Breast granuloma and C.R.S.T. syndrome

Summary One case of CRST syndrome with breast granuloma is presented. The presumed diagnosis were infectious or neoplastic diseases. High doses of corticosteroids led to improvement in breast nodules.     

Antigen stored in dendritic cells after macropinocytosis is released unprocessed from late endosomes to target B cells

B lymphocytes can be triggered in lymph nodes by nonopsonized antigens (Ag), potentially in their native form. However, the mechanisms that promote encounter of B lymphocytes with unprocessed antigens in lymph nodes are still elusive. We show here that antigens are detected in B cells in the draining lymph nodes of mice injected with live, but not fixed, dendritic cells (DCs) loaded with antigens. This highlights active processes in DCs to promote Ag transfer to B lymphocytes. In addition, antigen-loaded DCs found in the draining lymph node were CD103+. Using 3 different model Ag, we then show that immature DCs efficiently take up Ag by macropinocytosis and store the internalized material in late endocytic compartments. We find that DCs have a unique ability to release antigens from these compartments in the extracellular medium, which is controlled by Rab27. B cells take up the regurgitated Ag and the chemokine CXCL13, essential to attract B cells in lymph nodes, enhances this transfer. Our results reveal a unique property of DCs to regurgitate unprocessed Ag that could play an important role in B-cell activation.     

Allogeneic haematopoietic stem cell transplantation for chronic lymphocytic leukaemia: outcome in a 20-year cohort

The curative potential of allogeneic haematopoietic stem cell transplant (allo HSCT) in chronic lymphocytic leukaemia CLL is established, with a demonstrated role for graft-versus-leukaemia and less certainty for other factors in determining outcome. The first two decades of CLL patients proceeding to allo HSCT at the Leukaemia/Bone Marrow Transplant Program of British Columbia (n = 49 consecutive, 1991-2009) were studied to clarify factors predicting outcome. The donor was related in 29 (59%) and unrelated in 20 (41%). Conditioning was reduced-intensity in 27 (55%) and myeloablative in 22 (45%). Thirty-one of 49 patients survive with median follow-up of 5 years (0·2-15). Cumulative incidence of non-relapse mortality; complete remission (CR); clearance of fluorescence in situ hybridization (FISH) abnormality and progression at 10 years was 36%; 69%; 55% and 22%. Overall survival (OS) was 63% at 2 years; 55% at 5 years and beyond. Factors predicting OS (P value by log rank <0·05) were: comorbidity index <3, FISH rank (Dohner) and 17p deletion, alemtuzumab pre-HSCT, achievement of CR post-HSCT, donor chimerism >90%, clearance of FISH abnormality post-HSCT and absence of high-grade (3-4) graft-versus-host disease. Results from this province-wide, two-decade cohort demonstrated that a substantial proportion of patients with high-risk CLL become long term disease-free survivors.     

Sorafenib and Mek inhibition is synergistic in medullary thyroid carcinoma in vitro

Clinical trials using kinase inhibitors have demonstrated transient partial responses and disease control in patients with progressive medullary thyroid cancer (MTC). The goal of this study was to identify potential combinatorial strategies to improve on these results using sorafenib, a multikinase inhibitor with activity in MTC, as a base compound to explore signaling that might predict synergystic interactions. Two human MTC cell lines, TT and MZ-CRC-1, which harbor endogenous C634W or M918T RET mutations, respectively, were exposed to sorafenib, everolimus, and AZD6244 alone and in combination. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide (MTT) and poly (ADP-ribose) polymerase (PARP) cleavage assays were performed to measure cell survival and apoptosis. Western blots were performed to confirm activity of the compounds and to determine possible mechanisms of resistance and predictors of synergy. As a solitary agent, sorafenib was the most active compound on MTT assay. Western blots confirmed that sorafenib, everolimus, and AZD6244 inhibited their anticipated targets. At concentrations below its IC(50), sorafenib-treated TT and MZ-CRC-1 cells demonstrated transient inhibition and then re-activation of Erk over 6?h. In concordance, synergistic effects were only identified using sorafenib in combination with the Mek inhibitor AZD6244 (P<0.001 for each cell line). Cells treated with everolimus demonstrated activation of Akt and Ret via TORC2 complex-dependent and TORC2 complex-independent mechanisms respectively. Everolimus was neither additive nor syngergistic in combination with sorafenib or AZD6244. In conclusion, sorafenib combined with a Mek inhibitor demonstrated synergy in MTC cells in vitro. Mechanisms of resistance to everolimus in MTC cells likely involved TORC2-dependent and TORC2-independent pathways.     

Image-guided interstitial high-dose-rate brachytherapy for dose escalation in the radiotherapy treatment of locally advanced lung cancer: A single-institute experience

PurposeTo evaluate the clinical outcome after CT-guided interstitial high-dose-rate (HDR) brachytherapy for dose escalation in the radiotherapy treatment of inoperable locally advanced non–small-cell lung cancer (NSCLC).Methods and MaterialsFrom 2005 to 2015, 16 patients with unresectable NSCLC were treated. Median age was 65.7 years (range, 52–86). The median tumor volume was 95.3 cm³ (range, 20.0–2000.0). The median prescribed HDR was 15.0 Gy (range, 7.0–32.0) delivered in twice-daily fractions of 6.0–8.0 Gy in 4 patients and in once-daily fractions of 7.0–15.0 Gy in 12 patients, respectively.ResultsAfter a median followup of 12.5 months, median overall survival and local control was 12.9 and 24.9 months, respectively. The corresponding median overall survival and local control rates at 1, 2, and 3 years were 56.2%, 37.5%, and 12.5% as well as 68.9%, 57.4%, and 43%, respectively. Apart from one Grade 1 cough episode persisting for 1 week and one patient developing a minor hemopneumothorax requiring no postprocedural drainage, no other adverse events were recorded.ConclusionsCT-guided interstitial HDR brachytherapy is a safe modality for radiation dose escalation which may play a role in the definitive radiotherapy treatment of locally advanced NSCLC.