Tumour length as an independent prognostic factor in resectable oesophageal carcinoma.

INTRODUCTION: Oesophageal longitudinal tumour length has been investigated as a prognostic indicator for disease recurrence and overall survival in resectable oesophageal carcinoma. However, there is conflicting evidence regarding its use in clinical practice. This study aims to assess the prognostic significance of histological tumour length in potentially curative oesophageal resections for cancer. MATERIALS AND METHODS: Patients with locally advanced oesophageal carcinoma (squamous or adenocarcinoma) were identified in a single centre between July 2000 and December 2016. Patient demographics, tumour characteristics and survival outcomes were assimilated. Unifactorial and multifactorial analysis was performed to assess tumour length correlation with oncological outcomes. RESULTS: A total of 281 patients were included; 226 (80.4%) male and 55 (19.6%) female, with a median age of 66 years; 39 patients (13.9%) developed local recurrence and 104 (37%) distant metastases. Disease progression rate was 44.8% with a median progression-free survival of 21 months and median overall survival of 30 months. Median tumour length was 3cm (interquartile range 2-4.5cm). Multivariate analysis demonstrated longer tumours to be significantly associated with a higher rate of local recurrence (p=0.028), metastases (p=0.016), disease progression (p=0.001) and shorter progression-free survival (p=0.001). DISCUSSION: This study demonstrates histological tumour length as an independent prognostic factor for local recurrence, metastases, disease progression and progression-free survival. Further larger multicentre studies are required to define the role of longitudinal tumour length as a marker to identify patients who are at higher risk of poor oncological outcomes following surgery.

Serious toxicity associated with continuous nevirapine-based HAART in pregnancy.

OBJECTIVE: This study was designed to determine the safety of nevirapine (NVP)-based highly active antiretroviral therapy (HAART) in a cohort of HIV-positive pregnant women. DESIGN: This was a prospective cohort study of HIV-positive pregnant women. POPULATION AND SETTING: All HIV-positive women treated with HAART during pregnancy from January 1997 to February 2004 at the British Columbia (BC) Women's Hospital in Vancouver, BC, Canada. METHODS: Demographic and clinical data were collected to compare antiretroviral drug toxicities in women treated antenatally with NVP-based or non-NVP-based HAART. Multivariate analyses were then used to investigate determinants of toxicity. RESULTS: From 1997 to 2004, 103 HIV-positive pregnant women received HAART. Equivalent numbers of women were initially treated with NVP-based (54%) and non-NVP-based (46%) HAART. The groups did not differ by clinical or demographic parameters and duration of HAART exposure was similar between groups. Toxicities necessitating treatment discontinuation were observed in 6 of 56 NVP-exposed women (2 cases each of grade 2, 3, and 4 toxicity) compared with 1 of 47 in the non-NVP-exposed women. First time use of NVP approached significance as a predictor for toxicity, with a toxicity rate of 12.5% (6/48) observed among those taking NVP for the first time (adjusted OR 2.68, 95% CI 0.49-14.6). CONCLUSION: Continuous NVP use in pregnancy resulted in a relatively higher rate of toxicity, and all cases of NVP toxicity occurred in women exposed to NVP for the first time during pregnancy.

A germline mutation of the thyrotropin receptor gene associated with thyrotoxicosis and mitral valve prolapse in a Chinese family.

Activating mutations of the TSH receptor (TSH-R) have been reported to result in toxic adenomas, multinodular goiters, sporadic neonatal hyperthyroidism, and familial autosomal dominant nonautoimmune hyperthyroidism. To date, all descriptions of such mutations, whether somatic or genomic, have been confined to the Caucasian population. We describe a Chinese family in whom a germline proline to serine substitution in position 639 resulted in familial thyrotoxicosis. This constitutively activating mutation has been previously described in a hyperfunctioning thyroid nodule. The three children in this family developed thyrotoxicosis during childhood; their father was diagnosed as thyrotoxic at the age of 38 yr. Two of the children and the father had mitral valve prolapse (MVP) associated with mitral regurgitation. There was a close temporal relationship between the onset of thyrotoxicosis and the diagnosis of mitral valvular disease in these patients. An increased prevalence of MVP has been reported in Graves' disease and chronic lymphocytic thyroiditis, but the pathophysiological mechanisms linking MVP and autoimmune thyroid disease are still not understood. This is the first report of an association between activating TSH-R mutations and MVP. We postulate that TSH-R activation may increase the clinical expression of MVP in genetically predisposed individuals.

Two Chinese families with Pendred's syndrome--radiological imaging of the ear and molecular analysis of the pendrin gene.

We report two families in whom the index cases satisfied the classical diagnostic criteria of Pendred's syndrome. In family I, two siblings were deaf, and one was normal. In family II, both parents and two offspring were deaf. Computed tomography scans performed in five of six of these deaf individuals showed enlarged vestibular aqueducts in all cases, and Mondini cochlea only in family II. Affected members in family I were compound heterozygotes inheriting the paternal allele with a novel mutation S398del in exon 10 and a maternal allele with two mutations IVS13+9C-->G in intron 13, in addition to H723R. In family II, the mother and one child carried both the novel intronic IVS8-2A-->G and H723R mutations, whereas the father and index case were homozygous for the IVS8-2A-->G mutation. A perchlorate discharge test was positive in 50% of cases tested. In conclusion, we concur that radiological and molecular studies should be performed for confirmation of Pendred's syndrome. We report, for the first time, a Pendred's syndrome family in which affected members had three mutations, as well as a second family in whom the intermarriage of two Pendred's syndrome patients resulted in Pendred's syndrome offspring.

Production of bioactive amino-terminal domain of the thyrotropin receptor via insertion in the plasma membrane by a glycosylphosphatidylinositol anchor.

A chimeric cDNA construct encoding the extracellular amino-terminal domain (ECD) of the thyrotropin receptor fused to the signal for addition of glycosylphosphatidylinositol from the Thy-1 gene directs efficient expression of the ECD at the plasma membrane of transfected CHO cells. A cell line (GT14) expressing over 106 receptors/cell was isolated, which allows direct detection, by flow cytometry, of autoantibodies from the majority of patients with Graves' disease or autoimmune idiopathic myxedema. Treatment of GT14 cells with a glycosylphosphatidylinositol-specific phospholipase C (PI-PLC) releases a soluble 80 kDa molecule which neutralizes the autoantibodies from Graves patients. Whereas it does not bind TSH when released from the cells by PI-PLC in free form, the soluble ECD displays clear TSH binding activity when it is released as a complex with a monoclonal antibody recognizing a conformational epitope of the ECD. Our results allow production of bioactive ECD of the thyrotropin receptor in high yield, with possible applications in structural analyses.

Palliation of malignant intestinal obstruction using octreotide.

Vomiting due to malignant intestinal obstruction is an unpleasant terminal event in many cancer patients, which responds poorly to conventional therapies. Somatostatin and its long-acting analogues reduce intestinal secretion. For this reason, octreotide was used in a phase I/II study of patients with intractable vomiting secondary to intestinal obstruction due to malignant disease. Vomiting was controlled or the volume of nasogastric aspirate was markedly reduced in 18 of 24 (75%) patients receiving a subcutaneous infusion of octreotide (median initial dose 300, range 100-600 micrograms/day) for a median of 9.4 (range 1-38) days. A further 2 patients had partial relief of their symptoms. Octreotide is an effective treatment of nausea and vomiting due to malignant bowel obstruction.

Platelet-activating factor in sperm from fertile and subfertile men.

STUDY OBJECTIVE: To examine the proposed role of platelet-activating factor (PAF) as a mediator of sperm function first by quantitating the concentration of PAF in sperm and second by incubating sperm with PAF and assessing the change in sperm motion parameters with a computerized motion analysis system. DESIGN: Retrospective, case-control study. SETTING: University hospital urology clinic. PATIENTS: Concentrations of PAF were measured in sperm from 6 randomly chosen normal donors and 8 asthenozoospermic patients. The change in sperm motion parameters was assessed in sperm from 10 randomly chosen normal donors and 7 asthenozoospermic patients. RESULTS: Platelet-activating factor concentrations were significantly higher (P less than 0.05) in spermatozoa from asthenozoospermic patients (149 +/- 18.0 fmol/10(6) sperm) than in sperm from normal donors (91.9 +/- 13.0 fmol/10(6) sperm). Exogenous PAF did not enhance the percent motility of precapacitated or capacitated sperm from either patients or donors, and computerized semen analysis revealed no enhancement of sperm motion parameters in asthenozoospermic patients after addition of PAF to either precapacitated or capacitated sperm. CONCLUSION: Platelet-activating factor does not appear to have therapeutic value as a means of enhancing sperm motility.

Thyrotoxicosis due to the simultaneous occurrence of silent thyroiditis and Graves' disease.

Silent thyroiditis (ST) and Graves' disease (GD) are two clinical entities belonging to the wide spectrum of autoimmune thyroid diseases (AITD). The two diseases are closely linked because sequential development of GD followed by ST, or the reverse course of events, ie, ST followed by GD, have been documented. However, the pathogenetic basis of the above association remains unknown. Some authors have suggested that the concomitant existence of ST and activation of GD can occur in thyrotoxic postpartum women with normal radioiodoine uptake. The simultaneous occurrence of the two diseases in different parts of the same thyroid gland has, however, to our knowledge, not been documented. We report the case of a 40-year-old thyrotoxic female with atypical presentation of GD. The titers of the antithyrotropin receptor antibodies were elevated and her initial 99mTc-pertechnetate thyroid scan showed the coexistence of ST and GD in different parts of the thyroid gland. Through serial thyroid scans, we document the recovery from ST in parts of the gland and demonstrate the progression to Graves' hyperthyroidism in the entire gland.

Graves' ophthalmopathy in the absence of elevated free thyroxine and triiodothyronine levels: prevalence, natural history, and thyrotropin receptor antibody levels.

The aims of this study were to (a) determine the prevalence of patients without elevated thyroid hormone levels in Graves' ophthalmopathy (GO) using current generation free thyroid hormone assays, (b) measure the prevalence of thyrotropin receptor antibodies (TRAb) in these cases, and (c) identify possible predictors of hyperthyroidism. Over a 30-month period, 1020 cases of thyroid eye disease were evaluated, of which only 19 (1.9%) met the diagnostic criteria. Ten (1%) had subclinical thyrotoxicosis, 7 (0.7%) were euthyroid, and 2 (0.2%) were hypothyroid as determined by a third-generation thyrotropin (TSH) assay. TRAb levels were measured in 16 of these 19 patients. The prevalence of TRAb varied according to the assay used. Polyethylene glycol-extracted thyroid-stimulating immunoglobulin (PEG-TSI), unfractionated thyroid-stimulating immunoglobulin (uTSI), first-generation porcine TSH-binding inhibitory immunoglobulin (pTBII), and second-generation human TSH-binding inhibitory immunoglobulin (hTBII) assays were positive in 93.8%, 50%, 18.8%, and 81.3% of patients, respectively. TRAb was detected by at least one method in all patients. Patients were followed up for 15 to 45 months. Hyperthyroidism developed in 4 patients (25%). Suppressed TSH levels and elevated TBII were predictors of hyperthyroidism. When sensitive assays are used, the prevalence of GO patients without elevated thyroid hormone levels is extremely low. The sensitivities of assays for TRAb detection differ substantially in these cases. PEG extraction improves the detection rate of TSI (p = 0.02), and hTBII assays improve the detection of TBII in these patients (p = 0.002). The high prevalence of TRAb in such cases supports a role for these antibodies in the pathogenesis of thyroid-associated eye disease.

The combination of absent thyroid peroxidase antibodies and high thyroid-stimulating immunoglobulin levels in Graves' disease identifies a group at markedly increased risk of ophthalmopathy.

Among Graves' Disease (GD) patients, we have observed an unexpectedly high prevalence of antithyroperoxidase antibody (TPOAb) and antithyroglobulin antibody (TgAb) negativity in those with severe ophthalmopathy. To study the possible role of thyroid autoantibodies in the pathogenesis of Graves' ophthalmopathy (GO), TPOAb, TgAb, thyroid-stimulating immunoglobulin (TSI), and thyrotropin-binding inhibitory immunoglobulin (TBII) levels were measured, and the presence or absence of GO was assessed by a single observer in 100 consecutive patients with newly diagnosed, untreated GD who were nonsmokers. Ophthalmopathy was present in 43 patients. TSI levels (p = 0.001), and the prevalence of TPOAb-negativity (p = 0.002) were significantly higher in patients with ophthalmopathy compared to those without. Logistic regression analysis showed that TSI levels (p = 0.005) and the absence of TPOAb (p = 0.0025) were independent predictors of GO. No correlation between TBII or TgAb and eye disease was found. The prevalence of GO increased with each quartile of TSI levels. The prevalence was 20%, 36%, 52%, and 64% in the first, second, third and fourth quartiles of TSI, respectively. The odds ratio of GO (with 95% confidence intervals) when TSI levels were above the median level (1640%) was 3.6 (1.5-8.0), when TPOAb was negative it was 5.0 (1.7-14.4), and with both risk factors it was 36.6 (4.3-313.5). The prevalence of ophthalmopathy in this last group was 92.9%. The combination of negative TPOAb and high TSI levels appears to be associated with a markedly increased risk of clinically evident ophthalmopathy.

Iodostearic acid in the treatment of advanced gastrointestinal carcinoma.

This phase II non-comparative trial evaluated the efficacy of intramuscular iodostearic acid in the treatment of 30 patients with advanced carcinoma of the gastrointestinal tract. These included 17 patients with colorectal carcinoma, seven with pancreatic carcinoma, four with gastric carcinoma, one with hepatocellular carcinoma and one with cholangiocarcinoma. Iodostearic acid emulsion (2 ml/1.2 g) followed by depomedrone (0.5 ml/10 mg) was injected intramuscularly twice weekly. No serious toxic effects were observed, the main side effects being local pain at the injection site and hot flushes. There were no partial or complete responses. Stable disease was seen in six of 30 patients (20%) at 3 months and three of 30 patients (10%) at 6 months. In conclusion, intramuscular iodostearic acid is relatively non-toxic, however, it appears to be of little value in the treatment of patients with advanced gastrointestinal carcinomas.

Is screening once at age 65 an effective method for detection of abdominal aortic aneurysms?

OBJECTIVE: To evaluate whether a single screening at 65 or screening at 65 and 70 are the methods of choice to detect the majority of abdominal aortic aneurysms (AAA) suitable for treatment. SETTING: District general hospital, district general practice and community. METHODS: Data were collated from four studies (a pilot, a control trial, and two cohorts) of abdominal ultrasound screening of an invited group of 11 666 men and women aged 65-80 to derive age related prevalence, invitation acceptance rates, and operative mortality. Deaths from AAA rupture were obtained from district registrars' returns. RESULTS: The prevalence of AAA increased with age being greater overall in men (6.8%) than in women (1.2%). From ages 65 to 80 the prevalence in men increased from 5.4% to 10.4%, and in women from 0.6% to 2.1%. In men and women 4% of patients dying from AAA rupture were aged 65 or under and 85% of deaths occurred over the age of 70. Acceptance rates for screening decreased between 65 and 80 from 80.5% to 66.2% in men and from 72.7% to 58.3% in women. In elective or symptomatic patients operative mortality was zero up to the age of 70, increasing to 7.1% in older patients. CONCLUSIONS: Men should be screened at age 65 to obtain a high acceptance rate and to identify those with AAA most likely to benefit from treatment. The prevalence is relatively low at this age so an additional screen at age 70 is recommended, which would pick up a further 3.7% of patients with AAA, at which age intervention is likely to be of benefit.

Restless legs symptoms in thyroid disorders.

Dopaminergic dysfunction is associated with thyroid disorders and restless legs syndrome (RLS). In a 'face-to-face' interview, we evaluated for RLS using the diagnostic criteria of the International Restless Legs Syndrome Study Group (IRLSSG) in patients diagnosed biochemically with either hyper- or hypothyroidism, and in controls without thyroid disorders. Amongst 146 consecutive patients with biochemically confirmed thyroid disorders, none satisfied all the IRLSSG criteria of RLS, similar to the control population (0.2%, 1/434). However, we found 8.2% (12/146) with RLS-like symptoms (satisfied the first 3 IRLSSG criteria) compared to 0.9% (4/434) in the controls (p < 0.0001). Four (33.3%) of these patients reported complete resolution of these symptoms after treatment for their thyroid condition. In conclusion, while RLS-like symptoms were observed in some patients with thyroid disorders, our study demonstrates no significant difference of RLS prevalence between patients with thyroid disorders and euthyroid controls.

Cushing's syndrome in a patient with a corticotropin-releasing hormone-producing pheochromocytoma.

OBJECTIVE: To present the first case of Cushing's syndrome attributable solely to ectopic production of corticotropin-releasing hormone by a pheochromocytoma. METHODS: We summarize the clinical features and results of laboratory investigations in a patient with symptoms characteristic of Cushing's syndrome. RESULTS: Although Cushing's syndrome is usually caused by ectopic production of adrenocorticotropic hormone (ACTH), our current patient had clinical and biochemical evidence of hypercortisolism in conjunction with "normal" ACTH levels and nonsuppressible serum and urinary cortisol levels on low-dose and high-dose dexamethasone suppression testing. An abdominal computed tomographic scan revealed a 7.7-cm mass in the left adrenal gland. Light microscopic examination and immunohistochemical staining showed a pheochromocytoma with mild cortical hyperplasia. Immunostaining was positive for corticotropin-releasing hormone but negative for ACTH. CONCLUSION: To our knowledge, this is the first case of Cushing's syndrome in a patient with pheochromocytoma caused only by ectopic secretion of corticotropin-releasing hormone without accompanying secretion of ACTH.

Bacterial endocarditis in a transplanted heart.

A 51-year-old man presented with an abscess in his sternotomy scar 33 months after orthotopic heart transplantation. After surgical drainage he developed a febrile illness which led to renal and pulmonary failure. Twenty-three days after the illness began, blood cultures grew Staphylococcus aureus and he died 11 days later. Post-mortem examination revealed acute bacterial endocarditis with dense colonies of gram-positive cocci on the mitral valve leaflets and microabscesses in the myocardium of the transplanted heart.

Ulnar nerve anatomy and compression.

Compression of the ulnar nerve can be understood in terms of the anatomic and dynamic factors. Although the ulnar nerve may be compressed at any point along its course, it is particularly susceptible at the elbow and the wrist. Clinically relevant anatomy will be reviewed in an attempt to provide the reader with a logical framework for successfully diagnosing and managing typical and atypical ulnar nerve compression lesions.

Heterodigital arterialized flaps for large finger wounds: results and indications.

Deep defects of the hand and fingers with an unhealthy bed exposing denuded tendon, bone, joint, or neurovascular structures require flap coverage. However, the location and size of the defects often preclude the use of local flap coverage. Free-flap coverage is often not desirable either, because the recipient vessels may be unhealthy from surrounding infection or trauma. In such situations, a regional pedicled flap is preferable. A solution to this is the heterodigital arterialized flap. This flap is supplied by the digital artery and a dorsal vein of the finger for venous drainage. Unlike the neurovascular island flap, the digital nerve is left in situ in the donor finger, thus avoiding many of the neurologic complications associated with the Littler flap. The digital artery island flap is centered on the midlateral line of the donor finger. It extends from the middorsal line to the midpalmar line. The maximal length of the flap is from the base of the finger to the distal interphalangeal joint. By preserving the pulp and the digital nerve, a sensate pulp on the donor finger remains that reduces donor-finger morbidity and also preserves fingertip cosmesis. Twenty-nine flaps were performed in 29 patients and the outcomes in the donor finger and the reconstructed finger were reviewed. The flap survival was 100 percent. There were no cases of flap ischemia or flap congestion. Good venous drainage of the flap through the additional dorsal vein was helpful in preventing the occurrence of early postoperative venous congestion, which is common in island flaps of the fingers, which depend on only the venae comitantes for drainage. Donor-finger morbidity, measured in terms of range of motion and two-point discrimination in the pulp, was minimal. Ninety-seven percent of the donor fingers achieved excellent or good total active motion according to the criteria of Strickland and Glogovac. Pulp sensation in the donor fingers was normal in 28 of the 29 donor fingers. No cold intolerance of the donor finger or the adjacent finger is reported in this series.

Diagnostic difficulties associated with phaeochromocytoma--4 case illustrations.

The diagnosis of phaeochromocytoma can be extremely difficult with 40%-76% of cases escaping diagnosis during life. Until recently, the only available biochemical test for the detection of phaeochromocytoma in Singapore has been the 24-hour urinary vanillyl mandelic acid (VMA). Urinary VMA has been reported to have a high specificity (85%-100%) but variable sensitivity (28%-90%) in the diagnosis of this disease. In 1993, high performance liquid chromatography (HPLC) assays for the measurement of urinary catecholamines and metanephrines were introduced at the Singapore General Hospital. Since 1993, 4 cases of phaeochromocytoma have been detected at our institution. We report here, the diverse clinical presentations of these patients. The urinary-free catecholamine and catecholamine metabolite levels of these patients were compared with corresponding levels from 12 non-phaeochromocytoma patients. Using the reference value of 65.6 mumol/day, we found the urinary VMA to be a highly sensitive (100%) test with a specificity of only 31%. In contrast, a urinary total metanephrine level > or = 9,000 nmol/day was both sensitive (100%) as well as specific (100%).

A man with osteoblastic metastasis and hypocalcaemia.

We report a case of an 80-year-old man with osteoblastic metastases from advanced carcinoma of the prostate presenting with a grand mal seizure resulting from severe hypocalcaemia. He had low serum phosphate and ionised calcium levels, elevated serum skeletal alkaline phosphatase and intact parathormone levels. 99mTc radioisotope bone scan revealed a "super bone scan" suggestive of osteomalacia. The serum 1, 25-dihydroxycholecalciferol level was unexpectedly elevated. The biochemical abnormalities persisted despite high dose calcium replacement, but improved with supraphysiological doses of 1,25 (OH)2 vitamin D3 (Rocaltrol) therapy. We hypothesise that the hypocalcaemia in this patient was due to vitamin D resistance secondary to a humoral factor secreted by the tumour.

The effect of chemotherapy on soft tissue and bone healing in the rabbit model.

UNLABELLED: The effect of chemotherapy on soft tissue and bone healing was studied in a rabbit femoral fracture model. Adriamycin was administered at various intervals preoperatively. Results were compared against a control group in which adriamycin was omitted. Post-chemotherapy blood count profiles were monitored. All animals were operated on with a standard skin incision, osteotomy of the femur and fixation with an intramedullary wire. Soft tissue was assessed with daily clinical scoring and tested for wound breaking strength at two weeks postoperatively. Bone healing was assessed at the time of sacrifice six weeks postoperatively by four-point bending to failure. Clinical scoring of wounds did not show significant differences between control and adriamycin-treated groups. Results of wound breaking strength and four-point bending to failure showed significant impairment for animals given adriamycin four and seven days preoperatively, and no significant impairment when given 14 days preoperatively. CLINICAL RELEVANCE: Contrary to previous studies, our results suggest that it is feasible to combine neoadjuvant chemotherapy and early surgery without compromise of soft tissue healing. Our results show that adriamycin impairs bone healing. We postulate that adriamycin has a temporary and reversible inhibitory effect on bone biology. The clinical implications of these findings are discussed.