaging (MRI) is inaccurate. A new lymph node–specific contrast agent, ferumoxtran-10, composed of ultrasmall particles of iron oxide (USPIO), may enhance the detection of lymph node metastases independent of node size. Our aim was to compare the diagnostic performance of MRI with USPIO against standard size criteria. Methods Forty-four patients with endometrial (n = 15) or cervical (n = 29) cancer were included. MRI was performed before and after administration of USPIO. Two independent observers viewed the MR images before lymph node sampling. Lymph node metastases were predicted using size criteria and USPIO criteria. Lymph node sampling was performed in all patients. Results Lymph node sampling provided 768 pelvic or para-aortic nodes for pathology, of which 335 were correlated on MRI; 17 malignant nodes were found in 11 o...

PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma

Abstract: Bortezomib (formerly PS-341) has significant activity in patients with relapsed multiple myeloma (MM), its efficacy is increased with the addition of dexamethasone and it demonstrates synergy with doxorubicin, thus providing the rationale for combination therapy with bortezomib, doxorubicin and dexamethasone (PAD). Patients with untreated MM received four 21-d cycles of PAD, comprising bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11, along with dexamethasone 40 mg on days 1-4, 8-11 and 15-18 during cycle 1 and days 1-4 during cycles 2-4. During days 1-4, patients also received 0, 4.5 or 9 mg/m(2) of doxorubicin at dose levels 1, 2, and 3 respectively. Following peripheral blood stem cell (PBSC) collection, patients received high-dose melphalan (MEL200) with PBSC transplantation (PBSCT). After PAD induction alone, 20 of 21 patients (95%) achieved at least a partial response (PR), including complete response (CR) in five patients (24%). Twenty of 21 had PBSC mobilized, and 18 of 20 received MEL200/PBSCT. In an intention-to-treat analysis, response rates were: CR 43%, near CR 14%, very good PR 24%, PR 14% and stable disease 5%. PAD was effective, did not prejudice subsequent PBSC collection, and should be further evaluated in prospective randomized trials.

Characterization of cells with a high aldehyde dehydrogenase activity from cord blood and acute myeloid leukemia samples.

Abstract: Aldehyde dehydrogenase (ALDH) is a cytosolic enzyme that is responsible for the oxidation of intracellular aldehydes. Elevated levels of ALDH have been demonstrated in murine and human progenitor cells compared with other hematopoietic cells, and this is thought to be important in chemoresistance. A method for the assessment of ALDH activity in viable cells recently has been developed and made commercially available in a kit format. In this study, we confirmed the use of the ALDH substrate kit to identify cord blood stem/progenitor cells. Via multicolor flow cytometry of cord blood ALDH+ cells, we have expanded on their phenotypic analysis. We then assessed the incidence, morphology, phenotype, and nonobese diabetic/ severe combined immunodeficiency engraftment ability of ALDH+ cells from acute myeloid leukemia (AML) samples. AML samples had no ALDH+ cells at all, an extremely rare nonmalignant stem/progenitor cell population, or a less rare, leukemic stem cell population. Hence, in addition to identifying nonmalignant stem cells within some AML samples, a high ALDH activity also identifies some patients' CD34+/ CD38- leukemic stem cells. The incidence of normal or leukemic stem cells with an extremely high ALDH activity may have important implications for resistance to chemotherapy. Identification and isolation of leukemic cells on the basis of ALDH activity provides a tool for their isolation and further analysis.

Exacerbations and Time Spent Outdoors in Chronic Obstructive Pulmonary Disease

Abstract: Patients with chronic obstructive pulmonary disease have a progressive reduction in activity, although its time scale and the contribution of exacerbations are unknown. A rolling cohort of 147 patients (101 male; mean age, 88.5 years; and forced expiratory volume in 1 second as percent predicted, 38.4%) were monitored for a median of 1,044 days (interquartile range, 685 to 1,779) over an 8-year period starting in March 1996. Patients recorded any increase in daily respiratory symptoms and time spent outside their home. They completed the St. George's Respiratory Questionnaire yearly. They experienced 1,465 exacerbations and time outdoors decreased by -0.16 hours/day per year (p < 0.001). This decline was faster in frequent exacerbators (p = 0.011). Before exacerbation, the patients stayed indoors all day for 2.1 days/week (on any day 34.1% were at home), but for 5 weeks postexacerbation they spent 2.5 days/week at home (p < 0.001) (44.4% remaining at home at onset; p = 0.021). St. George's total, activity, and impact scores were independently associated with time outdoors (p < 0.005), but not with symptom score. In conclusion, time spent outside the home declines over time and acutely at exacerbation. Patients with frequent exacerbations are more likely to become housebound and need targeting in rehabilitation programs.

Diagnosis and Management of Pituitary Carcinomas

Abstract: Pituitary carcinomas are rare, making up some 0.2% of all pituitary tumors, but represent a particular challenge to clinical practice. The diagnosis of a pituitary carcinoma requires evidence of metastatic disease, either outside the central nervous system (CNS) or as separate noncontiguous foci within the CNS. They may present as typical pituitary adenomas, which reveal their malignant character only as time progresses, or as peculiarly aggressive tumors ab initio. Recent changes in histopathological classification have clarified many of the features of such tumors, including immunohistochemical staining for Ki-67 and p53, but to date none has been found to be pathognomonic. The majority of carcinomas are secretory, usually arising from corticotroph tumors or prolactinomas, but all histological types and secretory patterns are represented. Treatment is by surgery, transsphenoidal wherever possible, and conventional and stereotactic radiotherapy, but ultimately, a plethora of therapies may be required, including various attempts at medical therapy. Chemotherapy in some instances probably prolongs survival, but, in general, their progress from the diagnosis of carcinomatous changes is progressive and inexorable. However, we do not believe there will be any real prospect of long-term survival until the development and use of therapies targeted at specific molecular abnormalities.

The clinical staging of rectal cancer

Abstract: The ability of rectal digital examination to recognize significant stages of local extent and lymph node involvement in adenocarcinoma of the lower two-thirds of the rectum was investigated. Seventy patients with a palpable rectal cancer were examined by 2 or 3 out of a panel of 10 clinicians including 2 consultants and 8 registrars. A defined protocol was used and the results were recorded on a proforma. Clinical findings were compared with the results of pathological examination of the resected specimen or the final surgical assessment when the growth was not removed. In 38 patients computed tomography of the primary growth was performed and the results were also compared to the pathological findings. Four groups of cases with different degrees of extent of spread were recognized by digital examination in 67–83 per cent by consultants and in 44–78 per cent by registrars. Computed tomography correctly identified growths with extensive local spread in 89 per cent of cases, but was no more reliable than digital examination in the assessment of other degrees of spread or of lymph node involvement. Based on the results, a clinical staging system is proposed, comprising four stages of local extent as follows—stage 1: confined to rectum; stage 2: confined to rectum or slight extrarectal spread; stage 3: moderate or extensive extrarectal spread; stage 4: involvement of other organs or unresectability. Two stages of lymph node involvement are also proposed: namely, node negative and node positive. Each stage corresponds to different survival and local recurrence rates after surgery. Combined with other factors, such as level and size of tumour, histological grade and the general state of the patient, the clinical staging system may facilitate the choice of treatment. It might extend the use of major sphincter-saving procedures, indentify many patients suitable for local treatment and define those with a considerable risk of local recurrence where combined surgery and radiotherapy might be considered.

Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells

Abstract: To examine the impact of tumors on the immune system, we compared global gene expression profiles of peripheral blood T cells from previously untreated patients with B cell chronic lymphocytic leukemia (CLL) with those from age-matched healthy donors. Although the cells analyzed were not part of the malignant clone, analysis revealed differentially expressed genes, mainly involved in cell differentiation in CD4 cells and defects in cytoskeleton formation, vesicle trafficking, and cytotoxicity in CD8 cells of the CLL patients. In coculture experiments using CLL cells and T cells from healthy allogeneic donors, similar defects developed in both CD4 and CD8 cells. These changes were induced only with direct contact and were not cytokine mediated. Identification of the specific pathways perturbed in the T cells of cancer-bearing patients will allow us to assess steps to repair these defects, which will likely be required to enhance antitumor immunity.

Mapping pelvic lymph nodes: guidelines for delineation in intensity-modulated radiotherapy.

Abstract: Purpose: To establish guidelines for delineating the clinical target volume for pelvic nodal irradiation by mapping the location of lymph nodes in relation to the pelvic anatomy. Methods and Materials: Twenty patients with gynecologic malignancies underwent magnetic resonance imaging with administration of iron oxide particles. All visible lymph nodes were outlined. Five clinical target volumes were generated for each patient using modified margins of 3, 5, 7, 10, and 15 mm around the iliac vessels. The nodal contours were then overlaid and individual nodes analyzed for coverage. The volume of normal tissue within each clinical target volume and planning target volume was also measured to aid selection of the margin that could provide maximal nodal, but minimal normal tissue, coverage. Results: In total, 1216 nodal contours were evaluated. The nodal coverage was 56%, 76%, 88%, 94%, and 99% using vessel margins of 3, 5, 7, 10, and 15 mm, respectively. The mean volume of bowel within the planning target volume was 146.9 cm 3 with a 7-mm margin, 190 cm 3 with a 10-mm margin, and 266 cm 3 with a 15-mm margin. Minor modification to the 7-mm margin ensured 99% coverage of the pelvic nodes. Conclusion: Blood vessels with a modified 7-mm margin offer a good surrogate target for pelvic lymph nodes. By making appropriate adjustments, coverage of specific nodal groups may be increased and the volume of normal tissue irradiated decreased. On the basis of these findings, recommended guidelines for outlining pelvic nodes have been produced. © 2005 Elsevier Inc.

Preclinical evaluation of the proteasome inhibitor bortezomib in cancer therapy.

Abstract: Bortezomib is a highly selective, reversible inhibitor of the 26S proteasome that is indicated for single-agent use in the treatment of patients with multiple myeloma who have received at least 2 prior therapies and are progressing on their most recent therapy. Clinical investigations have been completed or are under way to evaluate the safety and efficacy of bortezomib alone or in combination with chemotherapy in multiple myeloma, both at relapse and presentation, as well as in other cancer types. The antiproliferative, proapoptotic, antiangiogenic, and antitumor activities of bortezomib result from proteasome inhibition and depend on the altered degradation of a host of regulatory proteins. Exposure to bortezomib has been shown to stabilize p21, p27, and p53, as well as the proapoptotic Bid and Bax proteins, caveolin-1, and inhibitor κB-α, which prevents activation of nuclear factor κB-induced cell survival pathways. Bortezomib also promoted the activation of the proapoptotic c-Jun-NH2 terminal kinase, as well as the endoplasmic reticulum stress response. The anticancer effects of bortezomib as a single agent have been demonstrated in xenograft models of multiple myeloma, adult T-cell leukemia, lung, breast, prostate, pancreatic, head and neck, and colon cancer, and in melanoma. In these preclinical in vivo studies, bortezomib treatment resulted in decreased tumor growth, angiogenesis, and metastasis, as well as increased survival and tumor apoptosis. In several in vitro and/or in vivo cancer models, bortezomib has also been shown to enhance the antitumor properties of several antineoplastic treatments. Importantly, bortezomib was generally well tolerated and did not appear to produce additive toxicities when combined with other therapies in the dosing regimens used in these preclinical in vivo investigations. These findings provide a rationale for further clinical trials using bortezomib alone or in combination regimens with chemotherapy, radiation therapy, immunotherapy, or novel agents in patients with hematologic malignancies or solid tumors.

Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes

Abstract: The purpose of this Phase II study was to evaluate if alum-formulated human recombinant GAD65 is safe and does not compromise beta cell function. The study was conducted as a randomized, double blind, placebo-controlled, dose-escalation clinical trial in a total of 47 Latent Autoimmune Diabetes in Adults (LADA) patients who received either placebo or 4, 20, 100, or 500 μg Diamyd subcutaneously at Weeks 1 and 4. Safety evaluations, including neurology, beta cell function tests, diabetes status assessment, hematology, biochemistry, and cellular and humoral immunological markers, were repeatedly assessed over 24 weeks. None of the patients had significant study-related adverse events (AE). Fasting c-peptide levels at 24 weeks were increased compared with placebo (P=.0015) in the 20 μg but not in the other dose groups. In addition, both fasting (P=.0081) and stimulated (P=.0236) c-peptide levels increased from baseline to 24 weeks in the 20 μg dose group. GADA log levels clearly increased (P=.0002) in response to 500 μg Diamyd. The CD4+CD25+/CD4+CD25− cell ratio increased (P=.0128) at 24 weeks in the 20 μg group. No sudden increase in HbA1c or plasma glucose or decrease in beta cell function was observed in any of the dose groups. These positive findings for clinical safety further support the clinical development of Diamyd as a therapeutic to prevent autoimmune diabetes.

Factors affecting continence after surgery for anal fistula

Abstract: Anorectal physiology and continence were assessed prospectively before and after surgery in 50 patients with chronic perianal sepsis. Functional and physiological parameters were unchanged after surgery in 13 control patients who had sepsis but who did not undergo division of the anal sphincter. Group 1 comprised 22 patients with internal sphincter division alone (15 intersphincteric, seven trans-sphincteric treated by a loose seton technique) and group 2 consisted of 15 patients with a trans-sphincteric fistula laid completely open. In group 1 the median (interquartile range (i.q.r.)) resting pressure in the distal 1 cm of the anal canal was reduced from 68 (60-90) cmH2O before surgery to 44 (35-60) cmH2O after operation (P < 0.001); squeeze pressure was less affected, but function deteriorated in 11 of the 22 patients. The median (i.q.r.) resting pressure in group 2 patients also fell, from 68 (34-84) cmH2O before operation to 28 (20-54) cmH2O afterwards (P = 0.003); median (i.q.r.) maximum squeeze pressure decreased more, from 124 (76-170) cmH2O to 72 (48-112) cmH2O (P = 0.002). Functional deficit occurred in eight of the 15 patients. Incontinence was related to low resting pressure, reflecting internal sphincter integrity, and to local epithelial electrosensitivity (reflecting scarring), but not to squeeze pressure, fistula type or surgical treatment.

High versus low ligation of the inferior mesenteric artery in rectal cancer.

Abstract: The argument for and against high ligation of the inferior mesenteric artery in rectal cancer has yet to be resolved. Between 1948 and 1983, 4250 patients underwent surgery for rectal carcinoma at St. Mark's Hospital, London. From these, 250 patients were selected who had undergone curative anterior resection of a Dukes' C adenocarcinoma and their records were examined. In 150 (60 per cent) the inferior mesenteric artery was ligated above the origin of the left colic artery. The outcome was analysed using the Dukes', Gastrointestinal Tumour Study Group and Astler-Coller classifications, either alone or in combination. Tumour differentiation and extent of local invasion were also considered. Despite this detailed analysis, no improved survival was seen in patients when the inferior mesenteric artery was ligated above the origin of the left colic artery.

Aorto-enteric fistulae: an uncommon complication of abdominal aortic aneurysms.

Abstract: Three cases of aorto-enteric fistula which have been treated successfully by resection of the aortic aneurysm are described. Only 5 other successful cases have been reported. One hundred and thirty-one cases are reviewed and analysed, and though more than half of these survived for 24 hours or longer after the first gastro-intestinal haemorrhage, no untreated long-term survival has been recorded. We feel that urgent assessment and early corrective surgery is the only treatment which offers a reasonable chance of survival.

Risk factors in childbirth causing damage to the pelvic floor innervation.

Abstract: The innervation of the pelvic floor musculature is damaged in both stress urinary incontinence and idiopathic (neurogenic) anorectal incontinence. Because childbirth has been considered to be a causative factor in stress incontinence we have assessed the effect of childbirth on the innervation of the pelvic floor musculature in 122 consecutively referred women. They were investigated 48–72 h and 2 months after delivery; 51 were also studied 6 months prior to delivery. In 45 of these 51 women delivered vaginally, EMG studies of the external anal sphincter muscle showed that the fibre density (FD) increased from 1.38±0.14 before delivery to 1.57±0.19 2 months after delivery (p<0.01). There was no change in the FD in the external anal sphincter muscle after delivery in 20 women delivered by Caesarean section. The pudendal nerve terminal motor latency (PNTML) measured 48–72 h after delivery was increased in the 102 women delivered vaginally compared to 34 nulliparous control subjects. Analysis of the whole group of 122 women showed that multiparity, forceps delivery, increased duration of the second stage of labour, third degree perineal tear and high birth weight were important factors leading to pudendal nerve damage. Epidural anaesthesia had no effect on pudendal nerve function. Modification of these obstetric risk factors may ultimately reduce the frequency of stress urinary and faecal incontinence in women.

Glucose Homeostasis and Safety in Patients with Acromegaly Converted from Long-Acting Octreotide to Pegvisomant

Abstract: Context: In clinical practice, patients with acromegaly may be switched from therapy with long-acting somatostatin analogs to pegvisomant. The effect of changing therapies on glucose homeostasis and safety has not been reported. Objectives: The objectives of this study were to monitor changes in IGF-I levels, glycemic control, and safety, particularly liver function and tumor size. Design: This was a multicenter, open-label, 32-wk trial study. Setting: The study was performed at outpatient clinics. Patients: Fifty-three patients with acromegaly previously treated with octreotide long-acting release (LAR) participated in this study. Intervention: Pegvisomant (10 mg/d) was initiated 4 wk after the last dose of octreotide LAR and was adjusted based on serum IGF-I concentrations at wk 12, 20, and 28. Main Outcome Measures: The main outcome measures were changes in IGF-I, glycosylated hemoglobin A1c (HbA1c), fasting plasma glucose, and safety during the first 12 wk after conversion. Results: At the end of pegvisomant treatment, IGF-I was normalized in 78% of patients. At wk 32, median fasting glucose concentration and HbA1c were reduced (1.4 mmol/liter and 0.4%, respectively; both P 0.0001) in the study population. Improvements in glycemic control occurred in patients with normal IGF-I concentrations at wk 4[ n 15; fasting glucose, 1.7 mmol/liter (P 0.0001); HbA1c 0.2% (P 0.03)]. Decreases in fasting glucose and HbA1c levels were observed in patients with and without diabetes. HbA1c was reduced by more than 1.0% in patients with diabetes. Median pituitary tumor volume did not change, although tumor volume increased in two patients with macroadenomas. Conclusions: Conversion from octreotide LAR to pegvisomant was safe and well tolerated. Improved glycemic control indicates that pegvisomant should be considered in patients with acromegaly and diabetes. (J Clin Endocrinol Metab 90: 5684–5691, 2005)

Meta-Analysis to Evaluate the Role of Interferon in Follicular Lymphoma

Abstract: Purpose To determine whether interferon (IFN) -α2, when given with or following chemotherapy, influences response rate, remission duration, and survival in newly diagnosed patients with follicular lymphoma. Patients and Methods Ten phase III studies evaluating the role of IFN-α2 in 1,922 newly diagnosed patients with follicular lymphoma were analyzed. Updated individual patient data were used to perform meta-analyses for response, survival, and remission duration. Results The addition of IFN-α2 to initial chemotherapy did not significantly influence response rate. An overall meta-analysis for survival showed a significant difference in favor of IFN-α2, but also showed significant heterogeneity between studies. Further analyses were carried out in order to explain this heterogeneity, and to define the circumstances in which IFN-α2 prolonged survival. The survival advantage was seen when IFN-α2 was given: (1) in conjunction with relatively intensive initial chemotherapy (2P = .00005), (2) at a dose ≥ 5 mill...

Gemcitabine Plus Carboplatin Versus Mitomycin, Ifosfamide, and Cisplatin in Patients With Stage IIIB or IV Non-Small-Cell Lung Cancer: A Phase III Randomized Study of the London Lung Cancer Group

Abstract: Purpose This phase III randomized trial compared two chemotherapy regimens, gemcitabine plus carboplatin and mitomycin, ifosfamide, and cisplatin, in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC). The regimens were compared with regard to effects on survival, response rates, toxicity, and quality of life. Patients and Methods Eligible patients had previously untreated stage IIIB or IV NSCLC suitable for cisplatin-based chemotherapy. Randomly assigned patients were to receive four cycles, each at 3-week intervals, of carboplatin area under the curve of 5 on day 1 plus gemcitabine 1,200 mg/m2 on days 1 and 8 (GCa) or mitomycin 6 mg/m2, ifosfamide 3g/m2, and cisplatin 50 mg/m2 on day 1 (MIC). Results Between February 1999 and August 2001, 422 patients (GCa, n = 212; MIC, n = 210) were randomly assigned in the United Kingdom. The majority of patients received the intended four cycles (GCa, 64%; MIC, 61%). There was a significant survival advantage for GCa compared with MIC (haza...

Treatment of advanced neuroendocrine tumours with radiolabelled somatostatin analogues.

Abstract: Neuroendocrine tumours (NETs) constitute a heterogeneous group of tumours that frequently express cell membrane-specific peptide receptors, such as somatostatin receptors (SSTRs), and of which gastroenteropancreatic (GEP), carcinoid and pancreatic islet cell tumours exhibit the highest expression of SSTRs. Radiolabelled receptor-binding somatostatin analogues (octreotide and lanreotide) act as vehicles to guide radioactivity to tissues expressing SSTRs, and can thus be used for their diagnosis and treatment. After the localization of NETs bearing SSTRs with (111)In-octreotide (OctreoScan), a number of radioisotopes with different physical properties have been used for their treatment. The administration of high doses of the Auger electron and gamma-emitter (111)In-diethylenetriaminepenta-acetic acid (DTPA)(0),octreotide in patients with metastatic tumours has been associated with considerable symptomatic improvement but relatively few and short-lived objective tumour responses. The use of another radiolabelled somatostatin analogue coupled with (90)Y, a pure beta-emitter, (90)Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)(0),Tyr(3),octreotide ((90)Y-DOTATOC, OctreoTher), was associated with 10-30% objective tumour response rates, and appears to be particularly effective in larger tumours. (111)In- and (90)Y-DOTA-lanreotide has also been used for the treatment of NETs although its therapeutic efficacy is probably inferior to that of octreotide-based radiopharmaceuticals. More recently, treatment with (177)Lu-DOTA(0),Tyr(3)octreotate ((177)Lu-DOTATATE), which has a higher affinity for the SSTR subtype 2, resulted in approximately 30% complete or partial tumour responses; this radiopharmaceutical is particularly effective in smaller tumours. Furthermore, treatment using both (90)Y-DOTATOC and (177)Lu-DOTA(0),Tyr(3)octreotate seems promising, as the combination of these radiopharmaceuticals could be effective in tumours bearing both small and large lesions. Tumour regression is positively correlated with a high level of uptake on (111)In-octreotide scintigraphy, limited tumour mass and good performance status. In general, better responses have been obtained in GEP tumours than other NETs. The side effects of this form of therapy are relatively few and mild, particularly when kidney-protective agents are used. Treatment with radiolabelled somatostatin analogues presents a promising tool for the management of patients with inoperable or disseminated NETs, and particularly GEP tumours.

Preoperative radiotherapy for esophageal carcinoma.

Abstract: Background The existing randomized evidence has failed to conclusively demonstrate the benefit or otherwise of preoperative radiotherapy in treating patients with potentially resectable esophageal carcinoma. Objectives This meta-analysis aimed to assess whether there is benefit from adding radiotherapy prior to surgery and whether or not any pre-defined patient subgroups benefit more or less from preoperative radiotherapy Search strategy MEDLINE and CancerLit searches were supplemented by information from trial registers and by hand searching relevant meeting proceedings and by discussion with relevant trialists, organisations and industry. The search strategy was run again in MEDLINE, EMBASE and the Cochrane Library on 30th April 2001, two years after original publication. No new trials were found. The search strategy was re-run August 2002 and August 2003 on MEDLINE, EMBASE , CancerLit and The Cochrane Library, and July 2004 and 2005 on MEDLINE, EMBASE and the Cochrane Library. No new relevant trials were identified on any of these occasions. Selection criteria Trials were eligible for inclusion in this meta-analysis provided they randomized patients with potentially resectable carcinoma of the esophagus (of any histological type) to receive radiotherapy or no radiotherapy prior to surgery. Trials must have used a randomization method which precluded prior knowledge of treatment assignment and completed accrual by December 1993, to ensure sufficient follow-up by the time of the first analysis (September 1995). Data collection and analysis A quantitative meta-analysis using updated data from individual patients from all properly randomized trials (published or unpublished) comprising 1147 patients (971 deaths) from five randomized trials. This approach was used to assess whether preoperative radiotherapy improves overall survival and whether it is differentially effective in patients defined by age, sex and tumour location. Main results With a median follow-up of 9 years, in a group patients with mostly squamous carcinomas, the hazard ratio (HR) of 0.89 (95% CI 0.78-1.01) suggests an overall reduction in the risk of death of 11% and an absolute survival benefit of 3% at 2 years and 4% at 5 years. This result is not conventionally statistically significant (p=0.062). No clear differences in the size of the effect by sex, age or tumor location were apparent. Authors' conclusions Based on existing trials, there was no clear evidence that preoperative radiotherapy improves the survival of patients with potentially resectable esophageal cancer. These results indicate that if such preoperative radiotherapy regimens do improve survival, then the effect is likely to be modest with an absolute improvement in survival of around 3 to 4%. Trials or a meta-analysis of around 2000 patients (90% power, 5% significance level) would be needed to reliably detect such an improvement (from 15 to 20%).

Theobromine inhibits sensory nerve activation and cough

Abstract: SPECIFIC AIMSCough is a condition that affects the vast majority of people at some point in their lives and is the most common complaint for which medical attention is sought. Currently, no effective treatment exists. The aim of this study was to investigate the utility of a novel antitussive called theobromine, a methylxanthine derivative present in cocoa and chocolate, on cough and airway sensory nerve function in humans.PRINCIPAL FINDINGS1. Theobromine as a potential antitussiveSeveral synthetic antitussives are characterized by the presence of a 1,2,4-oxadiazole ring in their chemical structure. With the renaissance of the methylxanthine theophylline to treat asthma in the 1970s, a series of novel compounds with an oxadiazolylalkyl substituent at the N7 atom on the basic xanthine skeleton was synthesized and investigated as potential antiasthmatic and antitussive agents.With two of these compounds selected for preclinical testing, 3,7-dihydro-3-methyl-7-/(5-methyl-1,2,4-oxadiazol-3yl)methyl/-1H-purine...