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Background: oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. Methods: all available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki67 2wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. Findings: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki67 2wk (p2wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. Interpretation: our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse. Funding: Cancer Research UK (CRUK/07/015).

Background Cryoglobulins are cold-precipitable immunoglobulins that may be found in association with systemic vasculitis including cryoglobulinaemic glomerulonephritis (CGN). Type 1 cryoglobulins consist of isolated monoclonal immunoglobulin (mIg), whereas mixed cryoglobulins are typically immune complexes comprising either monoclonal (type 2) or polyclonal (type 3) Ig with rheumatoid activity against polyclonal IgG. Only CGN related to type 1 cryoglobulins has been clearly associated with monoclonal gammopathy of undetermined significance (MGUS) using the conventional serum-, urine- or tissue-based methods of paraprotein detection. Methods We retrospectively assessed our patient cohort of CGN related to mixed (type 2 or 3) cryoglobulins for those with a monoclonal band on serum protein electrophoresis (SPEP), with exclusion of infectious cases and those involving malignant clonal plasma cell or B cell disorders. Results We identified four patients with a median age of 54 years, including three women. Two patients had type 2 cryoglobulinaemia, one had type 3 cryoglobulinaemia, and one lacked definitive typing of the serum cryoprecipitate. The serum monoclonal band identified on SPEP was IgM-κ in all four cases. Treatments included corticosteroids, cyclophosphamide, plasma exchange, and rituximab. At median 3.5 years’ follow-up, no patient had developed a haematological malignancy or advanced chronic kidney disease. Other potential causes of mixed cryoglobulinaemia were also present in our cohort, notably primary Sjögren’s syndrome in three cases. Conclusions Our study raises questions regarding the attribution of causation to MGUS, and the role of clonally directed therapies outside the setting of haematological malignancy.

Pyelonephritis post-renal transplantation is common and in up to 50% of cases can be asymptomatic. Transplant pyelonephritis shares a lot of histopathological features with acute cellular rejection. We present a case of asymptomatic acute graft pyelonephritis where a renal biopsy was complicated by sepsis, and discuss the difficulties in interpretation of renal histology in the setting of transplant pyelonephritis where rejection may also be a possibility, but differentiation is challenging.

Rapid changes in tissue-typing technology, including the widespread availability of highly specific molecular typing methods and solid-phase assays for the detection of allele-specific anti-HLA antibodies, make it increasingly challenging to remain up to date with developments in organ matching. Terms such as epitopes and eplets abound in the transplantation literature, but often it can be difficult to see what they might mean for the patient awaiting transplantation. In this review, we provide the historical context for current practice in tissue typing and explore the potential role of HLA epitopes in kidney transplantation. Despite impressive gains in preventing and managing T-cell-mediated rejection and the associated improvements in graft survival, the challenge of the humoral alloresponse remains largely unmet and is the major cause of late graft loss. Describing HLA antigens as a series of antibody targets, or epitopes, rather than based on broad seroreactivity patterns or precise amino acid sequences may provide a more practical and clinically relevant system to help avoid antibody-mediated rejection, reduce sensitization, and select the most appropriate organs in the setting of pre-existing alloantibodies. We explain the systems proposed to define HLA epitopes, summarize the evidence to date for their role in transplantation, and explore the potential benefits of incorporating HLA epitopes into clinical practice as this field continues to evolve toward everyday practice.

Sir, We report the case of a patient with thalidomide-induced third-degree heart block when used in context of myeloma and acute renal failure. An 88-year-old female patient was commenced on thalidomide 50 mg daily along with pulsed dexamethasone for treatment of newly diagnosed multiple myeloma. After 3 weeks of treatment, the dose of thalidomide was increased to 100 mg daily. Electrocardiogram (ECG) at baseline presentation and on 50 mg od showed normal sinus rhythm with a ventricular rate of 83/min. There was no evidence of delayed atrio-ventricular conduction (PR interval 130 ms) and normal QRS. After 3 days of 100 mg thalidomide, the patient started feeling light-headed on minimal exertion. A repeat ECG showed third-degree heart block with a ventricular rate of 31 beats per minute and left bundle block. The patient had no history of ischaemic heart disease. Serum electrolytes, thyroid function tests, cardiac enzymes and chest x-ray were within normal limits. We observed this patient for 24 h, and the ECG abnormality did not improve. After counselling about the need for ongoing treatment with thalidomide treatment for her myeloma and the risks of infections with a permanent pacemaker, she went on to have a permanent pacemaker fitted. Due to its anti-angiogenesis activity thalidomide has been used for the treatment of multiple myeloma. The combination of thalidomide and dexamethasone, often in combination with cylcophosphamide, is now one of the most common regimens for patients with newly diagnosed multiple myeloma [1]. As thalidomide predominately undergoes pH-dependent spontaneous hydrolysis in all body fluids into multiple metabolites and is passively excreted, its pharmacokinetics are not expected to change in patients with impaired liver or kidney function. Hence, no dose reduction is recommended for patients with renal impairment or those on dialysis. Thalidomide has a number of well-recognized side effects such as teratogenicity, skin rash, peripheral neuropathy, pneumonitis and venous thromboembolism (VTE). However, the incidence of heart block has been rarely reported. There have been similar case reports of conduction abnormalities with thalidomide [2]. We conclude that cardiac monitoring should be instituted and screened for when treating patients with this drug. Regular ECGs should be performed when rate disturbance is noted on this therapy. Conflict of interest statement. None declared.

Chronic bile duct ligation is associated with the development of oxidant injury, biliary cirrhosis, portal hypertension, and a hyperdynamic circulation. We have previously demonstrated that the hyperdynamic circulation in the partial portal vein‐ligated rat can be prevented by the administration of N-acetylcysteine. To extend these findings, we have examined the effect of lipoic acid, a thiolcontaining antioxidant, on hemodynamics, oxidative stress, and nitric oxide (NO) production in bile duct‐ligated (BDL) cirrhotic rats. Lipoic acid was given continuously in drinking water to normal and BDL rats; control rats received ordinary drinking water, and animals were studied at 24 days following surgery. Lipoic acid prevented the development of the hyperdynamic circulation (cardiac index [CI]: 15.7 6 2.0 vs. 29.5 6 2.1 mL ? min 21 ? 100 g 21 ; P F .05) and significantly attenuated the rise in portal pressure (PP) (12.7 6 0.8 vs. 15.2 6 0.5 mm Hg; P F .05). Hepatic nitric oxide synthase (NOS) activity and plasma nitrite/nitrate concentration increased significantly following bile duct ligation, and both of these were prevented by lipoic acid. Lipoic acid had no effect on the biochemical or histological parameters of liver function in the cirrhotic group. We conclude that lipoic acid prevents the development of the hyperdynamic circulation in the rat model of biliary cirrhosis, and that this is associated with decreased synthesis of NO. (HEPATOLOGY 1999;29:1358-1363.)

Acute cholestasis-induced renal failure: Effects of antioxidants and ligands for the thromboxane A2 receptor.BackgroundAcute biliary obstruction is associated with the development of renal impairment and oxidative stress. The F2-isoprostanes, formed during oxidant injury, are renal vasoconstrictors acting via thromboxane (TX)-like receptors. We determined whether the formation of F2-isoprostanes is increased in experimental cholestasis and whether thiol containing antioxidants or ligands for the TXA2 receptor could improve renal function.MethodsThe effects on renal function of acute bile duct ligation (BDL) in the rat were studied for two days. The consequences of administration of N-acetylcysteine (NAC), α-lipoic acid (LA), the TX receptor antagonist (TXRA) BAYu3405, or placebo were then examined.ResultsBDL caused a reduction in creatinine clearance from 1.10 ± 0.05 to 0.55 ± 0.05 ml/min and sodium excretion from 52 ± 3 to 17 ± 3 μmol/hr. Urinary F2-isoprostanes increased from 14 ± 2 to 197 ± 22 pg/ml following BDL. Renal functional changes were ameliorated by NAC (creatinine clearance 0.73 ± 0.05 ml/min), LA (0.64 ± 0.03 ml/min), and a TXRA (0.90 ± 0.15 ml/min); P < 0.05. Similarly, sodium excretion was increased from 17 ± 3 μmol/hr (placebo) to 34 ± 3 μmol/hr (NAC), 29 ± 3 μmol/hr (LA), and 38 ± 5 μmol/hr (TXRA); P < 0.005. Hepatic glutathione concentrations increased from 6.5 ± 0.3 μmol/g (normal liver) to 8.8 ± 0.5 μmol/g (NAC) and 7.7 ± 0.3 μmol/g (LA), P < 0.01. However, only LA markedly inhibited F2-isoprostane formation (197 ± 22 to 36 ± 11 pg/ml creatinine clearance; P < 0.05). Urinary TXB2 excretion was elevated after BDL (2.2 ± 0.5 to 111.1 ± 20.3 pg/min) but was unaffected by NAC and LA.ConclusionNAC, LA, and TXRA can partially prevent renal dysfunction in experimental cholestasis. The effects of the antioxidants are independent of their ability to inhibit lipid peroxidation or TX synthesis.

Muscle injury (rhabdomyolysis) and subsequent deposition of myoglobin in the kidney causes renal vasoconstriction and renal failure. We tested the hypothesis that myoglobin induces oxidant injury to the kidney and the formation of F2-isoprostanes, potent renal vasoconstrictors formed during lipid peroxidation. In low density lipoprotein (LDL), myoglobin induced a 30-fold increase in the formation of F2-isoprostanes by a mechanism involving redox cycling between ferric and ferryl forms of myoglobin. In an animal model of rhabdomyolysis, urinary excretion of F2-isoprostanes increased by 7.3-fold compared with controls. Administration of alkali, a treatment for rhabdomyolysis, improved renal function and significantly reduced the urinary excretion of F2-isoprostanes by approximately 80%. EPR and UV spectroscopy demonstrated that myoglobin was deposited in the kidneys as the redox competent ferric myoglobin and that it's concentration was not decreased by alkalinization. Kinetic studies demonstrated that the reactivity of ferryl myoglobin, which is responsible for inducing lipid peroxidation, is markedly attenuated at alkaline pH. This was further supported by demonstrating that myoglobin-induced oxidation of LDL was inhibited at alkaline pH. These data strongly support a causative role for oxidative injury in the renal failure of rhabdomyolysis and suggest that the protective effect of alkalinization may be attributed to inhibition of myoglobin-induced lipid peroxidation.

however, his liver extended 4 cm below the right costalmargin and the spleen was just palpable. Urine outputWe report two cases of renal, hepatic and respiratory was 20 ml/h with only red cells detected in his urine,failure occurring with the haemophagocytic syndrome of which

The following abstracts won prizes at the 153rd East Midlands Surgical Society meeting held on 9 November 2012 at Leicester General Hospital. First prize was won by George et al. The paper by Ogunbiyi et al was placed second and the paper by Khanna et al was placed third.

Nearly 30% of patients with autoimmune thyroid disease have proteinuria w1x. Membranous glomerulonephritis is the most common finding when thyroid disease is associated with nephrotic range proteinuria. There are only three previous reports of autoimmune thyroid disease and minimal change glomerular disease (MCD). We report the case of a patient in whom Graves’ disease and MCD were diagnosed simultaneously and in whom relapse of the Graves’ disease was invariably accompanied by relapse of MCD.

Rhabdomyolysis causes renal dysfunction associated with renal vasoconstriction, tubular toxicity and luminal obstruction. There is now accumulating evidence that renal injury, caused by lipid peroxidation, is important in the pathogenesis of renal failure. The proposed central role of free iron in this process is examined. Current data have shown that the heme center of myoglobin can initiate lipid peroxidation and renal injury without invoking release of free iron, and this process is due to redox cycling of the heme group from ferrous to ferric and to ferryl oxidation states. Alkaline conditions prevent myoglobin-induced lipid peroxidation by stabilizing the reactive ferryl myoglobin complex. This review explores the evidence for each of these mechanisms.

Partial portal vein ligation (PPVL) leads to the development of a hyperdynamic circulation. It is associated with elevated levels of tumor necrosis factor (TNF-alpha) and nitric oxide (NO) production, both of which can result in oxidant injury. In this study, we have investigated whether PPVL is associated with the development of oxidative stress, by measuring urinary F2-isoprostanes. In addition, we have examined whether N-acetylcysteine (NAC) can ameliorate oxidant injury and prevent the development of the hyperdynamic circulation. Urinary excretion of F2-isoprostanes increased sixfold following PPVL together with a significant increase in plasma nitrite and nitrate. Treatment with NAC inhibited the formation of F2-isoprostanes as well as the increase in plasma nitrite and nitrate. Hemodynamic studies in anesthetized rats showed that following PPVL, cardiac output and portal pressure increased, and systemic vascular resistance decreased, consistent with the development of a hyperdynamic circulation. These changes were prevented by chronic administration of NAC. We conclude that NAC prevents the development of the hyperdynamic circulation and that the formation of reactive oxygen species may be important in the pathogenesis of these hemodynamic changes.