Assessment of potential process quality indicators for systemic treatment of breast cancer in Belgium: a population-based study.

BACKGROUND: Quality indicators (QIs) for the management of breast cancer (BC) have been published in Europe and internationally. In Belgium, a task force was established to select measurable process indicators of systemic treatment for BC, focusing on appropriateness of delivered care. The objective of this study was to evaluate the results of the selected QIs, both nationally and among individual centres. PATIENTS AND METHODS: Female Belgian residents with unilateral primary invasive BC diagnosed between 2010 and 2014 were selected from the Belgian Cancer Registry database. The national number enabled linkage with the national reimbursement database, which contains information on all reimbursed medical procedures. A total of 12 process indicators were measured on the population and hospital level. Intercentre variability was assessed by median results and interquartile ranges. RESULTS: A total of 48 872 patients were included in the study. QIs concerning specific BC subtypes only applied to patients diagnosed in 2014 (n = 9855). Clinical stage (cStage) I patients (n = 17 116) were staged with positron emission tomography/computed tomography. Among patients who were pT1aN0 human epidermal growth factor receptor 2 (HER2) positive (n = 47), 25.5% (n = 12) received adjuvant trastuzumab. Among patients with de novo metastatic luminal A/B-like HER2-negative BC (n = 295), 17.3% (n = 51) received upfront chemotherapy. (Neo)adjuvant chemotherapy was administered in 52.4% (n = 12 592) of operated women with cStage I-III, in 37.0% (n = 1270) of operated women with cStage I-III luminal A/B-like HER2-negative BC, and in 19.1% of operated women with cStage I luminal A/B-like HER2-negative BC. In the population of operated patients with cStage I-III, of those younger than 70 years that started adjuvant endocrine therapy (n = 3591), 81.7% (n = 2932) continued treatment for ≥4.5 years. Among patients in cStage I-III older than 70 years (n = 8544), 19.0% (n = 1622) received (neo)adjuvant chemotherapy, whereas among patients with cStage I-III luminal A/B-like HER2-negative BC (n = 1388), 13.0% (n = 181) received (neo)adjuvant chemotherapy. In patients with cStage I-II luminal A/B-like HER2-negative BC older than 70 years (n = 1477), 11.6% (n = 171) were not operated and received upfront endocrine treatment. CONCLUSION: Well-considered QIs using population-based data can evaluate quality of care and expose disparities among treatment centres. Their use in daily practice should be implemented in all centres treating BC.

Carboxylate isosteres for caspase inhibitors: the acylsulfonamide case revisited.

As part of an ongoing effort to discover inhibitors of caspase-1 with an optimized selectivity and biopharmaceutical profile, acylsulfonamides were explored as carboxylate isosteres for caspase inhibitors. Acylsulfonamide analogues of the clinically investigated caspase-1 inhibitor VRT-043198 and of the pan-caspase inhibitor Z-VAD-CHO were synthesized. The isostere-containing analogues with an aldehyde warhead had inhibitory potencies comparable to the carboxylate references. In addition, the conformational and tautomeric characteristics of these molecules were determined using 1H- and 13C-based NMR. The propensity of acylsulfonamides with an aldehyde warhead to occur in a ring-closed conformation at physiological pH significantly increases the sensitivity to hydrolysis of the acylsulfonamide moiety, yielding the parent carboxylate containing inhibitors. These results indicate that the acylsulfonamide analogues of the aldehyde-based inhibitor VRT-043198 might have potential as a novel type of prodrug for the latter. Finally, inhibition of caspase 1 and 11 mediated inflammation in mouse macrophages was found to correlate with the potencies of the compounds in enzymatic assays.

[Treatment of recurrent Dupuytren's disease]. / Rezidiveingriffe beim Morbus Dupuytren.

BACKGROUND: The tendency of recurrence or progression is a frequent problem in Dupuytren's disease. The management of recurrence is adapted to the individual situation and the patient's needs. In mild cases a non-operative approach is recommended. Revision surgery is reserved for disabling situations with acceptable circulation and sensation in absence of dystrophy. It is complicated by a combined formation of scar tissue and new cords. This increases the risk of soft tissue loss and injuries to the neurovascular bundles, which impair sensation and circulation and may result in loss of the finger. TECHNIQUE: The strategy consists of preoperative planning of the soft tissue reconstruction, meticulous preparation of the neurovascular bundles, arthrolyses and skin closure by Z­plasty or transposition flaps. The corrective arthrodesis of the proximal interphalangeal joint may be an alternative to improve function without the risks of revision surgery. In cases of severe impaired circulation, sensation or dystrophy of the finger, amputation or ray resection may be indicated.

[The lateral-dorsal transposition flap for closure of a palmar soft tissue defect of the proximal phalanx on the little finger after limited fasciectomy in recurrent Dupuytren's contracture]. / Laterodorsaler Transpositionslappen zum Verschluss eines Weichteildefekts am palmaren Kleinfingergrundglied nach Auflösung einer Dupuytren-Rezidivbeugekontraktur.

OBJECTIVE: Closure of a palmar soft tissue defect of the proximal phalanx after limited fasciectomy in recurrent Dupuytren's contracture. INDICATIONS: A palmar soft tissue defect between the distal flexion crease of the palm and the flexion crease of the proximal interphalangeal joint (PIP) after limited fasciectomy in Dupuytren's contracture. CONTRAINDICATIONS: Scars at the lateral-dorsal portion of the proximal phalanx (e.g., after burns). SURGICAL TECHNIQUE: Modified incision after Bruner ("mini-Bruner"). Removal of the involved fascial cord. If necessary, arthrolysis of the PIP. Raising the lateral-dorsal transposition flap from distal to proximal and rotating it into the palmar soft tissue defect of the proximal phalanx. Closure of the donor site with a skin transplant. POSTOPERATIVE MANAGEMENT: Dorsal plaster of Paris with extended fingers and compressive dressing in the palm for 2 days. Afterwards static dorsal splint and daily physiotherapy. RESULTS: Between 2002 and 2007, a total of 32 lateral-dorsal transposition flaps in 30 patients with recurrent Dupuytren's disease of the little finger underwent surgery. In a retrospective study, 19 patients with 20 flaps were available for follow-up evaluation after a mean of 6 years. All flaps had healed. The median flexion contracture of the metacarpophalangeal joint was 0° (preoperatively, 20°), and of the PIP 20° (preoperatively, 85°) according to Tubiana stage 1 (preoperatively, Tubiana stage 3). The median grip strength of both the operated and the contralateral hand was 39 kg. The DASH score averaged 11 points. Overall, 11 patients were very satisfied, 6 patients were satisfied, 1 patient was less satisfied, and 1 patient was unsatisfied.

Airway structural cells regulate TLR5-mediated mucosal adjuvant activity.

Antigen-presenting cell (APC) activation is enhanced by vaccine adjuvants. Most vaccines are based on the assumption that adjuvant activity of Toll-like receptor (TLR) agonists depends on direct, functional activation of APCs. Here, we sought to establish whether TLR stimulation in non-hematopoietic cells contributes to flagellin's mucosal adjuvant activity. Nasal administration of flagellin enhanced T-cell-mediated immunity, and systemic and secretory antibody responses to coadministered antigens in a TLR5-dependent manner. Mucosal adjuvant activity was not affected by either abrogation of TLR5 signaling in hematopoietic cells or the presence of flagellin-specific, circulating neutralizing antibodies. We found that flagellin is rapidly degraded in conducting airways, does not translocate into lung parenchyma and stimulates an early immune response, suggesting that TLR5 signaling is regionalized. The flagellin-specific early response of lung was regulated by radioresistant cells expressing TLR5 (particularly the airway epithelial cells). Flagellin stimulated the epithelial production of a small set of mediators that included the chemokine CCL20, which is known to promote APC recruitment in mucosal tissues. Our data suggest that (i) the adjuvant activity of TLR agonists in mucosal vaccination may require TLR stimulation of structural cells and (ii) harnessing the effect of adjuvants on epithelial cells can improve mucosal vaccines.

[Dupuytren's disease - patient satisfaction and functional results one year after partial fasciectomy and injection of collagenase]. / Morbus Dupuytren - Patientenzufriedenheit und funktionelle Ergebnisse ein Jahr nach partieller Aponeurektomie und Injektion von Kollagenase.

INTRODUCTION: The gold standard in the treatment of Dupuytren's disease is the partial fasciectomy (PF). Injection of a collagenase directly into the Dupuytren cord is an alternative method. In contrast to needle fasciotomy, destruction of the cord is achieved enzymatically and not mechanically. 24 h after injection, the treated finger can be extended passively to disrupt the Dupuytren cord. PATIENTS AND METHODS: Functional outcome and patient satisfaction were prospectively analysed in 2 comparable groups of patients with the same stage of disease. Follow-up was one year. Patients in the first group underwent partial fasciectomy (PF) (n=13), whereas patients in the second group were treated by an injection of collagenase (CG) in the diseased tissue (n=14). Besides clinical examination, outcome was evaluated by validated questionnaires (DASH/MHQ) and a customised questionnaire. RESULTS: Extension after PF (mean residual contracture 7.5°) was better than after collagenase injection (mean residual contracture 13.2°). Side-effects like numbness, impaired blood circulation and pain were less after injection of collagenase than after PF and of shorter duration. Recovery of grip strength was faster in the CG than after PF and collagenase injection was regarded as less discomforting. The results of the questionnaires showed a reduction of hand function 1 month after surgery, whereas better results were observed 1 month after collagenase injection. Recovery in the CG was significantly faster than after PF. DISCUSSION: Collagenase injection, as a less invasive technique, has less and milder side-effects than surgery and demonstrated a better total reduction of Dupuytren's contracture initially, although the residual contractures were higher in the CG after follow-up of 1 year. Patient satisfaction was higher after collagenase injection due to subjectively perceived less negative impact and a comparable functional outcome.

[Arterialized venous free flaps for resurfacing hand and finger defects]. / Freie, arterialisierte venöse Lappenplastiken zur Deckung an Hand und Fingern.

BACKGROUND: Soft tissue defects on the hand and on the fingers with exposed functional structures require a thin and sturdy closure. If skin grafts or local flaps are not possible the arterialized venous free flaps represent a good alternative. PATIENTS AND METHODS: This retrospective study included all arterialized venous free flaps used for hand and finger defects since 2005. We evaluated type and technique (for example antegrade vs. retrograde arterial inflow and the number of veins) and size of the flaps. Flap harvesting time was also examined. RESULTS: 11 venous flaps were used for resurfacing hand and finger defects. Most of them were retrogradely arterialized. 10 of 11 flaps healed uneventfully. Due to a thrombosis in an outflowing vein one flap was lost at the sixth postoperative day. Median size of the arterialized flaps was 6×4 cm and the median time for flap harvest was 38 (27-51) min. The donor site was primarily closed in 2 cases and in 9 cases with a skin graft. CONCLUSION: Arterialized venous free flaps represent a reliable and safe option for resurfacing hand and finger defects. Easy and fast harvesting due to the visible venous vascular system is an advantage. The flaps are thin, pliable and can be easily adjusted to the needs of the defect. Using conservative measures it is possible to control side effects like venous pooling, swelling and purplish discoloration. With arterialized venous free flaps early hand therapy is possible, in contrast to heterodigital and local flaps. In comparison to other free flaps it is not necessary to sacrifice an artery at the donor site.

Heterogeneous reaction between Li and anatase TiO2 nanoparticles under ultra-high vacuum.

We demonstrate heterogeneous chemistry between Li and anatase TiO2 nanoparticles under UHV. The reduction of TiO2 upon formation of lithium oxide proceeds via two different schemes: one that reduces Ti(4+) to Ti(3+) and one that reduces Ti(4+) directly to Ti(2+). The second scheme sets in only after a critical degree of reduction (i.e. Li amount) has been reached (Li/Ti = 0.28) and is associated with restructuring of the film. Two films with different morphologies were compared and the results demonstrate that the reaction between Li and larger TiO2 structures (30-50 nm) is kinetically restricted while such effects were significantly less prominent for small particles (10 nm).

High resolution photoemission and x-ray absorption spectroscopy of a lepidocrocite-like TiO2 nanosheet on Pt(110) (1 × 2).

The electronic structure of TiO(2) nanosheets on the Pt(110)-(1 × 2) surface has been investigated by using high resolution photoemission spectroscopy and x-ray absorption spectroscopy (XAS). The Ti 2p XAS spectra of the deposited TiO(2) films have been theoretically evaluated and, from the comparison with the experimental data, the assignment to a lepidocrocite-like structure is confirmed. Coexistence of TiO(2) islands with PtO(2) stripes for incomplete nanosheets is confirmed by high resolution photoemission data. The location of the valence and conduction band edges of the nanosheet has been experimentally determined allowing us to describe in details subtle electronic effects due to the interface with the substrate. The locations of the valence band maximum and the leading peak in the O 1s XAS spectrum indicate a band gap similar to anatase but with the Fermi level closer to mid-gap than found for bulk, n-type TiO(2).

Adsorption of methylamine on Ni 3 Al(111) and NiAl(110)--a high resolution photoelectron spectroscopy and density functional theory study.

Methylamine adsorption on the ordered Ni(3)Al(111) and NiAl(110) surfaces has been investigated by high resolution photoelectron spectroscopy and density functional theory calculations. Methylamine adsorbs molecularly at both surfaces at low temperature (90 K). The experiments show that methylamine interacts with the surface aluminium atoms on both surfaces, resulting in a positive binding energy shift relative to the Al 2p bulk contributions. A shift towards lower binding energy is also observed on NiAl(110) attributed to first and second layer surface Al atoms not bonded to methylamine. According to total energy calculations methylamine binds through its N atom to Al on-top sites on NiAl(110) while the Ni on-top site is found to be slightly preferred over the Al on-top site on Ni(3)Al(111). Calculated adsorbate induced shifts are, however, in good agreement with the experimental values only when methylamine is situated in the Al on-top site on both surfaces. In both cases, a lone pair bonding mechanism is found.

Caspase-mediated cleavage of Beclin-1 inactivates Beclin-1-induced autophagy and enhances apoptosis by promoting the release of proapoptotic factors from mitochondria.

Autophagy and apoptosis are two important and interconnected stress-response mechanisms. However, the molecular interplay between these two pathways is not fully understood. To study the fate and function of autophagic proteins at the onset of apoptosis, we used a cellular model system in which autophagy precedes apoptosis. IL-3 depletion of Ba/F3 cells caused caspase (casp)-mediated cleavage of Beclin-1 and PI3KC3, two crucial components of the autophagy-inducing complex. We identified two casp cleavage sites in Beclin-1, TDVD(133) and DQLD(149), cleavage at which yields fragments lacking the autophagy-inducing capacity. Noteworthy, the C-terminal fragment, Beclin-1-C, localized predominantly at the mitochondria and sensitized the cells to apoptosis. Moreover, on isolated mitochondria, recombinant Beclin-1-C was able to induce the release of proapoptotic factors. These findings point to a mechanism by which casp-dependent generation of Beclin-1-C creates an amplifying loop enhancing apoptosis upon growth factor withdrawal.

The mitochondrial serine protease HtrA2/Omi: an overview.

The HtrA family refers to a group of related oligomeric serine proteases that combine a trypsin-like protease domain with at least one PDZ interaction domain. Mammals encode four HtrA proteases, named HtrA1-4. The protease activity of the HtrA member HtrA2/Omi is required for mitochondrial homeostasis in mice and humans and inactivating mutations associated with neurodegenerative disorders such as Parkinson's disease. Moreover, HtrA2/Omi is released in the cytosol, where it contributes to apoptosis through both caspase-dependent and -independent pathways. Here, we review the current knowledge of HtrA2/Omi biology and discuss the signaling pathways that underlie its mitochondrial and apoptotic functions from an evolutionary perspective.