Citations

Abstract BAFF and a proliferation-inducing ligand (APRIL), which control B cell homeostasis, are therapeutic targets in autoimmune diseases. TACI-Fc (atacicept), a soluble fusion protein containing the extracellular domain of the BAFF–APRIL receptor TACI, was applied in clinical trials. However, disease activity in multiple sclerosis unexpectedly increased, whereas in systemic lupus erythematosus, atacicept was beneficial. In this study, we show that an endogenous soluble TACI (sTACI) exists in vivo. TACI proteolysis involved shedding by a disintegrin and metalloproteinase 10 releasing sTACI from activated B cells. The membrane-bound stub was subsequently cleaved by γ-secretase reducing ligand-independent signaling of the remaining C-terminal fragment. The shed ectodomain assembled ligand independently in a homotypic way. It functioned as a decoy receptor inhibiting BAFF- and APRIL-mediated B cell survival and NF-κB activation. We determined sTACI levels in autoimmune diseases with established hyperactivation of the BAFF–APRIL system. sTACI levels were elevated both in the cerebrospinal fluid of the brain-restricted autoimmune disease multiple sclerosis correlating with intrathecal IgG production, as well as in the serum of the systemic autoimmune disease systemic lupus erythematosus correlating with disease activity. Together, we show that TACI is sequentially processed by a disintegrin and metalloproteinase 10 and γ-secretase. The released sTACI is an immunoregulator that shares decoy functions with atacicept. It reflects systemic and compartmentalized B cell accumulation and activation.

ABSTRACT A process employing patient- or parent-collected pharyngeal swabs for group A Streptococcus (GAS) testing would expedite diagnosis and treatment, reduce patient exposure to the health care setting, and decrease health care costs. Our aim was to determine the concordance between patient- or parent-collected (self-collected) and health care worker (HCW)-collected pharyngeal swabs for detection of GAS by PCR. From 9 October 2012 to 21 March 2013, patients presenting with a sore throat meeting criteria for GAS testing and not meeting criteria for severe disease were offered the opportunity to collect their own pharyngeal swab. The HCW also collected a swab. Paired swabs were tested by GAS real-time PCR, allowing semiquantitative comparisons between positive results. Of the 402 participants, 206 had a swab collected by the patient and 196 a swab collected by the parent. The percent positivity results were 33.3% for HCW-collected swabs and 34.3% for self-collected swabs ( P = 0.41). The overall concordance between the two collection strategies was 94.0% (95% confidence interval [CI], 91.3 to 96.0). Twenty-four of the paired swabs had discordant results, with 10 and 14 positives detected only with the HCW- and self-collected swabs, respectively ( P = 0.41). The person collecting the swab in the self-collected arm, the order of collection, and prior swab collection training did not influence results. Among the 124 specimens that were positive by both collection methods, the amount of GAS DNA was higher in the self-collected versus the HCW-collected swabs ( P = 0.008). Self-collected pharyngeal swabs provide a reliable alternative to HCW collection for detection of GAS and offer a strategy for improved health care delivery.

Background and aims Peripancreatic fat necrosis occurs frequently in necrotising pancreatitis. Distinguishing markers from mediators of severe acute pancreatitis (SAP) is important since targeting mediators may improve outcomes. We evaluated potential agents in human pancreatic necrotic collections (NCs), pseudocysts (PCs) and pancreatic cystic neoplasms and used pancreatic acini, peripheral blood mononuclear cells (PBMC) and an acute pancreatitis (AP) model to determine SAP mediators. Methods We measured acinar and PBMC injury induced by agents increased in NCs and PCs. Outcomes of caerulein pancreatitis were studied in lean rats coadministered interleukin (IL)-1β and keratinocyte chemoattractant/growth-regulated oncogene, triolein alone or with the lipase inhibitor orlistat. Results NCs had higher fatty acids, IL-8 and IL-1β versus other fluids. Lipolysis of unsaturated triglyceride and resulting unsaturated fatty acids (UFA) oleic and linoleic acids induced necro-apoptosis at less than half the concentration in NCs but other agents did not do so at more than two times these concentrations. Cytokine coadministration resulted in higher pancreatic and lung inflammation than caerulein alone, but only triolein coadministration caused peripancreatic fat stranding, higher cytokines, UFAs, multisystem organ failure (MSOF) and mortality in 97% animals, which were prevented by orlistat. Conclusions UFAs, IL-1β and IL-8 are elevated in NCs. However, UFAs generated via peripancreatic fat lipolysis causes worse inflammation and MSOF, converting mild AP to SAP.

AbstractBreast cancer risk factors and clinical outcomes vary by tumour marker expression. However, individual studies often lack the power required to assess these relationships, and large‐scale analyses are limited by the need for high throughput, standardized scoring methods. To address these limitations, we assessed whether automated image analysis of immunohistochemically stained tissue microarrays can permit rapid, standardized scoring of tumour markers from multiple studies. Tissue microarray sections prepared in nine studies containing 20 263 cores from 8267 breast cancers stained for two nuclear (oestrogen receptor, progesterone receptor), two membranous (human epidermal growth factor receptor 2 and epidermal growth factor receptor) and one cytoplasmic (cytokeratin 5/6) marker were scanned as digital images. Automated algorithms were used to score markers in tumour cells using the Ariol system. We compared automated scores against visual reads, and their associations with breast cancer survival. Approximately 65–70% of tissue microarray cores were satisfactory for scoring. Among satisfactory cores, agreement between dichotomous automated and visual scores was highest for oestrogen receptor (Kappa = 0.76), followed by human epidermal growth factor receptor 2 (Kappa = 0.69) and progesterone receptor (Kappa = 0.67). Automated quantitative scores for these markers were associated with hazard ratios for breast cancer mortality in a dose‐response manner. Considering visual scores of epidermal growth factor receptor or cytokeratin 5/6 as the reference, automated scoring achieved excellent negative predictive value (96–98%), but yielded many false positives (positive predictive value = 30–32%). For all markers, we observed substantial heterogeneity in automated scoring performance across tissue microarrays. Automated analysis is a potentially useful tool for large‐scale, quantitative scoring of immunohistochemically stained tissue microarrays available in consortia. However, continued optimization, rigorous marker‐specific quality control measures and standardization of tissue microarray designs, staining and scoring protocols is needed to enhance results.

Objective To evaluate the clinical and radiographic predictors of the need for partial or circumferential resection of the inferior vena cava ( IVC ) requiring complex vascular reconstruction during venous tumour thrombectomy for renal cell carcinoma ( RCC ). Patients and Methods Data were collected on 172 patients with RCC and IVC (levels I– IV ) venous tumour thrombus who underwent radical nephrectomy with tumour thrombectomy at the Mayo Clinic between 2000 and 2010. Preoperative imaging was re‐reviewed by one of two radiologists blinded to details of the patient's surgical procedure. Univariable and multivariable associations of clinical and radiographic features with IVC resection were evaluated by logistic regression. A secondary analysis was used to assess the ability of the model to predict histological invasion of the IVC by the tumour thrombus. Results Of the 172 patients, 38 (22%) underwent IVC resection procedures during nephrectomy. Optimum radiographic thresholds were determined to predict the need for IVC resection based on preoperative imaging included a renal vein diameter at the renal vein ostium ( RV o) of 15.5 mm, maximum anterior–posterior ( AP ) diameter of the IVC of 34.0 mm and AP and coronal diameters of the IVC at the RV o of 24 and 19 mm, respectively. On multivariable analysis, the presence of a right‐sided tumour (odds ratio 3.3; P = 0.017), an AP diameter of the IVC at the RV o of ≥24.0 mm (odds ratio 4.4; P = 0.017), and radiographic identification of complete occlusion of the IVC at the RV o (odds ratio 4.9; P < 0.001) were associated with a significantly increased risk of IVC resection. The c‐index for the model was 0.81. Conclusions We present a multivariable model of the radiographic features associated with the need for IVC resection during tumour thrombectomy. Pending external validation, this model may be used for preoperative planning, patient counselling and planned involvement of vascular surgical colleagues in anticipation of the need for complex vascular repair.

AbstractSarcopenia, or loss of skeletal muscle mass, is associated with increased mortality and morbidity in liver transplant (LT) candidates. Six‐minute walk distance (6MWD) and health‐related quality of life (HRQOL) as assessed by short form 36 scores (SF‐36) also impact clinical outcomes in these patients. This study explored the relationship between the sarcopenia, 6MWD, and HRQOL in LT candidates. Sarcopenia was evaluated based on skeletal muscle mass index (SMI) quantified from abdominal computed tomography. Patients were followed until death, removal from the wait list or the end of the study period. Two hundred and thirteen patients listed for LT were included. The mean SMI, 6MWD and mean gait speed were 54.3 ± 9.7, 370.5 m and 1 m/s, respectively. Sarcopenia was noted in 22.2% of LT candidates. There was no correlation between sarcopenia, 6MWD, and SF‐36 scores. The 6MWD, but not sarcopenia, was an independent predictor of mortality (hazard ratio = 2.1 [0.9–4.7]). In summary, sarcopenia did not emerge as a significant predictor of waitlist mortality and also failed to correlate with either functional capacity or HRQOL in LT candidates. In patients with ESLD awaiting LT, 6MWD appears to be a more useful prognostic indicator than the presence of sarcopenia.

Abstract Purpose: Reovirus is a wild-type oncolytic virus that is ubiquitous in the environment; most patients are therefore preimmune. Therapeutic administration leads to an increase in neutralizing antireovirus antibody (NARA) titer. We hypothesized that if NARA limited reovirus antitumor activity, the effect might be attenuated by coadministration of cyclophosphamide. Experimental design: In a phase I study, patients with advanced cancer received cyclophosphamide 3 days before intravenous reovirus serotype 3 Dearing (RT3D). The primary objective was to reduce the resulting rise in NARA titer. Cyclophosphamide dose was escalated from 25–1,000 mg/m2 through nine cohorts; we aimed to define a well-tolerated immunomodulatory dose. Results: The combination was well tolerated in 36 patients, with grade 3/4 toxicities only seen at or above the maximum tolerated dose of cyclophosphamide, which was 800 mg/m2 combined with reovirus. Immunosuppressive effect, defined as maintaining NARA titer rise below a predefined threshold, was observed in only one patient. Furthermore, despite expected myelosuppression seen at higher cyclophosphamide doses, no changes in T-cell subsets, including Tregs, occurred with dose escalation. Viable virus was detected in association with peripheral blood mononuclear cells (PBMC) from 14% of patients 10 days after the last RT3D injection, despite high plasma NARA titer, demonstrating a potential mechanism for prolonged evasion of neutralization by reovirus. Conclusions: Coadministration of cyclophosphamide with reovirus is safe, but does not attenuate host antiviral responses. Alternative immunomodulation approaches should be explored, but association with PBMCs may allow reovirus to persist and evade even high levels of neutralizing antibodies. Clin Cancer Res; 21(6); 1305–12. ©2014 AACR.

The majority of intermediate‐risk rhabdomyosarcoma (RMS) patients have gross residual disease (Group III) after their first operative procedure. It is currently not known if local control rates can be maintained when, following induction chemotherapy, the radiation therapy (RT) dose is decreased after a delayed primary excision (DPE). To answer this question we evaluated patients enrolled on COG D9803 (1999–2005) who had Group III tumors of the bladder dome, extremity or trunk (thorax, abdomen and pelvis) were candidates for DPE at Week 12 if the primary tumor appeared resectable. RT dose was then adjusted by the completeness of DPE: no evidence of disease 36 Gy, microscopic residual 41.4 Gy and gross residual disease (GRD) 50.4 Gy. A total of 161 Group III patients were evaluated (24 bladder dome, 63 extremity and 74 trunk). Seventy‐three patients (45%) underwent DPE which achieved removal of all gross disease in 61 (84%) who were then eligible for reduced RT dose (43/73 received 36 Gy, 19/73 received 41.4 Gy). The local 5‐year failure rate (0% for bladder dome, 7% for extremity and 20% for trunk) was similar to IRS‐IV, which did not encourage DPE and did not allow for DPE adapted RT dose reduction. In conclusion, DPE was performed in 45% of Group III RMS patients with tumors at select anatomic sites (bladder dome, extremity and trunk) and 84% of those who had DPE were eligible for RT dose reduction. Local control outcomes were similar to historic results with RT alone.